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Sample records for fluconazole increases nevirapine

  1. Fluconazole and Pregnancy

    Science.gov (United States)

    Fluconazole and Pregnancy In every pregnancy, a woman starts out with a 3-5% chance of having ... risk. This sheet talks about whether exposure to fluconazole may increase the risk for birth defects over ...

  2. Renal histoarchitectural changes in nevirapine therapy: possible ...

    African Journals Online (AJOL)

    Results: Nevirapine caused histoarchitectural damage in the glomerular apparatus with resultant increase in ... Keywords: Kidney, histoarchitecture, kolaviron, antiretroviral drugs. ..... tive and economic indicator of the toxicology and thus.

  3. Pharmacological and clinical evidence of nevirapine immediate- and extended-release formulations

    Directory of Open Access Journals (Sweden)

    Ena J

    2012-11-01

    Full Text Available Javier Ena, Concepción Amador, Conxa Benito, Francisco PasquauHIV Unit, Hospital Marina Baixa, Villajoyosa, SpainAbstract: We reviewed the current information available on nevirapine immediate- and extended-release formulations and its role in single-dose and combination antiretroviral therapy. Nevirapine was approved in 1996 and was the first non-nucleoside reverse-transcriptase inhibitor available for the treatment of HIV-1 infection. Nevirapine has demonstrated good efficacy and a well-characterized safety profile. A major drawback is the low genetic barrier, allowing the emergence of resistance in the presence of single mutations in the reverse-transcriptase gene. This shortcoming is particularly relevant when nevirapine is administered in a single dose to prevent mother-to-child transmission of HIV-1 infection, compromising the efficacy of future non-nucleoside reverse transcriptase–inhibitor regimens. Studies published recently have probed the noninferiority of nevirapine compared to ritonavir-boosted atazanavir with both tenofovir disoproxil fumarate and emtricitabine in antiretroviral treatment–naïve patients. In 2011, a new formulation of nevirapine (nevirapine extended release that allowed once-daily dosing was approved by the Food and Drug Administration and by the European Medicines Agency. VERxVe, a study comparing nevirapine extended release with nevirapine immediate release in antiretroviral treatment–naïve patients, and TRANxITION, a study carried out in antiretroviral treatment–experienced patients who switched therapy from nevirapine immediate release to nevirapine extended release, provided data on the noninferiority of the new formulation of nevirapine compared with nevirapine immediate release in terms of efficacy and safety. Nevirapine extended release will further increase the durability and persistence of nevirapine-containing antiretroviral therapy, allowing once-daily dosing regimens.Keywords: nevirapine

  4. Fluconazole Injection

    Science.gov (United States)

    ... and fungal infections of the eye, prostate (a male reproductive organ), skin and nails. Fluconazole injection is ... Motrin, others) and naproxen (Aleve, Anaprox, Naprelan); oral contraceptives (birth control pills); oral medication for diabetes such ...

  5. Incidence and determinants of nevirapine and efavirenz-related skin rashes in West Africans: nevirapine's epitaph?

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    Fred Stephen Sarfo

    Full Text Available Non-nucleoside reverse transcriptase inhibitor (NNRTI associated rash is common and frequently leads to discontinuation of NNRTIs. This study assessed the risk of developing rashes and discontinuing NNRTIs and associated factors in a large clinic in central Ghana. In this retrospective cohort study, clinical data were obtained in patients starting efavirenz or nevirapine between 2004-2010. Factors associated with rashes were explored using a multivariate Cox proportional hazards regression model. Of 3,999 patients who started NNRTI-based ART, 281 (7.0% experienced at least one episode of NNRTI-related rash with an incidence of 2.63 events/100 person-years, occurring in 10.2% and 5.6% of patients taking nevirapine and efavirenz respectively. Most rashes (94% were grade 1 or 2 and were reported a median of 2 months following initiation of ART. In multivariate analysis developing a rash was associated with nevirapine use (aHR 1.67, 95% CI 1.28-2.10, female gender (aHR of 1.39, 95% CI 1.01-1.92 and lower baseline CD4 counts (aHR 0.88, 95% CI 0.82-0.95 per 50 cells/mm³ increment. Patients with nevirapine-associated rash were 11 times more likely to discontinue treatment as patients with efavirenz-associated rash. In contrast to findings in other studies, NNRTI-associated rashes in Ghanaians appear more common in patients with lower baseline CD4 counts. Given the increased frequency of rashes with nevirapine and subsequent discontinuations in many patients, along with other treatment-limiting toxicities, this provides further impetus for the replacement of nevirapine by efavirenz as the first-line NNRTI treatment of choice in Africa.

  6. Fluconazole and amphotericin-B resistance are associated with increased catalase and superoxide dismutase activity in Candida albicans and Candida dubliniensis

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    Carlos Eduardo Blanco Linares

    2013-12-01

    Full Text Available Introduction Candida dubliniensis, a new species of Candida that has been recovered from several sites in healthy people, has been associated with recurrent episodes of oral candidiasis in AIDS and HIV-positive patients. This species is closely related to C. albicans. The enzymatic activity of C. dubliniensis in response to oxidative stress is of interest for the development of drugs to combat C. dubliniensis. Methods Fluconazole- and amphotericin B-resistant strains were generated as described by Fekete-Forgács et al. (2000. Superoxide dismutase (SOD and catalase assays were performed as described by McCord and Fridovich (1969 and Aebi (1984, respectively. Results We demonstrated that superoxide dismutase (SOD and catalase activities were significantly higher (p<0.05 in the fluconazole- and amphotericin B-resistant strains of C. dubliniensis and C. albicans than in the sensitive strains. The catalase and SOD activities were also significantly (p<0.01 higher in the sensitive and resistant C. albicans strains than in the respective C. dubliniensis strains. Conclusions These data suggest that C. albicans is better protected from oxidative stress than C. dubliniensis and that fluconazole, like amphotericin B, can induce oxidative stress in Candida; oxidative stress induces an adaptive response that results in a coordinated increase in catalase and SOD activities.

  7. Serum Nevirapine and Efavirenz concentrations and effect of concomitant rifampicin in HIV infected children on antiretroviral therapy.

    Science.gov (United States)

    Shah, Ira; Swaminathan, Soumya; Ramachandran, Geetha; Kumar, A K Hemanth; Goray, Apurva; Chaddha, Udit; Tayal, Swati; Lala, Mamatha

    2011-12-01

    To determine factors affecting serum levels of Efavirenz and Nevirapine and analyze the effect of Rifampicin on Nevirapine drug levels. A cross-sectional study was conducted on 30 HIV infected children on Antiretroviral therapy (ART) with Nevirapine or Efavirenz. Patients on simultaneous Rifampicin and Nevirapine were given higher doses of Nevirapine with regular monitoring of liver function tests. Trough levels (before morning dose of Nevirapine) and levels after 2 hours of administration of Nevirapine and levels of Efavirenz were assessed using HPLC and were checked to see if they fall within the therapeutic range. Thirty patients (14 males) were enrolled in the study with 20 on Nevirapine and 10 (33.3%) on Efavirenz. Seven (23.3%) patients were simultaneously taking rifampicin. The mean Nevirapine dose given to the patients was 350.9±59.8 mg/m2/day (on simultaneous rifampicin) and 309.2±54.6 mg/m2/day (not on concurrent rifampicin). Thirteen (81.3%) of the 16 patients with trough Nevirapine had values in the normal range, 1 (6.3%) had low Nevirapine trough levels and 2 (12.5%) had high Nevirapine trough levels. Of the post 2 hours Nevirapine levels, 1 (5%) had low levels and 3 (15%) had high Nevirapine blood levels. Factors like age (P=0.4, P=0.4087), nourishment (P=0.2679, P=0.4132), ART combination (P=0.4199, P=0.4132), form of the drug (tablet/syrup) (P=0.1964, P=0.4696) or if it was being given as single or in a fixed dose combination (P=0.4179, P=0.4696) and even concurrent rifampicin administration (P=0.284, P=0.472) did not significantly affect the trough and post 2 hours Nevirapine values, respectively. All the five patients being given concurrent rifampicin had normal trough and post 2 hours levels of Nevirapine. The Efavirenz drug levels were 1.9±1.1 g/mL. Of the 10 patients on Efavirenz, 2 (20%) had high and 1 (10%) had low blood levels. Concurrent Rifampicin administration does not alter blood levels of Nevirapine; provided the dose of Nevirapine

  8. Nevirapine nanosuspension: comparative investigation of production methods

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    Ranjita Shegokar

    2011-07-01

    Full Text Available Increasing number of antiretroviral drugs coming from high throughput screening besides their high dose has poor solubility profile. Formulation development of these drugs is a major obstacle to their clinical application. To overcome extremely low water solubility and associated poor bioavailability they can be formulated as nanosuspensions. This paper is not only focuses on production of parenteral nevirapine nanosuspensions but also on scaling up of formulations for clinical use. Lab scale (APV LAB 40, 40 mL and medium scale (Avestin C50, 2 kg production was performed using piston gap high pressure homogenization (HPH, while the feasibility for pilot scale up was checked using a bead milling technique in continuous mode (PM, Bühler PML-2. Nanosuspension was characterized for particle sizes, zeta potential, crystallanity and stability. The mean particle sizes for lab scale, medium scale and pilot scale production obtained were 481 nm, 429 nm and 211 nm, respectively. Independent of the production method (lab and pilot scale all processed formulations showed more or less similar zeta potential (~15 mV in conductivity adjusted water. Long term stability over 1 year showed significant increase in particle size at all storage conditions for lab scale and medium scale production (high energy size reduction whereas they remained physically stable (with negligible increase for the milled product (low energy size reduction. As the technology has been scaled up successfully for nevirapine nanosuspension, the product can be considered for commercial exploitation. The prepared nevirapine nanosuspensions can be administered for parenteral or oral use.

  9. Fluconazol og amning

    DEFF Research Database (Denmark)

    Pedersen, Andreas James Thestrup; Hessellund, Anne; Bergmann, Troels Korshøj;

    2016-01-01

    Når lokalbehandling til candidainfektion ikke er nok, er næste valg systemisk behandling. Men hvad, hvis kvinden ammer? Kan systemisk behandling med tablet fluconazol anvendes? Svaret er ja – men langvarig behandling (> 2 uger) bør undgås. Fluconazol vil udskilles i brystmælk, men mængden af...... fluconazol, som barnet derved indtager, er lav....

  10. Switching to nevirapine-based regimens after undetectable viral load is not associated with increased risk of discontinuation due to toxicity

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    Patricia Patterson

    2014-11-01

    Full Text Available Introduction: Due to its good tolerability, favourable cardiovascular risk-profile, low-pill burden and cost, nevirapine-based regimens are an attractive simplification strategy for patients with suppressed viral load (VL. However, current guidelines recommend caution if nevirapine (NVP is prescribed in males and females with CD4 counts above 400 or 250 cells/µL, respectively. The aim of this study is to determine the prevalence and risk factors associated with development of toxicity or treatment discontinuation in patients switching to NVP-based regimens. Materials and Methods: Retrospective chart review of HIV-infected patients with suppressed VL who switched from a PI-based regimen to a NVP-based regimen in four HIV clinics in Argentina, between 1997 and 2013. Bivariate and multivariate analyses were performed to explore factors associated with treatment discontinuation. High CD4 count was defined as CD4-cell count ≥400 or 250 cells/µL in males and females, respectively. Results: Of 218 patients included, 165 (75.7% were male; 21 (9.6% were co-infected with HCV and/or HBV. Median baseline (BSL CD4 count: 138 cells/µL (IQR: 64–276. At switch, patients had a median age of 38 years (IQR: 33.4–43.8 and had been suppressed for a median of 1.4 years (IQR: 0.6–2.2; 138 patients (63.3% had high CD4-cell counts: among females, median CD4 count at switch was 462 (IQR: 330–709 cells/µL; among males, 433 (IQR: 305–595 cells/µL. Thirty-six patients (13.5% presented NVP-related toxicity (30 skin toxicity, 6 hepatic toxicity, 29 (13.3% discontinued NVP. Median time to development to toxicity: 32 days (IQR: 15–75. In bivariate analysis, chronic hepatitis was the only variable associated with development of toxicity (OR: 2.90, 95% CI 1.08–7.78. In multivariate analysis, no statistical significant associations were observed between either development of toxicity or treatment discontinuation and gender, chronic hepatitis, age or CD4-cell

  11. Fluconazole-Induced Type 1 Kounis Syndrome.

    Science.gov (United States)

    Singh Mahal, Hardeep

    2016-01-01

    The administration of fluconazole is commonly used in both inpatient and outpatient settings for the management of candidiasis infection. Although it is associated with a relatively safe side effect profile, some patients experience adverse effects associated with increased morbidity. We describe 1 such patient, a 42-year-old woman with a history of severe eczema who developed fluconazole-induced type 1 Kounis syndrome. Review of literature indicates that this as the first case reported of fluconazole-induced type 1 Kounis syndrome.

  12. Genotypic and phenotypic nevirapine resistance correlates with virological failure during salvage therapy including abacavir and nevirapine

    DEFF Research Database (Denmark)

    Jørgensen, L B; Katzenstein, T L; Gerstoft, J;

    2000-01-01

    OBJECTIVE: To study the development of resistance during 8 weeks of salvage therapy with abacavir and nevirapine in combination with other reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs). METHODS: Samples obtained at baseline and after 8 weeks of therapy from 16 heavily...... and after 2, 4 and 8 weeks of therapy. RESULTS: The majority of patients was genotypically and phenotypically resistant to lamivudine, abacavir, zidovudine and PIs, whereas 50% of the patients showed resistance to nevirapine at baseline in at least one of the methods used. After 8 weeks of salvage therapy...... higher transient reduction in viral load was observed in patients with nevirapine-sensitive HIV at baseline compared to patients with resistant HIV at baseline. CONCLUSION: The transient effect of salvage therapy including abacavir and nevirapine was due to the effect of nevirapine. The lack of effect...

  13. Exposure of Allium cepa root cells to zidovudine or nevirapine induces cytogenotoxic changes.

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    Onwuamah, Chika K; Ekama, Sabdat O; Audu, Rosemary A; Ezechi, Oliver C; Poirier, Miriam C; Odeigah, Peter G C

    2014-01-01

    Antiretroviral drugs have proved useful in the clinical management of HIV-infected persons, though there are concerns about the effects of exposure to these DNA-reactive drugs. We investigated the potential of the plant model Allium cepa root tip assay to demonstrate the cytogenotoxicity of zidovudine and nevirapine and as a replace-reduce-refine programme amenable to resource-poor research settings. Cells mitotic index were determined in squashed root cells from Allium cepa bulbs exposed to zidovudine or nevirapine for 48 hr. The concentration of zidovudine and nevirapine inhibiting 50% root growth after 96 hr exposure was 65.0 µM and 92.5 µM respectively. Root length of all antiretroviral-exposed roots after 96 hr exposure was significantly shorter than the unexposed roots while additional root growth during a subsequent 48 hr recovery period in the absence of drug was not significantly different. By ANOVA, there was a significant association between percentage of cells in mitosis and zidovudine dose (p=0.004), but not nevirapine dose (p=0.68). Chromosomal aberrations such as sticky chromosomes, chromatin bridges, multipolar mitoses and binucleated cells were observed in root cells exposed to zidovudine and nevirapine for 48 hr. The most notable chromosomal aberration was drug-related increases in sticky chromosomes. Overall, the study showed inhibition in root length growth, changes in the mitotic index, and the induction of chromosomal aberrations in Allium bulbs treated for 96 hr or 48 hr with zidovudine and nevirapine. The study reveals generalized cytogenotoxic damage induced by exposure to zidovudine and nevirapine, and further show that the two compounds differ in their effects on mitosis and the types of chromosomal aberrations induced.

  14. Exposure of Allium cepa root cells to zidovudine or nevirapine induces cytogenotoxic changes.

    Directory of Open Access Journals (Sweden)

    Chika K Onwuamah

    Full Text Available Antiretroviral drugs have proved useful in the clinical management of HIV-infected persons, though there are concerns about the effects of exposure to these DNA-reactive drugs. We investigated the potential of the plant model Allium cepa root tip assay to demonstrate the cytogenotoxicity of zidovudine and nevirapine and as a replace-reduce-refine programme amenable to resource-poor research settings. Cells mitotic index were determined in squashed root cells from Allium cepa bulbs exposed to zidovudine or nevirapine for 48 hr. The concentration of zidovudine and nevirapine inhibiting 50% root growth after 96 hr exposure was 65.0 µM and 92.5 µM respectively. Root length of all antiretroviral-exposed roots after 96 hr exposure was significantly shorter than the unexposed roots while additional root growth during a subsequent 48 hr recovery period in the absence of drug was not significantly different. By ANOVA, there was a significant association between percentage of cells in mitosis and zidovudine dose (p=0.004, but not nevirapine dose (p=0.68. Chromosomal aberrations such as sticky chromosomes, chromatin bridges, multipolar mitoses and binucleated cells were observed in root cells exposed to zidovudine and nevirapine for 48 hr. The most notable chromosomal aberration was drug-related increases in sticky chromosomes. Overall, the study showed inhibition in root length growth, changes in the mitotic index, and the induction of chromosomal aberrations in Allium bulbs treated for 96 hr or 48 hr with zidovudine and nevirapine. The study reveals generalized cytogenotoxic damage induced by exposure to zidovudine and nevirapine, and further show that the two compounds differ in their effects on mitosis and the types of chromosomal aberrations induced.

  15. A validated new method for nevirapine quantitation in human plasma via high-performance liquid chromatography.

    Science.gov (United States)

    Silverthorn, Courtney F; Parsons, Teresa L

    2006-01-01

    A fully validated and clinically relevant assay was developed for the assessment of nevirapine concentrations in neonate blood plasma samples. Solid-phase extraction with an acid-base wash series was used to prepare subject samples for analysis. Samples were separated by high performance liquid chromatography and detected at 280 nm on a C8 reverse-phase column in an isocratic mobile phase. The retention times of nevirapine and its internal standard were 5.0 and 6.9 min, respectively. The method was validated by assessment of accuracy and precision (statistical values 0.996) and the average recovery was 93% (n = 18). The lower limit of quantification (relative standard deviation <20%) was determined to be 25 ng/mL for 50 microL of plasma, allowing detection of as little as 1.25 ng of nevirapine in a sample. This value represents an increase in sensitivity of up to 30-fold over previously published methods.

  16. [The clinical and biological tolerance of nevirapine among patients with AIDS under treatment at the Hospital of the Point G].

    Science.gov (United States)

    Coulibaly, S M; Oumar, A A; Ag Aboubacrine, S; Coulibaly, S; Koumare, B Y; Mariko, E; Traoré, H A; Harama, M

    2007-01-01

    The national policy of assumption of responsibility of the PVVIH decided to put 80% of new inclusions under Triomune, 1st therapeutic line made up of 3TC + D4T + Nevirapine. The use of Nevirapine among patients VIH+ plays a very important part in improvement of the quality of their life. The goal of this study was to evaluate the clinical and biological tolerance of Nevirapine at the PVVIH under treatment ARV and having Nevirapine in their diagram. We had collected 102 files of patients. The average age was 38 years. Association Lamivudine + Stavudine + Nevirapine was the diagram most frequently prescribed (82.4%). The skin, mucous and neurological signs, digestive disorders, muscular signs, cardiopulmonary signs were frequently observed in the first month of the treatment but these symptoms became less frequent in the third month and disappeared at the 6th month. We observed disorders in hepatic and renal functional parameters, rise in the lymphocytes. We obtained a considerable increase in the rate of CD4 between the beginning of the treatment and the 6th month. The treatment schema of 3TC + D4T + Nevirapine gives an excellent clinical and biological tolerance. But, the study must continue to confirm these results over a longer period.

  17. Nevirapine-induced side effects in pregnant women: experience of a Brazilian university hospital.

    Science.gov (United States)

    Kondo, William; Carraro, Elaine Aparecida; Prandel, Elaine; Dias, Josiane Mourão; Perini, Juliane; Macedo, Rodolfo Lara de; Cornelsen, Taynah Cristina; Sbalquiero, Renato; Sasaki, Maria das Graças

    2007-12-01

    Nevirapine-based therapy is associated with increased frequency of adverse events among HIV-infected pregnant women. The aim of this article was to evaluate the incidence of adverse effects in HIV-infected women who started nevirapine during pregnancy. A retrospective study was performed in our center between January 2003 and December 2006 analyzing all women prescribed nevirapine during pregnancy. Women presenting any risk factor for hepatotoxicity were excluded from the analysis. Patients were divided into two groups according to the presence or absence of adverse effects, and a correlation to CD4 counts was performed. Liver function abnormality was graded according to the Division of AIDS toxicity guidelines. A total of 170 women initiated nevirapine during pregnancy, but only 133 were included in the study. Twenty-seven women (20.3%) presented adverse effects, skin rash accounting for 77.8% (21/27 women) and liver function abnormalities for 22.2% (6/27) of the cases. Baseline CD4 counts, viral loads and transaminases were similar in both groups. All nevirapine side effects were developed in less than seven weeks. Four of 31 women with CD4 counts or = 250 cells/microL (22.5%) developed adverse events. All patients who experienced hepatotoxicity had pretreatment CD4 counts > or =250 cells/microL. The incidence of adverse events with nevirapine in our study was high, but most of them were cutaneous. There was no correlation between high CD4 counts and adverse events when analyzing both cutaneous and hepatic reactions; nevertheless, hepatotoxicity occurred only in pregnant women with CD4 counts > or =250 cells/microL.

  18. Vulvovaginal candidiasis: species distribution, fluconazole resistance and drug efflux pump gene overexpression.

    Science.gov (United States)

    Zhang, Jie-Yu; Liu, Jin-Hui; Liu, Fa-Di; Xia, Yan-Hua; Wang, Jing; Liu, Xi; Zhang, Zhi-Qin; Zhu, Na; Yan-Yan; Ying, Ying; Huang, Xiao-Tian

    2014-10-01

    The increasing incidence of vulvovaginal candidiasis (VVC) and the emergence of fluconazole resistance are an indisputable fact. However, little information is available regarding the correlation between fluconazole resistance in vaginal Candida albicans and the expression of drug efflux pump genes. In this study, we investigated the species distribution, fluconazole susceptibility profiles and the mechanisms of fluconazole resistance in Candida strains. In total, 785 clinical Candida isolates were collected from patients with VVC. C. albicans was the most frequently isolated species(n = 529) followed by C. glabrata (n = 164) and C. krusei (n = 57). Of all Candida isolates, 4.7% were resistant to fluconazole. We randomly selected 18 fluconazole resistant isolates of C. albicans to evaluate the expression of CDR1, CDR2, MDR1 and FLU1 genes. Compared with fluconazole-susceptible C. albicans isolates, CDR1 gene expression displayed 3.16-fold relative increase, which was statistically significant. CDR2, MDR1 and FLU1 overexpression was observed in several fluconazole-resistant C. albicans isolates, but statistical significance was not achieved. These results demonstrate a high frequency of non-albicans species (32.6%); however, C. albicans is the most common Candida species implicated in vaginitis, and this strain displays considerable fluconazole resistance. Meanwhile, our study further indicates that fluconazole resistance in C. albicans may correlate with CDR1 gene overexpression.

  19. The antiretroviral efficacy of highly active antiretroviral therapy and plasma nevirapine concentrations in HIV-TB co-infected Indian patients receiving rifampicin based antituberculosis treatment

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    Sinha Sanjeev

    2011-11-01

    Full Text Available Abstract Background Rifampicin reduces the plasma concentrations of nevirapine in human immunodeficiency virus (HIV and tuberculosis (TB co-infected patients, who are administered these drugs concomitantly. We conducted a prospective interventional study to assess the efficacy of nevirapine-containing highly active antiretroviral treatment (HAART when co-administered with rifampicin-containing antituberculosis treatment (ATT and also measured plasma nevirapine concentrations in patients receiving such a nevirapine-containing HAART regimen. Methods 63 cases included antiretroviral treatment naïve HIV-TB co-infected patients with CD4 counts less than 200 cells/mm3 started on rifampicin-containing ATT followed by nevirapine-containing HAART. In control group we included 51 HIV patients without tuberculosis and on nevirapine-containing HAART. They were assessed for clinical and immunological response at the end of 24 and 48 weeks. Plasma nevirapine concentrations were measured at days 14, 28, 42 and 180 of starting HAART. Results 97 out of 114 (85.1% patients were alive at the end of 48 weeks. The CD4 cell count showed a mean increase of 108 vs.113 cells/mm3 (p=0.83 at 24 weeks of HAART in cases and controls respectively. Overall, 58.73% patients in cases had viral loads of less than 400 copies/ml at the end of 48 weeks. The mean (± SD Nevirapine concentrations of cases and control at 14, 28, 42 and 180 days were 2.19 ± 1.49 vs. 3.27 ± 4.95 (p = 0.10, 2.78 ± 1.60 vs. 3.67 ± 3.59 (p = 0.08, 3.06 ± 3.32 vs. 4.04 ± 2.55 (p = 0.10 respectively and 3.04 μg/ml (in cases. Conclusions Good immunological and clinical response can be obtained in HIV-TB co-infected patients receiving rifampicin and nevirapine concomitantly despite somewhat lower nevirapine trough concentrations. This suggests that rifampicin-containing ATT may be co administered in resource limited setting with nevirapine-containing HAART regimen without substantial reduction in

  20. Synergistic effect of the flavonoid catechin, quercetin, or epigallocatechin gallate with fluconazole induces apoptosis in Candida tropicalis resistant to fluconazole.

    Science.gov (United States)

    da Silva, Cecília Rocha; de Andrade Neto, João Batista; de Sousa Campos, Rosana; Figueiredo, Narjara Silvestre; Sampaio, Letícia Serpa; Magalhães, Hemerson Iury Ferreira; Cavalcanti, Bruno Coêlho; Gaspar, Danielle Macêdo; de Andrade, Geanne Matos; Lima, Iri Sandro Pampolha; de Barros Viana, Glauce Socorro; de Moraes, Manoel Odorico; Lobo, Marina Duarte Pinto; Grangeiro, Thalles Barbosa; Nobre Júnior, Hélio Vitoriano

    2014-01-01

    Flavonoids are a class of phenolic compounds commonly found in fruits, vegetables, grains, flowers, tea, and wine. They differ in their chemical structures and characteristics. Such compounds show various biological functions and have antioxidant, antimicrobial, anti-inflammatory, and antiapoptotic properties. The aim of this study was to evaluate the in vitro interactions of flavonoids with fluconazole against Candida tropicalis strains resistant to fluconazole, investigating the mechanism of synergism. Three combinations formed by the flavonoids (+)-catechin hydrated, hydrated quercetin, and (-)-epigallocatechin gallate at a fixed concentration with fluconazole were tested. Flavonoids alone had no antifungal activity within the concentration range tested, but when they were used as a cotreatment with fluconazole, there was significant synergistic activity. From this result, we set out to evaluate the possible mechanisms of cell death involved in this synergism. Isolated flavonoids did not induce morphological changes or changes in membrane integrity in the strains tested, but when they were used as a cotreatment with fluconazole, these changes were quite significant. When evaluating mitochondrial damage and the production of reactive oxygen species (ROS) only in the cotreatment, changes were observed. Flavonoids combined with fluconazole were shown to cause a significant increase in the rate of damage and the frequency of DNA damage in the tested strains. The cotreatment also induced an increase in the externalization of phosphatidylserine, an important marker of early apoptosis. It is concluded that flavonoids, when combined with fluconazole, show activity against strains of C. tropicalis resistant to fluconazole, promoting apoptosis by exposure of phosphatidylserine in the plasma membrane and morphological changes, mitochondrial depolarization, intracellular accumulation of ROS, condensation, and DNA fragmentation.

  1. Therapeutic drug monitoring of nevirapine in resource-limited settings.

    NARCIS (Netherlands)

    L'homme, R.F.A.; Muro, E.P.; Droste, J.A.H.; Wolters, L.R.; Kolmer, NW van Ewijk-Benek; Schimana, W.; Burger, D.M.

    2008-01-01

    BACKGROUND: We developed a simple and inexpensive thin-layer chromatography (TLC) assay for semiquantitative detection of saliva concentrations of nevirapine in resource-limited settings. The method was validated in an African target population. METHODS: Paired plasma and saliva nevirapine concentra

  2. Therapeutic drug monitoring of nevirapine in resource-limited settings.

    NARCIS (Netherlands)

    L'homme, R.F.A.; Muro, E.P.; Droste, J.A.H.; Wolters, L.R.; Kolmer, NW van Ewijk-Benek; Schimana, W.; Burger, D.M.

    2008-01-01

    BACKGROUND: We developed a simple and inexpensive thin-layer chromatography (TLC) assay for semiquantitative detection of saliva concentrations of nevirapine in resource-limited settings. The method was validated in an African target population. METHODS: Paired plasma and saliva nevirapine concentra

  3. Effect of Efflux Transporter Inhibition on the Distribution of Fluconazole in the Rat Brain.

    Science.gov (United States)

    Wang, Wei; Zheng, Na; Zhang, Jiatang; Huang, Xusheng; Yu, Shengyuan

    2017-03-24

    Multidrug resistance-associated proteins (MRPs) and organic anion transporters (OATs) are expressed on the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB), preventing the entry of or the pumping out of numerous molecules. Fluconazole is widely used to treat fungal meningoencephalitis. The effect of these transporters on the distribution of fluconazole in the brain is unclear. We used microdialysis to compare the distribution of fluconazole in the rat brain with and without co-administration of probenecid, a MRP and OAT inhibitor. Additionally, we also observed the difference in fluconazole distribution between the two barriers. The results showed that probenecid increased the penetration of fluconazole into the BBB but did not alter the penetration of fluconazole into the BCSFB of rats. The penetration of the BBB and BCSFB by fluconazole did not statistically differ according to physiological condition. These results demonstrate that transporters that can be inhibited by probenecid may be involved in fluconazole resistance at the BBB and provide a laboratory basis for predicting brain extracellular fluid (ECF) concentration using the cerebrospinal fluid (CSF) concentration of fluconazole.

  4. Development of a liposomal nanodelivery system for nevirapine

    Directory of Open Access Journals (Sweden)

    Krishnan Uma M

    2010-07-01

    Full Text Available Abstract Background The treatment of AIDS remains a serious challenge owing to high genetic variation of Human Immunodeficiency Virus type 1 (HIV-1. The use of different antiretroviral drugs (ARV is significantly limited by severe side-effects that further compromise the quality of life of the AIDS patient. In the present study, we have evaluated a liposome system for the delivery of nevirapine, a hydrophobic non-nucleoside reverse transcriptase inhibitor. Liposomes were prepared from egg phospholipids using thin film hydration. The parameters of the process were optimized to obtain spherical liposomes below 200 nm with a narrow polydispersity. The encapsulation efficiency of the liposomes was optimized at different ratios of egg phospholipid to cholesterol as well as drug to total lipid. The data demonstrate that encapsulation efficiency of 78.14% and 76.25% were obtained at egg phospholipid to cholesterol ratio of 9:1 and drug to lipid ratio of 1:5, respectively. We further observed that the size of the liposomes and the encapsulation efficiency of the drug increased concomitantly with the increasing ratio of drug and lipid and that maximum stability was observed at the physiological pH. Thermal analysis of the drug encapsulated liposomes indicated the formation of a homogenous drug-lipid system. The magnitude of drug release from the liposomes was examined under different experimental conditions including in phosphate buffered saline (PBS, Dulbecco's Modified Eagle's Medium (DMEM supplemented with 10% fetal bovine serum or in the presence of an external stimulus such as low frequency ultrasound. Within the first 20 minutes 40, 60 and 100% of the drug was released when placed in PBS, DMEM or when ultrasound was applied, respectively. We propose that nevirapine-loaded liposomal formulations reported here could improve targeted delivery of the anti-retroviral drugs to select compartments and cells and alleviate systemic toxic side effects as a

  5. Fluconazole resistance in Candida species: a current perspective

    Directory of Open Access Journals (Sweden)

    Berkow EL

    2017-07-01

    Full Text Available Elizabeth L Berkow, Shawn R Lockhart Mycotic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, GA, USA Abstract: Candida albicans and the emerging non-albicans Candida spp. have significant clinical relevance among many patient populations. Current treatment guidelines include fluconazole as a primary therapeutic option for the treatment of these infections, but it is only fungistatic against Candida spp. and both inherent and acquired resistance to fluconazole have been reported. Such mechanisms of resistance include increased drug efflux, alteration or increase in the drug target, and development of compensatory pathways for producing the target sterol, ergosterol. While many mechanisms of resistance observed in C. albicans are also found in the non-albicans species, there are also important and unexpected differences between species. Furthermore, mechanisms of fluconazole resistance in emerging Candida spp., including the global health threat Candida auris, are largely unknown. In order to preserve the utility of one of our fundamental antifungal drugs, fluconazole, it is essential that we fully appreciate the manner by which Candida spp. manifest resistance to it. Keywords: Candida, fluconazole resistance, ERG11, drug efflux, ergosterol

  6. [Hepatotoxicity in healthy infants exposed to nevirapine during pregnancy].

    Science.gov (United States)

    Iveli, Pablo; Noguera-Julian, Antoni; Soler-Palacín, Pere; Martín-Nalda, Andrea; Rovira-Girabal, Núria; Fortuny-Guasch, Clàudia; Figueras-Nadal, Concepció

    2016-01-01

    The use of nevirapine in HIV-infected pregnant women is discouraged due to its potential to cause hepatotoxicity. There is limited information available on the toxicity in non-HIV infected newborn exposed to this drug during pregnancy. The aim of the study is to determine the extent of hepatotoxicity in the newborn exposed to nevirapine and HIV during pregnancy. A cross-sectional, observational, multicenter study was conducted on a cohort of healthy infants born to HIV-infected mothers, in whom the first determination of alanine aminotransferase (ALT), before 6weeks of age, was collected. Patients were allocated to 2groups according to exposure to nevirapine during pregnancy. Hepatotoxicity was rated according to the AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS). This study included 160newborns from 159pregnancies (88exposed to nevirapine-based regimens and 71 exposed to protease inhibitors-based therapies). No cases of hepatotoxicity were observed according to the DAIDS Table for Grading. Two cases of ALT above normal values (2.8%; 95%CI: 0.3-9.8%) were observed in patients not exposed to nevirapine, and one case (1.1%; 95%CI: 0.0-6.1%) in the group exposed to nevirapine (P=.585). The lack of differences between groups suggests that highly active antiretroviral treatment regimens including nevirapine administered during pregnancy do not involve a higher risk of liver disease compared to other treatment combinations. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  7. Oral fluconazole in tinea versicolor

    Directory of Open Access Journals (Sweden)

    Sankara Rao I

    1997-01-01

    Full Text Available 25 patients with extensive tinea versicolor were treated with single oral dose of 400 mg of fluconazole. 25 patients returned for follow-up. Follow-up at 3 weeks, 6 weeks and 8 weeks showed 100% clinical cure rate and 92% mycological cure rate. No significant side effects were noticed. The majority of patients found the treatment effective, safe and convenient.

  8. Synergistic activity of chloroquine with fluconazole against fluconazole-resistant isolates of Candida species.

    Science.gov (United States)

    Li, Yali; Wan, Zhe; Liu, Wei; Li, Ruoyu

    2015-02-01

    The in vitro activity of chloroquine and the interactions of chloroquine combined with fluconazole against 37 Candida isolates were tested using the broth microdilution, disk diffusion, and Etest susceptibility tests. Synergistic effect was detected with 6 of 9 fluconazole-resistant Candida albicans isolates, with Candida krusei ATCC 6258, and with all 12 fluconazole-resistant Candida tropicalis isolates.

  9. Triclosan antagonizes fluconazole activity against Candida albicans.

    LENUS (Irish Health Repository)

    Higgins, J

    2012-01-01

    Triclosan is a broad-spectrum antimicrobial compound commonly used in oral hygiene products. Investigation of its activity against Candida albicans showed that triclosan was fungicidal at concentrations of 16 mg\\/L. However, at subinhibitory concentrations (0.5-2 mg\\/L), triclosan antagonized the activity of fluconazole. Although triclosan induced CDR1 expression in C. albicans, antagonism was still observed in cdr1Δ and cdr2Δ strains. Triclosan did not affect fluconazole uptake or alter total membrane sterol content, but did induce the expression of FAS1 and FAS2, indicating that its mode of action may involve inhibition of fatty acid synthesis, as it does in prokaryotes. However, FAS2 mutants did not exhibit increased susceptibility to triclosan, and overexpression of both FAS1 and FAS2 alleles did not alter triclosan susceptibility. Unexpectedly, the antagonistic effect was specific for C. albicans under hypha-inducing conditions and was absent in the non-filamentous efg1Δ strain. This antagonism may be due to the membranotropic activity of triclosan and the unique composition of hyphal membranes.

  10. Effect of diurnal variation, CYP2B6 genotype and age on the pharmacokinetics of nevirapine in African children

    Science.gov (United States)

    Bienczak, Andrzej; Cook, Adrian; Wiesner, Lubbe; Mulenga, Veronica; Kityo, Cissy; Kekitiinwa, Addy; Walker, A. Sarah; Owen, Andrew; Gibb, Diana M.; Burger, David; McIlleron, Helen; Denti, Paolo

    2017-01-01

    Objectives To characterize the effects of CYP2B6 polymorphisms, diurnal variation and demographic factors on nevirapine pharmacokinetics in African children. Methods Non-linear mixed-effects modelling conducted in NONMEM 7.3 described nevirapine plasma concentration–time data from 414 children aged 0.3–15 years. Results Nevirapine pharmacokinetics was best described using a one-compartment disposition model with elimination through a well-stirred liver model accounting for a first-pass effect and transit-compartment absorption. Intrinsic clearance was affected by diurnal variation (characterized using a cosine function with peak amplitude 29% at 12 noon) and CYP2B6 metabolizer status [extensive metabolizer (EM) 516GG|983TT, reference; intermediate metabolizer (IM) 516GT|983TT or 516GG|983TC, 17% lower; slow metabolizer (SM) 516TT|983TT or 516GT|983TC, 50% lower; ultra-slow metabolizer (USM) 516GG|983CC, 68% lower]. Age was found to affect pre-hepatic bioavailability: 31.7% lower at birth and increasing exponentially. Median (90% CI) evening Cmin values in the different metabolizer groups were 5.01 (3.01–7.47), 6.55 (3.65–13.32), 11.59 (5.44–22.71) and 12.32 (12.32–27.25) mg/L, respectively. Evening Cmin values were 8 mg/L. Cmin was not markedly affected by administration time, but was altered by unequal splitting of the daily dose. Conclusions Diurnal variation does not greatly affect nevirapine exposure. However, when daily doses cannot be split equally, the larger dose should be given in the morning. To achieve homogeneous exposures, nevirapine doses for SM and USM should be reduced by 50%, and children weighing <6 kg with EM or IM metabolizer status should receive the same dose as children weighing 6–10 kg. PMID:27707991

  11. Comparison of twice-daily stavudine plus once- or twice-daily didanosine and nevirapine in early stages of HIV infection: the scan study.

    Science.gov (United States)

    García, F; Knobel, H; Sambeat, M A; Arrizabalaga, J; Aranda, M; Romeu, J; Dalmau, D; Segura, F; Gomez-Sirvent, J L; Ferrer, E; Cruceta, A; Gallart, T; Pumarola, T; Miró, J M; Gatell, J M

    2000-11-10

    To evaluate the safety and effectiveness of once-daily didanosine and nevirapine plus twice-daily stavudine versus twice-daily administration of all three drugs. This open-label, randomized, multicentre study enrolled 94 antiretroviral-naive patients with chronic HIV infection, CD4+ cell counts > 500 x 10(6) cells/l, and viral loads > 5000 copies/ml. Patients were treated with either 40 mg stavudine (twice daily) plus 400 mg didanosine (once daily) and 400 mg nevirapine (once daily) or 40 mg stavudine (twice daily) plus 200 mg didanosine (twice daily) and 200 mg nevirapine (twice daily). After 12 months, 68% of patients who received twice-daily didanosine and nevirapine had viral loads < 200 copies/ml in the intention-to-treat and 79% in the on-treatment analysis, respectively. The corresponding values for patients treated with didanosine and nevirapine, taken once-daily, were 73 and 85%. The percentages of patients in each group with viral loads < 5 copies/ml at 12 months were 40% (once daily ) and 45% (twice daily) for the intention-to-treat analysis. Five of 11 patients (45%) with plasma viral loads < 5 copies/ml at 12 months had detectable virus in tonsillar tissue. Genotypic resistance to nevirapine was noted in seven of the 14 patients with detectable viral load at month 12. Mean changes in CD4+ cell counts for patients treated with stavudine plus once- or twice-daily didanosine and nevirapine were 154 and 132 x 10(6) cells/l, respectively. Treatment was interrupted due to adverse events in seven patients (8%) (four who received once-daily didanosine and nevirapine and three treated with twice-daily doses). The combination of twice-daily stavudine plus once-daily didanosine and nevirapine was as safe and well tolerated as twice-daily administration of all three agents. Both regimens were equally effective in reducing viral loads and in increasing CD4+ cell counts.

  12. Nevirapine-induced rash with eosinophilia and systemic symptoms (DRESS

    Directory of Open Access Journals (Sweden)

    Shaman Gill

    2013-01-01

    Full Text Available Drug rash with eosinophilia and systemic symptoms (DRESS syndrome is an adverse reaction commonly occurring with antiepileptic agents. It was earlier referred to by various names such as dilantin hypersensitivity syndrome and anticonvulsant hypersensitivity syndrome. It is characterized by the triad of fever, skin eruption, and systemic involvement. DRESS syndrome has also been reported with a number of other drugs including allopurinol, minocycline, terbinafine, sulfonamides, azathioprine, dapsone, and antiretroviral agents such as abacavir and nevirapine. We describe a rare case of nevirapine-induced hypersensitivity syndrome that was successfully treated with oral steroids.

  13. Evidence of CYP3A Allosterism In Vivo: Analysis of Fluconazole and Midazolam Interaction

    Science.gov (United States)

    Yang, Jing; Atkins, William M.; Isoherranen, Nina; Paine, Mary F.; Thummel, Kenneth E.

    2013-01-01

    The allosteric effect of fluconazole (effector) on the formation of 1’-hydroxymidazolam (1’-OH-MDZ) and 4-hydroxymidazolam (4-OH-MDZ) from the CYP3A4/5 substrate, midazolam (MDZ), was examined in healthy volunteers. Following pre-treatment of fluconazole, AUC4-OH/AUCMDZ increased 35–62%, while AUC1’-OH/AUCMDZ decreased 5–37%; AUC1’-OH/AUC4-OH ratio decreased 46–58% by fluconazole and had no association with CYP3A5 genotype. 1’-OH-MDZ formation in vitro was more susceptible than 4-OH-MDZ formation to inhibition by fluconazole. Fluconazole decreased the intrinsic formation clearance ratio of 1’-OH-MDZ/4-OH-MDZ to an extent that was quantitatively comparable to in vivo observations. The elimination clearance of midazolam metabolites appeared unaffected by fluconazole. This study demonstrated that fluconazole alters midazolam product formation both in vivo and in vitro in a manner consistent with an allosteric interaction. The 1'-OH-MDZ/4-OH-MDZ ratio may serve as a biomarker of such interactions between midazolam, CYP3A4/5 and other putative effectors. PMID:22048224

  14. Risk of discontinuation of nevirapine due to toxicities in antiretroviral-naive and -experienced HIV-infected patients with high and low CD4+ T-cell counts

    DEFF Research Database (Denmark)

    Mocroft, Amanda; Staszewski, Schlomo; Weber, Rainer;

    2007-01-01

    It is unknown whether the increased risk of toxicities in antiretroviral-naive HIV-infected patients initiating nevirapine-based (NVPc) combination antiretroviral therapy (cART) with high CD4+ T-cell counts is also observed when NVPc is initiated in cARTexperienced patients.......It is unknown whether the increased risk of toxicities in antiretroviral-naive HIV-infected patients initiating nevirapine-based (NVPc) combination antiretroviral therapy (cART) with high CD4+ T-cell counts is also observed when NVPc is initiated in cARTexperienced patients....

  15. Allogeneic hematopoietic cell transplantation without fluconazole and fluoroquinolone prophylaxis.

    Science.gov (United States)

    Heidenreich, D; Kreil, S; Nolte, F; Reinwald, M; Hofmann, W-K; Klein, S A

    2016-01-01

    Fluoroquinolone (FQ) and fluconazole prophylaxis is recommended for patients undergoing allogeneic hematopoietic cell transplantation (alloHCT). However, due to an uncertain scientific basis and the increasing emergence of resistant germs, this policy should be questioned. Therefore, FQ and fluconazole prophylaxis was omitted in alloHCT at our center. In this retrospective analysis, all consecutive patients (n = 63) who underwent first alloHCT at our institution from September 2010 to September 2013 were included. Patients neither received FQ nor fluconazole prophylaxis. Day 100 mortality, incidence of febrile neutropenia, bacterial infections, and invasive fungal diseases (IFD) were assessed. Sixteen patients who started conditioning under antimicrobial treatment/prophylaxis due to pre-existing neutropenia (3/16), IFD (12/16), or aortic valve replacement (1/16) were excluded from the analysis. Finally, 47 patients were transplanted without prophylaxis as intended. Day 100 mortality was 9 %. Febrile neutropenia occurred in 62 % (29/47); 17/47 patients (36 %) experienced a blood stream infection (BSI) with detection of Gram-positive bacteria in 14 patients, Gram-negative bacteria in five patients, and candida in one patient, respectively. Coagulase-negative staphylococci were the most frequently isolated Gram-positive bacteria; 12/21 isolated Gram-positive and 3/6 Gram-negative bacteria were FQ resistant. In 21 % (10/47) of the patients, IFD (1x proven, 1x probable, and 8x possible) were diagnosed. To conclude, all three criteria, day 100 mortality, the incidence of IFD, and BSI, are in the range of published data for patients transplanted with FQ and fluconazole prophylaxis. These data demonstrate that alloHCT is feasible without FQ and fluconazole prophylaxis.

  16. Cross-resistance to fluconazole induced by exposure to the agricultural azole tetraconazole: an environmental resistance school?

    Science.gov (United States)

    Rocha, Marcos Fábio Gadelha; Alencar, L P; Paiva, M A N; Melo, Luciana Magalhães; Bandeira, Silviane Praciano; Ponte, Y B; Sales, Jamille Alencar; Guedes, G M M; Castelo-Branco, D S C M; Bandeira, T J P G; Cordeiro, R A; Pereira-Neto, W A; Brandine, G S; Moreira, José Luciano Bezerra; Sidrim, José Júlio Costa; Brilhante, Raimunda Sâmia Nogueira

    2016-05-01

    This study aimed to investigate the influence of tetraconazole and malathion, both used in agricultural activities, on resistance to fluconazole, itraconazole and voriconazole in Candida parapsilosis ATCC 22019. The susceptibility to tetraconazole, malathion, fluconazole, itraconazole and voriconazole, through broth microdilution. Then, 12 independent replicates, were separated and exposed to four treatment groups, each one containing three replicates: G1: tetraconazole; G2: malathion; G3: fluconazole (positive control); G4: negative control. Replicates from G1, G2 and G3, were exposed to weekly increasing concentrations of tetraconazole, malathion and fluconazole, respectively, ranging from MIC/2 to 32 × MIC, throughout 7 weeks. The exposure to tetraconazole, but not malathion, decreased susceptibility to clinical azoles, especially fluconazole. The tetraconazole-induced fluconazole resistance is partially mediated by the increased activity of ATP-dependent efflux pumps, considering the increase in antifungal susceptibility after the addition of the efflux pump inhibitor, promethazine, and the increase in rhodamine 6G efflux and CDR gene expression in the G1 replicates. Moreover, MDR expression was only detected in G1 and G3 replicates, suggesting that MDR pumps are also involved in tetraconazole-induced fluconazole resistance. It is noteworthy that tetraconazole and fluconazole-treated replicates behaved similarly, therefore, resistance to azoles of clinical use may be a consequence of using azoles in farming activities.

  17. Mutations in transcription factor Mrr2p contribute to fluconazole resistance in clinical isolates of Candida albicans.

    Science.gov (United States)

    Wang, Ying; Liu, Jin-Yan; Shi, Ce; Li, Wen-Jing; Zhao, Yue; Yan, Lan; Xiang, Ming-Jie

    2015-11-01

    The Candida albicans zinc cluster proteins are a family of transcription factors (TFs) that play essential roles in the development of antifungal drug resistance. Gain-of-function mutations in several TFs, such as Tac1p, Mrr1p and Upc2p, have been previously well documented in azole-resistant clinical C. albicans isolates. Mrr2p (multidrug resistance regulator 2) is a novel TF controlling expression of the ABC transporter gene CDR1 and mediating fluconazole resistance. In this study, the relationship between naturally occurring mutations in MRR2 and fluconazole resistance in clinical C. albicans isolates was investigated. Among a group of 20 fluconazole-resistant clinical C. albicans and 10 fluconazole-susceptible C. albicans, 12 fluconazole-resistant isolates overexpressed CDR1 by at least two-fold compared with the fluconazole-susceptible isolates. Of these 12 resistant isolates, three (C7, C9, C15) contained 11 identical missense mutations, 6 of which occurred only in the azole-resistant isolates. The contribution of these mutations to CDR1 overexpression and therefore to fluconazole resistance was further verified by generating recombinant strains containing the mutated MRR2 gene. The mutated MRR2 alleles from isolate C9 contributed to an almost six-fold increase in CDR1 expression and an eight-fold increase in fluconazole resistance; the missense mutations S466L and T470N resulted in an increase in CDR1 expression of more than two-fold and a four-fold increase in fluconazole resistance. In contrast, the other four missense mutations conferred only two- to four-fold increases in fluconazole resistance, with no significant increase in CDR1 expression. These findings provide some insight into the mechanism by which MRR2 regulates C. albicans multidrug resistance.

  18. Fluconazole

    Science.gov (United States)

    ... because they are being treated with chemotherapy or radiation therapy before a bone marrow transplant (replacement of ... open them easily. To protect young children from poisoning, always lock safety caps and immediately place the ...

  19. Fluconazole Pharmacokinetics in Burn Patients

    Science.gov (United States)

    Boucher, Bradley A.; King, Stephen R.; Wandschneider, Heidi L.; Hickerson, William L.; Hanes, Scott D.; Herring, Vanessa L.; Canada, Todd W.; Hess, Mary M.

    1998-01-01

    The pharmacokinetics of fluconazole in nine adult patients with severe (30 to 95% total body surface area) burns were studied. There was no significant difference in half-life (t1/2), clearance (CL), or volume of distribution (V) over time in five patients on days 3 and 8 of the study (P > 0.05). Combined parameter estimates (means ± standard deviations) for all nine patients for the two study periods were as follows: t1/2, 24.4 ± 5.8 h; CL, 0.36 ± 0.09 ml/min/kg; and V, 0.72 ± 0.12 liters/kg. These estimates of t1/2 and CL in burn patients were approximately 13% shorter and 30% more rapid, respectively, than the most extreme estimates reported for other populations. PMID:9559811

  20. Differentially expressed proteins in fluconazole-susceptible and fluconazole-resistant isolates of Candida glabrata.

    Science.gov (United States)

    Shen, Yinzhong; Zhang, Lijun; Jia, Xiaofang; Zhang, Yongxin; Lu, Hongzhou

    2015-06-01

    The current study aimed to identify the differences presented in the proteome of fluconazole-susceptible isolates of Candida glabrata compared to those with fluconazole-resistant ones. Two-dimensional differential gel electrophoresis was applied to identify proteins that were differentially expressed in fluconazole-susceptible and fluconazole-resistant isolates of C. glabrata. Eight proteins including aspartyl-tRNA synthetase, translation elongation factor 3, 3-phosphoglycerate kinase, ribosomal protein L5, coproporphyrinogen III oxidase, pyruvate kinase, G-beta like protein, and F1F0-ATPase alpha subunit were found to be more abundantly represented, while four proteins including vitamin B12-(cobalamin)-independent isozyme of methionine synthase, microtubule-associated protein, adenylosuccinate synthetase, and aldose reductase were found to be less abundantly represented in fluconazole-resistant strains versus those with fluconazole-susceptible ones. These differentially expressed proteins were primarily associated with energy metabolism, stress response, and macromolecule synthesis. Proteins associated with energy metabolism, stress response, and macromolecule synthesis may play a role in the development of fluconazole resistance in the clinical isolates of C. glabrata. Multiple different mechanisms are involved in the development of fluconazole resistance in C. glabrata. These findings provide a scientific basis for discovering new genes and mechanisms associated with fluconazole resistance in C. glabrata.

  1. Induction of ROS generation by fluconazole in Candida glabrata: activation of antioxidant enzymes and oxidative DNA damage.

    Science.gov (United States)

    Mahl, Camila Donato; Behling, Camile Saul; Hackenhaar, Fernanda S; de Carvalho e Silva, Mélany Natuane; Putti, Jordana; Salomon, Tiago B; Alves, Sydney Hartz; Fuentefria, Alexandre; Benfato, Mara S

    2015-07-01

    In this study, we assessed the generation of reactive oxygen species (ROS) induced by subinhibitory concentration of fluconazole in susceptible and resistant Candida glabrata strains at stationary growth phase and measured their oxidative responses parameters: glutathione peroxidase (GPx), superoxide dismutase (SOD), glutathione-S-transferase (GST), consumption of hydrogen peroxide, and total glutathione, as well as oxidative damage in lipids, proteins, and DNA. Data showed that fluconazole increased generation of ROS and GPx and SOD enzymatic activity in treated cells; however, these enzymatic activities did not differ between resistant and susceptible strains. Susceptible strains exhibited higher GST activity than resistant, and when susceptible cells were treated with fluconazole, GST activity decreased. Fluconazole treatment cause oxidative damage only in DNA. There are a possible participation of ROS, as organic peroxides and O2(•-), in antifungal mechanism of fluconazole, which results in higher GPx and SOD enzymatic activities and oxidative DNA damage in C. glabrata.

  2. Divergent electrophysiologic profile of fluconazole and voriconazole in an experimental whole-heart model of proarrhythmia.

    Science.gov (United States)

    Frommeyer, Gerrit; Fischer, Christina; Lange, Philipp S; Leitz, Patrick; Fehr, Michael; Bogossian, Harilaos; Milberg, Peter; Eckardt, Lars

    2016-04-05

    In several case reports a prolongation of the QT-interval and even proarrhythmic effects of fluconazole and voriconazole were reported. The aim of the present study was to investigate if application of fluconazole or voriconazole has the potential to provoke polymorphic ventricular tachycardia in a sensitive model of proarrhythmia. In female rabbits, fluconazole (10, 30 and 50 µM, n=6) and voriconazole (10, 30 and 50 µM, n=6) were infused after obtaining baseline data. Eight endocardial and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG showed a significant QT prolongation after application of fluconazole as compared with baseline (10 µM:+12 ms, 30 µM:+22 ms, 50 µM:+37 ms; Pfluconazole induced a significant increase (30 µM:+15 ms, 50 µM:+16 ms; Pfluconazole led to the reproducible induction of EADs in 4 of 6 hearts and polymorphic ventricular tachycardia in 3 of 6 hearts (36 episodes). In the present study, voriconazole demonstrated a safe electrophysiologic profile despite significant QT prolongation. In contrast, fluconazole led to a more marked prolongation of myocardial repolarization combined with a more marked increase of dispersion of repolarization. These results imply that application of fluconazole might be torsadogenic and the QT-interval should be closely monitored.

  3. Resistance reversal induced by a combination of fluconazole and tacrolimus (FK506) in Candida glabrata.

    Science.gov (United States)

    Li, Hui; Chen, Zuozhong; Zhang, Caiqing; Gao, Yuan; Zhang, Xiang; Sun, Shujuan

    2015-01-01

    There is an increasing concern about Candida glabrata due to its high isolation frequency in candidiasis recently and notorious drug resistance to fluconazole. Drug combination is one effective approach to counteract drug resistance. This study aimed to test whether a combination of fluconazole and tacrolimus (FK506) had a synergistic effect on C. glabrata, and to seek the potential mechanisms underlying the synergistic effects. In vitro effects of fluconazole and FK506 against C. glabrata with different susceptibilities were investigated by a chequerboard method and a time-kill curve method. The mechanistic studies against the resistant C. glabrata were performed from two aspects: quantification of expression levels of fluconazole resistance genes (ERG11, CDR1, PDH1 and SNQ2) by real-time quantitative PCR and functional assays of drug efflux pumps. The addition of FK506 resulted in a decrease in the MIC of fluconazole from 32 to 8 µg ml(-1) against the dose-dependent susceptible C. glabrata, and from 256 to 16 µg ml(-1) against the resistant C. glabrata, respectively. The synergy was further confirmed by the time-kill assay. The expression levels of the ERG11 and SNQ2 genes were significantly downregulated after exposure to the drug combination, whereas that of the CDR1 gene was significantly upregulated, and no significant change in expression of PDH1 gene was observed. Flow cytometric assays showed that FK506 reduced the efflux of fluconazole. Tacrolimus enhanced the susceptibility of fluconazole against resistant C. glabrata by reducing the expression levels of the ERG11 and SNQ2 genes and inhibiting fluconazole efflux.

  4. Triclosan antagonises fluconazole activity against Candida albicans

    OpenAIRE

    2012-01-01

    Epub October 4th Triclosan is a broad-spectrum antimicrobial compound commonly used in oral hygiene products. Investigation of its activity against Candida albicans showed that triclosan was fungicidal at concentrations of 16 mg/L. However, at subinhibitory concentrations (0.5-2 mg/L) triclosan antagonized the activity of fluconazole. Although triclosan induced CDR1 expression in C. albicans, antagonism was still observed in cdr1? and cdr2? strains. Triclosan did not affect fluconazole upt...

  5. Determination of nevirapine in the presence of cucurbit(7uril with a gold electrode

    Directory of Open Access Journals (Sweden)

    ELÍAS BLANCO

    2014-02-01

    Full Text Available The electrochemical oxidation of nevirapine, an anti-HIV drug, at a gold electrode was studied by voltammetric techniques. Nevirapine showed a signal that interfered with a working electrode wave. This interference was solved by the use of cucurbit(7uril allowing nevirapine to be determined in tablets (80.4 % recovery, presence of stavudine and lamivudine and urine (98.4 %.

  6. Fluconazole alters the polysaccharide capsule of Cryptococcus gattii and leads to distinct behaviors in murine Cryptococcosis.

    Science.gov (United States)

    Santos, Julliana Ribeiro Alves; Holanda, Rodrigo Assunção; Frases, Susana; Bravim, Mayara; Araujo, Glauber de S; Santos, Patrícia Campi; Costa, Marliete Carvalho; Ribeiro, Maira Juliana Andrade; Ferreira, Gabriella Freitas; Baltazar, Ludmila Matos; Miranda, Aline Silva; Oliveira, Danilo Bretas; Santos, Carolina Maria Araújo; Fontes, Alide Caroline Lima; Gouveia, Ludmila Ferreira; Resende-Stoianoff, Maria Aparecida; Abrahão, Jonatas Santos; Teixeira, Antônio Lúcio; Paixão, Tatiane Alves; Souza, Danielle G; Santos, Daniel Assis

    2014-01-01

    Cryptococcus gattii is an emergent human pathogen. Fluconazole is commonly used for treatment of cryptococcosis, but the emergence of less susceptible strains to this azole is a global problem and also the data regarding fluconazole-resistant cryptococcosis are scarce. We evaluate the influence of fluconazole on murine cryptococcosis and whether this azole alters the polysaccharide (PS) from cryptococcal cells. L27/01 strain of C. gattii was cultivated in high fluconazole concentrations and developed decreased drug susceptibility. This phenotype was named L27/01F, that was less virulent than L27/01 in mice. The physical, structural and electrophoretic properties of the PS capsule of L27/01F were altered by fluconazole. L27/01F presented lower antiphagocytic properties and reduced survival inside macrophages. The L27/01F did not affect the central nervous system, while the effect in brain caused by L27/01 strain began after only 12 hours. Mice infected with L27/01F presented lower production of the pro-inflammatory cytokines, with increased cellular recruitment in the lungs and severe pulmonary disease. The behavioral alterations were affected by L27/01, but no effects were detected after infection with L27/01F. Our results suggest that stress to fluconazole alters the capsule of C. gattii and influences the clinical manifestations of cryptococcosis.

  7. Cryptococcus neoformans Yap1 is required for normal fluconazole and oxidative stress resistance.

    Science.gov (United States)

    Paul, Sanjoy; Doering, Tamara L; Moye-Rowley, W Scott

    2015-01-01

    Cryptococcus neoformans is a pathogen that is the most common cause of fungal meningitis. As with most fungal pathogens, the most prevalent clinical antifungal used to treat Cryptococcosis is orally administered fluconazole. Resistance to this antifungal is an increasing concern in treatment of fungal disease in general. Our knowledge of the specific determinants involved in fluconazole resistance in Cryptococcus is limited. Here we report the identification of an important genetic determinant of fluconazole resistance in C. neoformans that encodes a basic region-leucine zipper transcription factor homologous to Saccharomyces cerevisiae Yap1. Expression of a codon-optimized form of the Cn YAP1 cDNA in S. cerevisiae complemented defects caused by loss of the endogenous S. cerevisiae YAP1 gene and activated transcription from a reporter gene construct. Mutant strains of C. neoformans lacking YAP1 were hypersensitive to a range of oxidative stress agents but importantly also to fluconazole. Loss of Yap1 homologues from other fungal pathogens like Candida albicans or Aspergillus fumigatus was previously found to cause oxidant hypersensitivity but had no detectable effect on fluconazole resistance. Our data provide evidence for a unique biological role of Yap1 in wild-type fluconazole resistance in C. neoformans.

  8. Formulation and evaluation of lecithin organogel for topical delivery of fluconazole.

    Science.gov (United States)

    Jadhav, Kisan R; Kadam, Vilasrao J; Pisal, Sambhaji S

    2009-04-01

    The purpose of the present study was to develop and investigate the suitability of microemulsion based lecithin organogel formulations for topical delivery of fluconazole in order to bypass its gastrointestinal adverse effects. The ternary phase diagrams were developed and various organogel formulations were prepared using pharmaceutically acceptable surfactant (lecithin) and ethyl oleate (EO). Solubility of fluconazole in EO and EO-lecithin reverse micellar system was determined. The transdermal permeability of fluconazole from different concentrations of lecithin organogels containing EO as oil phase was analyzed using Keshary-Chien diffusion cell through excised rat skin. Solubility of fluconazole in EO-lecithin reverse micellar system was almost 3 folds higher than that in EO. Gelation and immobilization of oil require critical solubility-insolubility balance of gelator. The occurrence of gel phase was lecithin concentration dependent and was observed in 10-60% w/v of system. Organogel containing 300 mM of lecithin showed the higher drug release and better relative consistency. Hence, it was selected for antifungal activity. The increase in antifungal activity of fluconazole in lecithin organogel may be because of the surfactant action of the lecithin and EO that may help in the diffusion of drug. The histopathological data showed that EO-lecithin organogels were safe enough for the topical purpose. Hence, the present lecithin based organogel appears beneficial for topical delivery of fluconazole in terms of easy preparation, safety, stability and low cost.

  9. Fluconazole Binding and Sterol Demethylation in Three CYP51 Isoforms Indicate Differences in Active Site Topology

    Energy Technology Data Exchange (ETDEWEB)

    Bellamine, A.; Lepesheva, Galina I.; Waterman, Mike (Vanderbilt)

    2010-11-16

    14{alpha}-Demethylase (CYP51) is a key enzyme in all sterol biosynthetic pathways (animals, fungi, plants, protists, and some bacteria), catalyzing the removal of the C-14 methyl group following cyclization of squalene. Based on mutations found in CYP51 genes from Candida albicans azole-resistant isolates obtained after fluconazole treatment of fungal infections, and using site-directed mutagenesis, we have found that fluconazole binding and substrate metabolism vary among three different CYP51 isoforms: human, fungal, and mycobacterial. In C. albicans, the Y132H mutant from isolates shows no effect on fluconazole binding, whereas the F145L mutant results in a 5-fold increase in its IC{sub 50} for fluconazole, suggesting that F145 (conserved only in fungal 14{alpha}-demethylases) interacts with this azole. In C. albicans, F145L accounts, in part, for the difference in fluconazole sensitivity reported between mammals and fungi, providing a basis for treatment of fungal infections. The C. albicans Y132H and human Y145H CYP51 mutants show essentially no effect on substrate metabolism, but the Mycobacterium tuberculosis F89H CYP51 mutant loses both its substrate binding and metabolism. Because these three residues align in the three isoforms, the results indicate that their active sites contain important structural differences, and further emphasize that fluconazole and substrate binding are uncoupled properties.

  10. Fluconazole Alters the Polysaccharide Capsule of Cryptococcus gattii and Leads to Distinct Behaviors in Murine Cryptococcosis

    Science.gov (United States)

    Santos, Julliana Ribeiro Alves; Holanda, Rodrigo Assunção; Frases, Susana; Bravim, Mayara; Araujo, Glauber de S.; Santos, Patrícia Campi; Costa, Marliete Carvalho; Ribeiro, Maira Juliana Andrade; Ferreira, Gabriella Freitas; Baltazar, Ludmila Matos; Miranda, Aline Silva; Oliveira, Danilo Bretas; Santos, Carolina Maria Araújo; Fontes, Alide Caroline Lima; Gouveia, Ludmila Ferreira; Resende-Stoianoff, Maria Aparecida; Abrahão, Jonatas Santos; Teixeira, Antônio Lúcio; Paixão, Tatiane Alves; Souza, Danielle G.; Santos, Daniel Assis

    2014-01-01

    Cryptococcus gattii is an emergent human pathogen. Fluconazole is commonly used for treatment of cryptococcosis, but the emergence of less susceptible strains to this azole is a global problem and also the data regarding fluconazole-resistant cryptococcosis are scarce. We evaluate the influence of fluconazole on murine cryptococcosis and whether this azole alters the polysaccharide (PS) from cryptococcal cells. L27/01 strain of C. gattii was cultivated in high fluconazole concentrations and developed decreased drug susceptibility. This phenotype was named L27/01F, that was less virulent than L27/01 in mice. The physical, structural and electrophoretic properties of the PS capsule of L27/01F were altered by fluconazole. L27/01F presented lower antiphagocytic properties and reduced survival inside macrophages. The L27/01F did not affect the central nervous system, while the effect in brain caused by L27/01 strain began after only 12 hours. Mice infected with L27/01F presented lower production of the pro-inflammatory cytokines, with increased cellular recruitment in the lungs and severe pulmonary disease. The behavioral alterations were affected by L27/01, but no effects were detected after infection with L27/01F. Our results suggest that stress to fluconazole alters the capsule of C. gattii and influences the clinical manifestations of cryptococcosis. PMID:25392951

  11. Nevirapine patch testing in Thai human immunodeficiency virus infected patients with nevirapine drug hypersensitivity.

    Science.gov (United States)

    Prasertvit, Piyatida; Chareonyingwattana, Angkana; Wattanakrai, Penpun

    2017-08-06

    Antiretroviral drug hypersensitivity in HIV patients is common. Publications have shown that Abacavir (ABC) patch testing is useful in confirming ABC hypersensitivity in 24-50% of cases with a 100% sensitivity of HLA-B*5701 in patch test positive cases. However, Nevirapine (NVP) patch testing has not been reported. (1) To evaluate the usefulness and safety of NVP patch testing in Thai HIV patients with NVP hypersensitivity. (2) To assess the correlation of positive patch tests with HLA-B*3505. Patients were classified into two groups: (1) study group of 20 HIV NVP hypersensitivity patients and (2) control group of 15 volunteers without NVP hypersensitivity. Both groups were patch tested with purified and commercialized form of NVP in various vehicles. Two HIV patients with NVP hypersensitivity were patch test positive. All controls tested negative. Three HIV patients were positive for HLA-B*3505 and the two patients with positive patch testing were both HLA-B*3505 positive. NVP patch testing in Thai HIV patients is safe and can be used to help confirm the association between NVP and hypersensitivity skin reactions. NVP patch test results significantly correlated with HLA-B*3505. The sensitivity of HLA-B*3505 for positive patch test was 100%. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Nevirapine induced Stevens-Johnson syndrome in an HIV infected patient

    Directory of Open Access Journals (Sweden)

    Harminder Singh

    2011-01-01

    Full Text Available Nevirapine, a non-nucleoside reverse transcriptase inhibitor (NNRTI, is widely prescribed as a part of the combination therapy of human immunodeficiency virus (HIV infection because of its efficacy and good tolerability. Here, we report a case of Stevens-Johnson syndrome (SJS secondary to nevirapine. The patient had a diffuse, exfoliating exanthema with generalized bullous eruptions that involved the face, trunk and both extremities with elevated hepatic alanine aminotransferase and aspartate aminotransferase enzyme activities. The condition improved with stoppage of nevirapine-based highly active antiretroviral therapy (HAART regimen, so we attributed this adverse event to nevirapine. A strict vigilance of adverse drug reaction is required in HAART.

  13. Investigating the continuous synthesis of a nicotinonitrile precursor to nevirapine

    Directory of Open Access Journals (Sweden)

    Ashley R. Longstreet

    2013-11-01

    Full Text Available 2-Chloro-3-amino-4-picoline (CAPIC is a strategic building block for the preparation of nevirapine, a widely-prescribed non-nucleosidic reverse transcriptase inhibitor for the treatment of HIV-infected patients. A continuous synthesis to the bromo derivative of a CAPIC intermediate, 2-bromo-4-methylnicotinonitrile, that terminates in a dead-end crystallization is described. The route uses inexpensive, acyclic commodity-based raw materials and has the potential to enable lower cost production of nevirapine as well as other value added structures that contain complex pyridines. The route terminates in a batch crystallization yielding high purity CAPIC. This outcome is expected to facilitate regulatory implementation of the overall process.

  14. Assessment of cetirizine, an antihistamine, to prevent cutaneous reactions to nevirapine therapy: results of the viramune-zyrtec double-blind, placebo-controlled trial.

    Science.gov (United States)

    Launay, O; Roudière, L; Boukli, N; Dupont, B; Prévoteau du Clary, F; Patey, O; David, F; Lortholary, O; Devidas, A; Piketty, C; Rey, E; Urbinelli, R; Allaert, F A; Tréluyer, J M; Caumes, E

    2004-04-15

    We conducted a 12-week, multicenter, randomized, double-blind, placebo-controlled trial of cetirizine to assess the ability of antihistamines to prevent nevirapine-associated rash in patients infected with human immunodeficiency virus type 1. Patients initiating treatment with nevirapine were randomized to receive either cetirizine, 10 mg q.d. (104 patients), or placebo (96 patients) during the first 6 weeks of therapy. Rash occurred in 22 (11%) of 200 patients; 10 (9.6%) were in the cetirizine group and 12 (12.5%) were in the placebo group (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.31-1.81; P=.5). Five of 22 rashes were cases of hypersensitivity syndrome. The rate of nevirapine discontinuation due to rash was similar in the 2 groups (7.7% and 6.25% in the cetirizine and placebo groups, respectively; P=.4). Multivariate analysis showed no treatment-group effect but indicated that age >40 years (OR, 3.83; 95% CI, 1.4-10.46; P=.008) was associated with an increased risk of rash. Cetirizine has no preventive effect on nevirapine-associated rash.

  15. [Disseminated histoplasmosis treated by boluses of fluconazole].

    Science.gov (United States)

    Mandengue Ebenye, C; Takuefou Mfangam, B; Nouédoui, C; Atangana, P J A

    2015-01-01

    We report a case in which an HIV-infected man was cured of disseminated histoplasmosis (Histoplasma capsulatum var duboisii) after treatment by high-dose fluconazole (1,600 mg taken four times daily) for 2 months, combined with active antiretroviral therapy. The choice of fluconazole at this dosage was motivated by its availability as a generic and thus inexpensive medication, the patient's precarious status, and his critical clinical condition. At the end of the second month of treatment, the patient chose to stop the fluconazole, which he could no longer afford, while continuing the antiretroviral treatment, which was free. The clinical and laboratory improvement observed from the first week has continued to progress for more than 8 months after fluconazole treatment stopped. This single case needs - and deserves - to be confirmed in a series of patients. Nonetheless it makes it possible to envision fluconazole as a low-cost and efficacious antifungal agent for the treatment of disseminated histoplasmosis in AIDS patients in sub-Saharan Africa.

  16. Good performance of an immunoassay based method for nevirapine measurements in human breast milk

    DEFF Research Database (Denmark)

    Salado-Rasmussen, Kirsten; Persson Theilgaard, Zahra; Chiduo, Mercy;

    2011-01-01

    Understanding the distribution of antiretro-virals in breastfeeding HIV-positive mothers is essential, both for prevention of mother-to-child HIV transmission and for research on the development of drug resistance. The ARK nevirapine (NVP)-test is an immunoassay method for nevirapine measurements...

  17. Effect of Denture-Related Stomatitis Fluconazole Treatment on Oral Candida albicans Susceptibility Profile and Genotypic Variability.

    Science.gov (United States)

    Figueiral, Maria Helena; Fonseca, Patrícia; Lopes, Maria Manuel; Pinto, Eugénia; Pereira-Leite, Teresa; Sampaio-Maia, Benedita

    2015-01-01

    Denture-related stomatitis (DRS) is the most common condition affecting removable-denture wearers, and Candida albicans the most frequent pathogenic agent. Systemic antifungal treatment is indicated but recurrences are frequent. The aim of this study was to characterize the oral load, fluconazole susceptibility profile and genotypic variability of oral C. albicans isolates from patients with DRS before (T0), immediately after fluconazole treatment (Tat) and after 6-months follow-up (T6m). Eighteen patients presenting DRS and treated with fluconazole were followed at the Faculty of Dentistry of Oporto University. Seventy C. albicans isolates were obtained and identified using standard cultural and biochemical multi-testing. Fluconazole susceptibility was tested by E-test(®). Microsatellite-primed PCR was performed to assess the genotypic variability of C. albicans isolates. The patients' mean age was 58.0±3.2 years, and 55.6%/44.4% had total/partial dentures. Before treatment, 22.2%, 44.4% and 33.3% of the patients presented DRS type I, II or III, respectively. Fluconazole treatment healed or improved DRS in 77.8% of the patients, accompanied by an 83.5% reduction in oral C. albicans load. However, after 6-months, oral C. albicans load increased significantly and DRS severity was similar to the one observed before treatment. Moreover, the prevalence of patients presenting fluconazole resistant isolates of C. albicans increased significantly throughout the study: T0-5.6%, Tat-10.0% and T6m-42.9%. A change in the genotypic variability of C. albicans isolates was also verified, being mostly associated to fluconazole susceptibility profile change. In conclusion, fluconazole presents a good short-term DRS treatment efficiency, but may be associated to a long-term emergence of C. albicans fluconazole resistance.

  18. Retrospective Study of Cryptococcal Meningitis With Elevated Minimum Inhibitory Concentration to Fluconazole in Immunocompromised Patients.

    Science.gov (United States)

    Nasri, Hashem; Kabbani, Sarah; Bou Alwan, Melhim; Wang, Yun F; Rebolledo, Paulina A; Kraft, Colleen S; Nguyen, Minh L; Anderson, Albert M; Rouphael, Nadine

    2016-04-01

    Background.  Mortality for cryptococcal meningitis remains significant, in spite of available treatment. Resistance to first-line maintenance therapy, particularly fluconazole, has been reported. Methods.  A retrospective chart review was performed on immunocompromised patients with cryptococcal meningitis, who had susceptibility testing performed between January 2001 and December 2011, at 3 hospitals in Atlanta, Georgia. Results.  A total of 35 immunocompromised patients with cryptococcal meningitis were identified, 13 (37.1%) of whom had an elevated minimum inhibitory concentration (MIC) to fluconazole (MIC ≥16 µg/mL). Eighty percent of patients were males with African American predominance, the median age was 37 years, and 80% of the patients were human immunodeficiency virus (HIV) positive. Subsequent recurrence of cryptococcal meningitis was more likely in HIV patients compared with solid organ transplant patients (P = .0366). Overall, there was a statistically significant increase in an elevated MIC to fluconazole in patients who had a history of prior azole use (odds ratio, 10.12; 95% confidence interval, 2.04-50.16). Patients with an elevated MIC to fluconazole and those with a high cerebrospinal fluid cryptococcal antigen load (≥1:512) were more likely to have central nervous system complications (P = .0358 and P = .023, respectively). Although no association was observed between an elevated MIC to fluconazole and mortality, those who received voriconazole or high-dose fluconazole (≥800 mg) for maintenance therapy were more likely to survive (P = .0288). Conclusions.  Additional studies are required to further investigate the morbidity and mortality associated with an elevated MIC to fluconazole in cryptococcal meningitis, to determine when it is appropriate to perform susceptibility testing, and to evaluate its cost effectiveness.

  19. Fluconazole and itraconazole in pityriasis versicolor

    Directory of Open Access Journals (Sweden)

    Jaswal Ritu

    1999-01-01

    Full Text Available Pityriasis versicolor is a common superficial fungal infection caused by Malassezia species. It has a high incidence and prevalence in tropical climates. Although it responds well to treatment, relapses and recurrences are frequent. In the present study the therapeutic response of single dose fluconazole (400 mg with itraconazole (100mg twice daily ? 7 days was compared in sixty patients of pityriasis versicolor. No significant statistical difference (p>0.05% was observed between efficacy of two drugs. Therapy with fluconazole is preferable in view of single dose administration and lesser cost as compared to itraconazole.

  20. The in vitro and in vivo efficacy of fluconazole in combination with farnesol against Candida albicans isolates using a murine vulvovaginitis model.

    Science.gov (United States)

    Bozó, Aliz; Domán, Marianna; Majoros, László; Kardos, Gábor; Varga, István; Kovács, Renátó

    2016-11-01

    Farnesol is a quorum-sensing molecule that inhibits biofilm formation in Candida albicans. Previous in vitro data suggest that, in combination with certain antifungals, farnesol may have an adjuvant anti-biofilm agent. However, the in vivo efficacy of farnesol is very questionable. Therefore, the in vitro and in vivo activity of fluconazole combined with farnesol was evaluated against C. albicans biofilms using fractional inhibitory concentration index (FICI) determination, time-kill experiments and a murine vulvovaginitis model. The median biofilm MICs of fluconazole-sensitive C. albicans isolates ranged between 4 -> 512 mg/L and 150-300 μM for fluconazole and farnesol, respectively. These values were 512 -> 512 mg/L and > 300 μM for fluconazole-resistant clinical isolates. Farnesol decreased the median MICs of fluconazole by 2-64-fold for biofilms. Based on FICI, synergistic interaction was observed only in the case of the sessile SC5314 reference strain (FICIs: 0.16-0.27). In time-kill studies, only the 512 mg/L fluconazole and 512 mg/L fluconazole + 75 μM farnesol reduced biofilm mass significantly at each time point in the case of all isolates. The combination reduced the metabolic activity of biofilms for all isolates in a concentration- and time-dependent manner. Our findings revealed that farnesol alone was not protective in a murine vulvovaginitis model. Farnesol was not beneficial in combination with fluconazole for fluconazole-susceptible isolates, but partially increased fluconazole activity against one fluconazole-resistant isolate, but not the other one.

  1. Comparative Hepatotoxicity of Fluconazole, Ketoconazole, Itraconazole, Terbinafine, and Griseofulvin in Rats

    Science.gov (United States)

    Ncube, Denver

    2017-01-01

    Oral ketoconazole was recently the subject of regulatory safety warnings because of its association with increased risk of inducing hepatic injury. However, the relative hepatotoxicity of antifungal agents has not been clearly established. The aim of this study was to compare the hepatotoxicity induced by five commonly prescribed oral antifungal agents. Rats were treated with therapeutic oral doses of griseofulvin, fluconazole, itraconazole, ketoconazole, and terbinafine. After 14 days, only ketoconazole had significantly higher ALT levels (p = 0.0017) and AST levels (p = 0.0008) than the control group. After 28 days, ALT levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, griseofulvin, and terbinafine, respectively. The AST levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, terbinafine, and griseofulvin, respectively. All drugs significantly elevated ALP levels after 14 days and 28 days of treatment (p fluconazole, terbinafine, and griseofulvin. However, histopathological changes revealed that fluconazole was the most hepatotoxic, followed by ketoconazole, itraconazole, terbinafine, and griseofulvin, respectively. Given the poor correlation between liver enzymes and the extent of liver injury, it is important to confirm liver injury through histological examination.

  2. Fluconazole inhibits human adrenocortical steroidogenesis in vitro

    NARCIS (Netherlands)

    R. van der Pas (Rob); L.J. Hofland (Leo); J. Hofland (Johannes); A.E. Taylor (A.); W. Arlt (Wiebke); J. Steenbergen (Jacobie); P.M. van Koetsveld (Peter); W.W. de Herder (Wouter); F.H. de Jong (Frank); R.A. Feelders (Richard)

    2012-01-01

    textabstractThe antifungal agent ketoconazole is often used to suppress cortisol production in patients with Cushing's syndrome (CS). However, ketoconazole has serious side effects and is hepatotoxic. Here, the in vitro effects of ketoconazole and fluconazole, which might be less toxic, on human adr

  3. Antioxidant modulation of nevirapine induced hepatotoxicity in rats.

    Science.gov (United States)

    Awodele, Olufunsho; Popoola, Temidayo; Rotimi, Kunle; Ikumawoyi, Victor; Okunowo, Wahab

    2015-03-01

    HIV/AIDS related mortality has been dramatically reduced by the advent of antiretroviral therapy (ART). However, ART presents with associated adverse effects. One of such adverse effects is hepatotoxicity observed with nevirapine (NVP) containing ART. Since previous studies showed that NVP hepatotoxicity may be due to oxidative stress via generation of oxidative radicals, this study sought to evaluate the protective effects of antioxidants in alleviating NVP induced hepatotoxicity. Rats were divided into 6 groups with 8 animals per group and received doses of the antioxidants jobelyn (10.7 mg/kg/day), vitamin C (8 mg/kg/day), vitamin E (5 mg/kg/day) and/or NVP (6 mg/kg/day) for 60 days. The animals were sacrificed on day 61 by cervical dislocation, blood samples were collected for biochemical and hematological examination. The liver of the sacrificed animals was weighed and subjected to histopathological examination. There was a statistically significant (prats. A significantly (prats showed no visible pathology across the groups. Observations from this study suggest a potentially positive modulatory effect of antioxidants and may be indicative for the inclusion of antioxidants in nevirapine containing ART.

  4. The influence of tea tree oil (Melaleuca alternifolia) on fluconazole activity against fluconazole-resistant Candida albicans strains.

