WorldWideScience

Sample records for antifungal drug resistance

  1. Molecular basis of antifungal drug resistance in yeasts

    DEFF Research Database (Denmark)

    Morio, Florent; Jensen, Rasmus Hare; Le Pape, Patrice

    2017-01-01

    Besides inherent differences in in vitro susceptibilities, clinically-relevant yeast species may acquire resistance upon exposure to most antifungal drugs used in the clinic. In recent years, major fundamental research studies have been conducted to improve our understanding of the molecular basis......., in the context of antifungal drug resistance. Also included are the methods currently available for in vitro antifungal susceptibility testing and for molecular detection of mutations associated with resistance. Finally, the genetic drivers of antifungal resistance are discussed in light of the spectra...

  2. Mechanisms of antifungal drug resistance in Candida dubliniensis.

    LENUS (Irish Health Repository)

    Coleman, David C

    2010-06-01

    Candida dubliniensis was first described in 1995 and is the most closely related species to the predominant human fungal pathogen Candida albicans. C. dubliniensis is significantly less prevalent and less pathogenic than C. albicans and is primarily associated with infections in HIV-infected individuals and other immunocompromised cohorts. The population structure of C. dubliniensis consists of three well-defined major clades and is significantly less diverse than C. albicans. The majority of C. dubliniensis isolates are susceptible to antifungal drugs commonly used to treat Candida infections. To date only two major patterns of antifungal drug resistance have been identified and the molecular mechanisms of these are very similar to the resistance mechanisms that have been described previously in C. albicans. However, significant differences are evident in the predominant antifungal drug mechanisms employed by C. dubliniensis, differences that reflect its more clonal nature, its lower prevalence and characteristics of its genome, the complete sequence of which has only recently been determined.

  3. Nationwide Study of Candidemia, Antifungal Use, and Antifungal Drug Resistance in Iceland, 2000 to 2011

    Science.gov (United States)

    Asmundsdottir, Lena Ros; Erlendsdottir, Helga

    2013-01-01

    Candidemia is often a life-threatening infection, with highly variable incidence among countries. We conducted a nationwide study of candidemia in Iceland from 2000 to 2011, in order to determine recent trends in incidence rates, fungal species distribution, antifungal susceptibility patterns, and concurrent antifungal consumption. A total of 208 infection episodes in 199 patients were identified. The average incidence during the 12 years was 5.7 cases/100,000 population/year, which was significantly higher than that from 1990 to 1999 (4.3/100,000/year; P = 0.02). A significant reduction in the use of blood cultures was noted in the last 3 years of the study, coinciding with the economic crisis in the country (P 60 years, and varied by gender. Age-specific incidence among males >80 years old was 28.6/100,000/year, and it was 8.3/100,000/year for females in this age group (P = 0.028). The 30-day survival rate among adult patients remained unchanged compared to that from 1990 to 1999 (70.4% versus 69.5%, P = 0.97). Candida albicans was the predominant species (56%), followed by C. glabrata (16%) and C. tropicalis (13%). The species distribution remained stable compared to that from previous decades. Fluconazole use increased 2.4-fold from 2000 to 2011, with no increase in resistance. In summary, the incidence of candidemia in Iceland has continued to increase but may have reached a steady state, and no increase in antifungal drug resistance has been noted. Decreased use of blood cultures toward the end of the study may have influenced detection rates. PMID:23269738

  4. Whole Genome Sequencing of Candida glabrata for Detection of Markers of Antifungal Drug Resistance.

    Science.gov (United States)

    Biswas, Chayanika; Chen, Sharon C-A; Halliday, Catriona; Martinez, Elena; Rockett, Rebecca J; Wang, Qinning; Timms, Verlaine J; Dhakal, Rajat; Sadsad, Rosemarie; Kennedy, Karina J; Playford, Geoffrey; Marriott, Deborah J; Slavin, Monica A; Sorrell, Tania C; Sintchenko, Vitali

    2017-12-28

    Candida glabrata can rapidly acquire mutations that result in drug resistance, especially to azoles and echinocandins. Identification of genetic mutations is essential, as resistance detected in vitro can often be correlated with clinical failure. We examined the feasibility of using whole genome sequencing (WGS) for genome-wide analysis of antifungal drug resistance in C. glabrata. The aim was torecognize enablers and barriers in the implementation WGS and measure its effectiveness. This paper outlines the key quality control checkpoints and essential components of WGS methodology to investigate genetic markers associated with reduced susceptibility to antifungal agents. It also estimates the accuracy of data analysis and turn-around-time of testing. Phenotypic susceptibility of 12 clinical, and one ATCC strain of C. glabrata was determined through antifungal susceptibility testing. These included three isolate pairs, from three patients, that developed rise in drug minimum inhibitory concentrations. In two pairs, the second isolate of each pair developed resistance to echinocandins. The second isolate of the third pair developed resistance to 5-flucytosine. The remaining comprised of susceptible and azole resistant isolates. Single nucleotide polymorphisms (SNPs) in genes linked to echinocandin, azole and 5-flucytosine resistance were confirmed in resistant isolates through WGS using the next generation sequencing. Non-synonymous SNPs in antifungal resistance genes such as FKS1, FKS2, CgPDR1, CgCDR1 and FCY2 were identified. Overall, an average of 98% of the WGS reads of C. glabrata isolates mapped to the reference genome with about 75-fold read depth coverage. The turnaround time and cost were comparable to Sanger sequencing. In conclusion, WGS of C. glabrata was feasible in revealing clinically significant gene mutations involved in resistance to different antifungal drug classes without the need for multiple PCR/DNA sequencing reactions. This represents a

  5. Oropharyngeal candidiasis and resistance to antifungal drugs in patients receiving radiation for head and neck cancer

    Directory of Open Access Journals (Sweden)

    Maryam Rad DMD, MSc

    2012-04-01

    Full Text Available BACKGROUND: Oropharyngeal candidiasis is a common infection in patient receiving radiotherapy for head and neckcancer. Accurate and rapid identification of candida species is very important in clinical laboratory, because theincidence of candidiasis continues to rise after radiotherapy. The genus Candida has about 154 species that showdifferent level of resistance to antifungal drugs and have high degree of phenotypic similarity. The aim of this study wasto investigate oral yeast colonization and infection and resistance to antifungal drugs in these patients.METHODS: Thirty patients receiving a 6-week course of radiation therapy for treatment of head and neck cancer at theOncology Unit in Shafa Hospital, in 2008, were enrolled in the study. Specimens from patients were cultured weeklyfor Candida. All isolates were plated on CHROM agar and RPMI-based medium. They were subcultured and submittedfor antifungal susceptibility testing (nystatin, fluconazole, clotrimazole and ketoconazole and molecular typing.RESULTS: Infection (clinical and microbiological evidence occurred in 50% of the patients and Candida colonization(only microbiological evidence occurred in 70% of subjects in the first week. Candida albicans alone was isolated in94.9% of patient visits with positive cultures. Candida tropicalis was isolated from 5.1% of patient visits with positivecultures. All isolates were susceptible to nystatin, but did not respond to the other antifungal drugsCONCLUSIONS: The irradiation-induced changes of the intraoral environment such as xerostomia lead to increasedintraoral colonization by Candida species. All yeast isolates were susceptible to nystatin. Thus prophylactic therapywith nystatin should be considered for these patients.