    Science.gov (United States)

    Mertas, Anna; Garbusińska, Aleksandra; Szliszka, Ewelina; Jureczko, Andrzej; Kowalska, Magdalena; Król, Wojciech

    2015-01-01

    The aim of this study was to evaluate the activity of fluconazole against 32 clinical strains of fluconazole-resistant Candida albicans, and C. albicans ATCC 10231 reference strain, after their exposure to sublethal concentrations of tea tree oil (TTO) or its main bioactive component terpinen-4-ol. For all tested fluconazole-resistant C. albicans strains TTO and terpinen-4-ol minimal inhibitory concentrations (MICs) were low, ranging from 0.06% to 0.5%. The 24-hour exposure of fluconazole-resistant C. albicans strains to fluconazole with sublethal dose of TTO enhanced fluconazole activity against these strains. Overall, 62.5% of isolates were classified as susceptible, 25.0% exhibited intermediate susceptibility, and 12.5% were resistant. For all of the tested clinical strains the fluconazole MIC decreased from an average of 244.0 μg/mL to an average of 38.46 μg/mL, and the fluconazole minimal fungicidal concentrations (MFC) decreased from an average of 254.67 μg/mL to an average of 66.62 μg/mL. Terpinen-4-ol was found to be more active than TTO, and strongly enhanced fluconazole activity against fluconazole-resistant C. albicans strains. The results of this study demonstrate that combining natural substances such as TTO and conventional drug such as fluconazole, may help treat difficult yeast infections.

  5. The Influence of Tea Tree Oil (Melaleuca alternifolia on Fluconazole Activity against Fluconazole-Resistant Candida albicans Strains

    Directory of Open Access Journals (Sweden)

    Anna Mertas

    2015-01-01

    Full Text Available The aim of this study was to evaluate the activity of fluconazole against 32 clinical strains of fluconazole-resistant Candida albicans, and C. albicans ATCC 10231 reference strain, after their exposure to sublethal concentrations of tea tree oil (TTO or its main bioactive component terpinen-4-ol. For all tested fluconazole-resistant C. albicans strains TTO and terpinen-4-ol minimal inhibitory concentrations (MICs were low, ranging from 0.06% to 0.5%. The 24-hour exposure of fluconazole-resistant C. albicans strains to fluconazole with sublethal dose of TTO enhanced fluconazole activity against these strains. Overall, 62.5% of isolates were classified as susceptible, 25.0% exhibited intermediate susceptibility, and 12.5% were resistant. For all of the tested clinical strains the fluconazole MIC decreased from an average of 244.0 μg/mL to an average of 38.46 μg/mL, and the fluconazole minimal fungicidal concentrations (MFC decreased from an average of 254.67 μg/mL to an average of 66.62 μg/mL. Terpinen-4-ol was found to be more active than TTO, and strongly enhanced fluconazole activity against fluconazole-resistant C. albicans strains. The results of this study demonstrate that combining natural substances such as TTO and conventional drug such as fluconazole, may help treat difficult yeast infections.

  6. Fluconazole for empiric antifungal therapy in cancer patients with fever and neutropenia

    Directory of Open Access Journals (Sweden)

    Peterson Josh F

    2006-12-01

    Full Text Available Abstract Background Several clinical trials have demonstrated the efficacy of fluconazole as empiric antifungal therapy in cancer patients with fever and neutropenia. Our objective was to assess the frequency and resource utilization associated with treatment failure in cancer patients given empiric fluconazole antifungal therapy in routine inpatient care. Methods We performed a retrospective cohort study of cancer patients treated with oral or intravenous fluconazole between 7/97 and 6/01 in a tertiary care hospital. The final study cohort included cancer patients with neutropenia (an absolute neutrophil count below 500 cells/mm3 and fever (a temperature above 38°C or 100.4°F, who were receiving at least 96 hours of parenteral antibacterial therapy prior to initiating fluconazole. Patients' responses to empiric therapy were assessed by reviewing patient charts. Results Among 103 cancer admissions with fever and neutropenia, treatment failure after initiating empiric fluconazole antifungal therapy occurred in 41% (95% confidence interval (CI 31% – 50% of admissions. Patients with a diagnosis of hematological malignancy had increased risk of treatment failure (OR = 4.6, 95% CI 1.5 – 14.8. When treatment failure occurred the mean adjusted increases in length of stay and total costs were 7.4 days (95% CI 3.3 – 11.5 and $18,925 (95% CI 3,289 – 34,563, respectively. Conclusion Treatment failure occurred in more than one-third of neutropenic cancer patients on fluconazole as empiric antifungal treatment for fever in routine clinical treatment. The increase in costs when treatment failure occurs is substantial.

  7. Compatibility studies of nevirapine in physical mixtures with excipients for oral HAART

    Energy Technology Data Exchange (ETDEWEB)

    Oliveira, G.G.G. de; Ferraz, H.G. [Department of Pharmacy, Faculty of Pharmaceutical Health, University of Sao Paulo, Sao Paulo 05508-900 (Brazil); Severino, P. [Department of Biotechnological Processes, School of Chemical Engineering, University of Campinas, Campinas 13083-970 (Brazil); Department of Pharmaceutical Technology, Faculty of Health Sciences, Fernando Pessoa University, Porto 4200-150 (Portugal); Souto, E.B., E-mail: eliana@ufp.edu.pt [Department of Pharmaceutical Technology, Faculty of Health Sciences, Fernando Pessoa University, Porto 4200-150 (Portugal); Institute for Biotechnology and Bioengineering, Centre for Genomics and Biotechnology, University of Tras-os-Montes e Alto Douro (IBB-CGB/UTAD), 5001-801 Vila Real (Portugal)

    2013-03-01

    Nevirapine is a hydrophobic non-nucleoside reverse transcriptase inhibitor, used in first line regimens of highly active antiretroviral therapy (HAART). The drug has more than one crystalline form, which may have implications for its behaviour during production and also for its in vivo performance. This study was aimed at exploring the suitability of thermoanalytical methods for the solid-state characterization of commercial crystalline forms of nevirapine. The drug powder was characterized by ultraviolet spectrophotometry, stereoscopy, scanning electron microscopy, wide-angle X-ray diffraction, measurements of density, flowability, solubility and intrinsic dissolution rate (IDR), differential scanning calorimetry, thermogravimetric analysis, and photostability measurements. The results showed that nevirapine has high stability and is not susceptible to degradation under light exposure. The drug showed compatibility with the excipients tested (lactose, microcrystalline cellulose, polyvinylpyrrolidone and polyvinyl acetate copolymer (PVP/PVA), and hydroxypropylmethylcellulose (HPMC)). Nevirapine has low solubility, an acid medium being the most appropriate medium for assessing the release of the drug from dosage forms. However, the data obtained from IDR testing indicate that dissolution is the critical factor for the bioavailability of this drug. - Graphical abstract: Bulk nevirapine powder analysed by scanning electron microscopy and the drug solubility profile in various buffer solutions. The pH values of the media in which the tests were conducted are also presented. Highlights: Black-Right-Pointing-Pointer Nevirapine shows more than one crystalline form, that influence its in vivo and in vitro behaviour. Black-Right-Pointing-Pointer DSC and TGA were used for solid-state characterization of crystalline forms of nevirapine. Black-Right-Pointing-Pointer Nevirapine is compatible with lactose, microcrystalline cellulose, PVP/PVA copolymers and HPMC. Black

  8. Candida ciferrii, a new fluconazole-resistant yeast causing systemic mycosis in immunocompromised patients.

    Science.gov (United States)

    Gunsilius, E; Lass-Flörl, C; Kähler, C M; Gastl, G; Petzer, A L

    2001-03-01

    Systemic infections related to fluconazole-resistant yeasts are increasingly observed in immunocompromised patients receiving fluconazole as a prophylactic antifungal treatment. Here, we report a case of invasive candidiasis caused by Candida ciferrii in a patient with acute myeloid leukemia and who suffered a relapse after autologous peripheral blood progenitor cell transplantation. Erythematous skin papulae and spotted pulmonary infiltrations were present. A skin biopsy led to the diagnosis of invasive candidiasis, emphasizing the diagnostic usefulness of this procedure. The yeast was identified as Candida ciferrii and in vitro susceptibility testing revealed its resistance to fluconazole. Until now, Candida ciferrii has not been known to cause invasive fungal infections in humans. Thus, we add another fungus to the list of flucanozole-resistant yeasts and suggest that in vitro susceptibility testing of isolated fungi should be performed for the selection of appropriate antimycotic drugs.

  9. Long-term durability of nevirapine-based ART in a cohort of 82 patients after induction with protease inhibitor treatment

    Directory of Open Access Journals (Sweden)

    J Rump

    2012-11-01

    Full Text Available Purpose of the study: There is still an open question how to start antiretro-viral therapy (ART. This retrospective study shows results of a de-escalation strategy starting with a protease inhibitor (PI, followed by a nevirapine-based regimen over a period of five years. Methods: All patients were ART-naïve and received PI in combination with two NRTIs. The PI was changed to nevirapine, when viral load (VL stayed at least 12 months below the detection limit (50 or 40 copies/ml plasma. The median time to negative VL was measured. CD4, VL and liver tests were followed in 82 patients over at least 5 years before ART, during PI phase and over a median of 48 months after change to nevirapine. Resistance tests were performed - if possible - in patients before initiating ART. Summary of results: 20 female and 62 male patients were treated for an average of 28 months with PI (43×lopinavir, 5×indinavir, 6×invirase/r and 3×fortovase/r, 8×nelfinavir, 14×atazanavir/r, 3×norvir-mono plus two backbone NRTI in various combinations. There were 2 cases of hepatitis B and 5 HCV positives in the cohort. The mean CD4 before starting ART was 246/µl and the average VL was 421,038 copies/ml plasma (ranging from 1,050–9,000,000 copies/ml plasma. The median time to negative VL was 188 days. CD4 cells were rising by 364/µl during PI treatment to 610/µl. This was followed by a steady increase of another 70 cells/µl during the first year after changing to nevirapine. The median follow up after de-escalation to nevirapine was 48 months. Although the median CD4 was above 400/µl in all patients when changed to nevirapine, no severe liver toxicity was seen in the cohort. Change to NNRTI was safe in the group of 20 women with CD4 cells above 400/µl. Allergic skin reactions where seen in 7 out of 82 patients during the first 3 months after changing to nevirapine. No events of resistancies were seen in the group of 82 patients before and under treatment

  10. Fluconazole therapy for treatment of invasive candidiasis in Intensive Care patients. Is it still valid from a pharmacological point of view?

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    Mario Musu

    2014-01-01

    Full Text Available Fluconazole – antimycotic belonging to the first generation azoles – is widely used as treatment for invasive candidiasis and candidemia in numerous clinical settings as Neonatal Intensive Care Unit (NICU and adult Intensive Care Unit (ICU, as well as oncology, onco-hematology and solid organ transplantation. More recently use of antimycotics has spread to medical divisions, where fungal infections represent an emerging problem due to population’s ageing, malnourishment and important comorbidities. Fluconazole is effective against numerous Candida species, particularly against albicans, tropicalis and parapsilosis strains. On the other hand, C. krusei is intrinsically resistant to fluconazole and C. glabrata can be sensitive or resistant in a dose dependent fashion. Epidemiological variability is noteworthy and depends on the geographical location of the institution, the clinical setting, and the frequency and intensity of fluconazole employment for invasive candidiasis. In many ICUs fluconazole sensitive C. albicans is cultured in 50% of positive samples, while the remaining 50% show growth of variably sensitive fungal species, often resistant to fluconazole. Due to increasingly frequent emergence of resistant strains of Candida spp., American guidelines (IDSA in 2009, and European ones (ESCMID in 2012, recommended substitution of fluconazole with echinocandines as first line therapy in patients with severe disease, as defined by an APACHE II score greater than 15. Thus fluconazole must be limited to low risk cases, treatment of sensitive strains and de-escalation from echinocandin therapy, after microbiological diagnosis and drug resistance profile characterization.

  11. Nevirapine-induced Stevens-Johnson syndrome from a tertiary care hospital in Central India

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    Vandana Badar

    2014-04-01

    Full Text Available A 42 year old man, a known case of AIDS receiving antiretroviral therapy – stavudine, lamivudine, and nevirapine since 4 weeks, was admitted with erythematous rash, with blisters, and abnormal liver function test. A diagnosis of Steven-Johnson syndrome was made excluding other opportunistic infection and differential diagnosis. Nevirapine was discontinued until the patient recovered. After recovery patient was started with stavudine, lamivudine, and efavirenz treatment without re-challenge with nevirapine. [Int J Basic Clin Pharmacol 2014; 3(2.000: 408-409

  12. Evaluation of the disc diffusion method with a comparison study for fluconazole susceptibility of Candida strains

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    Objective To performance susceptibility testing of antifungal agents. Due to the increasing number of resistant strains, susceptibility testing of antifungal agents is gaining importance. Methods We compared the results of standard macrotube dilution reference method with two different microdilution methods, as well as the disc diffusion method in order to test the susceptibility of 150 Candida strains to fluconazole. Results Overall correlation between microdilution and macrodilution methods was 86%. It was 91% between the Minimal Inhibitory Concentrations obtained from macrodilution and disc diffusion zone diameters. Conclusion The disc diffusion test was evaluated as a low-cost, reproducible, and efficient way of assessing the in vitro susceptibility of Candida strains to fluconazole.

  13. THE EFFECT OF FLUCONAZOLE AND AMPHOTERICIN B ON MACROPHAGE FUNCTIONS

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    Glazar Irena

    2015-12-01

    Full Text Available Background: Different antimicrobial drugs inhibit functions of the microbial cells but, unfortunately, some of these drugs can also affect the host cells, including macrophages. Since these cells represent the baseline defense against microbial agents, it is important that they are fully activated. Materials and Methods: In the present study we investigated the effect of amphotericin B and fluconazole on the functions of peritoneal macrophages from Balb/c mice treated with these antimycotics. For each antimycotic the therapeutic dose used in clinical practice (calculated on the mouse body weight and two-fold higher doses were administered intraperitoneally once a day for three consecutive days. The control group was treated with saline in the same way. Four different tests, candidacidal assay, nitroblue tetrazolium test, adherence capability and phagocytic capability, were used to determine macrophage functions. Results: Our results confirmed positive effect of high dose amphotericin B on phagocytic capability (31.00±4.46 %, metabolic changes (27.93±6.63 % and adherence capacity (59.24±8.67 %. Lower doses of drug amphotericin B (2 mg/kg significantly increased the adherence index of macrophages (71.99±5.55 % and intensity of the NBT intracellular reduction (30.20±3.83 %. Maximum dose of fluconazole expressed significantly higher phagocytic index (30.77±2.17 %, metabolic changes (24.00±4.07 % and candidacidal activities (27.73±6.73 %, while lower doses of fluconazole (15 mg/kg significantly increased the adherence index of macrophages (75.58±5.47 % as well as the phagocytic index (29.23±2.40 %. Other results were similar as in control group. Conclusion: Positive immunomodulatory effects of fluconazole and amphotericin B may be clinically relevant especially in compromised patients who are predisposed to opportunistic fungal infections and require a long-term antimycotic therapy. Synergistic action of macrophages and antimycotics can

  14. Superior Effectiveness of Zidovudine Compared With Tenofovir When Combined With Nevirapine-based Antiretroviral Therapy in a Large Nigerian Cohort

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    Scarsi, Kimberly K.; Eisen, Geoffrey; Darin, Kristin M.; Meloni, Seema T.; Rawizza, Holly E.; Tchetgen Tchetgen, Eric J.; Agbaji, Oche O.; Onwujekwe, Daniel I.; Gashau, Wadzani; Nkado, Reuben; Okonkwo, Prosper; Murphy, Robert L.; Kanki, Phyllis J.

    2016-01-01

    Background. Despite sparse efficacy data, tenofovir–emtricitabine or tenofovir–lamivudine plus nevirapine is used in many resource-constrained settings. Methods. This retrospective cohort study included patients initiating nevirapine-based antiretroviral therapy (ART) with either tenofovir–emtricitabine or lamivudine (tenofovir group) or zidovudine–lamivudine (zidovudine group). Clinical, virologic, and immunologic evaluations were performed at baseline and every 6 months. Virologic failure was defined as 2 consecutive human immunodeficiency virus (HIV)-RNA values >1000 copies/mL. Patients were included from ART initiation until time of failure, regimen switch, discontinuation, or last HIV-RNA measurement. Cox proportional hazards regression was used to model factors influencing time to failure. Bias due to dependent censoring was investigated via inverse probability weighted pooled logistic regression. Results. A total of 5547 patients were evaluated; 1484 (26.8%) were in the tenofovir group and 4063 (73.2%) were in the zidovudine group. In the adjusted model, tenofovir regimen (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.21–1.79) and higher baseline log10 HIV-RNA (HR, 1.15; 95% CI, 1.03–1.28) were associated with virologic failure. Higher baseline log10 CD4+ cell count (HR, 0.50; 95% CI, .40–.63) and increasing age (HR, 0.98; 95% CI, .97–.99) decreased the risk of virologic failure. Inverse probability weighting results were consistent with the primary analysis. Conclusions. Compared with zidovudine–lamivudine, the use of tenofovir–lamivudine or emtricitabine in combination with nevirapine was a strong predictor of virologic failure in our cohort, which was not explained by other risk factors or criteria for regimen selection. PMID:26561532

  15. Disruption of the transcriptional regulator Cas5 results in enhanced killing of Candida albicans by Fluconazole.

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    Vasicek, Erin M; Berkow, Elizabeth L; Bruno, Vincent M; Mitchell, Aaron P; Wiederhold, Nathan P; Barker, Katherine S; Rogers, P David

    2014-11-01

    Azole antifungal agents such as fluconazole exhibit fungistatic activity against Candida albicans. Strategies to enhance azole antifungal activity would be therapeutically appealing. In an effort to identify transcriptional pathways that influence the killing activity of fluconazole, we sought to identify transcription factors (TFs) involved in this process. From a collection of C. albicans strains disrupted for genes encoding TFs (O. R. Homann, J. Dea, S. M. Noble, and A. D. Johnson, PLoS Genet. 5:e1000783, 2009, http://dx.doi.org/10.1371/journal.pgen.1000783), four strains exhibited marked reductions in minimum fungicidal concentration (MFCs) in both RPMI and yeast extract-peptone-dextrose (YPD) media. One of these genes, UPC2, was previously characterized with regard to its role in azole susceptibility. Of mutants representing the three remaining TF genes of interest, one (CAS5) was unable to recover from fluconazole exposure at concentrations as low as 2 μg/ml after 72 h in YPD medium. This mutant also showed reduced susceptibility and a clear zone of inhibition by Etest, was unable to grow on solid medium containing 10 μg/ml fluconazole, and exhibited increased susceptibility by time-kill analysis. CAS5 disruption in highly azole-resistant clinical isolates exhibiting multiple resistance mechanisms did not alter susceptibility. However, CAS5 disruption in strains with specific resistance mutations resulted in moderate reductions in MICs and MFCs. Genome-wide transcriptional analysis was performed in the presence of fluconazole and was consistent with the suggested role of CAS5 in cell wall organization while also suggesting a role in iron transport and homeostasis. These findings suggest that Cas5 regulates a transcriptional network that influences the response of C. albicans to fluconazole. Further delineation of this transcriptional network may identify targets for potential cotherapeutic strategies to enhance the activity of the azole class of antifungals.

  16. Antifungal activity of synthetic antiseptics and natural compounds against Candida dubliniensis before and after in vitro fluconazole exposure

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    Cássia Franco Reginato

    Full Text Available ABSTRACT INTRODUCTION: This study evaluated the susceptibilities of oral candidiasis-derived Candida albicans, fluconazole-resistant (FR Candida dubliniensis, and fluconazole-susceptible (FS C. dubliniensis to synthetic antiseptics [chlorhexidine gluconate (CHX, cetylpyridinium chloride (CPC, and triclosan (TRC] and natural compounds (carvacrol, eugenol and thymol. METHODS: Susceptibility tests were performed based on the M27-A3 reference method. The fluconazole-resistant C. dubliniensis strains were obtained after prolonged in vitro exposure to increasing fluconazole concentrations. The geometric mean values for minimum inhibitory concentrations and minimum fungicidal concentrations were compared among the groups. RESULTS: Fluconazole-susceptible C. dubliniensis was more sensitive to CPC and TRC than FR C. dubliniensis and C. albicans were. However, eugenol and thymol were more active against FR C. dubliniensis. The fungicidal activities of CHX and TRC were similar for the three groups, and FR C. dubliniensis and C. albicans had similar sensitivities to CPC. CONCLUSIONS: The resistance of C. dubliniensis to fluconazole affects its sensitivity the synthetic antiseptics and natural compounds that were tested.

  17. The expression of genes involved in the ergosterol biosynthesis pathway in Candida albicans and Candida dubliniensis biofilms exposed to fluconazole.

    LENUS (Irish Health Repository)

    2009-03-01

    The expression of the ERG1, ERG3, ERG7, ERG9, ERG11 and ERG25 genes in response to incubation with fluconazole and biofilm formation was investigated using reverse-transcription PCR and real-time PCR in Candida albicans and Candida dubliniensis clinical isolates. The viability of biofilm was measured using an 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction assay and confocal scanning laser microscopy (CSLM). Expression of the ERG11 gene was found to be low or moderate and it was regulated by fluconazole addition more so than by biofilm formation. Very low or non-detectable expression of ERG1, ERG7 and ERG25 genes was detected in C. albicans. The expression of the ERG9 increased in the presence of fluconazole in some isolates. Following incubation with fluconazole, formation of biofilm by C. dubliniensis was coupled with up-regulation of the ERG3 and ERG25 genes as have been observed previously in C. albicans. Planktonic cells of both Candida species released from biofilm displayed similar resistance mechanisms to fluconazole like attached cells. The XTT reduction assay and CSLM revealed that although incubation with fluconazole decreased the biofilm thickness, these were still comprised metabolically active cells able to disseminate and produce biofilm. Our data indicate that biofilm represents a highly adapted community reflecting the individuality of clinical isolates.

  18. Population pharmacokinetics of nevirapine in Malaysian HIV patients: a non-parametric approach.

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    Mustafa, Suzana; Yusuf, Wan Nazirah Wan; Woillard, Jean Baptiste; Choon, Tan Soo; Hassan, Norul Badriah

    2016-07-01

    Nevirapine is the first non-nucleoside reverse-transcriptase inhibitor approved and is widely used in combination therapy to treat HIV-1 infection. The pharmacokinetics of nevirapine was extensively studied in various populations with a parametric approach. Hence, this study was aimed to determine population pharmacokinetic parameters in Malaysian HIV-infected patients with a non-parametric approach which allows detection of outliers or non-normal distribution contrary to the parametric approach. Nevirapine population pharmacokinetics was modelled with Pmetrics. A total of 708 observations from 112 patients were included in the model building and validation analysis. Evaluation of the model was based on a visual inspection of observed versus predicted (population and individual) concentrations and plots weighted residual error versus concentrations. Accuracy and robustness of the model were evaluated by visual predictive check (VPC). The median parameters' estimates obtained from the final model were used to predict individual nevirapine plasma area-under-curve (AUC) in the validation dataset. The Bland-Altman plot was used to compare the AUC predicted with trapezoidal AUC. The median nevirapine clearance was of 2.92 L/h, the median rate of absorption was 2.55/h and the volume of distribution was 78.23 L. Nevirapine pharmacokinetics were best described by one-compartmental with first-order absorption model and a lag-time. Weighted residuals for the model selected were homogenously distributed over the concentration and time range. The developed model adequately estimated AUC. In conclusion, a model to describe the pharmacokinetics of nevirapine was developed. The developed model adequately describes nevirapine population pharmacokinetics in HIV-infected patients in Malaysia.

  19. Antifungal activity of Rubus chingii extract combined with fluconazole against fluconazole-resistant Candida albicans.

    Science.gov (United States)

    Han, Bing; Chen, Jia; Yu, Yi-qun; Cao, Yong-bing; Jiang, Yuan-ying

    2016-02-01

    This study aimed to investigate the antifungal activity of Rubus chingii extract in combination with fluconazole (FLC) against FLC-resistant Candida albicans 100 in vitro. A R. chingii extract and FLC-resistant C. albicans fungus suspension were prepared. The minimum inhibitory concentration and fractional inhibitory concentration index of R. chingii extract combined with FLC against C. albicans were determined, after which growth curves for C. albicans treated with R. chingii extract, FLC alone and a combination of these preparations were constructed. Additionally, the mechanisms of drug combination against C. albicans were explored by flow cytometry, gas chromatographic mass spectrometry and drug efflux pump function detection. R. chingii extract combined with FLC showed significant synergy. Flow cytometry suggested that C. albicans cells mainly arrest in G1 and S phases when they have been treated with the drug combination. The drug combination resulted in a marked decrease in the ergosterol content of the cell membrane. Additionally, efflux of Rhodamine 6G decreased with increasing concentrations of R. chingii extract. R. chingii extract combined with FLC has antifungal activity against FLC-resistant C. albicans.

  20. Solvated crystalline forms of nevirapine: thermoanalytical and spectroscopic studies.

    Science.gov (United States)

    Chadha, Renu; Arora, Poonam; Saini, Anupam; Jain, Dharamvir Singh

    2010-09-01

    The study is aimed at exploring the utility of thermoanalytical methods in the solid-state characterization of various crystalline forms of nevirapine. The different forms obtained by recrystallization of nevirapine from various solvents were identified using differential scanning calorimetry and thermogravimetric analysis (TGA). The appearance of desolvation peak accompanied by weight loss in TGA indicated the formation of solvates: hemi-ethanolate (Form I), hemi-acetonitrilate (Form II), hemi-chloroformate (Form III), hemi-THF solvate (Form IV), mixed hemi-ethanolate hemi-hydrate (Form V), and hemi-toluenate (Form VI). The higher desolvation temperatures of all the solvates except toluenate than their respective boiling point indicate tighter binding of solvent. Emphasis has been laid on the determination of heat capacity and heat of solution utilizing microreaction calorimeter to further distinguish the various forms. The enthalpy of solution (ΔH(sol)), an indirect measure of the lattice energy of a solid, was well correlated with the crystallinity of all the solid forms obtained. The magnitude of ΔH(sol) was found to be -14.14 kJ/mol for Form I and -2.83 kJ/mol for Form V in phosphate buffer of pH 2, exhibiting maximum ease of molecular release from the lattice in Form I. The heat capacity for solvation (ΔC(p)) was found to be positive, providing information about the state of solvent molecules in the host lattice. The solubility and dissolution rate of the forms were also found to be in agreement with their enthalpy of solution. Form (I), being the most exothermic, was found to be the most soluble of all the forms.

  1. Synergistic effects of tacrolimus and azole antifungal compounds in fluconazole-susceptible and fluconazole-resistant Candida glabrata isolates

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    Laura Bedin Denardi

    2015-03-01

    Full Text Available In vitro interaction between tacrolimus (FK506 and four azoles (fluconazole, ketoconazole, itraconazole and voriconazole against thirty clinical isolates of both fluconazole susceptible and -resistant Candida glabrata were evaluated by the checkerboard microdilution method. Synergistic, indifferent or antagonism interactions were found for combinations of the antifungal agents and FK506. A larger synergistic effect was observed for the combinations of FK506 with itraconazole and voriconazole (43%, followed by that of the combination with ketoconazole (37%, against fluconazole-susceptible isolates. For fluconazole-resistant C. glabrata, a higher synergistic effect was obtained from FK506 combined with ketoconazole (77%, itraconazole (73%, voriconazole (63% and fluconazole (60%. The synergisms that we observed in vitro, notably against fluconazole-resistant C. glabrata isolates, are promising and warrant further analysis of their applications in experimental in vivo studies.

  2. Systemic Candida parapsilosis Infection Model in Immunosuppressed ICR Mice and Assessing the Antifungal Efficiency of Fluconazole

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    Yu’e Wu

    2015-01-01

    Full Text Available This study was to establish a systemic C. parapsilosis infection model in immunosuppressed ICR mice induced by cyclophosphamide and evaluate the antifungal efficiency of fluconazole. Three experiments were set to confirm the optimal infectious dose of C. parapsilosis, outcomes of infectious model, and antifungal efficiency of fluconazole in vivo, respectively. In the first experiment, comparisons of survival proportions between different infectious doses treated groups showed that the optimal inoculum for C. parapsilosis was 0.9 × 105 CFU per mouse. The following experiment was set to observe the outcomes of infection at a dose of 0.9 × 105 CFU C. parapsilosis. Postmortem and histopathological examinations presented fugal-specific lesions in multiorgans, especially in kidneys, characterized by inflammation, numerous microabscesses, and fungal infiltration. The CFU counts were consistent with the histopathological changes in tissues. Th1/Th2 cytokine imbalance was observed with increases of proinflammatory cytokines and no responses of anti-inflammatory cytokines in sera and kidneys. In the last experiment, model based evaluation of fluconazole indicated that there were ideal antifungal activities for fluconazole at dosages of 10–50 mg/kg/d. Data demonstrates that the research team has established a systemic C. parapsilosis infection model in immunosuppressed ICR mice, affording opportunities for increasing our understanding of fungal pathogenesis and treatment.

  3. Fluconazole susceptibility of Brazilian Candida isolates assessed by a disk diffusion method

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    Arnaldo L. Colombo

    Full Text Available The increasing magnitude of antifungal resistance as well as the advent of new antifungal drugs has generated a renewed interest in fungal susceptibility testing. We used a previously described disk diffusion method to evaluate the susceptibility profile of a large collection of recent clinical Candida spp. isolates against fluconazole. A total of 1,784 yeast isolates were tested, including the following species: Candida albicans (1,036, C. tropicalis (279, C. parapsilosis (202, C. glabrata (119, C. guilliermondii (90, C. krusei (32, C. lusitaniae (7, Candida spp. (14 and other yeasts (5. Susceptibility ranking to fluconazole obtained with all yeasts tested was: C. parapsilosis @ C. tropicalis @ C. guilliermondii > C. glabrata > C. krusei. The majority (94% of all yeast isolates tested were susceptible to fluconazole. Isolates of C. glabrata and C. krusei exhibited the highest rate of DDS/resistance among all isolates tested but they represented only 9% of all yeasts routinely sent to our lab. Careful periodical surveillance is needed in order to identify any changes in the susceptibility patterns of fluconazole with the increased use of this antifungal agent in Brazilian tertiary care hospitals.

  4. Secular trend in candidemia and the use of fluconazole in Finland, 2004-2007

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    Kotilainen Pirkko

    2010-10-01

    Full Text Available Abstract Background In a previous study we observed an increasing trend in candidemia in Finland in the 1990s. Our aim was now to investigate further population-based secular trends, as well as outcome, and evaluate the association of fluconazole consumption and prophylaxis policy with the observed findings. Methods We analyzed laboratory-based surveillance data on candidemia from the National Infectious Diseases Register during 2004-2007 in Finland. Data on fluconazole consumption, expressed as defined daily doses, DDDs, was obtained from the National Agency for Medicines, and regional prophylaxis policies were assessed by a telephone survey. Results A total of 603 candidemia cases were identified. The average annual incidence rate was 2.86 cases per 100,000 population (range by year, 2.59-3.09; range by region, 2.37-3.85. The highest incidence was detected in males aged >65 years (12.23 per 100,000 population. Candida albicans accounted for 67% of cases, and C. glabrata ranked the second (19%, both without any significant change in proportions. C. parapsilosis accounted for 5% of cases and C. krusei 3% of cases. The one-month case-fatality varied between 28-32% during the study period. Fluconazole consumption increased from 19.57 DDDs per 100,000 population in 2000 to 25.09 in 2007. Systematic fluconazole prophylaxis was implemented for premature neonates, patients with acute leukemias and liver transplant patients. Conclusion The dominant proportion of C. albicans remained stable, but C. glabrata was the most frequent non-albicans species. The proportion of C. glabrata had increased from our previous study period in the presence of increasing use of fluconazole. The rate of candidemia in Finland is still low but mortality high like in other countries.

  5. The trend of susceptibilities to amphotericin B and fluconazole of Candida species from 1999 to 2002 in Taiwan

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    Cheng Hsiao-Hsu

    2005-11-01

    Full Text Available Abstract Background Candida species have various degrees of susceptibility to common antifungal drugs. The extent of resistance to amphotericin B and fluconazole of Candida glabrata isolates causing candidemia has been reported. Active surveillance may help us to monitor the trend of susceptibility to antifungal drugs and to determine if there is an emerging co-resistance to both drugs of Candida species, specifically, of C. glabrata in Taiwan. Methods The susceptibilities to amphotericin B and fluconazole of Candida species collected in 1999 and 2002 of the Taiwan Surveillance of Antimicrobial Resistance of Yeasts (TSARY were determined by the microdilution method. Results The antifungal susceptibilities of 342 and 456 isolates collected from 11 hospitals participating in both TSARY 1999 and TSARY 2002, respectively, have been determined. The resistance rate to amphotericin B has increased from 0.3% in the TSARY1999 to 2.2% in the TSARY 2002. In contrast, the resistance rate to fluconazole has decreased from 8.8% to 2.2%. Nevertheless, significantly more C. glabrata isolates were not susceptible to fluconazole in the TSARY 2002 (47.4% than that in the TSARY 1999 (20.8%. There were 9.8% and 11% of C. glabrata isolates having susceptible-dose dependent and resistant phenotype to fluconazole in the TSARY 1999, verse 45.3% and 2.1% in the TSARY 2002. Conclusion There was an increase of resistance rate to amphotericin B in C. glabrata. On the other hand, although the resistance rate to fluconazole has decreased, almost half of C. glabrata isolates were not susceptible to this drug. Hence, continuous monitoring the emerging of co-resistance to both amphotericin B and fluconazole of Candida species, specifically, of C. glabrata, will be an important early-warning system.

  6. Outbreak of candidemia caused by fluconazole resistant Candida parapsilosis strains in an intensive care unit.

    Science.gov (United States)

    Pinhati, Henrique Marconi Sampaio; Casulari, Luiz Augusto; Souza, Ana Carolina Remondi; Siqueira, Ricardo Andreotti; Damasceno, Camila Maria Gomes; Colombo, Arnaldo Lopes

    2016-08-20

    Candidemia is an increasing problem in tertiary care hospitals worldwide. Here, we report the first outbreak of candidemia caused by fluconazole-resistant C. parapsilosis (FRCP) strains in Brazil. This was a cross-sectional study of clinical and microbiological data of all candidemic episodes diagnosed from July 2011 to February 2012 in a 200-bed tertiary care hospital. Initial yeast identification and susceptibility testing were performed using the VITEK 2 - System. Isolates of Candida spp. resistant to fluconazole were sent to a reference laboratory (LEMI-UNIFESP) for further molecular identification and confirmation of resistance by CLSI microdilution test. A multivariate analysis was conducted to identify factors associated with FRCP infection. We identified a total of 40 critically ill patients with candidemia (15 women) with a median age of 70 years. The incidence of candidemia was 6 cases/1,000 patients admissions, including 28 cases (70 %) of infection with C. parapsilosis, 21 of which (75 %) were resistant to fluconazole. In only 19 % of FRCP candidemia cases had fluconazole been used previously. The results of our study indicated that diabetes is a risk factor for FRCP candidemia (p = 0.002). Overall, mortality from candidemia was 45 %, and mortality from episodes of FRCP infections was 42.9 %. The clustering of incident cases in the ICU and molecular typing of strains suggest horizontal transmission of FRCP. Accurate vigilant monitoring for new nosocomial strains of FRCP is required.

  7. Switch from efavirenz to nevirapine, with full dose after one week: efficacy, safety and pharmacokinetics

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    A Curran

    2012-11-01

    Full Text Available Purpose of the study: In a prior study in patients switching from efavirenz (EFV due to neurologic side effects, we compared nevirapine (NVP full dose (200 mg twice-daily from the beginning to the standard dosage (200 mg once-daily for two weeks and then increase to 200 mg twice-daily [1]. Adequate concentrations were seen with the experimental arm but with a trend towards higher toxicity, with 25% of patients having to stop NVP due to rash or hepatitis. Our hypothesis is that NVP 200 mg daily for 1 week and then increasing it to 200 mg twice-daily will achieve adequate plasmatic concentrations with better tolerability. Methods: Patients taking an EFV-based regimen were offered to switch to NVP without changing the backbone. Patients received NVP 200 mg once-daily for 1 week and 200 mg twice-daily thereafter. EFV and NVP plasma trough levels were determined at days 0, 3, 7, 14, 30 and 90. Blood tests were performed at each visit and AE recorded. Chi-squared and Fisher exact test were used for qualitative variables and Mann-Whitney U and Wilcoxon signed rank tests for quantitative variables. Summary of results: 22 patients were included, 73% male, median age 48 years, median CD4 569 cell/mm3, all with CV <25 copies/mL and 41% had HCV co-infection. Reasons for switch were CNS symptoms in 50%, dyslipidemia in 46% and pregnancy desire in 4%. Backbone was TDF+FTC in 73% and ABC+3TC in 27%. Median NVP trough concentrations were 2.2, 2.7, 4.3, 4.5 and 5.5 µg/mL at 3, 7, 14, 30 and 90 days, respectively. 35% of patients had NVP plasma trough levels >3 µg/mL at day 7 and 88% at day 14. EFV concentrations were subtherapeutic (<1 µg/mL at day 7 and undetectable in all but one patient at day 14. There was a significant increase in GGT (+22 mg/dL, p=.013 and significant decreases in total cholesterol (−16 mg/dL, p=.035 and triglycerides (−50 mg/dL, p=.005 after 3 months. In the first month, two patients had to stop NVP due to rash and one due to rash

  8. Lipase Gene Expression of Resistant and Sensitive Candida Albicans to Fluconazole Isolated from Patients Suffering from Oral Candidiasis and Vaginal Candidiasis

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    NasrollahiOmran, A. (PhD

    2015-01-01

    Full Text Available Background and Objective: With the development of drug resistance in strains of fungi, there is a considerable resistance of Candida albicans strains to fluconazole. Molecular studies are developing to determine the relationship of such a drug resistance with the increased gene expression of enzymes produced in drug-resistant Candida isolates. We aimed to evaluate the relationship between extracellular lipase gene (LIP8 expression of Candida albicans isolated from candidiasis and sensitivity or resistance to fluconazole. Material and Methods: Drug susceptibility of Candida albicans was performed in oral and vaginal candidiasis to determine the proportion of strains sensitive or resistant to fluconazole using NCCLS method. To evaluate and compare the expression of these genes in the susceptible and resistant strains, RT real-time PCR reaction was used. Results: Of 46 Candida albicans, 20 were susceptible, 12 were semi-susceptible and 14 were resistant to fluconazole. By using PCR reaction, the results showed that the expression of this gene in fluconazole-susceptible isolates was moderate, while it was high in the isolates resistant to fluconazole. Conclusion: The results of lipase gene (LIP8 expression showed that the additional expression of some genes of the enzymes responsible for virulence of Candida may also play a role in resistance to fluconazole.

  9. Fluconazole susceptibility of 3,056 clinical isolates of Candida species from 2005 to 2009 in a tertiary-care hospital.

    Science.gov (United States)

    Ying, Y; Zhang, J; Huang, S B; Liu, F D; Liu, J H; Zhang, J; Hu, X F; Zhang, Z Q; Liu, X; Huang, X T

    2015-01-01

    In recent years, Candida infections have been increasing significantly. This study was to investigate the distribution and fluconazole susceptibility of such infections. Totally, 3,056 clinical isolates were analysed, C. albicans was the most prevalent species from respiratory and vaginal specimens. However, non-albicans species constituted the majority of isolates from blood, urine, intensive care unit (ICU), organ transplant and burned patients. Similarly, Candida spp. from different specimens and clinical services had different degrees of susceptibility to fluconazole. Isolates from vagina and burned patients had the highest resistance rate, while all of the isolates from ascites and dermatological services were susceptible to fluconazole.

  10. Fluconazole susceptibility of 3,056 clinical isolates of Candida species from 2005 to 2009 in a tertiary-care hospital

    Directory of Open Access Journals (Sweden)

    Y Ying

    2015-01-01

    Full Text Available In recent years, Candida infections have been increasing significantly. This study was to investigate the distribution and fluconazole susceptibility of such infections. Totally, 3,056 clinical isolates were analysed, C. albicans was the most prevalent species from respiratory and vaginal specimens. However, non-albicans species constituted the majority of isolates from blood, urine, intensive care unit (ICU, organ transplant and burned patients. Similarly, Candida spp. from different specimens and clinical services had different degrees of susceptibility to fluconazole. Isolates from vagina and burned patients had the highest resistance rate, while all of the isolates from ascites and dermatological services were susceptible to fluconazole.

  11. Fluconazole resistance in cryptococcal disease: emerging or intrinsic?

    Science.gov (United States)

    Cheong, Jenny Wan Sai; McCormack, Joe

    2013-04-01

    With the widespread use of long-term fluconazole prophylaxis and suppressive treatment, the potential development of fluconazole resistance poses a threat to the management of cryptococcal disease. Interpretive breakpoints for the in vitro antifungal susceptibility testing of C. neoformans have not been established and it is unclear whether the fluconazole minimum inhibitory concentration (MIC) is clinically relevant. To gain insight into the management of patients with cryptococcosis who fail fluconazole therapy, we conducted a PubMed literature search for cases of fluconazole-resistant cryptococcosis reported from 1991 to 2011. A total of 20 such cases were identified in which most patients had AIDS and 30% had never had prior exposure to fluconazole. Fluconazole failure in patients with cryptococcal disease cannot be fully attributed to emerging resistance of the etiologic agent and heteroresistance is a potential alternative mechanism. There is a need to refine the definition of fluconazole-resistant cryptococcosis and additional studies of such patients will improve treatment strategies and outcomes.

  12. Pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving sustained low-efficiency diafiltration.

    Science.gov (United States)

    Sinnollareddy, Mahipal G; Roberts, Michael S; Lipman, Jeffrey; Robertson, Thomas A; Peake, Sandra L; Roberts, Jason A

    2015-02-01

    Fluconazole is a widely used antifungal agent in critically ill patients. It is predominantly (60-80%) excreted unchanged in urine. Sustained low-efficiency diafiltration (SLED-f) is increasingly being utilised in critically ill patients because of its practical advantages over continuous renal replacement therapy. To date, the effect of SLED-f on fluconazole pharmacokinetics and dosing has not been studied. The objective of this study was to describe the pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving SLED-f and to compare this with other forms of renal replacement therapy. Serial blood samples were collected at pre- and post-filter ports within the SLED-f circuit during SLED-f and from an arterial catheter before and after SLED-f from three patients during one session. Fluconazole concentrations were measured using a validated chromatography method. Median clearance (CL) and 24-h area under the concentration-time curve (AUC0-24) were 2.1L/h and 152 mg·h/L, respectively, whilst receiving SLED-f. Moreover, 72% of fluconazole was cleared by a single SLED-f session (6h) compared with previous reports of 33-38% clearance by a 4-h intermittent haemodialysis session. CL and AUC0-24 were comparable with previous observations in a pre-dilution mode of continuous venovenous haemodiafiltration. The observed rebound concentration of fluconazole post SLED-f was 200mg daily are likely to be required to achieve the PK/PD target for common pathogens because of significant fluconazole clearance by SLED-f.

  13. A Risk Score for Fluconazole Failure among Patients with Candidemia.

    Science.gov (United States)

    Ostrosky-Zeichner, Luis; Harrington, Rachel; Azie, Nkechi; Yang, Hongbo; Li, Nanxin; Zhao, Jing; Koo, Valerie; Wu, Eric Q

    2017-05-01

    This study aimed to develop a prediction model to identify patients with candidemia who were at high risk of failing fluconazole treatment. Adult patients in the United States with candidemia who received fluconazole during hospitalization were selected from the Cerner Health Facts Hospital Database (04/2004 to 03/2013). Fluconazole failure was defined as switching/adding another antifungal, positive Candida culture ≥10 days after fluconazole initiation, or death during hospitalization. Patients were randomized into modeling and validation samples. Using the modeling sample, a regression analysis of least absolute shrinkage and selection operator was used to select risk predictors of fluconazole failure (demographics, Candida species, initiation of fluconazole before positive culture and after admission, and comorbidities, procedures, and treatments during the 6 months before admission and fluconazole initiation). The prediction model was evaluated using the validation sample. We found that of 987 identified patients (average age of 61 years, 51% male, 72% Caucasian), 49% failed and 51% did not fail fluconazole treatment. Of those who failed, 70% switched or added another antifungal, 21% had a second positive Candida test, and 42% died during hospitalization. Nine risk factors were included in the prediction model: days to start fluconazole after admission, Candida glabrata or Candida krusei infection, hematological malignancy, venous thromboembolism (VTE), enteral nutrition, use of nonoperative intubation/irrigation, and other antifungal use. All but VTE were associated with a higher risk of failure. The model's c-statistic was 0.65, with a Hosmer-Lemeshow test P value of 0.23. In summary, this prediction model identified patients with a high risk of fluconazole failure, illustrating the potential value and feasibility of personalizing candidemia treatment. Copyright © 2017 American Society for Microbiology.

  14. The development of fluconazole resistance in Candida albicans - an example of microevolution of a fungal pathogen.

    Science.gov (United States)

    Morschhäuser, Joachim

    2016-03-01

    The yeast Candida albicans is a member of the microbiota in the gastrointestinal and urogenital tracts of most healthy persons, but it can also cause symptomatic infections, especially in immunocompromised patients. During the life-long association with its human host, C. albicans generates genetically altered variants that are better adapted to changes in their environment. A prime example of this microevolution is the development of resistance to the commonly used drug fluconazole, which inhibits ergosterol biosynthesis, during antimycotic therapy. Fluconazole resistance can be caused by mutations in the drug target, by changes in the sterol biosynthesis pathway, and by gain-of-function mutations in transcription factors that result in the constitutive upregulation of ergosterol biosynthesis genes and multidrug efflux pumps. Fluconazole also induces genomic rearrangements that result in gene amplification and loss of heterozygosity for resistance mutations, which further increases drug resistance. These genome alterations may affect extended chromosomal regions and have additional phenotypic consequences. A striking case is the loss of heterozygosity for the mating type locus MTL in many fluconazole-resistant clinical isolates, which allows the cells to switch to the mating-competent opaque phenotype. This, in turn, raises the possibility that sexual recombination between different variants of an originally clonal, drug-susceptible population may contribute to the generation of highly fluconazole-resistant strains with multiple resistance mechanisms. The gain-of-function mutations in transcription factors, which result in deregulated gene expression, also cause reduced fitness. In spite of this, many clinical isolates that contain such mutations do not exhibit fitness defects, indicating that they have overcome the costs of drug resistance with further evolution by still unknown mechanisms.

  15. Design, synthesis, and evaluation of caffeic acid amides as synergists to sensitize fluconazole-resistant Candida albicans to fluconazole.

    Science.gov (United States)

    Dai, Li; Zang, Chengxu; Tian, Shujuan; Liu, Wei; Tan, Shanlun; Cai, Zhan; Ni, Tingjunhong; An, Maomao; Li, Ran; Gao, Yue; Zhang, Dazhi; Jiang, Yuanying

    2015-01-01

    A series of caffeic acid amides were designed, synthesized, and their synergistic activity with fluconazole against fluconazole-resistant Candida albicans was evaluated in vitro. The title caffeic acid amides 3-30 except 26 exhibited potent activity, and the subsequent SAR study was conducted. Compound 3, 5, 21, and 34c, at a concentration of 1.0 μg/ml, decreased the MIC₈₀ of fluconazole from 128.0 μg/ml to 1.0-0.5 μg/ml against the fluconazole-resistant C. albicans. This result suggests that the caffeic acid amides, as synergists, can sensitize drug-resistant fungi to fluconazole. The SAR study indicated that the dihydroxyl groups and the amido groups linking to phenyl or heterocyclic rings are the important pharmacophores of the caffeic acid amides.

  16. Pharmacokinetics of nevirapine in HIV-infected children under 3 years on rifampicin-based antituberculosis treatment.

    NARCIS (Netherlands)

    Oudijk, J.M.; McIlleron, H.; Mulenga, V.; Chintu, C.; Merry, C.; Walker, A.S.; Cook, A.; Gibb, D.M.; Burger, D.M.

    2012-01-01

    OBJECTIVE:: There is an urgent need to optimize cotreatment for children with tuberculosis and HIV infection. We described nevirapine pharmacokinetics in Zambian children aged less than 3 years, cotreated with nevirapine, lamivudine and stavudine in fixed-dose combination (using WHO weight bands)

  17. Echinocandin to fluconazole step-down therapy in critically ill patients with invasive, susceptible Candida albicans infections.

    Science.gov (United States)

    van der Geest, Patrick J; Rijnders, Bart J A; Vonk, Alieke G; Groeneveld, A B Johan

    2016-03-01

    Invasive Candida spp. infections are increasingly diagnosed in critically ill patients. For initial treatment, an echinocandin is recommended with a possible step-down to fluconazole when the patients' condition is improving and the isolate appears susceptible, but there are no data to support such policy. We studied the safety and efficacy of step-down therapy in critically ill patients with culture proven deep seated or bloodstream infections by C. albicans susceptible to fluconazole. All patients admitted into the intensive care unit from January 2010 to December 2014, who had a culture proven invasive C. albicans infection and received initial treatment with an echinocandin for at least 4 days were included. Data on patient characteristics, treatment and vital outcomes were assessed. Of the 56 patients, 32 received step-down fluconazole therapy, at median day 5, whereas the echinocandin was continued in the other 24. No differences where seen in baseline characteristics or risk factors for invasive C. albicans infection between the two groups. Response rates were similar and no difference where seen in 28-day or 90-day mortality between the groups. Step-down therapy to fluconazole may be safe and effective in critically ill patients with invasive infections by C. albicans, susceptible to fluconazole, who have clinically improved as early as 4 days after start of treatment with an echinocandin.

  18. A prospective study of mortality from cryptococcal meningitis following treatment induction with 1200 mg oral fluconazole in Blantyre, Malawi.

    Directory of Open Access Journals (Sweden)

    Katherine M Gaskell

    Full Text Available We have previously reported high ten-week mortality from cryptococcal meningitis in Malawian adults following treatment-induction with 800 mg oral fluconazole (57% [33/58]. National guidelines in Malawi and other African countries now advocate an increased induction dose of 1200 mg. We assessed whether this has improved outcomes.This was a prospective observational study of HIV-infected adults with cryptococcal meningitis confirmed by diagnostic lumbar puncture. Treatment was with fluconazole 1200 mg/day for two weeks then 400mg/day for 8 weeks. Mortality within the first 10 weeks was the study end-point, and current results were compared with data from our prior patient cohort who started on fluconazole 800 mg/day.47 participants received fluconazole monotherapy. Despite a treatment-induction dose of 1200 mg, ten-week mortality remained 55% (26/47. This was no better than our previous study (Hazard Ratio [HR] of death on 1200 mg vs. 800 mg fluconazole: 1.29 (95% CI: 0.77-2.16, p = 0.332. There was some evidence for improved survival in patients who had repeat lumbar punctures during early therapy to lower intracranial pressure (HR: 0.27 [95% CI: 0.07-1.03, p = 0.055].There remains an urgent need to identify more effective, affordable and deliverable regimens for cryptococcal meningitis.

  19. Decreasing candidaemia rate in abdominal surgery patients after introduction of fluconazole prophylaxis*

    DEFF Research Database (Denmark)

    Holzknecht, B J; Thorup, J; Arendrup, M C

    2011-01-01

    in the two abdominal surgery departments increased from 4.6 to 12.2 defined daily doses per 100 bed-days (p intensive care units. We could not detect any increase in fluconazole-resistant strains (14/29 pre- and 2/7 post...... infections (BSIs) in abdominal surgery patients were compared before (1 January 2006 to 30 June 2007) and after the intervention (1 January 2008 to 30 June 2009). The departments' activity was assessed by number of bed-days, admissions and surgical procedures, and the consumption of antifungals was analysed....... The candidaemia rate decreased from 1.5/1000 admissions in the pre-intervention to 0.3/1000 admissions in the post-intervention period (p 0.002). Numbers of BSIs and bed-days remained stable, and numbers of admissions and surgical procedures performed increased during the study period. Fluconazole consumption...

  20. Nevirapine-Based Antiretroviral Therapy Impacts Artesunate and Dihydroartemisinin Disposition in HIV-Infected Nigerian Adults

    Directory of Open Access Journals (Sweden)

    Fatai A. Fehintola

    2012-01-01

    Full Text Available Background. Nevirapine- (NVP- based antiretroviral therapy (ART and artesunate-amodiaquine are frequently coprescribed in areas of HIV and malaria endemicity. We explored the impact of this practice on artesunate and dihydroartemisinin pharmacokinetics. Methods. We conducted a parallel-group pharmacokinetic comparison between HIV-infected patients receiving NVP-based ART (n=10 and ART-naive controls (n=11. Artesunate-amodiaquine 200/600 mg was given daily for three days. Measurement of drug concentrations occurred between 0 and 96 hours after the final dose. Pharmacokinetic parameters were determined using noncompartmental analysis. Results. Comparing the NVP group to controls, clearance of artesunate was reduced 50% (1950 versus 2995 L/h; P=0.03, resulting in a 45% increase in the AUC0-96 (105 versus 69 ug∗hr/L; P=0.02. The half-life of dihydroartemisinin was shorter in the NVP group (1.6 versuss 3.2 h; P=0.004, but other dihydroartemisinin pharmacokinetic parameters were unchanged. A lower conversion of artesunate to dihydroartemisinin was observed in the NVP group (dihydroartemisinin: artesunate AUC0-96=5.6 versuss 8.5 in NVP and control groups, respectively, P=0.008. Conclusion. Although NVP-containing ART impacted some pharmacokinetic parameters of artesunate and dihydroartemisinin, overall exposure was similar or better in the NVP group.

  1. Good performance of an immunoassay based method for nevirapine measurements in human breast milk

    DEFF Research Database (Denmark)

    Salado-Rasmussen, Kirsten; Theilgaard, Zahra Persson; Chiduo, Mercy

    2011-01-01

    Abstract Background: Understanding the distribution of antiretro-virals in breastfeeding HIV-positive mothers is essential, both for prevention of mother-to-child HIV transmission and for research on the development of drug resistance. The ARK nevirapine (NVP)-test is an immunoassay method...... from HIV-uninfected women. Clinical samples from HIV-infected women receiving a single-dose of nevirapine were analyzed. Results: Precision and accuracy were evaluated with two concentrations of quality control materials analyzed in three replicates on four different days and was...

  2. Host factors do not influence the colonization or infection by fluconazole resistant Candida species in hospitalized patients

    Directory of Open Access Journals (Sweden)

    Ho Yu-Huai

    2008-12-01

    Full Text Available Abstract Nosocomial yeast infections have significantly increased during the past two decades in industrialized countries, including Taiwan. This has been associated with the emergence of resistance to fluconazole and other antifungal drugs. The medical records of 88 patients, colonized or infected with Candida species, from nine of the 22 hospitals that provided clinical isolates to the Taiwan Surveillance of Antimicrobial Resistance of Yeasts (TSARY program in 1999 were reviewed. A total of 35 patients contributed fluconazole resistant strains [minimum inhibitory concentrations (MICs ≧ 64 mg/l], while the remaining 53 patients contributed susceptible ones (MICs ≦ 8 mg/l. Fluconazole resistance was more frequent among isolates of Candida tropicalis (46.5% than either C. albicans (36.8% or C. glabrata (30.8%. There was no significant difference in demographic characteristics or underlying diseases among patients contributing strains different in drug susceptibility.

  3. Decreasing candidaemia rate in abdominal surgery patients after introduction of fluconazole prophylaxis*

    DEFF Research Database (Denmark)

    Holzknecht, Barbara; Thorup, Jens Frederik; Arendrup, M C;

    2011-01-01

    -intervention, p 0.43). The introduction of fluconazole prophylaxis was followed by a significantly decreased candidaemia rate. However, the observational study design does not allow conclusions regarding causality. No increase in resistance was detected, but follow-up was short and continuing surveillance......Clin Microbiol Infect ABSTRACT: Although abdominal surgery is an established risk factor for invasive candidiasis, the precise role of antifungal prophylaxis in these patients is not agreed upon. In 2007, fluconazole was added to the prophylactic antibiotic treatment for patients...... in the two abdominal surgery departments increased from 4.6 to 12.2 defined daily doses per 100 bed-days (p resistant strains (14/29 pre- and 2/7 post...

  4. Lipid-based nutrient supplements do not affect efavirenz but lower plasma nevirapine concentrations in Ethiopian adult HIV patients

    DEFF Research Database (Denmark)

    Abdissa, A; Olsen, Mette Frahm; Yilma, D

    2015-01-01

    OBJECTIVES: Lipid-based nutrient supplements (LNSs) are increasingly used in HIV programmes in resource-limited settings. However, the possible effects of LNSs on the plasma concentrations of antiretroviral drugs have not been assessed. Here, we aimed to assess the effects of LNSs on plasma...... efavirenz and nevirapine trough concentrations in Ethiopian adult HIV-infected patients. METHODS: The effects of LNSs were studied in adults initiating antiretroviral therapy (ART) in a randomized trial. Patients with body mass index (BMI) > 17 kg/m(2) (n = 282) received daily supplementation of an LNS.......9; -0.9 μg/mL; P = 0.01), respectively, compared with the group not receiving supplements. There were no differences between groups with respect to efavirenz plasma concentrations. The CYP2B6 516 G>T polymorphism was associated with a 5 μg/mL higher plasma efavirenz concentration compared with the wild...

  5. Outbreak of candidemia caused by fluconazole resistant Candida parapsilosis strains in an intensive care unit

    OpenAIRE

    Pinhati, Henrique Marconi Sampaio; Casulari,Luiz Augusto; Souza, Ana Carolina Remondi; Siqueira, Ricardo Andreotti; Damasceno, Camila Maria Gomes; Colombo, Arnaldo Lopes

    2016-01-01

    Background Candidemia is an increasing problem in tertiary care hospitals worldwide. Here, we report the first outbreak of candidemia caused by fluconazole-resistant C. parapsilosis (FRCP) strains in Brazil. Methods This was a cross-sectional study of clinical and microbiological data of all candidemic episodes diagnosed from July 2011 to February 2012 in a 200-bed tertiary care hospital. Initial yeast identification and susceptibility testing were performed using the VITEK 2 - System. Isolat...

  6. Confluent And Reticulated Papillomatosis : Treatment Response to Fluconazole

    Directory of Open Access Journals (Sweden)

    Ravikumar B C

    1997-01-01

    Full Text Available A case of confluent and reticulated papillomatosis with classical flexual pigmented papules distributed in reticular pattern is described. Patient responded well to a one- month course of Fluconazole therapy.

  7. Combination therapy of disseminated coccidioidomycosis with caspofungin and fluconazole

    Directory of Open Access Journals (Sweden)

    Ja Kim Min

    2006-02-01

    Full Text Available Abstract Background The current recommended therapy for diffuse coccidioidal pneumonia involves initial treatment with amphotericin B deoxycholate or high-dose fluconazole, followed by an azole after clinical improvement. Amphotericin B is more frequently used as initial therapy if the patient's deterioration is rapid. Case presentation A 31-year-old Korean male with coccidioidomycosis presented to the hospital with miliary infiltrates on chest X-ray (CXR and skin rash on the face and trunk. Initially, the patient did not respond to amphotericin B deoxycholate therapy. However, following caspofungin and fluconazole combination therapy, the patient showed favourable radiological, serological, and clinical response. Conclusion This appears to be the first case of diffuse coccidioidal pneumonia with skin involvement in an immunocompetent patient who was treated successfully with caspofungin and fluconazole. Combination therapy with caspofungin and fluconazole may, therefore, be an alternative treatment for diffuse coccidioidal pneumonia that does not respond to amphotericin B deoxycholate therapy.

  8. Influence of sustained low-efficiency diafiltration (SLED-f) on interstitial fluid concentrations of fluconazole in a critically ill patient: Use of microdialysis.

    Science.gov (United States)

    Sinnollareddy, Mahipal G; Roberts, Michael S; Lipman, Jeffrey; Peake, Sandra L; Roberts, Jason A

    2015-07-01

    Acute kidney injury is a common complication in critically ill patients, and hybrid techniques including sustained low-efficiency dialysis/diafiltration (SLED-f) are being increasingly utilised in intensive care units. Most fungal infections occur in the interstitial fluid (ISF) of tissues and successful treatment of a fungal infection relies on the ability of an antifungal agent to achieve adequate concentrations at the site of infection. Tissue distribution of antimicrobials is impaired in critically ill patients owing to a variety of disease-related physiological changes, e.g. sepsis. Fluconazole is a widely used antifungal agent used to treat Candida spp. infections in critically ill patients. The implications for ISF concentrations of enhanced elimination during renal replacement therapy have not yet been reported for fluconazole. The aim of this single-patient case report was to describe the influence of SLED-f on subcutaneous (SC) ISF concentrations of fluconazole and the implications for achieving pharmacokinetic/pharmacodynamic targets. Serial blood and ISF samples were collected at pre- and post-filter ports within the SLED-f circuit and subcutaneously inserted microdialysis probe, respectively. Fluconazole concentrations were measured using a validated chromatography method. The SC ISF-to-plasma partition coefficient of fluconazole in this patient was 0.91, indicating rapid equilibrium. SC ISF fluconazole concentrations consistently decreased after initiating SLED-f. The majority of the fluconazole was eliminated from the SC ISF as a result of redistribution. Considering the extensive tissue re-distribution of fluconazole and observed elimination from tissue compartments, higher doses may be required to treat deep-seated fungal infections.

  9. Comparison of microdilution and disc diffusion methods in assessing the in vitro activity of fluconazole and Melaleuca alternifolia (tea tree) oil against vaginal Candida isolates.

    Science.gov (United States)

    Ergin, A; Arikan, S

    2002-10-01

    The in vitro activity of fluconazole and Melaleuca alternifolia (tea tree) oil was evaluated against 99 vaginal Candida strains by the broth microdilution and disc diffusion methods. The microdilution method was performed in accordance with NCCLS-M27A guidelines. An investigational method was used for the disc diffusion test. Fluconazole and tea tree oil minimum inhibitory concentrations (MICs) obtained at 48 h tended to increase 1- to 2-fold or remain the same compared to 24 h readings for most of the isolates tested. C. krusei and C. norvegensis had significantly higher MICs and smaller inhibition zones for fluconazole compared to other species. Tea tree oil MICs were found to be similar, in general, for all Candida spp. tested. The geometric mean MIC of tea tree oil for all isolates was 2.2% (range, 0.25-4%) at 24 h and 3.0% (range, 1-8%) at 48 h. Tea tree oil mean inhibition zone diameter was 24 mm (range, 14-42 mm) at 24 h and 15.8 mm (range, 10-35 mm) at 48 h. In vitro activity of tea tree oil against fluconazole-resistant Candida strains was of particular interest. The isolates had similar tea tree oil MICs and inhibition zone diameters regardless of their fluconazole susceptibility profile. Tea tree oil MIC ranges (inhibition zone diameter ranges) were 2-4% (12-21 mm) and 2% (35 mm) at 48 h for C. krusei and C. norvegensis, respectively. These results suggest that tea tree oil MICs of the fluconazole-resistant isolates are comparable to those of fluconazole-susceptible isolates. This in vitro finding is promising for potential use of topical tea tree oil formulations in the treatment of candidiasis due to fluconazole-resistant strains.

  10. Thermoanalytical study of polymorphic transformation in Fluconazole drug

    Energy Technology Data Exchange (ETDEWEB)

    Desai, S.R.; Shaikh, M.M.; Dharwadkar, S.R

    2003-03-24

    Polymorphic transformation in Fluconazole (I) drug has been studied employing differential scanning calorimetry (DSC), X-ray diffraction and FT-IR techniques. Fluconazole (I) exhibited the sharp melting point at 138.4 deg. C. Considerable under cooling was, however, observed for the drug during cooling. No indication of freezing of molten Fluconazole (I) was evident in the DSC curve recorded up to a temperature of 25 deg. C in the cooling cycle. Reheating of the sample obtained after cooling, produced the DSC pattern much different compared to that obtained in the first heating and consisted of a sharp exothermic peak beginning at 81 deg. C preceding the twin endothermic peak with an onset temperature of 135.3 deg. C. In addition to these two peaks, a small endothermic peak was also observed around 31 deg. C, which could be attributed to a glass transition with an associated relaxation. The precise glass transition temperature derived from the data collected from six different independent experiments was found to be (31.67{+-}0.13) deg. C. X-ray diffraction pattern of the Fluconazole (I) indicated that the as received sample was crystalline. The molten Fluconazole on cooling, however, produced a glassy amorphous mass. The amorphous product on heating to temperature >81 deg. C transformed to Fluconazole (II) which subsequently changed to Fluconazole (I) prior to melting. The split endothermic peak beginning at 135.3 deg. C recorded for the solidified Fluconazole sample is consistent with the observations made by X-ray diffraction. The observations made by employing DSC and X-ray diffraction were corroborated by FT-IR data on the samples isolated at different stages in the experiments.

  11. Is empiric therapy with fluconazole appropriate for esophageal candidiasis?

    Science.gov (United States)

    Sajith, Kattiparambil Gangadharan; Dutta, Amit Kumar; Sahni, Rani Diana; Esakimuthu, Saritha; Chacko, Ashok

    2014-03-01

    We studied the prevalence of fluconazole resistance in esophageal candidiasis. Patients with suspected esophageal candidiasis during gastroscopy underwent culture of white plaques. Minimum inhibitory concentration (MIC) >64 μg/mL of fluconazole for Candida was indicative of resistance. Sensitivity of itraconazole was tested in a subset of resistant strains. Sixty-five patients were included. Mean (SD) age was 50.03 (13.5) years and 67.7 % were males. Predisposing factors for candidiasis were found in 42 (64.6 %) patients. C. albicans was identified in 64 (97.4 %) patients and C. glabrata in one patient. Fluconazole resistance was seen in 38 (59.4 %) patients with C. albicans and also in the one patient with C. glabrata. All the fluconazole resistant isolates of C. albicans had MIC >128 μg/mL suggesting very high resistance. Twelve patients with fluconazole resistance had itraconazole resistance as well. The study shows a high rate of fluconazole resistance in patients with esophageal candidiasis.

  12. Fluconazole prophylaxis in preterm infants: a systematic review.

    Science.gov (United States)

    Rios, Juliana Ferreira da Silva; Camargos, Paulo Augusto Moreira; Corrêa, Luísa Petri; Romanelli, Roberta Maia de Castro

    This article aims to review the use of antifungal prophylaxis with intravenous fluconazole in premature newborns and the occurrence of Invasive Candidiasis. This is a systematic review with search at databases: PubMed, Capes Portal, Virtual Health Library (BVS - Biblioteca Virtual em Saúde)/Lilacs, Scopus and Cochrane. The keywords used were: "Antifungal", "Candida" "Fluconazole prophylaxis" and "Preterm infants". Invasive Candidiasis was evaluated in all the twelve items. In eleven of them, there was a statistically significant difference between the groups receiving prophylactic fluconazole, with lower frequency of Invasive Candidiasis, compared to placebo or no prophylaxis group. Colonization by Candida species was also evaluated in five studies; four of them presented statistically lower proportion of colonization in patients with Fluconazole prophylaxis, compared to placebo or no drugs. In one study, there was a significant difference, favoring the use of fluconazole, and reduction of death. Studies indicate the effectiveness of prophylaxis with fluconazole, with reduction in the incidence of colonization and invasive fungal disease. The benefits of prophylaxis should be evaluated considering the incidence of candidiasis in the unit, the mortality associated with candidiasis, the safety and toxicity of short and long-term medication, and the potential for development of resistant pathogens. Copyright © 2017 Sociedade Brasileira de Infectologia. Published by Elsevier Editora Ltda. All rights reserved.

  13. The activity of echinocandins, amphotericin B and voriconazole against fluconazole-susceptible and fluconazole-resistant Brazilian Candida glabrata isolates

    Directory of Open Access Journals (Sweden)

    Débora Alves Nunes Mario

    2012-05-01

    Full Text Available The extensive use of azole antifungal agents has promoted the resistance of Candida spp to these drugs. Candida glabrata is a problematic yeast because it presents a high degree of primary or secondary resistance to fluconazole. In Brazil, C. glabrata has been less studied than other species. In this paper, we compared the activity of three major classes of antifungal agents (azoles, echinocandins and polyenes against fluconazole-susceptible (FS and fluconazole-resistant (FR C. glabrata strains. Cross-resistance between fluconazole and voriconazole was remarkable. Among the antifungal agents, the echinocandins were the most effective against FS and FR C. glabrata and micafungin showed the lowest minimal inhibitory concentrations.

  14. a study of nevirapine toxicity in hiv infected pregnant women at the ...

    African Journals Online (AJOL)

    Esem

    been shown to be true also in developing countries even in. 3,4 the face of breastfeeding . ... Protease inhibitor. (PI) based regimens form the back-bone of second line .... Alternative hypothesis(one sided) The incidence of nevirapine toxicity in ...

  15. Low-dose ketoconazole-fluconazole combination versus fluconazole in single doses for the treatment of vaginal candidiasis

    Directory of Open Access Journals (Sweden)

    Jan Susilo

    2011-08-01

    Full Text Available Background: Vaginal candidiasis (VC is one of the most common fungal diseases. Candida albicans is the most common causative fungus and has been isolated from more than 80% of specimens obtained from women with VC. Ketoconazole is the first orally active antifungal, the dosage for VC is 200 mg twice daily for 5 days. Fluconazole is the newer oral antifungal, its dosage for VC is a single oral dose of 150 mg. Since fluconazole 150 mg is considerably expensive, a single dose of 100 mg ketoconazole and 40 mg fluconazole in combination has been tested for the treatment of VC. The results showed that from 11 women with confirmed VC, 1-2 weeks after drug administration, the mycological culture was negative in 8 women, positive in 1 woman, and 2 woman lost to follow-up. This promising result led to the present study with the objective to confirm the efficacy and safety of the above combination in a formal clinical trial.Methods: A total of 165 female patients, aged 18 years or older, with the diagnosis of VC from clinical symptoms (pruritus or burning or excessive discharge and positive microscopic smear (pseudohyphae and/or yeast cells were randomized to receive a single dose of either keto-fluco combination (n = 85 or fluconazole (n = 80, and returnedfor follow-up visit on day 8.Results: Among these patients, 39 patients had negative baseline culture, leaving 126 patients eligible for efficacy evaluation. The mycological eradication in the keto-fluco group was 74.5% (41 patients from a total of 55 patients with available mycological culture, while that in the fluconazole group was 70.2% (40 patients from 57 patients with available culture and this difference was not significant. The clinical favorable response (clinical cure and clinical improvement in the keto-fluco arm (n = 60 was 98.3%, while that in the fluconazole group (n = 66 was 100%. Adverse events were found in 5 patients, 3 patients in the keto-fluco group (3/85 = 3.5% and 2

  16. Synergistic Effect of Fluconazole and Calcium Channel Blockers against Resistant Candida albicans.

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    Shuyuan Liu

    Full Text Available Candidiasis has increased significantly recently that threatens patients with low immunity. However, the number of antifungal drugs on the market is limited in comparison to the number of available antibacterial drugs. This fact, coupled with the increased frequency of fungal resistance, makes it necessary to develop new therapeutic strategies. Combination drug therapy is one of the most widely used and effective strategy to alleviate this problem. In this paper, we were aimed to evaluate the combined antifungal effects of four CCBs (calcium channel blockers, amlodipine (AML, nifedipine (NIF, benidipine (BEN and flunarizine (FNZ with fluconazole against C. albicans by checkerboard and time-killing method. In addition, we determined gene (CCH1, MID1, CNA1, CNB1, YVC1, CDR1, CDR2 and MDR1 expression by quantitative PCR and investigated the efflux pump activity of resistant candida albicans by rhodamine 6G assay to reveal the potential mechanisms. Finally, we concluded that there was a synergy when fluconazole combined with the four tested CCBs against resistant strains, with fractional inhibitory concentration index (FICI <0.5, but no interaction against sensitive strains (FICI = 0.56 ~ 2. The mechanism studies revealed that fluconazole plus amlodipine caused down-regulating of CNA1, CNB1 (encoding calcineurin and YVC1 (encoding calcium channel protein in vacuole membrane.

  17. Synergistic Effect of Fluconazole and Calcium Channel Blockers against Resistant Candida albicans.

    Science.gov (United States)

    Liu, Shuyuan; Yue, Longtao; Gu, Wenrui; Li, Xiuyun; Zhang, Liuping; Sun, Shujuan

    2016-01-01

    Candidiasis has increased significantly recently that threatens patients with low immunity. However, the number of antifungal drugs on the market is limited in comparison to the number of available antibacterial drugs. This fact, coupled with the increased frequency of fungal resistance, makes it necessary to develop new therapeutic strategies. Combination drug therapy is one of the most widely used and effective strategy to alleviate this problem. In this paper, we were aimed to evaluate the combined antifungal effects of four CCBs (calcium channel blockers), amlodipine (AML), nifedipine (NIF), benidipine (BEN) and flunarizine (FNZ) with fluconazole against C. albicans by checkerboard and time-killing method. In addition, we determined gene (CCH1, MID1, CNA1, CNB1, YVC1, CDR1, CDR2 and MDR1) expression by quantitative PCR and investigated the efflux pump activity of resistant candida albicans by rhodamine 6G assay to reveal the potential mechanisms. Finally, we concluded that there was a synergy when fluconazole combined with the four tested CCBs against resistant strains, with fractional inhibitory concentration index (FICI) fluconazole plus amlodipine caused down-regulating of CNA1, CNB1 (encoding calcineurin) and YVC1 (encoding calcium channel protein in vacuole membrane).

  18. Effects of fluconazole on the secretome, the wall proteome, and wall integrity of the clinical fungus Candida albicans

    NARCIS (Netherlands)

    Sorgo, A.G.; Heilmann, C.J.; Dekker, H.L.; Bekker, M.; Brul, S.; de Koster, C.G.; de Koning, L.J.; Klis, F.M.

    2011-01-01

    Fluconazole is a commonly used antifungal drug that inhibits Erg11, a protein responsible for 14α-demethylation during ergosterol synthesis. Consequently, ergosterol is depleted from cellular membranes and replaced by toxic 14α-methylated sterols, which causes increased membrane fluidity and drug pe

  19. [Derivatization of berberine based on its synergistic antifungal activity with fluconazole against fluconazole-resistant Candida albicans].

    Science.gov (United States)

    Tian, Shu-Juan; Gao, Yue; Zang, Cheng-Xu; Cai, Zhan; Ni, Ting-jun-hong; Tan, Shan-Lun; Cao, Yong-Bing; Jiang, Yuan-Ying; Zhang, Da-Zhi

    2014-11-01

    Abstract: Our previous work revealed berberine can significantly enhance the susceptibility of fluconazole against fluconazole-resistant Candida albicans, which suggested that berberine has synergistic antifungal activity with fluconazole. Preliminary SAR of berberine needs to be studied for the possibility of investigating its target and SAR, improving its drug-likeness, and exploring new scaffold. In this work, 13-substitutited benzyl berberine derivatives and N-benzyl isoquinoline analogues were synthesized and characterized by 1H NMR and MS. Their synergetic activity with fluconazole against fluconazole-resistant Candida albicans was evaluated in vitro. The 13-substitutited benzyl berberine derivatives 1a-1e exhibited comparable activity to berberine, which suggested that the introduction of functional groups to C-13 can maintain its activity. The N-benzyl isoquinolines, which were designed as analogues of berberine with its D ring opened, exhibited lower activity than berberine. However, compound 2b, 2c, and 4b showed moderate activity, which indicated that berberine may be deconstructed to new scaffold with synergistic antifungal activity with fluconazole. The results of our research may be helpful to the SAR studies on its other biological activities.

  20. Interspecies differences of candida species causing recurrent vulvovaginal candidiasis in response to fluconazole treatment

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    Siamak Naji

    2017-07-01

    Methods: The cross-sectional study was performed at Kowsar Gynecology Center, Motahhari educational hospital and Medical Mycology Center, Faculty of Medicine, Urmia, Iran, from October 2013 to July 2015. Those patients referred to the clinic with symptoms of vaginal discharge, itching or burning that swab samples from endo-exocervix and distal fornix discharge were taken. The vaginal discharge samples submitted to Medical Mycology Center, Urmia School of Medicine for the direct microscopic examination and cultures. Identification at the level of species was performed using CHROMagar Candida and Corn meal agar media. The molecular test polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP used for confirming culture results. For the susceptibility assay, disc diffusion method was performed with fluconazole and clotrimazole. Results: In these study 198 samples collected from patients with symptoms of vulvovaginal candidiasis, 77 vulvovaginal candidiasis cases were identified. Candida species are common in primary and recurrent cases in terms of frequency, Candida albicans (85.7%, Candida krusei (10.2% and Candida glabrata (4.1% were identified respectively. Total of 27 cases of recurrent vulvovaginal candidiasis, 10 cases were resistant to both clotrimazole and fluconazole (37% was observed that the most common species are resistant to treatment were Candida albicans by (82.1%, Candida krusei (14.3% and Candida glabrata (3.6% respectively. Drug resistance in Candida albicans, Candida krusei and Candida glabrata causing recurrent vulvovaginal candidiasis included 69.1%, 75% and 100% respectively. Conclusion: Our findings have shown frequency of resistant non-albicans Candida species to fluconazole and clotrimazole is increasing. There is a considerable difference between Candida albicans and non-albicans species, Candida glabrata for the resistance to fluconazole and clotrimazole.

  1. Comparison of human and soil Candida tropicalis isolates with reduced susceptibility to fluconazole.

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    Yun-Liang Yang

    Full Text Available Infections caused by treatment-resistant non-albicans Candida species, such as C. tropicalis, has increased, which is an emerging challenge in the management of fungal infections. Genetically related diploid sequence type (DST strains of C. tropicalis exhibiting reduced susceptibility to fluconazole circulated widely in Taiwan. To identify the potential source of these wildly distributed DST strains, we investigated the possibility of the presence in soil of such C. tropicalis strains by pulsed field gel electrophoresis (PFGE and DST typing methods. A total of 56 C. tropicalis isolates were recovered from 26 out of 477 soil samples. Among the 18 isolates with reduced susceptibility to fluconazole, 9 belonged to DST149 and 3 belonged to DST140. Both DSTs have been recovered from our previous studies on clinical isolates from the Taiwan Surveillance of Antimicrobial Resistance of Yeasts (TSARY program. Furthermore, these isolates were more resistant to agricultural azoles. We have found genetically related C. tropicalis exhibiting reduced susceptibility to fluconazole from the human hosts and environmental samples. Therefore, to prevent patients from acquiring C. tropicalis with reduced susceptibility to azoles, prudent use of azoles in both clinical and agricultural settings is advocated.

  2. Fluconazole treatment enhances extracellular release of red pigments in the fungus Monascus purpureus.

    Science.gov (United States)

    Koli, Sunil H; Suryawanshi, Rahul K; Patil, Chandrashekar D; Patil, Satish V

    2017-03-15

    Traditional methods for the production of food grade pigments from fungus Monascus spp. are mostly relying on submerged fermentation. However, cell bound nature and intracellular accumulation of pigments in Monascus spp is the major hurdle in pigment production by submerged fermentation. The present study focused on the investigation of the effect of the antifungal agent, fluconazole on red pigment production from Monascus purpureus (NMCC-PF01). At the optimized concentration of fluconazole (30 μg/ml), pigment production was found to be enhanced by 88% after 96 h and it remained constant even after further incubation up to 168 h. An ergosterol, a sterol specific for fungi was also extracted and estimated as a function of fungal growth. The concentration of ergosterol in fluconazole-treated fermentation broth was reduced by 49% as compared to control broth. Thus it could be responsible for facilitating the release of intracellular and cell bound pigments. Nevertheless, the role of cell transporters in transporting out the red pigments cannot be ignored and deserves further attention. Qualitative analysis of red pigment by TLC, UV spectroscopy and mass spectrometric analysis (ESIMS) has confirmed the presence of well-known pigment, Rubropunctamine. In addition, this fermentation process produces citrinin-free pigments. This novel approach will be useful to facilitate increased pigment production by the release of intracellular or cell bound Monascus pigments.

  3. Fluconazole-Warfarin Interaction: A case report with deadly consequences

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    Elliot V Hersh

    2017-06-01

    Full Text Available Adverse drug-drug interactions are more common in the elderly because of the commonality of polypharmacy. When one of the interacting drugs has a low therapeutic index, the consequences can be life-threatening or fatal. This case describes a fatal cerebral haemorrhage in an 80-year old male on stable doses of warfarin prescribed by his cardiologist, who was prescribed fluconazole 200mg, once daily, for 14 days by an oral and maxillofacial surgeon to treat an intraoral fungal infection. The oral surgeon was aware that the patient was on warfarin and his INR two days prior to the appointment was 2.4. While a drug interaction alert was sent to the patient’s primary care family physician regarding fluconazole and the simvastatin she had been prescribing, the interaction was not reviewed by her for another 9- days. She then informed the patient that “it was fine” to finish the fluconazole. However, this phone conversation prompted the patient to discontinue the fluconazole after 8 doses. Two days later, the patient was confused and driving his car erratically. His son rushed him to the hospital where a CAT scan revealed a large frontal intraparenchymal haemorrhage. His INR was a 9.6. This event illustrates that this well-documented adverse drug interaction needs to be better highlighted in dental and medical training. Warfarin’s primary metabolic pathway involves the cytochrome P-450 2C9 isoform and fluconazole is a strong inhibitor of this enzyme, with the potential outcome being excessive warfarin blood levels. Frequent INR monitoring with potential warfarin dosage adjustments downward if fluconazole is prescribed, or the complete avoidance of fluconazole is recommended in patients taking warfarin. The importance of communication and coordinated care between different health care providers cannot be overstated.

  4. Molecularly imprinted solid phase extraction of fluconazole from pharmaceutical formulations.

    Science.gov (United States)

    Manzoor, S; Buffon, R; Rossi, A V

    2015-03-01

    This work encompasses a direct and coherent strategy to synthesise a molecularly imprinted polymer (MIP) capable of extracting fluconazole from its sample. The MIP was successfully prepared from methacrylic acid (functional monomer), ethyleneglycoldimethacrylate (crosslinker) and acetonitrile (porogenic solvent) in the presence of fluconazole as the template molecule through a non-covalent approach. The non-imprinted polymer (NIP) was prepared following the same synthetic scheme, but in the absence of the template. The data obtained from scanning electronic microscopy, infrared spectroscopy, thermogravimetric and nitrogen Brunauer-Emmett-Teller plot helped to elucidate the structural as well as the morphological characteristics of the MIP and NIP. The application of MIP as a sorbent was demonstrated by packing it in solid phase extraction cartridges to extract fluconazole from commercial capsule samples through an offline analytical procedure. The quantification of fluconazole was accomplished through UPLC-MS, which resulted in LOD≤1.63×10(-10) mM. Furthermore, a high percentage recovery of 91±10% (n=9) was obtained. The ability of the MIP for selective recognition of fluconazole was evaluated by comparison with the structural analogues, miconazole, tioconazole and secnidazole, resulting in percentage recoveries of 51, 35 and 32%, respectively.