  6. Special Issue: Novel Antifungal Drug Discovery

    Directory of Open Access Journals (Sweden)

    Maurizio Del Poeta

    2016-12-01

    Full Text Available This Special Issue is designed to highlight the latest research and development on new antifungal compounds with mechanisms of action different from the ones of polyenes, azoles, and echinocandins. The papers presented here highlight new pathways and targets that could be exploited for the future development of new antifungal agents to be used alone or in combination with existing antifungals. A computational model for better predicting antifungal drug resistance is also presented.

  7. In vitro activities of four antifungal drugs against Trichophyton rubrum isolates exhibiting resistance to fluconazole.

    Science.gov (United States)

    Santos, D A; Hamdan, J S

    2007-07-01

    Thirty-two clinical isolates of Trichophyton rubrum exhibiting resistance to fluconazole [minimum inhibitory concentrations (MICs) > or = 64 microg ml(-1)] were selected to test the antifungal activity of ketoconazole, itraconazole, griseofulvin and terbinafine. We followed the guidelines of the National Committee for Clinical Laboratory Standards for testing filamentous fungi. The strains Candida parapsilosis (ATCC 22019), Candida krusei (ATCC 6258), T. rubrum (ATCC 40051) and Trichophyton mentagrophytes (ATCC 40004) were included for quality control. The microdilution plates were incubated at 28 degrees C and were read visually after 7 days of incubation and endpoint determination readings were performed visually. The MIC ranges for the four antifungals were: 0.0625-2 microg ml(-1) for ketoconazole, 0.25-2.0 microg ml(-1) for griseofulvin, < or =0.031-1.0 microg ml(-1) for itraconazole and < or =0.031 microg ml(-1) for terbinafine (for all tested isolates). Terbinafine was the most potent drug against T. rubrum, in vitro, followed by itraconazole, ketoconazole and griseofulvin. Much work is still needed to correlate the MICs of these drugs with clinical outcomes to develop interpretative breakpoints for T. rubrum and other dermatophytes.

  8. Yeasts acquire resistance secondary to antifungal drug treatment by adaptive mutagenesis.

    Directory of Open Access Journals (Sweden)

    David Quinto-Alemany

    Full Text Available Acquisition of resistance secondary to treatment both by microorganisms and by tumor cells is a major public health concern. Several species of bacteria acquire resistance to various antibiotics through stress-induced responses that have an adaptive mutagenesis effect. So far, adaptive mutagenesis in yeast has only been described when the stress is nutrient deprivation. Here, we hypothesized that adaptive mutagenesis in yeast (Saccharomyces cerevisiae and Candida albicans as model organisms would also take place in response to antifungal agents (5-fluorocytosine or flucytosine, 5-FC, and caspofungin, CSP, giving rise to resistance secondary to treatment with these agents. We have developed a clinically relevant model where both yeasts acquire resistance when exposed to these agents. Stressful lifestyle associated mutation (SLAM experiments show that the adaptive mutation frequencies are 20 (S. cerevisiae -5-FC, 600 (C. albicans -5-FC or 1000 (S. cerevisiae--CSP fold higher than the spontaneous mutation frequency, the experimental data for C. albicans -5-FC being in agreement with the clinical data of acquisition of resistance secondary to treatment. The spectrum of mutations in the S. cerevisiae -5-FC model differs between spontaneous and acquired, indicating that the molecular mechanisms that generate them are different. Remarkably, in the acquired mutations, an ectopic intrachromosomal recombination with an 87% homologous gene takes place with a high frequency. In conclusion, we present here a clinically relevant adaptive mutation model that fulfils the conditions reported previously.

  9. Candida Species Biofilms’ Antifungal Resistance

    Science.gov (United States)

    Silva, Sónia; Rodrigues, Célia F.; Araújo, Daniela; Rodrigues, Maria Elisa; Henriques, Mariana

    2017-01-01

    Candida infections (candidiasis) are the most prevalent opportunistic fungal infection on humans and, as such, a major public health problem. In recent decades, candidiasis has been associated to Candida species other than Candida albicans. Moreover, biofilms have been considered the most prevalent growth form of Candida cells and a strong causative agent of the intensification of antifungal resistance. As yet, no specific resistance factor has been identified as the sole responsible for the increased recalcitrance to antifungal agents exhibited by biofilms. Instead, biofilm antifungal resistance is a complex multifactorial phenomenon, which still remains to be fully elucidated and understood. The different mechanisms, which may be responsible for the intrinsic resistance of Candida species biofilms, include the high density of cells within the biofilm, the growth and nutrient limitation, the effects of the biofilm matrix, the presence of persister cells, the antifungal resistance gene expression and the increase of sterols on the membrane of biofilm cells. Thus, this review intends to provide information on the recent advances about Candida species biofilm antifungal resistance and its implication on intensification of the candidiasis. PMID:29371527

  10. The dual role of candida glabrata drug:H+ antiporter CgAqr1 (ORF CAGL0J09944g) in antifungal drug and acetic acid resistance

    Science.gov (United States)

    Costa, Catarina; Henriques, André; Pires, Carla; Nunes, Joana; Ohno, Michiyo; Chibana, Hiroji; Sá-Correia, Isabel; Teixeira, Miguel C.

    2013-01-01

    Opportunistic Candida species often have to cope with inhibitory concentrations of acetic acid, in the acidic environment of the vaginal mucosa. Given that the ability of these yeast species to tolerate stress induced by weak acids and antifungal drugs appears to be a key factor in their persistence and virulence, it is crucial to understand the underlying mechanisms. In this study, the drug:H+ antiporter CgAqr1 (ORF CAGL0J09944g), from Candida glabrata, was identified as a determinant of resistance to acetic acid, and also to the antifungal agents flucytosine and, less significantly, clotrimazole. These antifungals were found to act synergistically with acetic acid against this pathogen. The action of CgAqr1 in this phenomenon was analyzed. Using a green fluorescent protein fusion, CgAqr1 was found to localize to the plasma membrane and to membrane vesicles when expressed in C. glabrata or, heterologously, in Saccharomyces cerevisiae. Given its ability to complement the susceptibility phenotype of its S. cerevisiae homolog, ScAqr1, CgAqr1 was proposed to play a similar role in mediating the extrusion of chemical compounds. Significantly, the expression of this gene was found to reduce the intracellular accumulation of 3H-flucytosine and, to a moderate extent, of 3H-clotrimazole, consistent with a direct role in antifungal drug efflux. Interestingly, no effect of CgAQR1 deletion could be found on the intracellular accumulation of 14C-acetic acid, suggesting that its role in acetic acid resistance may be indirect, presumably through the transport of a still unidentified physiological substrate. Although neither of the tested chemicals induces changes in CgAQR1 expression, pre-exposure to flucytosine or clotrimazole was found to make C. glabrata cells more sensitive to acetic acid stress. Results from this study show that CgAqr1 is an antifungal drug resistance determinant and raise the hypothesis that it may play a role in C. glabrata persistent colonization and

  11. Clinico-mycological study of dermatophytic infections and their sensitivity to antifungal drugs in a tertiary care center

    Directory of Open Access Journals (Sweden)

    Soniya Mahajan

    2017-01-01

    Conclusion: Inadequate and irregular use of antifungal drugs has led to the emergence of resistant strains, which cause poor treatment outcomes. Thus, it is very important to test for antifungal sensitivity to check for resistance to antifungals.