  5. Antifungal activities of fluconazole and ketoconazole agentsagainst Malassezia species

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    Mehdi Nazeri1

    2009-01-01

    Full Text Available (Received 12 Oct, 2008; Accepted 20 Apr, 2009AbstractBackground and purpose: Malassezia, a yeast-like fungus found in normal skin flora is known to be associated with various skin diseases, along with systemic infections. Our aim was to determine the in -vitro susceptibility of Malassezia spp. to ketoconazole and fluconazole.Materials and methods: In this study, we identified 99 Malassezia isolates from patients with pityriasis vesicular by morphological and biochemical criteria. In vitro susceptibility testing was in macro-broth dilutions, conducted based on the National Committee for Clinical Laboratory Standards (NCCLS M27-A proposed standard. The results were analyzed statistically by Mann-Whitney.Results: The Malassezia isolates were identified as M. globosa (42, M. furfur (39, M. obtusa (10, M. sympodialis (6, and M.slooffiae (2. The rate of MFC of ketoconazole against Malassezia spp. was 0.06-2 µg/ml, while the MFC of fluconazole against Malassezia spp. was 2-64 µg/ml. The minimal inhibitory concentration (MIC90 of ketoconazole against Malassezia spp. was 0.03-1 µg/ml, while the minimal inhibitory concentration (MIC90 of fluconazole against Malassezia spp. was 0.5-32 µg/ml.Conclusion: Although fluconazole can be an effective treatment option for pityriasis versicolor, in our study, fluconazole MICs were higher than ketoclonazole. J Mazand Univ Med Sci 2009; 19(69: 22-27 (Persian

  6. Long-term therapy with nevirapine and tropism

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    S Bressan

    2012-11-01

    Full Text Available Objective: A more potent effect on the residual viraemia was ascribed to nevirapine (NVP with respect to other antiretroviral drugs; moreover a selection of X4 strains was described in patients (pts with undetectable viraemia; our aim was to study viro-immunological parameters and tropism for co-receptor in pts on a long term successful therapy with NVP. Methods: 14 pts on HAART from 130 months (GL, median value, range 118–156 months without occurrence of blips, as assessable with the available methods at that time, were retrospectively selected from a single center cohort (Bolzano. Tropism for V3 was determined by population sequencing on blood, and using geno2pheno algorithm; cellular HIV DNA load was analysed by in-house Real-Time. A further eighteen months (mo follow up was then observed. Data were compared with those obtained from a control group of 50 naïve pts (GS, evaluated after a 36-mo successful therapy (median, range 12–84 with various drug combinations, with median baseline (BL CD4 of 50/μl, comparable value with the GL cohort. Results: In 7 pts a R5-tropic (GLR5, FPR median 84.8% and in 7 an X4-tropic strain (GLX4, FPR median 1.1% was demonstrated. BL data of GLR5 were 46 y old, CD4 54/l, HIV-RNA 104,000 cps/ml; HAART from 142 mo, with NVP from 125 (one after 70 mo on NVP switched to protease from 57; at follow up CD4 were 679/l, HIV-DNA 60 cps/106 PBMCs (range<5–252. GLX4 were 46 y, at BL 38 CD4/l, HIV-RNA 250,000 cps/ml; in HAART from 121 mo, with NVP from 97; at follow up CD4 902/l, HIV-DNA 60 cps/106 PBMCs (range<5–225. Six out of seven pts of the two groups were on treatment with abacavir+lamivudine (ABC+3TC and one with tenofovir+emtricitabine. In the subsequent 18 mo four blips were observed (21–71 cps/ml; the backbone was changed to raltegravir in two GLR5 and one GLX4 for convenience. In the 50 GS pts at follow up an X4 strain was found in 50% of 14 efavirenz-treated, in 16% of 6 NVP, and 63% of 30 protease

  7. Simultaneous And Extended Delivery Of Stavudine, Lamivudine And Nevirapine In Fixed Dose Combination Using Sandwiched Osmotic Tablets For Hiv Therapy.

    Science.gov (United States)

    Priya, M Ranga; Rajendran, N N

    2015-01-01

    Current HIV-therapy recommends combination of stavudine, lamivudine and nevirapine. Stavudine and lamivudine are administered as fixed combination while nevirapine as separate dosage form which often results in poor compliance and adherence to therapy by patients and therefore, there is a need to develop dosage forms that can overcome the problems of currently available dosage forms for treatment of HIV infection. The present study developed a single unit osmotic system for simultaneous and extended delivery of stavudine, lamivudine and nevirapine that can ensure patients compliance and adherence to HIV-therapy. Sandwich osmotic pump tablets (SOPTs) of stavudine, lamivudine and nevirapine in fixed dose combination were designed and evaluated for the effect of variables such as PEO (polymer), KCl (osmogen), and orifice diameter on the physicochemical characteristics and the release behavior of the drugs. A 24 h zero order release of stavudine, lamivudine and nevirapine from the formulations was observed and the release rate of the drugs was found to be affected by PEO, KCl, and orifice diameter. The in vitro release data of SOPT correlated with in vivo predictions by super - position method. The results of the study propose that a single unit osmotic system (SOPT) of stavudine, lamivudine and nevirapine is beneficial to overcome the disadvantages of currently available dosage forms for effective control of HIV infection.

  8. Fluconazole population pharmacokinetics and dosing for prevention and treatment of invasive Candidiasis in children supported with extracorporeal membrane oxygenation.

    Science.gov (United States)

    Watt, Kevin M; Gonzalez, Daniel; Benjamin, Daniel K; Brouwer, Kim L R; Wade, Kelly C; Capparelli, Edmund; Barrett, Jeffrey; Cohen-Wolkowiez, Michael

    2015-07-01

    Candida infections are a leading cause of infectious disease-related death in children supported by extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK); thus, standard fluconazole dosing may result in suboptimal drug exposures. The objective of our study was to determine the PK of fluconazole in children on ECMO. Forty children with 367 PK samples were included in the analysis. The PK data were analyzed using nonlinear mixed-effect modeling (NONMEM). A one-compartment model best described the data. Weight was included in the base model for clearance (CL) and volume of distribution (V). The final model included the effect of serum creatinine (SCR) level on CL and the effect of ECMO on V as follows: CL (in liters per hour) = 0.019 × weight × (SCR/0.4)(-0.29) × exp(ηCL) and V (in liters) = 0.93 × weight × 1.4(ECMO) × exp(ηV). The fluconazole V was increased in children supported by ECMO. Consequently, children on ECMO require a higher fluconazole loading dose for prophylaxis (12 mg/kg of body weight) and treatment (35 mg/kg) paired with standard maintenance doses to achieve exposures similar to those of children not on ECMO.

  9. 氟康唑类似物的研究进展%Research progress of fluconazole derivatives

    Institute of Scientific and Technical Information of China (English)

    许克寒; 黄蕾; 吴俊琪; 戚麟; 金永生; 俞世冲

    2016-01-01

    氟康唑是第三代三唑类抗真菌药物,具有水溶性好、广谱和低毒等优点,是临床上治疗真菌感染的首选药物.随着氟康唑耐药菌株的不断出现,研制新型氟康唑类似物成为重要的科研课题.通过对氟康唑结构的修饰,获得新型氟康唑类似物,为进一步的新药合成研究提供线索.%Fluconazole,the third generation of triazole-antifungal drug,becomes the first choice in the treatment of fun-gal infection due to its broad antifungal spectrum,good water solubility and low toxicity.With an increasingly drug-resistant strain,developing new fluconazole derivatives is becoming an attractive topic.This review mainly indicates that people can get new fluconazole derivatives used by clinic through structural modification of fluconazole,which will give clues for advanced re-search.

  10. Effects of the moderate CYP3A4 inhibitor, fluconazole, on the pharmacokinetics of fesoterodine in healthy subjects.

    Science.gov (United States)

    Malhotra, Bimal; Dickins, Maurice; Alvey, Christine; Jumadilova, Zhanna; Li, Xiaoxi; Duczynski, Gregory; Gandelman, Kuan

    2011-08-01

    Available data suggest that fesoterodine dosage should not exceed 4 mg once daily when taken concomitantly with potent CYP3A4 inhibitors, such as ketoconazole. Currently, no information is available on whether dose adjustment is necessary when fesoterodine is administered with a moderate CYP3A4 inhibitor. This study shows that adjustment of fesoterodine dose is not warranted when co-administered with a moderate CYP3A4 inhibitor. To assess the effects of fluconazole, a moderate CYP3A4 inhibitor, on the pharmacokinetics (PK) and safety/tolerability of fesoterodine. In this open-label, randomized, two-way crossover study, 28 healthy subjects (18-55 years) received single doses of fesoterodine 8 mg alone or with fluconazole 200 mg. PK endpoints, including the area under the plasma concentration-time curve from 0 to infinity (AUC(0,∞)), maximum plasma concentration (C(max) ), time to C(max) (t(max) ), and half-life (t(1/2) ), were assessed for 5-hydroxymethyl tolterodine (5-HMT), the active moiety of fesoterodine. Concomitant administration of fesoterodine with fluconazole increased AUC(0,∞) and C(max) of 5-HMT by approximately 27% and 19%, respectively, with corresponding 90% confidence intervals of (18%, 36%) and (11%, 28%). There was no apparent effect of fluconazole on 5-HMT t(max) or t(½) . Fesoterodine was generally well tolerated regardless of fluconazole co-administration, with no reports of death, serious adverse events (AEs) or severe AEs. Following co-administration of fesoterodine with fluconazole, 13 subjects (48%) experienced a total of 40 AEs; following administration of fesoterodine alone, six subjects (22%) experienced a total of 19 AEs. The majority of AEs were of mild intensity. There were no clinically significant changes in laboratory or physical examination parameters. Fesoterodine 8 mg single dose was well tolerated when administered alone or with fluconazole. Based on the observed increase in 5-HMT exposures being within the inherent

  11. Fluconazole induced herpes labialis-like lesions in an adult male

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    Harish C. Goel

    2009-12-01

    Full Text Available Fluconazole is a bistriazole commonly prescribed for thetreatment of various fungal infections caused by yeasts and dermatophytes. However, there have been several reports of rare Adverse Drug Reactions (ADRs like Fixed Dose Eruption (FDE, Toxic Epidermal Necrolysis and Stevens Johnson Syndrome following oral administration of fluconazole. We report a rare case of fluconazole induced oral mucosal lesions, mimicking herpes labialis, in a 34 year old male patient receiving oral fluconazole for the treatment of allergic fungal sinusitis.

  12. Empirical and targeted therapy of candidemia with fluconazole versus echinocandins: a propensity score-derived analysis of a population-based, multicentre prospective cohort.

    Science.gov (United States)

    López-Cortés, L E; Almirante, B; Cuenca-Estrella, M; Garnacho-Montero, J; Padilla, B; Puig-Asensio, M; Ruiz-Camps, I; Rodríguez-Baño, J

    2016-08-01

    We compared the clinical efficacy of fluconazole and echinocandins in the treatment of candidemia in real practice. The CANDIPOP study is a prospective, population-based cohort study on candidemia carried out between May 2010 and April 2011 in 29 Spanish hospitals. Using strict inclusion criteria, we separately compared the impact of empirical and targeted therapy with fluconazole or echinocandins on 30-day mortality. Cox regression, including a propensity score (PS) for receiving echinocandins, stratified analysis on the PS quartiles and PS-based matched analyses, were performed. The empirical and targeted therapy cohorts comprised 316 and 421 cases, respectively; 30-day mortality was 18.7% with fluconazole and 33.9% with echinocandins (p 0.02) in the empirical therapy group and 19.8% with fluconazole and 27.7% with echinocandins (p 0.06) in the targeted therapy group. Multivariate Cox regression analysis including PS showed that empirical therapy with fluconazole was associated with better prognosis (adjusted hazard ratio 0.38; 95% confidence interval 0.17-0.81; p 0.01); no differences were found within each PS quartile or in cases matched according to PS. Targeted therapy with fluconazole did not show a significant association with mortality in the Cox regression analysis (adjusted hazard ratio 0.77; 95% confidence interval 0.41-1.46; p 0.63), in the PS quartiles or in PS-matched cases. The results were similar among patients with severe sepsis and septic shock. Empirical or targeted treatment with fluconazole was not associated with increased 30-day mortality compared to echinocandins among adults with candidemia.

  13. Nevirapine-Resistant HIV-1 DNA in Breast Milk After Single-Dose Nevirapine With or Without Zidovudine for Prevention of Mother-to-Child Transmission.

    Science.gov (United States)

    Gantt, Soren; Payant, Rachel; Carlsson, Jacquelyn; Micek, Mark A; Blanco, Ana Judith; Beck, Ingrid A; Matunha, Laurinda; Montoya, Pablo; Matediana, Eduardo; Gloyd, Stephen; Frenkel, Lisa M

    2012-09-01

    Among 30 human immunodeficiency virus type 1 (HIV-1)-infected women who received single-dose nevirapine (NVP), 17 (57%) had NVP-resistant HIV-1 detected in breast milk. NVP resistance in breast milk persisted for at least 8 months postpartum and was apparently transmitted to at least 1 infant. NVP resistance was detected less often in women who also received zidovudine. © The Author 2012. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  14. Release profiles and morphological characterization by atomic force microscopy and photon correlation spectroscopy of 99mTechnetium-fluconazole nanocapsules.

    Science.gov (United States)

    de Assis, Danielle Nogueira; Mosqueira, Vanessa Carla Furtado; Vilela, José Mário Carneiro; Andrade, Margareth Spangler; Cardoso, Valbert Nascimento

    2008-02-12

    Several classes of antifungal have been employed in candidiasis treatment, but patients with advanced immunodeficiency can present unsatisfactory results after therapy. In these cases, high doses of drugs or the use of multiple agents are sometimes used, and hence increasing the risk of serious side effects. Considering theses difficulties, the encapsulation of antifungal agents in nanoparticulate carriers has been used with the objective of modifying the pharmacokinetic of drugs resulting in more efficient treatments with less side effects. The purpose of this work was the preparation, characterization and the investigation of the release profiles of radiolabeled fluconazole nanocapsules. The size, homogeneity and zeta potential of NC preparations were determined with a Zetasizer 3000HS. The morphology and the structural organization were evaluated by atomic force microscopy (AFM). The release study in vitro of NC was evaluated in physiologic solution with or without 70% mouse plasma. The labeling yield of fluconazole with 99mTc was 94% and the radiolabeled drug was stable within 24h period. The encapsulation percentage of 99mTc-fluconazole in PLA-POLOX NC and PLA-PEG NC was approximately of 30%. The average diameter calculated by photon correlation spectroscopy (PCS) varied from 236 to 356 nm, while the average diameter determined by AFM varied from 238 to 411 nm. The diameter/height relation decreased significantly when 25% glutaraldehyde was used for NC fixation on mica. The zeta potential varied from -55 to -69 nm and surface-modified NC showed lower absolute values than conventional NC. The in vitro release of 99mTc-fluconazole in plasma medium of the conventional and surface-modified NC was greater than in saline. The drug release in plasma medium from conventional NC was faster than for surface-modified NC. The results obtained in this work suggest that the nanocapsules containing fluconazole could be used to identify infectious foci, due to the properties

  15. A New Validated RP- HPLC Method for the Determination of Nevirapine in Human Plasma

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    C. H. Venkata Kumar

    2010-01-01

    Full Text Available A rapid, selective and sensitive high performance liquid chromatographic method for the estimation of nevirapine in human plasma has been developed. Chromatography was carried out on a Hypersil BDS C18 column using a mixture of ammonium acetate buffer (pH 4.0 ± 0.05 and acetonitrile (85:15 v/v as the mobile phase. The eluents were monitored for the drug by UV detection at 254 nm. Oxcarbazepine was used as an internal standard for this study. The retention times for nevirapine and oxcarbazepine were found to be 7.2 and 14.7 min respectively. The method was found to be linear in the concentration range of 50 ng/mL to 5003.7 ng/mL. The method was validated as per FDA guidelines and was found to be suitable for bioequivalence and pharmacokinetic studies.

  16. Outcome of protease inhibitor substitution with nevirapine in HIV-1 infected children

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    Gomez M Luisa

    2008-10-01

    Full Text Available Abstract Background Protease inhibitors (PIs have been associated with metabolic complications. There is a trend to switch to simpler therapy to improve these disturbances. We report a case-series describing the effects in metabolic abnormalities in seven HIV-infected children, previously treated with protease inhibitor (PI after switching to nevirapine. Methods Seven children with stable PI-containing regimen and a long lasting HIV-1 RNA Results Seven HIV-infected children were enrolled. Median age: 130 months (99,177. Median baseline CD4%: 32%. All had HIV-1 RNA Conclusion PI substitution with nevirapine improved lipid profile in our patients, although this strategy did not show significant changes in body fat or lipodystrophy.

  17. The Pressure-Induced Polymorphic Transformations in Fluconazole.

    Science.gov (United States)

    Gorkovenko, Ekaterina A; Kichanov, Sergey E; Kozlenko, Denis P; Belushkin, Alexandr V; Wąsicki, Jan; Nawrocik, Wojciech; Mielcarek, Jadwiga; Dubrovinsky, Leonid S; Lathe, Christian; Savenko, Boris N

    2015-12-01

    The structural properties and Raman spectra of fluconazole have been studied by means of X-ray diffraction and Raman spectroscopy at pressures up to 2.5 and 5.5 GPa, respectively. At a pressure of 0.8 GPa, a polymorphic phase transition from the initial form I to a new triclinic form VIII has been observed. At higher pressure of P = 3.2 GPa, possible transformation into another new polymorphic form IX has been detected. The unit cell parameters and volumes, and vibration modes as functions of pressure have been obtained for the different forms of fluconazole.

  18. Mutation of G234 amino acid residue in Candida albicans drug-resistance-related protein Rta2p is associated with fluconazole resistance and dihydrosphingosine transport

    Science.gov (United States)

    Zhang, Shi-Qun; Miao, Qi; Li, Li-Ping; Zhang, Lu-lu; Yan, Lan; Jia, Yu; Cao, Yong-Bing; Jiang, Yuan-Ying

    2015-01-01

    Widespread and repeated use of azoles has led to the rapid development of drug resistance in Candida albicans. Our previous study found Rta2p, a membrane protein with 7 transmembrane domains, was involved in calcineurin-mediated azole resistance and sphingoid long-chain base release in C. albicans. Conserved amino acids in the transmembrane domain of Rta2p were subjected to site-directed mutagenesis. The sensitivity of C. albicans to fluconazole in vitro was examined by minimum inhibitory concentration and killing assay, and the therapeutic efficacy of fluconazole in vivo was performed by systemic mice candidiasis model. Furthermore, dihydrosphingosine transport activity was detected by NBD labeled D-erythro-dihydrosphingosine uptake and release assay, and the sensitivity to sphingolipid biosynthesis inhibitors. We successfully constructed 14 mutant strains of Rta2p, screened them by minimum inhibitory concentration and found Ca2+ did not completely induce fluconazole resistance with G158E and G234S mutations. Furthermore, we confirmed that G234S mutant enhanced the therapeutic efficacy of fluconazole against systemic candidiasis and significantly increased the accumulation of dihydrosphingosine by decreasing its release. However, G158E mutant didn't affect drug therapeutic efficacy in vivo and dihydrosphingosine transport in C. albicans. G234 of Rta2p in C. albicans is crucial in calcineurin-mediated fluconazole resistance and dihydrosphingosine transport. PMID:26220356

  19. Mutation of G234 amino acid residue in candida albicans drug-resistance-related protein Rta2p is associated with fluconazole resistance and dihydrosphingosine transport.

    Science.gov (United States)

    Zhang, Shi-Qun; Miao, Qi; Li, Li-Ping; Zhang, Lu-Lu; Yan, Lan; Jia, Yu; Cao, Yong-Bing; Jiang, Yuan-Ying

    2015-01-01

    Widespread and repeated use of azoles has led to the rapid development of drug resistance in Candida albicans. Our previous study found Rta2p, a membrane protein with 7 transmembrane domains, was involved in calcineurin-mediated azole resistance and sphingoid long-chain base release in C. albicans. Conserved amino acids in the transmembrane domain of Rta2p were subjected to site-directed mutagenesis. The sensitivity of C. albicans to fluconazole in vitro was examined by minimum inhibitory concentration and killing assay, and the therapeutic efficacy of fluconazole in vivo was performed by systemic mice candidiasis model. Furthermore, dihydrosphingosine transport activity was detected by NBD labeled D-erythro-dihydrosphingosine uptake and release assay, and the sensitivity to sphingolipid biosynthesis inhibitors. We successfully constructed 14 mutant strains of Rta2p, screened them by minimum inhibitory concentration and found Ca(2+) did not completely induce fluconazole resistance with G158E and G234S mutations. Furthermore, we confirmed that G234S mutant enhanced the therapeutic efficacy of fluconazole against systemic candidiasis and significantly increased the accumulation of dihydrosphingosine by decreasing its release. However, G158E mutant didn't affect drug therapeutic efficacy in vivo and dihydrosphingosine transport in C. albicans. G234 of Rta2p in C. albicans is crucial in calcineurin-mediated fluconazole resistance and dihydrosphingosine transport.

  20. [Investigation of mutations in transcription factors of efflux pump genes in fluconazole-resistant Candida albicans strains overexpressing the efflux pumps].

    Science.gov (United States)

    Kalkandelen, Kemal Turan; Doluca Dereli, Mine

    2015-10-01

    In recent years, a significant rise in the number of immunocompromised patients have been observed due to cancer chemotherapy, organ transplantation and HIV infection. As a result of this, the frequency of Candida albicans infections in the clinics have been increased. Fluconazole, as being a well tolerated, easy to use drug with minor side effects, is often the first choice antifungal agent for this patient group, both for therapy and prophylaxis. Especially the long-term use of this drug, causes the selection of resistant strains and leads to the development of fluconazole resistance. The most frequently observed resistance mechanism against fluconazole in C.albicans strains is the transportation of the drug out of the cell via efflux pumps. The efflux pumps mainly involved are Cdr1, Cdr2 ve Mdr1 encoded by CDR1, CDR2 and MDR1 genes. It has been shown that, the overexpression of these efflux pump genes was caused by functional mutations in TAC1 and MRR1 genes which encode the transcription factors Tac1p and Mrr1p. This study was aimed to analyze TAC1 and MRR1 genes of 15 C.albicans strains which consist of six fluconazole-susceptible, four susceptible with trailing effect and five fluconazole-resistant isolates plus one resistant strain (DSY292), known to overexpress Mdr1 efflux pump due to P683H mutation in MRR1 gene and one fluconazole-sensitive ATCC 14053 C.albicans strain in terms of mutations with polymerase chain reaction and sequence analysis. Two of the fluconazole-resistant isolates which had overexpression of Cdr1 and Cdr2 pumps known to have overexpression of TAC1 gene, revealed R673Q and A736V mutations. A P683H point mutation, that overexpressed the Mdr1 pump was detected in a fluconazole-resistant strain, which was known to cause MRR1 overexpression. In conclusion, mutations in the transcription factors of the efflux pump genes may play an important role in the resistance against fluconazole among our selected C.albicans strains.

  1. Sex differences in apolipoprotein A1 and nevirapine-induced toxicity

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    Aline Marinho

    2014-11-01

    Full Text Available Nevirapine (NVP is associated with severe liver and skin toxicity through sulfotransferase (SULT bioactivation of the phase I metabolite 12-hydroxy-NVP [1–3]. The female sex, a well-known risk factor for NVP-induced toxicity, is associated with higher SULT expression (4 and lower plasma levels of 12-hydroxy-NVP [3]. Interestingly, apolipoprotein A1 (ApoA1 increases SULT2B1 activity and ApoA1 synthesis is increased by NVP [5, 6]. Herein, we explore the effect of ApoA1 levels on NVP metabolism and liver function. The study protocol was firstly approved by the hospitals’ Ethics Committees. All included individuals were HIV-infected patients treated with NVP for at least one month. The plasma concentrations of NVP and its phase I metabolites were quantified by HPLC [7]. ApoA1 levels were assessed by an immunoturbidimetric assay. Forty-nine HIV-infected patients on NVP were included (53% men, 59% Caucasian. NVP plasma levels were correlated with HDL-cholesterol (Spearman r=0.2631; p=0.0441 and ApoA1 (Spearman r=0.3907; p=0.0115. Women had higher ApoA1 levels than men (Student's t Test; p=0.0051. In both sexes, 12-hydroxy-NVP levels were negatively correlated with ApoA1 (male: Spearman r=−0.3810; p=0.0499 female: Spearman r=−0.5944; p=0.0415. In men, ApoA1 was positively correlated with aspartate aminotransferase (AST, Spearman r=0.5507; p=0.0413, while in women ApoA1 was associated (Spearman r=0.6408; p=0.0056 with alanine aminotransferase (ALT. These results show sex differences in NVP-induced ApoA1 synthesis. The higher ApoA1 levels in women might stabilize SULT2B1 [6]. This would explain the lower levels of 12-hydroxy-NVP [3] and the higher hepatotoxicity found in women, due to increased sulfonation of this metabolite. These data support a role for ApoA1 in the sex dimorphic mechanism leading to NVP-induced toxicity.

  2. Potent Synergy between Spirocyclic Pyrrolidinoindolinones and Fluconazole against Candida albicans.

    Science.gov (United States)

    Premachandra, Ilandari Dewage Udara Anulal; Scott, Kevin A; Shen, Chengtian; Wang, Fuqiang; Lane, Shelley; Liu, Haoping; Van Vranken, David L

    2015-10-01

    A spiroindolinone, (1S,3R,3aR,6aS)-1-benzyl-6'-chloro-5-(4-fluorophenyl)-7'-methylspiro[1,2,3a,6a-tetrahydropyrrolo[3,4-c]pyrrole-3,3'-1H-indole]-2',4,6-trione, was previously reported to enhance the antifungal effect of fluconazole against Candida albicans. A diastereomer of this compound was synthesized, along with various analogues. Many of the compounds were shown to enhance the antifungal effect of fluconazole against C. albicans, some with exquisite potency. One spirocyclic piperazine derivative, which we have named synazo-1, was found to enhance the effect of fluconazole with an EC50 value of 300 pM against a susceptible strain of C. albicans and going as low as 2 nM against some resistant strains. Synazo-1 exhibits true synergy with fluconazole, with an FIC index below 0.5 in the strains tested. Synazo-1 exhibited low toxicity in mammalian cells relative to the concentrations required for antifungal synergy.

  3. [New developments in antifungal therapy: fluconazole, itraconazole, voriconazole, caspofungin

    NARCIS (Netherlands)

    Wout, J.W. van 't; Kuijper, E.J.; Verweij, P.E.; Kullberg, B.J.

    2004-01-01

    The azole antifungal voriconazole and the echinocandin caspofungin have recently become available for the treatment of invasive mycoses. Fluconazole remains the drug of choice for candidemia, except for infections with one of the resistent species such as Candida krusei and some strains of Candida g

  4. Myopati hos en patient i behandling med simvastatin og fluconazol

    DEFF Research Database (Denmark)

    Pedersen, Jens Kristian; Lydolph, Magnus Christian; Somnier, Finn

    2016-01-01

    A 69-year-old female was admitted due to progressive loss of muscle strength following addition of fluconazole to long-term simvastatin treatment. Rhabdomyolysis was suspected and both drugs were discontinued. Forced diuresis was initiated together with a short course of prednisolone. After 21...

  5. Use of fluconazole in daily practice: still room for improvement.

    NARCIS (Netherlands)

    Natsch, S.S.; Steeghs, M.H.M.; Hekster, Y.A.; Meis, J.F.G.M.; Meer, J.W.M. van der; Kullberg, B.J.

    2001-01-01

    One hundred courses of fluconazole treatment in a university hospital and 81 courses in a non-university teaching hospital have been analysed in a prospective audit to evaluate prescribing practices. The quality of treatments was assessed by an infectious disease specialist and a pharmacist accordin

  6. Clinical Pharmacology of Fluconazole in Neonates: Effects and Pharmacokinetics

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    Gian Maria Pacifici

    2016-03-01

    Full Text Available Fluconazole is commonly used both to prevent and to treat invasive neonatal Candida albicans infection. This drug is a potent, selective, triazole inhibitor of the fungal enzymes involved in ergosterol synthesis. It is largely excreted unchanged in the urine. In infants with a birth weight

  7. Plasma nevirapine concentrations predict virological and adherence failure in Kenyan HIV-1 infected patients with extensive antiretroviral treatment exposure

    Science.gov (United States)

    Kimulwo, Maureen J.; Okendo, Javan; Aman, Rashid A.; Ogutu, Bernhards R.; Kokwaro, Gilbert O.; Ochieng, Dorothy J.; Muigai, Anne W. T.; Oloo, Florence A.

    2017-01-01

    Treatment failure is a key challenge in the management of HIV-1 infection. We conducted a mixed-model survey of plasma nevirapine (NVP) concentrations (cNVP) and viral load in order to examine associations with treatment and adherence outcomes among Kenyan patients on prolonged antiretroviral therapy (ART). Blood plasma was collected at 1, 4 and 24 hours post-ART dosing from 58 subjects receiving NVP-containing ART and used to determine cNVP and viral load (VL). Median duration of treatment was 42 (range, 12–156) months, and 25 (43.1%) of the patients had virologic failure (VF). cNVP was significantly lower for VF than non- VF at 1hr (mean, 2,111ng/ml vs. 3,432ng/ml, p = 0.003) and at 4hr (mean 1,625ng/ml vs. 3,999ng/ml, p = 0.001) but not at 24hr post-ART dosing. Up to 53.4%, 24.1% and 22.4% of the subjects had good, fair and poor adherence respectively. cNVP levels peaked and were > = 3μg.ml at 4 hours in a majority of patients with good adherence and those without VF. Using a threshold of 3μg/ml for optimal therapeutic nevirapine level, 74% (43/58), 65.5% (38/58) and 86% (50/58) of all patients had sub-therapeutic cNVP at 1, 4 and 24 hours respectively. cNVP at 4 hours was associated with adherence (p = 0.05) and virologic VF (p = 0.002) in a chi-square test. These mean cNVP levels differed significantly in non-parametric tests between adherence categories at 1hr (p = 0.005) and 4hrs (p = 0.01) and between ART regimen categories at 1hr (p = 0.004) and 4hrs (p<0.0001). Moreover, cNVP levels correlated inversely with VL (p< = 0.006) and positively with adherence behavior. In multivariate tests, increased early peak NVP (cNVP4) was independently predictive of lower VL (p = 0.002), while delayed high NVP peak (cNVP24) was consistent with increased VL (p = 0.033). These data strongly assert the need to integrate plasma concentrations of NVP and that of other ART drugs into routine ART management of HIV-1 patients. PMID:28235021

  8. Electrochemical studies of nevirapine, an anti-HIV drug, and its assay in tablets and biological samples

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    JALDAPPAGARI SEETHARAMAPPA

    2012-06-01

    Full Text Available The electrochemical oxidation of nevirapine, an anti-HIV drug, at a glassy carbon electrode has been studied by voltammetric techniques. Nevirapine showed one well defined irreversible oxidation peak with a potential of 0.749 V in phosphate buffer at pH 10. The effects of different electrolytes, pH and scan rate on the electrochemical behaviour of nevira¬pine were examined to determine the optimum reaction conditions. The oxidation peak current was found to vary linearly with the concentration of nevirapine in the range of 5.0 – 350 µM. The limit of detection and limit of quantification values were calculated and found to be 1.026 µM and 3.420 µM, respectively. The low relative standard deviation values of inter-day and intra-day assays highlighted the good reproducibility of the proposed m¬ethod for assay of nevirapine. Further, a sensitive and accurate differential pulse voltammetric method was developed for the determination of nevirapine concentrations in pharma¬ceutical formulations.

  9. The Effect on mortality of fluconazole or echinocandins treatment in candidemia in internal medicine wards [corrected].

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    Francesco G De Rosa

    Full Text Available The incidence of candidemia has increased over the past two decades, with an increased number of cases in Internal Medicine and a prevalence ranging from 24% to 57%. This single-center retrospective study was performed to evaluate the epidemiology and the risk factors associated with mortality of candidemia in patients admitted to Internal Medicine wards (IMWs of the City of Health and Sciences, Molinette Hospital, Turin, from January 2004 to December 2012. For each patient, demographic, clinical and microbiological data were collected. A case of candidemia was defined as a patient with at least one blood culture positive for Candida spp. Amongst 670 episodes of candidemia, 274 (41% episodes occurred in IMWs. The mortality was 39% and was associated at multivariate analysis with sepsis, cirrhosis and neurologic diseases, whilst removal of central venous catheter ≤48h was significantly associated with survival. In the 77 patients treated with early antifungal therapy the mortality was 29% and was not significantly different with caspofungin or fluconazole, whilst in patients with definitive therapy the mortality was significantly lower with echinocandins compared to fluconazole (11.7% Vs. 39%; p=0.0289, a finding confirmed by multivariate analysis. The mortality was significantly associated with sepsis, cirrhosis and neurologic diseases, whilst CVC removal ≤48h was associated with survival. In patients with early therapy, fluconazole or caspofungin were equally effective. However, echinocandins were significantly more effective as definitive treatment, a finding not explained by differences in treatment delays. Further studies are needed to understand the full potential of these different therapeutic strategies in IMWs.

  10. A novel voltammetric sensor for nevirapine, based on modified graphite electrode by MWCNs/poly(methylene blue)/gold nanoparticle.

    Science.gov (United States)

    Gholivand, Mohammad Bagher; Ahmadi, Elahe; Haseli, Mozhdeh

    2017-06-15

    In the present study, a graphite electrode (GE) modified by conductive film (containing functionalized multi-walled carbon nanotubes (f-MWCNTs), poly methylene blue p(MB) and gold nanoparticles (AuNPs)) was introduced for determination of nevirapine (NVP) as an anti-HIV drug by applying the differential pulse anodic stripping voltammetry (DPASV) technique. Modification of the electrode was investigated by scanning electron microscopy (SEM) and impedance electrochemical spectroscopy (EIS). All electrochemical effective parameters on detection of NVP were optimized and the oxidation peak current of drug was used for its monitoring. The obtained results confirmed that the oxidation peak currents increased linearly by increasing in NVP concentrations in the range of 0.1-50 μM and a detection limit of 53 nM was achieved. The proposed sensor (AuNPs/p(MB)/f-MWCNTs/GE) was successfully applied for the determination of NVP in blood serum and pharmaceutical samples. It revealed the excellent stability, repeatability and reproducibility as well. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Exposure to fluconazole and risk of congenital malformations in the offspring: A systematic review and meta-analysis.

    Science.gov (United States)

    Alsaad, Abdulaziz M S; Kaplan, Yusuf C; Koren, Gideon

    2015-04-01

    Vulvovaginal candidiasis (VVC) affects up to 75% of women at least once during their lifetime, mostly during the reproductive age, and recurrence rate is about 50%. Because half of all pregnancies are unplanned and pregnant women have an increased risk of VVC recurrence, the likelihood of inadvertently being exposed to fluconazole in pregnancy is increased. Thus, we aimed to examine the risk of congenital malformations in the offspring of women exposed to fluconazole in the first trimester of pregnancy. The rate for overall malformations was 1.10 (95% CI 0.98-1.25), for heart defect was 1.29 (95% CI 1.05-1.58), for craniofacial defects was 1.25 (95% CI 0.88-1.77), and for limb/musculoskeletal defects was 0.82 (95% CI 0.59-1.13). In conclusion, the use of fluconazole in the first trimester does not appear to increase the overall risk for congennital malformations. More studies are needed to address the potential increased rate of heart defects.

  12. Treatment with pCramoll Alone and in Combination with Fluconazole Provides Therapeutic Benefits in C. gattii Infected Mice

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    Jannyson J. Jandú

    2017-05-01

    Full Text Available Cryptococcus gattii is one of the main causative agents of cryptococcosis in immunocompetent individuals. Treatment of the infection is based on the use of antimycotics, however, the toxicity of these drugs and the increase of drug-resistant strains have driven the search for more effective and less toxic therapies for cryptococcosis. pCramoll are isolectins purified from seeds of Cratylia mollis, a native forage plant from Brazil, which has become a versatile tool for biomedical application. We evaluated the effect of pCramoll alone and in combination with fluconazole for the treatment of mice infected with C. gatti. pCramoll alone or in combination with fluconazole increased the survival, reduced the morbidity and improved mice behavior i.e., neuropsychiatric state, motor behavior, autonomic function, muscle tone and strength and reflex/sensory function. These results were associated with (i decreased pulmonary and cerebral fungal burden and (ii increased inflammatory infiltrate and modulatory of IFNγ, IL-6, IL-10, and IL-17A cytokines in mice treated with pCramoll. Indeed, bone marrow-derived macrophages pulsed with pCramoll had increased ability to engulf C. gattii, with an enhanced production of reactive oxygen species and decrease of intracellular fungal proliferation. These findings point toward the use of pCramoll in combination with fluconazole as a viable, alternative therapy for cryptococcosis management.

  13. Sensitization of Candida albicans biofilms to fluconazole by terpenoids of plant origin.

    Science.gov (United States)

    Doke, Sonali Kashinath; Raut, Jayant Shankar; Dhawale, Shashikant; Karuppayil, Sankunny Mohan

    2014-01-01

    Infections associated with the biofilms of Candida albicans are a challenge to antifungal treatment. Combinatorial therapy involving plant molecules with antifungal drugs would be an effective complementary approach against drug-resistant Candida biofilms. The aim of this study was to evaluate the efficacy of three bioactive terpenoids (carvacrol, eugenol and thymol) in combination with fluconazole against planktonic cells, biofilm development and mature biofilms of C. albicans. Activities of the selected molecules were tested using a microplate-based methodology, while their combinations with fluconazole were performed in a checkerboard format. Biofilms were quantitated by XTT-metabolic assay and confirmed by microscopic observations. Combinations of carvacrol and eugenol with fluconazole were found synergistic against planktonic growth of C. albicans, while that of thymol with fluconazole did not have any interaction. Biofilm development and mature biofilms were highly resistant to fluconazole, but susceptible to three terpenoids. Sensitization of cells by sub-inhibitory concentrations of carvacrol and eugenol resulted in prevention of biofilm formation at low fluconazole concentrations, i.e. 0.032 and 0.002 mg ml(-1), respectively. Addition of thymol could not potentiate activity of fluconazole against biofilm formation by C. albicans. Fractional inhibitory concentration indices (FICI) for carvacrol-fluconazole and eugenol-fluconazole combinations for biofilm formation were 0.311 and 0.25, respectively. The FICI value of 1.003 indicated a status of indifference for the combination of thymol and fluconazole against biofilm formation. Eugenol and thymol combinations with fluconazole did not have useful interaction against mature biofilms of C. albicans, but the presence of 0.5 mg ml(-1) of carvacrol caused inhibition of mature biofilms at a significantly low concentration (i.e. 0.032 mg ml(-1)) of fluconazole. The study indicated that carvacrol and eugenol

  14. Effects of short-course zidovudine on the selection of nevirapine-resistant HIV-1 in women taking single-dose nevirapine.

    Science.gov (United States)

    Micek, Mark A; Blanco, Ana Judith; Carlsson, Jacquelyn; Beck, Ingrid A; Dross, Sandra; Matunha, Laurinda; Seidel, Kristy; Montoya, Pablo; Gantt, Soren; Matediana, Eduardo; Jamisse, Lilia; Gloyd, Stephen; Frenkel, Lisa M

    2012-06-15

    Single-dose nevirapine (sdNVP) given to prevent mother-to-child-transmission of HIV-1 selects NVP-resistance. Short-course zidovudine (ZDV) was hypothesized to lower rates of NVP-resistance. HIV-1 infected pregnant women administered sdNVP with or without short-course ZDV were assessed for HIV-1 mutations (K103N, Y181C, G190A, and V106M) prior to delivery and postpartum. Postpartum NVP-resistance was lower among 31 taking ZDV+sdNVP compared to 33 taking only sdNVP (35.5% vs. 72.7%; χ2 P = .003). NVP mutants decayed to <2% in 24/35 (68.6%) at a median 6 months postpartum, with no differences based on ZDV use (logrank P = .99). Short-course ZDV was associated with reduced NVP-resistance mutations among women taking sdNVP.

  15. Antifungal effect of Trachyspermum ammi against susceptible and fluconazole-resistant strains of Candida albicans.

    Science.gov (United States)

    Sharifzadeh, A; Khosravi, A R; Shokri, H; Sharafi, G

    2015-06-01

    Trachyspermum ammi (T. ammi) has been known as having many therapeutic properties and its antimicrobial activity has currently received a renewed interest. This study aimed to verify the effectiveness of T. ammi essential oil to inhibit the growth of Candida albicans (C. albicans) strains isolated from HIV(+) patients with oropharyngeal candidiasis (OPC). The essential oil was obtained by hydrodistillation in a Clevenger apparatus and analyzed by gas chromatography. Susceptibility tests were expressed as inhibition zone by the disk diffusion method and minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) by the broth microdilution method. Thymol (63.4%), p-cymene (19%) and γ-terpinen (16.9%) were found as the most abundant constituents. The disk diffusion results revealed that 67% of oral C. albicans isolates were susceptible, 9% susceptible-dose dependent and 24% resistant to fluconazole. In the broth microdilution method, 68% of isolates were susceptible, 5% susceptible-dose dependent and 27% resistant to fluconazole. The increase in concentration led to a significant reduction in yeasts that were growing in exponential phase. In addition, with increasing in T. ammi oil concentration, the time of remaining cells in lag phase was significantly increased. This study showed that all clinical C. albicans isolates were susceptible to T. ammi essential oil, indicating a significant reduction in the yeast growth in exponential phase. Copyright © 2015. Published by Elsevier Masson SAS.

  16. Pharmacokinetics of fluconazole in cerebrospinal fluid and serum of rabbits: validation of an animal model used to measure drug concentrations in cerebrospinal fluid.

    Science.gov (United States)

    Madu, A; Cioffe, C; Mian, U; Burroughs, M; Tuomanen, E; Mayers, M; Schwartz, E; Miller, M

    1994-09-01

    Complete concentration-time data describing the pharmacokinetics of fluconazole in the cerebrospinal fluid (CSF) following a single dose are not available for humans or animals. We studied the pharmacokinetics of fluconazole with an indwelling intracisternal needle as described by R.G. Dacey and M.A. Sande (Antimicrob. Agents Chemother. 6:437-441, 1974). To determine whether the presence of an intracisternal needle alters pharmacokinetics in the CSF, we validated this model with uninfected rabbits by measuring pharmacokinetic constants following direct intracisternal and intravenous administration of fluconazole. Following direct injection, there was no alteration of elimination rates in the CSF with increasing sample number or time. Following intravenous administration, the penetration and kinetic constants were the same in individual animals from which multiple CSF samples were obtained as in a composite subject constructed by pooling virgin samples from different animals. The presence of the intracisternal needle did not alter CSF chemistry or leukocyte counts, and erythrocyte contamination was < 0.001%. While drug concentrations were measured by a microbiological assay, we also compared the sensitivity and reproducibility of a high-performance liquid chromatography (HPLC) assay with those of the microbiological assay. Following a single intravenous dose, the maximum concentration of the drug in serum, the time to maximum concentration of the drug in serum, the terminal elimination half-life in the CSF, and the percent penetration by fluconazole were 6.12 micrograms/ml, 1 h, 9.0 h, and 84.3%, respectively. We conclude that the sampling of CSF via an indwelling needle does not alter fluconazole pharmacokinetics, cause inflammation, or alter chemical parameters; that the microbiological assay is at least equivalent in sensitivity and reproducibility to the HPLC assay; and that robust parameters describing the pharmacokinetics of fluconazole are possible with this

  17. Detection of HIV drug resistance mutations in pregnant women receiving single dose Nevirapine in south India

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    Mini S Jacob

    2011-01-01

    Full Text Available Background: Single dose of Nevirapine to prevent mother to child transmission of HIV is the commonest preventive regimen in resource-limited countries. Objectives: The objective of this study was to detect drug-resistant virus after single dose of Nevirapine (sdNVP provided to delivering HIV seropositive (HIV+ve women and to evaluate the time taken for its decay. Results: Of the 36 consenting HIV+ve pregnant women enrolled into the study, the mean hemoglobin and total lymphocyte counts were 10.8 g/dl and 1843 cells/mm 3 , respectively. Mean CD4 counts in 64% of women was 363 cells/mm 3 and mean viral load for 16/36 women was 28,143 copies/ml of plasma. Nevirapine-resistance mutations were detected in 28% of women at delivery; using OLA (Oligonucleotide Ligation Assay. K103N mutations were seen in 19.4% of women while the Y181C mutation was seen in 5%. Both the mutations were detected in 2.7% of women. Sequential blood samples collected at delivery, 7-10 days, 6 weeks, 4 months, 6 months and one year postpartum showed that 81% of K103N mutations and 66.7% of Y181C mutations were detected at 6 weeks postpartum . Wild-type virus had replaced the mutants by one year postpartum in all women except one. Conclusion : These observations are relevant for future treatment with antiretroviral therapy in these women for their HIV disease.

  18. In vitro antifungal activity of fluconazole and voriconazole against non-Candida yeasts and yeast-like fungi clinical isolates.

    Science.gov (United States)

    Mandras, Narcisa; Roana, Janira; Scalas, Daniela; Fucale, Giacomo; Allizond, Valeria; Banche, Giuliana; Barbui, Anna; Li Vigni, Nicolò; Newell, Vance A; Cuffini, Anna Maria; Tullio, Vivian

    2015-10-01

    The risk of opportunistic infections caused by non-Candida yeasts and yeast-like fungi is increasingly common, mainly in immunocompromised patients. Appropriate first-line therapy has not been defined and standardized, mainly due to the low number of cases reported. To improve empirical treatment guidelines, we describe the susceptibility profile to fluconazole and voriconazole of 176 non-Candida yeasts and yeast-like fungi collected from hospitals in Piedmont, North West Italy from January 2009 to December 2013. The results showed that most isolates are susceptible to voriconazole (94%), but less susceptible to fluconazole (78%), suggesting that voriconazole could be used as first-line therapy in infections caused by these fungi.

  19. Nevirapine uptake into the central nervous system of the Guinea pig: an in situ brain perfusion study.

    Science.gov (United States)

    Gibbs, J E; Gaffen, Z; Thomas, S A

    2006-05-01

    The presence of human immunodeficiency virus (HIV) in the central nervous system (CNS) is associated with the development of HIV-1-associated dementia (HAD), a major cause of HIV-related mortality. To eradicate HIV in the CNS, anti-HIV drugs need to reach the brain and cerebrospinal fluid (CSF) in therapeutic concentrations. This involves passage through the blood-brain and blood-CSF barriers. Using a well established guinea pig in situ brain perfusion model, this study investigated whether nevirapine [6H-dipyrido(3,2-b:2',3'-e)(1,4)diazepin-6-one,11-cyclopropyl-5,11-dihydro-4-methyl], a non-nucleoside reverse transcriptase inhibitor (NNRTI), could effectively accumulate in the CNS. [(3)H]Nevirapine was coperfused with [(14)C]mannitol (a vascular/paracellular permeability marker) through the carotid arteries for up to 30 min, and accumulation in the brain, CSF, and choroid plexus was measured. [(3)H]Nevirapine uptake into the cerebrum was greater than uptake of [(14)C]mannitol, indicating significant passage across the blood-brain barrier and accumulation into the brain (this was further confirmed with capillary depletion and high-performance liquid chromatography analyses). Likewise, [(3)H]nevirapine showed a great ability to cross the blood-CSF barrier and accumulate in the CSF, compared with [(14)C]mannitol. The CNS accumulation of [(3)H]nevirapine was unaffected by 100 muM nevirapine, suggesting that passage across the blood-brain barrier can occur by diffusion. Furthermore, coperfusion with 100 muM efavirenz [2H-3,1-benzoxazin-2-one, 6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-, (4S)-; another NNRTI] did not significantly alter CNS accumulation of [(3)H]nevirapine, indicating that the efficacy of nevirapine in the CNS would not be altered by the addition of this drug to a combination therapy. Together, these data indicate that this anti-HIV drug should be beneficial in the eradication of HIV within the CNS and the subsequent treatment of

  20. Coverage of nevirapine-based services to prevent mother-to-child HIV transmission in 4 African countries.

    Science.gov (United States)

    Stringer, Elizabeth M; Ekouevi, Didier K; Coetzee, David; Tih, Pius M; Creek, Tracy L; Stinson, Kathryn; Giganti, Mark J; Welty, Thomas K; Chintu, Namwinga; Chi, Benjamin H; Wilfert, Catherine M; Shaffer, Nathan; Dabis, Francois; Stringer, Jeffrey S A

    2010-07-21

    Few studies have objectively evaluated the coverage of services to prevent transmission of human immunodeficiency virus (HIV) from mother to child. To measure the coverage of services to prevent mother-to-child HIV transmission in 4 African countries. Cross-sectional surveillance study of mother-infant pairs using umbilical cord blood samples collected between June 10, 2007, and October 30, 2008, from 43 randomly selected facilities (grouped as 25 service clusters) providing delivery services in Cameroon, Côte d'Ivoire, South Africa, and Zambia. All sites used at least single-dose nevirapine to prevent mother-to-child HIV transmission and some sites used additional prophylaxis drugs. Population nevirapine coverage, defined as the proportion of HIV-exposed infants in the sample with both maternal nevirapine ingestion (confirmed by cord blood chromatography) and infant nevirapine ingestion (confirmed by direct observation). A total of 27,893 cord blood specimens were tested, of which 3324 were HIV seropositive (12%). Complete data for cord blood nevirapine results were available on 3196 HIV-seropositive mother-infant pairs. Nevirapine coverage varied significantly by site (range: 0%-82%). Adjusted for country, the overall coverage estimate was 51% (95% confidence interval [CI], 49%-53%). In multivariable analysis, failed coverage of nevirapine-based services was significantly associated with maternal age younger than 20 years (adjusted odds ratio [AOR], 1.44; 95% CI, 1.18-1.76) and maternal age between 20 and 25 years (AOR, 1.28; 95% CI, 1.07-1.54) vs maternal age of older than 30 years; 1 or fewer antenatal care visits (AOR, 2.91; 95% CI, 2.40-3.54), 2 or 3 antenatal care visits (AOR, 1.93; 95% CI, 1.60-2.33), and 4 or 5 antenatal care visits (AOR, 1.56; 95% CI, 1.34-1.80) vs 6 or more antenatal care visits; vaginal delivery (AOR, 1.22; 95% CI, 1.03-1.44) vs cesarean delivery; and infant birth weight of less than 2500 g (AOR, 1.34; 95% CI, 1.11-1.62) vs birth

  1. Co-crystals of the antiretroviral nevirapine: crystal structures, thermal analysis and dissolution behaviour

    OpenAIRE

    Aucamp, Marique Elizabeth; Engel, Emile; Liebenberg, Wilna; Stieger, Nicole; Caira, Mino R.; Susan A. Bourne

    2012-01-01

    Synthesis and physicochemical characterization of co-crystals of the antiretroviral drug nevirapine (NV) with the pharmaceutically acceptable co-formers saccharin, rac-tartaric acid, maleic acid, glutaric acid and salicylic acid are reported for the first time. The respective stoichiometric NV : co-former ratios are 2 : 1, 1 : 1, 1 : 1, 1 : 1 and 2 : 1. In the 1 : 1 co-crystals, the predicted R22(8) NV(amide)–carboxylic acid supramolecular synthon occurs, whereas in the 2 : 1 species, the co-...

  2. The Possible Efficacy of Artichoke in Fluconazole Related Hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Hüseyin Kurt

    2014-01-01

    Full Text Available Although fluconazole related hepatotoxicity (FRH is rare, mortal acute hepatic necrosis and jaundice were reported in immunocompromised states such as acquired immunodeficiency syndrome (AIDS and bone marrow transplant (BMT. We present a case of a patient with multiple sclerosis who developed hepatotoxicity with the use of a single 150 mg fluconazole tablet for fungal vaginitis, 10 days after methylprednisolone pulse treatment. Our patient’s alanine aminotransferase (ALT and aspartate aminotransferase (AST levels were decreased, 1200 U/L and 800 U/L, respectively, and bilirubin levels were consistent at 37 mg/dL. Artichoke which has anticholestatic and antioxidant properties was used by our patient. She consumed a 30 mg artichoke leaf extract tea 3 times a day. The bilirubin levels significantly declined at the end of the first week and all liver function tests were normalized within 2 months.

  3. Treatment of experimental cryptococcosis with SCH 39304 and fluconazole.

    Science.gov (United States)

    Negroni, R; Costa, M R; Finquelievich, J L; Iovannitti, C; Agorio, I; Tiraboschi, I N; Loebenberg, D

    1991-01-01

    The efficacy of two triazoles, SCH 39304 and fluconazole, in the treatment of disseminated cryptococcosis in Wistar rats was determined. A total of 160 rats were inoculated intracardiacally with 2 x 10(5) cells of Cryptococcus neoformans. Both drugs were administered by gavage once daily, at three doses (8, 16, and 32 mg/kg/day). Two treatment schedules were followed: (i) treatment began 1 week after infection and continued for 3 weeks and (ii) prophylaxis treatment began 3 days before infection and continued an additional 3 weeks. Evaluation was based on (i) macroscopic examination of lungs, (ii) microscopic examination of brains and lungs, (iii) histopathology of brains and lungs, and (iv) determination of number of CFU in brains. The number of CFU was the best measure of activity. SCH 39304 was more active than fluconazole in both regimens, and, prophylactically, SCH 39304 was able to achieve biological cures. PMID:1929309

  4. Caspofungin versus fluconazole as prophylaxis of invasive fungal infection in high-risk liver transplantation recipients: A propensity score analysis.

    Science.gov (United States)

    Fortún, Jesús; Muriel, Alfonso; Martín-Dávila, Pilar; Montejo, Miguel; Len, Oscar; Torre-Cisneros, Julian; Carratalá, Jordi; Muñoz, Patricia; Fariñas, Carmen; Moreno, Asunción; Fresco, Gema; Goikoetxea, Josune; Gavaldá, Joan; Pozo, Juan Carlos; Bodro, Marta; Vena, Antonio; Casafont, Fernando; Cervera, Carlos; Silva, José Tiago; Aguado, José M

    2016-04-01

    Targeted prophylaxis has proven to be an efficient strategy in liver transplantation recipients (LTRs). The aim of this study was to compare the effectiveness and safety of caspofungin with that of fluconazole in high-risk (HR) LTRs. Caspofungin and fluconazole were compared in a multicenter, retrospective, cohort study in HR-LTRs in Spain. Outcomes were assessed at 180 days after transplantation. A propensity score approach was applied. During the study period (2005-2012), we analyzed 195 HR-LTRs from 9 hospitals. By type of prophylaxis, 97 patients received caspofungin and 98 received fluconazole. Of a total of 17 (8.7%) global invasive fungal infections (IFIs), breakthrough IFIs accounted for 11 (5.6%) and invasive aspergillosis (IA) accounted for 6 (3.1%). By univariate analysis, no differences were observed in the prevention of global IFIs. However, caspofungin was associated with a significant reduction in the rate of breakthrough IFIs (2.1% versus 9.2%, P = 0.04). In patients requiring dialysis (n = 62), caspofungin significantly reduced the frequency of breakthrough IFIs (P = 0.03). The propensity score analysis confirmed a significant reduction in the frequency of IA in patients receiving caspofungin (absolute risk reduction, 0.06; 95% confidence interval [CI], 0.001-0.11; P = 0.044). Linear regression analysis revealed a significant decrease in blood alanine aminotransferase levels and a significant increase in bilirubin levels after administration of caspofungin. Caspofungin and fluconazole have similar efficacy for the prevention of global IFIs in HR-LTRs in this observational, multicenter cohort study. However, caspofungin was associated with a significant reduction of breakthrough IFIs and, after adjusting for confounders, caspofungin was associated with a lower rate of IA. This benefit is probably more favorable in patients on dialysis. Caspofungin is safe in HR-LTRs, although bilirubin levels may be increased.

  5. Sensibilidad al fluconazol de aislamientos de Trichophyton rubrum

    Directory of Open Access Journals (Sweden)

    Norma T Gross-Martínez

    2014-03-01

    Full Text Available Antecedentes: Trichophyton rubrum es el dermatofito más frecuentemente aislado a nivel mundial y afecta principalmente: piel glabra, uñas de las manos y de los pies. El fluconazol es utilizado con frecuencia para el tratamiento de las onicomicosis en nuestra población, por lo que el objetivo de la presente investigación fue estudiar la sensibilidad a este antifúngico, de aislamientos costarricenses de T. rubrum. Métodos: se investigó la sensibilidad in vitro al fluconazol de 80 aislamientos de T. rubrum, obtenidos de muestras de piel y sus anexos. El método utilizado fue el de microdilución M-38A, descrito por el “National Committee for Clinical Laboratory Standards”. Las diluciones finales del fluconazol fueron de 0,25 a 128 μg/ml. Resultados: la mayoría de los aislamientos fueron obtenidos de uñas de los pies (68,75%. El 86,25% de los aislamientos analizados presentaron una concentración mínima inhibitoria entre 0,25-8 μg/ml, el 8,75% entre 16-32 μg/ml y un 5% > 64 μg/ml. De estos aislamientos resistentes, dos fueron de uñas de los pies y dos de plantas de pie. Conclusión: debido a que la mayoría de los aislamientos de T. rubrum demostraron ser sensibles al fluconazol, solo se recomienda realizar la prueba de sensibilidad a este antifúngico en casos de falla terapéutica, especialmente en pacientes con onicomicosis en la cual el tratamiento es prolongado.

  6. Detection and quantification of fluconazole within Candida glabrata biofilms.

    Science.gov (United States)

    Rodrigues, Célia F; Silva, Sónia; Azeredo, Joana; Henriques, Mariana

    2015-06-01

    Candida infections are often associated with biofilms and consequent high resistance to most common drugs (e.g. azoles). These resistance mechanisms are not only associated with the biofilm yeast physiology, but also with the presence of a diffusional barrier imposed by the biofilm matrix; however, the real biochemical role of the biofilm components remains very unclear. So, in order to further clarify this issue, we intend to determine, for the first time, fluconazole in biofilms within both supernatants and matrices. Candida biofilms were formed in the presence of fluconazole, and it was recovered from both supernatant and matrix cell-free fractions. Then, high-pressure liquid chromatography was used to identify and quantify the amount of drug that was present in the two fractions. Moreover, this study also showed that the presence of fluconazole in both fractions indicated that the drug administrated did not completely reach the cells, so this phenomena can easily be associated with lower biofilm susceptibility, since the drug administered did not completely reach the cells.

  7. Utility of in-house fluconazole disk diffusion susceptibility testing in the treatment of candidemia.

    Science.gov (United States)

    Kubiak, David W; Farmakiotis, Dimitrios; Arons, Viktoria; Hollins, Randy M; Rostas, Sara E; Weiser, Linda M; Baden, Lindsey R; Marty, Francisco M; Koo, Sophia

    2016-03-01

    Among 302 first candidemia episodes, 210 (69.6%) were initially treated with an echinocandin or polyene (E/P) antifungal drug. In 137 (72.5%) patients with fluconazole-susceptible isolates, treatment was changed to fluconazole based on disk diffusion susceptibility testing. Clinical outcomes were not compromised in patients receiving E/P who were de-escalated to fluconazole for treatment of candidemia based on disk diffusion results.

  8. Utility of in-house fluconazole disk diffusion susceptibility testing in the treatment of candidemia

    Science.gov (United States)

    Kubiak, David W.; Farmakiotis, Dimitrios; Arons, Viktoria; Hollins, Randy M.; Rostas, Sara E.; Weiser, Linda M.; Baden, Lindsey R.; Marty, Francisco M.; Koo, Sophia

    2016-01-01

    Among 302 first candidemia episodes, 210 (69.6%) were initially treated with an echinocandin or polyene (E/P) antifungal drug. In 137 (72.5%) patients with fluconazole-susceptible isolates, treatment was changed to fluconazole based on disk diffusion susceptibility testing. Clinical outcomes were not compromised in patients receiving E/P who were de-escalated to fluconazole for treatment of candidemia based on disk diffusion results. PMID:26763713

  9. Extractive Spectrophotometric Determination of Fluconazole by Ion-pair Complex Formation with Bromocresol Green

    Institute of Scientific and Technical Information of China (English)

    JALALI,Fahimeh; RAJABI,Mohammad J.

    2007-01-01

    An extraction-spectrophotometric method for the determination of trace amounts of fluconazole was described.Fluconazole was effectively extracted as a 1 : 1 ion-pair complex with bromocresole green (BCG) at pH 3.0 into chloroform, followed by spectrophotometric determination at 420 nm. Beer's law was obeyed over the range of 4-procedure was applied to the determination of fluconazole in pharmaceutical preparations as well as its recovery from a blood serum sample.

  10. Association phenothiazine and laser on growth of C. tropicalis fluconazole-resistant

    Science.gov (United States)

    Gomes Júnior, Rafael Araújo; de Oliveira, Susana C. P. S.; Monteiro, Juliana S. C.; Santos, Gustavo M. P.; Sampaio, Fernando J. P.; Gesteira, Maria F. M.; Zanin, Fátima A. A.; Brugnera, Aldo; Pinheiro, Antônio Luiz B.; Vannier-Santos, Marcos A.

    2014-02-01

    Candidiasis is caused by Candida species found on the skin, gastrointestinal tract and mucous cavities of the humans and may be acute, chronic, localized or systemic. Alhough C. albicans is the species most often identified as responsible for this type of infection C. Tropicalis has been considered an emerging cause. The effect of the association of phenothiazine - PTZ and laser on fluconazole-resistant C.tropicalis growth was tested. 2.5 x 106 CFU/mL 100mg/mL of phenothiazine with the pre-irradiation time of 10 min were irradiated with laser light (660 nm; 4.8 and 12 J/cm2 (L1 and L2 respectively) 40 mW) followed by incubation in RPMI for 24h. The following conditions were tested: control (control), laser (L1 and L2), phenothiazine (F1 and F2), and PACT (F1L1 and F2L2). Statistically significant diferences were seen between groups (L-F +) and (F + L +) for both conditions of the laser, with a growth inhibition of the yeast around 67 and 51%, respectively, however, when using only the laser there was an increase of 18% in the survival of these cells. PACT's efficacy on fluconazole-resistant C. tropicalis depended on both the time of pre-irradiation and concentration of the PTZ.

  11. Synergistic Interactions of Eugenol-tosylate and Its Congeners with Fluconazole against Candida albicans.

    Science.gov (United States)

    Ahmad, Aijaz; Wani, Mohmmad Younus; Khan, Amber; Manzoor, Nikhat; Molepo, Julitha

    2015-01-01

    We previously reported the antifungal properties of a monoterpene phenol "Eugenol" against different Candida strains and have observed that the addition of methyl group to eugenol drastically increased its antimicrobial potency. Based on the results and the importance of medicinal synthetic chemistry, we synthesized eugenol-tosylate and its congeners (E1-E6) and tested their antifungal activity against different clinical fluconazole (FLC)- susceptible and FLC- resistant C. albicans isolates alone and in combination with FLC by determining fractional inhibitory concentration indices (FICIs) and isobolograms calculated from microdilution assays. Minimum inhibitory concentration (MIC) results confirmed that all the tested C. albicans strains were variably susceptible to the semi-synthetic derivatives E1-E6, with MIC values ranging from 1-62 μg/ml. The test compounds in combination with FLC exhibited either synergy (36%), additive (41%) or indifferent (23%) interactions, however, no antagonistic interactions were observed. The MICs of FLC decreased 2-9 fold when used in combination with the test compounds. Like their precursor eugenol, all the derivatives showed significant impairment of ergosterol biosynthesis in all C. albicans strains coupled with down regulation of the important ergosterol biosynthesis pathway gene-ERG11. The results were further validated by docking studies, which revealed that the inhibitors snugly fitting the active site of the target enzyme, mimicking fluconazole, may well explain their excellent inhibitory activity. Our results suggest that these compounds have a great potential as antifungals, which can be used as chemosensitizing agents with the known antifungal drugs.

  12. Candida albicans biofilm inhibition by synergistic action of terpenes and fluconazole.

    Science.gov (United States)

    Pemmaraju, Suma C; Pruthi, Parul A; Prasad, R; Pruthi, Vikas

    2013-11-01

    The current treatment options for Candida albicans biofilm-device related infections are very scarce due to their intrinsic increased tolerance to antimycotics. The aim of this work was to study synergistic action of terpenes (eugenol, menthol and thymol) with fluconazole (FLA) on C. albicans biofilm inhibition. The minimum inhibitory concentration (MIC) assayed using CLSI M27-A3 broth micro-dilution method showed antifungal activity against C. albicans MTCC 227 at a concentration of 0.12 % (v/v) for both thymol and eugenol as compared to 0.25 % (v/v) for menthol. FLA was taken as positive control. The effect of these terpenes on metabolic activity of preformed C. albicans biofilm cells was evaluated using 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction assay in 96-well polystyrene microtiter plate. Thymol and eugenol were more effective at lower concentrations of > or = 1.0 % (v/v) than menthol. Synergistic studies using checkerboard micro-dilution assay showed fractional inhibitory concentration index (sigma FIC = 0.31) between thymol/FLA followed by eugenol/FLA (sigma FIC = 0.37) and menthol/FLA (sigma FIC terpenes with fluconazole on C. albicans biofilm, which could be future medications for biofilm infections.

  13. Eradication of C. albicans and T. rubrum with photoactivated indocyanine green, Citrus aurantifolia essential oil and fluconazole.

    Science.gov (United States)

    Fekrazad, Reza; Poorsattar Bejeh Mir, Arash; Ghasemi Barghi, Vadood; Shams-Ghahfarokhi, Masoomeh

    2015-06-01

    We aimed to evaluate the efficacy of alternative therapies rather than the current antifungal conventional therapy and with assessing the hypothesis of photoactivation of citrus essential oil, fluconazole and Indocyanine green to treat two common mucocutaneous fungal infections. Suspensions of Candida albicans and Tricophyton rubrum containing 10(6)cells/ml was prepared. Equal samples were treated with infrared (IR) laser irradiation (810 nm, 55 J/cm(2)) in the presence of Indocyanine green (Emundo, 1 mg/ml) (IRLE), photoactivated Citrus aurantifolia essential oil (EO) with sequential exposure to natural and tungsten lights (CE), control non-activated essential oil (CC), laser alone (IRL), indocyanine green alone (E) and neither of treatments as the control group (C). Additional fluconazole (FL, 25.6 μg/ml) and IR activated fluconazole (IRLFL) groups were designed for T. rubrum fungi. Inoculums were serially diluted to 10(-2) and 10(-4) and streaked on Sabouraud dextrose agar plates. Final outcomes were assessed as the percent of reduction. Cell reduction rates (%) in C. albicans groups were 99.99 (CE), 91.67 (IRLE), 86.67 (CC), 72.37 (E) and 67.27 (RL). Whereas, a 99.99 (CE), 89.99 (CC), 74.5 (IRLE), 64.5 (E), 38.5 (IRLF), 37.5 (RL), and 31 (FL) percent eradication was achieved in T. rubrum groups. Photoactivation of Citrus EO increased the killing capability by 10-13%. A modest 7.5% augmented effect was observed with IR activation of Fluconazole. Both Citrus EO and photothermal-photodynamic therapy with ICG and IR diode laser exhibited remarkable lethal effect on fungal cells. Candida viable cells are more susceptible to laser only and ICG only treatments than Tricophyton cells. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Antagonism of Fluconazole and a Proton Pump Inhibitor against Candida albicans.

    Science.gov (United States)

    Liu, Ning-Ning; Köhler, Julia R

    2016-02-01

    Hospitalized ill patients, at risk for invasive candidiasis, often receive multiple medications, including proton pump inhibitors (PPIs). The antifungal fluconazole perturbs the vacuolar proton ATPase. The PPI omeprazole antagonized Candida albicans growth inhibition by fluconazole. A C. albicans codon-adapted pHluorin, Ca.pHluorin, was generated to measure cytosolic pH. The fungal cytosol was acidified by omeprazole and realkalinized by coexposure to fluconazole. Vacuolar pH was alkalinized by fluconazole. Off-target effects of any medication on fungal pathogens may occur.

  15. Effect of Moringa oleifera Lam. leaf powder on the pharmacokinetics of nevirapine in HIV-infected adults: a one sequence cross-over study.

    Science.gov (United States)

    Monera-Penduka, Tsitsi G; Maponga, Charles C; Wolfe, Alan R; Wiesner, Lubbe; Morse, Gene D; Nhachi, Charles F B

    2017-01-01

    Moringa oleifera Lam., an herb commonly consumed by HIV-infected people on antiretroviral therapy, inhibits cytochrome P450 3A4, 1A2 and 2D6 activity in vitro; and may alter the pharmacokinetics (PK) of antiretroviral drugs metabolized via the same pathways. However, in vitro drug interaction activity may not translate to a clinically significant effect. Therefore, the effect of moringa leaf powder on the PK of nevirapine in HIV-infected people was investigated. Adult patients at steady-state dosing with nevirapine were admitted for 12-h intensive PK sampling following a 21-day herbal medicine washout. Blood sampling was repeated after 14 days of nevirapine and moringa (1.85 g leaf powder/day) co-administration. Nevirapine plasma concentrations were determined by liquid chromatography-tandem mass spectrometry. To assess the effect of moringa on nevirapine PK, the change in nevirapine area under the plasma concentration-time curve (AUC) was determined. The mean difference in pre- and post-moringa nevirapine, maximum concentration (Cmax) and concentration at 12 h (C12h) were also calculated. The PK parameters were compared by assessing the post/pre geometric mean ratios (GMRs) and associated 90% confidence intervals (CIs). Pharmacokinetics analyses were performed on the results from 11 participants for whom complete data were obtained. The post/pre GMRs and associated 90% CIs for nevirapine were 1.07 (1.00-1.14) for the AUC; 1.06 (0.98-1.16) for Cmax and 1.03 (0.92-1.16) for C12h. Co-administration of Moringa oleifera Lam. leaf powder at the traditional dose did not significantly alter the steady-state PK of nevirapine. Trial registration number NCT01410058 (ClinicalTrials.gov).

  16. Effectiveness of a Treatment Switch to Nevirapine plus Tenofovir and Emtricitabine (or Lamivudine) in Adults with HIV-1 Suppressed Viremia

    DEFF Research Database (Denmark)

    Llibre, Josep M; Bravo, Isabel; Ornelas, Arelly

    2015-01-01

    BACKGROUND: Switching subjects with persistently undetectable HIV-1 viremia under antiretroviral treatment (ART) to once-daily tenofovir/emtricitabine (or lamivudine) + nevirapine is a cost-effective and well-tolerated strategy. However, the effectiveness of this approach has not been established...

  17. Comparison of genotypic resistance profiles and virological response between patients starting nevirapine and efavirenz in EuroSIDA

    DEFF Research Database (Denmark)

    Bannister, Wendy P; Ruiz, Lidia; Cozzi-Lepri, Alessandro

    2008-01-01

    OBJECTIVE: To compare virological outcome and genotypic resistance profiles in HIV-1-infected patients starting non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens. METHODS: NNRTI-naive patients were included who started treatment with nevirapine (NVP) or efavirenz (EFV) wi...

  18. Brief report : enzyme inducers reduce elimination half-life after a single dose of nevirapine in healthy women

    NARCIS (Netherlands)

    L'homme, R.F.A.; Dijkema, T.; Ven, A.J.A.M. van der; Burger, D.M.

    2006-01-01

    OBJECTIVE: Single-dose nevirapine (SD-NVP) to prevent mother-to-child transmission (MTCT) of HIV is associated with development of NVP resistance, probably because of its long half-life in combination with a low genetic barrier to resistance. The objective of this study was to find enzyme inducers t

  19. Shared peptide binding of HLA Class I and II alleles associate with cutaneous nevirapine hypersensitivity and identify novel risk alleles

    DEFF Research Database (Denmark)

    Pavlos, Rebecca; McKinnon, Elizabeth J.; Ostrov, David A.

    2017-01-01

    Genes of the human leukocyte antigen (HLA) system encode cell-surface proteins involved in regulation of immune responses, and the way drugs interact with the HLA peptide binding groove is important in the immunopathogenesis of T-cell mediated drug hypersensitivity syndromes. Nevirapine (NVP), is...

  20. A comparison of the long-term durability of nevirapine, efavirenz and lopinavir in routine clinical practice in Europe

    DEFF Research Database (Denmark)

    Reekie, J; Reiss, P; Ledergerber, B;

    2011-01-01

    The durability of combination antiretroviral therapy (cART) regimens can be measured as time to discontinuation because of toxicity or treatment failure, development of clinical disease or serious long-term adverse events. The aim of this analysis was to compare the durability of nevirapine...

  1. Synergistic effect of fluconazole and doxycycline against Candida albicans biofilms resulting from calcium fluctuation and downregulation of fluconazole-inducible efflux pump gene overexpression.

    Science.gov (United States)

    Gao, Yuan; Li, Hui; Liu, Shuyuan; Zhang, Xiang; Sun, Shujuan

    2014-07-01

    Candida albicans biofilms are intrinsically resistant to antimicrobial agents. Previous work demonstrated that the antifungal activity of fluconazole against C. albicans biofilms is notably enhanced by doxycycline. In order to explore the synergistic mechanism of fluconazole and doxycycline, we investigated the changes of efflux pump gene expression, intracellular calcium concentration and cell cycle distribution after drug intervention in this study. The expression levels of CDR1, CDR2 and MDR1 were determined by real-time PCR, and the results showed that fluconazole alone could stimulate the high expression of CDR1, CDR2 and MDR1, and the combination of doxycycline and fluconazole downregulated the gene overexpression induced by fluconazole. Intracellular calcium concentration was determined using Fluo-3/AM by observing the fluorescence with flow cytometry. A calcium fluctuation, which started 4 h and peaked 8 h after the treatment with fluconazole, was observed. The combined drugs also initiated a calcium fluctuation after 4 h treatment and showed a peak at 16 h, and the peak was higher than that stimulated by fluconazole alone. The cell cycle was measured using flow cytometry. Fluconazole alone and the combined drugs both induced a reduction in the percentages of S-phase cells and an elevation in the percentages of cells in the G2/M phase. The results of this research showed that the synergism of fluconazole and doxycycline against C. albicans biofilms is associated with blockade of the efflux pump genes CDR1, CDR2 and MDR1, and stimulation of high intracellular calcium concentration. The findings of this study are of great significance in the search for new antifungal mechanisms.

  2. Couples' voluntary counselling and testing and nevirapine use in antenatal clinics in two African capitals: a prospective cohort study

    Directory of Open Access Journals (Sweden)

    Conkling Martha

    2010-03-01

    Full Text Available Abstract Background With the accessibility of prevention of mother to child transmission (PMTCT services in sub-Saharan Africa, more women are being tested for HIV in antenatal care settings. Involving partners in the counselling and testing process could help prevent horizontal and vertical transmission of HIV. This study was conducted to assess the feasibility of couples' voluntary counseling and testing (CVCT in antenatal care and to measure compliance with PMTCT. Methods A prospective cohort study was conducted over eight months at two public antenatal clinics in Kigali, Rwanda, and Lusaka, Zambia. A convenience sample of 3625 pregnant women was enrolled. Of these, 1054 women were lost to follow up. The intervention consisted of same-day individual voluntary counselling and testing (VCT and weekend CVCT; HIV-positive participants received nevirapine tablets. In Kigali, nevirapine syrup was provided in the labour and delivery ward; in Lusaka, nevirapine syrup was supplied in pre-measured single-dose syringes. The main outcome measures were nurse midwife-recorded deliveries and reported nevirapine use. Results In eight months, 1940 women enrolled in Kigali (984 VCT, 956 CVCT and 1685 women enrolled in Lusaka (1022 VCT, 663 CVCT. HIV prevalence was 14% in Kigali, and 27% in Lusaka. Loss to follow up was more common in Kigali than Lusaka (33% vs. 24%, p = 0.000. In Lusaka, HIV-positive and HIV-negative women had significantly different loss-to-follow-up rates (30% vs. 22%, p = 0.002. CVCT was associated with reduced loss to follow up: in Kigali, 31% of couples versus 36% of women testing alone (p = 0.011; and in Lusaka, 22% of couples versus 25% of women testing alone (p = 0.137. Among HIV-positive women with follow up, CVCT had no impact on nevirapine use (86-89% in Kigali; 78-79% in Lusaka. Conclusions Weekend CVCT, though new, was feasible in both capital cities. The beneficial impact of CVCT on loss to follow up was significant, while

  3. Nevirapine resistance and breast-milk HIV transmission: effects of single and extended-dose nevirapine prophylaxis in subtype C HIV-infected infants.

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    Anitha Moorthy

    Full Text Available BACKGROUND: Daily nevirapine (NVP prophylaxis to HIV-exposed infants significantly reduces breast-milk HIV transmission. We assessed NVP-resistance in Indian infants enrolled in the "six-week extended-dose nevirapine" (SWEN trial who received single-dose NVP (SD-NVP or SWEN for prevention of breast-milk HIV transmission but who also acquired subtype C HIV infection during the first year of life. METHODS/FINDINGS: Standard population sequencing and cloning for viral subpopulations present at > or =5% frequency were used to determine HIV genotypes from 94% of the 79 infected Indian infants studied. Timing of infection was defined based on when an infant's blood sample first tested positive for HIV DNA. SWEN-exposed infants diagnosed with HIV by six weeks of age had a significantly higher prevalence of NVP-resistance than those who received SD-NVP, by both standard population sequencing (92% of 12 vs. 38% of 29; p = 0.002 and low frequency clonal analysis (92% of 12 vs. 59% of 29; p = 0.06. Likelihood of infection with NVP-resistant HIV through breast-milk among infants infected after age six weeks was substantial, but prevalence of NVP-resistance did not differ among SWEN or SD-NVP exposed infants by standard population sequencing (15% of 13 vs. 15% of 20; p = 1.00 and clonal analysis (31% of 13 vs. 40% of 20; p = 0.72. Types of NVP-resistance mutations and patterns of persistence at one year of age were similar between the two groups. NVP-resistance mutations did differ by timing of HIV infection; the Y181C variant was predominant among infants diagnosed in the first six weeks of life, compared to Y188C/H during late breast-milk transmission. CONCLUSIONS/SIGNIFICANCE: Use of SWEN to prevent breast-milk HIV transmission carries a high likelihood of resistance if infection occurs in the first six weeks of life. Moreover, there was a continued risk of transmission of NVP-resistant HIV through breastfeeding during the first year of life, but did not

  4. Impact of fluconazole versus posaconazole prophylaxis on the incidence of fungal infections in patients receiving induction chemotherapy for acute myeloid leukemia

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    Camille Devanlay

    2015-06-01

    Full Text Available Background: Invasive fungal infections (IFIs remain one of the worrying complications in patients with acute myeloid leukemia (AML due to their incidence and high level of attributable mortality. In light of these risks, antifungal prophylaxis has always been debated. We conducted a single-center retrospective study of two prophylactic antifungal agents (fluconazole/posaconazole in 91 consecutive patients receiving induction chemotherapy for AML between 2005 and 2009, in order to evaluate the impact on the incidence of IFI and on the mycological flora of the patients. Methods: In total, 39 patients received prophylactic fluconazole versus 52 who received posaconazole. The baseline characteristics of the two groups were comparable. Results: Overall, 17 patients developed an IFI, with no difference in frequency between the two groups. Utilization of empirical or pre-emptive therapy was similar irrespective of the type of prophylaxis used. Mycological examination of stools revealed an increase in non-albicans Candida colonization in the fluconazole group during hospitalization and the appearance of Saccharomyces cerevisiae colonization in patients receiving posaconazole. Conclusion: The present study does not distinguish between fluconazole and posaconazole as a primary effective prevention against fungal infections. More prospective studies and meta-analyses are warranted.

  5. Evaluation of polycaprolactone matrices for sustained vaginal delivery of nevirapine in the prevention of heterosexual HIV transmission.

    Science.gov (United States)

    Dang, Nhung; Sivakumaran, Haran; Harrich, David; Shaw, P Nicholas; Coombes, Allan G A

    2014-07-01

    Nevirapine (NVP) was loaded in polycaprolactone (PCL) matrices to produce vaginal inserts with the aim of preventing HIV transmission. NVP dispersions in PCL were prepared, at 10% (w/w) theoretical loading, measured with respect to the PCL content of the matrices, in the form of (1) NVP only, (2) a physical mixture of NVP with polyethylene glycol (PEG) 6000 or (c) a solid dispersion (SD) with PEG produced by co-dissolution in ethanol. Characterisation of SD by differential scanning calorimetry and attenuated total reflectance-Fourier transform infrared spectroscopy suggested transformation of the crystalline structure of NVP to an amorphous form which consequently increased the dissolution rate of drug. A low-loading efficiency of 13% was obtained for NVP-loaded matrices and less than 20% for matrices prepared using physical mixtures of drug and PEG. The loading efficiency was improved significantly to around 40% when a 1:4 NVP-PEG SD was used for matrix production. After 30 days, 40% of the drug content was released from NVP-loaded matrices, 55% from matrices containing 1:4 NVP-PEG physical mixtures and 60% from matrices loaded with 1:4 NVP-PEG SDs. The in vitro anti-viral activity of released NVP was assessed using a luciferase reporter gene assay following the infection of HeLa cells with pseudo-typed HIV-1. NVP released from PCL matrices in simulated vaginal fluid retained over 75% anti-HIV activity compared with the non-formulated NVP control. In conclusion, 1:4 NVP-PEG SDs when loaded in PCL matrices increase drug loading efficiency and improve release behaviour.

  6. Candida albicans septicemia in a premature infant successfully treated with oral fluconazole

    DEFF Research Database (Denmark)

    Bodé, S; Pedersen-Bjergaard, Lars; Hjelt, K

    1992-01-01

    A premature male infant, birth-weight 1460 g, was treated successfully for a Candida albicans septicemia with orally administered fluconazole for 20 days. Dosage was 5 mg/kg/day. No side effects were seen. Fluconazole may present a major progress in treatment of invasive C. albicans infections in...... in neonatology....