  12. Structure-activity relationships among antifungal nylon-3 polymers: identification of materials active against drug-resistant strains of Candida albicans.

    Science.gov (United States)

    Liu, Runhui; Chen, Xinyu; Falk, Shaun P; Mowery, Brendan P; Karlsson, Amy J; Weisblum, Bernard; Palecek, Sean P; Masters, Kristyn S; Gellman, Samuel H

    2014-03-19

    Fungal infections are a major challenge to human health that is heightened by pathogen resistance to current therapeutic agents. Previously, we were inspired by host-defense peptides to develop nylon-3 polymers (poly-β-peptides) that are toxic toward the fungal pathogen Candida albicans but exert little effect on mammalian cells. Based on subsequent analysis of structure-activity relationships among antifungal nylon-3 polymers, we have now identified readily prepared cationic homopolymers active against strains of C. albicans that are resistant to the antifungal drugs fluconazole and amphotericin B. These nylon-3 polymers are nonhemolytic. In addition, we have identified cationic-hydrophobic copolymers that are highly active against a second fungal pathogen, Cryptococcus neoformans, and moderately active against a third pathogen, Aspergillus fumigatus.

  13. Structure–Activity Relationships among Antifungal Nylon-3 Polymers: Identification of Materials Active against Drug-Resistant Strains of Candida albicans

    Science.gov (United States)

    2015-01-01

    Fungal infections are a major challenge to human health that is heightened by pathogen resistance to current therapeutic agents. Previously, we were inspired by host-defense peptides to develop nylon-3 polymers (poly-β-peptides) that are toxic toward the fungal pathogen Candida albicans but exert little effect on mammalian cells. Based on subsequent analysis of structure–activity relationships among antifungal nylon-3 polymers, we have now identified readily prepared cationic homopolymers active against strains of C. albicans that are resistant to the antifungal drugs fluconazole and amphotericin B. These nylon-3 polymers are nonhemolytic. In addition, we have identified cationic–hydrophobic copolymers that are highly active against a second fungal pathogen, Cryptococcus neoformans, and moderately active against a third pathogen, Aspergillus fumigatus. PMID:24606327

  14. Changes in Incidence and Antifungal Drug Resistance in Candidemia: Results From Population-Based Laboratory Surveillance in Atlanta and Baltimore, 2008–2011

    Science.gov (United States)

    Cleveland, Angela Ahlquist; Farley, Monica M.; Harrison, Lee H.; Stein, Betsy; Hollick, Rosemary; Lockhart, Shawn R.; Magill, Shelley S.; Derado, Gordana; Park, Benjamin J.; Chiller, Tom M.

    2015-01-01

    Background Candidemia is common and associated with high morbidity and mortality; changes in population-based incidence rates have not been reported. Methods We conducted active, population-based surveillance in metropolitan Atlanta, Georgia, and Baltimore City/County, Maryland (combined population 5.2 million), during 2008–2011. We calculated candidemia incidence and antifungal drug resistance compared with prior surveillance (Atlanta, 1992–1993; Baltimore, 1998–2000). Results We identified 2675 cases of candidemia with 2329 isolates during 3 years of surveillance. Mean annual crude incidence per 100 000 person-years was 13.3 in Atlanta and 26.2 in Baltimore. Rates were highest among adults aged ≥65 years (Atlanta, 59.1; Baltimore, 72.4) and infants (aged candidemia epidemiology over the past 2 decades. Adults aged ≥65 years replaced infants as the highest incidence group; adjusted incidence has declined significantly in infants. Use of antifungal prophylaxis, improvements in infection control, or changes in catheter insertion practices may be contributing to these declines. Further surveillance for antifungal resistance and efforts to determine effective prevention strategies are needed. PMID:22893576

  15. The Elements of Antifungal Drug Discovery

    DEFF Research Database (Denmark)

    Kjellerup, Lasse

    compounds (ZACs). Zinc is an important micronutrient and the immune system is known to operate with a similar mechanism to the ZACs by scavenging zinc from the site of infection, thus preventing the growth of pathogens through zinc starvation. In addition to the observations made about the ZAC compounds......In this PhD thesis I will explore the development of antifungal drugs. Fungal infections are estimated to cause the death of 1.5 million patients each year. There is currently a need for new antifungal drugs as the existing drugs are hampered by lack of broad-spectrum antifungal activity...

  16. Genetic determinants of antifungal resistance in Candida species ...

    African Journals Online (AJOL)

    In the previous decades, it has been an increase in cases of resistance to antifungal agents used in the prophylaxis and treatment of infections caused by Candida species. The emergence of resistance to drug classes, it is usually explained by genome alterations ranging from point mutations to gain or loss of whole ...

  17. ANTIBACTERIAL AND ANTIFUNGAL EFFECT OF ETHANOL EXTRACTS, HEXANE AND METHANOLIC FROM THE LEAVES OF Kalanchoe pinnata (Lam. PERS (Malva corama AGAINST MULTI-DRUG RESISTANT STRAINS

    Directory of Open Access Journals (Sweden)

    Paloma de Souza Santana

    2016-03-01

    Full Text Available The infections caused by bacteria and fungi, as well as the subsequent resistance of these microorganisms continue with high incidencesthus studies of medicinal plants and their combination with conventional therapy, are becoming essential. This study examined the antibacterial, antifungal and modifier of resistance to antibiotics and antifungal extracts of ethanol, hexane and methanol from the leaves of Kalanchoe pinnata, used in folk medicine. The phytochemical was performed qualitatively by visual observation of color changes and formation of precipitates after addition of specific reagents, such as ferric chloride (Fecl310% sodium hydroxide (NaOH10%, hydrochloric acid (HCl 1%, acid  acetic acid 5%, ammonium hydroxide (NH4OH 10%, chloroform and  reagent Draggendorff 10%. The analysis for antimicrobial activity was through the microdilution test for determination of minimum inhibitory concentration (MIC and modifying the action of antibiotics (gentamicin and amikacin and antifungals (ketoconazole and fluconazole in association with the extracts. The phytochemicals assays indicated the presence of secondary metabolites such as flavonoids, alkaloids and flabobênicos tannins. In assessing the MIC results were obtained <1024μg/ mL for Candida albicans and Candida krusei. There was synergism between extracts of Kalanchoe pinnata leaves with aminoglycosides and antifungal, reducing the concentration of CIM of multidrug-resistant strains. Our results demonstrate that the extracts of Kalanchoe pinnata have bioactive constituents with antimicrobial activity in vitro. Keywords: Kalcinchoe pinnata, Microorganisms, Synergistic effect, Antifungal, Antibacterial.

  18. Drug Resistance

    Science.gov (United States)

    ... infected with a drug-resistant strain of HIV. Drug-resistance testing results are used to decide which HIV medicines to include in a person’s first HIV regimen. After treatment is started, drug-resistance testing is repeated if ...

  19. Bibliometric analysis of literature on antifungal triazole resistance: 1980 - 2015.

    Science.gov (United States)

    Sweileh, Waleed M; Sawalha, Ansam F; Al-Jabi, Samah; Zyoud, Sa'ed H

    2017-03-01

    Triazole antifungal agents play an important role in the treatment of a wide range of fungal infections. Little is known about antifungal triazole drug resistance when compared to antibiotic resistance. Therefore, this study was carried out to give a bibliometric overview of literature on triazole antifungal drug resistance. Keywords related to triazole drug class and resistance were used in a search query in the Scopus search engine. The time span was set from 1980 to 2015. Data pertaining to growth of publications, the most active countries and institutions, the most cited articles, and mapping of molecular mechanisms of resistance were analyzed. A total of 1648 journal articles were retrieved with an average of 20.46 citations per article. Annual growth of triazole resistance showed an increasing pattern during the study period. The United States of America (n=446; 27.06%) ranked first in productivity followed by the United Kingdom (UK) (n=176; 10.68%), and China (n=133; 8.07%). Radboud University Nijmegen Medical Centre (n=69, 4.19%) in the Netherlands ranked first in productivity, while the journal Antimicrobial Agents and Chemotherapy ranked first (n=255; 15.47%) in publishing articles on triazole resistance. Mapping mechanisms of resistance showed that efflux pump and mutations in target enzyme are major mechanisms described in resistance to triazoles. There was a growth of publications on triazole resistance in the past two decades with the bulk of publications on triazole resistance in Candida species. The data presented here will serve as baseline information for future comparative purposes.

  20. Invasive Fungal Infections in Patients with Hematological Malignancies: Emergence of Resistant Pathogens and New Antifungal Therapies.

    Science.gov (United States)

    Gamaletsou, Maria N; Walsh, Thomas J; Sipsas, Nikolaos V

    2018-03-01

    Invasive fungal infections caused by drug-resistant organisms are an emerging threat to heavily immunosuppressed patients with hematological malignancies. Modern early antifungal treatment strategies, such as prophylaxis and empirical and preemptive therapy, result in long-term exposure to antifungal agents, which is a major driving force for the development of resistance. The extended use of central venous catheters, the nonlinear pharmacokinetics of certain antifungal agents, neutropenia, other forms of intense immunosuppression, and drug toxicities are other contributing factors. The widespread use of agricultural and industrial fungicides with similar chemical structures and mechanisms of action has resulted in the development of environmental reservoirs for some drug-resistant fungi, especially azole-resistant Aspergillus species, which have been reported from four continents. The majority of resistant strains have the mutation TR34/L98H, a finding suggesting that the source of resistance is the environment. The global emergence of new fungal pathogens with inherent resistance, such as Candida auris, is a new public health threat. The most common mechanism of antifungal drug resistance is the induction of efflux pumps, which decrease intracellular drug concentrations. Overexpression, depletion, and alteration of the drug target are other mechanisms of resistance. Mutations in the ERG11 gene alter the protein structure of C-demethylase, reducing the efficacy of antifungal triazoles. Candida species become echinocandin-resistant by mutations in FKS genes. A shift in the epidemiology of Candida towards resistant non-albicans Candida spp. has emerged among patients with hematological malignancies. There is no definite association between antifungal resistance, as defined by elevated minimum inhibitory concentrations, and clinical outcomes in this population. Detection of genes or mutations conferring resistance with the use of molecular methods may offer better

  1. Invasive Fungal Infections in Patients with Hematological Malignancies: Emergence of Resistant Pathogens and New Antifungal Therapies

    Directory of Open Access Journals (Sweden)

    Maria N. Gamaletsou

    2018-02-01

    Full Text Available Invasive fungal infections caused by drug-resistant organisms are an emerging threat to heavily immunosuppressed patients with hematological malignancies. Modern early antifungal treatment strategies, such as prophylaxis and empirical and preemptive therapy, result in long-term exposure to antifungal agents, which is a major driving force for the development of resistance. The extended use of central venous catheters, the nonlinear pharmacokinetics of certain antifungal agents, neutropenia, other forms of intense immunosuppression, and drug toxicities are other contributing factors. The widespread use of agricultural and industrial fungicides with similar chemical structures and mechanisms of action has resulted in the development of environmental reservoirs for some drug-resistant fungi, especially azole-resistant Aspergillus species, which have been reported from four continents. The majority of resistant strains have the mutation TR34/L98H, a finding suggesting that the source of resistance is the environment. The global emergence of new fungal pathogens with inherent resistance, such as Candida auris, is a new public health threat. The most common mechanism of antifungal drug resistance is the induction of efflux pumps, which decrease intracellular drug concentrations. Overexpression, depletion, and alteration of the drug target are other mechanisms of resistance. Mutations in the ERG11 gene alter the protein structure of C-demethylase, reducing the efficacy of antifungal triazoles. Candida species become echinocandin-resistant by mutations in FKS genes. A shift in the epidemiology of Candida towards resistant non-albicans Candida spp. has emerged among patients with hematological malignancies. There is no definite association between antifungal resistance, as defined by elevated minimum inhibitory concentrations, and clinical outcomes in this population. Detection of genes or mutations conferring resistance with the use of molecular methods

  2. Tolerability and safety of antifungal drugs

    Directory of Open Access Journals (Sweden)

    Francesco Scaglione

    2013-08-01

    Full Text Available When treating critically ill patients, as those with fungal infections, attention should be focused on the appropriate use of drugs, especially in terms of dose, safety, and tolerability. The fungal infection itself and the concomitant physiological disorders concur to increase the risk of mortality in these patients, therefore the use of any antifungal agent should be carefully evaluated, considering both the direct action on the target fungus and the adverse effects eventually caused. Among antifungal drugs, echinocandins have the greatest tolerability. In fact, unlike amphotericin B, showing nephrotoxicity, and azoles, which are hepatotoxic, the use of echinocandins doesn’t result in major adverse events.http://dx.doi.org/10.7175/rhc.v4i2s.873

  3. Isavuconazole, micafungin, and 8 comparator antifungal agents' susceptibility profiles for common and uncommon opportunistic fungi collected in 2013: temporal analysis of antifungal drug resistance using CLSI species-specific clinical breakpoints and proposed epidemiological cutoff values.