  7. Candida albicans septicemia in a premature infant successfully treated with oral fluconazole

    DEFF Research Database (Denmark)

    Bodé, S; Pedersen-Bjergaard, Lars; Hjelt, K

    1992-01-01

    A premature male infant, birth-weight 1460 g, was treated successfully for a Candida albicans septicemia with orally administered fluconazole for 20 days. Dosage was 5 mg/kg/day. No side effects were seen. Fluconazole may present a major progress in treatment of invasive C. albicans infections...

  8. Retinal toxicity of intravitreally injected plain and liposome formulation of fluconazole in rabbit eye

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    Velpandian Thirumurthy

    2006-01-01

    Full Text Available Purpose: Candidal endophthalmitis is a sight-threatening ocular infection that most frequently occurs as a complication of candidemia. Fluconazole has been effective against Candida albicans in various animal models. Our objective was to evaluate retinal toxicity of plain and liposome formulation of fluconazole at various dose levels after intravitreal injection. Materials and Methods: Twelve New Zealand albino rabbits weighing 2-2.5 kg were used. Two rabbits were used for every dose level. Liposome formulation containing 100 and 200 µg of fluconazole in sterile phosphate buffer solution and plain fluconazole at concentrations of 100, 200, 400 and 800 µg in 0.1 ml of sterile normal saline were injected intravitreally into the right eyes. The left eyes received 0.1 ml normal saline or 0.1 ml of liposome formulation without fluconazole. One week later, the animals were sacrificed, their eyes enucleated and processed for light microscopy and scanning electron microscopy. Results: It showed that plain fluconazole at a concentration of 100 µg and above caused retinal changes, with disorganization of the photoreceptor outer segments. However, liposome formulation of fluconazole (200 µg/0.1 ml did not show any significant microscopic changes of the retina. Conclusion: The liposome formulation decreased the retinal toxicity of fluconazole up to the studied concentration of 200 µg/0.1 ml.

  9. Transmission of nevirapine-resistant HIV type 1 via breast milk to infants after single-dose nevirapine in Beira, Mozambique.

    Science.gov (United States)

    Micek, Mark A; Dross, Sandra; Blanco, Ana Judith; Beck, Ingrid A; Matunha, Laurinda; Seidel, Kristy; Montoya, Pablo; Matediana, Eduardo; Gantt, Soren; Gloyd, Stephen; Frenkel, Lisa

    2014-08-15

    Acquisition of nevirapine (NVP)-resistant human immunodeficiency virus type 1 (HIV-1) by breast-feeding infants after receipt of single-dose NVP to prevent mother-to-child transmission is not well defined. A prospective observational study of 307 infants evaluated the rate of breast milk transmission of NVP-resistant HIV and the concentrations of mutants over time. NVP resistance was detected in 9 of 24 infants (37.5%; 95% confidence interval, 18.8%-59.4%) infected via breast milk. Eight had a pure mutant HIV population at the time infection was first detected, and majority mutant populations persisted in all 6 infants with follow-up specimens. Infection of breast-feeding infants with NVP-resistant HIV resulted in mutants persisting as the dominant virus, which may indefinitely compromise treatment with NVP-based antiretroviral regimens. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  10. Design, synthesis and antimicrobial evaluation of novel benzimidazole type of Fluconazole analogues and their synergistic effects with Chloromycin, Norfloxacin and Fluconazole.

    Science.gov (United States)

    Zhang, Hui-Zhen; Damu, Guri L V; Cai, Gui-Xin; Zhou, Cheng-He

    2013-06-01

    A novel series of benzimidazole type of Fluconazole analogues were synthesized and characterized by (1)H NMR, (13)C NMR, IR, MS and HRMS spectra. All the new compounds were screened for their antimicrobial activities in vitro by two-fold serial dilution technique. The bioactive evaluation showed that 3,5-bis(trifluoromethyl)phenyl benzimidazoles gave comparable or even stronger antibacterial and antifungal efficiency in comparison with reference drugs Chloromycin, Norfloxacin and Fluconazole. The combination of 2,4-difluorobenzyl benzimidazole derivative 5m and its hydrochloride 7 respectively with antibacterial Chloromycin, Norfloxacin or antifungal Fluconazole showed better antimicrobial efficiency with less dosage and broader antimicrobial spectrum than the separated use of them alone. Notably, these combined systems were more sensitive to Fluconazole-insensitive Aspergillus flavus and methicillin-resistant MRSA. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  11. Cryptococcal cerebrospinal fluid shunt infection treated with fluconazole

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    Daniel Eymard

    1993-01-01

    Full Text Available A 37-year-old woman with a cadaveric renal allotransplantation required intra-cranial shunting devices after a presumptive episode of tuberculous meningitis. Six months later, she developed a culture-proven cryptococcal meningitis. Without having her ventriculo-auricular shunt removed, she was successfully treated with a short course of amphotericin B (335 mg and flucytosine (nine days followed by prolonged therapy with oral fluconazole (400 mg daily for 72 days. Three years post treatment she had no evidence of relapse, and normal renal graft function.

  12. Synergic effect of combination of glycyrol and fluconazole against experimental cutaneous candidiasis due to Candida albicans.

    Science.gov (United States)

    Rhew, Zheong-Imm; Han, Yongmoon

    2016-10-01

    In this study, we investigated the anti-fungal activity of glycyrol, a coumarine isolated from licorice (Glycyrrhizae Radix), in a murine model of cutaneous candidiasis caused by Candida albicans. Compared to the infected sites, located on the mice's back, of the untreated control mice, the infected sites treated with glycyrol had reduced CFU (colony forming unit) values up to 60 and 85.5 % at 20 and 40 μg/mouse of glycyrol, respectively (P fluconazole (10 μg/mouse), demonstrating that the combination therapy is approximately 4 times more effective than fluconazole alone at 20 μg/mouse (P fluconazole alone at 40 μg/mouse (P fluconazole invade C. albicans more readily and attack fluconazole's target in the fungus membrane. In summary, our data indicate that glycyrol may contribute to the development of a novel agent that possesses antifungal activity against cutaneous candidiasis.

  13. Risk factors for treatment-limiting toxicities in patients starting nevirapine-containing antiretroviral therapy

    DEFF Research Database (Denmark)

    Kesselring, Anouk M; Wit, Ferdinand W; Sabin, Caroline A;

    2009-01-01

    BACKGROUND: This collaboration of seven observational clinical cohorts investigated risk factors for treatment-limiting toxicities in both antiretroviral-naive and experienced patients starting nevirapine-based combination antiretroviral therapy (NVPc). METHODS: Patients starting NVPc after 1...... to treatment-limiting toxicities and/or patient/physician choice (TOXPC, n = 10,186). Patients were classified according to prior antiretroviral treatment experience and CD4 cell count/viral load at start NVPc. Models were stratified by cohort and adjusted for age, sex, nadir CD4 cell count, calendar year...... of starting NVPc and mode of transmission. RESULTS: Median time from starting NVPc to TOXPC and HSR were 162 days [interquartile range (IQR) 31-737] and 30 days (IQR 17-60), respectively. In adjusted Cox analyses, compared to naive patients with a low CD4 cell count, treatment-experienced patients with high...

  14. The transcription factor Ndt80 does not contribute to Mrr1-, Tac1-, and Upc2-mediated fluconazole resistance in Candida albicans.

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    Christoph Sasse

    Full Text Available The pathogenic yeast Candida albicans can develop resistance to the widely used antifungal agent fluconazole, which inhibits ergosterol biosynthesis, by the overexpression of genes encoding multidrug efflux pumps or ergosterol biosynthesis enzymes. Zinc cluster transcription factors play a central role in the transcriptional regulation of drug resistance. Mrr1 regulates the expression of the major facilitator MDR1, Tac1 controls the expression of the ABC transporters CDR1 and CDR2, and Upc2 regulates ergosterol biosynthesis (ERG genes. Gain-of-function mutations in these transcription factors result in constitutive overexpression of their target genes and are responsible for fluconazole resistance in many clinical C. albicans isolates. The transcription factor Ndt80 contributes to the drug-induced upregulation of CDR1 and ERG genes and also binds to the MDR1 and CDR2 promoters, suggesting that it is an important component of all major transcriptional mechanisms of fluconazole resistance. However, we found that Ndt80 is not required for the induction of MDR1 and CDR2 expression by inducing chemicals. CDR2 was even partially derepressed in ndt80Δ mutants, indicating that Ndt80 is a repressor of CDR2 expression. Hyperactive forms of Mrr1, Tac1, and Upc2 promoted overexpression of MDR1, CDR1/CDR2, and ERG11, respectively, with the same efficiency in the presence and absence of Ndt80. Mrr1- and Tac1-mediated fluconazole resistance was even slightly enhanced in ndt80Δ mutants compared to wild-type cells. These results demonstrate that Ndt80 is dispensable for the constitutive overexpression of Mrr1, Tac1, and Upc2 target genes and the increased fluconazole resistance of strains that have acquired activating mutations in these transcription factors.

  15. Preparation and characterisation of fluconazole vaginal films for the treatment of vaginal Candidiasis

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    L Kumar

    2013-01-01

    Full Text Available Objective of the present study was to develop and evaluate vaginal films with essential in vitro studies. Films were developed using hydroxypropyl methylcellulose as a polymer and formulations were coded. The developed films were evaluated with Fourier transform infrared spectroscopy, drug content, viscosity, surface pH, thickness, mechanical characterisation and in vitro drug release study. Fourier transform infrared spectroscopy results confirmed that there is no chemical interaction between drug and stabilisers/excipients. The batch variation was not more than 5% for average thickness and weight of the films. The drug content for the prepared formulation was in the range of 72.32±0.18% to 94.48±0.54%. Viscosity of the formulations increased with the increase in concentration of polymer. Mechanical characterisation revealed that tensile strength and percentage elongation of the films improved as there is increase in degree of substitution of the polymer, but the values of modulus decreased which confirmed that all the prepared films are soft in nature. The in vitro study indicated that 1 and 2% concentrations of polymer are the least concentrations to control the release of drug whereas the 4% concentration of polymer is a good and more effective concentration to control the release. Only one prepared formulation released the drug by following anomalous transport whereas other film formulations released the fluconazole by following Fickian diffusion mechanism. Prepared vaginal films may be an important alternative for the treatment of vaginal candidiasis, because these prepared films suggest the benefits of controlled release of fluconazole at the site of absorption.

  16. Fluconazole in the therapy of Pityriasis versicolor

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    Poljački Mirjana N.

    2005-01-01

    Full Text Available The authors present the results of the systemic application of flukonazole in therapy of Pityriasis versicolor. It was arranged for the total number of 38 patients, 18 females and 20 males. The diagnosis of diseases was established on the base of the clinical examination, the native mycological examination and by the using of Wood lamps. The therapy was passed by the using of 300 mg flukonazole in a single dose, once weekly, during two weeks. The following period amounted to one week after the passed therapy. The therapeutic efficacy was assessed with regard to the clinical and mycological healing. The clinical efficacy was assessed semiquantitative on the base of increasing of the percentage rates of the total score of disease that was computed by collecting of the numeric values for every clinical argument typical for the disease, and the mycological efficacy on the base of the mycological findings and the fluorescence finding after lightening with the Wood's lamp. The controlling examinations were performed on day 0, 14 and 22. The results of investigations have shown that the complete clinical healing was achieved after two weeks of therapy in 94,74%, and the mycological healing in 92,11% patients. The rate of the mycological healing was evaluated after 1 week of following period equal to the rate of the clinical healing and it was also 94,74%. The undesirable effects of the drug applications weren't by any patient.

  17. 氟康唑脂质体凝胶的制备及体外透皮实验%Preparation of liposomal fluconazole gel and in vitro transdermal delivery

    Institute of Scientific and Technical Information of China (English)

    赵珊珊; 杜青; 曹德英

    2007-01-01

    Aim Liposomal fluconazole gel was prepared and its properties were studied. Methods The fluconazole liposomes were prepared by film dispersion method. Their shapes and sizes were observed by transmission electronic microscope and particle size analyzer, respectively. The skin permeation of liposomal gel was studied on rat skin by permeation cell. Results The entrapment efficiency of fluconazole liposomes was 47.68%. The fluconazole liposomes were oval or round in shape, and their average diameter was 250±8 nm. The accumulative skin permeation of liposomal fluconazole gel (25.27%) was lower than that of non-liposomal fluconazole gel (36.72%), but fluconazole retained in rat skin of liposomal gel (162±15 μg·cm-2) was higher than that of non-liposomal gel (48±6 μg·cm-2). Conclusion Liposomal fluconazole gel can significantly increase the deposited amounts of fluconazole in rat skin and it may be beneficial for topical use.%目的 制备氟康唑脂质体凝胶,并研究其性质.方法 以薄膜分散法制备氟康唑脂质体,透射电镜观察脂质体的形态,粒度分布仪测定粒径,透皮吸收扩散池测定脂质体凝胶的透皮吸收.结果 氟康唑脂质体的包封率为47.68%.脂质体粒径均匀,平均粒径为250士8 nm.氟康唑脂质体凝胶的累积透过量(25.27%)低于非脂质体凝胶(36.72%),而脂质体凝胶的药物皮内滞留量(162士15 μg·cm-2)大于非脂质体凝胶(48士6 μg·cm-2).结论 氟康唑脂质体凝胶剂可显著提高药物的皮内滞留量,有望成为氟康唑的一种外用新剂型.

  18. Clinical validation of the analysis of fluconazole in oral fluid in hospitalized children.

    Science.gov (United States)

    van der Elst, Kim C M; van Alst, Manouche; Lub-de Hooge, Marjolijn N; van Hateren, Kai; Kosterink, Jos G W; Alffenaar, Jan-Willem C; Schölvinck, Elisabeth H

    2014-11-01

    Fluconazole is a first-line antifungal agent for the treatment and prophylaxis of invasive candidiasis in pediatric patients. Pediatric patients are at risk of suboptimal drug exposure, due to developmental changes in gastrointestinal and renal function, metabolic capacity, and volume of distribution. Therapeutic drug monitoring (TDM) can therefore be useful to prevent underexposure of fluconazole in children and infants. Children, however, often fear needles and can have difficult vascular access. The purpose of this study was to develop and clinically validate a method of analysis to determine fluconazole in oral fluid in pediatric patients. Twenty-one paired serum and oral fluid samples were obtained from 19 patients and were analyzed using a validated liquid chromatography-tandem mass spectrometry (LC-MS-MS) method after cross-validation between serum and oral fluid. The results were within accepted ranges for accuracy and precision, and samples were stable at room temperature for at least 17 days. A Pearson correlation test for the fluconazole concentrations in serum and oral fluid showed a correlation coefficient of 0.960 (P fluconazole in pediatric patients and can be a noninvasive, painless alternative to perform TDM of fluconazole when blood sampling is not possible or desirable. When patients receive prolonged courses of antifungal treatment and use fluconazole at home, this method of analysis can extend the possibilities of TDM for patients at home.

  19. Liposomal thymoquinone effectively combats fluconazole-resistant Candida albicans in a murine model.

    Science.gov (United States)

    Khan, Masood Alam; Aljarbou, Ahmad N; Khan, Arif; Younus, Hina

    2015-05-01

    The aim of the present study was to develop a novel liposomal formulation of thymoquinone (TQ) to treat fluconazole-susceptible and -resistant Candida albicans (C. albicans) infections. The liposomal preparation of TQ (Lip-TQ) was used against a fluconazole-susceptible or -resistant isolate of C. albicans. Various doses of fluconazole (0, 5, 10, 20 and 40 mg/kg) or free TQ or Lip-TQ (0, 1, 2 and 5mg/kg) were used to treat C. albicans infected mice. Mice were observed for 40 days post C. albicans infection, and their kidneys were assessed for the fungal load. Fluconazole showed anti-fungal activity against the drug-susceptible, but not against the -resistant isolate of C. albicans. Free TQ showed its activity against both fluconazole-susceptible or -resistant C. albicans, however, Lip-TQ was found to be the most effective and imparted ∼ 100% and ∼ 90% survival of mice infected with fluconazole-susceptible and -resistant isolates of C. albicans, respectively. Mice treated with Lip-TQ showed highly reduced severity of infection in their tissue homogenates. Therefore, Lip-TQ may effectively be used in the treatment of C. albicans infections, including those which are not responding to fluconazole.

  20. Reversal of fluconazole resistance induced by a synergistic effect with Acca sellowiana in Candida glabrata strains.

    Science.gov (United States)

    R M Machado, Gabriella da; Pippi, Bruna; Dalla Lana, Daiane Flores; Amaral, Ana Paula S; Teixeira, Mário Lettieri; Souza, Kellen C B de; Fuentefria, Alexandre M

    2016-11-01

    The increased incidence of non-albicans Candida (NAC) resistant to fluconazole (FLZ) makes it necessary to use new therapeutic alternatives. Acca sellowiana (O.berg) Burret (Myrtaceae) is a guava with several proven biological activities. The interaction with fluconazole can be a feasible alternative to overcome this resistance. This study evaluates the in vitro antifungal activity of fractions obtained from the lyophilized aqueous extract of the leaves of A. sellowiana against resistant strains of NAC. The antifungal activity of the fractions was evaluated at 500 μg/mL by microdilution method. Checkerboard assay was performed to determine the effect of the combination of the F2 fraction and antifungal at concentrations: MIC/4, MIC/2, MIC, MIC × 2 and MIC × 4. Candida glabrata showed the lowest MIC values (500-3.90 μg/mL) and the F2 active fraction was the most effective. The association of F2 with FLZ showed a strong synergistic effect (FICI ≤ 0.5) against 100% of C. glabrata resistant isolates. Moreover, the F2 active fraction has demonstrated that probably acts in the cell wall of these yeasts. There was no observed acute dermal toxicity of lyophilized aqueous extract of leaves of A. sellowiana on pig ear skin cells. The interaction between substances present in the F2 active fraction is possibly responsible for the antifungal activity presented by this fraction. This study is unprecedented and suggests that the combination of F2 active fraction and FLZ might be used as an alternative treatment for mucocutaneus infections caused by C. glabrata resistant.

  1. Some pharmacokinetic indices of oral fluconazole administration to koalas (Phascolarctos cinereus) infected with cryptococcosis.

    Science.gov (United States)

    Govendir, M; Black, L A; Jobbins, S E; Kimble, B; Malik, R; Krockenberger, M B

    2016-08-01

    Three asymptomatic koalas serologically positive for cryptococcosis and two symptomatic koalas were treated with 10 mg/kg fluconazole orally, twice daily for at least 2 weeks. The median plasma Cmax and AUC0-8 h for asymptomatic animals were 0.9 μg/mL and 4.9 μg/mL·h, respectively; and for symptomatic animals 3.2 μg/mL and 17.3 μg/mL·h, respectively. An additional symptomatic koala was treated with fluconazole (10 mg/kg twice daily) and a subcutaneous amphotericin B infusion twice weekly. After 2 weeks the fluconazole Cmax was 3.7 μg/mL and the AUC0-8 h was 25.8 μg/mL*h. An additional three koalas were treated with fluconazole 15 mg/kg twice daily for at least 2 weeks, with the same subcutaneous amphotericin protocol co-administered to two of these koalas (Cmax : 5.0 μg/mL; mean AUC0-8 h : 18.1 μg/mL*h). For all koalas, the fluconazole plasma Cmax failed to reach the MIC90 (16 μg/mL) to inhibit C. gattii. Fluconazole administered orally at either 10 or 15 mg/kg twice daily in conjunction with amphotericin is unlikely to attain therapeutic plasma concentrations. Suggestions to improve treatment of systemic cryptococcosis include testing pathogen susceptibility to fluconazole, monitoring plasma fluconazole concentrations, and administration of 20-25 mg/kg fluconazole orally, twice daily, with an amphotericin subcutaneous infusion twice weekly.

  2. Fluconazole for ketoconazole-resistant oropharyngeal candidiasis in HIV-1 infected patients

    DEFF Research Database (Denmark)

    Thorsen, S; Mathiesen, Lars Reinhardt

    1990-01-01

    The efficacy of fluconazole in doses ranging from 50 to 200 mg/day in controlling oropharyngeal candidiasis was retrospectively evaluated in 16 consecutive HIV-1-infected patients. 13 patients received fluconazole due to failure of treatment with ketoconazole, and among these 11 (84%) initially...... showed complete or partial remission of oropharyngeal candidiasis. 3 (27%) of these subsequently developed failure of treatment within a median observation period of 38 days. No major toxicities were observed. Fluconazole appears promising in the therapy of ketoconazole-resistant candidiasis....

  3. The Effect of Gene Variants on Levonorgestrel Pharmacokinetics When Combined With Antiretroviral Therapy Containing Efavirenz or Nevirapine.

    Science.gov (United States)

    Neary, M; Lamorde, M; Olagunju, A; Darin, K M; Merry, C; Byakika-Kibwika, P; Back, D J; Siccardi, M; Owen, A; Scarsi, K K

    2017-09-01

    Reduced levonorgestrel concentrations from the levonorgestrel contraceptive implant was previously seen when given concomitantly with efavirenz. We sought to assess whether single nucleotide polymorphisms (SNPs) in genes involved in efavirenz and nevirapine metabolism were linked to these changes in levonorgestrel concentration. SNPs in CYP2B6, CYP2A6, NR1I2, and NR1I3 were analyzed. Associations of participant demographics and genotype with levonorgestrel pharmacokinetics were evaluated in HIV-positive women using the levonorgestrel implant plus efavirenz- or nevirapine-based antiretroviral therapy (ART), in comparison to ART-naïve women using multivariate linear regression. Efavirenz group: CYP2B6 516G>T was associated with lower levonorgestrel log10 Cmax and log10 AUC. CYP2B6 15582C>T was associated with lower log10 AUC. Nevirapine group: CYP2B6 516G>T was associated with higher log10 Cmax and lower log10 Cmin . Pharmacogenetic variations influenced subdermal levonorgestrel pharmacokinetics in HIV-positive women, indicating that the magnitude of the interaction with non-nucleoside reverse transcriptase inhibitors (NNRTIs) is influenced by host genetics. © 2017 American Society for Clinical Pharmacology and Therapeutics.

  4. Antiproliferation of Berberine in Combination with Fluconazole from the Perspectives of Reactive Oxygen Species, Ergosterol and Drug Efflux in a Fluconazole-Resistant Candida tropicalis Isolate

    Science.gov (United States)

    Shao, Jing; Shi, GaoXiang; Wang, TianMing; Wu, DaQiang; Wang, ChangZhong

    2016-01-01

    Candida tropicalis has emerged as an important pathogenic fungus in nosocomial infections due to its recalcitrant resistance to conventional antifungal agents, especially to fluconazole (FLC). Berberine (BBR) is a bioactive herbal-originated alkaloids and has been reported to possess antifungal functions against C. albicans. In this paper, we tried to figure out the antifungal mechanisms of BBR and/or FLC in a clinical C. tropicalis isolate 2006. In the microdilution test, the minimum inhibitory concentration (MIC) of BBR was found 16 μg/mL with fractional inhibitory concentration index (FICI) 0.13 in C. tropicalis 2006. The synergism of BBR and FLC was also confirmed microscopically. After the treatments of BBR and/or FLC, the studies revealed that (i) FLC facilitated BBR to increase reactive oxygen species (ROS), (ii) FLC enhanced the intranuclear accumulation of BBR, (iii) BBR decreased the extracellular rhodamine 123 (Rh123) via inhibiting efflux transporters, (iv) FLC assisted BBR to reduce ergosterol content, and (v) BBR in combined with FLC largely downregulated the expressions of Candida drug resistance 1 (CDR1) and CDR2 but impact slightly multidrug resistance 1 (MDR1), and upregulate the expression of ergosterol 11 (ERG11). These results suggested that BBR could become a potent antifungal drug to strengthen FLC efficacy in FLC-resistant C. tropicalis via ROS increase, intracellular BBR accumulation, ergosterol decrease and efflux inhibition. PMID:27721812

  5. In vitro activity of essential oils extracted from plants used as spices against fluconazole-resistant and fluconazole-susceptible Candida spp.

    Science.gov (United States)

    Pozzatti, Patrícia; Scheid, Liliane Alves; Spader, Tatiana Borba; Atayde, Margareth Linde; Santurio, Janio Morais; Alves, Sydney Hartz

    2008-11-01

    In the present study, the antifungal activity of selected essential oils obtained from plants used as spices was evaluated against both fluconazole-resistant and fluconazole-susceptible Candida spp. The Candida species studied were Candida albicans, Candida dubliniensis, Candida tropicalis, Candida glabrata, and Candida krusei. For comparison purposes, they were arranged in groups as C. albicans, C. dubliniensis, and Candida non-albicans. The essential oils were obtained from Cinnamomum zeylanicum Breyn, Lippia graveolens HBK, Ocimum basilicum L., Origanum vulgare L., Rosmarinus officinalis L., Salvia officinalis L., Thymus vulgaris L., and Zingiber officinale. The susceptibility tests were based on the M27-A2 methodology. The chemical composition of the essential oils was obtained by gas chromatography-mass spectroscopy and by retention indices. The results showed that cinnamon, Mexican oregano, oregano, thyme, and ginger essential oils have different levels of antifungal activity. Oregano and ginger essential oils were found to be the most and the least efficient, respectively. The main finding was that the susceptibilities of fluconazole-resistant C. albicans, C. dubliniensis, and Candida non-albicans to Mexican oregano, oregano, thyme, and ginger essential oils were higher than those of the fluconazole-susceptible yeasts (Pessential oil than their fluconazole-susceptible counterparts (Pessential oils studied was apparent when these 2 parameters were compared. Finally, basil, rosemary, and sage essential oils did not show antifungal activity against Candida isolates at the tested concentrations.

  6. Comparison of combined use of fluconazole and clotrimazole with the sequential dose of fluconazole in the treatment of recurrent Candida vaginitis

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    Tayebeh Gharibi

    2009-09-01

    Full Text Available Background: fluconazole is one of the systemic anti-fungal agents and clotrimazole vaginal cream is a topical agent against Candida Albicans. In this study, comparison between of the two regimes (Fluconazole with and without vaginal clotrimazole in recurrent Candida albicans was assessed .with that of sequential dose of fluconazole for the treatment of Candida vaginitis, this evaluation was done. Methods: A double blind randomized clinical trial was carried out on 80 married women (20-45 years old having chronic vaginal Candidiasis. The patients were divided in to two groups (40 in each. The first groups received two doses of fluconazole at two different timing (Zero and 72 hours along with clotrimazole vaginal cream 1% ( for 7 days . The second group recived only two doses of fluconazole (Zero time and 72 hours later. Then the patients were examined at 2 and 6 weeks after the treatment. Results: The signs and symptoms of disease (itching, erythema, excoriation, edema and fissure in both groups were significantly decreased after two weeks of the treatment (P = 0.00. The final examination of both groups also showed that the treatment was more effective in the first group compared to the second group. The difference was significant statistically (P<0.05. Conclusion: the data shows that adding topical clotrimazole in treatment of patients with recurrent Candida vaginitis Is more effective.

  7. 氟康唑对热带念珠菌活性氧和%Effect of fluconazole on reactive oxygen species and mitochondrial membrane potential of Candida tropicalis

    Institute of Scientific and Technical Information of China (English)

    邱莲女; 周永列; 胡庆丰; 朱永泽; 郭伟; 吕火烊

    2011-01-01

    To explore fluconazole's effect mechanism, we investigated the changes of viability rate, reactive oxygen species (ROS), mitochondrial membrane potential (△Ψm) and cell cycle of Candida tropicalis after treatment with fluconazole. The minimum inhibitory concentration (MIC) of the clinical isolates Candida tropicalis to fluconazole were tested by NCCLS M27-A microdilution method. After treatment wth different concentration of fluconazole, viability rate, the intracellular accumulation of ROS, the loss of mitochondrial membrane potential △Ψm and cell cycle of Candida tropicalis were detected with flow cytometry, respectively. After treatment with fluconazole, there were no significant variation among viability rate, ROS, mitochondrial membrane potential △Ψm and cell cycle in fluconazole-resistant strains, but a decrease of mitochondrial membrane potential △Ψm and viability rate,an increase of ROS accumulation were detected in a time-dose-dependent manner in fluconazole-susceptibile strains. A majority of Candida tropicalis were arrested in G2/M phase and apoptosis peak was seen. Free radicals scavenger glutathione inhibited ROS production, prevented G2/M arrest and decreased apoptosis in fluconazole-susceptibile strains. According to it, fluconazole maybe induce intracellular accumulation of ROS and decrease of mitochondrial membrane potential △Ψm, which could result in apoptosis of Candida tropicalis.%为了探讨氟康唑作用机制,观察它对热带念珠菌作用后存活率、活性氧(Reactive oxygenspecies,ROS)、线粒体膜电位(Mitochondrial membrane potential,,△Ψm)和细胞周期的变化.参照NCCLS M27-A 方案的微量稀释法测定氟康唑对热带念珠菌的最低抑菌浓度(MIC); 热带念珠菌与不同浓度氟康唑共同培养后用流式细胞术(Flow cytometry,FCM)分析热带念珠菌存活率、ROS、线粒体膜电位△Ψm 和细胞周期的变化.结果表明,氟康唑作用后,热带念珠菌氟康唑耐药株的

  8. Fluconazole and intrathecal injection of amphotericin B for treating cryptococcal meningitis

    Institute of Scientific and Technical Information of China (English)

    Shiguang Wen; Jian Yin; Shaosen Qin; Meiping Wen; Xiaoyan Zhang; Dongke Chen

    2006-01-01

    BACKGROUND: At present, fiuconazole and intrathecal injection of amphotericin B has been widely used to treat cryptococcal meningitis. However, the application of amphotericin B can shorten course and has good effects on the treatment of cryptococcal meningitis.OBJECTIVE: To observe the effects and poor response of the intrathecal injection of amphotericin B on the treatment of cryptococcal meningitis.DESIGN: Retrospective-case analysis.SETTING: Department of Neurology, Beijing Hospital of Ministry of Public Health.PARTICIPANTS: Eight patients with cryptococcal meningitis were selected from Department of Neurology,Beijing Hospital of Ministry of Public Health from January 1995 to January 2006. Among them, there were 3 males and 5 females aged from 17 to 41 years and the course ranged from 21 days to 3 months. Patients who had symptoms of febrile and headache, positive meninges excitation, positive latex agglutination of cryptococcus of cerebrospinal fluid and positive ink smear were selected in this study. All patients provided informed consent.METHODS: Eight patients were treated with the fluconazole and intrathecal injection of amphotericin B. ①Intracranial hypertension of patients was controlled with flowing cerebrospinal fluid by repeatedly piercing waist;meanwhile, patients were taken the intrathecal injection of amphotericin B combining with flucytosine or fiuconazole treatment. The dosage of amphotericin B was 1-5 mg/d at the beginning of administration, and then, the samples were added with 2 mg dexasine and 500 mL 5% glucose solution. The dosage was increased 5.0 mg per day till 50 mg per day, and the total dosage was 3.0-4.0 g. In addition, 2 mg dexasine was mixed with 4.0-5.0 mL cerebrospinal fluid, and then the solution was gradually injected into sheath for once a week. Fluconazole was dripped into vein with the volume of 400 mg per day, and then, 14 days later,fluconazole was orally taken by patients. ② Other therapies, such as decreasing

  9. Prevalence, susceptibility profile for fluconazole and risk factors for candidemia in a tertiary care hospital in southern Brazil

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    Valério Rodrigues Aquino

    2005-10-01

    Full Text Available Bloodstream infections caused by yeast, Candida spp, are quite important clinically and epidemiologically due to a high mortality rate and an increasing number of non-albicans species with a more resistant (differentiated susceptibility profile. We examined species prevalence and susceptibility profile for fluconazole and the risk for nosocomial infections by Candida spp at the Hospital de Clínicas de Porto Alegre, a general tertiary care hospital in southern Brazilian, through a retrospective study, beginning with positive cultures of hospitalized patients. The distribution by species in 131 documented episodes was as follows: Candida albicans (45%, C. parapsilosis (24.4%, C. tropicalis (15.3%, C. glabrata (6.9%, C. krusei (4.6% and 3.8% other species (C. pelicullosa, C. guilliermondii, C. lusitaniae and C. kefyr. The vast majority of samples (121- 92.4% were susceptible to fluconazole; the resistant or dose-dependent sensitive samples included only C. krusei and C. glabrata. Blood diseases (leukemia, lymphoma, or neoplasias (solid tumors, were found in 35.0% of the candidemia episodes. We noted the previous use of antibiotics in 128 (97.7% patients, with 79.7% using three or more antibiotics before the candidemia episode. Other risk factors included a central venous catheter in 94 (71.8% and abdominal surgery in 32 (24.4% patients. The overall mortality rate was 51.9%, which varied according to the underlying disease. We found that C. albicans was the most prevalent species, although the non-albicans species predominated. However, in vitro resistance to fluconazole was detected only among the species (C. glabrata and C. krusei that tend to be resistant to the azolic compounds. Previous use of antibiotic and the use of a central venous catheter were the main risk factors among patients with candidemia.

  10. Prevalence, susceptibility profile for fluconazole and risk factors for candidemia in a tertiary care hospital in southern Brazil

    Directory of Open Access Journals (Sweden)

    Valério Rodrigues Aquino

    Full Text Available Bloodstream infections caused by yeast, Candida spp, are quite important clinically and epidemiologically due to a high mortality rate and an increasing number of non-albicans species with a more resistant (differentiated susceptibility profile. We examined species prevalence and susceptibility profile for fluconazole and the risk for nosocomial infections by Candida spp at the Hospital de Clínicas de Porto Alegre, a general tertiary care hospital in southern Brazilian, through a retrospective study, beginning with positive cultures of hospitalized patients. The distribution by species in 131 documented episodes was as follows: Candida albicans (45%, C. parapsilosis (24.4%, C. tropicalis (15.3%, C. glabrata (6.9%, C. krusei (4.6% and 3.8% other species (C. pelicullosa, C. guilliermondii, C. lusitaniae and C. kefyr. The vast majority of samples (121- 92.4% were susceptible to fluconazole; the resistant or dose-dependent sensitive samples included only C. krusei and C. glabrata. Blood diseases (leukemia, lymphoma, or neoplasias (solid tumors, were found in 35.0% of the candidemia episodes. We noted the previous use of antibiotics in 128 (97.7% patients, with 79.7% using three or more antibiotics before the candidemia episode. Other risk factors included a central venous catheter in 94 (71.8% and abdominal surgery in 32 (24.4% patients. The overall mortality rate was 51.9%, which varied according to the underlying disease. We found that C. albicans was the most prevalent species, although the non-albicans species predominated. However, in vitro resistance to fluconazole was detected only among the species (C. glabrata and C. krusei that tend to be resistant to the azolic compounds. Previous use of antibiotic and the use of a central venous catheter were the main risk factors among patients with candidemia.

  11. Antifungal activity of naphthoquinoidal compounds in vitro against fluconazole-resistant strains of different Candida species: a special emphasis on mechanisms of action on Candida tropicalis.

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    João B A Neto

    Full Text Available In recent decades, the incidence of candidemia in tertiary hospitals worldwide has substantially increased. These infections are a major cause of morbidity and mortality; in addition, they prolong hospital stays and raise the costs associated with treatment. Studies have reported a significant increase in infections by non-albicans Candida species, especially C. tropicalis. The number of antifungal drugs on the market is small in comparison to the number of antibacterial agents available. The limited number of treatment options, coupled with the increasing frequency of cross-resistance, makes it necessary to develop new therapeutic strategies. The objective of this study was to evaluate and compare the antifungal activities of three semisynthetic naphthofuranquinone molecules against fluconazole-resistant Candida spp. strains. These results allowed to us to evaluate the antifungal effects of three naphthofuranquinones on fluconazole-resistant C. tropicalis. The toxicity of these compounds was manifested as increased intracellular ROS, which resulted in membrane damage and changes in cell size/granularity, mitochondrial membrane depolarization, and DNA damage (including oxidation and strand breakage. In conclusion, the tested naphthofuranquinones (compounds 1-3 exhibited in vitro cytotoxicity against fluconazole-resistant Candida spp. strains.

  12. Correlation between in vitro and in vivo antifungal activities in experimental fluconazole-resistant oropharyngeal and esophageal candidiasis.

    Science.gov (United States)

    Walsh, T J; Gonzalez, C E; Piscitelli, S; Bacher, J D; Peter, J; Torres, R; Shetti, D; Katsov, V; Kligys, K; Lyman, C A

    2000-06-01

    Oropharyngeal and esophageal candidiasis (OPEC) is a frequent opportunistic mycosis in immunocompromised patients. Azole-resistant OPEC is a refractory form of this infection occurring particularly in human immunodeficiency virus (HIV)-infected patients. The procedures developed by the Antifungal Subcommittee of the National Committee for Clinical Laboratory Standards (NCCLS) are an important advance in standardization of in vitro antifungal susceptibility methodology. In order to further understand the relationship between NCCLS methodology and antifungal therapeutic response, we studied the potential correlation between in vitro susceptibility to fluconazole and in vivo response in a rabbit model of fluconazole-resistant OPEC. MICs of fluconazole were determined by NCCLS methods. Three fluconazole-susceptible (FS) (MIC, /=64 microgram/ml) isolates of Candida albicans from prospectively monitored HIV-infected children with OPEC were studied. FR isolates were recovered from children with severe OPEC refractory to fluconazole, and FS isolates were recovered from those with mucosal candidiasis responsive to fluconazole. Fluconazole at 2 mg/kg of body weight/day was administered to infected animals for 7 days. The concentrations of fluconazole in plasma were maintained above the MICs for FS isolates throughout the dosing interval. Fluconazole concentrations in the esophagus were greater than or equal to those in plasma. Rabbits infected with FS isolates and treated with fluconazole had significant reductions in oral mucosal quantitative cultures (P OPEC due to C. albicans.

  13. Comparison of the therapeutic effects of Garcin(®) and fluconazole on Candida vaginitis

    National Research Council Canada - National Science Library

    Ebrahimy, Farzaneh; Dolatian, Mahrokh; Moatar, Fariborz; Majd, Hamid Alavi

    2015-01-01

    This study aimed to determine and compare the effects of garlic tablets (Garcin(®)) and fluconazole on Candida vaginitis in women who presented to a health centre in Koohdasht, Iran, from August 2011 to March 2012...

  14. Fluconazole and Echinocandin Resistance of Candida glabrata Correlates Better with Antifungal Drug Exposure Rather than with MSH2 Mutator Genotype in a French Cohort of Patients Harboring Low Rates of Resistance

    Science.gov (United States)

    Dellière, Sarah; Healey, Kelley; Gits-Muselli, Maud; Carrara, Bastien; Barbaro, Alessandro; Guigue, Nicolas; Lecefel, Christophe; Touratier, Sophie; Desnos-Ollivier, Marie; Perlin, David S.; Bretagne, Stéphane; Alanio, Alexandre

    2016-01-01

    Candida glabrata is a major pathogenic yeast in humans that is known to rapidly acquire resistance to triazole and echinocandin antifungal drugs. A mutator genotype (MSH2 polymorphism) inducing a mismatch repair defect has been recently proposed to be responsible for resistance acquisition in C. glabrata clinical isolates. Our objectives were to evaluate the prevalence of antifungal resistance in a large cohort of patients in Saint-Louis hospital, Paris, France, some of whom were pre-exposed to antifungal drugs, as well as to determine whether MSH2 polymorphisms are associated with an increased rate of fluconazole or echinocandin resistance. We collected 268 isolates from 147 patients along with clinical data and previous antifungal exposure. Fluconazole and micafungin minimal inhibition concentrations (MICs) were tested, short tandem repeat genotyping was performed, and the MSH2 gene was sequenced. According to the European Committee on Antimicrobial Susceptibility breakpoints, 15.7% of isolates were resistant to fluconazole (MIC > 32 mg/L) and 0.7% were resistant to micafungin (MIC > 0.03 mg/L). A non-synonymous mutation within MSH2 occurred in 44% of the isolates, and 17% were fluconazole resistant. In comparison, fluconazole resistant isolates with no MSH2 mutation represented 15% (P = 0.65). MSH2 polymorphisms were associated with the short tandem repeat genotype. The rate of echinocandin resistance is low and correlates with prior exposure to echinocandin. The mutator genotype was not associated with enrichment in fluconazole resistance but instead corresponded to rare and specific genotypes. PMID:28066361

  15. Effect of fluconazole on the pharmacokinetics and pharmacodynamics of oral and rectal bromazepam: an application of electroencephalography as the pharmacodynamic method.

    Science.gov (United States)

    Ohtani, Yasukiyo; Kotegawa, Tsutomu; Tsutsumi, Kimiko; Morimoto, Takuya; Hirose, Yumiko; Nakano, Shigeyuki

    2002-02-01

    Quantitative analysis of electroencephalography (EEG) is used increasingly to evaluate the pharmacodynamics of benzodiazepines. The present study aimed to apply the EEG method as well as more traditional approaches to an interaction study of bromazepam and fluconazole. Twelve healthy male volunteers participated in a randomized, double-blind, four-way crossover study. The subjects received single oral or rectal doses of bromazepam (3 mg) after 4-day pretreatment of oral fluconazole (100 mg daily) or its placebo. Plasma bromazepam concentrations were measured before and 0.5, 1, 2, 3, 4, 6, 12, 22, 46, and 70 hours after bromazepam administration. Pharmacodynamic effects of bromazepam were assessed using self-rated drowsiness, continuous number addition test, and EEG. Fluconazole caused no significant changes in pharmacokinetics and pharmacodynamics of oral or rectal bromazepam. Rectal administration significantly increased AUC (1.7-fold, p bromazepam. These changes following rectal dose may be due to avoidance of degradation occurring in the gastrointestinal tract. Rectal bromazepam also increased the area under the effect curves assessed by EEG (p bromazepam concentrations (r = 0.92, p bromazepam.

  16. Fluconazole Susceptibility in Cryptococcus gattii Is Dependent on the ABC Transporter Pdr11.

    Science.gov (United States)

    Yang, Mai Lee; Uhrig, John; Vu, Kiem; Singapuri, Anil; Dennis, Michael; Gelli, Angie; Thompson, George R

    2015-12-07

    Cryptococcus gattii isolates from the Pacific Northwest have exhibited higher fluconazole MICs than isolates from other sites. The mechanism of fluconazole resistance in C. gattii is unknown. We sought to determine the role of the efflux pumps Mdr1 and Pdr11 in fluconazole susceptibility. Using biolistic transformation of the parent isolate, we created a strain lacking Mdr1 (mdr1Δ) and another strain lacking Pdr11 (pdr11Δ). Phenotypic virulence factors were assessed by standard methods (capsule size, melanin production, growth at 30 and 37 °C). Survival was assessed in an intranasal murine model of cryptococcosis. Antifungal MICs were determined by the M27-A3 methodology. No differences in key virulence phenotypic components were identified. Fluconazole susceptibility was unchanged in the Mdr1 knockout or reconstituted isolates. However, fluconazole MICs decreased from 32 μg/ml for the wild-type isolate to fluconazole susceptibility in C. gattii. Genomic and expression differences between resistant and susceptible C. gattii clinical isolates should be assessed further in order to identify other potential mechanisms of resistance.

  17. Fluconazole is a potent inhibitor of antipyrine metabolism in vivo in mice

    Energy Technology Data Exchange (ETDEWEB)

    La Delfa, I.; Zhu, Q.M.; Mo, Z.; Blaschke, T.F.

    1989-01-01

    Fluconazole, a bis-triazole antifungal, is distinguished from imidazole antifungals (e.g. ketoconazole) by its potency and pharmacokinetic characteristics. Imidazole-containing compounds are well documented to inhibit the hepatic cytochrome P-450-dependent enzyme system; whether this effect occurs with a bis-triazole agent is unknown. The (/sup 14/C)antipyrine breath test was employed to investigate the effects of fluconazole on this enzyme system in CD-1 male mice. Control, ketoconazole (100 mg/kg), and fluconazole (1 and 10 mg/kg) were studied in single- and multiple-dose experiments. Fluconazole had potent inhibitory effects on the total (mean = -73% +/- 2%), demethylase (mean = -90% +/- 2%), and nondemethylase (mean = -60% +/- 4%) elimination rate constants (all p less than 0.001). The fraction of the administered radioactivity excreted as /sup 14/CO/sub 2/ was decreased by 50-80% in the fluconazole groups (p less than 0.001). These effects were seen after single- and multiple-dose studies; however, return to baseline occurred more quickly in the multiple-dose group. These effects were significantly more pronounced than those observed with equipotent doses of ketoconazole. These results provide evidence that fluconazole is a potent, partially selective, and reversible inhibitor of the cytochrome P-450-dependent enzyme system in mice. Future studies will be required to assess this property and possible interactions with drugs metabolized by this enzyme system in humans.

  18. Comparison of Fluconazole and Clotrimazole in the Treatment of Acute Candida Albicans Vulvovaginitis

    Directory of Open Access Journals (Sweden)

    Fatemeh Bahadori

    2008-12-01

    Full Text Available Objective: This study compared two antifungal drugs, fluconazole and clotrimazole for the treatment of vulvo vaginal candidiasis. Materials and Methods: This randomized clinical trial was conducted on 120 women with vulvo vaginal candidiasis during a six month period. All patients answered a standard questionnaire containing questions about symptoms of vulvovaginal candidiasis and presence of vaginal discharge and signs of vulvar and vaginal inflammation were documented according to physical examination. Two swabs of vaginal discharge were obtained for each woman, one for direct smear, another for culture. The culture medium was Sabouraud Dextrose Agar (SDA. Patients were randomized into two groups of clotrimazole (vaginal cream for 7 days and 150 mg fluconazole in a single dose. Clinical and paraclinical responses were calculated.Results: Clinical improvement occurred in 96 cases (80%. This value was 86.7% and 73.3%for clotrimazole and fluconazole, respectively (P-value=0.04. Paraclinical response on tenth day of treatment was observed in 87 patients (72.5%. This value was 66.7% and 78.3%for clotrimazole and fluconazole groups, respectively (P-value=0.110. Mean days of treatment was 4.06 ±1.30 days for clotrimazole and 2.70 ±0.78 days for fluconazole (p value =0.031.Conclusion: Most of the clinical and paraclinical responses to the drugs used for the treatment of vulvo vaginal candidiasis are in the favour of fluconazole.

  19. Investigação da Sensibilidade ao Fluconazol e Produção de Enzimas Hidrolíticas por Candida sp. Isoladas do Trato Respiratório de Pacientes Internados em um Hospital no Sul de Minas Gerais Investigation of Fluconazole Sensibility and Hydrolytic Enzimes Production by Candida sp. Isolated from the Respiratory Tract of Patients Admitted to a Hospital in Southern Minas Gerais

    Directory of Open Access Journals (Sweden)

    Bruna Fernanda Fernandes Ferreira

    2012-03-01

    Full Text Available Objetivo: Identificar e caracterizar isolados de Candida do trato respiratório de pacientes, em relação à sensibilidade ao fluconazol e produção de enzimas hidrolíticas (fosfolipase e proteinase. Materiais e Métodos: 52 espécies de amostras do trato respiratório no período de 2001 a 2007 foram identificadas pelo método ChroMagar®. As amostras foram submetidas a teste de provas enzimáticas, para obtenção do grau de virulência e testadas quanto à susceptibilidade ao fluconazol, através do método Etest®. Resultados: Candida albicans foi a espécie prevalente, enquanto as demais somaram um total de 67,3%. Todas as amostras foram produtoras de proteinase e 88,5% de fosfolipase e a maioria sensível ao fluconazol, com exceção de C. glabrata que apresentou relevante resistência. Conclusão: Os resultados demonstraram um aumento de isolamento das espécies de Candida nãoalbicans em amostras clínicas, além de uma relevante resistência ao fluconazol por C. glabrata. Objective: Identification and characterization of Candida isolates from respiratory tract of patients in relation to fluconazole sensitivity and production of hydrolytic enzymes (phospholipase and proteinase. Material and Methods: 52 species originated from respiratory tract samples in the period 2001 to 2007 were identified by CHROMagar ® method. The samples were subjected to enzymatic test to evaluate the virulence degree of strains and tested for susceptibility to fluconazole by Etest® method. Results: Candida albicans was the prevalent specie, while Candida non-albicans amounted to a total of 67.3%. All samples were proteinase producers and 88.5% of phospholipase, and majority were susceptible to fluconazole, highlighting only C. glabrata with relevant resistance. Conclusion: The results showed an increased isolation of Candida non-albicans in clinical samples, and a significant resistance to fluconazole by C. glabrata.

  20. Identification of Candida species in patients with oral lesion undergoing chemotherapy along with minimum inhibitory concentration to fluconazole

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    Mehrnoush Maheronnaghsh

    2016-01-01

    Conclusion: Data were shown that C. albicans is the most commonly identified species in oral candidiasis and majority of fluconazole resistant C. albicans were found in patients with gastrointestinal cancer and lymphoma. Therefore, we recommend an alternative drug instead of fluconazole as a first line of treatment for these type of cancers and administration of fluconazole in patients undergoing chemotherapy should be prescribed in accordance with the type of cancer.

  1. Nevirapine, sodium concentration and HIV-1 RNA in breast milk and plasma among HIV-infected women receiving short-course antiretroviral prophylaxis

    DEFF Research Database (Denmark)

    Salado-Rasmussen, Kirsten; Theilgaard, Zahra Persson; Chiduo, Mercy G.

    2015-01-01

    Introduction Risk factors for breast milk transmission of HIV-1 from mother to child include high plasma and breast milk viral load, low maternal CD4 count and breast pathology such as mastitis. Objective To determine the impact of nevirapine and subclinical mastitis on HIV-1 RNA in maternal plasma...... and breast milk after intrapartum single-dose nevirapine combined with either 1-week tail of Combivir (zidovudine/lamivudine) or single-dose Truvada (tenofovir/emtricitabine). Methods Maternal plasma and bilateral breast milk samples were collected between April 2008 and April 2011 at 1, 4 and 6 weeks...... postpartum from HIV-infected Tanzanian women. Moreover, plasma samples were collected at delivery from mother and infant. Results HIV-1 RNA was quantified in 1,212 breast milk samples from 273 women. At delivery, 96% of the women and 99% of the infants had detectable nevirapine in plasma with a median...

  2. Prevalence and Fluconazole Susceptibility Profile of Candida spp. Clinical Isolates in a Brazilian Tertiary Hospital in Minas Gerais, Brazil

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    Athayde Neves-Junior

    2015-08-01

    Full Text Available Candidiasis has become an important concern for clinical practice, especially with the increasing incidence of immunocompromised patients. In this scenario, the development resistance to fluconazole presents a challenge for treating these opportunistic infections. The aim of this study was to evaluate some epidemiology features of Candidainfections in a Brazilian University Hospital using data, previously unavailable. We observed that 44% of the 93 clinical isolates tested, belonged to Candida albicansspecies and 56% belonged to non-Candida albicansspecies (mainly Candida tropicalis and Candida glabrata. Most strains were isolated from urine samples where C. albicans was predominantly detected. 29 strains presented a fluconazole resistance phenotype and of these, 22 were chemosensitised by FK506, a classical inhibitor of ABC transporters related to azoles resistance. These data suggest the probable role of efflux pumps in this resistance phenotype. Our study highlights the need for developing effective control measures for fungal infections, rational use of antifungal drugs and development of new molecules able to abrogate the active transport of antifungals.

  3. Triclosan demonstrates synergic effect with amphotericin B and fluconazole and induces apoptosis-like cell death in Cryptococcus neoformans

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    Elaheh eMovahed

    2016-03-01

    Full Text Available Objectives: Cryptococcus neoformans is an opportunistic fungus that causes fatal meningoencephalitis especially in AIDS patients. There is an increasing need for discovery of new anti-cryptococcal drugs due to emergence of resistance cases in recent years. In this study, we aim to elucidate the antifungal effect of triclosan against C. neoformans.Methods: Minimal inhibitory concentration (MIC of triclosan in different C. neoformans strains was first examined. The in vitro interactions between triclosan and two standard anti-fungal drugs (amphotericin B and fluconazole were further evaluated by microdilution checkerboard assay. Mechanism of triclosan fungicidal activity was then investigated by viewing the cell morphology under transmission electron microscope.Results: We reported that triclosan potently inhibited the growth of C. neoformans. A combination of triclosan with amphotericin B or with fluconazole enhanced their fungicidal effects. Triclosan-treated C. neoformans displayed characteristics such as nuclear chromatin condensation, extensive intracellular vacuolation and mitochondrial swelling, indicating that triclosan triggered apoptosis-like cell death.Conclusion: In summary, our report suggests triclosan as an independent drug or synergent for C. neoformans treatment.

  4. Prevalence and Fluconazole Susceptibility Profile of Candida spp. Clinical Isolates in a Brazilian Tertiary Hospital in Minas Gerais, Brazil.

    Science.gov (United States)

    Neves-Junior, Athayde; Cartágenes-Pinto, Ana Carolina; Rocha, Débora A S; de Sá, Leandro F Reis; Junqueira, Maria de Lourdes; Ferreira-Pereira, Antonio

    2015-08-01

    Candidiasis has become an important concern for clinical practice, especially with the increasing incidence of immunocompromised patients. In this scenario, the development resistance to fluconazole presents a challenge for treating these opportunistic infections. The aim of this study was to evaluate some epidemiology features of Candida infections in a Brazilian University Hospital using data, previously unavailable. We observed that 44% of the 93 clinical isolates tested, belonged to Candida albicans species and 56% belonged to non-Candida albicans species (mainly Candida tropicalis and Candida glabrata). Most strains were isolated from urine samples where C. albicans was predominantly detected. 29 strains presented a fluconazole resistance phenotype and of these, 22 were chemosensitised by FK506, a classical inhibitor of ABC transporters related to azoles resistance. These data suggest the probable role of efflux pumps in this resistance phenotype. Our study highlights the need for developing effective control measures for fungal infections, rational use of antifungal drugs and development of new molecules able to abrogate the active transport of antifungals.

  5. Evaluation of the virological and metabolic effects of switching protease inhibitor combination antiretroviral therapy to nevirapine-based therapy for the treatment of HIV infection.

    Science.gov (United States)

    Tebas, Pablo; Yarasheski, Kevin; Henry, Keith; Claxton, Sherri; Kane, E; Bordenave, B; Klebert, Michael; Powderly, William G

    2004-06-01

    In spite of indisputable benefits, the use of antiretroviral therapy is associated with multiple metabolic complications. Switching to simpler regimens might maintain viral suppression, improve metabolic side effects, and provide insight into the pathogenesis of these complications. Our objective was to carefully characterize the virological and metabolic effects of switching from a successful protease inhibitor (PI)-based antiretroviral regimen to a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen with nevirapine (NVP). Forty patients, taking their first successful (less than 40 HIV RNA copies/ml) PI-based regimen, switched their PI to NVP. If patients did not tolerate NVP, substitution with efavirenz was allowed. The duration of the study was 48 weeks. At 12 weeks intervals subjects had multiple virological and metabolic parameters including glucose, insulin, C-peptide, glucagon, proinsulin, blood lipids, and lipoproteins. A subgroup of 18 patients also had body composition evaluations with DEXA scans and MRIs of the abdomen and the thighs as well as insulin tolerance tests. Ninety-five percent of the patients maintained viral suppression (95% CI 88-100%); only one patient failed and another developed hepatitis. There were improvements in glucose (decreased fasting glucose, insulin, and improved insulin tolerance) and lipid metabolism (decreased triglycerides and increased HDL), but no changes in body composition and bone mineral density. Our study supports a pathogenic role for PIs in the development of hypertriglyceridemia and insulin resistance, but a more limited role in the fat redistribution syndrome.

  6. Quality assessment of fluconazole capsules and oral suspensions compounded by pharmacies located in the United States.

    Science.gov (United States)

    Laporte, Carine M; Cruz-Espindola, Crisanta; Thungrat, Kamoltip; Schick, Anthea E; Lewis, Thomas P; Boothe, Dawn M

    2017-04-01

    OBJECTIVE To evaluate pharmaceutical characteristics (strength or concentration, accuracy, and precision), physical properties, and bacterial contamination of fluconazole compounded products. SAMPLE Fluconazole compounded products (30- and 240-mg capsules; 30- and 100-mg/mL oral suspensions) from 4 US veterinary compounding pharmacies. PROCEDURES Fluconazole compounded products were ordered 3 times from each of 4 pharmacies at 7- or 10-day intervals. Generic fluconazole products (50- and 200-mg tablets; 10- and 40-mg/mL oral suspensions) served as references. Compounded products were evaluated at the time of receipt; suspensions also were evaluated 3 months later and at beyond-use dates. Evaluations included assessments of strength (concentration), accuracy, precision, physical properties, and bacterial contamination. Acceptable accuracy was defined as within ± 10% of the labeled strength (concentration) and acceptable precision as within ± 10%. Fluconazole was quantified by use of high-performance liquid chromatography. RESULTS Physical characteristics of compounded products differed among pharmacies. Aerobic bacterial cultures yielded negative results. Capsules (30 and 240 mg) had acceptable accuracy (median, 96.3%; range, 87.3% to 135.2%) and precision (mean ± SD, 7.4 ± 6.0%). Suspensions (30 and 100 mg/mL) had poor accuracy (median, 73.8%; range, 53.9% to 95.2%) and precision (mean ± SD, 15.0 ± 6.9%). Accuracy and precision were significantly better for capsules than for suspensions. CONCLUSIONS AND CLINICAL RELEVANCE Fluconazole compounded products, particularly suspensions, differed in pharmaceutical and physical qualities. Studies to evaluate the impact of inconsistent quality on bioavailability or clinical efficacy of compounded fluconazole products are indicated, and each study should include data on the quality of the compounded product evaluated.

  7. Candida parapsilosis Resistance to Fluconazole: Molecular Mechanisms and In Vivo Impact in Infected Galleria mellonella Larvae.

    Science.gov (United States)

    Souza, Ana Carolina R; Fuchs, Beth Burgwyn; Pinhati, Henrique M S; Siqueira, Ricardo A; Hagen, Ferry; Meis, Jacques F; Mylonakis, Eleftherios; Colombo, Arnaldo L

    2015-10-01

    Candida parapsilosis is the main non-albicans Candida species isolated from patients in Latin America. Mutations in the ERG11 gene and overexpression of membrane transporter proteins have been linked to fluconazole resistance. The aim of this study was to evaluate the molecular mechanisms in fluconazole-resistant strains of C. parapsilosis isolated from critically ill patients. The identities of the nine collected C. parapsilosis isolates at the species level were confirmed through molecular identification with a TaqMan qPCR assay. The clonal origin of the strains was checked by microsatellite typing. The Galleria mellonella infection model was used to confirm in vitro resistance. We assessed the presence of ERG11 mutations, as well as the expression of ERG11 and two additional genes that contribute to antifungal resistance (CDR1 and MDR1), by using real-time quantitative PCR. All of the C. parapsilosis (sensu stricto) isolates tested exhibited fluconazole MICs between 8 and 16 μg/ml. The in vitro data were confirmed by the failure of fluconazole in the treatment of G. mellonella infected with fluconazole-resistant strains of C. parapsilosis. Sequencing of the ERG11 gene revealed a common mutation leading to a Y132F amino acid substitution in all of the isolates, a finding consistent with their clonal origin. After fluconazole exposure, overexpression was noted for ERG11, CDR1, and MDR1 in 9/9, 9/9, and 2/9 strains, respectively. We demonstrated that a combination of molecular mechanisms, including the presence of point mutations in the ERG11 gene, overexpression of ERG11, and genes encoding efflux pumps, are involved in fluconazole resistance in C. parapsilosis.

  8. Molecular mechanisms of fluconazole resistance in Candida parapsilosis isolates from a U.S. surveillance system.

    Science.gov (United States)

    Grossman, Nina T; Pham, Cau D; Cleveland, Angela A; Lockhart, Shawn R

    2015-02-01

    Candida parapsilosis is the second or third most common cause of candidemia in many countries. The Infectious Diseases Society of America recommends fluconazole as the primary therapy for C. parapsilosis candidemia. Although the rate of fluconazole resistance among C. parapsilosis isolates is low in most U.S. institutions, the resistance rate can be as high as 7.5%. This study was designed to assess the mechanisms of fluconazole resistance in 706 incident bloodstream isolates from U.S. hospitals. We sequenced the ERG11 and MRR1 genes of 122 C. parapsilosis isolates with resistant (30 isolates; 4.2%), susceptible dose-dependent (37 isolates; 5.2%), and susceptible (55 isolates) fluconazole MIC values and used real-time PCR of RNA from 17 isolates to investigate the regulation of MDR1. By comparing these isolates to fully fluconazole-susceptible isolates, we detected at least two mechanisms of fluconazole resistance: an amino acid substitution in the 14-α-demethylase gene ERG11 and overexpression of the efflux pump MDR1, possibly due to point mutations in the MRR1 transcription factor that regulates MDR1. The ERG11 single nucleotide polymorphism (SNP) was found in 57% of the fluconazole-resistant isolates and in no susceptible isolates. The MRR1 SNPs were more difficult to characterize, as not all resulted in overexpression of MDR1 and not all MDR1 overexpression was associated with an SNP in MRR1. Further work to characterize the MRR1 SNPs and search for overexpression of other efflux pumps is needed.

  9. Vaginal nystatin versus oral fluconazole for the treatment for recurrent vulvovaginal candidiasis.

    Science.gov (United States)

    Fan, Shangrong; Liu, Xiaoping; Wu, Cong; Xu, Lixuan; Li, Jianling

    2015-02-01

    Recurrent vulvovaginal candidiasis (RVVC) is a common condition that can physically and psychologically impact patients. We compared the efficacy and safety of vaginal nystatin suppositories for 14 days each month versus standard oral fluconazole regimens for the treatment for RVVC. Patients (n = 293) were enrolled in the study from April 2010 to September 2013. After the initial therapy, the mycological cure rates were 78.3% (119/152) and 73.8% (104/141) in the nystatin group and fluconazole group, respectively (95% CI, 0.749-2.197, p > 0.05). The mycological cure rates at the end of maintenance therapy were 80.7% (96/119) and 72.7% (72/99) in the two groups, respectively (95% CI, 0.954-3.293, p > 0.05).The mycological cure rates at the end without treatment for 6 months were 81.25% (78/96) and 82.19% (60/73) in the two groups, respectively (95% CI, 0.427-2.066, p > 0.05). The mycological cure rates of RVVC caused by C. albicans were 84.0% (89/106) and 81.8% (99/121) in the two groups, respectively. The mycological cure rates of RVVC caused by C. glabrata were 64.3% (27/42) and 12.5% (2/16) in the two groups, respectively. The initial and 6-month maintenance therapy were successful in five of the nine patients in the nystatin group with RVVC caused by fluconazole-resistant Candida, whereas in the fluconazole group, initial therapy failed in all patients with RVVC caused by fluconazole-resistant Candida (n = 7). We conclude that both fluconazole and nystatin therapies are effective in treating RVVC. Nystatin may also be effective for the treatment for RVVC caused by C. glabrata or fluconazole-resistant Candida.

  10. Prevention of mother-to-child transmission of HIV infection: Views and perceptions about swallowing nevirapine in rural Lilongwe, Malawi

    Directory of Open Access Journals (Sweden)

    Nyirenda Lot J

    2010-06-01

    Full Text Available Abstract Background In 2006 the World Health Organization described the status of prevention of mother to child transmission (PMTCT service implementation as unacceptable, with an urgent need for a renewed public health approach to improve access. For PMTCT to be effective it needs to be accessible, acceptable and affordable; however research in Africa into accessibility, uptake and acceptability of PMTCT services has been predominately urban based and usually focusing on women who deliver in hospitals. The importance of involving other community members to strengthen both PMTCT uptake and adherence, and to support women emotionally, has been advocated. Urban men's and rural traditional birth attendants' (TBAs involvement have improved uptake of HIV testing and of nevirapine. Methods A qualitative study was carried out in a rural district of Malawi's central region to explore the views about and perceptions of PMTCT antiretroviral treatment. Semi-structured interviews and focus group discussions were held with antenatal and postnatal women, fathers, grandmothers, TBAs, community leaders and PMTCT health workers. Results Two broad themes of findings emerged: those that relate to the hospital PMTCT service, and those that relate to the community. Trust in the hospital was strong, but distance, transport costs and perceived harsh, threatening health worker attitudes were barriers to access. Grandmothers were perceived to have influence on the management of labour, unlike fathers, but both were suggested as key people to ensure that babies are brought to the hospital for nevirapine syrup. TBAs were seen as powerful, local, and important community members, but some as uneducated. Conclusion PMTCT was seen as a community issue in which more than the mother alone can be involved. To support access to PMTCT, especially for rural women, there is need for further innovation and implementation research on involving TBAs in some aspects of PMTCT services

  11. Paracoccidioidomicose evidenciando comprometimento medular tratada com sucesso por fluconazol

    Directory of Open Access Journals (Sweden)

    Leandro Pajuaba de Moura

    1994-03-01

    Full Text Available O envolvimento do sistema nervoso central na paracoccidioidomicose tem sido raramente descrito na literatura e sua frequência varia de 9,99% a 27,27%, manifestando-se basicamente sob duas formas clínicas: meníngea e pseudotumoral (abscessos, granulomas, nódulos ou cistos. O Paracoccidioides brasiliensis incide principalmente nos hemisférios cerebrais, podendo acometer ainda cerebelo, ponte, bulbo, meninges cerebrais e raquidianas, sendo excepcional o comprometimento do parênquima medular. Os autores apresentam o caso de um paciente com paracoccidioidomicose com evidências clínicas de comprometimento medular, comprovada por exames complementares indiretos pouco invasivos. Destacam a resposta terapêutica inédita a novo agente antifúngico bistriazólico, o fluconazol, pela primeira vez utilizado nesta forma de apresentação clínica da doença. Salientam a rariedade do comprometimento medular, o diagnóstico através de propedêutica não cirúrgica e a excelente resposta a este novo tratamento.

  12. Growth patterns among HIV-exposed infants receiving nevirapine prophylaxis in Pune, India

    Directory of Open Access Journals (Sweden)

    Ram Malathi

    2012-10-01

    Full Text Available Abstract Background India has among the highest rates of infant malnutrition. Few studies investigating the growth patterns of HIV-exposed infants in India or the impact of timing of HIV infection on growth in settings such as India exist. Methods We used data from the Six Week Extended Nevirapine (SWEN trial to compare the growth patterns of HIV-infected and HIV-exposed but uninfected infants accounting for timing of HIV infection, and to identify risk factors for stunting, underweight and wasting. Growth and timing of HIV infection were assessed at weeks 1, 2, 4, 6, 10, 14 weeks and 6, 9, 12 months of life. Random effects multivariable logistic regression method was used to assess factors associated with stunting, underweight and wasting. Results Among 737 HIV-exposed infants, 93 (13% were HIV-infected by 12 months of age. Among HIV-infected and uninfected infants, baseline prevalence of stunting (48% vs. 46%, underweight (27% vs. 26% and wasting (7% vs. 11% was similar (p>0.29, but by 12 months stunting and underweight, but not wasting, were significantly higher in HIV-infected infants (80% vs. 56%, 52% vs. 29%, p Conclusion Baseline stunting and underweight was high in both HIV-infected and uninfected infants; growth indices diverged early and were impacted by timing of infection and SWEN prophylaxis. Early growth monitoring of all HIV-exposed infants is an important low-cost strategy for improving health and survival outcomes of these infants. Trial Registration NCT00061321

  13. Antifungal activity of essential oils from Iranian plants against fluconazole-resistant and fluconazole-susceptible Candida albicans

    Science.gov (United States)

    Sharifzadeh, Aghil; Shokri, Hojjatollah

    2016-01-01

    Objective: The purpose of this study was to assay the antifungal activity of selected essential oils obtained from plants against both fluconazole (FLU)-resistant and FLU-susceptible C. albicans strains isolated from HIV positive patients with oropharyngeal candidiasis (OPC). Materials and Methods: The essential oils were obtained by hydrodistillation method from Myrtus communis (My. communis), Zingiber officinale roscoe (Z. officinale roscoe), Matricaria chamomilla (Ma. chamomilla), Trachyspermum ammi (T. ammi) and Origanum vulgare (O. vulgare). The susceptibility test was based on the M27-A2 methodology. The chemical compositions of the essential oils were obtained by gas chromatography- mass spectroscopy (GC-MS). Results: In GC-MS analysis, thymol (63.40%), linalool (42%), α-pinene (27.87%), α-pinene (22.10%), and zingiberene (31.79%) were found to be the major components of T. ammi, O. vulgare, My. communis, Ma. chamomilla and Z. officinale roscoe, respectively. The results showed that essential oils have different levels of antifungal activity. O. vulgare and T. ammi essential oils were found to be the most efficient (Pessential oils were higher than those of the FLU-susceptible yeasts. Conclusion: Results of this study indicated that the oils from medicinal plants could be used as potential anti FLU-resistant C. albicans agents. PMID:27222835

  14. Antifungal activity of essential oils from Iranian plants against fluconazole-resistant and fluconazole-susceptible Candida albicans

    Directory of Open Access Journals (Sweden)

    Aghil Sharifzadeh

    2016-03-01

    Full Text Available Objectives: The purpose of this study was to assay the antifungal activity of selected essential oils obtained from plants against both fluconazole (FLU-resistant and FLU-susceptible C. albicans strains isolated from HIV positive patients with oropharyngeal candidiasis (OPC. Materials and Methods: The essential oils were obtained by hydrodistillation method from Myrtus communis (My. communis, Zingiber officinale roscoe (Z. officinale roscoe, Matricaria chamomilla (Ma. chamomilla, Trachyspermum ammi (T. ammi and Origanum vulgare (O. vulgare. The susceptibility test was based on the M27-A2 methodology. The chemical compositions of the essential oils were obtained by gas chromatography- mass spectroscopy (GC-MS. Results: In GC-MS analysis, thymol (63.40%, linalool (42%, α-pinene (27.87%, α-pinene (22.10%, and zingiberene (31.79% were found to be the major components of T. ammi, O. vulgare, My. communis, Ma. chamomilla and Z. officinale roscoe, respectively. The results showed that essential oils have different levels of antifungal activity. O. vulgare and T. ammi essential oils were found to be the most efficient (P

  15. Study the interactions between human serum albumin and two antifungal drugs: fluconazole and its analogue DTP.

    Science.gov (United States)

    Zhang, Shao-Lin; Yao, Huankai; Wang, Chenyin; Tam, Kin Y

    2014-11-01

    Binding affinities of fluconazole and its analogue 2-(2,4-dichlorophenyl)-1,3-di(1H-1,2,4-triazol-yl)-2-propanol (DTP) to human serum albumin (HSA) were investigated under approximately human physiological conditions. The obtained result indicated that HSA could generate fluorescent quenching by fluconazole and DTP because of the formation of non-fluorescent ground-state complexes. Binding parameters calculated from the Stern-Volmer and the Scatchard equations showed that fluconazole and DTP bind to HSA with binding affinities of the order 10(4)L/mol. The thermodynamic parameters revealed that the binding was characterized by negative enthalpy and positive entropy changes, suggesting that the binding reaction was exothermic. Hydrogen bonds and hydrophobic interaction were found to be the predominant intermolecular forces stabilizing the drug-protein. The effect of metal ions on the binding constants of fluconazole-HSA complex suggested that the presence of Mg(2+) and Zn(2+) ions could decrease the free drug level and extend the half-life in the systematic circulation. Docking experiments revealed that fluconazole and DTP binds in HSA mainly by hydrophobic interaction with the possibility of hydrogen bonds formation between the drugs and the residues Arg 222, Lys 199 and Lys 195 in HSA.

  16. Pharmacokinetics/pharmacodynamic correlations of fluconazole in murine model of cryptococcosis.

    Science.gov (United States)

    Santos, Julliana Ribeiro Alves; César, Isabela Costa; Costa, Marliete Carvalho; Ribeiro, Noelly Queiroz; Holanda, Rodrigo Assunção; Ramos, Lais Hott; Freitas, Gustavo José Cota; Paixão, Tatiane Alves; Pianetti, Gerson Antônio; Santos, Daniel Assis

    2016-09-20

    The emergence of fluconazole-resistant Cryptococcus gattii is a global concern, since this azole is the main antifungal used worldwide to treat patients with cryptococcosis. Although pharmacokinetic (PK) and pharmacodynamic (PD) indices are useful predictive factors for therapeutic outcomes, there is a scarcity of data regarding PK/PD analysis of antifungals in cryptococcosis caused by resistant strains. In this study, PK/PD parameters were determined in a murine model of cryptococcosis caused by resistant C. gattii. We developed and validated a suitable liquid chromatography-electrospray ionization tandem mass spectrometry method for PK studies of fluconazole in the serum, lungs, and brain of uninfected mice. Mice were infected with susceptible or resistant C. gattii, and the effects of different doses of fluconazole on the pulmonary and central nervous system fungal burden were determined. The peak levels in the serum, lungs, and brain were achieved within 0.5h. The AUC/MIC index (area under the curve/minimum inhibitory concentration) was associated with the outcome of anti-cryptococcal therapy. Interestingly, the maximum concentration of fluconazole in the brain was lower than the MIC for both strains. In addition, the treatment of mice infected with the resistant strain was ineffective even when high doses of fluconazole were used or when amphotericin B was tested, confirming the cross-resistance between these drugs. Altogether, our novel data provide the correlation of PK/PD parameters with antifungal therapy during cryptococcosis caused by resistant C. gattii.

  17. Cdr2p contributes to fluconazole resistance in Candida dubliniensis clinical isolates.

    LENUS (Irish Health Repository)

    2011-05-01

    The development of resistance to azole antifungals used in the treatment of fungal infections can be a serious medical problem. Here, we investigate the molecular mechanisms associated with reduced susceptibility to fluconazole in clinical isolates of Candida dubliniensis , showing evidence of the trailing growth phenomenon. The changes in membrane sterol composition were studied in the presence of subinhibitory fluconazole concentrations. Despite lanosterol and eburicol accumulating as the most prevalent sterols after fluconazole treatment, these ergosterol precursors still support growth of Candida isolates. The overexpression of ABC transporters was demonstrated by immunoblotting employing specific antibodies against Cdr1p and Cdr2p. The presence of a full-length 170 kDa protein Cdr1p was detected in two isolates, while a truncated form of Cdr1p with the molecular mass of 85 kDa was observed in isolate 966\\/3(2). Notably, Cdr2p was detected in this isolate, and the expression of this transporter was modulated by subinhibitory concentrations of fluconazole. These results suggest that C. dubliniensis can display the trailing growth phenomenon, and such isolates express similar molecular mechanisms like that of fluconazole-resistant isolates and can therefore be associated with recurrent infections.

  18. Comparison between fluconazole and ketoconazole effectivity in the treatment of pityriasis versicolor.

    Science.gov (United States)

    Yazdanpanah, Mohammad Javad; Azizi, Hoda; Suizi, Behnaz

    2007-07-01

    Topical drugs are often effective in limited lesions of pityriasis versicolor; but in extensive cases, systemic drugs are more suitable. Previous studies have shown that ketoconazole and fluconazole are effective in 42-97% and 74-100% of lesions respectively. Our purpose was to compare the effectiveness of a single dose of 400 mg ketoconazole with two doses of 300 mg of fluconazole with 2 weeks interval. Ninety patients with extensive pityriasis versicolor (body involved area > or =25%) were randomly assigned to treatment with either a single dose of 400 mg of ketoconazole or with two doses of 300 mg of fluconazole with 2 weeks interval. One month after the treatment, the improvement rate and side effects were evaluated by clinical examination and questionnaire. Sixty cases (66.7%) completed the study. They were 51 males and nine females, with a mean age of 30 years. At the follow-up visit (1 month after the end of treatment), the improvement rate for ketoconazole (87.9%) was not significantly different from fluconazole (81.5%), (Fisher test: P = 0.37). Due to the hepatotoxicity of ketoconazole, fluconazole appears to be more suitable in the treatment of extensive pityriasis versicolor.

  19. Combination of CuO nanoparticles and fluconazole: preparation, characterization, and antifungal activity against Candida albicans

    Science.gov (United States)

    Weitz, Iris S.; Maoz, Michal; Panitz, Daniel; Eichler, Sigal; Segal, Ester

    2015-08-01

    Combination therapy becomes an important strategy in the management of invasive fungal infections and emergence of resistant fungi mutants. In this work, we examine the combination of copper oxide (CuO) nanoparticles (NPs) with fluconazole as potential treatment against the pathogenic fungi, Candida albicans. CuO NPs ( 7 nm in size) were synthesized with acetate ligands assembled on their surface, as shown by both thermal gravimetric analysis and FTIR spectroscopy. Unlike the commercial CuO (both bulk and 50 nm particles), that are poorly dispersed in water, the interaction with water allows the fine dispersion of the coated CuO NPs and their excellent colloidal stability. The addition of fluconazole to the aqueous CuO dispersion induced spontaneous self-assembly of the NPs into linear pearl-like chains network, shown by cryogenic transmission electron microscopy (cryo-TEM). The antifungal activity of the CuO NPs and their combination with fluconazole (fluconazole-CuO NPs) was studied against C. albicans. The best MIC values were obtained at concentrations as low as 0.2 and 0.3 mg/mL, respectively. The results suggest that fluconazole-CuO NPs can provide a potential alternative treatment for C. albicans infections.

  20. Analysis of the relationship between fluconazole consumption and non-C. albicans Candida infections.

    Science.gov (United States)

    Tyczkowska-Sieron, E; Gaszynski, W; Tyczkowski, J; Glowacka, A

    2014-10-01

    The effect of fluconazole consumption on the incidence of nosocomial non-C. albicans Candida infections remains unclear. In this study we investigated such a relationship in an intensive care unit (Poland) over an 11-year period (2002-2012). Statistics relating to the number of candidiasis cases and the number of defined daily doses of fluconazole showed that only a very weak and not statistically significant linear correlation existed between these two variables (r(2) = 0.36, P = 0.052). However, the assumption of a 1-year delay in the infection response to changes in fluconazole concentrations resulted in a strong and statistically significant linear correlation (r(2) = 0.64, P = 0.0053). To more accurately determine the nature of this relationship, a simple epidemiological model was proposed that provided a better than linear correlation (r(2) = 0.78, P = 0.00077). We successfully used this approach to analyze results from the literature that were interpreted as evidence that fluconazole use is not a risk factor for development of non-C. albicans Candida infections. If a time delay in the infection response was assumed, a strong and statistically significant correlation was obtained. These findings suggest the need for a closer look at fluconazole therapy as a possible risk factor for development of non-C. albicans Candida infections.

  1. In vitro activity of fluconazole and amphotericin B against Candida inconspicua clinical isolates as determined by the time-kill method

    DEFF Research Database (Denmark)

    Szabó, Zsuzsanna; Sóczó, Georgina; Miszti, Cecilia

    2008-01-01

    Candida inconspicua is an emerging pathogen in immunocompromised patients possessing inherently decreased susceptibility to fluconazole. We determined the MICs and killing activity of fluconazole and amphotericin B against C. inconspicua clinical isolates as well as reference strain C. inconspicua...

  2. In vitro activity of fluconazole and amphotericin B against Candida inconspicua clinical isolates as determined by the time-kill method

    DEFF Research Database (Denmark)

    Szabó, Zsuzsanna; Sóczó, Georgina; Miszti, Cecilia

    2008-01-01

    Candida inconspicua is an emerging pathogen in immunocompromised patients possessing inherently decreased susceptibility to fluconazole. We determined the MICs and killing activity of fluconazole and amphotericin B against C. inconspicua clinical isolates as well as reference strain C. inconspicua...

  3. Stavudine- and nevirapine-related drug toxicity while on generic fixed-dose antiretroviral treatment: incidence, timing and risk factors in a three-year cohort in Kigali, Rwanda.

    Science.gov (United States)

    van Griensven, Johan; Zachariah, Rony; Rasschaert, Freya; Mugabo, Jules; Atté, Edi F; Reid, Tony

    2010-02-01

    This cohort study was conducted to report on the incidence, timing and risk factors for stavudine (d4T)- and nevirapine (NVP)-related severe drug toxicity (requiring substitution) with a generic fixed-dose combination under program conditions in Kigali, Rwanda. Probability of 'time to first toxicity-related drug substitution' was estimated using the Kaplan-Meier method and Cox-proportional hazards modeling was used to identify risk factors. Out of 2190 adults (median follow-up: 1.5 years), d4T was replaced in 175 patients (8.0%) for neuropathy, 69 (3.1%) for lactic acidosis and 157 (7.2%) for lipoatrophy, which was the most frequent toxicity by 3 years of antiretroviral treatment (ART). NVP was substituted in 4.9 and 1.3% of patients for skin rash and hepatotoxicity, respectively. Use of d4T 40 mg was associated with increased risk of lipoatrophy and early (strategies.

  4. Effects of fluconazole treatment of mice infected with fluconazole-susceptible and -resistant Candida tropicalis on fungal cell surface hydrophobicity, adhesion and biofilm formation

    Directory of Open Access Journals (Sweden)

    R L Kanoshiki

    2015-01-01

    Full Text Available Background : The incidence of Candida tropicalis less susceptible to fluconazole (FLC has been reported in many parts of the world. Objectives : The aim of this study was to examine the changes of putative virulence attributes of Candida tropicalis accompanying the development of resistance to FLC in vitro and in vivo. Materials and Methods : A FLC-resistant strain (FLC-R was obtained after sequential exposure of a clinical isolate FLC-sensitive (FLC-S to increasing concentrations of the antifungal. The course of infection by both strains was analyzed in BALB/c mice. Analyses of gene expression were performed by real-time polymerase chain reaction PCR. The cell surface hydrophobicity, adhesion and biofilm formation were also determined. Results : Development of resistance to FLC could be observed after 15 days of subculture in azole-containing medium. Overexpression of MDR1 and ERG11 genes were observed in FLC-R, and this strain exhibited enhanced virulence in mice, as assessed by the mortality rate. All mice challenged with the FLC-R died and FLC-treatment caused earlier death in mice infected with this strain. All animals challenged with FLC-S survived the experiment, regardless of FLC-treatment. Overall, FLC-R derivatives strains were significantly more hydrophobic than FLC-S strains and showed greater adherence and higher capacity to form biofilm on polystyrene surface. Conclusions : The expression of virulence factors was higher in FLC-R-C. tropicalis and it was enhanced after FLC-exposure. These data alert us to the importance of identifying microorganisms that show resistance to the antifungals to establish an appropriate management of candidiasis therapy.