    Science.gov (United States)

    Pfaller, M A; Rhomberg, P R; Messer, S A; Jones, R N; Castanheira, M

    2015-08-01

    The in vitro activities of isavuconazole, micafungin, and 8 comparator antifungal agents were determined for 1613 clinical isolates of fungi (1320 isolates of Candida spp., 155 of Aspergillus spp., 103 of non-Candida yeasts, and 35 non-Aspergillus molds) collected during a global survey conducted in 2013. The vast majority of the isolates of the 21 different species of Candida, with the exception of Candida glabrata (MIC90, 2 μg/mL), Candida krusei (MIC90, 1 μg/mL), and Candida guilliermondii (MIC90, 8 μg/mL), were inhibited by ≤0.25 μg/mL of isavuconazole. C. glabrata and C. krusei were largely inhibited by ≤1 μg/mL of isavuconazole. Resistance to fluconazole was seen in 0.5% of Candida albicans isolates, 11.1% of C. glabrata isolates, 2.5% of Candida parapsilosis isolates, 4.5% of Candida tropicalis isolates, and 20.0% of C. guilliermondii isolates. Resistance to the echinocandins was restricted to C. glabrata (1.3-2.1%) and C. tropicalis (0.9-1.8%). All agents except for the echinocandins were active against 69 Cryptococcus neoformans isolates, and the triazoles, including isavuconazole, were active against the other yeasts. Both the mold active triazoles as well as the echinocandins were active against 155 Aspergillus spp. isolates belonging to 10 species/species complex. In general, there was low resistance levels to the available systemically active antifungal agents in a large, contemporary (2013), global collection of molecularly characterized yeasts and molds. Resistance to azoles and echinocandins was most prominent among isolates of C. glabrata, C. tropicalis, and C. guilliermondii. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Drug resistance

    NARCIS (Netherlands)

    Gorter, J.A.; Potschka, H.; Noebels, J.L.; Avoli, M.; Rogawski, M.A.; Olsen, R.W.; Delgado-Escueta, A.V.

    2012-01-01

    Drug resistance remains to be one of the major challenges in epilepsy therapy. Identification of factors that contribute to therapeutic failure is crucial for future development of novel therapeutic strategies for difficult-to-treat epilepsies. Several clinical studies have shown that high seizure

  5. In vitro antifungal activity of topical and systemic antifungal drugs against Malassezia species.

    Science.gov (United States)

    Carrillo-Muñoz, Alfonso Javier; Rojas, Florencia; Tur-Tur, Cristina; de Los Ángeles Sosa, María; Diez, Gustavo Ortiz; Espada, Carmen Martín; Payá, María Jesús; Giusiano, Gustavo

    2013-09-01

    The strict nutritional requirements of Malassezia species make it difficult to test the antifungal susceptibility. Treatments of the chronic and recurrent infections associated with Malassezia spp. are usually ineffective. The objective of this study was to obtain in vitro susceptibility profile of 76 clinical isolates of Malassezia species against 16 antifungal drugs used for topical or systemic treatment. Isolates were identified by restriction fragment length polymorphism. Minimal inhibitory concentrations (MIC) were obtained by a modified microdilution method based on the Clinical Laboratory Standards Institute reference document M27-A3. The modifications allowed a good growth of all tested species. High in vitro antifungal activity of most tested drugs was observed, especially triazole derivatives, except for fluconazole which presented the highest MICs and widest range of concentrations. Ketoconazole and itraconazole demonstrated a great activity. Higher MICs values were obtained with Malassezia furfur indicating a low susceptibility to most of the antifungal agents tested. Malassezia sympodialis and Malassezia pachydermatis were found to be more-susceptible species than M. furfur, Malassezia globosa, Malassezia slooffiae and Malassezia restricta. Topical substances were also active but provide higher MICs than the compounds for systemic use. The differences observed in the antifungals activity and interspecies variability demonstrated the importance to studying the susceptibility profile of each species to obtain reliable information for defining an effective treatment regimen. © 2013 Blackwell Verlag GmbH.

  6. Synergy and antagonism between iron chelators and antifungal drugs in Cryptococcus.

    Science.gov (United States)

    Lai, Yu-Wen; Campbell, Leona T; Wilkins, Marc R; Pang, Chi Nam Ignatius; Chen, Sharon; Carter, Dee A

    2016-10-01

    Fungal infections remain very difficult to treat, and developing new antifungal drugs is difficult and expensive. Recent approaches therefore seek to augment existing antifungals with synergistic agents that can lower the therapeutic dose, increase efficacy and prevent resistance from developing. Iron limitation can inhibit microbial growth, and iron chelators have been employed to treat fungal infections. In this study, chequerboard testing was used to explore combinations of iron chelators with antifungal agents against pathogenic Cryptococcus spp. with the aim of determining how disruption to iron homeostasis affects antifungal susceptibility. The iron chelators ethylenediaminetetraacetic acid (EDTA), deferoxamine (DFO), deferiprone (DFP), deferasirox (DSX), ciclopirox olamine and lactoferrin (LF) were paired with the antifungal agents amphotericin B (AmB), fluconazole, itraconazole, voriconazole and caspofungin. All chelators except for DFO increased the efficacy of AmB, and significant synergy was seen between AmB and LF for all Cryptococcus strains. Addition of exogenous iron rescued cells from the antifungal effect of LF alone but could not prevent inhibition by AmB + LF, indicating that synergy was not due primarily to iron chelation but to other properties of LF that were potentiated in the presence of AmB. Significant synergy was not seen consistently for other antifungal-chelator combinations, and EDTA, DSX and DFP antagonised the activity of azole drugs in strains of Cryptococcus neoformans var. grubii. This study highlights the range of interactions that can be induced by chelators and indicates that most antifungal drugs are not enhanced by iron limitation in Cryptococcus. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  7. Fixed Drug Eruptions To Two Chemically Unrelated Antifungal Agents

    Directory of Open Access Journals (Sweden)

    Khandpur Sujay

    2001-01-01

    Full Text Available An interesting episode of fixed drug eruption to two chemically unrelated antifungal agents (griseofulvin and fluconazole prescribed for onychomycosis in a 66- year â€" old male is being presented. The lesions developed at different sites. Oral challenge led to recurrence with both the drugs. However patch test with 10% fluconazole in petrolatum was negative.