  5. Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: a 10.5-year analysis of susceptibilities of Candida Species to fluconazole and voriconazole as determined by CLSI standardized disk diffusion.

    Science.gov (United States)

    Pfaller, M A; Diekema, D J; Gibbs, D L; Newell, V A; Ellis, D; Tullio, V; Rodloff, A; Fu, W; Ling, T A

    2010-04-01

    Fluconazole in vitro susceptibility test results for 256,882 isolates of Candida spp. were collected from 142 sites in 41 countries from June 1997 to December 2007. Data were collected for 197,619 isolates tested with voriconazole from 2001 to 2007. A total of 31 different species of Candida were isolated. Increased rates of isolation of the common non-albicans species C. glabrata (10.2% to 11.7%), C. tropicalis (5.4% to 8.0%), and C. parapsilosis (4.8% to 5.6%) were noted when the time periods 1997 to 2000 and 2005 to 2007 were compared. Investigators tested clinical isolates of Candida spp. by the CLSI M44-A disk diffusion method. Overall, 90.2% of Candida isolates tested were susceptible (S) to fluconazole; however, 13 of 31 species identified exhibited decreased susceptibility (ciferrii remained S to voriconazole. An increase in fluconazole resistance over time was seen with C. parapsilosis, C. guilliermondii, C. lusitaniae, C. sake, and C. pelliculosa. Among the emerging fluconazole-R species were C. guilliermondii (11.4% R), C. inconspicua (53.2% R), C. rugosa (41.8% R), and C. norvegensis (40.7% R). The rates of isolation of C. rugosa, C. inconspicua, and C. norvegensis increased by 5- to 10-fold over the 10.5-year study period. C. guilliermondii and C. rugosa were most prominent in Latin America, whereas C. inconspicua and C. norvegensis were most common in Eastern European countries. This survey identifies several less-common species of Candida with decreased susceptibility to azoles. These organisms may pose a future threat to optimal antifungal therapy and underscore the importance of prompt and accurate species identification and antifungal susceptibility testing.

  6. Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: a 10.5-Year Analysis of Susceptibilities of Candida Species to Fluconazole and Voriconazole as Determined by CLSI Standardized Disk Diffusion ▿

    Science.gov (United States)

    Pfaller, M. A.; Diekema, D. J.; Gibbs, D. L.; Newell, V. A.; Ellis, D.; Tullio, V.; Rodloff, A.; Fu, W.; Ling, T. A.

    2010-01-01

    Fluconazole in vitro susceptibility test results for 256,882 isolates of Candida spp. were collected from 142 sites in 41 countries from June 1997 to December 2007. Data were collected for 197,619 isolates tested with voriconazole from 2001 to 2007. A total of 31 different species of Candida were isolated. Increased rates of isolation of the common non-albicans species C. glabrata (10.2% to 11.7%), C. tropicalis (5.4% to 8.0%), and C. parapsilosis (4.8% to 5.6%) were noted when the time periods 1997 to 2000 and 2005 to 2007 were compared. Investigators tested clinical isolates of Candida spp. by the CLSI M44-A disk diffusion method. Overall, 90.2% of Candida isolates tested were susceptible (S) to fluconazole; however, 13 of 31 species identified exhibited decreased susceptibility (ciferrii remained S to voriconazole. An increase in fluconazole resistance over time was seen with C. parapsilosis, C. guilliermondii, C. lusitaniae, C. sake, and C. pelliculosa. Among the emerging fluconazole-R species were C. guilliermondii (11.4% R), C. inconspicua (53.2% R), C. rugosa (41.8% R), and C. norvegensis (40.7% R). The rates of isolation of C. rugosa, C. inconspicua, and C. norvegensis increased by 5- to 10-fold over the 10.5-year study period. C. guilliermondii and C. rugosa were most prominent in Latin America, whereas C. inconspicua and C. norvegensis were most common in Eastern European countries. This survey identifies several less-common species of Candida with decreased susceptibility to azoles. These organisms may pose a future threat to optimal antifungal therapy and underscore the importance of prompt and accurate species identification and antifungal susceptibility testing. PMID:20164282

  7. Insufficient fluconazole exposure in pediatric cancer patients and the need for therapeutic drug monitoring in critically ill children

    NARCIS (Netherlands)

    van der Elst, Kim CM; Pereboom, Marieke; van den Heuvel, Edwin R; Kosterink, Jos G W; Scholvinck, Elisabeth H.; Alffenaar, Jan-Willem C

    2014-01-01

    Background. Fluconazole is recommended as first-line treatment in invasive candidiasis in children and infants. Although timely achievement of adequate exposure of fluconazole improves outcome, therapeutic drug monitoring is currently not recommended. Methods. We conducted a retrospective study of c

  8. Cyclosporine A decreases the fluconazole minimum inhibitory concentration of Candida albicans clinical isolates but not biofilm formation and cell growth.

    Science.gov (United States)

    Wibawa, T; Nurrokhman; Baly, I; Daeli, P R; Kartasasmita, G; Wijayanti, N

    2015-03-01

    Among the genus Candida, Candida albicans is the most abundant species in humans. One of the virulent factors of C. albicans is its ability to develop biofilm. Biofilm forming microbes are characterized by decreasing of its susceptibility to antibiotics and antifungal. The fungicidal effect of fluconazole may be enhanced by cyclosporine A in laboratory engineered C. albicans strains. The aim of this work is to analyze the synergistic effect of cyclosporine A with fluconazole in C. albicans clinical isolates and the effect of cycolsporine A alone in the biofilm formation. Six fluconazole resistant and six sensitive C. albicans clinical isolates were analyzed for its minimum inhibitory concentration (MICs), biofilm formation, and cell growths. A semi-quantitative XTT [2,3-bis(2-methoxy-4-nitro-5- sulfo-phenyl)-2H-tetrazolium-5-carboxanilide] reduction assay was conducted to measure the biofilm formation. Cyclosporine A has synergistic effect with fluconazole that was shown by decreasing MICs of both fluconazole resistant and sensitive C. albicans clinical isolates. However, cyclosporine A alone did not influence the biofilm formation and cell growth of both fluconazole resistant and sensitive C. albicans clinical isolates. These results indicated that cyclosporine A might be a promising candidate of adjuvant therapy for fluconazole against both fluconazole resistant and sensitive C. albicans clinical isolates.

  9. Risk of malformations and other outcomes in children exposed to fluconazole in utero

    DEFF Research Database (Denmark)

    Sørensen, Henrik Toft; Nielsen, Gunnar Lauge; Olesen, Charlotte;

    1999-01-01

    Aim Fluconazole is an active drug systematically used in the oral treatment of vaginal candidiasis and other fungal diseases. We examined the risk of malformations and other birth outcomes following pregnancy related exposures. Method From 1 January 1991 to 31 December 1996 we identified 165 women...... who had taken fluconazole just before or during pregnancy in the Pregnancy Outcome Section of the North Jutland Pharmacoepidemiological Prescription Database, Denmark, which is linked to the Danish Medical Birth Registry. We compared their birth outcomes (malformation, low birth weight and preterm...... delivery) with the outcomes among 13 327 women who did not receive any prescriptions during their pregnancies. Results The prevalence of malformation was 3.3% (four cases) among the 121 women, who had used fluconazole in the first trimester, and 5.2% (697 cases) in offspring to controls (odds ratio: 0...

  10. [Photochemical reaction types of the azole fungicide fluconazole under UV-vis irradiation].

    Science.gov (United States)

    Ge, Lin-Ke; Li, Kai; Yang, Kai; Na, Guang-Shui; Yu, Chun-Yan; Zhang, Peng; Yao, Zi-Wei

    2013-08-01

    This study selected the azole fungicide fluconazole as a model compound, and investigated its photodegradation kinetics and photoreaction types in pure water. It was found that under UV-vis irradiation (lambda > 200 nm), the fluconazole photodegraded fast and followed the pseudo-first-order kinetics, whereas under simulated sunlight (lambda > 290 nm), photodegradation did not occur. The ROS scavenging experiments and competition kinetic examination indicated that the compound underwent both direct photolysis and self-sensitized photooxidation via *OH other than 1O2. The bimolecular rate constant for the reaction between fluconazole and *OH was (5.95 +/- 0.58) x 10(9) L x (mol x s)(-1), and the corresponding environmental half-life was calculated to be (32.41 +/- 3.16) h in surface waters. Furthermore, it was deduced from the photodegradation product identification that the UV-vis degradation pathways involved photoinduced defluorination, hydrolysis and photooxidation.

  11. Analysis of ocular toxicity of fluconazole and voriconazole eyedrops using HET-CAM

    Directory of Open Access Journals (Sweden)

    A. Fernández-Ferreiro

    2014-07-01

    Full Text Available Abstract: Purpose: The objective of the study is to provide toxicological information through the HET-CAM test of Fluconazole and Voriconazole eye drops prepared commonly in Pharmacy Servi - ces for the treatment of fungal keratitis. Method: Experimental Study. The ocular toxicity of topical voriconazole 10 mg/ml and fluconazole 2 mg/ml were evalua ted by the hen‘s egg test (HET on the chorioallantoic membrane (CAM. The effects on blood vessels were based on its behavior during 300 seconds and processes that may occur at each time, then we calculated the irritation index (is, irritation score. Results and conclusions: Both eye drops, voriconazol and fluconazole have been proven to be safe, since the IS that we obtained was zero for both samples and did not present significant signs of irritation. Therefore, these eyedrops are conside red suitable for ocular use from a toxicological point of view.

  12. Discontinuation of nevirapine because of hypersensitivity reactions in patients with prior treatment experience, compared with treatment-naive patients: The ATHENA cohort study

    NARCIS (Netherlands)

    F.W.N.M. Wit (Ferdinand); A.M. Kesselring (Anouk); L.A. Gras (Luuk); C. Richter (Clemens); M.E. van der Ende (Marchina); K. Brinkman; J.M.A. Lange (Joep); F. de Wolf (Frank); P. Reiss (Peter)

    2008-01-01

    textabstractBackground. Recommendations that nevirapine (NVP) should be avoided in female individuals with CD4 cell counts >250 cells/μL and in male individuals with CD4 cell counts >400 cells/μL are based on findings in treatment-naive patients. It is unclear whether these guidelines also apply to

  13. Antifungal prophylaxis with posaconazole vs. fluconazole or itraconazole in pediatric patients with neutropenia.

    Science.gov (United States)

    Döring, M; Eikemeier, M; Cabanillas Stanchi, K M; Hartmann, U; Ebinger, M; Schwarze, C-P; Schulz, A; Handgretinger, R; Müller, I

    2015-06-01

    Pediatric patients with hemato-oncological malignancies and neutropenia resulting from chemotherapy have a high risk of acquiring invasive fungal infections. Oral antifungal prophylaxis with azoles, such as fluconazole or itraconazole, is preferentially used in pediatric patients after chemotherapy. During this retrospective analysis, posaconazole was administered based on favorable results from studies in adult patients with neutropenia and after allogeneic hematopoietic stem cell transplantation. Retrospectively, safety, feasibility, and initial data on the efficacy of posaconazole were compared to fluconazole and itraconazole in pediatric and adolescent patients during neutropenia. Ninety-three pediatric patients with hemato-oncological malignancies with a median age of 12 years (range 9 months to 17.7 years) that had prolonged neutropenia (>5 days) after chemotherapy or due to their underlying disease, and who received fluconazole, itraconazole, or posaconazole as antifungal prophylaxis, were analyzed in this retrospective single-center survey. The incidence of invasive fungal infections in pediatric patients was low under each of the azoles. One case of proven aspergillosis occurred in each group. In addition, there were a few cases of possible invasive fungal infection under fluconazole (n = 1) and itraconazole (n = 2). However, no such cases were observed under posaconazole. The rates of potentially clinical drug-related adverse events were higher in the fluconazole (n = 4) and itraconazole (n = 5) groups compared to patients receiving posaconazole (n = 3). Posaconazole, fluconazole, and itraconazole are comparably effective in preventing invasive fungal infections in pediatric patients. Defining dose recommendations in these patients requires larger studies.

  14. Scope and frequency of fluconazole trailing assessed using EUCAST in invasive Candida spp. isolates.

    Science.gov (United States)

    Marcos-Zambrano, Laura Judith; Escribano, Pilar; Sánchez-Carrillo, Carlos; Bouza, Emilio; Guinea, Jesús

    2016-10-01

    Trailing is a well-known phenomenon that is defined as reduced but persistent visible growth of Candida spp. at fluconazole concentrations above the MIC. Trailing is commonly detected using the CLSI M27-A3 method, although little is known about its frequency when investigated with EUCAST. We assessed the frequency and scope of fluconazole trailing after using EUCAST EDef 7.2. against a large number of Candida spp. isolates from patients with candidemia. We studied 639 fluconazole-susceptible non-krusei Candida spp. isolates from 570 patients admitted to Gregorio Marañón Hospital. Isolates were tested in vitro for fluconazole susceptibility according to the EUCAST EDef 7.2 procedure; trailing was defined as the presence of any residual growth in wells containing fluconazole concentrations above the MIC. According to the mean percentage of trailing observed, isolates were classified as residual trailers (0.1-5%), slight trailers (6%-10%), moderate trailers (11%-15%), and heavy trailers (>15%). The relationship between trailing and genotyping was assessed. The mean overall percentage of trailing was 6.8%, with C. albicans and C. tropicalis showing the highest percentages (9.75% and 9.29%, respectively; P 15%). Trailing was not genotype-specific. Fluconazole trailing was observed frequently when EUCAST was used for antifungal susceptibility testing, particularly in isolates of C. albicans and C. tropicalis The cut-off proposed enabled us to classify the isolates according to the degree of trailing and can be used as the basis for future studies to evaluate the clinical impact of this phenomenon. © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  15. Semi-national surveillance of fungaemia in Denmark 2004-2006: increasing incidence of fungaemia and numbers of isolates with reduced azole susceptibility

    DEFF Research Database (Denmark)

    Arendrup, M.C.; Fuursted, K.; Gahrn-Hansen, B.;

    2008-01-01

    .0%) isolates in 2006 (p 0.03). Overall, the proportion of isolates with decreased susceptibility to fluconazole exceeded 30% in 2006. The incidence of fungaemia in Denmark was three-fold higher than that reported from other Nordic countries and is increasing. Decreased susceptibility to fluconazole is frequent...

  16. Tratamiento con caspofungina de endocarditis por Candida tropicalis resistente a fluconazol Treatment with caspofungin of Candida tropicalis endocarditis resistant to fluconazol

    Directory of Open Access Journals (Sweden)

    Marcelo del Castillo

    2004-04-01

    Full Text Available Las endocarditis causadas por hongos, (Candida en particular, requieren tratamiento médico-quirúrgico, siendo la anfotericina B la droga de elección. Caspofungina es una equinocandina con gran actividad sobre Candida y Aspergillus. Se presenta un paciente con una endocarditis por Candida tropicalis resistente a fluconazol tratado con caspofungina bajo un esquema de salvataje, luego de haber presentado efectos adversos por anfotericina B. El paciente tuvo respuesta microbiológica.Fungal endocarditis, in particular due to Candida species, requires medical and surgical treatment and amphotericin B is the drug of choice. Caspofungin is an echinocandin very effective against Candida and Aspergillus. We present a patient with Candida tropicalis endocarditis, fluconazol resistant, treated with caspofungin, on a compassional basis as a result of adverse effects with amphotericin B. The patient had a microbiological response.

  17. Photodynamic inactivation of Candida albicans by a tetracationic tentacle porphyrin and its analogue without intrinsic charges in presence of fluconazole.

    Science.gov (United States)

    Quiroga, Ezequiel D; Mora, S Jimena; Alvarez, M Gabriela; Durantini, Edgardo N

    2016-03-01

    The photodynamic inactivation mediated by 5,10,15,20-tetrakis[4-(3-N,N-dimethylaminopropoxy)phenyl]porphyrin (TAPP) and 5,10,15,20-tetrakis[4-(3-N,N,N-trimethylaminepropoxy)phenyl]porphyrin (TAPP(4+)) were compared in Candida albicans cells. A strong binding affinity was found between these porphyrins and the yeast cells. Photosensitized inactivation of C. albicans increased with both photosensitizer concentration and irradiation time. After 30 min irradiation, a high photoinactivation (∼5 log) was found for C. albicans treated with 5 μM porphyrin. Also, the photoinactivation of yeast cells was still elevated after two washing steps. However, the photocytotoxicity decreases with an increase in the cell density from 10(6) to 10(8) cells/mL. The high photodynamic activity of these porphyrins was also established by growth delay experiments. This C. albicans strain was susceptible to fluconazole with a MIC of 1.0 μg/mL. The effect of photosensitization and the action of fluconazole were combined to eradicate C. albicans. After a PDI treatment with 1 μM porphyrin and 30 min irradiation, the value of MIC decreased to 0.25 μg/mL. In addition, a complete arrest in cell growth was found by combining both effects. TAPP was similarly effective to photoinactivate C. albicans than TAPP(4+). This porphyrin without intrinsic positive charges contains basic amino groups, which can be protonated at physiological pH. Moreover, an enhancement in the antifungal action was found using both therapies because lower doses of the agents were required to achieve cell death.

  18. Nosocomial candidiasis in Rio de Janeiro State: Distribution and fluconazole susceptibility profile.

    Science.gov (United States)

    Neufeld, Paulo Murillo; Melhem, Marcia de Souza Carvalho; Szeszs, Maria Walderez; Ribeiro, Marcos Dornelas; Amorim, Efigênia de Lourdes Teixeira; da Silva, Manuela; Lazéra, Marcia dos Santos

    2015-06-01

    One hundred and forty-one Candida species isolated from clinical specimens of hospitalized patients in Rio de Janeiro, Brazil, during 2002 to 2007, were analized in order to evaluate the distribution and susceptibility of these species to fluconazole. Candida albicans was the most frequent species (45.4%), followed by C. parapsilosis sensu lato (28.4%), C. tropicalis (14.2%), C. guilliermondii (6.4%), C. famata (2.8%), C. glabrata (1.4%), C. krusei (0.7%) and C. lambica (0.7%). The sources of fungal isolates were blood (47.5%), respiratory tract (17.7%), urinary tract (16.3%), skin and mucous membrane (7.1%), catheter (5.6%), feces (2.1%) and mitral valve tissue (0.7%). The susceptibility test was performed using the methodology of disk-diffusion in agar as recommended in the M44-A2 Document of the Clinical and Laboratory Standards Institute (CLSI). The majority of the clinical isolates (97.2%) was susceptible (S) to fluconazole, although three isolates (2.1%) were susceptible-dose dependent (S-DD) and one of them (0.7%) was resistant (R). The S-DD isolates were C. albicans, C. parapsilosis sensu lato and C. tropicalis. One isolate of C. krusei was resistant to fluconazole. This work documents the high susceptibility to fluconazole by Candida species isolated in Rio de Janeiro, Brazil.

  19. The effect of fluconazole on ritonavir and saquinavir pharmacokinetics in HIV-1-infected individuals.

    NARCIS (Netherlands)

    Koks, C.H.W.; Crommentuyn, K.M.; Hoetelmans, R.M.; Burger, D.M.; Koopmans † , P.P.; Mathô t, R.A.A.; Mulder, J.W.; Meenhorst, P.L.; Beijnen, J.H.

    2001-01-01

    AIMS: To study the effect of fluconazole on the steady-state pharmacokinetics of the protease inhibitors ritonavir and saquinavir in HIV-1-infected patients. METHODS: Five subjects treated with saquinavir and three with ritonavir received the protease inhibitor alone (saquinavir 1200 mg three times

  20. Synthesis of sup 18 F-labeled fluconazole and positron emission tomography studies in rabbits

    Energy Technology Data Exchange (ETDEWEB)

    Livni, E. (Massachusetts General Hospital, Boston, MA (United States). Dept. of Radiology); Fischman, A.J. (Massachusetts General Hospital, Boston, MA (United States). Radiology Dept. Havard Medical School, Boston, MA (United States). Dept. of Radiology Havard Medical School, Boston, MA (United States). Dept. of Medicine)

    1992-02-01

    (4-{sup 18}F) 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propanol ((4-{sup 18}F) fluconazole) was synthesized from its amino precursor. Fieldel-Crafts acylation of 3-fluoroacetanilide with chloroacetyl chloride produced 2'-fluoro-4'-aceteamido-2-(1H-1,2,4-triazole-1-yl) acetophenone in 12% yield. Sequential reaction with (1) dimethylsulphoxonium methylide and (2) 1,2,4-triazole followed by in situ hydrolysis resulted in 2-(2-fluoro-4-aminophenyl)-1,3-bis(1H-2,2,4-triazol-1-yl)-2-propanol in 19% yield. A modified Schiemann reaction on this product resulted in (4-{sup 18}F)fluconazole with a radiochemical yield of 1.0-2.0% (EOS) within 2h. (4-{sup 18}F)Fluconazole was used to measure the pharmacokinetics of fluconazole in rats by measurement of radioactivity in excised tissues and in rabbits by PET. In both species, there was rapid equilibration of (4-{sup 18}F)fluoconazole to a relatively uniform distribution of radioactivity in most organs. (Author).

  1. FLUCONAZOLE-INDUCED HEPATIC CYTOCHROME P450 GENE EXPRESSION AND ENZYMATIC ACTIVITIES IN RATS AND MICE

    Science.gov (United States)

    This study was undertaken to examine the effects of the triazole antifungal agent fluconazole on the expression of hepatic cytochrome P450 (Cyp) genes and the activities of Cyp enzymes in male Sprague-Dawley rats and male CD-1 mice. Alkoxyresorufin O-dealkylation (AROD) methods w...

  2. Addition of Caspofungin to Fluconazole Does Not Improve Outcome in Murine Candidiasis

    OpenAIRE

    Graybill, John R.; Bocanegra, Rosie; Najvar, Laura K.; Hernandez, Steve; Larsen, Robert A.

    2003-01-01

    Caspofungin is a potent antifungal inhibiting glucan synthesis in Candida species. However, caspofungin is not 100% curative in candidiasis. Therefore, we evaluated combinations of fluconazole with caspofungin for murine candidemia. We could not show any benefit of combined therapy over individual antifungal drugs.

  3. Evolutionary divergence in the fungal response to fluconazole revealed by soft clustering

    KAUST Repository

    Kuo, Dwight

    2010-07-23

    Background: Fungal infections are an emerging health risk, especially those involving yeast that are resistant to antifungal agents. To understand the range of mechanisms by which yeasts can respond to anti-fungals, we compared gene expression patterns across three evolutionarily distant species - Saccharomyces cerevisiae, Candida glabrata and Kluyveromyces lactis - over time following fluconazole exposure. Results: Conserved and diverged expression patterns were identified using a novel soft clustering algorithm that concurrently clusters data from all species while incorporating sequence orthology. The analysis suggests complementary strategies for coping with ergosterol depletion by azoles - Saccharomyces imports exogenous ergosterol, Candida exports fluconazole, while Kluyveromyces does neither, leading to extreme sensitivity. In support of this hypothesis we find that only Saccharomyces becomes more azole resistant in ergosterol-supplemented media; that this depends on sterol importers Aus1 and Pdr11; and that transgenic expression of sterol importers in Kluyveromyces alleviates its drug sensitivity. Conclusions: We have compared the dynamic transcriptional responses of three diverse yeast species to fluconazole treatment using a novel clustering algorithm. This approach revealed significant divergence among regulatory programs associated with fluconazole sensitivity. In future, such approaches might be used to survey a wider range of species, drug concentrations and stimuli to reveal conserved and divergent molecular response pathways.

  4. Biowaiver monograph for immediate-release solid oral dosage forms: fluconazole.

    Science.gov (United States)

    Charoo, Naseem; Cristofoletti, Rodrigo; Graham, Alexandra; Lartey, Paul; Abrahamsson, Bertil; Groot, D W; Kopp, Sabine; Langguth, Peter; Polli, James; Shah, Vinod P; Dressman, Jennifer

    2014-12-01

    Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence (BE) testing requirements for the approval of immediate release (IR) solid oral dosage forms containing fluconazole as the only active pharmaceutical ingredient (API) are reviewed. The decision is based on solubility, dissolution, permeability, therapeutic index, pharmacokinetic parameters, pharmacodynamic properties, and other relevant data. BE/bioavailability (BA) problems and drug-excipients interaction data were also reviewed and taken into consideration. According to the biopharmaceutics classification system (BCS), fluconazole in polymorphic forms II and III is a BCS class I drug and has a wide therapeutic index. BE of test formulations from many different manufacturers containing different excipients confirmed that the risk of bioinequivalence because of formulation and manufacturing factors is low. It was inferred that risk can be further reduced if in vitro studies are performed according to biowaiver guidelines. Thus, it is concluded that a biowaiver can be recommended for fluconazole IR dosage forms if (a) fluconazole is present as polymorphic form II or III or any other form/mixture showing high solubility, (b) the selection of excipients be limited to those found in IR drug products approved in International Conference on Harmonisation (ICH) countries for the same dosage form and used in their usual amounts, and (c) both the test and comparator dosage form are very rapidly dissolving, or, rapidly dissolving throughout the shelf life with similar dissolution profiles at pH 1.2, 4.5, and 6.8.

  5. Nosocomial candidiasis in Rio de Janeiro State: Distribution and fluconazole susceptibility profile

    Science.gov (United States)

    Neufeld, Paulo Murillo; Melhem, Marcia de Souza Carvalho; Szeszs, Maria Walderez; Ribeiro, Marcos Dornelas; Amorim, Efigênia de Lourdes Teixeira; da Silva, Manuela; Lazéra, Marcia dos Santos

    2015-01-01

    One hundred and forty-one Candida species isolated from clinical specimens of hospitalized patients in Rio de Janeiro, Brazil, during 2002 to 2007, were analized in order to evaluate the distribution and susceptibility of these species to fluconazole. Candida albicans was the most frequent species (45.4%), followed by C. parapsilosis sensu lato (28.4%), C. tropicalis (14.2%), C. guilliermondii (6.4%), C. famata (2.8%), C. glabrata (1.4%), C. krusei (0.7%) and C. lambica (0.7%). The sources of fungal isolates were blood (47.5%), respiratory tract (17.7%), urinary tract (16.3%), skin and mucous membrane (7.1%), catheter (5.6%), feces (2.1%) and mitral valve tissue (0.7%). The susceptibility test was performed using the methodology of disk-diffusion in agar as recommended in the M44-A2 Document of the Clinical and Laboratory Standards Institute (CLSI). The majority of the clinical isolates (97.2%) was susceptible (S) to fluconazole, although three isolates (2.1%) were susceptible-dose dependent (S-DD) and one of them (0.7%) was resistant (R). The S-DD isolates were C. albicans, C. parapsilosis sensu lato and C. tropicalis. One isolate of C. krusei was resistant to fluconazole. This work documents the high susceptibility to fluconazole by Candida species isolated in Rio de Janeiro, Brazil. PMID:26273262

  6. [Clinical observation on treatment of mycotic vaginitis with Sophora gel combined with Fluconazole capsules].

    Science.gov (United States)

    Wang, Na-mei; Cui, Lin; Ma, Chun-fen; Wang, Hui-xia

    2015-03-01

    Mycotic vaginitis is a common and frequently-occurring gynaecopathia and easy to attack repeatedly, so painful to patients. In this study, the authors observed the clinical efficacy of Sophora gel combined with Fluconazole capsules in treating mycotic vaginitis, in order to seek an effective method for treating mycotic vaginitis. Totally 85 patients with mycotic vaginitis treated in our hospital between December 2012 and July 2014 were randomly divided into the treatment group (43 patients) and the control group (42 patients). The treatment group was given vaginally Sophora gel (one piece every night for 14 days) and orally Fluconazole capsules (150 mg, once every three days, four times in total); The control group was only administered with Fluconazole capsules. The total efficacy, cure rate, recurrence rate and clinical symptom improvements of the two groups were observed. The results show that the total efficacy, the cure rate and the recurrence rate of the treatment group vs. the control group were respectively 97.7%, 90.7% and 2.6% vs. 83.3%, 71.4% and 20.0%, with statistical significance in their differences (P Fluconazole capsules can improve antifungal activity of drugs, relieve clinical symptoms, shorten the course of disease, enhance the cure rate and reduce the recurrence rate; So this therapy can be widely applied in clinic.

  7. Treatment of candida vaginitis: comparison of single and sequential dose of fluconazole

    Directory of Open Access Journals (Sweden)

    Farahnaz Kamali

    2003-09-01

    Full Text Available Fluconazole is one of the triazole antifungal agent for Candida albican. For comparison of single versus sequential dose of fluconazole, a double-blind randomized clinical trial was counducted on 80 married 20-45 years old women who had chronic vaginal candidiasis. The patients randomized into two groups, 40 patients received two ( zero and 72 hours doses of fluconazole and the other group received one 150 mg dose of the drug at zero and placebo at 72 hours later. The patients were examined at 2 & 6 weeks after treatment. The groups showed decreased signs and symptoms of vaginal candidiasis during examination periods, however there was no significant difference between groups (p>0.05. Wet mount & culture were negative in the 2nd week in two groups but at the 6th week after treatment, 95.3% and 72.5% of patients in control and case groups, respectively had negative results (p<0.05. Therefore, single and sequential doses of fluconazole have the same result for treatment of vaginal candidiasis but sequential dose reduces the relapse rate of the disease.

  8. Fixed drug eruption to fluconazole: A case report and review of literature

    Directory of Open Access Journals (Sweden)

    Varadraj V Pai

    2012-01-01

    Full Text Available Fixed drug eruption (FDE is mainly characterized by skin lesions that recur at the same anatomic sites upon repeated exposures to an offending agent. It represents the most common cutaneous adverse drug reaction pattern in Indian patients. Here, we report an FDE to fluconazole.

  9. Clinical Validation of the Analysis of Fluconazole in Oral Fluid in Hospitalized Children

    NARCIS (Netherlands)

    van der Elst, Kim C. M.; van Alst, Manouche; Lub-de Hooge, Marjolijn N.; van Hateren, Kai; Kosterink, Jos G. W.; Alffenaar, Jan-Willem C.; Scholvinck, Elisabeth H.

    2014-01-01

    Fluconazole is a first-line antifungal agent for the treatment and prophylaxis of invasive candidiasis in pediatric patients. Pediatric patients are at risk of suboptimal drug exposure, due to developmental changes in gastrointestinal and renal function, metabolic capacity, and volume of distributio

  10. The efficacy and safety of clotrimazole vaginal tablet vs. oral fluconazole in treating severe vulvovaginal candidiasis.

    Science.gov (United States)

    Zhou, Xiaofang; Li, Ting; Fan, Shangrong; Zhu, Yuxia; Liu, Xiaoping; Guo, Xuedong; Liang, Yiheng

    2016-07-01

    To compare the efficacy and safety of two doses of clotrimazole vaginal tablet 500 mg with two doses of oral fluconazole 150 mg in treating severe vulvovaginal candidiasis (SVVC), 240 consecutive patients with SVVC were studied at the Department of Obstetrics and Gynaecology of Peking University Shenzhen Hospital between June 2014, and September 2015. Patients were randomly assigned in a 1 : 1 ratio to receive treatment with either two doses of clotrimazole vaginal tablet or two doses of oral fluconazole. The clinical cure rates in the clotrimazole group and the fluconazole group at days 7-14 follow-up were 88.7% (102/115) and 89.1% (98/110) respectively; the clinical cure rates at days 30-35 in the two groups were 71.9% (82/114) and 78.0% (85/109) respectively. The mycological cure rates at days 7-14 follow-up in the two groups were 78.3% (90/115) and 73.6% (81/110) respectively. The mycological cure rates of the patients at days 30-35 in the two groups were 54.4% (62/114) and 56.0% (61/109) respectively (P > 0.05). The adverse events of clotrimazole were mainly local. This study demonstrated that two doses of clotrimazole vaginal tablet 500 mg were as effective as two doses of oral fluconazole 150 mg in the treatment of patients with SVVC and could be an appropriate treatment for this disorder.

  11. Development of Nevirapine Resistance in Children Exposed to the Prevention of Mother-to-Child HIV-1 Transmission Programme in Maputo, Mozambique.

    Science.gov (United States)

    Antunes, Francisco; Zindoga, Pereira; Gomes, Perpétua; Augusto, Orvalho; Mahumane, Isabel; Veloso, Luís; Valadas, Emília; Camacho, Ricardo

    2015-01-01

    Single-dose nevirapine (sd-NVP) has been the main option for prevention of mother-to-child transmission (PMTCT) of HIV-1 in low-resource settings. However, sd-NVP can induce the selection of HIV-1 resistant mutations in mothers and infants. In Mozambique, there are limited data regarding the profile of NVP resistance associated mutations (RAM) in the context of PMTCT. To assess the prevalence and the factors associated with NVP RAM among children born to HIV-1 infected mothers enrolled in the PMTCT programme adopted in Mozambique. One hundred and fifty seven children aged 6 to 48 weeks were sequentially included (July 2011 to March 2012) at four centres in Maputo. Genotyping of RAM was performed in samples with HIV-1 RNA≥ 100 copies/μL (Viroseq). Sequencing was performed with ABI 3100 (Applied Biosystems). Logistic regression modelling was undertaken to identify the factors associated with NVP RAM. Seventy-nine children had their samples genotyped. Their median age was 7.0 (3-12) months and 92.4% received prophylaxis with sd-NVP at birth plus daily NVP. 35.4% of mothers received antiretrovirals (ARVs) for PMTCT. ARV RAM were detected in 43 (54.4%) of the children. 45.6% of these children had at least one NVP RAM. The most common mutations associated with NVP resistance were K103N (n = 16) and Y181C (n = 15). NVP RAM was significantly associated with mother exposure to PMTCT (crude odds ratio [OR] 30.3, 95% CI 4.93-186.34) and with mother's CD4 count Mozambique. The mothers' exposure to PMTCT significantly increased the risk of NVP RAM.

  12. Data Mining Validation of Fluconazole Breakpoints Established by the European Committee on Antimicrobial Susceptibility Testing▿

    Science.gov (United States)

    Cuesta, Isabel; Bielza, Concha; Larrañaga, Pedro; Cuenca-Estrella, Manuel; Laguna, Fernando; Rodriguez-Pardo, Dolors; Almirante, Benito; Pahissa, Albert; Rodríguez-Tudela, Juan L.

    2009-01-01

    European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints classify Candida strains with a fluconazole MIC ≤ 2 mg/liter as susceptible, those with a fluconazole MIC of 4 mg/liter as representing intermediate susceptibility, and those with a fluconazole MIC > 4 mg/liter as resistant. Machine learning models are supported by complex statistical analyses assessing whether the results have statistical relevance. The aim of this work was to use supervised classification algorithms to analyze the clinical data used to produce EUCAST fluconazole breakpoints. Five supervised classifiers (J48, Correlation and Regression Trees [CART], OneR, Naïve Bayes, and Simple Logistic) were used to analyze two cohorts of patients with oropharyngeal candidosis and candidemia. The target variable was the outcome of the infections, and the predictor variables consisted of values for the MIC or the proportion between the dose administered and the MIC of the isolate (dose/MIC). Statistical power was assessed by determining values for sensitivity and specificity, the false-positive rate, the area under the receiver operating characteristic (ROC) curve, and the Matthews correlation coefficient (MCC). CART obtained the best statistical power for a MIC > 4 mg/liter for detecting failures (sensitivity, 87%; false-positive rate, 8%; area under the ROC curve, 0.89; MCC index, 0.80). For dose/MIC determinations, the target was >75, with a sensitivity of 91%, a false-positive rate of 10%, an area under the ROC curve of 0.90, and an MCC index of 0.80. Other classifiers gave similar breakpoints with lower statistical power. EUCAST fluconazole breakpoints have been validated by means of machine learning methods. These computer tools must be incorporated in the process for developing breakpoints to avoid researcher bias, thus enhancing the statistical power of the model. PMID:19433568

  13. Use of molecular methods in identification of Candida Species and evaluation of fluconazole resistance

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    Meltem Yalinay Cirak

    2003-12-01

    Full Text Available The aim of this study was to evaluate the use of one of the molecular typing methods such as PCR (polymerase chain reaction following by RFLP (restriction fragment length polymorphism analysis in the identification of Candida species and then to differentiate the identified azole susceptible and resistant Candida albicans strains by using AP-PCR (arbitrarily primed-polymerase chain reaction. The identification of Candida species by PCR and RFLP analysis was based on the size and primary structural variation of rDNA intergenic spacer regions (ITS. Forty-four clinical Candida isolates comprising 5 species were included to the study. The amplification products were digested individually with 3 different restriction enzymes: HaeIII, DdeI, and BfaI. All the isolates tested yielded the expected band patterns by PCR and RFLP analysis. The results obtained from this study demonstrate that Candida species can be differentiated as C. albicans and non-C. albicans strains only by using HaeIII restriction enzyme and BfaI maintains the differentiation of these non-C. albicans species. After identification Candida species with RFLP analysis, C. albicans strains were included to the AP-PCR test. By using AP-PCR, fluconazole susceptible and resistant strains were differentiated. Nine fluconazole susceptible and 24 fluconazole resistant C. albicans were included to the study. Fluconazole resistant strains had more bands when evaluating with the agarose gel electrophoresis but there were no specific discriminatory band patterns to warrant the differentiation of the resistance. The identification of Candida species with the amplification of intergenic spacer region and RFLP analysis is a practical, short, and a reliable method when comparing to the conventional time-consuming Candida species identification methods. The fluconazole susceptibility testing with AP-PCR seems to be a promising method but further studies must be performed for more specific results.

  14. Three generic nevirapine-based antiretroviral treatments in Chinese HIV/AIDS patients: multicentric observation cohort.

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    Taisheng Li

    Full Text Available BACKGROUND: The purpose of this study was to evaluate the efficacy and safety of three nevirapine-based antiretroviral treatments for adult antiretroviral-naïve Chinese patients with HIV-1 infection. METHODOLOGY: This was a prospective, multicenter study. 198 antiretroviral-naïve HIV-1 positive subjects with CD4 lymphocyte counts between 100/ul and 350/ul and plasma HIV-1 RNA levels more than 500 copies/ml were randomized to start three NVP-based antiretroviral treatments: group A, NVP+AZT+ddI; group B, NVP+3TC+d4T; group C, NVP+AZT+3TC. Viral responses, immunologic responses, adverse events and drug resistance were monitored at baseline and the end of week 4, 12, 24, 36, 52. Viralogical response and immunological response were also compared in different strata of baseline CD4 T lymphocyte counts and plasma HIV-1 RNA concentrations. At baseline, the plasma HIV-1 RNA was 4.44+/-0.68, 4.52+/-0.71 and 4.41+/-0.63 lg copies/ml in group A, B and C respectively (p = 0.628. At the end of the study, the plasma viral load reached 2.54+/-1.11, 1.89+/-0.46 and 1.92+/-0.58 lg copies/ml in group A, B and C respectively (p200/ul (subgroup H. But in subgroup L, viral response rate of three groups has no significant statistic difference. There were no statistically significant differences among three groups in immunological response within any of the CD4 or pVL strata. 3 out of 193 patients with available genotype at baseline showed primary drug resistant. Of 26 patients with virologic failure, 17 patients showed secondary drug resistant, 16 subjects in group A and 1 subject in group B. Logistic regression analysis indicated that presence of hepatotoxicity was associated with HCV-Ab positive (OR = 2.096, 95%CI: 1.106-3.973, P = 0.023 and higher CD4 baseline (CD4 count >250/ul (OR = 2.096, 95%CI: 1.07-4.107, P = 0.031. CONCLUSION: Our findings strongly support the use of 3TC+d4T and 3TC+AZT as the nucleoside analogue combination in NVP-based antiretroviral

  15. Three generic nevirapine-based antiretroviral treatments in Chinese HIV/AIDS patients: multicentric observation cohort.

    Science.gov (United States)

    Li, Taisheng; Dai, Yi; Kuang, Jiqiu; Jiang, Jingmei; Han, Yang; Qiu, Zhifeng; Xie, Jing; Zuo, Lingyan; Li, Yanling

    2008-01-01

    The purpose of this study was to evaluate the efficacy and safety of three nevirapine-based antiretroviral treatments for adult antiretroviral-naïve Chinese patients with HIV-1 infection. This was a prospective, multicenter study. 198 antiretroviral-naïve HIV-1 positive subjects with CD4 lymphocyte counts between 100/ul and 350/ul and plasma HIV-1 RNA levels more than 500 copies/ml were randomized to start three NVP-based antiretroviral treatments: group A, NVP+AZT+ddI; group B, NVP+3TC+d4T; group C, NVP+AZT+3TC. Viral responses, immunologic responses, adverse events and drug resistance were monitored at baseline and the end of week 4, 12, 24, 36, 52. Viralogical response and immunological response were also compared in different strata of baseline CD4 T lymphocyte counts and plasma HIV-1 RNA concentrations. At baseline, the plasma HIV-1 RNA was 4.44+/-0.68, 4.52+/-0.71 and 4.41+/-0.63 lg copies/ml in group A, B and C respectively (p = 0.628). At the end of the study, the plasma viral load reached 2.54+/-1.11, 1.89+/-0.46 and 1.92+/-0.58 lg copies/ml in group A, B and C respectively (pHIV-1 RNA to less than 50 copies/ml was achieved in more patients in group B and C than in group A (68.2%, 69% vs. 39.7%; p200/ul (subgroup H). But in subgroup L, viral response rate of three groups has no significant statistic difference. There were no statistically significant differences among three groups in immunological response within any of the CD4 or pVL strata. 3 out of 193 patients with available genotype at baseline showed primary drug resistant. Of 26 patients with virologic failure, 17 patients showed secondary drug resistant, 16 subjects in group A and 1 subject in group B. Logistic regression analysis indicated that presence of hepatotoxicity was associated with HCV-Ab positive (OR = 2.096, 95%CI: 1.106-3.973, P = 0.023) and higher CD4 baseline (CD4 count >250/ul) (OR = 2.096, 95%CI: 1.07-4.107, P = 0.031). Our findings strongly support the use of 3TC+d4T and 3TC

  16. Antifungal effects of phytocompounds on Candida species alone and in combination with fluconazole.

    Science.gov (United States)

    Lu, Mengjiao; Li, Tao; Wan, Jianjian; Li, Xiuyun; Yuan, Lei; Sun, Shujuan

    2017-02-01

    Invasive fungal infections caused by Candida spp. remain the most predominant nosocomial fungal infections. Owing to the increased use of antifungal agents, resistance of Candida spp. to antimycotics has emerged frequently, especially to fluconazole (FLC). To cope with this issue, new efforts have been dedicated to discovering novel antimycotics or new agents that can enhance the susceptibility of Candida spp. to existing antimycotics. The secondary metabolites of plants represent a large library of compounds that are important sources for new drugs or compounds suitable for further modification. Research on the anti-Candida activities of phytocompounds has been carried out in recent years and the results showed that a series of phytocompounds have anti-Candida properties, such as phenylpropanoids, flavonoids, terpenoids and alkaloids. Among these phytocompounds, some displayed potent antifungal activity, with minimum inhibitory concentrations (MICs) of ≤8 µg/mL, and several compounds were even more effective against drug-resistant Candida spp. than FLC or itraconazole (e.g. honokiol, magnolol and shikonin). Interestingly, quite a few phytocompounds not only displayed anti-Candida activity alone but also synergised with FLC against Candida spp., even leading to a reversal of FLC resistance. This review focuses on summarising the anti-Candida activities of phytocompounds as well as the interactions of phytocompounds with FLC. In addition, we briefly overview the synergistic mechanisms and present the structure of the antimycotic phytocompounds. Hopefully, this analysis will provide insight into antifungal agent discovery and new approaches against antifungal drug resistance. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  17. Application of caspofungin in China compared with amphotericin B and fluconazole

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    Zhang CY

    2014-09-01

    Full Text Available Chunyu Zhang,1 Jiaoying Cheng,2 Yan Jiang,3 Junyang Liu41Department of Health Reform and Development, China–Japan Friendship Hospital, Beijing, People’s Republic of China; 2Department of Obstetrics and Gynecology, China–Japan Friendship Hospital, Beijing, People’s Republic of China; 3National Management Center of 12320 Health Hotline, Chinese Center for Disease Control and Prevention, Beijing, People’s Republic of China; 4Department of Pharmacy, China–Japan Friendship Hospital, Beijing, People’s Republic of ChinaAbstract: Fungal infection has increased in the past 2 decades in China. There are three classes of antifungal drugs, polyenes, azoles, and echinocandins, that are applied frequently in China. Caspofungin, which disrupts the fungal cell wall glucan formation through inhibiting the enzyme 1,3-ß-glucan synthase, is one of the echinocandins. According to the results of clinical practices applied in China, caspofungin has shown to be superior to the other two classes of antifungal drugs, due to its efficacy in treating fungal infection (15% superior to fluconazole; fewer adverse events such as infusion-related reaction, hepatic dysfunction, and vomiting (25%–50% lower incidence rate; rapid resolution of symptoms (about 3 days quicker than amphotericin B; and absence of antagonism in combination with other antifungal drugs. However, caspofungin will remain as a second-line antifungal drug in the near future because of its high price and the policy of health insurance reimbursement in China.Keywords: fungal infection, caspofungin, efficacy, adverse event

  18. DNA microarray analysis of fluconazole resistance in a laboratory Candida albicans strain

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Several mechanisms are responsible for the acquired fluconazole (FLC) resistance in Candida albicans. In this study, we developed a FLC-resistant C. albicans strain through serial cultures of a FLC-susceptible C. albicans strain with inhibitory concentrations of FLC. Complimen-tary DNA microarray analysis and real-time reverse tran-scription-polymerase chain reaction were used to investi-gate gene expression changes during the acquisition of azole resistance in the susceptible parental strain and the resis-tant daughter strain. The differentially expressed genes rep-resented functions as diverse as transporters (e.g. CDRI, PDR17), ergosterol biosynthesis (e.g. ERG2, ERG9), sterol metabolism (e.g. ARE2, IPF6464), energy metabolism (e.g. ADH3, AOX2) and transcription factors (e.g. FCR1, ECM22). Functional analysis revealed that energy-depen-dent efflux activity of membrane transporters increased and that ergosterol content decreased with the accumulation of sterol intermediates in the resistant strain as compared with the susceptible strain. We found that a point mutation (N977K) in transcription factor TAC1 that resulted in hy-peractivity of Tac1 could be the reason for overexpression of CDR1, CDR2, and PDR17 in the resistant strain.Furthermore, a single amino acid difference (DI9E) in ERG3 that led to the inactivation of Erg3 could account for both sterol precursor accumulation and the changes in the ex-pression of ergosterol biosynthesis genes in this resistant strain. These findings expand the understanding of poten-tial novel molecular targets of FLC resistance in clinical C.albicans isolates.

  19. Synthetic antimicrobial β-peptide in dual-treatment with fluconazole or ketoconazole enhances the in vitro inhibition of planktonic and biofilm Candida albicans.

    Science.gov (United States)

    Mora-Navarro, Camilo; Caraballo-León, Jean; Torres-Lugo, Madeline; Ortiz-Bermúdez, Patricia

    2015-12-01

    Fungal infections are a pressing concern for human health worldwide, particularly for immunocompromised individuals. Current challenges such as the elevated toxicity of common antifungal drugs and the emerging resistance towards these could be overcome by multidrug therapy. Natural antimicrobial peptides, AMPs, in combination with other antifungal agents are a promising avenue to address the prevailing challenges. However, they possess limited biostability and susceptibility to proteases, which has significantly hampered their development as antifungal therapies. β-peptides are synthetic materials designed to mimic AMPs while allowing high tunability and increased biostability. In this work, we report for the first time the inhibition achieved in Candida albicans when treated with a mixture of a β-peptide model and fluconazole or ketoconazole. This combination treatment enhanced the biological activity of these azoles in planktonic and biofilm Candida, and also in a fluconazole-resistant strain. Furthermore, the in vitro cytotoxicity of the dual treatment was evaluated towards the human hepatoma cell line, HepG2, a widely used model derived from liver tissue, which is primarily affected by azoles. Analyses based on the LA-based method and the mass-action law principle, using a microtiter checkerboard approach, revealed synergism of the combination treatment in the inhibition of planktonic C. albicans. The dual treatment proved to be fungicidal at 48 and 72 h. Interestingly, it was also found that the viability of HepG2 was not significantly affected by the dual treatments. Finally, a remarkable enhancement in the inhibition of the highly azole-resistant biofilms and fluconazole resistant C. albicans strain was obtained.

  20. In vitro induction and stability evaluation of fluconazole resistance in Trichosporon asahii%阿萨希毛孢子菌对氟康唑耐药性的体外诱导及其稳定性研究

    Institute of Scientific and Technical Information of China (English)

    郭朝霞; 李海涛; 杨蓉娅; 祝贺; 王聪敏; 廖勇; 夏志宽

    2013-01-01

    目的 探讨体外以浓度梯级倍增的氟康唑诱导不同来源阿萨希毛孢子菌(T.asahii)获得耐药子代,并观察它们的耐药稳定性.方法 保存的11株T.asahii中筛选出的氟康唑MIC值较低的临床分离株CBS2479及环境分离株CBS8904,在含氟康唑浓度梯级倍增的PDA固体培养基中分别传代培养,每次转种前均用E-test法测定氟康唑对其MIC值,直至其>256 μg/ml;选用氟康唑MIC值>256 μg/ml的耐药菌株CBS2479R/CBS8904R分别在不含氟康唑的PDA培养基中连续传代培养,并监测每代菌株MIC值,观察其耐药稳定性.结果 氟康唑MIC值分别为0.25 μg/ml及1.5 μg/ml的T.asahiiCBS2479/CBS8904均被成功地诱导为氟康唑MIC值>256 μg/ml的耐药子代菌株CBS2479R/CBS8904R;将其在不含氟康唑PDA培养基中连续传代18d,CBS2479R氟康唑MIC值未见下降;CBS8904R氟康唑MIC值逐渐下降,至第18天时降为64 μg/ml.结论 氟康唑在体外能诱导不同来源的T.asahii均对其产生耐药性,不同来源的T.asahii其耐药子代的稳定性不同.%Objective To induce fluconazole resistance in T.asahii by culture in medium containing increasing concentrations of fluconazole,and to evaluate the stability of the induced resistance.Methods Two T.asahii strains with a highest sensitivity to fluoconazole,including a clinical isolate CBS2479 (minumum inhibitory concentration (MIC) =0.25 μg/ml) and an environmental isolate CBS8904 (MIC =1.5 μg/ml),were selected from 11 T.asahii strains stored in the laboratory of the Department of Dermatology,General Hospital of Beijing Military Region.Both strains were respectively and serially subcultured in potato dextrose agar (PDA) medium containing growing concentrations of fluconazole (from 0.5 MIC to 256 μg/ml).E-test was performed to evaluate the susceptibility of T.asahii to fluconazole after each passage.To evaluate the stability of fluconazole resistance,the T.asahii isolates with induced resistance (MIC > 256

  1. Avaliação biofarmacêutica in vitro de cápsulas de fluconazol In vitro biopharmaceutic evaluation of capsules containing fluconazole

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    Valentina Porta

    2002-09-01

    Full Text Available Atualmente, no mercado brasileiro, vários laboratórios farmacêuticos comercializam produtos a base do antifúngico fluconazol na forma de cápsulas de 150 mg. Pretendeu-se, neste trabalho, realizar avaliação biofarmacêutica in vitro de três formulações do mercado nacional contendo fluconazol, designadas por produtos A, B e C. Após desenvolvimento e padronização do método de dissolução, avaliou-se a cinética de dissolução de cápsulas de fluconazol provenientes de dois lotes de cada produto por meio dos parâmetros k (constante de velocidade de dissolução e t85% (tempo necessário para dissolução de 85% do fármaco presente na forma farmacêutica, derivados dos perfis de dissolução. Obteve-se k s de 0,1377 min-1 e 0,1079 min-1 para os lotes de A, 0,5421min-1 para os lotes de B e 0,0354 min-1 e 0,0146 min-1 para os lotes de C. t85% foi de 15,09 min e 20,06 min para os lotes de A, 5,64 min e 6,02 min para os lotes de B e 132,12 min e 56,05 min para os lotes de C. Concluiu-se que a dissolução de fluconazol em cápsulas segue cinética de primeira ordem para os três produtos avaliados, sendo que o produto B apresenta maior velocidade de dissolução do fármaco, seguido pelo produto A e pelo produto C.Many brazilian pharmaceutical industries manufacture capsules containing 150 mg of the antifungal agent fluconazole. The present study was designed to perform a in vitro biopharmaceutical evaluation of three commercial products available in Brazil, designated as products A, B and C. After a dissolution method was developed and standardized, the dissolution kinetics for samples of two batches of each product was analysed through k s (dissolution rate constant and t85% (time for dissolution of 85% of the drug in the dosage form, obtained from dissolution profiles. Results showed k s values of 0,1377 min-1 and 0,1079 min-1 for the tested batches of A, 0,5421min-1 for the tested batches of B and 0,0354 min-1 and 0,0146 min-1 for

  2. Candida species distribution and fluconazole susceptibility of blood isolates at a regional hospital in Passo Fundo, RS, Brazil

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    Maira Giseli C. Silva

    2015-06-01

    Full Text Available ABSTRACT Introduction: Candidemia is a bloodstream infection produced by Candida genus yeasts. Objective: The purpose of this study was to characterize the epidemiology and the fluconazole susceptibility in Candida species isolated from patients at a regional hospital in Passo Fundo, RS. Methods: Records from the laboratory were used to identify patients with positive blood cultures for Candida between 2010 and 2011. The in vitro activity of fluconazole was determined using the disk diffusion method. Results: Were analyzed 24 positive blood cultures for Candida and found a 54.16% mortality rate. C. albicans was the most prevalent species, followed by C. parapsilosis and C. krusei. For susceptibility to fluconazole, C. albicans, C. parapsilosis and C. tropicalis showed 100% sensitivity. However, C. krusei was 100% resistant; and C. glabrata, 50% resistant. Conclusion: The high mortality and fluconazole resistance rates emphasize the importance of the diagnosis of candidemia in a hospital environment.

  3. [Comparison of microdilution and disk diffusion methods for the detection of fluconazole and voriconazole susceptibility against clinical Candida glabrata isolates and determination of changing susceptibility with new CLSI breakpoints].

    Science.gov (United States)

    Hazırolan, Gülşen; Sarıbaş, Zeynep; Arıkan Akdağlı, Sevtap

    2016-07-01

    Candida albicans is the most frequently isolated species as the causative agent of Candida infections. However, in recent years, the isolation rate of non-albicans Candida species have increased. In many centers, Candida glabrata is one of the commonly isolated non-albicans species of C.glabrata infections which are difficult-to-treat due to decreased susceptibility to fluconazole and cross-resistance to other azoles. The aims of this study were to determine the in vitro susceptibility profiles of clinical C.glabrata isolates against fluconazole and voriconazole by microdilution and disk diffusion methods and to evaluate the results with both the previous (CLSI) and current species-specific CLSI (Clinical and Laboratory Standards Institute) clinical breakpoints. A total of 70 C.glabrata strains isolated from clinical samples were included in the study. The identification of the isolates was performed by morphologic examination on cornmeal Tween 80 agar and assimilation profiles obtained by using ID32C (BioMérieux, France). Broth microdilution and disk diffusion methods were performed according to CLSI M27-A3 and CLSI M44-A2 documents, respectively. The results were evaluated according to CLSI M27-A3 and M44-A2 documents and new vs. species-specific CLSI breakpoints. By using both previous and new CLSI breakpoints, broth microdilution test results showed that voriconazole has greater in vitro activity than fluconazole against C.glabrata isolates. For the two drugs tested, very major error was not observed with disk diffusion method when microdilution method was considered as the reference method. Since "susceptible" category no more exists for fluconazole vs. C.glabrata, the isolates that were interpreted as susceptible by previous breakpoints were evaluated as susceptible-dose dependent by current CLSI breakpoints. Since species-specific breakpoints remain yet undetermined for voriconazole, comparative analysis was not possible for this agent. The results obtained

  4. Performance of HIV Prevention of Mother-To-Child Transmission Programs in Sub-Saharan Africa: Longitudinal Assessment of 64 Nevirapine-Based Programs Implemented in 25 Countries, 2000-2011.

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    Joël Ladner

    Full Text Available To evaluate the performance and to identify predictive factors of performance in prevention of mother-to-child HIV transmission programs (PMTCT in sub-Saharan African countries.From 2000 to 2011, PMTCT programs included in the Viramune Donation Programme (VDP were prospectively followed. Each institution included in the VDP provided data on program implementation, type of management institution, number of PMTCT sites, key programs outputs (HIV counseling and testing, NVP regimens received by mothers and newborns. Nevirapine Coverage Ratio (NCR, defined as the number of women who should have received nevirapine (observed HIV prevalence x number of women in antenatal care, was used to measure performance. Included programs were followed every six months through progress reports.A total of 64 programs in 25 sub-Saharan African countries were included. The mean program follow-up was 48.0 months (SD = 24.5; 20,084,490 women attended in antenatal clinics were included. The overall mean NCR was 0.52 (SD = 0.25, with an increase from 0.37 to 0.57 between the first and last progress reports (p<.0001; NCR increased by 3.26% per year-program. Between the first and the last report, the number of women counseled and tested increased from 64.3% to 86.0% (p<.0001, the number of women post-counseled from 87.5% to 91.3% (p = 0.08. After mixed linear regression analysis, type of responsible institution, number of women attended in ANC, and program initiation in 2005-2006 were significant predictive factors associated with the NCR. The effect of the time period increased from earlier to later periods.A longitudinal assessment of large PMTCT programs shows that scaling-up of programs was increased in sub-Saharan African countries. The PMTCT coverage increased throughout the study period, especially after 2006. Performance may be better for programs with a small or medium number of women attended in ANC. Identification of factors that predict PMTCT program

  5. Ketoconazole- and fluconazole-induced embryotoxicity and skeletal anomalies in wistar rats: a comparative study

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    Vanessa Cristiane de Santana Amaral

    2008-12-01

    Full Text Available Ketoconazole and fluconazole are two broad-spectrum azole antifungals used for the treatment of superficial and systemic mycoses. Embryotoxicity and teratogenicity have been reported in some studies when those drugs are administered at high doses to pregnant rats. The aim of this study was to present a comparative study of embryotoxic effects as well as the skeletal anomalies in fetuses of Wistar rats which received ketoconazole and fluconazole at teratogenic doses on gestational days (GD 6 through 15 (organogenesis period. On gestational day (GD 21, the dams were euthanized and examined for standard parameters of reproductive outcome. Fetuses were stained with alizarin red and the bones of the head, trunk, forelimb and hindlimb were examined for detection of skeletal anomalies. The frequency of skeletal anomalies in the ketoconazole-treated group was significant when compared to the fluconazole and the control group.O cetoconazol e o fluconazol são dois antifúngicos azólicos, de amplo espectro, utilizados no tratamento de micoses superficiais e sistêmicas. Alguns estudos relatam a embriotoxicidade e teratogenicidade induzidas por estes fármacos quando os mesmos são administrados em altas doses a ratas prenhes. O objetivo deste trabalho foi apresentar um estudo comparativo dos efeitos embriotóxicos e das anomalias esqueléticas em fetos de ratas Wistar que receberam cetoconazol e fluconazol em doses teratogênicas do 6º ao 15º dia gestacional (GD (período da organogênese. No 21º GD as ratas foram eutanaziadas e examinadas quanto aos parâmetros padrões de performance reprodutiva. Os fetos foram corados com vermelho de alizarina e os ossos da cabeça, do tronco e dos membros anteriores e posteriores foram examinados para a verificação de anomalias esqueléticas. A freqüência de anomalias esqueléticas no grupo tratado com cetoconazol foi significante quando comparada à dos grupos fluconazol e controle.

  6. In Vivo Microdialysis To Determine Subcutaneous Interstitial Fluid Penetration and Pharmacokinetics of Fluconazole in Intensive Care Unit Patients with Sepsis.

    Science.gov (United States)

    Sinnollareddy, Mahipal G; Roberts, Michael S; Lipman, Jeffrey; Lassig-Smith, Melissa; Starr, Therese; Robertson, Thomas; Peake, Sandra L; Roberts, Jason A

    2016-02-01

    The objective of the study was to describe the subcutaneous interstitial fluid (ISF) pharmacokinetics of fluconazole in critically ill patients with sepsis. This prospective observational study was conducted at two tertiary intensive care units in Australia. Serial fluconazole concentrations were measured over 24 h in plasma and subcutaneous ISF using microdialysis. The concentrations in plasma and microdialysate were measured using a validated high-performance liquid chromatography system with electrospray mass spectrometer detector method. Noncompartmental pharmacokinetic analysis was performed. Twelve critically ill patients with sepsis were enrolled. The mean in vivo fluconazole recovery rates ± standard deviation (SD) for microdialysis were 51.4% ± 16.1% with a mean (±SD) fluconazole ISF penetration ratio of 0.52 ± 0.30 (coefficient of variation, 58%). The median free plasma area under the concentration-time curve from 0 to 24 h (AUC0-24) was significantly higher than the median ISF AUC0-24 (340.4 versus 141.1 mg · h/liter; P = 0.004). There was no statistical difference in median fluconazole ISF penetration between patients receiving and not receiving vasopressors (median, 0.28 versus 0.78; P = 0.106). Both minimum and the maximum concentrations of drug in serum (Cmax and Cmin) showed a significant correlation with the fluconazole plasma exposure (Cmax, R(2) = 0.86, P fluconazole was distributed variably, but incompletely, from plasma into subcutaneous interstitial fluid in this cohort of critically ill patients with sepsis. Given the variability of fluconazole interstitial fluid exposures and lack of clinically identifiable factors by which to recognize patients with reduced distribution/exposure, we suggest higher than standard doses to ensure that drug exposure is adequate at the site of infection.

  7. Recovery of fluconazole sensitive Candida ciferrii in a diabetic chronic obstructive pulmonary disease patient presenting with pneumonia

    Directory of Open Access Journals (Sweden)

    Kaushik Saha

    2013-01-01

    Full Text Available Chronic obstructive pulmonary disease (COPD exacerbations admitted in intensive care units (ICUs occur rarely due to fungal respiratory tract infections, but may occur when associated co-morbidities like diabetes mellitus coexist. Candida ciferrii is a new agent, recently was isolated from lung infections but usually resistant to fluconazole. Here, we report a rare case of pneumonia due to fluconazole sensitive Candida ciferrii in a COPD patient with known diabetes, admitted in our ICU.

  8. Recovery of fluconazole sensitive Candida ciferrii in a diabetic chronic obstructive pulmonary disease patient presenting with pneumonia.

    Science.gov (United States)

    Saha, Kaushik; Sit, Niranjan Kr; Maji, Arnab; Jash, Debraj

    2013-10-01

    Chronic obstructive pulmonary disease (COPD) exacerbations admitted in intensive care units (ICUs) occur rarely due to fungal respiratory tract infections, but may occur when associated co-morbidities like diabetes mellitus coexist. Candida ciferrii is a new agent, recently was isolated from lung infections but usually resistant to fluconazole. Here, we report a rare case of pneumonia due to fluconazole sensitive Candida ciferrii in a COPD patient with known diabetes, admitted in our ICU.

  9. Recovery of fluconazole sensitive Candida ciferrii in a diabetic chronic obstructive pulmonary disease patient presenting with pneumonia

    OpenAIRE

    Kaushik Saha; Niranjan Kr. Sit; Arnab Maji; Debraj Jash

    2013-01-01

    Chronic obstructive pulmonary disease (COPD) exacerbations admitted in intensive care units (ICUs) occur rarely due to fungal respiratory tract infections, but may occur when associated co-morbidities like diabetes mellitus coexist. Candida ciferrii is a new agent, recently was isolated from lung infections but usually resistant to fluconazole. Here, we report a rare case of pneumonia due to fluconazole sensitive Candida ciferrii in a COPD patient with known diabetes, admitted in our ICU.

  10. A pseudo-randomised clinical trial of in situ gels of fluconazole for the treatment of oropharngeal candidiasis

    OpenAIRE

    Shetty Veena A; Charyulu Narayana R; Nairy Harish M; Prabhakara Prabhu

    2011-01-01

    Abstract Background Oropharyngeal candidasis is a common opportunistic infection seen in immunocompromised patients. Fluconazole has a broad spectrum antifungal activity including a wide variety of candida species. Aim of the present investigation was to formulate and find out the relative efficacy of in situ gels of fluconazole. Method The in situ gels were prepared using polymers which exhibited sol-to-gel phase transition due to change in specific physico-chemical parameters, such as ion t...

  11. QbD-oriented development and validation of a bioanalytical method for nevirapine with enhanced liquid-liquid extraction and chromatographic separation.

    Science.gov (United States)

    Beg, Sarwar; Chaudhary, Vandna; Sharma, Gajanand; Garg, Babita; Panda, Sagar Suman; Singh, Bhupinder

    2016-06-01

    The present studies describe the systematic quality by design (QbD)-oriented development and validation of a simple, rapid, sensitive and cost-effective reversed-phase HPLC bioanalytical method for nevirapine in rat plasma. Chromatographic separation was carried out on a C18 column using isocratic 68:9:23% v/v elution of methanol, acetonitrile and water (pH 3, adjusted by orthophosphoric acid) at a flow rate of 1.0 mL/min using UV detection at 230 nm. A Box-Behnken design was applied for chromatographic method optimization taking mobile phase ratio, pH and flow rate as the critical method parameters (CMPs) from screening studies. Peak area, retention time, theoretical plates and peak tailing were measured as the critical analytical attributes (CAAs). Further, the bioanalytical liquid-liquid extraction process was optimized using an optimal design by selecting extraction time, centrifugation speed and temperature as the CMPs for percentage recovery of nevirapine as the CAA. The search for an optimum chromatographic solution was conducted through numerical desirability function. Validation studies performed as per the US Food and Drug Administration requirements revealed results within the acceptance limit. In a nutshell, the studies successfully demonstrate the utility of analytical QbD approach for the rational development of a bioanalytical method with enhanced chromatographic separation and recovery of nevirapine in rat plasma. Copyright © 2015 John Wiley & Sons, Ltd.

  12. Prevention of perinatal HIV I transmission by protease inhibitor based triple drug antiretroviral therapy versus nevirapine as single dose at the time of delivery.

    Science.gov (United States)

    Bendle, Meenakshi; Bajpai, Smrati; Choudhary, Ashwini; Pazare, Amar

    2012-12-01

    In India, parent to child transmission is the most important source of HIV infection in children below fifteen years of age. Transmission of HIV from mother to child can occur even at low or undetectable HIV virus levels. CD4 count or HIV RNA levels should not be the determining factor when deciding whether to use antiretroviral drugs for prevention of perinatal transmission of HIV. Use of single dose nevirapine during labour, in prevention of parent to child transmission (PPTCT) programme for pregnant females with CD4 count > 250 cells/cumm has less efficacy in reducing perinatal transmission. And there are high chances of development of nevirapine resistance to both mother and baby after single dose nevirapine exposure. Short course Protease inhibitor(PI) based triple drug combination ART from 28 weeks till delivery for perinatal prophylaxis is effective in reducing perinatal HIV transmission. PI's are safe in pregnancy and also have less chances of development of resistance when used for perinatal prophylaxis and stopped post delivery.Hence, it is opined that PI based combination ART should be offered to pregnant females in PPTCT programme, thereby preventing occurrence of paediatric HIV infection in India. This can have significant impact on the society at large.

  13. Fluconazole dosing predictions in critically-ill patients receiving prolonged intermittent renal replacement therapy: a Monte Carlo simulation approach.

    Science.gov (United States)

    Gharibian, Katherine N; Mueller, Bruce A

    2016-07-01

    Fluconazole is a renally-eliminated antifungal commonly used to treat Candida species infections. In critically-ill patients receiving prolonged intermittent renal replacement therapy (PIRRT), limited pharmacokinetic (PK) data are available to guide fluconazole dosing. We used previously-published fluconazole clearance data and PK data of critically-ill patients with acute kidney injury to develop a PK model with the goal of determining a therapeutic dosing regimen for critically-ill patients receiving PIRRT. Monte Carlo simulations were performed to create a virtual cohort of patients receiving different fluconazole dosing regimens. Plasma drug concentration-time profiles were evaluated on the probability of attaining a mean 24-hour area under the drug concentration-time curve to minimum inhibitory concentration ratio (AUC24h : MIC) of 100 during the initial 48 hours of antifungal therapy. At the susceptibility breakpoint of Candida albicans (2 mg/L), 93 - 96% of simulated subjects receiving PIRRT attained the pharmacodynamic target with a fluconazole 800-mg loading dose plus 400 mg twice daily (q12h or pre and post PIRRT) regimen. Monte Carlo simulations of a PK model of PIRRT provided a basis for the development of an informed fluconazole dosing recommendation when PK data was limited. This finding should be validated in the clinical setting.

  14. The A395T mutation in ERG11 gene confers fluconazole resistance in Candida tropicalis causing candidemia.

    Science.gov (United States)

    Tan, Jingwen; Zhang, Jinqing; Chen, Wei; Sun, Yi; Wan, Zhe; Li, Ruoyu; Liu, Wei

    2015-04-01

    The mechanism of fluconazole resistance in Candida tropicalis is still unclear. Recently, we isolated a fluconazole-resistant strain of C. tropicalis from the blood specimen of a patient with candidemia in China. In vitro antifungal susceptibility of the isolate was determined by using CLSI M27-A3 and E-test methods. The sequence of ERG11 gene was then analyzed, and the three-dimensional model of Erg11p encoded by ERG11 gene was also investigated. The sequencing of ERG11 gene revealed the mutation of A395T in this fluconazole-resistant isolate of C. tropicalis, resulting in the Y132F substitution in Erg11p. Sequence alignment and three-dimensional model comparison of Erg11ps showed high similarity between fluconazole-susceptible isolates of C. tropicalis and Candida albicans. The comparison of the three-dimensional models of Erg11ps demonstrated that the position of the Y132F substitution in this isolate of C. tropicalis is identical to the isolate of C. albicans with fluconazole resistance resulting from Y132F substitution in Erg11p. Hence, we ascertain that the Y132F substitution of Erg11p caused by A395T mutation in ERG11 gene confers the fluconazole resistance in C. tropicalis.

  15. Photodegradation of the azole fungicide fluconazole in aqueous solution under UV-254: kinetics, mechanistic investigations and toxicity evaluation.

    Science.gov (United States)

    Chen, Zhi-Feng; Ying, Guang-Guo; Jiang, Yu-Xia; Yang, Bin; Lai, Hua-Jie; Liu, You-Sheng; Pan, Chang-Gui; Peng, Fu-Qiang

    2014-04-01

    The azole fungicide fluconazole has been reported to be persistent in conventional wastewater treatment plants. This study investigated the photodegradation of fluconazole under UV-254 in aqueous solutions. The results revealed that the photodegradation of fluconazole was pH-dependent (2.0-12.0) following the pseudo-first-order kinetics with quantum yield values ranging from 0.023 to 0.090 mol einstein(-1), and it underwent a direct and self-sensitized mechanism involving (1)O2. The main photodegradation by-products were identified and semi-quantitated. The proposed photodegradation pathway included hydroxylative defluorination reaction. The 72 h-NOEC and 72 h-LOEC values for fluconazole using a freshwater unicellular green alga Pseudokirchneriella subcapitata were 10 μM and 15 μM. Overall, the photodegradation of fluconazole produced a significant decrease in algal toxicity. It also proved that the photodegradation by-products will not present extra toxicity to this alga than fluconazole itself.

  16. Aspergillus fumigatus Intrinsic Fluconazole Resistance Is Due to the Naturally Occurring T301I Substitution in Cyp51Ap.

    Science.gov (United States)

    Leonardelli, Florencia; Macedo, Daiana; Dudiuk, Catiana; Cabeza, Matias S; Gamarra, Soledad; Garcia-Effron, Guillermo

    2016-09-01

    Aspergillus fumigatus intrinsic fluconazole resistance has been demonstrated to be linked to the CYP51A gene, although the precise molecular mechanism has not been elucidated yet. Comparisons between A. fumigatus Cyp51Ap and Candida albicans Erg11p sequences showed differences in amino acid residues already associated with fluconazole resistance in C. albicans The aim of this study was to analyze the role of the natural polymorphism I301 in Aspergillus fumigatus Cyp51Ap in the intrinsic fluconazole resistance phenotype of this pathogen. The I301 residue in A. fumigatus Cyp51Ap was replaced with a threonine (analogue to T315 at Candida albicans fluconazole-susceptible Erg11p) by changing one single nucleotide in the CYP51A gene. Also, a CYP51A knockout strain was obtained using the same parental strain. Both mutants' antifungal susceptibilities were tested. The I301T mutant exhibited a lower level of resistance to fluconazole (MIC, 20 μg/ml) than the parental strain (MIC, 640 μg/ml), while no changes in MIC were observed for other azole- and non-azole-based drugs. These data strongly implicate the A. fumigatus Cyp51Ap I301 residue in the intrinsic resistance to fluconazole.

  17. 光滑念珠菌临床分离株对氟康唑耐药的分子机制%Molecular mechanisms of fluconazole resistance in clinical isolates of Candida glabrata

    Institute of Scientific and Technical Information of China (English)

    沈银忠; 卢洪洲; 张永信

    2010-01-01

    that the fluconazole-resistant isolates expressed ERG11 at higher levels than fluconazole-sensitive isolates (P=0.041). CDR1 expression was significantiv higher in the fluconazole-resistant isolates as compared with that in the fluconazole-sensitive isolates (P<0.001) and the expression was also significantly higher in the S-DD isolates as compared with that in the fluconazole-sensitive isolates (P=0.009). CDR2 upregulation was observed in the fluconazole-resistant isolates as compared with the susceptible isolates (P=0.018). With the decrease of susceptibility to fluconazole. the levels of expression of ERG11, CDR1 and CDR2 genes in the isolates appeared to be increased. Conclusions These results provide evidence that the overexpression of ERG11, CDR1 and CDR2 genes is associated with the increase of fluconazole resistance in clinical isolates of C glabrata. ERG11, CDR1 and CDR2 upregulation is a major molecular mechanism of fluconazole resistance in clinical isolates of C. glabrata.

  18. Synthesis and biological evaluation of fluconazole analogs with triazole-modified scaffold as potent antifungal agents.

    Science.gov (United States)

    Hashemi, Seyedeh Mahdieh; Badali, Hamid; Irannejad, Hamid; Shokrzadeh, Mohammad; Emami, Saeed

    2015-04-01

    In order to find new azole antifungals, we have recently designed a series of triazole alcohols in which one of the 1,2,4-triazol-1-yl group in fluconazole structure has been replaced with 4-amino-5-aryl-3-mercapto-1,2,4-triazole motif. In this paper, we focused on the structural refinement of the primary lead, by removing the amino group from the structure to achieve 5-aryl-3-mercapto-1,2,4-triazole derivatives 10a-i and 11a-i. The in vitro antifungal susceptibility testing of title compounds demonstrated that most compounds had potent inhibitory activity against Candida species. Among them, 5-(2,4-dichlorophenyl)triazole analogs 10h and 11h with MIC values of fluconazole against Candida species.

  19. Puerperal brain cryptococcoma in an HIV-negative woman successfully treated with fluconazole: a case report

    Directory of Open Access Journals (Sweden)

    José Edward Hagan

    2014-04-01

    Full Text Available Cryptococcus spp. cerebral abscesses are uncommon in immunocompetent subjects. The recommended induction treatment is the administration of amphotericin B plus flucytosine combined with resection for lesions ≥3cm. In this paper, we describe an HIV-negative woman diagnosed with a large cryptococcoma in the immediate postpartum period. The lesion was not resected, and due to amphotericin B intolerance, she received an extended course of fluconazole monotherapy. There was no disease recurrence during the 4 years of follow-up. The abrupt onset of her symptoms following delivery suggests that she developed a postpartum immune reconstitution syndrome. This case also demonstrates that in specific situations fluconazole monotherapy can be attempted in immunocompetent patients with cryptococcoma.

  20. Amphotericin B versus fluconazole for controlling fungal infections in neutropenic cancer patients

    DEFF Research Database (Denmark)

    Johansen, Helle Krogh; Gøtzsche, Peter C

    2014-01-01

    BACKGROUND: Systemic fungal infection is considered to be an important cause of morbidity and mortality in cancer patients, particularly those with neutropenia. Antifungal drugs are often given prophylactically, or empirically to patients with persistent fever. OBJECTIVES: To compare the effect...... of fluconazole and amphotericin B on morbidity and mortality in patients with cancer complicated by neutropenia. SEARCH METHODS: We searched PubMed from 1966 to 7 July 2014 and the reference lists of identified articles. SELECTION CRITERIA: Randomised clinical trials comparing fluconazole with amphotericin B....... DATA COLLECTION AND ANALYSIS: The two review authors independently assessed trial eligibility and risk of bias, and abstracted data. MAIN RESULTS: Seventeen trials (3798 patients, 381 deaths) were included. In two large three-armed trials, results for amphotericin B were combined with results...

  1. Candida bracarensis: Evaluation of Virulence Factors and its Tolerance to Amphotericin B and Fluconazole.

    Science.gov (United States)

    Moreira, André; Silva, Sónia; Botelho, Cláudia; Sampaio, Paula; Pais, Célia; Henriques, Mariana

    2015-12-01

    Candida bracarensis is an uncommon Candida species found during an epidemiological study of candidiasis performed in Braga, Portugal. Initially, it was identified as C. glabrata, but recently detailed analyses pointed out their differences. So, little information is still available about C. bracarensis virulence factors and antifungal susceptibilities. Therefore, the main goal of this work is to evaluate the ability of C. bracarensis to form biofilms, to produce hydrolytic enzymes (proteases, phospholipases and hemolysins), as well as its susceptibility to amphotericin B and fluconazole. It was shown, for the first time, that all C. bracarensis strains were able to form biofilms and display proteinase and hemolytic activities. Moreover, although planktonic cells presented antifungal susceptibility, amphotericin B and fluconazole were unable to inhibit biofilm formation and eradicate pre-formed biofilms. Due to the propensity of C. bracarensis to display antifungal resistance and virulence attributes, the control of these emerging pathogens is recommended.

  2. Novel triazole alcohol antifungals derived from fluconazole: design, synthesis, and biological activity.

    Science.gov (United States)

    Hashemi, Seyedeh Mahdieh; Badali, Hamid; Faramarzi, Mohammad Ali; Samadi, Nasrin; Afsarian, Mohammad Hosein; Irannejad, Hamid; Emami, Saeed

    2015-02-01

    A series of new triazole alcohol antifungals were designed by replacing one of the triazolyl moiety from fluconazole with a distinct 4-amino-3-mercapto-1,2,4-triazole motif, which is found in some antimicrobial agents. The antimicrobial susceptibility testing of target compounds demonstrated that the direct analogs of fluconazole (difluorophenethyl-triazoles) were less active against fungi, while compound 10h containing dichloro substitutions on both phenyl rings of the molecule had potent activity against yeasts including Candida albicans (four strains) and Cryptococcus neoformans (MICs = 2-8 μg/mL). Also, compound 10h was active against Candida parapsilosis, Epidermophyton floccosum, and Trichophyton mentagrophytes, while it showed no activity against Gram-positive and Gram-negative bacteria. Finally, a molecular docking study suggested that compound 10h interacts suitably with lanosterol 14α-demethylase, which is the key enzyme in ergosterol biosynthesis.

  3. DETERMINATION OF FLUCONAZOLE IN HUMAN PLASMA BY REVERSE PHASE HIGH PERFORMANCE LIQUID CHROMATOGRAPHY.

    Science.gov (United States)

    Safaei, Zahra; Alipour, Eskandar; Shafaati, Alireza; Zarghp, Afshin

    2015-01-01

    A rapid, simple and reproducible high performance liquid chromatographic method was developed and validated for determination of fluconazole in human plasma. The separation was performed on MZ C8 column (125 x 4 mm, 5 µm) using acetonitrile - potassium dihydrogen phosphate buffer (15 : 85, v/v), pH 3.0, as the mobile phase at a flow rate of 1.5 mL/min. The wavelength was set at 261 nm. The assay enables the measurement of fluconazole for therapeutic drug monitoring with a minimum quantification limit of 20 ng/mL. The method involves simple, protein precipitation procedure and analytical recovery was complete. The calibration curve was linear over the concentration range 0.1-4 µg/mL. The coefficients of variation for inter-day and intra-day assay were found to be less than 10%.

  4. Fluconazole pharmacokinetics in a morbidly obese, critically ill patient receiving continuous venovenous hemofiltration.

    Science.gov (United States)

    Lopez, Natasha D; Phillips, Kristy M

    2014-09-01

    Current fluconazole dosing strategies can be described using either standardized doses (800 or 400 mg) or as weight-based dosing recommendations (12 mg/kg loading dose followed by 6 mg/kg maintenance dose). The ideal method of fluconazole dosing is still unclear for certain patient populations, such as those receiving renal replacement therapy or the morbidly obese. We describe a 48-year-old man with a body mass index of 84 kg/m(2) who was receiving continuous venovenous hemofiltration (CVVH) and was treated with fluconazole by using a weight-based dose determined by lean body weight, infused at a rate of 200 mg/hour. Blood samples were collected at hour 0 (i.e., ~24 hrs after the loading dose was administered) and at 3.5, 6.8, and 11.3 hours after the start of the 600-mg maintenance dose, infused over 3 hours. Pharmacokinetic parameters calculated were maximum serum concentration 9.64 mg/L, minimum serum concentration 5.98 mg/L, area under the serum concentration-time curve from 0-24 hours (AUC0-24 ) 184.75 mg/L•hour, elimination rate constant 0.0199 hour(-1) , elimination half-life 34.8 hours, and total body clearance 3.25 L/hour. Our data, when combined with previously published literature, do not support using a linear dose-to-AUC approximation to estimate drug dosing needs in the critically ill patient population receiving CVVH. In addition, our results suggest that morbidly obese patients are able to achieve pharmacodynamic goals defined as an AUC:MIC ratio higher than 25 by using a lean body weight for fluconazole dosing calculations.

  5. Malassezia pachydermatis fungemia in a preterm neonate resistant to fluconazole and flucytosine

    Directory of Open Access Journals (Sweden)

    Noura Al-Sweih

    2014-07-01

    Full Text Available A case of Malassezia pachydermatis fungemia in a preterm neonate is described. The isolate was identified by rDNA sequencing and was resistant to fluconazole and flucytosine. Since M. pachydermatis does not require lipid supplementation for growth, it can be misidentified as a Candida species. The report highlights M. pachydermatis as a cause of late onset sepsis in preterm neonates and emphasizes the need for prior antifungal susceptibility testing.