  8. Mechanisms of Candida biofilm drug resistance

    Science.gov (United States)

    Taff, Heather T; Mitchell, Kaitlin F; Edward, Jessica A; Andes, David R

    2013-01-01

    Candida commonly adheres to implanted medical devices, growing as a resilient biofilm capable of withstanding extraordinarily high antifungal concentrations. As currently available antifungals have minimal activity against biofilms, new drugs to treat these recalcitrant infections are urgently needed. Recent investigations have begun to shed light on the mechanisms behind the profound resistance associated with the biofilm mode of growth. This resistance appears to be multifactorial, involving both mechanisms similar to conventional, planktonic antifungal resistance, such as increased efflux pump activity, as well as mechanisms specific to the biofilm lifestyle. A unique biofilm property is the production of an extracellular matrix. Two components of this material, β-glucan and extracellular DNA, promote biofilm resistance to multiple antifungals. Biofilm formation also engages several stress response pathways that impair the activity of azole drugs. Resistance within a biofilm is often heterogeneous, with the development of a subpopulation of resistant persister cells. In this article we review the molecular mechanisms underlying Candida biofilm antifungal resistance and their relative contributions during various growth phases. PMID:24059922

  9. Candidiasis and the impact of flow cytometry on antifungal drug discovery.

    Science.gov (United States)

    Ku, Tsun Sheng N; Bernardo, Stella; Walraven, Carla J; Lee, Samuel A

    2017-11-01

    Invasive candidiasis continues to be associated with significant morbidity and mortality as well as substantial health care costs nationally and globally. One of the contributing factors is the development of resistance to antifungal agents that are already in clinical use. Moreover, there are known treatment limitations with all of the available antifungal agents. Since traditional techniques in novel drug discovery are time consuming, high-throughput screening using flow cytometry presents as a potential tool to identify new antifungal agents that would be useful in the management of these patients. Areas covered: In this review, the authors discuss the use of automated high-throughput screening assays based upon flow cytometry to identify potential antifungals from a library comprised of a large number of bioactive compounds. They also review studies that employed the use of this research methodology that has identified compounds with antifungal activity. Expert opinion: High-throughput screening using flow cytometry has substantially decreased the processing time necessary for screening thousands of compounds, and has helped enhance our understanding of fungal pathogenesis. Indeed, the authors see this technology as a powerful tool to help scientists identify new antifungal agents that can be added to the clinician's arsenal in their fight against invasive candidiasis.

  10. Antifungal drug susceptibility of Candida albicans | Bii | East African ...

    African Journals Online (AJOL)

    Objective: To determine the susceptibility of clinical isolates of Candida albicans and to establish the minimum inhibitory concentrations (MIC) to commonly used antifungal drugs. Design: Laboratory based experiment. Setting: Mbagathi District Hospital, Nairobi, Kenya. Subjects: Candida albicans isolated between 1998 ...

  11. Mode of Antifungal Drugs Interaction with Cytochrome P- 450

    Directory of Open Access Journals (Sweden)

    M- Mahmodian

    1991-07-01

    Full Text Available Computer was used to identify the interactions of substrates and antifungal drugs with the enzyme, Cytochrome P-450; and then Molplot.bas computer program was applied to get three dimensional figures of 5-hydroxy camphor.oxidation products of camphor analogues, and antifungal drugs.Cartesian characteristics of atoms building molecules, are taken from Buildz. for program, which can calculate X,Y,Z coordinates of atoms by Zmatrix data. The other program which can calculate X,Y,Z coordinates, using fractional characteristics, is the Coord, for program that, gives our cartesian characteristics of the atoms of molecule, then by using these data, we obtain three dimensional figures and distance between active atoms in compounds under consideration. Results show that distance between two oxygen atoms in 5-exo-hydroxy- camphor and the other compounds obtained from oxidation of camphor analogues, with the distance of two oxygen atoms in antifungal compounds under discussion are equal. Therefore, we can conclude that, the antifungal molecule also interacts with enzyme's active site, by its own sites, in a similar manner to the 5-hydroxy camphor molecule, which is:"n1. Nitrogen atom (N of Imidazole and Triazole ring in antifungal molecule with Iron atom in heam molecule belonging to Cytochrome P-450 enzyme, are coordinated."n2. The other atoms such as : 0,S or N in structure of the antifungal drug are coordinated with hydrogen atom of hydroxyl group belong ing to Tyr-96 in the structure of enzyme, forming hydrogen bonding.

  12. Bibliometric analysis of literature on antifungal triazole resistance: 1980 – 2015

    Science.gov (United States)

    Sweileh, Waleed M.; Sawalha, Ansam F.; Al-Jabi, Samah; Zyoud, Sa’ed H.

    2017-01-01

    Background Triazole antifungal agents play an important role in the treatment of a wide range of fungal infections. Little is known about antifungal triazole drug resistance when compared to antibiotic resistance. Therefore, this study was carried out to give a bibliometric overview of literature on triazole antifungal drug resistance. Methods Keywords related to triazole drug class and resistance were used in a search query in the Scopus search engine. The time span was set from 1980 to 2015. Data pertaining to growth of publications, the most active countries and institutions, the most cited articles, and mapping of molecular mechanisms of resistance were analyzed. Results A total of 1648 journal articles were retrieved with an average of 20.46 citations per article. Annual growth of triazole resistance showed an increasing pattern during the study period. The United States of America (n=446; 27.06%) ranked first in productivity followed by the United Kingdom (UK) (n=176; 10.68%), and China (n=133; 8.07%). Radboud University Nijmegen Medical Centre (n=69, 4.19%) in the Netherlands ranked first in productivity, while the journal Antimicrobial Agents and Chemotherapy ranked first (n=255; 15.47%) in publishing articles on triazole resistance. Mapping mechanisms of resistance showed that efflux pump and mutations in target enzyme are major mechanisms described in resistance to triazoles. Conclusion There was a growth of publications on triazole resistance in the past two decades with the bulk of publications on triazole resistance in Candida species. The data presented here will serve as baseline information for future comparative purposes. PMID:28331838

  13. Drug Repurposing Approach Identifies a Synergistic Drug Combination of an Antifungal Agent and an Experimental Organometallic Drug for Melanoma Treatment.

    Science.gov (United States)

    Riedel, Tina; Demaria, Olivier; Zava, Olivier; Joncic, Ana; Gilliet, Michel; Dyson, Paul J

    2018-01-02

    By screening a drug library comprising FDA approved compounds, we discovered a potent interaction between the antifungal agent haloprogin and the experimental organometallic drug RAPTA-T, to synergistically induce cancer cell killing. The combination of these two small molecules, even at low doses, elicited an improved therapeutic response on tumor growth over either agent alone or the current treatment used in the clinic in the highly aggressive syngeneic B16F10 melanoma tumor model, where classical cytotoxic chemotherapeutic agents show little efficacy. The combination with the repurposed chemodrug haloprogin provides the basis for a new powerful treatment option for cutaneous melanoma. Importantly, because synergistic induction of tumor cell death is achieved with low individual drug doses, and cellular targets for RAPTA-T are different from those of classical chemotherapeutic drugs, a therapeutic strategy based on this approach could avoid toxicities and potentially resistance mechanisms, and could even inhibit metastatic progression.

  14. Anti-Candida albicans natural products, sources of new antifungal drugs: A review.

    Science.gov (United States)

    Zida, A; Bamba, S; Yacouba, A; Ouedraogo-Traore, R; Guiguemdé, R T

    2017-03-01

    Candida albicans is the most prevalent fungal pathogen in humans. Due to the development of drug resistance, there is today a need for new antifungal agents for the efficient management of C. albicans infections. Therefore, we reviewed antifungal activity, mechanisms of action, possible synergism with antifungal drugs of all natural substances experimented to be efficient against C. albicans for future. An extensive and systematic review of the literature was undertaken and all relevant abstracts and full-text articles analyzed and included in the review. A total of 111 documents were published and highlighted 142 anti-C. albicans natural products. These products are mostly are reported in Asia (44.37%) and America (28.17%). According to in vitro model criteria, from the 142 natural substances, antifungal activity can be considered as important for 40 (28.20%) and moderate for 24 (16.90%). Sixteen products have their antifungal activity confirmed by in vivo gold standard experimentation. Microbial natural products, source of antifungals, have their antifungal mechanism well described in the literature: interaction with ergosterol (polyenes), inhibition 1,3-β-d-glucan synthase (Echinocandins), inhibition of the synthesis of cell wall components (chitin and mannoproteins), inhibition of sphingolipid synthesis (serine palmitoyltransferase, ceramide synthase, inositol phosphoceramide synthase) and inhibition of protein synthesis (sordarins). Natural products from plants mostly exert their antifungal effects by membrane-active mechanism. Some substances from arthropods are also explored to act on the fungal membrane. Interestingly, synergistic effects were found between different classes of natural products as well as between natural products and azoles. Search for anti-C. albicans new drugs is promising since the list of natural substances, which disclose activity against this yeast is today long. Investigations must be pursued not only to found more new anti

  15. Repurposing antipsychotic drugs into antifungal agents: Synergistic combinations of azoles and bromperidol derivatives in the treatment of various fungal infections.

    Science.gov (United States)

    Holbrook, Selina Y L; Garzan, Atefeh; Dennis, Emily K; Shrestha, Sanjib K; Garneau-Tsodikova, Sylvie

    2017-10-20

    As the number of hospitalized and immunocompromised patients continues to rise, invasive fungal infections, such as invasive candidiasis and aspergillosis, threaten the life of millions of patients every year. The azole antifungals are currently the most prescribed drugs clinically that display broad-spectrum antifungal activity and excellent oral bioavailability. Yet, the azole antifungals have their own limitations and are unable to meet the challenges associated with increasing fungal infections and the accompanied development of resistance against azoles. Exploring combination therapy that involves the current azoles and another drug has been shown to be a promising strategy. Haloperidol and its derivative, bromperidol, were originally discovered as antipsychotics. Herein, we synthesize and report a series of bromperidol derivatives and their synergistic antifungal interactions in combination with a variety of current azole antifungals against a wide panel of fungal pathogens. We further select two representative combinations and confirm the antifungal synergy by performing time-kill assays. Furthermore, we evaluate the ability of selected combinations to destroy fungal biofilm. Finally, we perform mammalian cytotoxicity assays with the representative combinations against three mammalian cell lines. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  16. Drug-drug interactions of antifungal agents and implications for patient care.

    Science.gov (United States)

    Gubbins, Paul O; Amsden, Jarrett R

    2005-10-01

    Drug interactions in the gastrointestinal tract, liver and kidneys result from alterations in pH, ionic complexation, and interference with membrane transport proteins and enzymatic processes involved in intestinal absorption, enteric and hepatic metabolism, renal filtration and excretion. Azole antifungals can be involved in drug interactions at all the sites, by one or more of the above mechanisms. Consequently, azoles interact with a vast array of compounds. Drug-drug interactions associated with amphotericin B formulations are predictable and result from the renal toxicity and electrolyte disturbances associated with these compounds. The echinocandins are unknown cytochrome P450 substrates and to date are relatively devoid of significant drug-drug interactions. This article reviews drug interactions involving antifungal agents that affect other agents and implications for patient care are highlighted.

  17. Synergistic activity of antifungal drugs and lipopeptide AC7 against Candida albicans biofilm on silicone

    Directory of Open Access Journals (Sweden)

    Chiara Ceresa

    2017-04-01

    Full Text Available The occurrence of Candida albicans device-associated infections is tightly correlated to the ability of this fungus to form biofilms. The presence of this three-dimensional structure protects cells from host defenses, and significantly increases their resistance to antifungal agents. Lipopeptide biosurfactants are microbial products with interesting antibacterial, antifungal and anti-adhesive properties. Aim of the present study was to investigate a possible synergistic effect of lipopeptide AC7BS in combination with amphotericin B or fluconazole against C. albicans planktonic cells, biofilm formation and 24 h-old biofilms on medical-grade silicone elastomer disks, in simulated physiological conditions. In co-incubation experiments, AC7BS alone was not effective. However, the combination of AC7BS with the antifungal compounds resulted in a synergistic increase in the efficacy of the drugs against planktonic cells and biofilm, leading to a reduction of MICs and SMICs50. In pre-coating conditions, amphotericin B alone and AC7BS alone significantly inhibited C. albicans biofilms. When the two molecules were tested in association, a synergistic effect was observed on different phases of biofilm formation and a lower SMIC50 was detected. The observed synergism could be related to the combination of the AC7BS anti-adhesive activity and the AMB antifungal effect, but also to the ability of the biosurfactant to affect membranes, thus facilitating AMB entry in the cells. These results suggest that AC7BS can be considered a potential inhibitor of C. albicans biofilm on medical insertional materials and its use as coating agent may potentiate the effect of antifungal compounds such as AMB, when applied in combination.

  18. Antifungal therapy: drug-drug interactions at your fingertips

    NARCIS (Netherlands)

    Lempers, V.J.; Bruggemann, R.J.

    2016-01-01

    The Information Age has revolutionized the ability of healthcare professionals (HCPs) to oversee a substantial body of clinically relevant information literally at one's fingertips. In the field of clinical pharmacology, this may be particularly useful for managing drug-drug interactions (DDIs). A

  19. Antagonistic changes in sensitivity to antifungal drugs by mutations of an important ABC transporter gene in a fungal pathogen.