  6. Fluconazole and its place in the treatment of seborrheic dermatitis--new therapeutic possibilities.

    Science.gov (United States)

    Zisova, Lilija G

    2006-01-01

    Seborrheic dermatitis is a subacute or chronic disease of the skin, affecting the seborrhea afflicted areas and presenting with erythema and desquamation. The inflammatory reaction towards the fungi Malassezia spp. is considered to have a basic etiologic connection with this disease. Taking into consideration the pathogenesis, treatment of the dermatitis should be directed towards eradication of Malassezia spp., reduction of the skin lipids, and suppression of the inflammatory response. A wide variety of agents presented in different forms--ointments, shampoos and drugs--can offer quick, safe and effective treatment alternatives. The purpose of the present study was to monitor the therapeutic effects of the anti-fungal drug fluconazole in patients with seborrheic dermatitis. We compared two study groups of patients: Group I--27 patients with seborrheic dermatitis stage I, II and III, treated with fluconazole, 50 mg/day for two weeks. As topical therapy we applied clobetasol propionate 0.05% ointment. After the completion of the therapeutic course, 85% of the patients in this group were clinically cured and their symptoms faded away. Fifteen percent of the subjects in this group--mainly stage III seborrheic dermatitis patients, showed partial but significant clinical improvement. The specific fungal test for Malassezia spp. on Dixon agar was negative in 93% of the cases in this group. Group II--eleven patients with similar clinical indexes were treated with fluconazole 50 mg/day only, for the same time period. The therapeutic results in this group were also satisfactory--31.5% of the patients were cured and 68.5% showed clinical improvement. In 74% of the patients the specific test for Malassezia spp. was negative after treatment. Fluconazole treatment in patients with seborrheic dermatitis proves to be successful, effective and safe.

  7. Single and multiple dose Fluconazole in the treatment of candidia vulvovaginitis: a prospective comparative study

    Directory of Open Access Journals (Sweden)

    Ashrafinia M

    2007-09-01

    Full Text Available  Background: Vulvovaginal candidiasis, the most common type of vaginitis, is usually caused by Candidia albicans. Patients experience a variety of symptoms. There are many types of vulvovaginal candidiasis with various microbial causes, symptoms, host circumstances, recurrence rates, and responses to treatment. The purpose of this study was to find the best method of treatment of complicated vaginitis as determined by its high prevalence, varying symptoms and signs and patient complaints.Methods: In this open clinical trial without placebo control, we studied all patients aged 18 to 65 years, suffering from vaginitis symptoms that presented at the gynecological clinic of Arash Hospital, Tehran, Iran, during the year 2004. After obtaining informed consent, we assessed the response to a treatment of single 150 mg dose of fluconazole in one group, and sequential 150 mg doses of fluconazole in the other. The analysis was performed using SPSS statistical software (version 11.Results: With regard to symptom severity, no significant difference was found between the groups. The rate of excoriation and fissure formation demonstrated significant difference between the two groups (p=0.048. Assessment of clinical and mycological response proved that patients with severe vaginitis treated with sequential doses of fluconazole had a better general status than those in the other group. The difference between the severity of vaginitis and positive response to the treatment in culture was not significant among patients with recurrent vaginitis.Conclusion: Patients with mild to moderate recurrent vaginitis show better response to treatment. The high rate of positive culture on day 35 reconfirms the limitation of fluconazole and other azoles as fungistatic drugs.

  8. ML212: A small-molecule probe for investigating fluconazole resistance mechanisms in Candida albicans

    Directory of Open Access Journals (Sweden)

    Willmen Youngsaye

    2013-07-01

    Full Text Available The National Institutes of Health Molecular Libraries and Probe Production Centers Network (NIH-MLPCN screened >300,000 compounds to evaluate their ability to restore fluconazole susceptibility in resistant Candida albicans isolates. Additional counter screens were incorporated to remove substances inherently toxic to either mammalian or fungal cells. A substituted indazole possessing the desired bioactivity profile was selected for further development, and initial investigation of structure–activity relationships led to the discovery of ML212.

  9. Pharmacokinetics of fluconazole following intravenous and oral administration to koalas (Phascolarctos cinereus).

    Science.gov (United States)

    Black, L A; Krockenberger, M B; Kimble, B; Govendir, M

    2014-02-01

    Clinically normal koalas (n = 12) received a single dose of 10 mg/kg fluconazole orally (p.o.; n = 6) or intravenously (i.v.; n = 6). Serial plasma samples were collected over 24 h, and fluconazole concentrations were determined using a validated HPLC assay. A noncompartmental pharmacokinetic analysis was performed. Following i.v. administration, median (range) plasma clearance (CL) and steady-state volume of distribution (Vss ) were 0.31 (0.11-0.55) L/h/kg and 0.92 (0.38-1.40) L/kg, respectively. The elimination half-life (t1/2 ) was much shorter than in many species (i.v.: median 2.25, range 0.98-6.51 h; p.o.: 4.69, range 2.47-8.01 h), and oral bioavailability was low and variable (median 0.53, range 0.20-0.97). Absorption rate-limited disposition was evident. Plasma protein binding was 39.5 ± 3.5%. Although fluconazole volume of distribution (Varea ) displayed an allometric relationship with other mammals, CL and t1/2 did not. Allometrically scaled values were approximately sevenfold lower (CL) and sixfold higher (t1/2 ) than observed values, highlighting flaws associated with this technique in physiologically distinct species. On the basis of fAUC/MIC pharmacodynamic targets, fluconazole is predicted to be ineffective against Cryptococcus gattii in the koala as a sole therapeutic agent administered at 10 mg/kg p.o. every 12 h. © 2013 John Wiley & Sons Ltd.

  10. Molecular mechanisms associated with Fluconazole resistance in clinical Candida albicans isolates from India.

    Science.gov (United States)

    Mane, Arati; Vidhate, Pallavi; Kusro, Chanchal; Waman, Vaishali; Saxena, Vandana; Kulkarni-Kale, Urmila; Risbud, Arun

    2016-02-01

    Resistance to azole antifungals is a significant problem in Candida albicans. An understanding of resistance at molecular level is essential for the development of strategies to tackle resistance and rationale design of newer antifungals and target-based molecular approaches. This study presents the first evaluation of molecular mechanisms associated with fluconazole resistance in clinical C.albicans isolates from India. Target site (ERG11) alterations were determined by DNA sequencing, whereas real-time PCRs were performed to quantify target and efflux pump genes (CDR1, CDR2, MDR1) in 87 [Fluconazole susceptible (n = 30), susceptible-dose dependent (n = 30) and resistant (n = 27)] C.albicans isolates. Cross-resistance to fluconazole, ketoconazole and itraconazole was observed in 74.1% isolates. Six amino acid substitutions were identified, including 4 (E116D, F145L, E226D, I437V) previously reported ones and 2 (P406L, Q474H) new ones. CDR1 over-expression was seen in 77.7% resistant isolates. CDR2 was exclusively expressed with CDR1 and their concomitant over-expression was associated with azole cross-resistance. MDR1 and ERG11 over-expression did not seem to be associated with resistance. Our results show that drug efflux mediated by Adenosine-5'-triphosphate (ATP)-binding cassette transporters, especially CDR1 is the predominant mechanism of fluconazole resistance and azole cross-resistance in C. albicans and indicate the need for research directed towards developing strategies to tackle efflux mediated resistance to salvage azoles.

  11. Disseminated cryptococcosis and fluconazole resistant oral candidiasis in a patient with acquired immunodeficiency syndrome (AIDS).

    Science.gov (United States)

    Kothavade, Rajendra J; Oberai, Chetan M; Valand, Arvind G; Panthaki, Mehroo H

    2010-10-28

    Disseminated cryptococcosis and recurrent oral candidiasis was presented in a-heterosexual AIDS patient. Candida tropicalis (C.tropicalis) was isolated from the oral pseudomembranous plaques and Cryptococcus neoformans (C. neoformans) was isolated from maculopapular lesions on body parts (face, hands and chest) and body fluids (urine, expectorated sputum, and cerebrospinal fluid). In vitro drug susceptibility testing on the yeast isolates demonstrated resistance to fluconazole acquired by C. tropicalis which was a suggestive possible root cause of recurrent oral candidiasis in this patient.

  12. Analysis of Fluconazole in Human Urine Sample by High Performance Liquid Chromatography Method

    Science.gov (United States)

    Hermawan, D.; Ali, N. A. Md; Ibrahim, W. A. Wan; Sanagi, M. M.

    2013-04-01

    A method for determination of fluconazole, antifungal drug in human urine by using reversed-phased high performance liquid chromatography (RP-HPLC) with ultraviolet (UV) detector was developed. Optimization HPLC conditions were carried out by changing the flow rate and composition of mobile phase. The optimum separation conditions at a flow rate 0.85 mL/min with a composition of mobile phase containing methanol:water (70:30, v/v) with UV detection at a wavelength 254 nm was able to analyze fluconazole within 3 min. The excellent linearity was obtained in the range of concentration 1 to 10 μg/mL with r2 = 0.998. The limit of detection (LOD) and limit of quantitation (LOQ) were 0.39 μg/mL and 1.28 μg/mL, respectively. Solid phase extraction (SPE) method using octadecylsilane (C18) as a sorbent was used to clean-up and pre-concentrated of the urine sample prior to HPLC analysis. The average recoveries of fluconazole in spiked urine sample was 72.4% with RSD of 3.21% (n=3).

  13. Demonstration of Therapeutic Equivalence of Fluconazole Generic Products in the Neutropenic Mouse Model of Disseminated Candidiasis.

    Science.gov (United States)

    Gonzalez, Javier M; Rodriguez, Carlos A; Zuluaga, Andres F; Agudelo, Maria; Vesga, Omar

    2015-01-01

    Some generics of antibacterials fail therapeutic equivalence despite being pharmaceutical equivalents of their innovators, but data are scarce with antifungals. We used the neutropenic mice model of disseminated candidiasis to challenge the therapeutic equivalence of three generic products of fluconazole compared with the innovator in terms of concentration of the active pharmaceutical ingredient, analytical chemistry (liquid chromatography/mass spectrometry), in vitro susceptibility testing, single-dose serum pharmacokinetics in infected mice, and in vivo pharmacodynamics. Neutropenic, five week-old, murine pathogen free male mice of the strain Udea:ICR(CD-2) were injected in the tail vein with Candida albicans GRP-0144 (MIC = 0.25 mg/L) or Candida albicans CIB-19177 (MIC = 4 mg/L). Subcutaneous therapy with fluconazole (generics or innovator) and sterile saline (untreated controls) started 2 h after infection and ended 24 h later, with doses ranging from no effect to maximal effect (1 to 128 mg/kg per day) divided every 3 or 6 hours. The Hill's model was fitted to the data by nonlinear regression, and results from each group compared by curve fitting analysis. All products were identical in terms of concentration, chromatographic and spectrographic profiles, MICs, mouse pharmacokinetics, and in vivo pharmacodynamic parameters. In conclusion, the generic products studied were pharmaceutically and therapeutically equivalent to the innovator of fluconazole.

  14. Synthesis and characterization of metal(II) fluconazole complexes: Chain-like structure and photoluminescence

    Science.gov (United States)

    Gong, Yun; Hu, Chang Wen; Xia, Zhi Ning

    2007-06-01

    Three coordination polymers (flu) 2CuBr 2·2H 2O ( 1), (flu) 2Zn(ClO 4) 2·2H 2O ( 2), (flu) 4Ni 2(H 2O) 4(Mo 8O 26) · 6H 2O ( 3), (flu = fluconazole) have been hydrothermally synthesized and characterized by elemental analysis, IR and single-crystal X-ray diffraction. Compounds 1- 3 exhibit similar one dimensional chain-like structures linked by double stranded fluconazole-bridge. In the self-assembly of compounds 1- 3, the introduction of anions with different sizes and geometrical configurations lead to the flexible C-C chain of fluconazole to be rotated for suitable position and angle to hold them. Similar inter-chain hydrogen bonding interactions are observed in compounds 1 and 2, whereas compound 3 exhibits a different three dimensional supramolecular architecture in which different chains are linked by [Mo 8O 26] 4- via hydrogen bonding interactions. Complex 1 is nonemissive at room temperature and compounds 2- 3 exhibit different photoluminescence properties.

  15. Relationship between antifungal resistance of fluconazole resistant Candida albicans and mutations in ERG11 gene

    Institute of Scientific and Technical Information of China (English)

    FENG Li-juan; WAN Zhe; WANG Xiao-hong; LI Ruo-yu; LIU Wei

    2010-01-01

    Background The cytochrome P450 lanosterol 14α-demethylase(Erg11p) encoded by ERG11 gene is the primary target for azole antifungals.Changes in azole affinity of this enzyme caused by amino acid substitutions have been reported as a mechanism of azole antifungal resistance. This study aimed to investigate the relationship between amino acid substitutions in Erg11p from fluconazole resistant Candida albicans (C.albicans)isolates and their cross-resistance to azoles.Methods Mutations in ERG11 gene were screened in 10 clinical isolates of fluconazole resistant C.albicans strains.DNA sequence of ERG11 was determined by PCR based DNA sequencing.Results In the 10 isolates,19 types of amino acid substitutions were found,of which 10 substitutions (F72S, F103L, F145I, F198L, G206D, G227D, N349S, F416S, F422L and T482A) have not been reported previously. Mutations in ERG11 gene were detected in 9 isolates of fluconazole resistant C. albicans, but were not detected in 1 isolate. Conclusions Although no definite correlation was found between the type of amino acid substitutions in Erg11p and the phenotype of cross-resistance to azoles, the substitutions F72S, F145I and G227D in our study may be highly associated with resistance to azoles because of their special location in Erg11p.

  16. Solid-state characterization fluconazol generic products and impurities determination of marketed in Morocco

    Institute of Scientific and Technical Information of China (English)

    Houda Bourichi; Youness Brik; Philipe Hubert; Yahia Cherrah; Abdelaziz Bouklouze

    2012-01-01

    In this paper, we report the results of quality control based in pbysicochemical characteriza- tion and impurities determination of three samples of fluconazole drug substances marketed in Morocco. These samples were supplied by different pharmaceuticals companies. The sample A, as the discovered product, was supplied by Pfizer, while samples B and C (generics), were manufactured by two different Indian industries. Solid-state characterization of the three samples was realized with different physicochemical methods as: X-ray powder diffraction, Fourier-transformation infrared spectroscopy, differential scanning calorimetry. High performance liquid chromatography was used to quantify the impurities in the different samples. The results from the physicochemical methods cited above, showed difference in polymorph structure of the three drug substances. Sample A consisted in pure polymorph II1, sample B consisted in pure polymorph I1, sample C consisted in a mixture of fluconazole Form Ili, form II and the monohydrate. This result was confirmed by differential scanning calorimetry. Also it was demonstrated that solvents used during the re-crystallization step were among the origins of these differences in the structure form. On the other hand, the result of the stability study under humidity and temperature showed that fluconazole polymorphic transformation could be owed to the no compliance with the conditions of storage. The HPLC analysis of these compounds showed the presence of specific

  17. [Fluconazole 1200mg or 800mg for cryptococcal meningitis treatment in Ivory Coast].

    Science.gov (United States)

    Kouakou, G A; Ello, N F; Kassi, N A; Keita, M; Doumbia, A; Mossou, C; Kassi, F K; Tanon, A; Ehui, E; Eholié, S P

    2017-03-01

    Assessing the use of high-dose fluconazol monotherapy (1200mg or 800mg) in the treatment and prognosis of HIV-associated cryptococcal meningitis in Ivory Coast. A retrospective study carried out from August 2008 to August 2011 based on patients charts suffering from CM in the Abidjan Tropicals and Infectious Disease Unit. Mortality rate and associated factors were analyzed. Forty-six cases of cryptococcal meningitis (2.5% of hospitalizations) were included. The sex-ratio was of 1.2. The median age was 40.5 [35-47] years. The symptomatology was subacute (93.5%). The main clinical symptoms were syndrome of pure meningeal irritation (65%), fever (100%); 35% of patients had encephalomeningits. Twenty-one (45.7%) was ART-naïve patients. Fluconazole 1200mg was prescribed to 29 (63%) patients. Therapeutic lumbar punctures were performed in 42 (91.3) patients. The mortality rate was 50%. Significant predictors of mortality were encephalomeningitis and therapeutic lumbar puncture. Cryptococcal meningitis associated mortality remains high despite the use of high-dose fluconazole monotherapy. Therapeutic lumbar punctures help to improving the prognosis. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  18. FLUCONAZOLE AND BORIC ACID FOR TREATMENT OF VAGINAL CANDIDIASIS--NEW WORDS ABOUT OLD ISSUE.

    Science.gov (United States)

    Khameneie, K M; Arianpour, N; Roozegar, R; Aklamli, M; Amiri, M M

    2013-04-01

    To compare boric acid as an effective treatment for VVC compared to fluconazole. We also studied the efficiency of these drugs in preventing recurrence of VVC. A cross sectional, randomized, double-blind study. Gynaecology clinic of Imam Reza hospital, Tehran - Iran Women with signs and symptoms related to Vulvo Vaginal Candidiasis. Seventy five patients out of total 150 patients with signs and symptoms related to Vulvo Vaginal Candidiasis were treatedwith boric acidpowder everynight for a week and the remaining 75 patients received Fluconazole. The cure rate in first group was 46.7% but the cure rate in second group was 37.3%. The difference was not statistically significant (P>0.3). Difference between the efficacy of the two drugs was not significant either (P=0.47). The recurrence rate among patients in first group was 35% while it was 32% in second group. Their difference was not statistically significant (P=0.54). According to our findings, treatment of vaginal candidiasis with boric acid is as effective as fluconazole. The availability of boric acid and its relatively low cost suggests it as a safe and effective drug for treatment of candidiasis.

  19. [Identification and susceptibility against fluconazole and albaconazole of 100 yeasts' strains isolated from vaginal discharge].

    Science.gov (United States)

    Arechavala, Alicia I; Bianchi, Mario H; Robles, Ana María; Santiso, Gabriela; Negroni, Ricardo

    2007-12-31

    Vulvovaginal candidiasis is a condition that affects a great number of fertile women. It is considered the second cause of genital infection after vaginosis due to GAM complex. Candida albicans is the most frequent isolated species from vaginal discharge. However, sometimes more than one yeast species could be found in the same clinical sample that are more resistant to antifungal drugs. Nowadays, it is necessary to identify properly up to species level the isolated microorganism and to determine the antifungal susceptibility profile. One hundred strains obtained from vaginal discharge of 94 patients suffering acute vulvovaginal candidiasis were studied. The identification of the isolates showed: C. albicans 86%, Candida glabrata 6%, Candida inconspicua 3%, Candida krusei 2% and Candida intermedia, Candida holmii and Trichosporon asahii one case each. Minimal inhibitory concentrations (MIC) of all the yeasts against fluconazole and albaconazole were performed. C. glabrata, C. krusei and C. inconspicua were the most resistant against fluconazole, on the other hand albicans was susceptible to this drug. All the isolates presented MIC against albaconazole much lower than fluconazole.

  20. Combination of CuO nanoparticles and fluconazole: preparation, characterization, and antifungal activity against Candida albicans

    Energy Technology Data Exchange (ETDEWEB)

    Weitz, Iris S., E-mail: irisweitz@braude.ac.il; Maoz, Michal; Panitz, Daniel [ORT Braude College, Department of Biotechnology Engineering (Israel); Eichler, Sigal; Segal, Ester [Technion – Israel Institute of Technology, Department of Biotechnology and Food Engineering (Israel)

    2015-08-15

    Combination therapy becomes an important strategy in the management of invasive fungal infections and emergence of resistant fungi mutants. In this work, we examine the combination of copper oxide (CuO) nanoparticles (NPs) with fluconazole as potential treatment against the pathogenic fungi, Candidaalbicans. CuO NPs (∼7 nm in size) were synthesized with acetate ligands assembled on their surface, as shown by both thermal gravimetric analysis and FTIR spectroscopy. Unlike the commercial CuO (both bulk and 50 nm particles), that are poorly dispersed in water, the interaction with water allows the fine dispersion of the coated CuO NPs and their excellent colloidal stability. The addition of fluconazole to the aqueous CuO dispersion induced spontaneous self-assembly of the NPs into linear pearl-like chains network, shown by cryogenic transmission electron microscopy (cryo-TEM). The antifungal activity of the CuO NPs and their combination with fluconazole (fluconazole–CuO NPs) was studied against C. albicans. The best MIC values were obtained at concentrations as low as 0.2 and 0.3 mg/mL, respectively. The results suggest that fluconazole–CuO NPs can provide a potential alternative treatment for C. albicans infections.

  1. Demonstration of Therapeutic Equivalence of Fluconazole Generic Products in the Neutropenic Mouse Model of Disseminated Candidiasis.

    Directory of Open Access Journals (Sweden)

    Javier M Gonzalez

    Full Text Available Some generics of antibacterials fail therapeutic equivalence despite being pharmaceutical equivalents of their innovators, but data are scarce with antifungals. We used the neutropenic mice model of disseminated candidiasis to challenge the therapeutic equivalence of three generic products of fluconazole compared with the innovator in terms of concentration of the active pharmaceutical ingredient, analytical chemistry (liquid chromatography/mass spectrometry, in vitro susceptibility testing, single-dose serum pharmacokinetics in infected mice, and in vivo pharmacodynamics. Neutropenic, five week-old, murine pathogen free male mice of the strain Udea:ICR(CD-2 were injected in the tail vein with Candida albicans GRP-0144 (MIC = 0.25 mg/L or Candida albicans CIB-19177 (MIC = 4 mg/L. Subcutaneous therapy with fluconazole (generics or innovator and sterile saline (untreated controls started 2 h after infection and ended 24 h later, with doses ranging from no effect to maximal effect (1 to 128 mg/kg per day divided every 3 or 6 hours. The Hill's model was fitted to the data by nonlinear regression, and results from each group compared by curve fitting analysis. All products were identical in terms of concentration, chromatographic and spectrographic profiles, MICs, mouse pharmacokinetics, and in vivo pharmacodynamic parameters. In conclusion, the generic products studied were pharmaceutically and therapeutically equivalent to the innovator of fluconazole.

  2. The development of Cutina lipogels and gel microemulsion for topical administration of fluconazole.

    Science.gov (United States)

    El Laithy, H M; El-Shaboury, K M F

    2002-01-01

    The influence of the vehicle on the release and permeation of fluconazole, a topical antifungal drug dissolved in Jojoba oil was evaluated. Series of Cutina lipogels (Cutina CPA [cetyl palmitate], CBS [mixture of glyceryl stearate, cetearyl alcohol, cetyl palmitate, and cocoglycerides], MD [glyceryl stearate], and GMS [glyceryl monostearate]) in different concentrations as well as gel microemulsion were prepared. In-vitro drug release in Sorensen's citrate buffer (pH 5.5) and permeation through the excised skin of hairless mice, using a modified Franz diffusion cell, were performed. The rheological behavior and the apparent viscosity values for different gel bases were measured before and after storage under freezing conditions at -4 degrees C and were taken as measures for stability of network structure. Candida albicans was used as a model fungus to evaluate the antifungal activity of the best formula achieved. The results of in vitro drug release and its percutaneous absorption showed that the highest values from gel microemulsion were assured. The rheological behavior of the prepared systems showed pseudoplastic (shear-thinning) flow indicating structural breakdown of the existing intermolecular interactions between polymeric chains. Moreover, the stability study revealed no significant difference between viscosity before and after storage for different formulae except for CPA Cutina lipogel (using analysis of variance [ANOVA] test at level of significance.05). The antifungal activity of fluconazole showed the widest zone of inhibition with gel microemulsion. The gel microemulsion is an excellent vehicle for fluconazole topical drug delivery.

  3. Comparison of the therapeutic effects of Garcin(®) and fluconazole on Candida vaginitis.

    Science.gov (United States)

    Ebrahimy, Farzaneh; Dolatian, Mahrokh; Moatar, Fariborz; Majd, Hamid Alavi

    2015-10-01

    This study aimed to determine and compare the effects of garlic tablets (Garcin(®)) and fluconazole on Candida vaginitis in women who presented to a health centre in Koohdasht, Iran, from August 2011 to March 2012. The clinical trial was conducted on 110 married women (aged 18-44 years) who had complaints of itching or a burning sensation in the vaginal area. Candida vaginitis was diagnosed by pH measurement of vaginal secretions, direct microscopic evaluation and Sabouraud dextrose agar cultures of the vaginal discharge. On confirmation of diagnosis, the patients were randomly divided into two groups (n = 55). One group received 1,500 mg of Garcin tablets daily and the other received fluconazole tablets 150 mg daily, over a period of seven days. Four to seven days after the completion of treatment, patients were examined for treatment response and possible side effects. Complaints related to the disease improved by about 44% in the Garcin group and 63.5% in the fluconazole group (p 0.05). Results of microscopic evaluation and vaginal discharge culture showed significant differences before and after intervention in both groups (p vaginitis.

  4. Comparison of the therapeutic effects of Garcin® and fluconazole on Candida vaginitis

    Science.gov (United States)

    Ebrahimy, Farzaneh; Dolatian, Mahrokh; Moatar, Fariborz; Majd, Hamid Alavi

    2015-01-01

    INTRODUCTION This study aimed to determine and compare the effects of garlic tablets (Garcin®) and fluconazole on Candida vaginitis in women who presented to a health centre in Koohdasht, Iran, from August 2011 to March 2012. METHODS The clinical trial was conducted on 110 married women (aged 18–44 years) who had complaints of itching or a burning sensation in the vaginal area. Candida vaginitis was diagnosed by pH measurement of vaginal secretions, direct microscopic evaluation and Sabouraud dextrose agar cultures of the vaginal discharge. On confirmation of diagnosis, the patients were randomly divided into two groups (n = 55). One group received 1,500 mg of Garcin tablets daily and the other received fluconazole tablets 150 mg daily, over a period of seven days. Four to seven days after the completion of treatment, patients were examined for treatment response and possible side effects. RESULTS Complaints related to the disease improved by about 44% in the Garcin group and 63.5% in the fluconazole group (p 0.05). Results of microscopic evaluation and vaginal discharge culture showed significant differences before and after intervention in both groups (p vaginitis. PMID:26512149

  5. Hepatotoxicity and effectiveness of a Nevirapine-based antiretroviral therapy in HIV-infected patients with or without viral hepatitis B or C infection in Cameroon

    Directory of Open Access Journals (Sweden)

    Gwet Henri

    2010-03-01

    Full Text Available Abstract Background Coinfection with hepatitis B virus (HBV or hepatitis C virus (HCV in HIV-infected patients receiving a commonly used nevirapine-based antiretroviral therapy is a major concern for African clinicians owing to its high prevalence, the infrequent testing and treatment of viral hepatitis, and the impact of liver disease on the tolerability and effectiveness of anti-HIV treatment. We compared the hepatotoxicity and the immunological, virological and clinical effectiveness of a nevirapine-based antiretroviral therapy between patients infected with HIV only and patients coinfected with hepatitis B or C virus in Cameroon. Methods A retrospective cohort study was conducted among HIV-1-infected patients. Plasma HBV DNA and HCV RNA were tested in positive or indeterminate samples for HBsAg or HCV antibodies, respectively. All patients received nevirapine and lamivudine plus stavudine or zidovudine. Results Of 169 HIV-1-infected patients with a median baseline CD4 count of 135 cells/mm3 (interquartile range [IQR] 67-218, 21% were coinfected with HBV or HCV. In coinfected patients, the median viral load was 2.47 × 107 IU/mL for HBV (IQR 3680-1.59 × 108 and 928 000 IU/mL for HCV (IQR 178 400-2.06 × 106. Multivariate analyses showed that the risk of hepatotoxicity was 2-fold higher in coinfected patients (p p = 0.8, HIV-1 viral load below 400 copies/mL (p = 0.9, death (p = 0.3 and death or new AIDS-defining event (p = 0.1. Nevirapine was replaced by a protease inhibitor in 4 patients owing to hepatotoxicity. Conclusion This study suggests that the nevirapine-based antiretroviral therapy could be used safely as first-line treatment in patients with low CD4 cell count in Africa despite frequent coinfections with HBV or HCV and infrequent testing of these infections. Although testing for HBV and HCV should be systematically performed before initiating antiretroviral therapy, transaminases elevations at baseline or during treatment should be

  6. Effectiveness of a Treatment Switch to Nevirapine plus Tenofovir and Emtricitabine (or Lamivudine in Adults with HIV-1 Suppressed Viremia.

    Directory of Open Access Journals (Sweden)

    Josep M Llibre

    Full Text Available Switching subjects with persistently undetectable HIV-1 viremia under antiretroviral treatment (ART to once-daily tenofovir/emtricitabine (or lamivudine + nevirapine is a cost-effective and well-tolerated strategy. However, the effectiveness of this approach has not been established.We performed a retrospective study evaluating the rates of treatment failure, virological failure (VF, and variables associated, in all subjects initiating this switch combination in our clinic since 2001. Analyses were performed by a modified intention to treat, where switch due to toxicity equalled failure. The main endpoint was plasma HIV-RNA < 50 copies/mL.341 patients were treated for a median of 176 (57; 308 weeks. At week 48, 306 (89.7% subjects had HIV-1 RNA <50 copies/mL, 10 (2.9% experienced VF, and 25 (7.4% discontinued the treatment due to toxicity. During the whole follow-up 23 (6.7% individuals (17 on lamivudine, 6 on emtricitabine; p = 0.034 developed VF and treatment modification due to toxicity occurred in 36 (10.7%. Factors independently associated with VF in a multivariate analysis were: intravenous drug use (HR 1.51; 95%CI 1.12, 2.04, time with undetectable viral load before the switch (HR 0.98; 0.97, 0.99, number of prior NRTIs (HR 1.49; 1.15, 1.93 or NNRTIs (HR 3.22; 1.64, 6.25, and previous NVP (HR 1.54; 1.10, 2.17 or efavirenz (HR 5.76; 1.11, 29.87 unscheduled interruptions. VF was associated with emergence of usual nevirapine mutations (Y181C/I/D, K103N and V106A/I, M184V (n = 16; 12 with lamivudine vs. 4 with emtricitabine, p = 0.04, and K65R (n = 7.The rates of treatment failure at 48 weeks, or long-term toxicity or VF with this switch regimen are low and no unexpected mutations or patterns of mutations were selected in subjects with treatment failure.

  7. In vitro photodynamic inactivation effects of cationic benzylidene cyclopentanone photosensitizers on clinical fluconazole-resistant Candida albicans planktonic cells and biofilms

    Science.gov (United States)

    Zhou, Shaona; Fang, Yanyan; Ye, Zulin; Wang, Ying; Zhao, Yuxia; Gu, Ying

    2016-10-01

    Background: An increasing prevalence of Candida infections has emerged with the wide use of immune-suppressants and antibiotics. Photodynamic inactivation (PDI) as a new approach to treat localized Candida infections is an emerging and promising field nowadays. This study evaluated the efficacy of photodynamic therapy using two new Cationic benzylidene cyclopentanone photosensitizers(P1 and P2) against strains of clinical fluconazole-resistant Candida albicans. Methods: Suspensions and biofilms of Candida species were incubated with P1 and P2 concentrations (0.25 50 μM) for 30 min followed by 532nm laser irradiation. For planktonic suspensions, viability of cells was assayed by CFU counting. For biofilms, the metabolic activity was evaluated by XTT. Results: In PDI of a planktonic culture of clinical fluconazole-resistant Candida albicans, P2 showed the higher efficacy. After incubation with 25 μM of P2 for 30 min and irradiation with 532nm laser (36 J cm-2), the viability of C. albicans planktonic cells decreased by 3.84 log10. For biofilm cells, a higher light dose of 75 mW cm-2 was necessary to achieve 97.71% metabolic activity reduction. Conclusions: The results of this investigation demonstrated that benzylidene cyclopentanone photosensitizer, P2, is an efficient photosensitizer to kill C. albicans. Moreover, single-species biofilms were less susceptible to PDT than their planktonic counterparts.

  8. A comparison of the efficacy of nystatin and fluconazole incorporated into tissue conditioner on the in vitro attachment and colonization of Candida Albicans

    Directory of Open Access Journals (Sweden)

    Abbas Falah-Tafti

    2010-01-01

    Results: The 1% to 10% mixture of nystatin and tissue conditioner completely inhibited the attach-ment and colonization of Candida albicans, although for fluconazole only a 10% concentration caused complete inhibition. Nystatin showed a potentially higher effect in inhibition of candida at-tachment and colonization (P = 0.0001 compared to that of fluconazole and a statistically significant difference was seen between 5% and 1% fluconazole (P = 0.0001. Conclusion : Tissue conditioner with 1% to 10% nystatin or 10% fluconazole can completely inhi-bit the adhesion and colonization of Candida albicans.

  9. Comparison of microbiological assay and HPLC-UV for determination of fluconazole in capsules

    Directory of Open Access Journals (Sweden)

    Kelly Marques Queiroz

    2009-12-01

    Full Text Available The development of a specific agar diffusion bioassay for the quantitative determination of fluconazole formulated in capsules was carried out using a strain of Candida albicans ATCC 18804 as the test organism. A prospective validation of the method showed adequate linearity (r²=0.9995, precision (R.S.D. = 4.0% for intra-day and 4.5% for inter-day precision and accuracy (mean recovery = 102.9%. High performance liquid chromatography was chosen as a comparison method for the fluconazole determination. The contents of fluconazole determined by both methods, for four capsule samples, showed a strong correlation, confirmed by Pearson's correlation coefficient value (r = 0.9884. The bioassay is a suitable method for both research and pharmaceutical industry laboratories.Este trabalho visou ao desenvolvimento e validação de um método microbiológico por difusão em ágar para quantificação de fluconazol em cápsulas utilizando o isolado Candida albicans ATCC 18804 como reagente biológico. O método foi validado e foi verificada linearidade (r²=0,9995, precisão (D.P.R. = 4.0% para precisão intra-dia e 4,5% para precisão inter-dia e exatidão (recuperação média = 102,9%. Concomitantemente, foi realizado o doseamento de fluconazol nas cápsulas por meio de cromatografia líquida de alta eficiência. Os teores encontrados por ambos os métodos demonstraram alta correlação, confirmada pelo Coeficiente de Correlação de Pearson (r = 0,9884. O ensaio microbiológico desenvolvido pode ser considerado ferramenta valiosa tanto para a pesquisa científica quanto para a rotina da indústria farmacêutica.

  10. Heteroresistance to Fluconazole Is a Continuously Distributed Phenotype among Candida glabrata Clinical Strains Associated with In Vivo Persistence

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    Ronen Ben-Ami

    2016-08-01

    Full Text Available Candida glabrata causes persistent infections in patients treated with fluconazole and often acquires resistance following exposure to the drug. Here we found that clinical strains of C. glabrata exhibit cell-to-cell variation in drug response (heteroresistance. We used population analysis profiling (PAP to assess fluconazole heteroresistance (FLCHR and to ask if it is a binary trait or a continuous phenotype. Thirty (57.6% of 52 fluconazole-sensitive clinical C. glabrata isolates met accepted dichotomous criteria for FLCHR. However, quantitative grading of FLCHR by using the area under the PAP curve (AUC revealed a continuous distribution across a wide range of values, suggesting that all isolates exhibit some degree of heteroresistance. The AUC correlated with rhodamine 6G efflux and was associated with upregulation of the CDR1 and PDH1 genes, encoding ATP-binding cassette (ABC transmembrane transporters, implying that HetR populations exhibit higher levels of drug efflux. Highly FLCHRC. glabrata was recovered more frequently than nonheteroresistant C. glabrata from hematogenously infected immunocompetent mice following treatment with high-dose fluconazole (45.8% versus 15%, P = 0.029. Phylogenetic analysis revealed some phenotypic clustering but also variations in FLCHR within clonal groups, suggesting both genetic and epigenetic determinants of heteroresistance. Collectively, these results establish heteroresistance to fluconazole as a graded phenotype associated with ABC transporter upregulation and fluconazole efflux. Heteroresistance may explain the propensity of C. glabrata for persistent infection and the emergence of breakthrough resistance to fluconazole.

  11. Long-term efficacy and toxicity of abacavir/lamivudine/nevirapine compared to the most prescribed ARV regimens before 2013 in a French Nationwide Cohort Study.

    Science.gov (United States)

    de Boissieu, Paul; Dramé, Moustapha; Raffi, François; Cabie, André; Poizot-Martin, Isabelle; Cotte, Laurent; Garraffo, Rodolphe; Delobel, Pierre; Huleux, Thomas; Rey, David; Bani-Sadr, Firouzé

    2016-09-01

    Data on the long-term efficacy and safety of abacavir/lamivudine (ABC/3TC) and nevirapine (NVP) are scarce. This combination has the advantage of simplifying treatment and improving long-term tolerance. The aim of this study was to compare the rate of any discontinuation of antiretroviral (ARV) regimen because of virologic failure (VF), and/or adverse drug reaction (ADR) among patients receiving stable ARV regimens for at least 6 months.ABC/3TC/NVP was compared to ABC/3TC with either ritonavir-boosted darunavir (DRV/r) or ritonavir-boosted atazanavir (ATV/r), unboosted ATV, or tenofovir/emtricitabine (TDF/FTC) with either one of the following: ATV/r, unboosted ATV, DRV/r, efavirenz (EFV), or NVP, in the French prospective multicenter Dat'AIDS cohort.The study enrolled 16,511 patients treated with following ARV regimens: ABC/3TC/NVP (n = 1089), TDF/FTC/NVP (n = 1542), ABC/3TC/DRV/r (n = 1065), ABC/3TC/ATV/r (n = 1847), ABC/3TC/ATV (n = 563), TDF/FTC/ATV/r (n = 3519), TDF/FTC/DRV/r (n = 2767), TDF/FTC/ATV (n = 419), and TDF/FTC/EFV (n = 3700). Mean follow-up was 36 ± 24 months. Patients treated with ABC/3TC/NVP received this regimen as a switch regimen in 97% of cases. By multivariable analysis, the risk of treatment discontinuation due to VF was similar between ABC/3TC/NVP and other ARV regimens, except for TDF/FTC/ATV and ABC/3TC/ATV, which were associated with a higher risk of treatment interruption due to VF (hazard ratio [HR] 1.99; 95% confidence interval [CI] 1.29-3.06 and HR 2.19; 95% CI 1.51-3.18, respectively). Treatment discontinuation due to ADR was lowest with the ABC/3TC/NVP regimen. Other ARV regimens were associated with a 1.80- to 3.19-fold increase in the risk of treatment discontinuation due to ADR (P < 0.0001 for all comparisons).ABC/3TC/NVP as a simplification regimen is a long-term effective regimen with lower discontinuation due to long-term toxicity compared with other standard ARV regimens.

  12. Efavirenz- but not nevirapine-based antiretroviral therapy decreases exposure to the levonorgestrel released from a sub-dermal contraceptive implant

    Directory of Open Access Journals (Sweden)

    Kimberly Scarsi

    2014-11-01

    Full Text Available Introduction: Sub-dermal hormone implants, such as levonorgestrel (LNG, are a safe and desirable form of long-acting contraception, but their use among HIV-positive women on antiretroviral therapy (ART may be compromised given the potential for a cytochrome P450 3A-mediated drug–drug interaction. Our study aimed to characterize the pharmacokinetics of LNG released from a sub-dermal implant over six months in HIV-positive Ugandan women on nevirapine (NVP- or efavirenz (EFV-based ART. Material and Methods: This non-randomized, parallel group study compared LNG pharmacokinetics between HIV-positive Ugandan women not yet eligible for ART (control group, n=18 and those on stable NVP- (n=20 or EFV- (n=20 based ART. The two-rod (75 mg/rod LNG sub-dermal implant was inserted at study enrolment. LNG sampling was obtained pre-implant and at weeks 1, 4, 12 and 24 post-insertion. LNG concentrations were analyzed using a validated LC-MS/MS method, with an assay calibration range of 50–1500 pg/mL. Safety monitoring, including a pregnancy test, was conducted at each study visit. Results: At enrolment, participants had a mean age of 31 years; CD4+ cell counts were similar between the control, NVP and EFV groups (758, 645 and 568 cells/mm3, respectively; p=0.09; all women in the NVP and EFV groups had an undetectable HIV-RNA. Women in the control group had a higher baseline body weight (73 kg compared to those in the NVP (63 kg; p=0.03 or EFV groups (60 kg; p<0.01. By linear regression, weight was a significant predictor of LNG concentrations (1 kg increase in weight=5 pg/mL decrease in LNG, p=0.03. LNG concentrations are reported in the table. Conclusions: Over a 24-week period, LNG concentrations were 40–54% lower in women on EFV-based ART, despite their having a significantly lower body weight, compared to those not on ART. In women on NVP-based ART, LNG concentrations were 32–39% higher than those observed in the control group, a difference partially

  13. Development of Nevirapine Resistance in Children Exposed to the Prevention of Mother-to-Child HIV-1 Transmission Programme in Maputo, Mozambique.

    Directory of Open Access Journals (Sweden)

    Francisco Antunes

    Full Text Available Single-dose nevirapine (sd-NVP has been the main option for prevention of mother-to-child transmission (PMTCT of HIV-1 in low-resource settings. However, sd-NVP can induce the selection of HIV-1 resistant mutations in mothers and infants. In Mozambique, there are limited data regarding the profile of NVP resistance associated mutations (RAM in the context of PMTCT.To assess the prevalence and the factors associated with NVP RAM among children born to HIV-1 infected mothers enrolled in the PMTCT programme adopted in Mozambique.One hundred and fifty seven children aged 6 to 48 weeks were sequentially included (July 2011 to March 2012 at four centres in Maputo. Genotyping of RAM was performed in samples with HIV-1 RNA≥ 100 copies/μL (Viroseq. Sequencing was performed with ABI 3100 (Applied Biosystems. Logistic regression modelling was undertaken to identify the factors associated with NVP RAM.Seventy-nine children had their samples genotyped. Their median age was 7.0 (3-12 months and 92.4% received prophylaxis with sd-NVP at birth plus daily NVP. 35.4% of mothers received antiretrovirals (ARVs for PMTCT. ARV RAM were detected in 43 (54.4% of the children. 45.6% of these children had at least one NVP RAM. The most common mutations associated with NVP resistance were K103N (n = 16 and Y181C (n = 15. NVP RAM was significantly associated with mother exposure to PMTCT (crude odds ratio [OR] 30.3, 95% CI 4.93-186.34 and with mother's CD4 count < 350 cells/mm3 (crude OR 3.08, 95% CI 1.02-9.32. In the multivariable analysis the mother's exposure to PMTCT was the only variable significantly associated with NVP RAM (adjusted OR 48.65, 95% CI 9.33-253.66.We found a high prevalence of NVP RAM among children who were exposed to the drug regimen for PMTCT in Mozambique. The mothers' exposure to PMTCT significantly increased the risk of NVP RAM.

  14. Thermoresponsive fluconazole gels for topical delivery: rheological and mechanical properties, in vitro drug release and anti-fungal efficacy.

    Science.gov (United States)

    Gandra, Sarath C R; Nguyen, Sanko; Nazzal, Sami; Alayoubi, Alaadin; Jung, Rose; Nesamony, Jerry

    2015-01-01

    The aim of this study was to develop thermosensitive gels using poloxamers for topical delivery of fluconazole (FLZ). Eight different formulations containing 1% FLZ in poloxamer and a particular co-solvent (propylene glycol (PG) or Transcutol-P) of various concentrations were prepared. The gels were characterized for transition temperatures, rheological and mechanical properties. FLZ permeability and antifungal effect of the gels were also evaluated. Except for one formulation, all gels exhibited thermosensitive property, i.e. transformed from Newtonian (liquid-like) behavior at 20 °C to non-Newtonian (gel-like) behavior at 37 °C. Transcutol-P increased the transition temperature of the formulations, while the opposite effect was observed for PG. At 37 °C, formulations with high poloxamer concentrations (17%) resulted in high viscosity, compressibility and hardness. Formulations containing 17% poloxamer and 20% Transcutol-P and 10% PG, respectively, exhibited high adhesiveness. No significant differences in the in vitro antifungal activity of FLZ were observed among the formulations suggesting that the gel vehicles did not influence the biological effect of FLZ. FLZ permeability decreased with increasing poloxamer concentration. Formulations containing 17% poloxamer and 20% Transcutol-P and 10% PG seemed to be promising in situ gelling systems for the topical delivery of FLZ.

  15. DEVELOPMENT AND VALIDATION OF ANALYTICAL METHOD FOR FLUCONAZOLE AND IVERMECTIN IN TABLET FORMULATION BY USING RP-HPLC

    Directory of Open Access Journals (Sweden)

    Harod S. Sanjay

    2012-08-01

    Full Text Available A simple, efficient and reproducible RP-HPLC method for the simultaneous determination of Fluconazole and Ivermectin in bulk and tablet formulation has been developed and validated. The separation was carried out using Insertil C18 column (250 mm x 4.6 mm, 5 µ using Acetonitrile:Methanol:Water (75:15:10 v/v/v as mobile phase. The flow rate was 1.5 ml/min and detection was carried out 254 nm. The retention time of Fluconazole and Ivermectin were 2.313 and 9.617 respectively. The linear was established in the range of 50-150 µg/ml and 52-156 µg/ml for Fluconazole and Ivermectin respectively. Percentage recoveries for Fluconazole and Ivermectin were found to be 99.830±1.079 and 100.814±1.99 respectively. All the analytical validation parameters were determined and found in the limit as per ICH Guidelines which indicate the validity of the method. The developed method is also found to be precise and robust for the simultaneous determination of Fluconazole and Ivermectin in tablet formulation.

  16. In vitro activity of essential oils extracted from condiments against fluconazole-resistant and -sensitive Candida glabrata.

    Science.gov (United States)

    Soares, I H; Loreto, É S; Rossato, L; Mario, D N; Venturini, T P; Baldissera, F; Santurio, J M; Alves, S H

    2015-09-01

    In the present study, the antifungal activity of essential oils obtained from Origanum vulgare (oregano), Cinnamomum zeylanicum (cinnamon), Lippia graveolens (Mexican oregano), Thymus vulgaris (thyme), Salvia officinalis (sage), Rosmarinus officinalis (rosemary), Ocimum basilicum (basil) and Zingiber officinale (ginger) were assessed against Candida glabrata isolates. One group contained 30 fluconazole-susceptible C. glabrata isolates, and the second group contained fluconazole-resistant isolates derived from the first group after the in vitro induction of fluconazole-resistance, for a total of 60 tested isolates. The broth microdilution methodology was used. Concentrations of 50μg/mL, 100μg/mL, 200μg/mL, 400μg/mL, 800μg/mL, 1600μg/mL and 3200μg/mL of the essential oils were used, and the minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) were determined. Thyme, sage, rosemary, basil and ginger essential oils showed no antifungal activity at the tested concentrations. Antimicrobial activity less than or equal to 3200μg/mL was observed for oregano, Mexican oregano and cinnamon essential oils. Both the oregano and Mexican oregano essential oils showed high levels of antifungal activity against the fluconazole-susceptible C. glabrata group, whereas the cinnamon essential oil showed the best antifungal activity against the fluconazole-resistant C. glabrata isolates.

  17. Clinical effectiveness of posaconazole versus fluconazole as antifungal prophylaxis in hematology-oncology patients: a retrospective cohort study.

    Science.gov (United States)

    Kung, Hsiang-Chi; Johnson, Melissa D; Drew, Richard H; Saha-Chaudhuri, Paramita; Perfect, John R

    2014-06-01

    In preventing invasive fungal disease (IFD) in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), clinical trials demonstrated efficacy of posaconazole over fluconazole and itraconazole. However, effectiveness of posaconazole has not been investigated in the United States in real-world setting outside the environment of controlled clinical trial. We performed a single-center, retrospective cohort study of 130 evaluable patients ≥18 years of age admitted to Duke University Hospital between 2004 and 2010 who received either posaconazole or fluconazole as prophylaxis during first induction or first reinduction chemotherapy for AML or MDS. The primary endpoint was possible, probable, or definite breakthrough IFD. Baseline characteristics were well balanced between groups, except that posaconazole recipients received reinduction chemotherapy and cytarabine more frequently. IFD occurred in 17/65 (27.0%) in the fluconazole group and in 6/65 (9.2%) in the posaconazole group (P = 0.012). Definite/probable IFDs occurred in 7 (10.8%) and 0 patients (0%), respectively (P = 0.0013). In multivariate analysis, fluconazole prophylaxis and duration of neutropenia were predictors of IFD. Mortality was similar between groups. This study demonstrates superior effectiveness of posaconazole over fluconazole as prophylaxis of IFD in AML and MDS patients. Such superiority did not translate to reductions in 100-day all-cause mortality.

  18. Influence of moisture on the availability and persistence of clotrimazole and fluconazole in sludge-amended soil.

    Science.gov (United States)

    García-Valcárcel, Ana I; Tadeo, José L

    2012-03-01

    Applying sewage sludge to soil is a common practice in many parts of the world. Thus, pharmaceutical compounds, such as azoles, can be released into the environment after sludge is applied to soil. To understand the fate of clotrimazole and fluconazole (pharmaceuticals used as antifungals in humans) in soil after its amendment with sludge, a reliable and sensitive method has been developed to determine these compounds in the solid and aqueous phases of soil. Desorption of clotrimazole from soil amended with sludge was negligible, whereas a rapid desorption of fluconazole was observed. Dissipation rates of these azoles were determined in amended soil incubated at 25°C with moisture contents ranging from 4.5 to 20%. Clotrimazole was more persistent than fluconazole in dry soil, whereas the contrary occurred in wet soil. Partitioning soil:soil solution of these azoles varied with time and moisture contents. Clotrimazole was found in soil with negligible amounts in soil solution, whereas fluconazole was approximately partitioned 50:50 during the assay time (60 d) at any soil moisture content. Occasional rainfall coupled with a relatively low binding soil capacity can result in the contamination of surface and groundwaters by fluconazole, whereas clotrimazole will remain in the soil.

  19. Identification of Candida species in patients with oral lesion undergoing chemotherapy along with minimum inhibitory concentration to fluconazole

    Science.gov (United States)

    Maheronnaghsh, Mehrnoush; Tolouei, Sepideh; Dehghan, Parvin; Chadeganipour, Mostafa; Yazdi, Maryam

    2016-01-01

    Background: Various species of Candida, especially Candida albicans was known as the most important etiological agent of fungal infections. Oral candidiasis is the most common fungal infection in patients undergoing chemotherapy. The purpose of this study was to identify Candida species from oral lesions of these patients and antifungal susceptibility of the clinical isolates. Materials and Methods: Among 385 patients with cancer, 55 (14.3%) showed oral lesions. Oral swabs were performed to identify the yeasts using direct smear and CHROMagar medium. Micro dilution method was prepared in different concentrations of fluconazole and minimum inhibitory concentration and minimum fungicidal concentration of each species were compared. Results: Oral candidiasis confirmed in 36 cases by direct examination and culture. C. albicans and non-albicans represented in 26 (72.2%) and 10 (27.8%) of the isolates, respectively. 76.5% of C. albicans and 23.5% non-albicans isolates were resistant to fluconazole. Data were shown that 62% and 30.7% of resistant strains of C. albicans were found in patient with gastrointestinal cancer and lymphoma respectively. Conclusion: Data were shown that C. albicans is the most commonly identified species in oral candidiasis and majority of fluconazole resistant C. albicans were found in patients with gastrointestinal cancer and lymphoma. Therefore, we recommend an alternative drug instead of fluconazole as a first line of treatment for these type of cancers and administration of fluconazole in patients undergoing chemotherapy should be prescribed in accordance with the type of cancer. PMID:27656601

  20. Clinical effectiveness of posaconazole versus fluconazole as antifungal prophylaxis in hematology–oncology patients: a retrospective cohort study

    Science.gov (United States)

    Kung, Hsiang-Chi; Johnson, Melissa D; Drew, Richard H; Saha-Chaudhuri, Paramita; Perfect, John R

    2014-01-01

    In preventing invasive fungal disease (IFD) in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), clinical trials demonstrated efficacy of posaconazole over fluconazole and itraconazole. However, effectiveness of posaconazole has not been investigated in the United States in real-world setting outside the environment of controlled clinical trial. We performed a single-center, retrospective cohort study of 130 evaluable patients ≥18 years of age admitted to Duke University Hospital between 2004 and 2010 who received either posaconazole or fluconazole as prophylaxis during first induction or first reinduction chemotherapy for AML or MDS. The primary endpoint was possible, probable, or definite breakthrough IFD. Baseline characteristics were well balanced between groups, except that posaconazole recipients received reinduction chemotherapy and cytarabine more frequently. IFD occurred in 17/65 (27.0%) in the fluconazole group and in 6/65 (9.2%) in the posaconazole group (P = 0.012). Definite/probable IFDs occurred in 7 (10.8%) and 0 patients (0%), respectively (P = 0.0013). In multivariate analysis, fluconazole prophylaxis and duration of neutropenia were predictors of IFD. Mortality was similar between groups. This study demonstrates superior effectiveness of posaconazole over fluconazole as prophylaxis of IFD in AML and MDS patients. Such superiority did not translate to reductions in 100-day all-cause mortality. PMID:24644249

  1. The Impact of Antibacterial Agents on Dynamic Antifungal Effects of Fluconazole and Biofilm Penetration%抗菌药物对氟康唑动态抗真菌作用及透过生物膜的影响

    Institute of Scientific and Technical Information of China (English)

    杨久丽; 孙素梅; 刘书源; 孙淑娟

    2014-01-01

    Objective:To determine the combined dynamic antifungal effects of fluconazole and the tested antibacterial agents and evaluate the impact of the tested antibacterial agents on fluconazole penetration through biofilm. Methods:The dynamic killing curve was obtained based on the combined drugs against Candida albicans using viable bacterial counting method. The biofilm penetration test was evaluated by “sandwich” experimental method. Results:Synergistic effects on fluconazole were showed by using the tested antibacterial agents. The penetrating ability of fluconazole through biofilm by the drug resistant Candida albicans varied by different tested antibacterial drugs ,of which minocycline and rifampicin shown strongest impact on it but also on the synergistic effects of dynamic antifungal action. Levofloxacin ,azithromycin and others had a lower impact. Conclusion:The tested antibacterial agents can promote the fluconazole penetration of Candida albican ’ s biofilm and increase fluconazole’s dynamic antifungal effect.%目的:测定试验用抗菌药物与氟康唑联合的动态抗真菌作用,并评价试验用抗菌药物对氟康唑透过生物膜的影响。方法:采用活菌计数法描绘联合用药对白色念珠菌的动态杀菌曲线,以“三明治”透膜实验法评价试验用抗菌药物对氟康唑透过生物膜的影响。结果:试验抗菌药物对氟康唑有不同程度的增效作用,其中米诺环素和利福平对氟康唑透过耐药白色念珠菌生物膜的作用及其对氟康唑动态抗真菌的增效作用最强,氧氟沙星、阿奇霉素等次之。结论:试验用抗菌药物能促进氟康唑透过白色念珠菌生物膜,增强氟康唑的动态抗真菌作用。

  2. Tricuspid valve mycetoma in an infant successfully treated by excision and complex tricuspid valve repair followed by fluconazole therapy.

    Science.gov (United States)

    Anil Kumar, V; Francis, Edwin; Sreehari, Sreekala; Raj, Benedict

    2014-04-01

    Fungal valve endocarditis in children is an uncommon and lethal disease. The risk increases with use of central venous catheters (CVC), total parenteral nutrition (TPN), and use of broad-spectrum antibiotics during the neonatal period. Due to high mortality, a combination of surgery and antifungal therapy is usually recommended for treatment. Case report and review of the literature. We present a case of an asymptomatic infant with multiple Candida tricuspid valve mycetomas. Complete cure was achieved by combined tricuspid valve repair and fluconazole therapy. We also review 26 cases of tricuspid valve Candida endocarditis in children published in the literature. From being uniformly fatal five decades ago to a current survival rate of 64% to 100%, the prognosis of Candida endocarditis has changed dramatically with the use of antifungal therapy alone or in combination with surgery. Our case re-emphasizes the role of valve-sparing debridement with repair of the native valve using autologous pericardium in combination with long-term antifungal therapy as a feasible option in managing tricuspid valve Candida endocarditis.

  3. International and multicenter comparison of EUCAST and CLSI M27-A2 broth microdilution methods for testing susceptibilities of Candida spp. to fluconazole, itraconazole, posaconazole, and voriconazole.

    NARCIS (Netherlands)

    Espinel-Ingroff, A.; Barchiesi, F.; Cuenca-Estrella, M.; Pfaller, M.A.; Rinaldi, M.; Rodriguez-Tudela, J.L.; Verweij, P.E.

    2005-01-01

    The aim of this study was to compare MICs of fluconazole, itraconazole, posaconazole, and voriconazole obtained by the European Committee on Antibiotic Susceptibility Testing (EUCAST) and CLSI (formerly NCCLS) methods in each of six centers for 15 Candida albicans (5 fluconazole-resistant and 4 susc

  4. Pharmacokinetics of sequential intravenous and enteral fluconazole in critically ill surgical patients with invasive mycoses and compromised gastro-intestinal function

    NARCIS (Netherlands)

    Buijk, S L; Gyssens, I C; Mouton, J W; Verbrugh, H A; Touw, D J; Bruining, H A

    2001-01-01

    OBJECTIVES: (1) To determine the pharmacokinetics of sequential intravenous and enteral fluconazole in the serum of surgical intensive care unit (ICU) patients with deep mycoses. (2) To determine the concentrations of fluconazole reached at the site of infection. (3) To determine if enteral administ

  5. Correlation of the MIC and dose/MIC ratio of fluconazole to the therapeutic response of patients with mucosal candidiasis and candidemia.

    NARCIS (Netherlands)

    Rodriguez-Tudela, J.L.; Almirante, B.; Rodriguez-Pardo, D.; Laguna, F.; Donnelly, J.P.; Mouton, J.W.; Pahissa, A.; Cuenca-Estrella, M.

    2007-01-01

    We report on the correlation of the outcomes for two cohorts of patients who had been treated for candidemia (126 episodes) or oropharyngeal candidiasis (110 episodes) with various doses of fluconazole and the MIC of fluconazole obtained by using the EUCAST standard for fermentative yeasts. Of 145 e

  6. Vertebral infection with Candida albicans failing caspofungin and fluconazole combination therapy but successfully treated with high dose liposomal amphotericin B and flucytosine

    Directory of Open Access Journals (Sweden)

    Line Storm

    2014-10-01

    Full Text Available A patient with Candida spondylitis failed two weeks of fluconazole combined with caspofungin, and the infection relapsed despite six weeks of liposomal amphotericin B followed by two months of fluconazole. Six months therapy with high dose liposomal amphotericin B combined with flucytosine effectively cured the patient.

  7. Correlation of the MIC and dose/MIC ratio of fluconazole to the therapeutic response of patients with mucosal candidiasis and candidemia.

    NARCIS (Netherlands)

    Rodriguez-Tudela, J.L.; Almirante, B.; Rodriguez-Pardo, D.; Laguna, F.; Donnelly, J.P.; Mouton, J.W.; Pahissa, A.; Cuenca-Estrella, M.

    2007-01-01

    We report on the correlation of the outcomes for two cohorts of patients who had been treated for candidemia (126 episodes) or oropharyngeal candidiasis (110 episodes) with various doses of fluconazole and the MIC of fluconazole obtained by using the EUCAST standard for fermentative yeasts. Of 145

  8. International and multicenter comparison of EUCAST and CLSI M27-A2 broth microdilution methods for testing susceptibilities of Candida spp. to fluconazole, itraconazole, posaconazole, and voriconazole.

    NARCIS (Netherlands)

    Espinel-Ingroff, A.; Barchiesi, F.; Cuenca-Estrella, M.; Pfaller, M.A.; Rinaldi, M.; Rodriguez-Tudela, J.L.; Verweij, P.E.

    2005-01-01

    The aim of this study was to compare MICs of fluconazole, itraconazole, posaconazole, and voriconazole obtained by the European Committee on Antibiotic Susceptibility Testing (EUCAST) and CLSI (formerly NCCLS) methods in each of six centers for 15 Candida albicans (5 fluconazole-resistant and 4 susc

  9. Repurposing Resveratrol and Fluconazole To Modulate Human Cytochrome P450-Mediated Arachidonic Acid Metabolism.

    Science.gov (United States)

    El-Sherbeni, Ahmed A; El-Kadi, Ayman O S

    2016-04-04

    Cytochrome P450 (P450) enzymes metabolize arachidonic acid (AA) to several biologically active epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs). Repurposing clinically-approved drugs could provide safe and readily available means to control EETs and HETEs levels in humans. Our aim was to determine how to significantly and selectively modulate P450-AA metabolism in humans by clinically-approved drugs. Liquid chromatography-mass spectrometry was used to determine the formation of 15 AA metabolites by human recombinant P450 enzymes, as well as human liver and kidney microsomes. CYP2C19 showed the highest EET-forming activity, while CYP1B1 and CYP2C8 showed the highest midchain HETE-forming activities. CYP1A1 and CYP4 showed the highest subterminal- and 20-HETE-forming activity, respectively. Resveratrol and fluconazole produced the most selective and significant modulation of hepatic P450-AA metabolism, comparable to investigational agents. Monte Carlo simulations showed that 90% of human population would experience a decrease by 6-22%, 16-39%, and 16-35% in 16-, 18-, and 20-HETE formation, respectively, after 2.5 g daily of resveratrol, and by 22-31% and 14-23% in 8,9- and 14,15-EET formation after 50 mg of fluconazole. In conclusion, clinically-approved drugs can provide selective and effective means to modulate P450-AA metabolism, comparable to investigational drugs. Resveratrol and fluconazole are good candidates to be repurposed as new P450-based treatments.

  10. Echinocandins Compared to Fluconazole for Candidemia of a Urinary Tract Source: A Propensity Score Analysis.

    Science.gov (United States)

    Cuervo, Guillermo; Garcia-Vidal, Carolina; Puig-Asensio, Mireia; Vena, Antonio; Meije, Yolanda; Fernández-Ruiz, Mario; González-Barberá, Eva; Blanco-Vidal, María José; Manzur, Adriana; Cardozo, Celia; Gudiol, Carlota; Montejo, José Miguel; Pemán, Javier; Ayats, Josefina; Aguado, Jose María; Muñoz, Patricia; Marco, Francesc; Almirante, Benito; Carratalà, Jordi

    2017-05-15

    Whether echinocandins could be used to treat candidemia of a urinary tract source (CUTS) is unknown. We aimed to provide current epidemiological information of CUTS and to compare echinocandin to fluconazole treatment on CUTS outcomes. A multicenter study of adult patients with candidemia was conducted in 9 hospitals. CUTS was defined as a candidemia with concomitant candiduria by the same organism associated with significant urological comorbidity. The primary outcome assessed was clinical failure (defined by 7-day mortality or persistent candidemia) in patients treated with either an echinocandin or fluconazole. A propensity score was calculated and then entered into a regression model. Of 2176 episodes of candidemia, 128 were CUTS (5.88%). Most CUTS cases were caused by Candida albicans (52.7%), followed by Candida glabrata (25.6%) and Candida tropicalis (16.3%). Clinical failure occurred in 7 patients (20%) treated with an echinocandin and in 15 (17.1%) treated with fluconazole (P = .730). Acute renal failure (adjusted odds ratio [AOR], 3.01; 95% confidence interval [CI], 1.01-8.91; P = .047) was the only independent factor associated with clinical failure, whereas early urinary tract drainage procedures (surgical, percutaneous, or endoscopic) were identified as protective (AOR, 0.08; 95% CI, .02-.31; P < .001). Neither univariate nor multivariate analysis showed that echinocandin therapy altered the risk of clinical failure. Initial echinocandin therapy was not associated with clinical failure in patients with CUTS. Notably, acute renal failure predicted worse outcomes and performing an early urologic procedure was a protective measure.

  11. Two-year surveillance on fluconazole susceptibility of Candida spp isolates in a general and university hospital in Rome.

    Science.gov (United States)

    Testore, G P; Falco, F; Sarrecchia, C; Sordillo, P; Bontempo, G; Andreoni, M

    2001-01-01

    Fluconazole susceptibility was tested in 385 clinical yeast isolates (285 Candida albicans, 38 C. glabrata, 31 C. tropicalis, 31 other Candida subsp.) using the agar disk diffusion test. Yeasts were collected from specimens obtained from outpatients (69) and inpatients (intensive care unit: 79 isolates, major burn unit: 31 isolates, hematology ward: 45 isolates, gynecology ward: 67 isolates, other wards: 94 isolates). Three hundred and fifty-six (92%) yeast isolates showed to be susceptible, 18 (5%) were susceptible dose-dependent, and 10 (3%) were resistant to fluconazole. Of the resistant group, 3 isolates were C.albicans, while seven were Candida non-albicans (2 C. rugosa, 2 C. humicola, 1 C. tropicalis, 1 C. ciferrii, 1 C. glabrata). The disk-diffusion method was easy to perform and there were no difficulties in the interpretation of inhibition zone diameters. Fluconazole maintained a good activity against Candida spp despite its extensive use for the prophylaxis and treatment of fungal infections.

  12. Influence of pH of Candida albicans biofilm in the susceptibility to fluconazole

    OpenAIRE

    2012-01-01

    Resumo: Na cavidade oral, a colonização por Candida albicans em nichos com valores distintos de pH contribui para o desenvolvimento de candidose associada ao uso de prótese. O tratamento dessa infecção tem sido facilitado utilizando-se o fluconazol (FLZ). Entretanto, não está claro se o pH dos biofilmes de C. albicans interfere na susceptibilidade destes ao FLZ. Dessa forma, neste trabalho foi avaliada a influência do pH de biofilmes de C. albicans na susceptibilidade ao FLZ. Testes de suscep...

  13. Influence of doxorubicin on fluconazole susceptibility and efflux pump gene expression of Candida dubliniensis.

    LENUS (Irish Health Repository)

    Schulz, Bettina

    2012-05-01

    The effect of doxorubicin (DOX) on the fluconazole (FLU) susceptibility of C. dubliniensis was investigated. Isolates were exposed to DOX and FLU in a chequerboard assay and resistance gene expressions were analysed after DOX exposure. The susceptibility of the yeast to FLU was decreased in the presence of DOX in the chequerboard assay with FIC indices suggesting an antagonistic effect. Gene expression analyses showed an overexpression of CdCDR2. Hence, DOX was found to have an impact on resistance mechanisms in C. dubliniensis isolates.

  14. Actividad antifúngica del extracto de etanol Schinus molle y el fluconazol sobre Candida albicans

    OpenAIRE

    Saravia León, Natalia; Guillinta Vallejos, Guido

    2012-01-01

    Objetivo. Determinar la actividad antifúngica del extracto de etanol Schinus molle y fluconazol sobre Candida albicans. Material y métodos. El estudio es experimental y transversal. La planta se recolectó en el departamento de Huancavelica provincia de Junín, se utilizó las hojas para preparar el extracto etanolico de Schinus molle. Los discos de extracto de etanol Schinus molle se obtuvieron en la Facultad de Farmacia y Bioquímica de la Universidad Nacional Mayor de San Marcos. El f...

  15. 氟康唑对近平滑念珠菌生物膜的影响%Effect of fluconazole on biofilm of Candida parapsilosis

    Institute of Scientific and Technical Information of China (English)

    丁秀荣; 苏建荣

    2014-01-01

    目的:研究近平滑念珠菌不同时期生物膜对氟康唑的药物敏感性及氟康唑对其生物膜生成的影响。方法甲基四氮盐( XTT)减低法检测不同阶段生物膜对氟康唑的敏感性及生物膜的生成量。结果对氟康唑敏感的近平滑念珠菌在生物膜生成12 h后即对氟康唑耐药。在12、24和48 h时间点,治疗浓度为8μg/mL的氟康唑均可显著抑制氟康唑耐药株生物膜的生成;浓度0.5μg/mL的氟康唑可显著抑制氟康唑敏感株生物膜形成,但要抑制耐药株生物膜的形成则需更高浓度的氟康唑(≥1μg/mL)。结论近平滑念珠菌不同阶段生物膜对氟康唑耐药性不同,氟康唑可显著抑制近平滑念珠菌敏感株和耐药株生物膜的生成。%Objective To explore the sensitivity of Candida parapsilosis cells grown in developing biofilm to fluconazole and the effect of different concentration of fluconazole on Candida parapsilosis biofilm formation .Methods XTT reduction assay was used to evaluate the effect of fluconazole on developing biofilm of Candida parapsilosis and the inhibition of fluconazole on Candida parapsilosis biofilm formation.Results Twelve-hours biofilms of fluconazole-susceptible strains were resistant to fluconazole .At 12 h, 24 h, and 48 h time points, biofilm formation by fluconazole-resistant strains was significantly inhibited when fluconazole ( 8 μg/mL ) was present. Concentration of 0.5 μg/mL of fluconazole could reduce the biofilm formation by fluconazole-susceptible strains, but the concentration of fluconazole was higher (≥1 μg/mL) for fluconazole-resistant strains .Conclusion The sensitivity to fluconazole of Candida parapsilosis cells grown in developing biofilms was different .Fluconazole inhibited biofilm formation by a variety of laboratory isolated strains .

  16. A retrospective cohort analysis comparing pregnancy rates among HIV-positive women using contraceptives and efavirenz- or nevirapine-based antiretroviral therapy in Kenya

    Science.gov (United States)

    PATEL, Rena C.; ONONO, Maricianah; GANDHI, Monica; BLAT, Cinthia; HAGEY, Jill; SHADE, Starley B.; VITTINGHOFF, Eric; BUKUSI, Elizabeth A.; NEWMANN, Sara J.; COHEN, Craig R.

    2015-01-01

    SUMMARY Background Given recent concerns of efavirenz reducing the efficacy of contraceptive implants, we sought to determine if pregnancy rates differ among HIV-positive women using various contraceptive methods and efavirenz- or nevirapine-based antiretroviral therapy (ART) regimens. Methods We conducted a retrospective cohort analysis of HIV-positive women aged 15–45 years enrolled in HIV care facilities in western Kenya from January 2011 to December 2013. Pregnancy was diagnosed clinically and the primary exposure was a combination of contraceptive method and ART regimen. We used Poisson models, adjusting for repeated measures, as well as demographic, behavioral and clinical factors, to compare pregnancy rates among women on different contraceptive/ART combinations. Findings 24,560 women contributed 37,635 years of follow-up with 3,337 incident pregnancies. Among women using implants, adjusted pregnancy incidence for nevirapine- and efavirenz-based ART users were 1·1 (95% CI 0·72–1·5) and 3·3 (95% CI 1·8–4·8) per 100 women-years (w-y), respectively (adjusted incidence rate ratio (aIRR) 3·0, 95% CI 1·3–4·6). Among women using depomedroxyprogesterone acetate (DMPA), adjusted pregnancy incidence for nevirapine- and efavirenz-based ART users were 4·5 (95% CI 3·7–5·2) and 5·4 (95% CI 4·0–6·8) per 100 w-y, respectively (aIRR 1·2, 95% CI 0·91–1·5). Women using other contraceptive methods, except for intrauterine devices and permanent methods, experienced 3·1–4·1 higher rates of pregnancy than women using implants, with 1·6–2·8 higher rates specifically among women using efavirenz-based ART. Interpretation While HIV-positive women using implants on efavirenz-based ART faced three times higher risk of contraceptive failure than those on nevirapine-based ART, these women still experienced lower contraceptive failure rates than women on all other contraceptive methods, except for intrauterine devices and permanent methods

  17. Technetium-99m labelled fluconazole and antimicrobial peptides for imaging of Candida albicans and Aspergillus fumigatus infections

    Energy Technology Data Exchange (ETDEWEB)

    Lupetti, Antonella [Department of Infectious Diseases, Leiden University Medical Center (LUMC), Leiden (Netherlands); Dipartimento di Patologia Sperimentale, Biotecnologie Mediche, Univ. di Pisa (Italy); Welling, Mick M. [Department of Radiology, Division of Nuclear Medicine, LUMC, Leiden (Netherlands); Mazzi, Ulderico [Dipartimento di Scienze Farmaceutiche, Universita degli Studi di Padova (Italy); Nibbering, Peter H. [Department of Infectious Diseases, Leiden University Medical Center (LUMC), Leiden (Netherlands); Pauwels, Ernest K.J. [Department of Radiology, Division of Nuclear Medicine, LUMC, Leiden (Netherlands); Department of Radiology, Leiden University Medical Center (LUMC) (Netherlands)

    2002-05-01

    The aim of this study was to investigate whether technetium-99m labelled fluconazole can distinguish fungal from bacterial infections. Fluconazole was labelled with {sup 99m}Tc and radiochemical analysis showed less than 5% impurities. The labelling solution was injected into animals with experimental infections. For comparison, we used two peptides for infection detection, i.e. UBI 29-41 and hLF 1-11, and human IgG, all labelled with {sup 99m}Tc. Mice were infected with Candida albicans or injected with heat-killed C. albicans or lipopolysaccharides to induce sterile inflammation. Also, mice were infected with Staphylococcus aureus or Klebsiella pneumoniae. Next, accumulation of {sup 99m}Tc-fluconazole and {sup 99m}Tc-labelled peptides/IgG at affected sites was determined scintigraphically. {sup 99m}Tc-fluconazole detected C. albicans infections (T/NT ratio=3.6{+-}0.47) without visualising bacterial infections (T/NT ratio=1.3{+-}0.04) or sterile inflammatory processes (heat-killed C. albicans: T/NT ratio=1.3{+-}0.2; lipopolysaccharide: T/NT ratio=1.4{+-}0.1). C. albicans infections were already seen within the first hour after injection of {sup 99m}Tc-fluconazole (T/NT ratio=3.1{+-}0.2). A good correlation (R{sup 2}=0.864; P<0.05) between T/NT ratios for this tracer and the number of viable C. albicans was found. Although {sup 99m}Tc-UBI 29-41 and {sup 99m}Tc-hLF 1-11 were able to distinguish C. albicans infections from sterile inflammatory processes in mice, these {sup 99m}Tc-labelled peptides did not distinguish these fungal infections from bacterial infections. It is concluded that {sup 99m}Tc-fluconazole distinguishes infections with C. albicans from bacterial infections and sterile inflammations. (orig.)

  18. Multicenter evaluation of the new Vitek 2 yeast susceptibility test using new CLSI clinical breakpoints for fluconazole.

    Science.gov (United States)

    Pfaller, M A; Diekema, D J; Procop, G W; Wiederhold, N P

    2014-06-01

    A fully automated antifungal susceptibility test system recently updated to reflect the new species-specific clinical breakpoints (CBPs) of fluconazole for Candida (Vitek 2 AF03 yeast susceptibility test; bioMérieux, Inc., Durham, NC) was compared in three different laboratories with the Clinical and Laboratory Standards Institute (CLSI) reference broth microdilution (BMD) method by testing 2 quality control strains, 10 reproducibility strains (4 Candida species and 6 Cryptococcus neoformans strains), and 746 isolates of Candida species (702 isolates, 13 species) and 44 isolates of C. neoformans against fluconazole. Excellent essential agreement (EA) (within 2 dilutions) between the reference and Vitek 2 MICs was observed for fluconazole and Candida species (94.0%). The EA was lower for fluconazole and C. neoformans at 86.4%. The mean times to a result with the Vitek 2 test were 9.1 h for Candida species and 12.1 h for C. neoformans. Categorical agreement (CA) between the two methods was assessed by using the new species-specific CBPs. For less common species without fluconazole CBPs, the epidemiological cutoff values (ECVs) were used to differentiate wild-type (WT; MIC, ≤ ECV) from non-WT (MIC, >ECV) strains. The CAs between the two methods were 92.0% for Candida species (0.3% very major errors [VME] and 2.6% major errors [ME]) and 84.1% for C. neoformans (4.5% VME and 11.4% ME). The updated Vitek 2 AF03 IUO yeast susceptibility system is comparable to the CLSI BMD reference method for testing the susceptibility of clinically important yeasts to fluconazole when using the new (lower) CBPs and ECVs.

  19. DEVELOPMENT AND VALIDATION OF ANALYTICAL METHOD FOR FLUCONAZOLE AND IVERMECTIN IN TABLET FORMULATION BY USING RP-HPLC

    OpenAIRE

    Harod S. Sanjay; Manocha Nimita; Hingole Ashwin; Dubey P.K.

    2012-01-01

    A simple, efficient and reproducible RP-HPLC method for the simultaneous determination of Fluconazole and Ivermectin in bulk and tablet formulation has been developed and validated. The separation was carried out using Insertil C18 column (250 mm x 4.6 mm, 5 µ) using Acetonitrile:Methanol:Water (75:15:10 v/v/v) as mobile phase. The flow rate was 1.5 ml/min and detection was carried out 254 nm. The retention time of Fluconazole and Ivermectin were 2.313 and 9.617 respectively. The linear was e...

  20. Development, optimization and evaluation of polymeric electrospun nanofiber: A tool for local delivery of fluconazole for management of vaginal candidiasis.

    Science.gov (United States)

    Sharma, Rahul; Garg, Tarun; Goyal, Amit K; Rath, Goutam

    2016-01-01

    The present study is designed to explore the localized delivery of fluconazole using mucoadhesive polymeric nanofibers. Drug-loaded polymeric nanofibers were fabricated by the electrospinning method using polyvinyl alcohol (PVA) as the polymeric constituent. The prepared nanofibers were found to be uniform, non-beaded and non-woven, with the diameter of the fibers ranging from 150 to 180 nm. Further drug release studies indicate a sustained release of fluconazole over a period of 6 h. The results of studies on anti-microbial activity indicated that drug-loaded polymeric nanofibers exhibit superior anti-microbial activity against Candida albicans, when compared to the plain drug.

  1. Cost and resource utilization associated with fluconazole as first-line therapy for invasive candidiasis: a retrospective database analysis.

    Science.gov (United States)

    Craver, Christopher W; Tarallo, Miriam; Roberts, Craig S; Blanchette, Christopher M; Ernst, Frank R

    2010-12-01

    Fluconazole is a standard first-line therapy for candidemia/invasive candidiasis (C/IC), based on its efficacy, safety profile, and comparatively low acquisition cost. However, little is known about the total costs associated with fluconazole treatment for this indication, particularly in cases of clinical failure. The aim of this study was to examine overall costs, resource use, and treatment outcomes associated with fluconazole as first-line therapy for invasive Candida infections in the United States. A retrospective analysis of data from a US hospital-based (>500 hospitals), service-level database was performed. All patients aged >16 years with primary or secondary International Classification of Diseases, Ninth Revision, Clinical Modification codes for IC or septicemia, receiving intravenous fluconazole treatment, and discharged between October 1, 2004 and September 30, 2005 were selected. Costs and resource use were calculated from the start of antifungal therapy until discharge. Two groups were analyzed: patients who received fluconazole only and those who required a second-line antifungal. Separate analyses for the survivor subpopulations were also conducted. A total of 7170 patients met the inclusion criteria; 21.2% required an additional antifungal agent. Overall mortality was 27.1%, and total mean treatment cost for all patients was $44,482 (in 2005 US dollars). Patients treated with fluconazole alone incurred mean costs of $36,319. Mean hospital and intensive care unit stays in the fluconazole monotherapy group were 17.9 days and 7.1 days, respectively. Patients requiring additional therapy had a mortality rate of 34.5% and a mean treatment cost of $76,329; in this group, the mean hospital and intensive care unit stays were 31.7 days and 14.8 days, respectively. The overall resource use associated with fluconazole as first-line treatment for C/IC was high, especially in patients who required additional antifungal therapy. Future studies should examine

  2. Análise químico-farmacêutica do fluconazol e especialidade farmacêutica cápsula Chemical pharmaceutical analysis of fluconazole and its pharmaceutical speciality capsule

    Directory of Open Access Journals (Sweden)

    Helenilze Coelho

    2004-06-01

    Full Text Available O fluconazol, derivado triazólico, apresenta atividade antifúngica sendo indicado no tratamento de grande variedade de infecções fúngicas. Este trabalho foi desenvolvido com o objetivo de estabelecer parâmetros de controle de qualidade para a matéria-prima de fluconazol e forma farmacêutica cápsula, subsidiando a elaboração da monografia para a Farmacopéia Brasileira. A matéria-prima do fluconazol pode ser caracterizada pelos seguintes testes: aspecto, solubilidade e faixa de fusão. As impurezas do fluconazol podem ser detectadas por ensaio-limite de cloreto, sulfato, ferro, metais pesados, perda por dessecação e cinzas sulfatadas. Entre as provas de identificação pode-se reconhecer o fármaco por reações químicas de grupos funcionais e por técnicas instrumentais. Para determinação quantitativa do fluconazol na matéria-prima, empregou-se a volumetria com ácido perclórico, em meio acético e detecção do ponto final por indicadores e a espectrofotometria na região do ultravioleta, utilizando hidróxido de sódio 0,1 M a 261 nm. Os parâmetros estabelecidos para o controle de qualidade das amostras de cápsulas dos laboratórios analisados foram aspecto, variação do peso, desintegração, teste de dissolução e perfil de dissolução. O método de doseamento do fluconazol, na forma farmacêutica cápsula, por espectrofotometria na região do ultravioleta apresentou linearidade, especificidade, precisão e exatidão dentro dos critérios de aceitação. Os lotes dos laboratórios C, D apresentaram perfis de dissolução similares ao medicamento de referência (laboratório E, demonstrando haver um comportamento homogêneo para estes medicamentos. Os lotes dos laboratórios A e B não apresentaram homogeneidade quanto ao perfil de dissolução, quando comparado com os demais laboratórios.Fluconazole is a triazole derivated drug with an antifungal activity which is used in the treatment of a large variety of fungal

  3. Fluconazole-Induced Ploidy Change in Cryptococcus neoformans Results from the Uncoupling of Cell Growth and Nuclear Division.

    Science.gov (United States)

    Altamirano, Sophie; Fang, Diana; Simmons, Charles; Sridhar, Shreyas; Wu, Peipei; Sanyal, Kaustuv; Kozubowski, Lukasz

    2017-01-01

    Cryptococcus neoformans is a pathogenic yeast that causes lethal cryptococcal meningitis in immunocompromised patients. One of the challenges in treating cryptococcosis is the development of resistance to azole antifungals. Previous studies linked azole resistance to elevated numbers of copies of critical resistance genes in aneuploid cells. However, how aneuploidy is formed in the presence of azole drugs remains unclear. This study showed that treatment with inhibitory concentrations of an azole drug, fluconazole (FLC), resulted in a significant population of cells with increased DNA content, through the following defects: inhibition of budding, premature mitosis, and inhibition of cytokinesis followed by replication in the mother cell. Inhibition of and/or a delay in cytokinesis led to the formation of cells with two or more daughter cells attached (multimeric cells). To investigate which part of cytokinesis fails in the presence of FLC, the dynamics of the actomyosin ring (AMR), septins, and Cts1, a protein involved in cell separation, were analyzed with time-lapse microscopy. Following the constriction of the AMR, septins assembled and the septum was formed between the mother and daughter cells. However, final degradation of the septum was affected. Enlarged cells with aberrant morphology, including multimeric cells, exhibited an increased potential to proliferate in the presence of FLC. These findings suggest that pleiotropic effects of FLC on growth and mitotic division lead to an increase in DNA content, resulting in cells less sensitive to the drug. Cells with increased DNA content continue to proliferate and therefore increase the chance of forming resistant populations. IMPORTANCE Azoles are antifungals that are widely utilized due to relatively low toxicity and cost of treatment. One of their drawbacks, however, is that azoles are primarily cytostatic, leaving fungal cells capable of developing drug resistance. The human pathogen Cryptococcus neoformans

  4. Exploration of crystal simulation potential by fluconazole isomorphism and its application in improvement of pharmaceutical properties

    Science.gov (United States)

    Thakur, Amitha; Kumar, Dinesh; Thipparaboina, Rajesh; Shastri, Nalini R.

    2014-11-01

    Control of crystal morphology during crystallization is a paramount challenge in pharmaceutical processing. Hence, there is need to introduce computational methods for morphology prediction to manage production cost of drugs and improve related pharmaceutical and biopharmaceutical properties. Layer docking approach with molecular dynamics opens a new avenue for crystal habit prediction in presence of solvent. In the present study, attempts were made to correlate predicted and experimental crystal habits of fluconazole considering solvent interactions using layer docking approach. Simulated results from layer docking approach with methanol as solvent gave two dominant facets (0 1 1) and (1 0 1) with a surface area 22.43% and 19.82% respectively, which were in agreement with the experimental results. Experimentally grown modified crystal habit of fluconazole in methanol showed enhanced dissolution rate (pfluconazole recrystallized in methanol was significantly improved when compared to plain drug. This study demonstrates a methodical approach using computational tools for prediction and modification of crystal habit, to enhance dissolution of poorly soluble drugs, for future pharmaceutical applications.

  5. Production of Fluconazole-Loaded Polymeric Micelles Using Membrane and Microfluidic Dispersion Devices

    Directory of Open Access Journals (Sweden)

    Yu Lu

    2016-05-01

    Full Text Available Polymeric micelles with a controlled size in the range between 41 and 80 nm were prepared by injecting the organic phase through a microengineered nickel membrane or a tapered-end glass capillary into an aqueous phase. The organic phase was composed of 1 mg·mL−1 of PEG-b-PCL diblock copolymers with variable molecular weights, dissolved in tetrahydrofuran (THF or acetone. The pore size of the membrane was 20 μm and the aqueous/organic phase volumetric flow rate ratio ranged from 1.5 to 10. Block copolymers were successfully synthesized with Mn ranging from ~9700 to 16,000 g·mol−1 and polymeric micelles were successfully produced from both devices. Micelles produced from the membrane device were smaller than those produced from the microfluidic device, due to the much smaller pore size compared with the orifice size in a co-flow device. The micelles were found to be relatively stable in terms of their size with an initial decrease in size attributed to evaporation of residual solvent rather than their structural disintegration. Fluconazole was loaded into the cores of micelles by injecting the organic phase composed of 0.5–2.5 mg·mL−1 fluconazole and 1.5 mg·mL−1 copolymer. The size of the drug-loaded micelles was found to be significantly larger than the size of empty micelles.

  6. [Keratomycosis due to Fusarium oxysporum treated with the combination povidone iodine eye drops and oral fluconazole].

    Science.gov (United States)

    Diongue, K; Sow, A S; Nguer, M; Seck, M C; Ndiaye, M; Badiane, A S; Ndiaye, J M; Ndoye, N W; Diallo, M A; Diop, A; Ndiaye, Y D; Dieye, B; Déme, A; Ndiaye, I M; Ndir, O; Ndiaye, D

    2015-12-01

    In developing countries where systemic antifungal are often unavailable, treatment of filamentous fungi infection as Fusarium is sometimes very difficult to treat. We report the case of a keratomycosis due to Fusarium oxysporum treated by povidone iodine eye drops and oral fluconazole. The diagnosis of abscess in the cornea was retained after ophthalmological examination for a 28-year-old man with no previous ophthalmological disease, addressed to the Ophthalmological clinic at the University Hospital Le Dantec in Dakar for a left painful red eye with decreased visual acuity lasting for 15 days. The patient did not receive any foreign body into the eye. Samples by corneal scraping were made for microbiological analysis and the patient was hospitalized and treated with a reinforced eye drops based treatment (ceftriaxone+gentamicin). The mycological diagnosis revealed the presence of a mold: F. oxysporum, which motivated the replacement of the initial treatment by eye drops containing iodized povidone solution at 1% because of the amphotericin B unavailability. Due to the threat of visual loss, oral fluconazole was added to the local treatment with eye drops povidone iodine. The outcome was favorable with a healing abscess and visual acuity amounted to 1/200th. Furthermore, we noted sequels such as pannus and pillowcase. The vulgarization of efficient topical antifungal in developing countries would be necessary to optimize fungal infection treatment. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  7. Fungal infections in marrow transplant recipients under antifungal prophylaxis with fluconazole

    Directory of Open Access Journals (Sweden)

    Oliveira J.S.R.

    2002-01-01

    Full Text Available Fungal infection is one of the most important causes of morbidity and mortality in bone marrow transplant (BMT recipients. The growing incidence of these infections is related to several factors including prolonged granulocytopenia, use of broad-spectrum antibiotics, conditioning regimens, and use of immunosuppression to avoid graft-versus-host disease (GvHD. In the present series, we report five cases of invasive mold infections documented among 64 BMT recipients undergoing fluconazole antifungal prophylaxis: 1 A strain of Scedosporium prolificans was isolated from a skin lesion that developed on day +72 after BMT in a chronic myeloid leukemic patient. 2 Invasive pulmonary aspergillosis (Aspergillus fumigatus was diagnosed on day +29 in a patient with a long period of hospitalization before being transplanted for severe aplastic anemia. 3 A tumoral lung lesion due to Rhizopus arrhizus (zygomycosis was observed in a transplanted patient who presented severe chronic GvHD. 4 A tumoral lesion due to Aspergillus spp involving the 7th, 8th and 9th right ribs and local soft tissue was diagnosed in a BMT patient on day +110. 5 A patient with a history of Ph1-positive acute lymphocytic leukemia exhibited a cerebral lesion on day +477 after receiving a BMT during an episode of severe chronic GvHD. At that time, blood and spinal fluid cultures yielded Fusarium sp. Opportunistic infections due to fungi other than Candida spp are becoming a major problem among BMT patients receiving systemic antifungal prophylaxis with fluconazole.

  8. [In vitro activities of posaconazole, fluconazole, itraconazole, ketoconazole and voriconazole against Candida glabrata].

    Science.gov (United States)

    Blanco, M T; Cañadas, J; García-Martos, P; Marín, P; García-Tapia, A; Rodríguez, J

    2009-09-01

    This study has been conducted to asses the in vitro activity of the novel triazole antifungal agent posaconazole against 123 clinically important isolates of yeasts. Susceptibility was tested using the Sensititre YeastOne microdilution commercial method. Minimum inhibitory concentrations (MICs) were determined at the recommended endpoints and time intervals. The activity of posaconazole against Candida glabrata was compared with those of fluconazole, itraconazole, ketoconazole and voriconazole. The most susceptible species to posaconazole were C. albicans, C. parapsilosis, C. tropicalis and C. dubliniensis. Candida glabrata was the least susceptible. The percentage of strains with MIC for posaconazole >or= 1 mg/L was 9%, all of them were C. glabrata. The species with MIC for itraconazole >or= 0.5 mg/L were 36% (41 C. glabrata, 1 C. krusei, 1 C. guilliermondii, 1 C. ciferrii). Candida glabrata strains resistant to fluconazole, ketoconazole and voriconazole were 8%, 4% and 4%, respectively. Posaconazole exhibited good activity to the majority of Candida species. However, it was similar to itraconazole and less active than ketoconazole and voriconazole against C. glabrata.

  9. Production of Fluconazole-Loaded Polymeric Micelles Using Membrane and Microfluidic Dispersion Devices

    Science.gov (United States)

    Lu, Yu; Chowdhury, Danial; Vladisavljević, Goran T.; Koutroumanis, Konstantinos; Georgiadou, Stella

    2016-01-01

    Polymeric micelles with a controlled size in the range between 41 and 80 nm were prepared by injecting the organic phase through a microengineered nickel membrane or a tapered-end glass capillary into an aqueous phase. The organic phase was composed of 1 mg·mL−1 of PEG-b-PCL diblock copolymers with variable molecular weights, dissolved in tetrahydrofuran (THF) or acetone. The pore size of the membrane was 20 μm and the aqueous/organic phase volumetric flow rate ratio ranged from 1.5 to 10. Block copolymers were successfully synthesized with Mn ranging from ~9700 to 16,000 g·mol−1 and polymeric micelles were successfully produced from both devices. Micelles produced from the membrane device were smaller than those produced from the microfluidic device, due to the much smaller pore size compared with the orifice size in a co-flow device. The micelles were found to be relatively stable in terms of their size with an initial decrease in size attributed to evaporation of residual solvent rather than their structural disintegration. Fluconazole was loaded into the cores of micelles by injecting the organic phase composed of 0.5–2.5 mg·mL−1 fluconazole and 1.5 mg·mL−1 copolymer. The size of the drug-loaded micelles was found to be significantly larger than the size of empty micelles. PMID:27231945

  10. Inhibitory activity of hinokitiol against biofilm formation in fluconazole-resistant Candida species

    Science.gov (United States)

    Choi, Jeong Su; Lee, Seung Gwan; Park, Jee Yoon

    2017-01-01

    The aim of this study was to investigate the ability of hinokitiol to inhibit the formation of Candida biofilms. Biofilm inhibition was evaluated by quantification of the biofilm metabolic activity with XTT assay. Hinokitiol efficiently prevented biofilm formation in both fluconazole-susceptible and fluconazole-resistant strains of Candida species. We determined the expression levels of specific genes previously implicated in biofilm development of C. albicans cells by real-time RT-PCR. The expression levels of genes associated with adhesion process, HWP1 and ALS3, were downregulated by hinokitiol. Transcript levels of UME6 and HGC1, responsible for long-term hyphal maintenance, were also decreased by hinokitiol. The expression level of CYR1, which encodes the component of signaling pathway of hyphal formation-cAMP-PKA was suppressed by hinokitiol. Its upstream general regulator RAS1 was also suppressed by hinokitiol. These results indicate that hinokitiol may have therapeutic potential in the treatment and prevention of biofilm-associated Candida infections. PMID:28152096

  11. MALDI-TOF typing highlights geographical and fluconazole resistance clusters in Candida glabrata.

    Science.gov (United States)

    Dhieb, C; Normand, A C; Al-Yasiri, M; Chaker, E; El Euch, D; Vranckx, K; Hendrickx, M; Sadfi, N; Piarroux, R; Ranque, S

    2015-06-01

    Utilizing matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectra for Candida glabrata typing would be a cost-effective and easy-to-use alternative to classical DNA-based typing methods. This study aimed to use MALDI-TOF for the typing of C. glabrata clinical isolates from various geographical origins and test its capacity to differentiate between fluconazole-sensitive and -resistant strains.Both microsatellite length polymorphism (MLP) and MALDI-TOF mass spectra of 58 C. glabrata isolates originating from Marseilles (France) and Tunis (Tunisia) as well as collection strains from diverse geographic origins were analyzed. The same analysis was conducted on a subset of C. glabrata isolates that were either susceptible (MIC ≤ 8 mg/l) or resistant (MIC ≥ 64 mg/l) to fluconazole.According to the seminal results, both MALDI-TOF and MLP classifications could highlight C. glabrata population structures associated with either geographical dispersal barriers (p typing to investigate C. glabrata infection outbreaks and predict the antifungal susceptibility profile of clinical laboratory isolates.

  12. Garcinia xanthochymus Benzophenones Promote Hyphal Apoptosis and Potentiate Activity of Fluconazole against Candida albicans Biofilms.

    Science.gov (United States)

    Jackson, Desmond N; Yang, Lin; Wu, ShiBiao; Kennelly, Edward J; Lipke, Peter N

    2015-10-01

    Xanthochymol and garcinol, isoprenylated benzophenones purified from Garcinia xanthochymus fruits, showed multiple activities against Candida albicans biofilms. Both compounds effectively prevented emergence of fungal germ tubes and were also cytostatic, with MICs of 1 to 3 μM. The compounds therefore inhibited development of hyphae and subsequent biofilm maturation. Xanthochymol treatment of developing and mature biofilms induced cell death. In early biofilm development, killing had the characteristics of apoptosis, including externalization of phosphatidyl serine and DNA fragmentation, as evidenced by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) fluorescence. These activities resulted in failure of biofilm maturation and hyphal death in mature biofilms. In mature biofilms, xanthochymol and garcinol caused the death of biofilm hyphae, with 50% effective concentrations (EC50s) of 30 to 50 μM. Additionally, xanthochymol-mediated killing was complementary with fluconazole against mature biofilms, reducing the fluconazole EC50 from >1,024 μg/ml to 13 μg/ml. Therefore, xanthochymol has potential as an adjuvant for antifungal treatments as well as in studies of fungal apoptosis.

  13. Economic evaluation of posaconazole versus fluconazole prophylaxis in patients with graft-versus-host disease (GVHD) in the Netherlands

    NARCIS (Netherlands)

    J.P. Jansen (Jeroen); A.K. O'Sullivan (Amy); P.J. Lugtenburg (Pieternella); L.F.R. Span (Lambert); J.J.W.M. Janssen (Jeroen); W.B. Stam (Wiro)

    2010-01-01

    textabstractThe objective of this study was to evaluate the cost-effectiveness of posaconazole versus fluconazole for the prevention of invasive fungal infections (IFI) in graft-versus-host disease (GVHD) patients in the Netherlands. A decision analytic model was developed based on a double-blind ra

  14. Economic evaluation of posaconazole versus fluconazole prophylaxis in patients with graft-versus-host disease (GVHD) in the Netherlands

    NARCIS (Netherlands)

    Jansen, Jeroen P.; O'Sullivan, Amy K.; Lugtenburg, Elly; Span, Lambert F. R.; Janssen, Jeroen J. W. M.; Stam, Wiro B.

    2010-01-01

    The objective of this study was to evaluate the cost-effectiveness of posaconazole versus fluconazole for the prevention of invasive fungal infections (IFI) in graft-versus-host disease (GVHD) patients in the Netherlands. A decision analytic model was developed based on a double-blind randomized tri

  15. Single-dose oral fluconazole versus topical clotrimazole in patients with pityriasis versicolor: A double-blind randomized controlled trial.

    Science.gov (United States)

    Dehghan, Mohammad; Akbari, Negin; Alborzi, Nazila; Sadani, Somayeh; Keshtkar, Abas A

    2010-08-01

    This study was designed to compare the therapeutic effects of topical clotrimazole and systemic fluconazole in pityriasis versicolor. A double-blind randomized controlled trial was carried out in the dermatological clinic of Gorgan, northern Iran, between April 2006 and May 2007. All consecutive patients with pityriasis versicolor were included and randomly divided into two groups. In the first group (G1), patients underwent treatment with a single dose of fluconazole capsule (400 mg) and placebo cream. In the second group (G2), patients underwent treatment with clotrimazole cream (twice daily) and placebo capsule. The course of treatment was 2 weeks. All subjects were re-evaluated 2, 4 and 12 weeks after the end of the therapeutic course. After 2 weeks, the rate of complete resolution of disease was significantly higher in G2 than G1 (49.1% vs 30%). After 4 weeks, 41 patients (81.2%) of G1 and 52 patients (94.9%) of G2 showed complete resolution. After 12 weeks, 46 patients (92%) in G1 and 45 patients (81.8%) in G2 showed complete resolution. Recurrence rate in G1 and G2 were 6% and 18.2%, respectively. No complications were seen in either group. In this study, clinical response at week 4 was greater in the clotrimazole group than the fluconazole group. Recurrence at week 12 after treatment was less with oral fluconazole than clotrimazole cream. So, for better evaluation, more studies need to be done.

  16. Multilaboratory study of epidemiological cutoff values for detection of resistance in eight Candida species to fluconazole, posaconazole, and voriconazole

    NARCIS (Netherlands)

    Espinel-Ingroff, A.; Pfaller, M.A.; Bustamante, B.; Canton, E.; Fothergill, A.; Fuller, J.; Gonzalez, G.M.; Lass-Florl, C.; Lockhart, S.R.; Martin-Mazuelos, E.; Meis, J.F.G.M.; Melhem, M.S.; Ostrosky-Zeichner, L.; Pelaez, T.; Szeszs, M.W.; St-Germain, G.; Bonfietti, L.X.; Guarro, J.; Turnidge, J.

    2014-01-01

    Although epidemiological cutoff values (ECVs) have been established for Candida spp. and the triazoles, they are based on MIC data from a single laboratory. We have established ECVs for eight Candida species and fluconazole, posaconazole, and voriconazole based on wild-type (WT) MIC distributions fo

  17. Overexpression of Erg11p by the Regulatable GAL1 Promoter Confers Fluconazole Resistance in Saccharomyces cerevisiae

    OpenAIRE

    Kontoyiannis, Dimitrios P.; Sagar, Namita; Hirschi, Kendal D.

    1999-01-01

    The contribution of the dosage of target enzyme P-450 14α-demethylase (14αDM) to fluconazole resistance in both Candida albicans and Saccharomyces cerevisiae remains unclear. Here, we show that overexpression of Saccharomyces P-450 14αDM in S. cerevisiae, under the control of the regulatable promoter GAL1, results in azole resistance.

  18. Miconazole nitrate vaginal suppository 1,200 mg versus oral fluconazole 150 mg in treating severe vulvovaginal candidiasis.

    Science.gov (United States)

    Fan, Shangrong; Liu, Xiaopingliu; Liang, Yiheng

    2015-01-01

    Miconazole is a synthetic imidazole antifungal that has a broad spectrum of activity against Candida albicans and non-albicans Candida species. The aim of this study was to evaluate the efficacy and safety of miconazole nitrate vaginal suppository and oral fluconazole in treating severe vulvovaginal candidiasis (SVVC). In this prospective, randomized case control study, 577 cases of consecutive patients with SVVC were studied at the Gynecological Clinic of Peking University Shenzhen Hospital from January 1, 2009 through December 31, 2010. Patients with SVVC were treated with two doses of miconazole nitrate vaginal suppository 1,200 mg or two doses of fluconazole 150 mg. The patients were followed up for 7-14 and 30-35 days following the second dose of therapy. The mycological cure rates of the patients on days 7-14 of follow-up were 75.9% (220/290) and 84.0% (241/287) in the miconazole and fluconazole groups, respectively (p 0.05). The study demonstrated that two doses of miconazole nitrate vaginal suppository 1,200 mg were as effective as two doses of an oral fluconazole 150 mg regimen in the treatment of patients with SVVC. © 2015 S. Karger AG, Basel.

  19. Berberine Antifungal Activity in Fluconazole-Resistant Pathogenic Yeasts: Action Mechanism Evaluated by Flow Cytometry and Biofilm Growth Inhibition in Candida spp.

    Science.gov (United States)

    da Silva, Anderson Ramos; de Andrade Neto, João Batista; da Silva, Cecília Rocha; Campos, Rosana de Sousa; Costa Silva, Rose Anny; Freitas, Daniel Domingues; do Nascimento, Francisca Bruna Stefany Aires; de Andrade, Larissa Nara Dantas; Sampaio, Letícia Serpa; Grangeiro, Thalles Barbosa; Magalhães, Hemerson Iury Ferreira; Cavalcanti, Bruno Coêlho; de Moraes, Manoel Odorico; Nobre Júnior, Hélio Vitoriano

    2016-06-01

    The incidence of fungal infections and, in particular, the incidence of fungal antibiotic resistance, which is associated with biofilm formation, have significantly increased, contributing to morbidity and mortality. Thus, new therapeutic strategies need to be developed. In this context, natural products have emerged as a major source of possible antifungal agents. Berberine is a protoberberine-type isoquinoline alkaloid isolated from the roots, rhizomes, and stem bark of natural herbs, such as Berberis aquifolium, Berberis vulgaris, Berberis aristata, and Hydrastis canadensis, and of Phellodendron amurense Berberine has been proven to have broad antibacterial and antifungal activity. In the present study, the potential antifungal effect of berberine against fluconazole-resistant Candida and Cryptococcus neoformans strains, as well as against the biofilm form of Candida spp., was assessed. The antifungal effect of berberine was determined by a broth microdilution method (the M27-A3 method of the Clinical and Laboratory Standards Institute) and flow cytometry techniques, in which the probable mechanism of action of the compound was also assessed. For biofilm assessment, a colorimetric 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to determine the susceptibility of sessile cells. The isolates used in the study belonged to the Laboratory of Bioprospection and Experiments in Yeast (LABEL) of the Federal University of Ceará. After 24 and 72 h, fluconazole-resistant Candida and Cryptococcus neoformans strains showed berberine MICs equal to 8 μg/ml and 16 μg/ml, respectively. Cytometric analysis showed that treatment with berberine caused alterations to the integrity of the plasma and mitochondrial membranes and DNA damage, which led to cell death, probably by apoptosis. Assessment of biofilm-forming isolates after treatment showed statistically significant reductions in biofilm cell activity (P < 0.001).

  20. Cost-effectiveness of posaconazole versus fluconazole or itraconazole in the prevention of invasive fungal infections among high-risk neutropenic patients in Spain

    Directory of Open Access Journals (Sweden)

    Grau Santiago

    2012-04-01

    Full Text Available Abstract Background We evaluated the cost-effectiveness of posaconazole compared with standard azole therapy (SAT; fluconazole or itraconazole for the prevention of invasive fungal infections (IFI and the reduction of overall mortality in high-risk neutropenic patients with acute myelogenous leukaemia (AML or myelodysplastic syndromes (MDS. The perspective was that of the Spanish National Health Service (NHS. Methods A decision-analytic model, based on a randomised phase III trial, was used to predict IFI avoided, life-years saved (LYS, total costs, and incremental cost-effectiveness ratio (ICER; incremental cost per LYS over patients' lifetime horizon. Data for the analyses included life expectancy, procedures, and costs associated with IFI and the drugs (in euros at November 2009 values which were obtained from the published literature and opinions of an expert committee. A probabilistic sensitivity analysis (PAS was performed. Results Posaconazole was associated with fewer IFI (0.05 versus 0.11, increased LYS (2.52 versus 2.43, and significantly lower costs excluding costs of the underlying condition (€6,121 versus €7,928 per patient relative to SAT. There is an 85% probability that posaconazole is a cost-saving strategy compared to SAT and a 97% probability that the ICER for posaconazole relative to SAT is below the cost per LYS threshold of €30,000 currently accepted in Spain. Conclusions Posaconazole is a cost-saving prophylactic strategy (lower costs and greater efficacy compared with fluconazole or itraconazole in high-risk neutropenic patients.

  1. Long-term safety and tolerability of nevirapine and efavirenz-containing regimens in HIV/HCV-coinfected patients

    Directory of Open Access Journals (Sweden)

    A Mauelshagen

    2012-11-01

    Full Text Available Purpose: There is some controversy about the hepatic safety of nevirapine (NVP and current US guidelines discourage NVP use in HCV-coinfected patients. We evaluated the long-term safety and tolerability of antiretroviral therapies containing NVP or efavirenz (EFV in this difficult-to-treat population. Methods: This retrospective observational cohort study included all HIV/HCV-coinfected patients who initiated a regimen including NVP or EFV between January 2000 and July 2011 in two HIV centers. A detailed analysis of the HIV/HCV status at the time of NNRTI start was performed as well as of the reason for NNRTI discontinuation. Results: In total, 195 cases were identified (121 on EFV, 74 on NVP. Mean age was 38 years, 77% were men and intravenous drug use (59% was the most frequent mode of transmission. In 66%, HCV infection was viremic while 34% had an aviremic infection. The estimated median time on NNRTI was 5.2 years. During a total of 566 patient-years, no NNRTI-associated fatal event was observed. Treatment was discontinued due to adverse events (AEs in 23.1% patients on EFV and 23.0% in patients on NVP. The main AE leading to discontinuation were CNS side effects in patients on EFV (20.7% and hepatic events in patients on NVP (21.6%, grade 3 or 4 events: 9.5%. The majority of AEs in patients on NVP occurred during the first 12 months while AEs in patients on EFV were observed continuously during the observation period (Figure.Discontinuations due to hepatotoxicity were not more frequent in patients viremic for HCV compared to aviremic patients. Pre-treatment levels of ALT, GGT or CD4 cells were also not predictive for discontinuation of ART due to an hepatic event. Conclusions: Antiretroviral regimens, including NVP or EFV, were generally safe in HIV/HCV-coinfected patients. Severe AEs were rare. However, 23% of the patients discontinued their NNRTI regimen due to AEs. Discontinuations of NVP due to hepatotoxicity were not more frequent in

  2. Study to determine the improvement in neuropsychiatric symptoms after changing the responsible antiretroviral drug to nevirapine: the RELAX study

    Directory of Open Access Journals (Sweden)

    E Pedrol

    2012-11-01

    Full Text Available Objectives: Primary - evaluate the improvement in psychiatric symptoms attributable to changing the antiretroviral drug responsible for such symptoms to nevirapine (NVP. The tools used were a sleep test (the Pittsburgh Sleep Quality Index [PSQI] and the Hospital Anxiety and Depression Scale (HADS. Secondary - determine the neuropsychiatric disorders and evaluate adherence to treatment and quality of life. Methods: Prospective, observational post-authorisation study that included HIV-1 patients from 36 Spanish hospitals who satisfied the following criteria: age over 18 years; change of antiretroviral treatment to NVP due to CNS side-effects; a PSQI score >5 (significant sleep disturbance; a HADS score ≥10 on the day of starting NVP treatment; and no psychoactive drug treatment initiated during the 6 weeks prior to starting treatment with NVP. Other data gathered from the patients included clinical and demographic details and administration of the Epworth somnolence scale, the Medical Outcomes Study-short form 30 items (MOS-SF-30 quality of life scale and the Simplified Medication Adherence Questionnaire (SMAQ. Evaluations were performed at baseline, 1 and 3 months after the change. Results: 129 patients were included (73.6% men; mean age, 43.2 ± 9.8 years; 36.5% homosexual, 30.2% heterosexual; 28.7% drug users; 38% AIDS; 33.3% co-infection. The drug changed was efavirenz in 89.9% of cases. The reason for the change was sleep disturbances in 75.2%, anxiety in 65.1%, other psychiatric disturbances in 38.7%, attention disturbances in 31%, and other reasons in 31%; a mean of 2.4 neuropsychiatric disturbances were detected in each patient. CD4 rose from 582 ± 261 to 619 ± 299 (non-significant difference. Only three patients had developed an HIV viral load at the end of the study. The differences produced by the change are shown in Table 1. 29 patients withdrew from the study, for the following reasons: 9 for NVP-related toxicity (7 cases of rash

  3. Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: a 10.5-Year Analysis of Susceptibilities of Candida Species to Fluconazole and Voriconazole as Determined by CLSI Standardized Disk Diffusion ▿

    OpenAIRE

    Pfaller, M.A.; Diekema, D. J.; Gibbs, D. L.; Newell, V. A.; Ellis, D.; Tullio, V; Rodloff, A.; Fu, W; Ling, T. A.

    2010-01-01

    Fluconazole in vitro susceptibility test results for 256,882 isolates of Candida spp. were collected from 142 sites in 41 countries from June 1997 to December 2007. Data were collected for 197,619 isolates tested with voriconazole from 2001 to 2007. A total of 31 different species of Candida were isolated. Increased rates of isolation of the common non-albicans species C. glabrata (10.2% to 11.7%), C. tropicalis (5.4% to 8.0%), and C. parapsilosis (4.8% to 5.6%) were noted when the time perio...

  4. Investigation of ERG11 gene expression among fluconazole-resistant Candida albicans: first report from an Iranian referral paediatric hospital.

    Science.gov (United States)

    Teymuri, M; Mamishi, S; Pourakbari, B; Mahmoudi, S; Ashtiani, M T; Sadeghi, R H; Yadegari, M H

    2015-01-01

    The multiplicity of mechanisms of resistance to azole antifungal agents has been described. As fluconazole-resistant clinical Candida albicans isolates that constitutively over-express ERG11 have been identified in previous studies, the aim of this study is to investigate this molecular mechanism involved in fluconazole resistance of C. albicans clinical isolates. Fluconazole susceptibility testing was carried out on clinical isolates of Candida spp. obtained from hospitalised children in an Iranian referral children's hospital. A polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) technique was used to differentiate Candida spp. The resistant C. albicans isolates were subjected to RT-qPCR using primers that identify ERG11 gene expression. Of the 142 Candida spp. isolates studied, C. albicans was the most predominant isolate, occurring in 68.3% (97/142) of the patients. According to the CLSI method, the majority of the C. albicans isolates (91.7%, 89/97), categorised as susceptible (minimum inhibitory concentration [MIC] ≤8 μg/mL), five isolates were considered resistant (MIC ≤64 μg/mL) and three had dose-dependent susceptibility (MIC = 8.16-32 μg/mL). The ERG11 gene in the five fluconazole-resistant C. albicans isolates was upregulated 4.15-5.84-fold relative to the ATCC 10231 control strain. In this study, the expression of ERG11 was upregulated in all the fluconazole-resistant C. albicans isolates. There are limited data on the antifungal susceptibility of Candida spp. as well as the molecular mechanism of azole resistance in Iran, especially for isolates causing infections in children. Therefore, the surveillance of antifungal resistance patterns and investigation of other mechanisms of azole resistance in all Candida spp. isolates is recommended.

  5. Corneal layer plate removal with Fluconazole injected corneal stroma and autologous conjunctival transplantation for keratomycosis

    Directory of Open Access Journals (Sweden)

    Li-Dong Yang

    2013-08-01

    Full Text Available AIM: To investigate the clinical effect of corneal layer plate removal with Fluconazole injected corneal stroma and autologous conjunctival transplantation for keratomycosis.METHODS: There were 168 cases suffered keratomycosis that the focus located shallow of the cornea and was not obvious to drug, who registered in our hospital from March 2005 to June 2010. In surgery we removed plate layer to cormea clear, the region was greater than focus for 0.5mm,then we injected fluconazole which is 2g/L density in corneal stroma to make the edema area greater than Removal of area for 0.5mm. At last we took pedicle conjunctival flap to cover the plant bed by continuous suture. Postoperative day use drug to drop eye and to observe that whether recurrent of the keratomycosis and how was the edema degrade, the blood supply of conjunctival graft pieces, how about the stimulating signs of the surgery eye, the vision.RESULTS: The improvement rate was 96.2% after surgery for seven days and the cure rate was 95.5% after surgery for one months. We found in 157 eyes accepted trigeminy surgery there were 6 eyes recurrence and the recurrence rate was 3.8%. The mean time of corneal stromal edema faded away was 13.4 hours. After surgery for one month there were 39 eyes(24.8%whose vision removed than preoperative, there were 91 eyes(58.0%whose vision were same as preoperative and there were 27 eyes(17.2%whose vision lower than preoperative. In these operations the loss ratio of corneal endothelium was from 0%-8%, the mean was 2.9%. The irritative symptoms postoperative were mild for 87%, moderate for 10% and severe for 3%. By this surgery the mean length of stay was 7.3 days so the mean hospitalization expenses only were 2160 RMB. Three months after surgery, 4 cases were slight corneal ectasia.CONCLUSION: This operation combined corneal layer plate removal, Fluconazole injected corneal stroma and autologous conjunctival transplantation for keratomycosis which was in

  6. Validation of high-performance liquid chromatographic method for analysis of fluconazole in microemulsions and liquid crystals

    Directory of Open Access Journals (Sweden)

    Hilris Rocha e Silva

    2014-04-01

    Full Text Available In recent decades, there has been a significant increase in the incidence of fungal diseases. Certain fungal diseases cause cutaneous lesions and in the usual treatment, generally administred orally, the drug reaches the site of action with difficulty and its concentration is too low. An approach much explored in recent years is the development of nanotechnology-based drug delivery systems, and microemulsions (ME and liquid crystals (LC are promising. ME and LC were developed with oleic acid or copaiba oil as the oil phase, propoxyl (5OP ethoxyl (20 OE cetyl alcohol as surfactant and water. An analytical method to assess the incorporation of fluconazole (FLU in the systems under study was validated according to guidelines of the International Conference on Harmonization (ICH guidelines and the Brazilian Food, Drug and Sanitation Agency (ANVISA. The method was conducted on a C18-RP column (250 × 4.6 mm i.d., maintained at room temperature. The mobile phase consisted of acetonitrile and water (50:50, v/v, run at a flow rate of 1.0mL/min and using ultraviolet detection at 210nm. The chromatographic separation was obtained with a retention time of 6.3min, and was linear in the range of 20-400 µg/mL (r2=0.9999. The specificity showed no interference of the excipients. The accuracy was 100.76%. The limits of detection and quantitation were 0.057 and 0.172 µg.mL-1, respectively. Moreover, method validation demonstrated satisfactory results for precision and robustness. The proposed method was applied for the analysis of the incorporation of FLU in ME and LC, contributing to improve the quality control and to assure the therapeutic efficacy.

  7. Experimental and quantum chemical studies on corrosion inhibition performance of fluconazole in hydrochloric acid solution

    Indian Academy of Sciences (India)

    P Malekmohammadi Nouri; M M Attar

    2015-04-01

    The corrosion inhibition effect of fluconazole (FLU) was investigated on steel in 1 M hydrochloric acid solution. Weight loss measurements and atomic force microscope analysis were utilized to investigate the corrosion inhibition properties and film formation behaviour of FLU. Quantum chemical approach was also used to calculate some electronic properties of the molecule in neutral and protonated form in order to find any correlation between the inhibition effect and molecular structure of FLU molecule. The results showed that FLU can act as a good corrosion inhibitor for steel in hydrochloric acid solution at different temperatures and it can inhibit steel corrosion up to 95%. The adsorption followed the Langmuir isotherm and the thermodynamic parameters were also determined and discussed. Quantum chemical studies showed that in adsorption process of FLU molecules, nitrogen and oxygen atoms and benzene ring act as active centres.

  8. Voriconazole versus amphotericin B or fluconazole in cancer patients with neutropenia

    DEFF Research Database (Denmark)

    Jørgensen, Karsten Juhl; Gøtzsche, Peter C; Dalbøge, Christina S

    2014-01-01

    BACKGROUND: Opportunistic fungal infections are a major cause of morbidity and mortality in neutropenic cancer patients and antifungal therapy is used both empirically and therapeutically in these patients. OBJECTIVES: To compare the benefits and harms of voriconazole with those of amphotericin B...... and fluconazole when used for prevention or treatment of invasive fungal infections in cancer patients with neutropenia. SEARCH METHODS: Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2014, Issue 1 2014), MEDLINE (to January 2014). Letters, abstracts and unpublished trials were...... and adverse effects leading to discontinuation of therapy were extracted independently by two review authors. MAIN RESULTS: Three trials were included. One trial compared voriconazole to liposomal amphotericin B as empirical treatment of fever of unknown origin (suspected fungal infection) in neutropenic...

  9. Fluconazol method validation by RP-HPLC for determination in biological skin matrices.

    Science.gov (United States)

    Ayub, Alessandra C; Vianna-Soares, Cristina D; Ferreira, Lucas A M

    2007-01-01

    The bis-triazole antifungal fluconazole (FCZ) is used in the systemic treatment of superficial mycoses. The inconvenience of drug interactions and incidence of adverse reactions occurs in approximately 16% of patients, despite several advantages against systemic fungal infections. Because its pharmacokinetics profile is favorable to cutaneous accumulation, it presents a prominent importance in the treatment of superficial mycoses. This study shows FCZ method validation by reversed-phase high-performance liquid chromatography in the linear range of 2 to 32 microg/mL, which suitable for application in biological matrices after topical permeation studies. The method is tested in simulated FCZ alcoholic solution applied to skin extracts after in vitro permeation studies using Franz cells. Recovery shows good results (in the range 75.0% +/- 4.1% to 82.0% +/- 6.6%) regarding the biological matrices.

  10. EFFICACY OF SINGLE ORAL DOSE 150 mg FLUCONAZOLE IN TREATMENT OF VAGINAL CANDIDIASIS

    Directory of Open Access Journals (Sweden)

    Shabana

    2013-10-01

    Full Text Available ABSTRACT: AIMS : This study aimed to find out the efficacy of single oral dose 150mg of fluconazole in treatment of acute vulvovaginal candidiasis, to e valuate its safety assessment and the clinical and mycological efficacy assessment. MATERIALS AND METHODS: T his study is carried out in department of obstetrics and gynaecology Gandhi medical college sultania hospital Bhopal and with the help of microbiolo gy department Gandhi medical college Bhopal over a period of one year. It is a hospital based clinical prospective study. RESULTS : Maximum age incidence was found between 21 - 30years. Mostly patients belonged to low socioeconomic status and were uneducated. Maximum patients were married (98% and multiparous (92%, nulliparous formed the smallest group (8%. In factors predisposing to candidiasis, contraceptive methods were found to be important in which maximum incidence was found in patients using oral con traception about 32% and 12% of IUCD users were affected. Other factors were antibiotic treatment (5% and diabetes (2%. Vaginal discharge and pruritis were the two commonest symptoms found. Among the signs vaginal discharge and white plaques was the comm onest sign. On follow up visits 88 cases had complete clinical cure and only 6 cases showed failure and 9 recurrence s . In mycological assessment maximum 135 cases showed complete cure, 6 were failure and 9 recurrence. In overall results, excellent results were found in 88cases, good in 38 cases, fair in 9 cases and recurrence in 9 cases. Recurrences were mainly due to rectal carriers. CONCLUSION: In co n clusion fluconazole was found effective as a systemic single oral dose therapy for acute vulvovaginal cand idiasis. It is proved safe in terms of tolerance and preferred by patients. So in view of its favourable patients acceptability and compliance profile, it is considered as a first line therapeutic choice for treatment of women with vaginal candidiasis.

  11. Quercetin Assists Fluconazole to Inhibit Biofilm Formations of Fluconazole-Resistant Candida Albicans in In Vitro and In Vivo Antifungal Managements of Vulvovaginal Candidiasis.

    Science.gov (United States)

    Gao, Mei; Wang, Hui; Zhu, LiJuan

    2016-01-01

    Vulvovaginal candidiasis (VVC) is a common gynecological disease. Candida albicans is believed to be mainly implicated in VVC occurrence, the biofilm of which is one of the virulence factors responsible for resistance to traditional antifungal agents especially to fluconazole (FCZ). Quercetin (QCT) is a dietary flavonoid and has been demonstrated to be antifungal against C. albicans biofilm. 17 C. albicans isolates including 15 clinical ones isolated from VVC patients were employed to investigate the effects of QCT and/or FCZ on the inhibition of C. albicans biofilm. We observed that 64 µg/mL QCT and/or 128 µg/mL FCZ could (i) be synergistic against 10 FCZ-resistant planktonic and 17 biofilm cells of C. albicans, (ii) inhibit fungal adherence, cell surface hydrophobicity (CSH), flocculation, yeast-to-hypha transition, metabolism, thickness and dispersion of biofilms; (iii) down-regulate the expressions of ALS1, ALS3, HWP1, SUN41, UME6 and ECE1 and up-regulate the expressions of PDE2, NRG1 and HSP90, and we also found that (iv) the fungal burden was reduced in vaginal mucosa and the symptoms were alleviated in a murine VVC model after the treatments of 5 mg/kg QCT and/or 20 mg/kg FCZ. Together with these results, it could be demonstrated that QCT could be a favorable antifungal agent and a promising synergist with FCZ in the clinical management of VVC caused by C. albicans biofilm. © 2016 The Author(s) Published by S. Karger AG, Basel.

  12. Quercetin Assists Fluconazole to Inhibit Biofilm Formations of Fluconazole-Resistant Candida Albicans in In Vitro and In Vivo Antifungal Managements of Vulvovaginal Candidiasis

    Directory of Open Access Journals (Sweden)

    Mei Gao

    2016-11-01

    Full Text Available Background: Vulvovaginal candidiasis (VVC is a common gynecological disease. Candida albicans is believed to be mainly implicated in VVC occurrence, the biofilm of which is one of the virulence factors responsible for resistance to traditional antifungal agents especially to fluconazole (FCZ. Quercetin (QCT is a dietary flavonoid and has been demonstrated to be antifungal against C. albicans biofilm. Methods: 17 C. albicans isolates including 15 clinical ones isolated from VVC patients were employed to investigate the effects of QCT and/or FCZ on the inhibition of C. albicans biofilm. Results: We observed that 64 µg/mL QCT and/or 128 µg/mL FCZ could (i be synergistic against 10 FCZ-resistant planktonic and 17 biofilm cells of C. albicans, (ii inhibit fungal adherence, cell surface hydrophobicity (CSH, flocculation, yeast-to-hypha transition, metabolism, thickness and dispersion of biofilms; (iii down-regulate the expressions of ALS1, ALS3, HWP1, SUN41, UME6 and ECE1 and up-regulate the expressions of PDE2, NRG1 and HSP90, and we also found that (iv the fungal burden was reduced in vaginal mucosa and the symptoms were alleviated in a murine VVC model after the treatments of 5 mg/kg QCT and/or 20 mg/kg FCZ. Conclusion: Together with these results, it could be demonstrated that QCT could be a favorable antifungal agent and a promising synergist with FCZ in the clinical management of VVC caused by C. albicans biofilm.

  13. Single-dose fluconazole versus standard 2-week therapy for oropharyngeal candidiasis in HIV-infected patients: a randomized, double-blind, double-dummy trial.

    NARCIS (Netherlands)

    Hamza, O.J.; Matee, M.I.N.; Bruggemann, R.J.M.; Moshi, M.J.; Simon, E.N.; Mugusi, F.; Mikx, F.H.M.; Lee, H.A.L. van der; Verweij, P.E.; Ven, A.J.A.M. van der

    2008-01-01

    BACKGROUND: Oropharyngeal candidiasis is the most common opportunistic infection affecting patients with human immunodeficiency virus (HIV) infection. Because of convenience, cost, and reluctance to complicate antiretroviral treatment regimens, single-dose fluconazole may be a favorable regimen for

  14. Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: a randomised non-inferiority trial.

    NARCIS (Netherlands)

    Kullberg, B.J.; Sobel, J.D.; Ruhnke, M.; Pappas, P.; Viscoli, C.; Rex, J.H.; Cleary, J.D.; Rubinstein, E.; Church, L.W.; Brown, J.M.; Schlamm, H.T.; Oborska, I.T.; Hilton, F.; Hodges, M.R.

    2005-01-01

    BACKGROUND: Voriconazole has proven efficacy against invasive aspergillosis and oesophageal candidiasis. This multicentre, randomised, non-inferiority study compared voriconazole with a regimen of amphotericin B followed by fluconazole for the treatment of candidaemia in non-neutropenic patients. ME

  15. Comparison of visual 24-hour and spectrophotometric 48-hour MICs to CLSI reference microdilution MICs of fluconazole, itraconazole, posaconazole, and voriconazole for Candida spp.: a collaborative study.

    NARCIS (Netherlands)

    Espinel-Ingroff, A.; Barchiesi, F.; Cuenca-Estrella, M.; Fothergill, A.; Pfaller, M.A.; Rinaldi, M.; Rodriguez-Tudela, J.L.; Verweij, P.E.

    2005-01-01

    A multicenter (six-center) study evaluated the performance (interlaboratory reproducibility, compatibility with reference methods, and categorical agreement) of 24-h visual and 48-h spectrophotometric MICs. MICs of fluconazole, itraconazole, voriconazole, and posaconazole were compared to reference

  16. Comparison of visual 24-hour and spectrophotometric 48-hour MICs to CLSI reference microdilution MICs of fluconazole, itraconazole, posaconazole, and voriconazole for Candida spp.: a collaborative study.

    NARCIS (Netherlands)

    Espinel-Ingroff, A.; Barchiesi, F.; Cuenca-Estrella, M.; Fothergill, A.; Pfaller, M.A.; Rinaldi, M.; Rodriguez-Tudela, J.L.; Verweij, P.E.

    2005-01-01

    A multicenter (six-center) study evaluated the performance (interlaboratory reproducibility, compatibility with reference methods, and categorical agreement) of 24-h visual and 48-h spectrophotometric MICs. MICs of fluconazole, itraconazole, voriconazole, and posaconazole were compared to reference

  17. ACUTE EFFECT OF FLUCONAZOLE, ITRACONAZOLE AND VORICONAZOLE ON BLOOD GLUCOSE IN NORMOGLYCEAMIC & DIABETIC RATS: AN EXPERIMENTAL STUDY

    Directory of Open Access Journals (Sweden)

    Jadhav Amol, Nayak BB, Vakade Kiran P, Sanghishetti Vijay Prasad, Vijay Kumar AN, Vrushali Nibrad, Raul AR

    2015-01-01

    Full Text Available Anti-fungal and antimicrobials are frequently co-prescribed either to manage or treat either the secondary complications or other diseases. Among antifungal drugs Fluconazole, Itraconazole & Voriconazole are most commonly used. The present study was undertaken to further confirm the effect of Voriconazole as well as other antifungal drugs on blood Glucose level. Aim & Objectives: 1. To Study the effect of Fluconazole, Itraconazole & Voriaconazole in Normoglycemic & Diabetic Rats on Blood Glucose. 2. To compare the effects between all drugs. Material & Methodology: Grouping: Animals divided into 8 groups in each group 6 animals. Group 1- 4: Normoglycemic rats, Group 5-8 Diabetic rats (alloxan induced Group 1,5: received vehicle (Normal saline Group 2,6: received Fluconazole (18mg/kg BW, Group 3,7 received Itraconazole (18mg/kg BW Group 4,8 received Voriconazole (18mg/kg BW. The glucose levels were estimated by Glucometer method (Accu-check active at the interval of 0, ½ hr, 1hrs, 2hrs & 4hrs after drug administration. Results: Effect on blood glucose in Normoglycemic Rats: Voriconazole had a significant hypoglycaemic effect which appeared after 1 hr (‘p’ value= 0.0102 of administration & persisted up to 2 hrs (‘p’ value=0.0001. However effect of Voriconzole was found to be declined after 2 hrs. There was no significant change in blood glucose in normoglycemic rats with Fluconazole & Itraconazole. Effect on blood glucose in Diabetic Rats: (Table 2: Voriconazole had a significant hypoglycaemic effect which appeared after 1 hr (‘p’ value=0.013 of administration & persisted up to 2 hrs (‘p’ value=0.001 in acute studies. However effect of Voriconzole was found to be declined after 2 hrs. There was no significant change in blood glucose in diabetic rats with Fluconazole & Itraconazole treated. Conclusion: Itraconazole, Fluconazole can be safely used in diabetic with fungal infections. Voriconazole should be avoided in diabetics to

  18. A pseudo-randomised clinical trial of in situ gels of fluconazole for the treatment of oropharngeal candidiasis

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    Shetty Veena A

    2011-04-01

    Full Text Available Abstract Background Oropharyngeal candidasis is a common opportunistic infection seen in immunocompromised patients. Fluconazole has a broad spectrum antifungal activity including a wide variety of candida species. Aim of the present investigation was to formulate and find out the relative efficacy of in situ gels of fluconazole. Method The in situ gels were prepared using polymers which exhibited sol-to-gel phase transition due to change in specific physico-chemical parameters, such as ion triggered system using gellan gum (0.5% w/v along with sodium carboxylmethylcellulose (0.35%w/v. The study design was bicenter, 'pseudo-randomised, single blind trial conducted in Mangalore., India, which includes 15 HIV positive patients, 15 patients with partial or completes dentures, and 15 patients who were treated with (active control fluconazole tablets 100 mg/day for 14 days. Severity of disease was scored clinically before treatment and at clinical evaluations on day 3, 7, 14, 18, 21, 35, and 42. Semiquantitative microbiological cultures of oral swabs were also obtained on same days. Results All patients had mycological documented oropharyngeal candidiasis and were treated with fluconazole (0.5%w/v in situ gels for 14 days Severity of disease was scored clinically before treatment and at different predetermined time intervals along with semi quantitative culture of oral swabs. The clinical response rate showed 97% cure after 14 days in the treated with in situ gel. In comparison, the control group treated with fluconazole tablets showed 85% improvement in symptoms of oral candidiasis. The patients suffering from HIV infection showed relapse in oral candidiasis at the end of 21 days. The patients having oral candidiasis due to partial or complete dentures showed complete recovery and were free from signs and symptoms of oral candidiasis. Conclusions The in situ gel formulation of fluconazole was well tolerated with no severe adverse reaction and offers

  19. Effect of combination of acrylic polymers on the release of nevirapine formulated as extended release matrix pellets using extrusion and spheronization technique.

    Science.gov (United States)

    Sharma, Anshuli; Prasad, Anjaneya; Dua, Kamal; Singh, Gurvinder

    2014-01-01

    The aim of the present research work was to formulate and evaluate the extended release matrix pellets of nevirapine using extrusion and spheronization technique which will be an alternative technique for making extended release dosage forms and to compare the drug release profiles of the formulations with the reference product. In vitro dissolutions were carried out in 0.04M Phosphate buffer pH 6.8 with 2% w/v SLS (sodium lauryl sulphate) for 24 hours with USP type I apparatus at 75rpm. The drug release from the optimised formulation was comparable to that of the reference product and follows first order kinetics followed by non-fickian transport mechanism of drug release which confirms the drug release pattern involves complex mixture of diffusion and erosion. The similarity factor, f2 value of optimised formulation was found to be 70, which shows that the developed formulation was comparable to that of the reference product.

  20. Outcome of AIDS-associated cryptococcal meningitis initially treated with 200 mg/day or 400 mg/day of fluconazole

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    Morroni C

    2006-07-01

    Full Text Available Abstract Background AIDS-associated cryptococcal meningitis has a high mortality. Fluconazole was the only systemic antifungal therapy available in our centre. From 1999–2001 we used low-dose fluconazole (200 mg daily initially, and did not offer therapy to patients perceived to have poor prognoses. In 2001 donated fluconazole became available, allowing us to use standard doses (400 mg daily initially. Antiretroviral therapy was not available during the study period. Methods Retrospective chart review of adult patients before and after the fluconazole donation. Results 205 patients fulfilled the inclusion criteria, 77 before and 128 after the donation. Following the donation fewer patients received no antifungal treatment (5% vs 19%, p = 0.002, and more patients received standard-dose fluconazole (90% vs 6%, p 1,000 were independent predictors of in-hospital mortality. Concomitant rifampicin did not affect in-hospital survival. Thirteen patients were referred to the tertiary referral hospital and received initial treatment with amphotericin B for a mean of 6 days – their in-hospital survival was not different from patients who received only fluconazole (p = 0.9. Kaplan-Meier analysis showed no differences in length of survival by initial treatment with standard or low doses of fluconazole (p = 0.27 log rank test; median survival was 76 and 82 days respectively. Conclusion Outcome of AIDS-associated cryptococcal meningitis is similar with low or standard doses of fluconazole. The early mortality is high. Initial therapy with amphotericin B and other measures may be needed to improve outcome.

  1. Species distribution and in vitro fluconazole susceptibility of clinical Candida isolates in a Brazilian tertiary-care hospital over a 3-year period

    OpenAIRE

    Márcia Cristina Furlaneto; Juliana Frasnelli Rota; Regina Mariuza Borsato Quesada; Luciana Furlaneto-Maia; Renne Rodrigues; Silas Oda; Marcelo Tempesta de Oliveira; Rosana Serpa; Emanuele Júlio Galvão de França

    2011-01-01

    INTRODUCTION: In this study, we aimed at identifying Candida isolates obtained from blood, urine, tracheal secretion, and nail/skin lesions from cases attended at the Hospital Universitário de Londrina over a 3-year period and at evaluating fluconazole susceptibilities of the isolates. METHODS: Candida isolates were identified by polymerase chain reaction (PCR) using species-specific forward primers. The in vitro fluconazole susceptibility test was performed according to EUCAST-AFST reference...

  2. International and multicenter comparison of EUCAST and CLSI M27-A2 broth microdilution methods for testing susceptibilities of Candida spp. to fluconazole, itraconazole, posaconazole, and voriconazole.

    Science.gov (United States)

    Espinel-Ingroff, A; Barchiesi, F; Cuenca-Estrella, M; Pfaller, M A; Rinaldi, M; Rodriguez-Tudela, J L; Verweij, P E

    2005-08-01

    The aim of this study was to compare MICs of fluconazole, itraconazole, posaconazole, and voriconazole obtained by the European Committee on Antibiotic Susceptibility Testing (EUCAST) and CLSI (formerly NCCLS) methods in each of six centers for 15 Candida albicans (5 fluconazole-resistant and 4 susceptible-dose-dependent [S-DD] isolates), 10 C. dubliniensis, 7 C. glabrata (2 fluconazole-resistant isolates), 5 C. guilliermondii (2 fluconazole-resistant isolates), 10 C. krusei, 9 C. lusitaniae, 10 C. parapsilosis, and 5 C. tropicalis (1 fluconazole-resistant isolate) isolates. CLSI MICs were obtained visually at 24 and 48 h and spectrophotometric EUCAST MICs at 24 h. The agreement (within a 3-dilution range) between the methods was species, drug, and incubation time dependent and due to lower EUCAST than CLSI MICs: overall, 94 to 95% with fluconazole and voriconazole and 90 to 91% with posaconazole and itraconazole when EUCAST MICs were compared against 24-h CLSI results. The agreement was lower (85 to 94%) against 48-h CLSI endpoints. The overall interlaboratory reproducibility by each method was > or =92%. When the comparison was based on CLSI breakpoint categorization, the agreement was 68 to 76% for three of the four species that included fluconazole-resistant and S-DD isolates; 9% very major discrepancies ( or =64 microg/ml) were observed among fluconazole-resistant isolates and 50% with voriconazole ( or =4 microg/ml). Similar results were observed with itraconazole for seven of the eight species evaluated (28 to 77% categorical agreement). Posaconazole EUCAST MICs were also substantially lower than CLSI MIC modes (0.008 to 1 microg/ml versus 1 to > or =8 microg/ml) for some of these isolates. Therefore, the CLSI breakpoints should not be used to interpret EUCAST MIC data.

  3. Differential association of fluconazole dose and dose/MIC ratio with mortality in patients with Candida albicans and non-albicans bloodstream infection.

    Science.gov (United States)

    Brosh-Nissimov, T; Ben-Ami, R

    2015-11-01

    Targeting fluconazole therapy to achieve predefined pharmacodynamic goals has been suggested as a means of optimizing the treatment of patients with candidaemia. However, data regarding species-specific dosing targets are inconclusive. We retrospectively analysed a cohort of 75 adult patients with Candida bloodstream infection (BSI) who received initial treatment with fluconazole for ≥48 h (36 Candida albicans and 39 non-albicans Candida (NAC)). Fluconazole dose, the dose/MIC ratio and the 24-h area under the concentration-time curve (AUC24)/MIC ratio were determined for each patient, and classification and regression tree analysis was used to determine breakpoints for significant interactions with 30-day survival. Both fluconazole exposure parameters and patient-related and disease-related variables were assessed in univariable and multivariable survival models. The crude 30-day mortality rate was 32% (44% and 21% for C. albicans and NAC, respectively). An average fluconazole dose of >200 mg/day, a dose/MIC ratio of >400 and an AUC24/MIC ratio of >400 were associated with a higher 30-day survival rate and better microbiological response in patients with C. albicans BSI but not in those with NAC BSI. Baseline chronic kidney disease was a risk factor for fluconazole underdosing and mortality. Severity of sepsis (Sequential Organ Failure Assessment score) was the only significant predictor of death in patients with NAC BSI. We conclude that, although pharmacodynamic target-directed fluconazole dosing may help to optimize outcomes for patients with C. albicans BSI, additional studies are needed to define the role of fluconazole in the treatment of NAC BSI.

  4. International and Multicenter Comparison of EUCAST and CLSI M27-A2 Broth Microdilution Methods for Testing Susceptibilities of Candida spp. to Fluconazole, Itraconazole, Posaconazole, and Voriconazole

    Science.gov (United States)

    Espinel-Ingroff, A.; Barchiesi, F.; Cuenca-Estrella, M.; Pfaller, M. A.; Rinaldi, M.; Rodriguez-Tudela, J. L.; Verweij, P. E.

    2005-01-01

    The aim of this study was to compare MICs of fluconazole, itraconazole, posaconazole, and voriconazole obtained by the European Committee on Antibiotic Susceptibility Testing (EUCAST) and CLSI (formerly NCCLS) methods in each of six centers for 15 Candida albicans (5 fluconazole-resistant and 4 susceptible-dose-dependent [S-DD] isolates), 10 C. dubliniensis, 7 C. glabrata (2 fluconazole-resistant isolates), 5 C. guilliermondii (2 fluconazole-resistant isolates), 10 C. krusei, 9 C. lusitaniae, 10 C. parapsilosis, and 5 C. tropicalis (1 fluconazole-resistant isolate) isolates. CLSI MICs were obtained visually at 24 and 48 h and spectrophotometric EUCAST MICs at 24 h. The agreement (within a 3-dilution range) between the methods was species, drug, and incubation time dependent and due to lower EUCAST than CLSI MICs: overall, 94 to 95% with fluconazole and voriconazole and 90 to 91% with posaconazole and itraconazole when EUCAST MICs were compared against 24-h CLSI results. The agreement was lower (85 to 94%) against 48-h CLSI endpoints. The overall interlaboratory reproducibility by each method was ≥92%. When the comparison was based on CLSI breakpoint categorization, the agreement was 68 to 76% for three of the four species that included fluconazole-resistant and S-DD isolates; 9% very major discrepancies (≤8 μg/ml versus ≥64 μg/ml) were observed among fluconazole-resistant isolates and 50% with voriconazole (≤1 μg/ml versus ≥4 μg/ml). Similar results were observed with itraconazole for seven of the eight species evaluated (28 to 77% categorical agreement). Posaconazole EUCAST MICs were also substantially lower than CLSI MIC modes (0.008 to 1 μg/ml versus 1 to ≥8 μg/ml) for some of these isolates. Therefore, the CLSI breakpoints should not be used to interpret EUCAST MIC data. PMID:16081926

  5. Uso do fluconazol endovenoso no tratamento da endoftalmite fúngica endógena: relato de caso Intravenous fluconazole use in the treatment of fungic endogenous endophthalmitis: case report

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    Patrícia de Freitas Dotto

    2005-08-01

    Full Text Available Os autores descrevem um caso de endoftalmite endógena por Candida albicans, em recém-nascido prematuro, refratária ao tratamento com anfotericina B endovenosa e que apresentou resolução com o uso do fluconazol endovenoso. Ressaltam ainda os aspectos clínicos da endoftalmite endógena por Candida albicans por meio de revisão da literatura.The authors describe a case of endogenous Candida albicans endophthalmitis in one extremely low birth-weight newborn refractory to endovenous amphotericin B treatment that presented resolution with the use of endovenous fluconazole. Clinical aspects of endogenous Candida albicans endophthalmitis are also pointed out by a review of the literature.

  6. Seroprevalence of human immunodeficiency virus among antenatal patients and incidence of mother- to- child transmission using single dose nevirapine: a cohort study in Maharashtra

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    Sonal A. Bhuyar

    2015-10-01

    Full Text Available Background: Objective was to study the seroprevalence of human immunodeficiency virus (HIV in antenatal patients and to find out the incidence of mother to child transmission (MTCT using single dose nevirapine (sdNVP to mother- baby pairs in labour. Methods: This prospective study was conducted in the department of Obstetrics and Gynecology, Dr. PDMMC, Amravati, Maharashtra from February 2010 to May 2015. All pregnant women attending the antenatal clinic were subjected to pretest counseling and HIV testing after informed consent. The HIV +ve pregnant patients who opted for delivery at our hospital were included in the study. sdNVP was administered to mother- baby pairs according to NACO guidelines. Babies of these patients were followed up to 18 months of age for HIV testing. Results: 12077 antenatal patients underwent pretest counseling. 11957 antenatal patients were tested for HIV of which 28 were detected positive. Therefore, the seroprevalence in this study was found to be 0.23%. 23 patients delivered at our hospital during the study period and babies of 2 patients tested positive for HIV. Hence the incidence of MTCT was found to be 9.5% in our study. Conclusions: Universal screening of pregnant patients for HIV and judicious use of PPTCT regimens can significantly reduce MTCT of HIV and prevalence of pediatric HIV infection. Single dose nevirapine use over last few years has successfully reduced MTCT, but our aim should be to reduce it further with more effective ART regimens for the seropositive antenatal patients and their babies. [Int J Reprod Contracept Obstet Gynecol 2015; 4(5.000: 1436-1441

  7. NEW STABILITY INDICATING RP-LC METHOD FOR SIMULTANEOUS QUANTIFICATION OF RELATED IMPURITIES OF LAMIVUDINE, TENOFOVIR DISOPEOXIL FUMARATE AND NEVIRAPINE IN EXTENDED RELEASE TABLET DOSAGE FORMS

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    Lanka A.Rama Prasad

    2012-11-01

    Full Text Available The objective of the current study was to develop and validate precise, specific and stability-indicating reverse phase LC method for the simultaneous quantitative determination of Lamivudine, Tenofovir disoproxil fumarate and Nevirapine and their related impurities. The determination was done for extended release tablets dosage form where Tenofovir and Lamivudine are formulated into immediate release and Nevirapine into extended relase. The pharmaceutical formulation along with individual active ingredients was subjected to stress conditions of hydrolysis (acid and base, oxidation and thermal degradation as per International Conference on Harmonization (ICH prescribed stress conditions to show the stability-indicating power of the method. It was found Tenofovir disoproxil fumarate is very sensitive to various stress conditions and readily degrades into Monoester impurity. The chromatographic conditions were optimized using an impurity-spiked solution and the samples generated from forced degradation studies. Regression analysis shows an r value (correlation coefficient of greater than 0.997 for individual active drug substances and their all the related impurities. The chromatographic separation was achieved on a core shell technology C18 stationary phase. The method employed a linear gradient elution and the detection wavlength was set at 260 nm. The mobile phases consists of buffer and acetonitrile delivered at a flow rate of 0.8 mL•min–1. The stress samples were assayed against a qualified reference standard and the mass balance was found to be close to 98.5%. The developed RP-LC method was validated with respect to linearity, accuracy, precision and robustness.

  8. Nevirapine- versus lopinavir/ritonavir-based initial therapy for HIV-1 infection among women in Africa: a randomized trial.

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    Shahin Lockman

    Full Text Available Nevirapine (NVP is widely used in antiretroviral treatment (ART of HIV-1 globally. The primary objective of the AA5208/OCTANE trial was to compare the efficacy of NVP-based versus lopinavir/ritonavir (LPV/r-based initial ART.In seven African countries (Botswana, Kenya, Malawi, South Africa, Uganda, Zambia, and Zimbabwe, 500 antiretroviral-naïve HIV-infected women with CD4<200 cells/mm(3 were enrolled into a two-arm randomized trial to initiate open-label ART with tenofovir (TDF/emtricitabine (FTC once/day plus either NVP (n = 249 or LPV/r (n = 251 twice/day, and followed for ≥48 weeks. The primary endpoint was time from randomization to death or confirmed virologic failure ([VF] (plasma HIV RNA<1 log(10 below baseline 12 weeks after treatment initiation, or ≥400 copies/ml at or after 24 weeks, with comparison between treatments based on hazard ratios (HRs in intention-to-treat analysis. Equivalence of randomized treatments was defined as finding the 95% CI for HR for virological failure or death in the range 0.5 to 2.0. Baseline characteristics were (median: age = 34 years, CD4 = 121 cells/mm(3, HIV RNA = 5.2 log(10copies/ml. Median follow-up = 118 weeks; 29 (6% women were lost to follow-up. 42 women (37 VFs, five deaths; 17% in the NVP and 50 (43 VFs, seven deaths; 20% in the LPV/r arm reached the primary endpoint (HR 0.85, 95% CI 0.56-1.29. During initial assigned treatment, 14% and 16% of women receiving NVP and LPV/r experienced grade 3/4 signs/symptoms and 26% and 22% experienced grade 3/4 laboratory abnormalities. However, 35 (14% women discontinued NVP because of adverse events, most in the first 8 weeks, versus none for LPV/r (p<0.001. VF, death, or permanent treatment discontinuation occurred in 80 (32% of NVP and 54 (22% of LPV/r arms (HR = 1.7, 95% CI 1.2-2.4, with the difference primarily due to more treatment discontinuation in the NVP arm. 13 (45% of 29 women tested in the NVP versus six (15% of 40

  9. Initial fluconazole prophylaxis may not be required in adults with acute leukemia or myelodysplastic/myeloproliferative disorders after reduced intensity conditioning peripheral blood stem cell allogeneic transplantation.

    Science.gov (United States)

    Brissot, Eolia; Cahu, Xavier; Guillaume, Thierry; Delaunay, Jacques; Ayari, Sameh; Peterlin, Pierre; Le Bourgeois, Amandine; Harousseau, Jean-Luc; Milpied, Noel; Bene, Marie-Christine; Moreau, Philippe; Mohty, Mohamad; Chevallier, Patrice

    2015-04-01

    In the myeloablative transplant setting, the early use of fluconazole prophylaxis provides a benefit in overall survival. Recent changes in transplantation practices, including the use of peripheral blood stem cells (PBSC) and/or reduced intensity conditioning (RIC) regimen may have favorably impacted the epidemiology of invasive fungal infections (IFI) after allogeneic stem cell transplantation (allo-SCT). Yet, the impact of removing fluconazole prophylaxis after RIC PBSC allotransplant is ill known. Here, a retrospective analysis was performed comparing patients who received fluconazole as antifungal prophylaxis (n = 53) or not (n = 56) after allo-SCT for acute leukemia or myelodysplastic/myeloproliferative syndrome. Sixteen IFI were documented (14 %) at a median time of 103 days after transplantation, including eight before day +100, at a similar rate, whether the patients received fluconazole prophylaxis (13 %) or not (16 %). IFI were due mainly to Aspergillus species (87 %), and only two Candida-related IFI (13 %) were documented in the non-fluconazole group before day +100. The incidences of IFI (overall, before or after day +100) as well as 3-year overall and disease-free survival, non-relapse mortality, or acute and chronic graft-versus-host disease (GVHD) were similar between both groups. In conclusion, this study suggests that fluconazole may not be required at the initial phase of RIC allo-SCT using PBSC. This result has to be confirmed prospectively while Aspergillus prophylaxis should be discussed in this particular setting.

  10. An Evaluation of Theraphy with Fluconazole 150 mg Tablets Compared to Fluconazole 150 mg Tablets Plus Dermoxen Lenitiva Cream in The Time to Reduce Simptomatology in Women with Vulvovaginal Candidiasis

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    Davide Carati

    2014-06-01

    Full Text Available Aim of the study. Authors investigated first of all the time to onset of first relief of symptoms. Secondary measures included the time to overall relief of symptoms and the reoccurrence rate over the first 45 days after the first visit. Methods. A randomized, open-label, parallel study evaluated 47 women with moderate to severe symptoms of Vulvo Vaginal Candidiasis (VVC. Patients were divided into two groups of treatment: group 1 followed a therapy with Fluconazole 150 mg tablets, while group 2 had a therapy based on Fluconazole 150 mg tablets coadjuvated by Dermoxen Lenitiva cream. Results. The time at which 50% of patients experienced first relief of symptoms was 24.6 hours for Group 1, while for Group 2 it was 12.4 hours (P<0.05. There were significant differences between the two groups in respect to the time of first relief of symptoms and reoccurrence of infection within 45 days of treatment. Conclusions. Combined treatment with Fluconazole 150 mg tablets and by Dermoxen Lenitiva cream provides statistically significant improvement in the time of first relief of symptoms, complete relief of symptoms and relapse time in the treatment of VVC compared to fluconazole 150 mg tablets only.

  11. Susceptibility testing of Candida albicans isolated from oropharyngeal mucosa of HIV+ patients to fluconazole, amphotericin B and Caspofungin: killing kinetics of caspofungin and amphotericin B against fluconazole resistant and susceptible isolates Teste de suscetibilidade de Candida albicans isoladas da mucosa orofaringeana de pacientes HIV+, ao fluconazol, anfotericcina B e caspofungina: cinética de morte de caspofungina e anfotericina B contra isolados fluconazol resistentes e suscetíveis

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    Janine de Aquino Lemos

    2009-03-01

    Full Text Available A clear understanding of the pharmacodynamic properties of antifungal agents is important for the adequate treatment of fungal infections like candidiasis. For certain antifungal agents, the determination of Minimal Fungicidal Concentration (MFC and time kill curve could be clinically more relevant than the determination of the Minimal Inhibitory Concentration (MIC. In this study, MIC and MFC to fluconazole, amphotericin B and caspofungin against C. albicans isolates and the killing patterns obtained with caspofungin and amphotericin B against susceptible and resistant strains to fluconazole were determined. The results of MICs showed that all C. albicans isolates were highly susceptible to amphotericin B, but two isolates were fluconazole resistant. The comparative analysis between MIC and MFC showed that MFC of fluconazole was fourfold higher than MIC in 41.9% of the C. albicans isolates. Same values of MFC and MIC of amphotericin B and caspofungin were found for 71% of the isolates. Correlation between time kill curves and MFC of amphotericin B and caspofungin against all 4 isolates tested was observed. The caspofungin killing effect was more evident at MFC in 6 hours of incubation than at MIC in this time, suggesting dependence of concentration. The similarity of results of time-kill curve and MFC values indicate that determination of MFC is an alternative for the detection of the fungicidal activity of these drugs.Um claro entendimento das propriedades farmacodinâmicas dos agentes antifúngicos é de grande importância para o adequado tratamento das infecções fúngicas como a candidíase. Em alguns casos de escolha do agente antifúngico, a determinação da concentração fungicida minima (CFM e a curva do tempo de morte podem ser mais clinicamente relevantes do que a concentração inibitória minima (CIM. Nesse estudo, foi avaliado a CIM e a CFM de fluconazol, anfotericina B e caspofungina em Candida albicans e ainda os padrões de

  12. Synthesis, antifungal activity of caffeic acid derivative esters, and their synergism with fluconazole and nystatin against Candida spp.

    Science.gov (United States)

    Sardi, Janaína de Cássia Orlandi; Gullo, Fernanda Patrícia; Freires, Irlan Almeida; Pitangui, Nayla de Souza; Segalla, Maicon Petrônio; Fusco-Almeida, Ana Marisa; Rosalen, Pedro Luiz; Regasini, Luís Octávio; Mendes-Giannini, Maria José Soares

    2016-12-01

    We tested the antifungal potential of caffeic acid and 8 of its derivative esters against Candidaalbicans ATCC 90028 and 9 clinical isolatesand carried out a synergism assay with fluconazole and nystatin. Propyl caffeate (C3) showed the best antifungal activity against the tested strains. When in combination, C3 markedly reduced the MIC of fluconazole and nystatin with synergistic effect up to 64-fold. Finally, C3 showed a high IC50 value and selective indexagainst oral keratinocytes, demonstrating low toxicity against this cell type and selectivity for yeast cells. Further research should confirm its antifungal potential for development of combined therapy to treat C. albicans infections. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Synthesis and biological evaluation of novel fluconazole analogues bearing 1,3,4-oxadiazole moiety as potent antifungal agents.

    Science.gov (United States)

    Liao, Jun; Yang, Fan; Zhang, Lei; Chai, Xiaoyun; Zhao, Qingjie; Yu, Shichong; Zou, Yan; Meng, Qingguo; Wu, Qiuye

    2015-04-01

    A novel series of fluconazole based mimics incorporating 1,3,4-oxadiazole moiety were designed and synthesized. All the title compounds were characterized by (1)H-NMR, (13)C-NMR, and Q-TOF-MS. Preliminary results revealed that most of analogues exhibited significant antifungal activity against seven pathogenic fungi. Compounds 9g and 9k (MIC80 ≤ 0.125 μg/mL, respectively) were found more potent than the positive controls itraconazole and fluconazole as broad-spectrum antifungal agents. The observed docking results showed that the 1,3,4-oxadiazole moiety enhanced the affinity binding to the cytochrome P450 14α-demethylase (CYP51).

  14. Unbound fraction of fluconazole and linezolid in human plasma as determined by ultrafiltration: Impact of membrane type.

    Science.gov (United States)

    Kratzer, Alexander; Kees, Frieder; Dorn, Christoph

    2016-12-15

    Ultrafiltration is a rapid and convenient method to determine the free concentrations of drugs in plasma. Several ultrafiltration devices based on Eppendorf cups are commercially available, but are not validated for such use by the manufacturer. Plasma pH, temperature and relative centrifugal force as well as membrane type can influence the results. In the present work, we developed an ultrafiltration method in order to determine the free concentrations of linezolid or fluconazole, both neutral and moderately lipophilic antiinfective drugs for parenteral as well as oral administration, in plasma of patients. Whereas both substances behaved relatively insensitive in human plasma regarding variations in pH (7.0-8.5), temperature (5-37°C) or relative centrifugal force (1000-10.000xg), losses of linezolid were observed with the Nanosep Omega device due to adsorption onto the polyethersulfone membrane (unbound fraction 75% at 100mg/L and 45% at 0.1mg/L, respectively). No losses were observed with Vivacon which is equipped with a membrane of regenerated cellulose. With fluconazole no differences between Nanosep and Vivacon were observed. Applying standard conditions (pH 7.4/37°C/1000xg/20min), the mean unbound fraction of linezolid in pooled plasma from healthy volunteers was 81.5±2.8% using Vivacon, that of fluconazole was 87.9±3.5% using Nanosep or 89.4±3.3% using Vivacon. The unbound fraction of linezolid was 85.4±3.7% in plasma samples from surgical patients and 92.1±6.2% in ICU patients, respectively. The unbound fraction of fluconazole was 93.9±3.3% in plasma samples from ICU patients.

  15. Network Meta-analysis and Pharmacoeconomic Evaluation of Fluconazole, Itraconazole, Posaconazole, and Voriconazole in Invasive Fungal Infection Prophylaxis.

    Science.gov (United States)

    Zhao, Ying Jiao; Khoo, Ai Leng; Tan, Gloria; Teng, Monica; Tee, Caroline; Tan, Ban Hock; Ong, Benjamin; Lim, Boon Peng; Chai, Louis Yi Ann

    2015-11-02

    Invasive fungal infections (IFIs) are associated with high mortality rates and large economic burdens. Triazole prophylaxis is used for at-risk patients with hematological malignancies or stem cell transplants. We evaluated both the efficacy and the cost-effectiveness of triazole prophylaxis. A network meta-analysis (NMA) of randomized controlled trials (RCTs) evaluating fluconazole, itraconazole capsule and solution, posaconazole, and voriconazole was conducted. The outcomes of interest included the incidences of IFIs and deaths. This was coupled with a cost-effectiveness analysis from patient perspective over a lifetime horizon. Probabilities of transitions between health states were derived from the NMA. Resource use and costs were obtained from the Singapore health care institution. Data on 5,505 participants in 21 RCTs were included. Other than itraconazole capsule, all triazole antifungals were effective in reducing IFIs. Posaconazole was better than fluconazole (odds ratio [OR], 0.35 [95% confidence interval [CI], 0.16 to 0.73]) and itraconazole capsule (OR, 0.25 [95% CI, 0.06 to 0.97]), but not voriconazole (OR, 1.31 [95% CI, 0.43 to 4.01]), in preventing IFIs. Posaconazole significantly reduced all-cause deaths, compared to placebo, fluconazole, and itraconazole solution (OR, 0.49 to 0.54 [95% CI, 0.28 to 0.88]). The incremental cost-effectiveness ratio for itraconazole solution was lower than that for posaconazole (Singapore dollars [SGD] 12,546 versus SGD 26,817 per IFI avoided and SGD 5,844 versus SGD 12,423 per LY saved) for transplant patients. For leukemia patients, itraconazole solution was the dominant strategy. Voriconazole was dominated by posaconazole. All triazole antifungals except itraconazole capsule were effective in preventing IFIs. Posaconazole was more efficacious in reducing IFIs and all-cause deaths than were fluconazole and itraconazole. Both itraconazole solution and posaconazole were cost-effective in the Singapore health care

  16. Cryptoccocal meningitis in Yaoundé (Cameroon) HIV infected patients: Diagnosis, frequency and Cryptococcus neoformans isolates susceptibility study to fluconazole.

    Science.gov (United States)

    Kammalac Ngouana, T; Dongtsa, J; Kouanfack, C; Tonfack, C; Fomena, S; Mallié, M; Delaporte, E; Boyom, F-Fekam; Bertout, S

    2015-03-01

    Cryptococcal meningitis is a mycosis encountered especially in patients with Acquired Immunodeficiency Syndrome and is fatal in the absence of treatment. Information on epidemiology, diagnosis and susceptibility profile to antifungal drugs, are scarce in Cameroon. Authors evaluated the diagnosis possibilities of the cryptococcal meningitis in Cameroon, and studied the antifungal susceptibility of isolated strains to fluconazole, used as first line treatment of the disease in Cameroon. Between December 2009 and July 2011, 146 cerebrospinal fluids obtained from HIV patients with suspicion of meningitis were analysed. The diagnosis procedure involved macroscopic and cyto-chemical analysis, India ink test, culture on Sabouraud chloramphenicol medium and antigen latex agglutination test. Antifungal susceptibility testing of isolated strains to fluconazole was done by the E-test(®) method. The diagnosis of cryptococcal meningitis gave 28.08% positive cases. Among these patients, 80% were at stages III and IV and 20% at stage I of the HIV infection, according to the WHO previous classification. Cyto-chemical analysis showed current findings in the case of cryptococcal meningitis. India ink test and latex agglutination test exhibited very high sensitivity and specificity (>94%). Fluconazole antifungal susceptibility testing gave MICs lower than 32μg/mL to 92.7% of isolated strains and MICs greater than this value to 7.3% of isolates. These results showed that cryptococcal meningitis remains a real problem among HIV infected patients in Yaoundé. The emergence of fluconazole reduced susceptibility strains is worrying. Nevertheless, efficacy of rapid detection tests is interesting because this will help in rapid diagnosis and treatment of patients.

  17. Activities of Fluconazole, Caspofungin, Anidulafungin, and Amphotericin B on Planktonic and Biofilm Candida Species Determined by Microcalorimetry

    Science.gov (United States)

    Maiolo, Elena Maryka; Furustrand Tafin, Ulrika; Borens, Olivier

    2014-01-01

    We investigated the activities of fluconazole, caspofungin, anidulafungin, and amphotericin B against Candida species in planktonic form and biofilms using a highly sensitive assay measuring growth-related heat production (microcalorimetry). C. albicans, C. glabrata, C. krusei, and C. parapsilosis were tested, and MICs were determined by the broth microdilution method. The antifungal activities were determined by isothermal microcalorimetry at 37°C in RPMI 1640. For planktonic Candida, heat flow was measured in the presence of antifungal dilutions for 24 h. Candida biofilm was formed on porous glass beads for 24 h and exposed to serial dilutions of antifungals for 24 h, and heat flow was measured for 48 h. The minimum heat inhibitory concentration (MHIC) was defined as the lowest antifungal concentration reducing the heat flow peak by ≥50% (≥90% for amphotericin B) at 24 h for planktonic Candida and at 48 h for Candida biofilms (measured also at 24 h). Fluconazole (planktonic MHICs, 0.25 to >512 μg/ml) and amphotericin B (planktonic MHICs, 0.25 to 1 μg/ml) showed higher MHICs than anidulafungin (planktonic MHICs, 0.015 to 0.5 μg/ml) and caspofungin (planktonic MHICs, 0.125 to 0.5 μg/ml). Against Candida species in biofilms, fluconazole's activity was reduced by >1,000-fold compared to its activity against the planktonic counterparts, whereas echinocandins and amphotericin B mainly preserved their activities. Fluconazole induced growth of planktonic C. krusei at sub-MICs. At high concentrations of caspofungin (>4 μg/ml), paradoxical growth of planktonic C. albicans and C. glabrata was observed. Microcalorimetry enabled real-time evaluation of antifungal activities against planktonic and biofilm Candida organisms. It can be used in the future to evaluate new antifungals and antifungal combinations and to study resistant strains. PMID:24566186

  18. Standardization of a fluconazole bioassay and correlation of results with those obtained by high-pressure liquid chromatography.

    OpenAIRE

    Rex, J H; Hanson, L H; Amantea, M A; Stevens, D.A.; BENNETT,J.E.

    1991-01-01

    An improved bioassay for fluconazole was developed. This assay is sensitive in the clinically relevant range (2 to 40 micrograms/ml) and analyzes plasma, serum, and cerebrospinal fluid specimens; bioassay results correlate with results obtained by high-pressure liquid chromatography (HPLC). Bioassay and HPLC analyses of spiked plasma, serum, and cerebrospinal fluid samples (run as unknowns) gave good agreement with expected values. Analysis of specimens from patients gave equivalent results b...

  19. Response surface methodology in drug design: A case study on docking analysis of a potent antifungal fluconazole.

    Science.gov (United States)

    Bohlooli, Fatemeh; Sepehri, Saghi; Razzaghi-Asl, Nima

    2017-04-01

    Molecular docking is a valuable in silico technique for discovery/design of bioactive compounds. A current challenge within docking simulations is the incorporation of receptor flexibility. A useful strategy toward solving such problem would be the docking of a typical ligand into the multiple conformations of the target. In this study, a multifactor response surface model was constructed to estimate the AutoDock based binding free energy of fluconazole within multiple conformations of 14α-demethylase (CYP51) (cross docking) as a validated antifungal target. On the basis of developed models, individual and interactive effects of important experimental parameters on cross docking of fluconazole were elucidated. For this purpose, a set of high-resolution holo crystallographic structures from CYP51 of human pathogen Trypanosoma cruzi were retrieved to statistically model the binding mode and affinity of fluconazole. The changes of AutoDock binding free energy for the complexes of CYP51-fluconazole were elucidated with the simultaneous variations of six independent variables including grid size, grid spacing, number of genetic algorithm (GA) runs, maximum number of energy evaluations, torsion degrees for ligand and quaternion degrees for ligand. It was revealed that grid spacing (distance between adjacent grid points) and maximum number of energy evaluations were two significant model terms. It was also revealed that grid size, torsion degrees for ligand and quaternion degrees for ligand had insignificant effects on estimated binding energy while the effect of GA runs was non-significant. The interactive effect of "torsion degrees for ligand" with number of GA runs was found to be the significant factor. Other important interactive effects were the interaction of "number of GA runs" with "grid spacing" and "number of energy evaluations" with "grid size". Furthermore; results of modeling studies within several CYP51 conformations exhibited that "number of GA runs" and

  20. Time to overcome fluconazole resistant Candida isolates: Solid lipid nanoparticles as a novel antifungal drug delivery system.

    Science.gov (United States)

    Moazeni, Maryam; Kelidari, Hamid Reza; Saeedi, Majid; Morteza-Semnani, Ketayoun; Nabili, Mojtaba; Gohar, Atefeh Abdollahi; Akbari, Jafar; Lotfali, Ensieh; Nokhodchi, Ali

    2016-06-01

    Antifungal therapy results in complications in management due to changes in the patterns of epidemiology and drug susceptibility of invasive fungal infections. In this study, we prepared fluconazole-loaded solid lipid nanoparticles (FLZ-SLNs) and investigated the efficacy of the optimal formulation on fluconazole (FLZ)-resistant strains of several Candida species. FLZ-SLN was produced using probe ultrasonication techniques. The morphology of the obtained SLNs was characterized by field emission scanning electron microscopy. The minimum inhibitory concentrations for the new formulations against fluconazole-resistant strains of Candida were investigated using CLSI document M27-A3. The FLZ-SLNs presented a spherical shape with a mean diameter, zeta potential and entrapment efficiency of 84.8nm, -25mV and 89.6%, respectively. The drug release from FLZ-SLNs exhibited burst release behaviour at the initial stage (the first 30min) followed by a sustained release over 24h FLZ-resistant yeast strains behaved as susceptible strains after treatment with FLZ-SLNs (≤8μg/ml). The MIC50 drug concentrations were 2μg/ml, 1μg/ml and 2μg/ml for FLZ-resistant strains of Candida albicans, Candida parapsilosis and Candida glabrata, respectively. In this study, we evaluated novel delivery systems for combating Candida strains that exhibit low susceptibility against the conventional formulation of FLZ as a first-line treatment.

  1. Antifungal peptides: a potential new class of antifungals for treating vulvovaginal candidiasis caused by fluconazole-resistant Candida albicans.

    Science.gov (United States)

    Ng, Siew Mei Samantha; Yap, Yi Yong Alvin; Cheong, Jin Wei Darryl; Ng, Fui Mee; Lau, Qiu Ying; Barkham, Timothy; Teo, Jeanette Woon Pei; Hill, Jeffrey; Chia, Cheng San Brian

    2017-03-01

    Vulvovaginal candidiasis/candidosis is a common fungal infection afflicting approximately 75% of women globally caused primarily by the yeast Candida albicans. Fluconazole is widely regarded as the antifungal drug of choice since its introduction in 1990 due to its high oral bioavailability, convenient dosing regimen and favourable safety profile. However, its widespread use has led to the emergence of fluconazole-resistant C. albicans, posing a universal clinical concern. Coupled to the dearth of new antifungal drugs entering the market, it is imperative to introduce new drug classes to counter this threat. Antimicrobial peptides (AMPs) are potential candidates due to their membrane-disrupting mechanism of action. By specifically targeting fungal membranes and being rapidly fungicidal, they can reduce the chances of resistance development and treatment duration. Towards this goal, we conducted a head-to-head comparison of 61 short linear AMPs from the literature to identify the peptide with the most potent activity against fluconazole-resistant C. albicans. The 11-residue peptide, P11-6, was identified and assayed against a panel of clinical C. albicans isolates followed by fungicidal/static determination and a time-kill assay to gauge its potential for further drug development. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

  2. Entomophthoramycosis by Conidiobolus coronatus. Report of a case successfully treated with the combination of itraconazole and fluconazole Entomoftoramicose por Conidiobolus coronatus. Relato de um caso tratado com a associação de itraconazol com fluconazol

    Directory of Open Access Journals (Sweden)

    Antonio Carlos Francesconi do VALLE

    2001-08-01

    Full Text Available Rhinoentomophthoramycosis caused by Conidiobolus coronatus in a 61-year old woman was unsuccessfully treated during 8 years with all the antifungals available in the Brazilian market, including potassium iodide for 1 month, sulfamethoxazole plus trimethoprim for 2 months, amphotericin B, total dose of 1130 mg, cetoconazole, 400 mg/day for 6 months, fluconazole, 200 mg/day, for at least 2 months and, itraconazole, 400 mg/day for 2 months, followed by 200 mg/day for 4 more months. Complete clinical and mycological cure was achieved using itraconazol 400 mg/day in association with fluconazol 200 mg/day during 24 months. After cure she was submitted to plastic surgery to repair her facial deformation. Today she remains clinically and mycologically cured after 59/60 months (5 years! without any specific antifungal. We thus suggest the use of the combination of itraconazole and fluconazole as an additional option for the treatment of this mycosis.É relatado um caso de rinoentomoftoramicose por Conidiobolus coronatus em mulher de 61 anos submetida a tratamento com todos os antifúngicos disponíveis no mercado brasileiro, durante 8 anos, sem sucesso, incluindo iodeto de potássio por 1 mês, sulfametoxazol associado ao trimetoprim por 2 meses, anfotericina B em dose total de 1130 mg, cetoconazol, 400 mg/dia por 6 meses, fluconazol, 200 mg/dia, por pelo menos 2 meses, e itraconazol, 400 mg/dia, por 2 meses, seguido de 200 mg/dia por mais 4 meses. A cura clínica e micológica completa foi obtida com a associação de itraconazol 400mg/dia com fluconazol 200 mg/dia, durante 24 meses. Após a cura a paciente foi submetida a cirurgia restauradora. Atualmente a paciente encontra-se há 59 meses sem medicação específica permanecendo clínica e micologicamente curada.

  3. Effect of system variables involved in packed column SFC of nevirapine as model analyte using response surface methodology: application to retention thermodynamics, solute transfer kinetic study and binary diffusion coefficient determination.

    Science.gov (United States)

    Kaul, Neerej; Agrawal, Himani; Paradkar, A R; Mahadik, K R

    2005-08-31

    A multifactor optimization technique is successfully applied to study the effect of simultaneously varying the system variables on feasibility of nevirapine analysis by packed column supercritical fluid chromatography (PC-SFC). The optimal conditions were determined with the aid of the response surface methodology using 3(3) factorial designs. The method is based on methanol-modified carbon dioxide as the mobile phase at flow rate of 3.0 ml/min with elution through a JASCO Finepak SIL-5, [C18 (5-micron, 25 cm x 4.6 mm, i.d.)] column using photodiode array detection. The method has been successfully used to analyze commercial solid dosage form to assess the chromatographic performance of SFC system. The present work briefs the thermodynamic applications of PC-SFC with an emphasis on the results of nevirapine. The foremost of such applications is the determination of solute diffusion coefficient in supercritical mobile phase by Taylor-Aris peak broadening technique.

  4. Comportamento de amostras ambientais e clínicas de Cryptococcus neoformans frente a fungicidas de uso agronômico e ao fluconazol Behaviour azole fungicide and fluconazole in Cryptococcus neoformans clinical and environmental isolates

    Directory of Open Access Journals (Sweden)

    Elislene Dias Drummond

    2007-04-01

    Full Text Available Avaliou-se a atividade de fungicidas azólicos de uso agronômico (epoxiconazol, difenoconazol e ciproconazol em comparação ao antifúngico de uso terapêutico fluconazol sobre 23 amostras ambientais de Cryptococcus neoformans var neoformans isoladas de fezes de pombos, as quais foram coletadas em fazendas com práticas agrícolas empregando compostos azólicos e 11 amostras clínicas isoladas de pacientes portadores de criptococose. Os testes de sensibilidade foram realizados pela técnica de diluição em agar. A concentração inibitória mínima capaz de inibir 50% dos isolados ambientais (CIM 50 foi de 6,0µg/mL para epoxiconazol, 1,0µg/mL para difenoconazol, 2,0µg/mL para ciproconazol e 64,0µg/mL para fluconazol. Entre os isolados clínicos os valores de CIM 50 foram 2,0µg/mL, 0,38µg/mL, 1,0µg/mL e 16,0µg/mL para epoxiconazol, difenoconazol, ciproconazol e fluconazol, respectivamente. Os valores de CIM 50 em relação aos isolados de origem ambiental foram maiores do que os valores para os isolados de origem clínica. Em nosso estudo, frente ao mesmo antifúngico, as amostras ambientais apresentaram comportamento significativamente diferente em relação às amostras clínicas (p The activity of azole fungicides for agronomical use (epoxiconazole, difenoconazole and cyproconazole was evaluated in comparison with the therapeutic antifungal agent fluconazole, on 23 environmental samples of Cryptococcus neoformans var neoformans isolated from pigeon feces that were collected from farms with agricultural practices using azole compounds, and on 11 clinical samples isolated from patients with cryptococcosis. Sensitivity tests were performed using the agar dilution technique. The minimum inhibitory concentration capable of inhibiting 50% of the environmental isolates (MIC 50 was 6.00µg/ml to epoxiconazole, 1.00µg/ml for difenoconazole, 2.00µg/ml for cyproconazole and 64.00µg/ml for fluconazole. Among the clinical isolates the MIC 50

  5. Efficacy of the clinical agent VT-1161 against fluconazole-sensitive and -resistant Candida albicans in a murine model of vaginal candidiasis.

    Science.gov (United States)

    Garvey, E P; Hoekstra, W J; Schotzinger, R J; Sobel, J D; Lilly, E A; Fidel, P L

    2015-09-01

    Vulvovaginal candidiasis (VVC) and recurrent VVC (RVVC) remain major health problems for women. VT-1161, a novel fungal CYP51 inhibitor which has potent antifungal activity against fluconazole-sensitive Candida albicans, retained its in vitro potency (MIC50 of ≤0.015 and MIC90 of 0.12 μg/ml) against 10 clinical isolates from VVC or RVVC patients resistant to fluconazole (MIC50 of 8 and MIC90 of 64 μg/ml). VT-1161 pharmacokinetics in mice displayed a high volume of distribution (1.4 liters/kg), high oral absorption (73%), and a long half-life (>48 h) and showed rapid penetration into vaginal tissue. In a murine model of vaginal candidiasis using fluconazole-sensitive yeast, oral doses as low as 4 mg/kg VT-1161 significantly reduced the fungal burden 1 and 4 days posttreatment (P fluconazole (MIC of 64 μg/ml) but fully sensitive in vitro to VT-1161 was used. When an isolate partially sensitive to VT-1161 (MIC of 0.12 μg/ml) and moderately resistant to fluconazole (MIC of 8 μg/ml) was used, VT-1161 remained efficacious, whereas fluconazole was efficacious on day 1 but did not sustain efficacy 4 days posttreatment. Both agents were inactive in treating an infection with an isolate that demonstrated weaker potency (MICs of 2 and 64 μg/ml for VT-1161 and fluconazole, respectively). Finally, the plasma concentrations of free VT-1161 were predictive of efficacy when in excess of the in vitro MIC values. These data support the clinical development of VT-1161 as a potentially more efficacious treatment for VVC and RVVC.

  6. Species distribution and susceptibility profile to fluconazole, voriconazole and MXP-4509 of 551 clinical yeast isolates from a Romanian multi-centre study.

    Science.gov (United States)

    Minea, B; Nastasa, V; Moraru, R F; Kolecka, A; Flonta, M M; Marincu, I; Man, A; Toma, F; Lupse, M; Doroftei, B; Marangoci, N; Pinteala, M; Boekhout, T; Mares, M

    2015-02-01

    This is the first multi-centre study regarding yeast infections in Romania. The aim was to determine the aetiological spectrum and susceptibility pattern to fluconazole, voriconazole and the novel compound MXP-4509. The 551 isolates were identified using routine laboratory methods, matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS) and DNA sequence analysis. Susceptibility testing was performed using the European Committee for Antimicrobial Susceptibility Testing (EUCAST) method and breakpoints. The yeasts originated from superficial infections (SUP, 51.5 %), bloodstream infections (BSI, 31.6 %) and deep-seated infections (DEEP, 16.9 %), from patients of all ages. Nine genera and 30 species were identified. The 20 Candida species accounted for 94.6 % of all isolates. C. albicans was the overall leading pathogen (50.5 %). Lodderomyces elongisporus is reported for the first time as a fungaemia cause in Europe. C. glabrata and Saccharomyces cerevisiae, as well as the non-Candida spp. and non-albicans Candida spp. groups, showed decreased fluconazole susceptibility (fluconazole resistance was 10.2 %. C. krusei accounted for 27 of the 56 fluconazole-resistant isolates. The overall voriconazole resistance was 2.5 % and was due mainly to C. glabrata and C. tropicalis isolates. Fluconazole resistance rates for the three categories of infection were similar to the overall value; voriconazole resistance rates differed: 4 % for BSI, 3.2 % for DEEP and 1.4 % for SUP. The antifungal activity of MXP-4509 was superior to voriconazole against C. glabrata and many fluconazole-resistant isolates. There was a large percentage of non-albicans Candida isolates. A large part of the high fluconazole resistance was not acquired but intrinsic, resulting from the high percentage of C. krusei.

  7. A tetraploid intermediate precedes aneuploid formation in yeasts exposed to fluconazole.

    Science.gov (United States)

    Harrison, Benjamin D; Hashemi, Jordan; Bibi, Maayan; Pulver, Rebecca; Bavli, Danny; Nahmias, Yaakov; Wellington, Melanie; Sapiro, Guillermo; Berman, Judith

    2014-03-01

    Candida albicans, the most prevalent human fungal pathogen, is generally diploid. However, 50% of isolates that are resistant to fluconazole (FLC), the most widely used antifungal, are aneuploid and some aneuploidies can confer FLC resistance. To ask if FLC exposure causes or only selects for aneuploidy, we analyzed diploid strains during exposure to FLC using flow cytometry and epifluorescence microscopy. FLC exposure caused a consistent deviation from normal cell cycle regulation: nuclear and spindle cycles initiated prior to bud emergence, leading to "trimeras," three connected cells composed of a mother, daughter, and granddaughter bud. Initially binucleate, trimeras underwent coordinated nuclear division yielding four daughter nuclei, two of which underwent mitotic collapse to form a tetraploid cell with extra spindle components. In subsequent cell cycles, the abnormal number of spindles resulted in unequal DNA segregation and viable aneuploid progeny. The process of aneuploid formation in C. albicans is highly reminiscent of early stages in human tumorigenesis in that aneuploidy arises through a tetraploid intermediate and subsequent unequal DNA segregation driven by multiple spindles coupled with a subsequent selective advantage conferred by at least some aneuploidies during growth under stress. Finally, trimera formation was detected in response to other azole antifungals, in related Candida species, and in an in vivo model for Candida infection, suggesting that aneuploids arise due to azole treatment of several pathogenic yeasts and that this can occur during the infection process.

  8. Preparation of fluconazole buccal tablet and influence of formulation expedients on its properties

    Institute of Scientific and Technical Information of China (English)

    MOHAMED Saifulla P; MUZZAMMIL Shariff; PRAMOD Kumar TM

    2011-01-01

    The aim of present study was to prepare buccal tablets of fluconazole for oral candidiasis.The dosage forms were designed to release the drug above the minimum inhibitory concentration for prolonged period of time so as to reduce the frequency of administration and to overcome the side effects of systemic treatment.The buccal tablets were prepared by using Carbopol 71G and Noveon AA-1 by direct compression method.Microcrystalline cellulose was used as the filler and its effect was also studied.The prepared dosage forms were evaluated for physicochemical properties,in vitro release studies and mueoadhesive properties using sheep buccal mucosa as a model tissue.Tablets containing 50% of polymers(Carbopol & Noveon)were found to be the best with moderate swelling along with favorable bioadhesion force,residence time and in vitro drug release.The in vitro drug release studies revealed that drug released for 8 h,which in turn may reduce dosing frequency and improved patient compliance in oral candidiasis patients.

  9. A tetraploid intermediate precedes aneuploid formation in yeasts exposed to fluconazole.

    Directory of Open Access Journals (Sweden)

    Benjamin D Harrison

    2014-03-01

    Full Text Available Candida albicans, the most prevalent human fungal pathogen, is generally diploid. However, 50% of isolates that are resistant to fluconazole (FLC, the most widely used antifungal, are aneuploid and some aneuploidies can confer FLC resistance. To ask if FLC exposure causes or only selects for aneuploidy, we analyzed diploid strains during exposure to FLC using flow cytometry and epifluorescence microscopy. FLC exposure caused a consistent deviation from normal cell cycle regulation: nuclear and spindle cycles initiated prior to bud emergence, leading to "trimeras," three connected cells composed of a mother, daughter, and granddaughter bud. Initially binucleate, trimeras underwent coordinated nuclear division yielding four daughter nuclei, two of which underwent mitotic collapse to form a tetraploid cell with extra spindle components. In subsequent cell cycles, the abnormal number of spindles resulted in unequal DNA segregation and viable aneuploid progeny. The process of aneuploid formation in C. albicans is highly reminiscent of early stages in human tumorigenesis in that aneuploidy arises through a tetraploid intermediate and subsequent unequal DNA segregation driven by multiple spindles coupled with a subsequent selective advantage conferred by at least some aneuploidies during growth under stress. Finally, trimera formation was detected in response to other azole antifungals, in related Candida species, and in an in vivo model for Candida infection, suggesting that aneuploids arise due to azole treatment of several pathogenic yeasts and that this can occur during the infection process.

  10. Flucytosine + fluconazole association in the treatment of a murine experimental model of cryptococcosis

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    A. J. Bava

    1994-12-01

    Full Text Available The efficacy of flucytosine (5-FC and fluconazole (FLU association in the treatment of a murine experimental model of cryptococcosis, was evaluated. Seven groups of 10 Balb C mice each, were intraperitoneally inoculated with 10(7 cells of Cryptococcus neoformans. Six groups were allocated to receive 5-FC (300 mg/kg and FLU (16 mg/ kg, either combined and individually, by daily gavage beginning 5 days after the infection, for 2 and 4 weeks. One group received distilled water and was used as control. The evaluation of treatments was based on: survival time; macroscopic examination of brain, lungs, liver and spleen at autopsy; presence of capsulated yeasts in microscopic examination of wet preparations of these organs and cultures of brain homogenate. 5-FC and FLU, individually or combined, significantly prolonged the survival time of the treated animals with respect to the control group (p<0.01. Animals treated for 4 weeks survived significantly longer than those treated for 2 weeks (p<0.01. No significant differences between the animals treated with 5-FC and FLU combined or separately were observed in the survival time and morphological parameters. The association of 5-FC and FLU does not seem to be more effective than 5-FC or FLU alone, in the treatment of this experimental model of cryptococcosis.

  11. Evidence of Fluconazole-Resistant Candida Species in Tortoises and Sea Turtles.

    Science.gov (United States)

    Brilhante, Raimunda Sâmia Nogueira; Rodrigues, Pedro Henrique de Aragão; de Alencar, Lucas Pereira; Riello, Giovanna Barbosa; Ribeiro, Joyce Fonteles; de Oliveira, Jonathas Sales; Castelo-Branco, Débora de Souza Collares Maia; Bandeira, Tereza de Jesus Pinheiro Gomes; Monteiro, André Jalles; Rocha, Marcos Fábio Gadelha; Cordeiro, Rossana de Aguiar; Moreira, José Luciano Bezerra; Sidrim, José Júlio Costa

    2015-12-01

    The aim of this study was to evaluate the antifungal susceptibility of Candida spp. recovered from tortoises (Chelonoidis spp.) and sea turtles (Chelonia mydas, Caretta caretta, Lepidochelys olivacea, Eretmochelys imbricata). For this purpose, material from the oral cavity and cloaca of 77 animals (60 tortoises and 17 sea turtles) was collected. The collected specimens were seeded on 2% Sabouraud dextrose agar with chloramphenicol, and the identification was carried out by morphological and biochemical methods. Sixty-six isolates were recovered from tortoises, out of which 27 were C. tropicalis, 27 C. famata, 7 C. albicans, 4 C. guilliermondii and 1 C. intermedia, whereas 12 strains were obtained from sea turtles, which were identified as Candida parapsilosis (n = 4), Candida guilliermondii (n = 4), Candida tropicalis (n = 2), Candida albicans (n = 1) and Candida intermedia (n = 1). The minimum inhibitory concentrations for amphotericin B, itraconazole and fluconazole ranged from 0.03125 to 0.5, 0.03125 to >16 and 0.125 to >64, respectively. Overall, 19 azole-resistant strains (14 C. tropicalis and 5 C. albicans) were found. Thus, this study shows that Testudines carry azole-resistant Candida spp.

  12. Effects of Lamellar Keratectomy and Intrastromal Injection of 0.2% Fluconazole on Fungal Keratitis

    Directory of Open Access Journals (Sweden)

    Xinying You

    2015-01-01

    Full Text Available Purpose. To evaluate effects of lamellar keratectomy and intrastromal injection of 0.2% fluconazole (LKIIF on fungal keratitis. Methods. Data for 54 eyes of consecutive patients with fungal keratitis treated with LKIIF were retrospectively analyzed. The lesions in these eyes did not heal or were aggravated after antifungal chemotherapy for 7 days. The maximum lesion diameters were ≤5 mm and maximum depth was not more than half of full corneal thickness. Cases were followed up for at least 90 days. Results. Forty-six eyes were cured (85.2%. The wound healing times were 3–16 days and were less than 7 days in 28 cases (51.9%. In cured eyes, uncorrected visual acuity (UCVA and best-corrected visual acuity (BCVA were both 20/250–20/20. The UCVA improved in 38 eyes and was unchanged in seven eyes. BCVA improved in 44 eyes and was unchanged in two eyes. When followed up for more than 90 days, 89% (41 of 46 eyes showed improvement in UCVA and 11% were unchanged. Regarding BCVA, 98% improved and one eye was unchanged. No other complications were observed except neovascularization in one eye and thinner corneas. Conclusions. LKIIF was quick and effective for small fungal keratitis confined to half of the corneal thickness.

  13. In vitro activity of Caspofungin combined with Fluconazole on mixed Candida albicans and Candida glabrata biofilm.

    Science.gov (United States)

    Pesee, Siripen; Angkananuwat, Chayanit; Tancharoensukjit, Sudarat; Muanmai, Somporn; Sirivan, Pattaraporn; Bubphawas, Manita; Tanarerkchai, Nissara

    2016-05-01

    The objective of this study was to evaluate the antifungal effect of caspofungin (CAS) combined with fluconazole (FLU) on the biofilm biomass and cultivable viability and microstructure of Candida albicans and Candida glabrata mixed biofilm in vitro.Biofilms were formed in a 96-well microtiter plate for crystal violet assay and colony forming unit (CFU) method and grown on plastic coverslip disks for scanning electron microscopy. MIC50 of CAS and FLU against single Candida spp.and mixed Candida spp.biofilms were evaluated using crystal violet assay. Additional,C. albicans and C. glabrata mixed biofilms were incubated with subinhibitory CAS concentration plus FLU and their percentages of Candida biofilm reduction were calculated. We found that percentages of biofilm reduction were significantly decreased when CAS at 0.25MIC and FLU (0.25 or 0.5MIC) were combined (PCandida glabrata were demonstrated in every group, the total viable cells derived from CAS/FLU combination-treated biofilms at any ratio were not significantly different from positive control. Overall, CAS/FLU combinations appeared to affect the quantity and cell architecture, but number of viable cell, of Candida albicans and Candida glabrata mixed biofilm. This antifungal effect was CAS concentration dependent.

  14. Hydrogen ADPs with Cu Kα data? Invariom and Hirshfeld atom modelling of fluconazole.

    Science.gov (United States)

    Orben, Claudia M; Dittrich, Birger

    2014-06-01

    For the structure of fluconazole [systematic name: 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol] monohydrate, C13H12F2N6O·H2O, a case study on different model refinements is reported, based on single-crystal X-ray diffraction data measured at 100 K with Cu Kα radiation to a resolution of sin θ/λ of 0.6 Å(-1). The structure, anisotropic displacement parameters (ADPs) and figures of merit from the independent atom model are compared to `invariom' and `Hirshfeld atom' refinements. Changing from a spherical to an aspherical atom model lowers the figures of merit and improves both the accuracy and the precision of the geometrical parameters. Differences between results from the two aspherical-atom refinements are small. However, a refinement of ADPs for H atoms is only possible with the Hirshfeld atom density model. It gives meaningful results even at a resolution of 0.6 Å(-1), but requires good low-order data.

  15. Calcium-activated-calcineurin reduces the In vitro and In vivo sensitivity of fluconazole to Candida albicans via Rta2p.

    Directory of Open Access Journals (Sweden)

    Yu Jia

    Full Text Available Due to the emergence of drug-resistance, first-line therapy with fluconazole (FLC increasingly resulted in clinical failure for the treatment of candidemia. Our previous studies found that in vitro RTA2 was involved in the calcineurin-mediated resistance to FLC in C. albicans. In this study, we found that calcium-activated-calcineurin significantly reduced the in vitro sensitivity of C. albicans to FLC by blocking the impairment of FLC to the plasma membrane via Rta2p. Furthermore, we found that RTA2 itself was not involved in C. albicans virulence, but the disruption of RTA2 dramatically increased the therapeutic efficacy of FLC in a murine model of systemic candidiasis. Conversely, both re-introduction of one RTA2 allele and ectopic expression of RTA2 significantly reduced FLC efficacy in a mammalian host. Finally, we found that calcium-activated-calcineurin, through its target Rta2p, dramatically reduced the efficacy of FLC against candidemia. Given the critical roles of Rta2p in controlling the efficacy of FLC, Rta2p can be a potential drug target for antifungal therapies.

  16. Comparison of fluconazole pharmacokinetics in serum, aqueous humor, vitreous humor, and cerebrospinal fluid following a single dose and at steady state.

    Science.gov (United States)

    Mian, U K; Mayers, M; Garg, Y; Liu, Q F; Newcomer, G; Madu, C; Liu, W; Louie, A; Miller, M H

    1998-10-01

    The objective of this study was to characterize the pharmacokinetic parameters and penetration of fluconazole following a single dose in the serum, aqueous humor, vitreous humor and cerebrospinal fluid (CSF) of non pigmented rabbits using serial sampling techniques and to determine if the pharmacokinetic parameters in the eye and CSF are similar. Twenty healthy male rabbits received intravenous fluconazole 20 mg/kg as a single dose or 20 mg/kg every 12 hours for 4 doses. Serum, aqueous humor, vitreous humor and CSF samples were taken 15 minutes after the initial intravenous injection and hourly thereafter for six hours. Fluconazole concentrations were determined by microbiological assay. Pharmacokinetic analyses were performed using a nonlinear least-square regression program. Fluconazole's penetration in all anatomical compartments was > 70% than in the serum. Similar elimination half-lives and time to reach maximum concentrations were noted in all compartments. While mean concentrations in each anatomical compartment were similar in animals receiving a single dose or among those at serum steady state, the mean concentrations achieved in the serum, aqueous and vitreous humors and CSF were between 1.82 and 2.17 times higher at serum steady state than following a single dose. At serum concentrations that are comparable to those in humans, the penetration of fluconazole into the noninflamed aqueous and vitreous humors and CSF were > or = 70%. The CSF and ocular pharmacokinetic parameters closely resembled each other, so that either could be used as a surrogate for the other.

  17. Overexpression and mutation as a genetic mechanism of fluconazole resistance in Candida albicans isolated from human immunodeficiency virus patients in Indonesia.

    Science.gov (United States)

    Rosana, Yeva; Yasmon, Andi; Lestari, Delly Chipta

    2015-09-01

    Fluconazole is the standard treatment for oropharyngeal candidiasis, which is the third most common opportunistic infection in human immunodeficiency virus (HIV)/AIDS patients in Indonesia. Overuse of this drug could lead to the emergence of resistance. The objective of this study was to analyse the role of ERG11, CDR1, CDR2 and MDR1 gene overexpression and mutations in the ERG11 gene as a genetic mechanism of fluconazole resistance in Candida albicans isolated from HIV patients in Indonesia. Overexpression of ERG11, CDR1, CDR2 and MDR1 was analysed by real-time reverse transcription PCR, while ERG11 gene mutation analysis was performed using sequencing methods. Seventeen isolates out of 92 strains of C. albicans isolated from 108 HIV patients were found to be resistant to azole antifungals. The highest gene overexpression of ERG11 was found in C. albicans resistant to single fluconazole, while the highest gene overexpression of CDR2 was detected in all isolates of C. albicans resistant to multiple azoles. Amino acid substitutions were observed at six positions, i.e. D116E, D153E, I261V, E266D, V437I and V488I. The amino acid substitution I261V was identified in this study and was probably associated with fluconazole resistance. The combination of overexpression of CDR2 and ERG11 and mutation in the ERG11 gene was found to be a genetic mechanism of fluconazole resistance in C. albicans isolated from HIV patients in Indonesia.

  18. Comparing two service delivery models for the prevention of mother-to-child transmission (PMTCT of HIV during transition from single-dose nevirapine to multi-drug antiretroviral regimens

    Directory of Open Access Journals (Sweden)

    Mugwaneza Placidie

    2010-12-01

    Full Text Available Abstract Background Mother-to-child transmission (MTCT of HIV has been eliminated from the developed world with the introduction of multi-drug antiretroviral (md-ARV regimens for the prevention of MTCT (PMTCT; but remains the major cause of HIV infection among sub-Saharan African children. This study compares two service delivery models of PMTCT interventions and documents the lessons learned and the challenges encountered during the transition from single-dose nevirapine (sd-nvp to md-ARV regimens in a resource-limited setting. Methods Program data collected from 32 clinical sites was used to describe trends and compare the performance (uptake of HIV testing, CD4 screening and ARV regimens initiated during pregnancy of sites providing PMTCT as a stand-alone service (stand-alone site versus sites providing PMTCT as well as antiretroviral therapy (ART (full package site. CD4 cell count screening, enrolment into ART services and the initiation of md-ARV regimens during pregnancy, including dual (zidovudine [AZT] +sd-nvp prophylaxis and highly active antiretroviral therapy (HAART were analysed. Results From July 2006 to December 2008, 1,622 pregnant women tested HIV positive (HIV+ during antenatal care (ANC. CD4 cell count screening during pregnancy increased from 60% to 70%, and the initiation of md-ARV regimens increased from 35.5% to 97% during this period. In 2008, women attending ANC at full package sites were 30% more likely to undergo CD4 cell count assessment during pregnancy than women attending stand-alone sites (relative risk (RR = 1.3; 95% confidence interval (CI: 1.1-1.4. Enrolment of HIV+ pregnant women in ART services was almost twice as likely at full package sites than at stand-alone sites (RR = 1.9; 95% CI: 1.5-2.3. However, no significant differences were detected between the two models of care in providing md-ARV (RR = 0.9; 95% CI: 0.9-1.0. Conclusions All sites successfully transitioned from sd-nvp to md-ARV regimens for PMTCT

  19. Arachidonic acid affects biofilm formation and PGE2 level in Candida albicans and non-albicans species in presence of subinhibitory concentration of fluconazole and terbinafine.

    Science.gov (United States)

    Mishra, Nripendra Nath; Ali, Shakir; Shukla, Praveen K

    2014-01-01

    Candida albicans utilizes arachidonic acid (AA) released during the course of infection (Candidiasis) from phospholipids of infected host cell membranes and synthesizes extracellular prostaglandin(s) which play an important role in hyphae formation and host cell damage. C. albicans biofilms secrete significantly more prostaglandin(s) and evidence suggests that Candida biofilms have dramatically reduced susceptibility to majority of antifungal drugs. AA influences the saturation level of lipids and fluidity of yeast cell membranes. Therefore the aim of this study was to evaluate the effect of AA alone or in combination with antifungal agents on biofilm formation and production of prostaglandin (PGE2) in C. albicans, C. parapsilosis, C. glabrata, C. tropicalis, and C. albicans amphotericin B resistant strain (AmBR). Maximum biofilm formation was found to be in the case of C. albicans compared to C. non-albicans species. However, among the non-albicans species C. tropicalis exhibited highest biofilm formation. Treatment with AA in combination with subinhibitory concentrations of fluconazole and terbinafine separately exhibited significant (p<0.05) reduction in biofilm formation against C. glabrata, C. parapsilosis, C. tropicalis and AmBR as compared to their individual effect. Further, these two antifungal agents in combination with AA caused an increase in production of prostaglandin from fungal cell itself which was significant (p<0.05) in case of all the strains tested.

  20. Determination of Fluconazole capsules by HPLC%HPLC法测定氟康唑胶囊的含量

    Institute of Scientific and Technical Information of China (English)

    张莉

    2012-01-01

      Objective Purpose Fluconazole capsule content was determinated by HPLC.Methods C18 column with methanol - phosphate buffer (pH 7.0) (45∶55) as mobile phase,The flow rate was 1.0 mL/min,detection wavelength of 261 nm,column temperature of 30℃.Results Fluconazole in 0.123 4~0.987 6 mg/mL within the range of peak area showed good linear relationship,r=0.999 2,average recovery was 98.9%.Conclusion The HPLC method is accurate, reliable, reproducible, which can be used as a method for the determination of the content of fluconazole capsule.%  目的建立氟康唑胶囊含量测定的高效液相色谱方法(HPLC).方法采用C18色谱柱,以甲醇-磷酸盐缓冲液(pH 7.0)(45∶55)为流动相,流速为1.0 mL/min,检测波长为261 nm,柱温为30℃.结果氟康唑在0.1234~0.9876 mg/mL范围内与峰面积呈良好的线性关系,r=0.9992,平均加样回收率为98.9%.结论HPLC法准确、可靠、重复性好,可作为氟康唑胶囊的含量测定方法.

  1. Combined intrastromal injection of amphotericin B and topical fluconazole in the treatment of resistant cases of keratomycosis: a retrospective study.

    Science.gov (United States)

    Nada, Waled Mahdy; Al Aswad, Mahmoud A; El-Haig, Wael M

    2017-01-01

    To evaluate the efficacy of combination therapy of a single intrastromal injection of amphotericin B and topical fluconazole in resistant cases of fungal keratitis, and also topical amphotericin B as monotherapy in terms of the duration of the recovery period and toxic drug effects. This retrospective 2-year study reviewed 68 cases of unilateral fungal keratitis diagnosed by clinical features and positive laboratory culture results. Forty-one cases were resistant and did not respond to monotherapy with an antifungal agent. Thus, they were treated with a single intrastromal injection of amphotericin B in addition to topical fluconazole as combined antifungal therapy, representing group A. Twenty-seven cases were treated with topical amphotericin B as antifungal monotherapy, representing group B. Topical atropine 1% and different antibiotic eye drops were added to the antifungal agents in both groups. Follow-up of patient records was performed monitoring cure rate, duration of recovery period, and toxic drug effects such as pain, burning sensation, and corneal melting. The results revealed that group A, treated with combination therapy, showed recovery of 34 cases (82.9%) with a mean duration of 24±6.42 days, significantly different from group B which showed recovery of 16 cases (59.3%) with a mean duration of 39.66±13.6 days. Group A also showed less manifestation of drug toxicity than group B. Combined intrastromal injection of amphotericin B and topical fluconazole can provide a good modality in the treatment of resistant cases of fungal keratitis, exhibiting highly potent antifungal effects, shorter recovery period, and reduced corneal toxicity.

  2. A376S in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy

    DEFF Research Database (Denmark)

    Paredes, Roger; Puertas, Maria Carmen; Bannister, Wendy

    2011-01-01

    Background. The clinical relevance of mutations in the connection subdomain and the ribonuclease (RNase) H domain of HIV-1 reverse transcriptase (RT) is uncertain. Methods. The risk of virological failure to nonnucleoside RT inhibitor (NNRTI)-based antiretroviral therapy (ART) was evaluated in NN...

  3. ROLE OF FLUCONAZOLE IN THE PREVENTION OF RADIATION-INDUCED MUCOSITIS IN HEAD AND NECK CANCER PATIENTS

    Directory of Open Access Journals (Sweden)

    Mukesh Shanthilal

    2016-07-01

    Full Text Available BACKGROUND This study is aimed to evaluate the effect of fluconazole on prevention of oral candidacies and in reduction of severity of oral mucositis induced by radiotherapy. METHODS The study was conducted on 48 head and neck cancers patients. Cases were randomised into study (22/48 and control groups (26/48. Both groups received radiotherapy with or without chemotherapy. Oral swabs were collected before start of radiation three weeks later and at the end of radiation. Oral swabs were cultured for candidial growth. Study group patients received oral fluconazole 50 mg/day throughout the course of radiation and control group patients received no fluconazole prophylaxis. Patients were examined weekly for oral mucositis and were graded according to CTC version 2.0. RESULTS Oral swabs were taken from all patients before start of radiotherapy showed candidial growth in 22.9% (11/48. During the course of radiation treatment, oral candidial culture was positive in 42.3% (11/26 of control group patients and 40.9% (9/22 of study group (p=0.644. There was statistically significant reduction in the severity of mucositis in the study arm (p=0.021. In the study arm, there was grade 0 in 27.2% (6/22, grade 1 in 27.2% (6/22, grade 2 in 31.8% (7/22, grade 3 in 22.7% (5/22, and no grade 4. In the control arm, there was no grade 0 noted, grade 1 was seen in 19.2% (5/26, grade 2 in 61.5% (16/26, grade 3 in 15.3% (4/26, and no grade 4. Patients in whom candidial culture was negative had less severe mucositis as compared to patients with positive candidial culture (p=0.029. CONCLUSION Prophylactic use of oral fluconazole is effective in reducing the severity of oral mucositis by reducing oral candidiasis.

  4. In vitro Susceptibility of Fluconazole, Clotrimazole and Toucrium Polium Smoke Product on Candida Isolates of Vaginal Candidiasis

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    B Bonyadpour

    2009-07-01

    Full Text Available ABSTRACT: Introduction & Objective: It has been estimated that up to 75% of women in their child-bearing age have been affected by vulvovaginal candidiasis at least once in their life time. Almost 45% of women experience this infection two or more times. The antifungal azole group, in topical and oral forms, is the common way of therapy. Herbal products are often used for vulvovaginal therapy. Nowadays, Toucrium polium (TP products are being used as traditional medicine to reduce signs of Candida vaginitis. There is no study regarding to antifungal activity of TP smoke product in Iran. The aim of this study was to evaluate the In vitro activity of TP smoke product against Candida, isolated from women with Candida vaginitis, compared with antifungal drugs which are ordinary used to cure Candida vaginitis. Materials & Methods: The present study was conducted at the University of Medical Sciences of Shiraz in 1387 (2008. During seven months, samples were taken from 450 patients suffering from urogenital infections and 105 Candida vaginitis were detected. Germ tube test was used for identification of fungal species. TP smoke product was prepared in suitable potency. Antifungal activity of fluconazole, clotrimazole and TP product were evaluated by disk diffusion method. Sterile blank disks were loaded by TP smoke product in potency of 10-240 microliter/disk. Inhibition zone around the disks were measured and compared with each other. Results: 105 Candida species were isolated from the patients. Candida species were identified by germ tube test as Candida albicans 74 (70.5% and Candida non-albicans 31(29.5%.The mean of inhibition zone around the clotrimazole disks was 22±5.39 along with one case of resistance. Forty seven species had resistance to fluconazole while 94% and 55.2.% of all samples were sensitive to clotrimazole and fluconazole respectively. All of the clinical isolates and standard Candida species were sensitive to TP smoke product

  5. Multi-nucleoside reverse transcriptase inhibitor resistant HIV type-1 in a patient from Sierra Leone failing stavudine, lamivudine and nevirapine.

    Science.gov (United States)

    Hamers, Raph L; Wensing, Annemarie Mj; Back, Nicole Kt; Arcilla, Maria S; Frissen, Jos Ph

    2011-01-01

    We report a 33-year-old HIV type-1 (HIV-1)-infected male from Sierra Leone who harboured extensive drug resistance mutations to all nucleoside reverse transcriptase inhibitors (NRTIs) and non-NRTIs, including the multi-NRTI-resistance Q151M complex, K65R, M184I and Y181I, after using standard first-line generic fixed-dose stavudine, lamivudine and nevirapine (Triomune™) for 36 months. In the context of non-B subtypes in resource-limited countries, first-line stavudine-containing regimens have been associated with more extensive and complex mutation patterns, compared with subtype B viruses. Whether the extensive and complex NRTI resistance patterns found among African patients failing first-line antiretroviral therapy is explained by viral genetic diversity or by different patient monitoring strategies remains to be elucidated. Emerging multi-NRTI resistance in sub-Saharan Africa would not only compromise second-line treatment options and the success of antiretroviral rollout, but could also contribute to the spread of drug-resistant variants worldwide.

  6. Simultaneous quantitation of lamivudine, zidovudine and nevirapine in human plasma by liquid chromatography–tandem mass spectrometry and application to a pharmacokinetic study

    Directory of Open Access Journals (Sweden)

    Murali Krishna Matta

    2012-10-01

    Full Text Available A rapid and sensitive LC–MS/MS method for the simultaneous quantitation of lamivudine, zidovudine and nevirapine in human plasma using abacavir as internal standard has been developed and validated. The analytes and IS were extracted from plasma by solid phase extraction using Oasis HLB cartridges and separated on a Hypurity Advance C18 column using a mixture of acetonitrile:0.1% formic acid (76:24, v/v at a flow rate of 0.8 mL/min. Detection involved an API-4000 LC–MS/MS with electrospray ionization in the positive ion mode and multiple-reaction monitoring for analysis. The method was validated according to FDA guidelines and shown to provide intra- and inter-day precision and accuracy within acceptable limits in a run time of only 3.5 min. The method was successfully applied to a pharmacokinetic study involving a single oral administration of a combination tablet to human male volunteers.

  7. Proteomic Analysis of Serum and Urine of HIV-Monoinfected and HIV/HCV-Coinfected Patients Undergoing Long Term Treatment with Nevirapine

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    Jeerang Wongtrakul

    2014-01-01

    Full Text Available Nevirapine (NVP is an effective nonnucleoside reverse transcriptase inhibitor (NNRTI of particular interest as it is often used in resource limited countries. However, one of the main concerns with the use of NVP is hepatotoxicity and elevation of liver enzymes as a consequence of highly active antiretroviral therapy (HAART containing NVP is more often reported in HIV patients coinfected with hepatitis C virus than in HIV-monoinfected patients. To discover possible markers of NVP induced hepatotoxicity, serum and urine samples from twenty-five HIV or HIV/HCV patients, all of whom had received NVP continuously for at least four months, and healthy controls were subjected to in-solution or in-gel proteomic analysis. A total of 83 differentially regulated proteins consisted of 34 proteins identified in serum by in-solution analysis, 2 proteins identified from serum in a 2D gel electrophoresis analysis, and 47 proteins identified in urine in an in-solution analysis. Three proteins, namely, haptoglobin, Rho-related BTB domain containing protein 3, and death-associated protein kinase 3, were selected for further validation by Western blot analysis and results showed that haptoglobin has potential for further development as an additional marker of NVP induced hepatotoxicity.

  8. Durability of Stavudine, Lamivudine and Nevirapine among Advanced HIV-1 Infected Patients with/without Prior Co-administration of Rifampicin: A 144-week Prospective Study

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    Prasithisirikul Wisit

    2008-10-01

    Full Text Available Abstract Background To date, data on the durability of a regimen of stavudine, lamivudine and nevirapine are very limited, particularly from the resource-limited settings. Methods A prospective cohort study was conducted among 140 antiretroviral-naïve patients who were enrolled to initiate d4T, 3TC and NVP between November 2004 and March 2005. The objectives were to determine immunological and virological responses after 144 weeks of antiretroviral therapy. Seventy patients with tuberculosis also received rifampicin during the early period of antiviral treatment (TB group. Results Of all, median (IQR baseline CD4 cell count was 31 (14–79 cells/mm3; median (IQR baseline HIV-1 RNA was 433,500 (169,000–750,000 copies/mL. The average body weight was 55 kilograms. By intention-to-treat analysis at 144 weeks, the overall percentage of patients who achieved plasma HIV-1 RNA P = 0.731. Eight (5.8% patients discontinued d4T due to neuropathy and/or symptomatic lactic acidosis. Conclusion The overall durability and efficacy of antiviral response of d4T, 3TC and NVP are satisfied and they are not different between HIV-1 infected patients with and without co-administration of rifampicin due to tuberculosis. However, stavudine-related adverse effects are concerns. Trial registration ClinicalTrials.gov Identifier NCT00703898

  9. Synergistic activity of tenofovir and nevirapine combinations released from polycaprolactone matrices for potential enhanced prevention of HIV infection through the vaginal route.

    Science.gov (United States)

    Dang, Nhung T T; Sivakumaran, Haran; Harrich, David; Shaw, Paul N; Davis-Poynter, Nicholas; Coombes, Allan G A

    2014-10-01

    Polycaprolactone (PCL) matrices were simultaneously loaded with the antiviral agents, tenofovir (TFV) and nevirapine (NVP), in combination to provide synergistic activity in the prevention of HIV transmission through the vaginal route. TFV and NVP were incorporated in PCL matrices at theoretical loadings of 10%TFV-10% NVP, 5%TFV-5%NVP and 5%TFV-10%NVP, measured with respect to the PCL content of the matrices. Actual TFV loadings ranged from 2.1% to 4.2% equating to loading efficiencies of about 41-42%. The actual loadings of NVP were around half those of TFV (1.2-1.9%), resulting in loading efficiencies ranging from 17.2% to 23.5%. Approximately 80% of the initial content of TFV was released from the PCL matrices into simulated vaginal fluid (SVF) over a period of 30 days, which was almost double the cumulative release of NVP (40-45%). The release kinetics of both antivirals over 30 days were found to be described most satisfactorily by the Higuchi model. In vitro assay of release media containing combinations of TFV and NVP released from PCL matrices confirmed a potential synergistic/additive effect of the released antivirals on HIV-1 infection of HeLa cells. These findings indicate that PCL matrices loaded with combinations of TFV and NVP provide an effective strategy for the sustained vaginal delivery of antivirals with synergistic/additive activity.

  10. Simple and sensitive stability-indicating ion chromatography method for the determination of cyclopropylamine in nevirapine and moxifloxacin hydrochloride drug substances.

    Science.gov (United States)

    Kothapalli, Pavan Kumar S R; Khagga, Mukkanti; Mekala, Nageswara Rao; Sigamani, John Prasanna; Vundavilli, Jagadeesh Kumar; Masani, Narendra Kumar; Sharma, Hemant Kumar

    2012-01-01

    A simple and sensitive ion chromatography method has been developed for the determination of cyclopropylamine (CPA) in nevirapine (NEV) and moxifloxacin HCl (MOX) pharmaceutical drug substances. Efficient chromatographic separation was achieved on a Metrosep C4, 5 μm (250 mm × 4.0 mm) column. The mobile phase consists of 5 mM hydrochloric acid containing 10% (v/v) acetonitrile and was delivered in an isocratic mode at a flow rate of 0.9 mL min(-1) at 27°C. A conductometric detector was used for the detection of the analyte. The drug substances were subjected to stress conditions including oxidation, thermal, photolytic and humidity for the evaluation of the stability-indicating nature of the method. The method was validated for specificity, precision, linearity, accuracy and solution stability. The limit of detection (LOD) and limit of quantification (LOQ) values are 0.10 μg mL(-1) and 0.37 μg mL(-1) respectively. The linearity range of the method is between 0.37 μg mL(-1) and 1.5 μg mL(-1) and the correlation coefficient is found to be 0.9971. The average recoveries of CPA in NEV and MOX are 97.0% and 98.0%, respectively.

  11. Reuse of single-dose nevirapine in subsequent pregnancies for the prevention of mother-to-child HIV transmission in Lusaka, Zambia: A cohort study

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    Sinkala Moses

    2008-12-01

    Full Text Available Abstract Background Single-dose nevirapine (SDNVP for the prevention of mother-to-child HIV transmission (PMTCT results in the selection of resistance mutants among HIV-infected mothers. The effects of these mutations on the efficacy of SDNVP use in a subsequent pregnancy are not well understood. Methods We compared risks of perinatal HIV transmission between multiparous women who had previously received a dose of SDNVP (exposed and those that had not (unexposed and who were given SDNVP for the index pregnancy within a PMTCT clinical study. We also compared transmission risks among exposed and unexposed women who had two consecutive pregnancies within the trial. Logistic regression modeling was used to adjust for possible confounders. Results Transmission risks did not differ between 59 SDNVP-exposed and 782 unexposed women in unadjusted analysis or after adjustment for viral load and disease stage (adjusted odds ratio 0.6, 95% confidence interval [CI] 0.2 to 2.0. Among 43 women who had two consecutive pregnancies during the study, transmission risks were 7% (95% CI 1% to 19% at both the first (unexposed and second (exposed delivery. The results were unchanged, if infant death was included as an outcome. Conclusion These data suggest that the efficacy of SDNVP may not be diminished when reused in subsequent pregnancies.

  12. Determination of Plasma Concentration of Fluconazol and Midazolam Combinations for Children by HPLC Method%氟康唑联用咪达唑仑血药浓度测定方法及相互作用

    Institute of Scientific and Technical Information of China (English)

    陆晓彤; 刘艳; 徐阿晶; 舒扬; 张春; 王芳; 林志燕

    2012-01-01

    Objective: To establish a biological sample pre-treatment method to extract fluconazole and midazolam simultaneously. HPLC methods were separately established to determine fluconazol, midazolam and 1 -hydroxymidazolam in serum. Whether the plasma concentration of midazolam affected by fluconzole and midazolam combinations was also investigated in this study. Methods: The blood samples ( 1 mL) were extracted with ethyl acetate (5 mL). The organic extract was concentrated to dryness under a mild nitrogen fumes stream. The residue was dissolved in methanol ( 100 μL) , and 20 μL of it was used for HPLC analyze under different conditions. Results: Fluconazol, midazolam and 1 -hydroxymidazolam could be extracted in the same condition. The calibration curves for fluconazol had a good linearity over the range of 0. 5 ~ 20 μg · mL-1 (r = 0. 9970, n = 6). The calibration curves for midazolam had a good linearity over the range of 0.03 ~7. 29 μg · mL-1 (r = 0. 9985, n= 16). The calibration curves for 1-hydroxymidazolam had a good linearity over the range of 0.09 ~7.29 μg · mL (r = 0.9993, n = 5). Compared to the children treated with single in midazolam, the plasma concentration of midazolam in children who were treated with combined fluconazole and midazolam increased significantly. Conclusions: The method is sensitive, accurate, simple, rapid and applicable for clinical plasma drug level monitoring of fluconazol, midazolam and its metabolites. The plasma concentration of midazolam in children who were treated with combined fluconazole and midazolam was higher than that in the children treated only with midazolam.%目的:建立可同时进行氟康唑和咪达唑仑生物样品前处理的方法,应用RP-HPLC法分别测定氟康唑、咪达唑仑、1-羟基咪达唑仑的血药浓度;同时考察氟康唑与咪达唑仑联用对咪达唑仑血药浓度的影响.方法:1 mL血清样品加入内标后以5 mL乙酸乙酯提取,有机相用氮气吹干,以100 μL甲

  13. Multilocus sequence analyses reveal extensive diversity and multiple origins of fluconazole resistance in Candida tropicalis from tropical China

    Science.gov (United States)

    Wu, Jin-Yan; Guo, Hong; Wang, Hua-Min; Yi, Guo-Hui; Zhou, Li-Min; He, Xiao-Wen; Zhang, Ying; Xu, Jianping

    2017-01-01

    Candida tropicalis is among the most prevalent human pathogenic yeast species, second only to C. albicans in certain geographic regions such as East Asia and Brazil. However, compared to C. albicans, relatively little is known about the patterns of genetic variation in C. tropicalis. This study analyzed the genetic diversity and relationships among isolates of C. tropicalis from the southern Chinese island of Hainan. A total of 116 isolates were obtained from seven geographic regions located across the Island. For each isolate, a total of 2677 bp from six gene loci were sequenced and 79 (2.96%) polymorphic nucleotide sites were found in our sample. Comparisons with strains reported from other parts of the world identified significant novel diversities in Hainan, including an average of six novel sequences (with a range 1 to 14) per locus and 80 novel diploid sequence types. Most of the genetic variation was found within individual strains and there was abundant evidence for gene flow among the seven geographic locations within Hainan. Interestingly, our analyses identified no significant correlation between the diploid sequence types at the six loci and fluconazole susceptibility, consistent with multiple origins of fluconazole resistance in the Hainan population of C. tropicalis. PMID:28186162

  14. 氟康唑衍生物的设计与合成%Design and synthesis of fluconazole derivatives

    Institute of Scientific and Technical Information of China (English)

    高一军; 孟庆国; 王楠; 李文娟; 张雷; 柴晓云; 王文艳; 孙海军; 毕毅; 吴秋业

    2012-01-01

    Objective; To design and synthesize fluconazole derivatives. Methods; Based on the previous result of computer-aided drug design, we systematically altered the structure of fluconazole according to the structure-activity relationships of the azoles in antifungal compounds and synthesized target compounds in six steps. Results; Thirteen new compounds were synthesized. The structures were confirmed by 'H-NMR and MS. Conclusion; The design of synthetic route is reasonable. Target compounds are correct and can be used for further study of pharmacological activities.%目的:设计并合成氟康唑衍生物.方法:基于前期计算机辅助药物设计结果,以氟康唑为先导化合物,保留2,4-二氟苯基、叔醇羟基和一个三氮唑,在3位C上引入不同的取代氨基,设计经取代,酯化,澳代,缩合,皂化,缩合6步反应合成目标化合物.结果:合成了13个新化合物,结构经1H-NMR,MS确证.结论:合成路线设计合理,目标化合物结构正确,可供下一步的药理研究.

  15. Induction with lopinavir-based treatment followed by switch to nevirapine-based regimen versus non-nucleoside reverse transcriptase inhibitors-based treatment for first line antiretroviral therapy in HIV infected children three years and older.

    Directory of Open Access Journals (Sweden)

    Gerardo Alvarez-Uria

    Full Text Available The World Health Organization recommends non-nucleoside reverse transcriptase inhibitors (NNRTIs-based antiretroviral therapy (ART for children three years and older. In younger children, starting ART with lopinavir boosted with ritonavir (LPVr results in lower risk of virological failure, but data in children three years and older are scarce, and long-term ART with LPVr is problematic in resource-poor settings.Retrospective cohort of children three years and older who started triple ART including LPVr or a NNRTI between 2007 and 2013 in a rural setting in India. Children who started LPVr were switched to nevirapine-based ART after virological suppression. We analysed two outcomes, virological suppression (HIV-RNA 1000 copies/ml after virological suppression using Cox proportional hazard regression. A sensitivity analysis was performed using inverse probability of treatment weighting (IPTW based of propensity score methods.Of 325 children having a viral load during the first year of ART, 74/83 (89.2% in the LPVr group achieved virological suppression versus 185/242 (76.5% in the NNRTI group. In a multivariable analysis, the use of LPVr-based ART was associated with higher probability of virological suppression (adjusted odds ratio 3.19, 95% confidence interval [CI] 1.11-9.13. After IPTW, the estimated risk difference was 12.2% (95% CI, 2.9-21.5. In a multivariable analysis including 292 children who had virological suppression and available viral loads after one year of ART, children switched from LPVr to nevirapine did not have significant higher risk of virological failure (adjusted hazard ratio 1.18, 95% CI 0.36-3.81.In a cohort of HIV infected children three years and older in a resource-limited setting, an LPVr induction- nevirapine maintenance strategy resulted in more initial virological suppression and similar incidence of virological failure after initial virological suppression than NNRTI-based regimens.

  16. Species distribution and susceptibility profile to fluconazole, voriconazole and MXP-4509 of 551 clinical yeast isolates from a Romanian multi-centre study

    NARCIS (Netherlands)

    Minea, B; Nastasa, V; Moraru, R F; Kolecka, A; Flonta, M M; Marincu, I; Man, A; Toma, F; Lupse, M; Doroftei, B; Marangoci, N; Pinteala, M; Boekhout, T; Mares, M

    2015-01-01

    This is the first multi-centre study regarding yeast infections in Romania. The aim was to determine the aetiological spectrum and susceptibility pattern to fluconazole, voriconazole and the novel compound MXP-4509. The 551 isolates were identified using routine laboratory methods, matrix-assisted l

  17. A prospective longitudinal study of the clinical outcomes from cryptococcal meningitis following treatment induction with 800 mg oral fluconazole in Blantyre, Malawi.

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    Camilla Rothe

    Full Text Available Cryptococcal meningitis is the most common neurological infection in HIV infected patients in Sub Saharan Africa, where gold standard treatment with intravenous amphotericin B and 5 flucytosine is often unavailable or difficult to administer. Fluconazole monotherapy is frequently recommended in national guidelines but is a fungistatic drug compromised by uncertainty over optimal dosing and a paucity of clinical end-point outcome data.From July 2010 until March 2011, HIV infected adults with a first episode of cryptococcal meningitis were recruited at Queen Elizabeth Central Hospital, Blantyre, Malawi. Patients were treated with oral fluconazole monotherapy 800 mg daily, as per national guidelines. ART was started at 4 weeks. Outcomes and factors associated with treatment failure were assessed 4, 10 and 52 weeks after fluconazole initiation.Sixty patients were recruited. 26/60 (43% died by 4 weeks. 35/60 (58.0% and 43/56 (77% died or failed treatment by 10 or 52 weeks respectively. Reduced consciousness (Glasgow Coma Score 3 of 5 and confusion (Abbreviated Mental Test Score <8 of 10 were all common at baseline and associated with death or treatment failure. ART prior to recruitment was not associated with better outcomes.Mortality and treatment failure from cryptococcal meningitis following initiation of treatment with 800 mg oral fluconazole is unacceptably high. To improve outcomes, there is an urgent need for better therapeutic strategies and point-of-care diagnostics, allowing earlier diagnosis before development of neurological deficit.

  18. Amphotericin B colloidal dispersion (Amphocil) vs fluconazole for the prevention of fungal infections in neutropenic patients : data of a prematurely stopped clinical trial

    NARCIS (Netherlands)

    Timmers, G J; Zweegman, S; Simoons-Smit, A M; van Loenen, A C; Touw, D; Huijgens, P C

    2000-01-01

    We conducted an open label, randomised clinical trial to compare amphotericin B colloidal dispersion (ABCD, Amphocil) 2 mg/kg/day intravenously with fluconazole 200 mg/day orally, for the prevention of fungal disease in neutropenic patients with haematological malignancies. In the event of unresolve

  19. Cryptococcus neoformans-Cryptococcus gattii species complex: an international study of wild-type susceptibility endpoint distributions and epidemiological cutoff values for fluconazole, itraconazole, posaconazole, and voriconazole.

    NARCIS (Netherlands)

    Espinel-Ingroff, A.; Aller, A.I.; Canton, E.; Castanon-Olivares, L.R.; Chowdhary, A.; Cordoba, S.; Cuenca-Estrella, M.; Fothergill, A.; Fuller, J.; Govender, N.; Hagen, F.; Illnait-Zaragozi, M.T.; Johnson, E.; Kidd, S.; Lass-Florl, C.; Lockhart, S.R.; Martins, M.A.; Meis, J.F.G.M.; Melhem, M.S.; Ostrosky-Zeichner, L.; Pelaez, T.; Pfaller, M.A.; Schell, W.A.; St-Germain, G.; Trilles, L.; Turnidge, J.

    2012-01-01

    Epidemiological cutoff values (ECVs) for the Cryptococcus neoformans-Cryptococcus gattii species complex versus fluconazole, itraconazole, posaconazole, and voriconazole are not available. We established ECVs for these species and agents based on wild-type (WT) MIC distributions. A total of 2,985 to

  20. Rationale for reading fluconazole MICs at 24 hours rather than 48 hours when testing Candida spp. by the CLSI M27-A2 standard method.

    Science.gov (United States)

    Ostrosky-Zeichner, Luis; Rex, John H; Pfaller, Michael A; Diekema, Daniel J; Alexander, Barbara D; Andes, David; Brown, Steven D; Chaturvedi, Vishnu; Ghannoum, Mahmoud A; Knapp, Cindy C; Sheehan, Daniel J; Walsh, Thomas J

    2008-11-01

    We investigated if CLSI M27-A2 Candida species breakpoints for fluconazole MIC are valid when read at 24 h. Analysis of a data set showed good correlation between 48- and 24-h MICs, as well as similar outcomes and pharmacodynamic efficacy parameters, except for isolates in the susceptible dose-dependent category, such as Candida glabrata.

  1. An open multicentre comparative study of the efficacy, safety and tolerance of fluconazole and itraconazole in the treatment of cancer patients with oropharyngeal candidiasis.

    NARCIS (Netherlands)

    Oude Lashof, A.M.L.; Bock, R. de; Herbrecht, R.; Pauw, B.E. de; Krcmery, V.; Aoun, M.; Akova, M.; Cohen, J.; Siffnerova, H.; Egyed, M.; Ellis, M.; Marinus, A.; Sylvester, R.J.; Kullberg, B.J.

    2004-01-01

    Oropharyngeal candidiasis is a frequent infection in cancer patients who receive cytotoxic drugs. In this study, the efficacy, safety and tolerance of fluconazole and itraconazole were compared in non-neutropenic cancer patients with oropharyngeal candidiasis. Of 279 patients who were randomised bet

  2. ACTIVIDAD ANTIMICÓTICA DEL ACEITE ESENCIAL DE LAS HOJAS DE Minthostachys mollis (MUÑA COMPARADO CON EL FLUCONAZOL EN CULTIVO DE Candida albicans

    Directory of Open Access Journals (Sweden)

    Katherine M Alcalá-Marcos

    2011-01-01

    Full Text Available Objetivo.- Demostrar el efecto antimicótico del aceite esencial de las hojas de Minthostachys mollis (muña en comparación con el Fluconazol en cultivo de Candida albicans. Materiales y Método.- Estudio experimental. El efecto antimicótico se estudió midiendo 80 halos de inhibición distribuidos en 5 grupos mediante el método Kirby-Bauer. Se utilizó una cepa clínica de Candida albicans. Los grupos de estudio fueron grupo muña 25% (GM25%, grupo muña 50% (GM50%, grupo muña 100% (GM100%, un grupo control positivo (Fluconazol, y un grupo control negativo (aceite mineral. El análisis estadístico se realizó mediante la Prueba de Kruskal-Wallis y el Test de Dunn usando el paquete SPSS v.17.0. Se consideró un nivel de significancia 0,05.Conclusión.- El aceite esencial de las hojas de Minthostachys mollis (al 100% tuvo mayor efecto contra la Candida albicans que el Fluconazol; además, el efecto antimicótico del Fluconazol fue mayor que la Minthostachys mollis al 25%, y fue el mismo que la Minthostachys mollis al 50%.

  3. Actividad antimicótica del aceite esencial de las hojas de Minthostachys mollis (muña comparado con el Fluconazol en cultivo de Candida albicans

    Directory of Open Access Journals (Sweden)

    Katherine M Alcalá-Marcos

    2012-09-01

    Full Text Available Objetivo.- Demostrar el efecto antimicótico del aceite esencial de las hojas de Minthostachys mollis (muña en comparación con el Fluconazol en cultivo de Candida albicans. Materiales y Método.- Estudio experimental. El efecto antimicótico se estudió midiendo 80 halos de inhibición distribuidos en 5 grupos mediante el método Kirby-Bauer. Se utilizó una cepa clínica de Candida albicans. Los grupos de estudio fueron grupo muña 25% (GM25%, grupo muña 50% (GM50%, grupo muña 100% (GM100%, un grupo control positivo (Fluconazol, y un grupo control negativo (aceite mineral. El análisis estadístico se realizó mediante la Prueba de Kruskal-Wallis y el Test de Dunn usando el paquete SPSS v.17.0. Se consideró un nivel de significancia  0,05.Conclusión.- El aceite esencial de las hojas de Minthostachys mollis (al 100% tuvo mayor efecto contra la Candida albicans que el Fluconazol; además, el efecto antimicótico del Fluconazol fue mayor que la Minthostachys mollis al 25%, y fue el mismo que la Minthostachys mollis al 50%.

  4. Cryptococcus neoformans-Cryptococcus gattii species complex: an international study of wild-type susceptibility endpoint distributions and epidemiological cutoff values for fluconazole, itraconazole, posaconazole, and voriconazole.

    NARCIS (Netherlands)

    Espinel-Ingroff, A.; Aller, A.I.; Canton, E.; Castanon-Olivares, L.R.; Chowdhary, A.; Cordoba, S.; Cuenca-Estrella, M.; Fothergill, A.; Fuller, J.; Govender, N.; Hagen, F.; Illnait-Zaragozi, M.T.; Johnson, E.; Kidd, S.; Lass-Florl, C.; Lockhart, S.R.; Martins, M.A.; Meis, J.F.G.M.; Melhem, M.S.; Ostrosky-Zeichner, L.; Pelaez, T.; Pfaller, M.A.; Schell, W.A.; St-Germain, G.; Trilles, L.; Turnidge, J.

    2012-01-01

    Epidemiological cutoff values (ECVs) for the Cryptococcus neoformans-Cryptococcus gattii species complex versus fluconazole, itraconazole, posaconazole, and voriconazole are not available. We established ECVs for these species and agents based on wild-type (WT) MIC distributions. A total of 2,985 to

  5. Influence of different susceptibility testing methods and media on determination of the relevant fluconazole minimum inhibitory concentrations for heavy trailing Candida isolates with low-high phenotype.

    Science.gov (United States)

    Alp, Sehnaz; Sancak, Banu; Hascelik, Gulsen; Arikan, Sevtap

    2010-11-01

    We investigated the incidence of trailing growth with fluconazole in 101 clinical Candida isolates (49 C. albicans and 52 C. tropicalis) and tried to establish the convenient susceptibility testing method and medium for fluconazole minimum inhibitory concentration (MIC) determination. MICs were determined by CLSI M27-A2 broth microdilution (BMD) and Etest methods on RPMI-1640 agar supplemented with 2% glucose (RPG) and on Mueller-Hinton agar supplemented with 2% glucose and 0.5 μg ml(-1) methylene blue (GMB). BMD and Etest MICs were read at 24 and 48 h, and susceptibility categories were compared. All isolates were determined as susceptible with BMD, Etest-RPG and Etest-GMB at 24 h. While all isolates were interpreted as susceptible at 48 h on Etest-RPG and Etest-GMB, one C. albicans isolate was interpreted as susceptible-dose dependent (S-DD) and two C. tropicalis isolates were interpreted as resistant with BMD. On Etest-RPG, trailing growth caused widespread microcolonies within the inhibition zone and resulted in confusion in MIC determination. On Etest-GMB, because of the nearly absence of microcolonies within the zone of inhibition, MICs were evaluated more easily. We conclude that, for the determination of fluconazole MICs of trailing Candida isolates, the Etest method has an advantage over BMD and can be used along with this reference method. Moreover, GMB appears more beneficial than RPG for the fluconazole Etest. © 2009 Blackwell Verlag GmbH.

  6. Rationale for Reading Fluconazole MICs at 24 Hours Rather than 48 Hours When Testing Candida spp. by the CLSI M27-A2 Standard Method▿

    Science.gov (United States)

    Ostrosky-Zeichner, Luis; Rex, John H.; Pfaller, Michael A.; Diekema, Daniel J.; Alexander, Barbara D.; Andes, David; Brown, Steven D.; Chaturvedi, Vishnu; Ghannoum, Mahmoud A.; Knapp, Cindy C.; Sheehan, Daniel J.; Walsh, Thomas J.

    2008-01-01

    We investigated if CLSI M27-A2 Candida species breakpoints for fluconazole MIC are valid when read at 24 h. Analysis of a data set showed good correlation between 48- and 24-h MICs, as well as similar outcomes and pharmacodynamic efficacy parameters, except for isolates in the susceptible dose-dependent category, such as Candida glabrata. PMID:18809944

  7. XML In Vitro Comparison of MIC Crude Extracts of Active Actinomycetes Isolated with Terbinafine, Griseofulvin Ketoconazole and Fluconazole against Microsporum Canis, Microsporum Gypseum and Trichophyton Mentagrophytes

    Directory of Open Access Journals (Sweden)

    Keikha, N. (MSc

    2015-05-01

    Full Text Available Background and Objective: Dermatophytes are the fungi that have the ability to attack the keratinized tissues such as the skin, hair and nails. Infections caused by these organisms are named dermatophytosis. We aimed to compare Minimum inhibitory concentration (MIC of Crude extracts of Active Actinomycete Isolates with Terbinafine, Griseofulvin, Ketoconazole and Fluconazole Drugs against Microsporum Canis, Microsporum gypseum and Trichophyton mentagrophytes. Material and Methods: In this experimental study, in order to find MIC by actionmycete, 100 isolates were studied and then crude extracts of the active actinomycete isolates were prepared in sterile conditions. Finally, the crude extracts obtained at different concentrations were used to obtain the MIC of Microsporum Canis, Microsporum gypseum and Trichophyton mentagrophytes. Moreover, various concentrations of the drugs such as terbinafine, griseofulvin, ketoconazole and fluconazole in solvent Dimethyl sulfoxide (DMSO were prepared and their growth inhibitory effect was evaluated and then compared with the results obtained from the crude extract of active actinomycete isolates. Results: the crude extracts obtained from active Actioiomycetes isolates and the drugs such as terbinafine, griseofulvin, ketoconazole and fluconazole, in a dose-dependent manner, could inhibit the growth of Microsporum Canis, Microsporum gypseum and Trichophyton Mentagrophytes. Conclusion: compared to MIC of Crude extract of active actinomycete isolates, Terbinafine has a significant effect on the growth inhibition in all of the fungal Dermatophytes and then griseofulvin, ketoconazole and fluconazole are in the next rank, respectively.

  8. Molecular mechanisms of fluconazole resistance in clinical isolates of Candida tropicalis%热带念珠菌临床分离株对氟康唑耐药分子机制的研究

    Institute of Scientific and Technical Information of China (English)

    周永安; 窦娟; 张全斌; 马云霞

    2011-01-01

    Objective This study aimed to investigate the molecular mechanisms responsible for fluconazole resistance in clinical isolates of this pathogenic yeast .Methods A total of 41 Candida tropicalis strains were collected from the clinical laboratory of Taiyuan City Central Hospital .Antifungal susceptibility testing was performed by ATB FUNGU 3 method.The 14 α-demethylase (ERG11) gene in all clinical iso-lates of Candida tropicalis were amplified by PCR,and their nucleotide sequences were determined in order to detect point mutations.Likewise,efflux transporters (CDR1 and MDR1) and ERG11 genes were tested by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) for their expression in Candida tropicalis cells at the mRNA level.Results The fluconazole-resistant rate of 41 Candida tropicalis was 12.2%.The amino acid substitutions in ERG11p of R245K,Y221F and V362I were found in fluconazole-re-sistant isolates.And no amino acid substitution was detected in fluconazole -susceptible ones.The mRNA level of CDR1,MDR1 and ERG11 genes in fluconazole-resistant isolates all showed overexpression compared with fluconazole-susceptible ones.Conclusions Missense mutations in ERG11 gene associated with overexpres-sion of CDR1,MDR1 and ERG11 gene seemed to be responsible for the acquired fluconazole resistance of these clinical isolates.

  9. Stability-indicating UHPLC method for determination of nevirapine in its bulk form and tablets: identification of impurities and degradation kinetic study.

    Science.gov (United States)

    Reis, Naialy Fernandes Araújo; de Assis, Jéssica Camille; Fialho, Sílvia Ligório; Pianetti, Gerson Antônio; Fernandes, Christian

    2016-07-15

    Nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor, is a drug widely used in the treatment of Acquired Immunodeficiency Syndrome (AIDS). The evaluation of NVP stability is of fundamental importance in order to guarantee drug product efficacy, safety and quality. In this study, NVP active pharmaceutical ingredient (API) and tablets were subjected to a detailed study of forced degradation, employing several degrading agents (acid, alkaline, water, metal ions, humidity, heat, light and oxidation agents). In order to determine NVP and the degradation products formed, a stability-indicating UHPLC method using fused core column was developed and validated. The separation was carried out using a Poroshell 120C18 column (100×2.1mm i.d.; 2.7μm particle size) and the mobile phase was composed of acetonitrile and water in a gradient elution, at a flow rate of 0.2ml/min. Chemical structures and mechanisms for the formation of three degradation products were proposed by means of LC/MS-MS. Also, NVP degradation kinetic was studied and its order of degradation evaluated. NVP was degraded in acidic and oxidative conditions and the degradation profile for NVP tablets and API were similar. The stability-indicating method proved to be selective for NVP and its degradation products. Calibration curve was linear in the range of 8-48μg/ml and the method showed to be precise, accurate and robust for both NVP API and tablets, with detection and quantification limits of 0.092μg/ml and 0.174μg/ml, respectively.

  10. Outcomes for efavirenz versus nevirapine-containing regimens for treatment of HIV-1 infection: a systematic review and meta-analysis.

    Directory of Open Access Journals (Sweden)

    Prinitha Pillay

    Full Text Available INTRODUCTION: There is conflicting evidence and practice regarding the use of the non-nucleoside reverse transcriptase inhibitors (NNRTI efavirenz (EFV and nevirapine (NVP in first-line antiretroviral therapy (ART. METHODS: We systematically reviewed virological outcomes in HIV-1 infected, treatment-naive patients on regimens containing EFV versus NVP from randomised trials and observational cohort studies. Data sources include PubMed, Embase, the Cochrane Central Register of Controlled Trials and conference proceedings of the International AIDS Society, Conference on Retroviruses and Opportunistic Infections, between 1996 to May 2013. Relative risks (RR and 95% confidence intervals were synthesized using random-effects meta-analysis. Heterogeneity was assessed using the I(2 statistic, and subgroup analyses performed to assess the potential influence of study design, duration of follow up, location, and tuberculosis treatment. Sensitivity analyses explored the potential influence of different dosages of NVP and different viral load thresholds. RESULTS: Of 5011 citations retrieved, 38 reports of studies comprising 114 391 patients were included for review. EFV was significantly less likely than NVP to lead to virologic failure in both trials (RR 0.85 [0.73-0.99] I(2 = 0% and observational studies (RR 0.65 [0.59-0.71] I(2 = 54%. EFV was more likely to achieve virologic success than NVP, though marginally significant, in both randomised controlled trials (RR 1.04 [1.00-1.08] I(2 = 0% and observational studies (RR 1.06 [1.00-1.12] I(2 = 68%. CONCLUSION: EFV-based first line ART is significantly less likely to lead to virologic failure compared to NVP-based ART. This finding supports the use of EFV as the preferred NNRTI in first-line treatment regimen for HIV treatment, particularly in resource limited settings.

  11. 氟康唑滴眼凝胶的制备与质量控制%Preparation and quality control of Fluconazole Ophthalmic Gel

    Institute of Scientific and Technical Information of China (English)

    满玉清; 魏传梅; 刘明华; 左小信; 胡丽敏

    2015-01-01

    Objective To prepare Fluconazole Ophthalmic Gel and establish its quality control standards. Methods the matrix formulation was optimized by orthogonal design;HPLC was used to determine the content of fluconazole,and in-vestigate the stimulating and stability of the preparation. Results The best prescription of Fluconazole Ophthalmic Gel for quality(mass to volume ratio)were:carbomer - 940 0. 3% ,borax 0. 4% and glycerol 2% . The linear range of fluconazole was 1. 0 ~ 8. 0 μg(r = 0. 999 8),and the average recovery was 99. 43%(RSD = 0. 75% );The prescription was stable and nonirritating. Conclusion The prescription of Fluconazole Ophthalmic Gel was reasonable,and the quality was controlla-ble.%目的:制备氟康唑滴眼凝胶并建立质量控制方法。方法采用正交设计对基质处方进行优化;用高效液相色谱法测定氟康唑的含量,并进行制剂刺激性及稳定性考察。结果氟康唑眼凝胶最佳基质处方为(质量体积比):卡波姆-9400.3%,硼砂0.4%,甘油2%;氟康唑进样量在1.0~8.0μg 的范围内线性关系良好( r =0.9998),加样回收率为99.43%(RSD =0.75%);制剂无刺激性,稳定性好。结论氟康唑滴眼凝胶处方合理,质量可控。

  12. Fluconazole exposure rather than clonal spreading is correlated with the emergence of Candida glabrata with cross-resistance to triazole antifungal agents.

    Science.gov (United States)

    Chen, Tun-Chieh; Chen, Yen-Hsu; Chen, Yee-Chun; Lu, Po-Liang

    2012-06-01

    The emergence of antifungal resistance in Candida species has raised concern in recent years, especially resistance toward triazole. Several newer triazole antifungal agents have been introduced which have a broader spectrum for fungal infections, such as voriconazole. However, cross-resistance among triazoles is a major concern with regard to their clinical application. Antifungal susceptibility was performed using E-test for 166 clinical isolates (29 blood and 137 nonblood isolates) in 2003 and 2004. We applied pulsed-field gel electrophoresis for genotyping. Ninety isolates of C. albicans, 47 isolates of C. tropicalis, 27 isolates of C. glabrata, and two isolates of C. krusei were included. All isolates were susceptible to amphotericin B. Eleven (40.7%) of the 27 C. glabrata had intermediate resistance to caspofungin. Forty-seven (28.3%) of the 166 isolates were not susceptible to fluconazole, including two C. albicans, 16 C. tropicalis, 27 C. glabrata, and two C. krusei isolates. All except seven of the C. glabrata isolates were susceptible to voriconazole. All the triazole drugs had a positive correlation among their minimum inhibitory concentrations (MICs). Fluconazole MIC was a good predictor for susceptibility to voriconazole, as determined using a receiver operating characteristic curve. Furthermore, a high diversity of pulsotypes for the 27 clinical isolates of C. glabrata was observed. Previous fluconazole exposure within 3 months was associated with reduced triazole susceptibility for C. glabrata. We demonstrated a significant positive correlation of MIC values among the four tested triazole drugs. No amphotericin B and caspofungin resistant isolates were found in this study. The cross-resistance to triazole among C. glabrata isolates was associated with previous fluconazole exposure as opposed to clonal spreading. Selection pressure due to fluconazole use may play a major role in triazole cross-resistance.

  13. In vitro fluconazole and voriconazole susceptibilities of Candida bloodstream isolates in Korea: use of the CLSI and EUCAST epidemiological cutoff values.

    Science.gov (United States)

    Jang, Min Joong; Shin, Jong Hee; Lee, Wee Gyo; Kim, Mi-Na; Lee, Kyungwon; Lee, Hye Soo; Lee, Mi-Kyung; Chang, Chulhun L; Jang, Hee-Chang; Song, Eun Song; Kim, Soo Hyun; Shin, Myung-Geun; Suh, Soon-Pal; Ryang, Dong-Wook

    2013-05-01

    At present, the clinical breakpoints (CBPs) of both fluconazole and voriconazole are available only for 3 common Candida species in the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) methods. Epidemiological cutoff values (ECVs) were recently applied to both methods to detect the emergence of acquired resistance (i.e., non-wild-type isolates) among 5 common Candida species. We performed a nationwide study to determine the fluconazole and voriconazole susceptibility of Candida bloodstream isolates (BSIs) using both the CLSI and EUCAST methods. A total of 423 BSIs of 5 Candida species were collected from 8 hospitals. The azole susceptibilities were assessed on the basis of the species-specific CBPs and ECVs. Of the 341 BSIs of 3 common Candida species (i.e., C. albicans, C. tropicalis, and C. parapsilosis), 0.3% and 0.9%, 0.0% and 1.5% of isolates were categorized as fluconazole and voriconazole resistant according to the CLSI and EUCAST CBPs, respectively. Of 423 total BSIs, 1.4% and 2.6% had fluconazole minimum inhibitory concentrations (MICs) exceeding the ECVs according to the CLSI and EUCAST, respectively; 1.0% and 2.1% had voriconazole MICs exceeding the ECVs according to the CLSI and EUCAST, respectively. Categorical agreement between the methods using ECVs was 98.3% for fluconazole and 98.3% for voriconazole. The EUCAST and CLSI methods using ECVs provide highly concordant results. Moreover, non-wild-type isolates with possibly acquired azole resistance were rare among the BSIs of 5 common Candida species in Korea.

  14. Development and validation of a high-performance liquid chromatographic assay for the determination of fluconazole in human whole blood using solid phase extraction.

    Science.gov (United States)

    Zhang, Shimin; Mada, Sripal Reddy; Torch, Marilyn; Goyal, Rakesh K; Venkataramanan, Raman

    2008-06-01

    A sensitive and specific high-performance liquid chromatographic ultraviolet method for the determination of fluconazole in human whole blood has been developed and validated. Whole blood samples were processed by a solid phase extraction procedure using an Oasis HLB extraction cartridge before chromatography. Phenacetin was used as the internal standard. Chromatography was performed using Waters C18 Symmetry analytical column, 5 microm, 4.6 x 250 mm, using an isocratic elution with a mobile phase consisting of acetonitrile and water (36:64, v/v) at a flow rate of 0.8 mL/min. The retention times of fluconazole and phenacetin were 4.7 and 8.3 minutes, respectively, and the total run time was 10 minutes. Quantitative analysis was performed using a Waters UV-VIS detector at a wavelength of 210 nm. The assay was linear over the concentration range of 0.5 to 15 microg/mL for fluconazole. The extraction recoveries at concentrations of 2.5, 5, and 10 microg/mL were 105.9%, 98.4%, and 95%, respectively. The method can quantify 0.5 microg/mL fluconazole using 300 microL of whole blood. At concentrations of 2.5, 5, and 10 microg/mL, the intraday precision expressed as coefficient of variation was 3.47%, 8.81%, and 1.14% and the interday precision was 5.21%, 5.48%, and 7.18%, respectively. This method is simple, uses a low blood volume for analysis, and allows reproducible and accurate measurement of fluconazole in whole blood samples from pediatric patients.

  15. A randomized clinical trial of the efficacy and safety of terconazole vaginal suppository versus oral fluconazole for treating severe vulvovaginal candidiasis.

    Science.gov (United States)

    Li, Ting; Zhu, Yuxia; Fan, Shangrong; Liu, Xiaoping; Xu, Huicong; Liang, Yiheng

    2015-06-01

    Terconazole is a new, broad-spectrum, triazole antifungal agent. The aim of this study was to compare the efficacy and safety of a 6-day course of a terconazole vaginal suppository (80 mg) with two doses of oral fluconazole (150 mg) for the treatment of severe vulvovaginal candidiasis (SVVC). In this prospective, randomized case-control study, 140 consecutive patients with SVVC were enr