    Directory of Open Access Journals (Sweden)

    Wenjun Guan

    2010-06-01

    Full Text Available Fungal pathogens can be lethal, especially among immunocompromised populations, such as patients with AIDS and recipients of tissue transplantation or chemotherapy. Prolonged usage of antifungal reagents can lead to drug resistance and treatment failure. Understanding mechanisms that underlie drug resistance by pathogenic microorganisms is thus vital for dealing with this emerging issue. In this study, we show that dramatic sequence changes in PDR5, an ABC (ATP-binding cassette efflux transporter protein gene in an opportunistic fungal pathogen, caused the organism to become hypersensitive to azole, a widely used antifungal drug. Surprisingly, the same mutations conferred growth advantages to the organism on polyenes, which are also commonly used antimycotics. Our results indicate that Pdr5p might be important for ergosterol homeostasis. The observed remarkable sequence divergence in the PDR5 gene in yeast strain YJM789 may represent an interesting case of adaptive loss of gene function with significant clinical implications.

  20. Azole Antifungal Resistance in Candida albicans and Emerging Non-albicans Candida Species

    Science.gov (United States)

    Whaley, Sarah G.; Berkow, Elizabeth L.; Rybak, Jeffrey M.; Nishimoto, Andrew T.; Barker, Katherine S.; Rogers, P. David

    2017-01-01

    Within the limited antifungal armamentarium, the azole antifungals are the most frequent class used to treat Candida infections. Azole antifungals such as fluconazole are often preferred treatment for many Candida infections as they are inexpensive, exhibit limited toxicity, and are available for oral administration. There is, however, extensive documentation of intrinsic and developed resistance to azole antifungals among several Candida species. As the frequency of azole resistant Candida isolates in the clinical setting increases, it is essential to elucidate the mechanisms of such resistance in order to both preserve and improve upon the azole class of antifungals for the treatment of Candida infections. This review examines azole resistance in infections caused by C. albicans as well as the emerging non-albicans Candida species C. parapsilosis, C. tropicalis, C. krusei, and C. glabrata and in particular, describes the current understanding of molecular basis of azole resistance in these fungal species. PMID:28127295

  1. Proteomic profiling of the antifungal drug response of Aspergillus fumigatus to voriconazole.

    Science.gov (United States)

    Amarsaikhan, Nansalmaa; Albrecht-Eckardt, Daniela; Sasse, Christoph; Braus, Gerhard H; Ogel, Zumrut B; Kniemeyer, Olaf

    2017-10-01

    Antifungal resistance is an emerging problem and one of the reasons for treatment failure of invasive aspergillosis (IA). Voriconazole has become a standard therapeutic for the treatment of this often fatal infection. We studied the differentially expressed proteins as a response of Aspergillus fumigatus to voriconazole by employing the two-dimensional difference gel electrophoresis (DIGE) technique. Due to addition of drug, a total of 135 differentially synthesized proteins were identified by MALDI-TOF/TOF-mass spectrometry. In particular, the level of proteins involved in the general stress response and cell detoxification increased prominently. In contrast, cell metabolism and energy proteins were down-regulated, which suggests the cellular effort to maintain balance in energy utilization while trying to combat the cellular stress exerted by the drug. We detected several so-far uncharacterized proteins which may play a role in stress response and drug metabolism and which could be future targets for antifungal treatment. A mutant strain, which is deleted in the cross-pathway control gene cpcA, was treated with voriconazole to investigate the contribution of the general control of amino acid biosynthesis to drug resistance. We compared the mutant strain's protein expression profile with the wild-type strain. The absence of CpcA led to an increased resistance to voriconazole and a reduced activation of some general stress response proteins, while the transcript level of the triazole target gene erg11A (cyp51A) remained unchanged. In contrast, the sensitivity of strain ΔcpcA to terbinafine and amphotericin B was slightly increased. These findings imply a role of CpcA in the cellular stress response to azole drugs at the post transcriptional level. Copyright © 2017 Elsevier GmbH. All rights reserved.

  2. Synergistic combinations of antifungals and antivirulence agents to fight against Candida albicans

    DEFF Research Database (Denmark)

    Cui, Jinhui; Ren, Biao; Tong, Yaojun

    2015-01-01

    -drug resistance, demand innovative strategies for new effective antifungal drugs. Synergistic combinations of antifungals and anti-virulence agents highlight the pragmatic strategy to reduce the development of drug resistant and potentially repurpose known antifungals, which bypass the costly and time......-consuming pipeline of new drug development. Anti-virulence and synergistic combination provide new options for antifungal drug discovery by counteracting the difficulty or failure of traditional therapy for fungal infections....

  3. Environmental isolation, biochemical identification, and antifungal drug susceptibility of Cryptococcus species

    Directory of Open Access Journals (Sweden)

    Valter Luis Iost Teodoro

    2013-12-01

    Full Text Available Introduction The incidence of opportunistic fungal infections has increased in recent years and is considered an important public health problem. Among systemic and opportunistic mycoses, cryptococcosis is distinguished by its clinical importance due to the increased risk of infection in individuals infected by human immunodeficiency virus. Methods To determine the occurrence of pathogenic Cryptococcus in pigeon excrement in the City of Araraquara, samples were collected from nine environments, including state and municipal schools, abandoned buildings, parks, and a hospital. The isolates were identified using classical tests, and susceptibility testing for the antifungal drugs (fluconazole, itraconazole, voriconazole, and amphotericin B independently was also performed. After collection, the excrement samples were plated on Niger agar and incubated at room temperature. Results A total of 87 bird dropping samples were collected, and 66.6% were positive for the genus Cryptococcus. The following species were identified: Cryptococcus neoformans (17.2%, Cryptococcus gattii (5.2%, Cryptococcus ater (3.5%, Cryptococcus laurentti (1.7%, and Cryptococcus luteolus (1.7%. A total of 70.7% of the isolates were not identified to the species level and are referred to as Cryptococcus spp. throughout the manuscript. Conclusions Although none of the isolates demonstrated resistance to antifungal drugs, the identification of infested areas, the proper control of birds, and the disinfection of these environments are essential for the epidemiological control of cryptococcosis.

  4. Invasive Aspergillus terreus morphological transitions and immunoadaptations mediating antifungal resistance

    Directory of Open Access Journals (Sweden)

    Bengyella L

    2017-11-01

    Full Text Available Louis Bengyella,1–3 Elsie Laban Yekwa,4 Muhammad Nasir Subhani,5 Ernest Tambo,6,7 Kiran Nawaz,5 Bakoena Ashton Hetsa,2 Sehrish Iftikhar,5 Sayanika Devi Waikhom,1 Pranab Roy8 1Department of Biomedical Science, The School of Basic and Biomedical Sciences, University of Health and Allied Sciences, Ho, Ghana; 2Department of Biotechnology, Faculty of Applied and Computer Sciences, Vaal University of Technology, Vanderbijlpark, South Africa; 3Department of Biotechnology, University of Burdwan, Bardhaman, India; 4Division of Medical Virology, Stellenbosch University, Stellenbosch, South Africa; 5Department of Plant Pathology, Institute of Agricultural Sciences, University of the Punjab, Lahore, Pakistan; 6Department of Biochemistry and Pharmaceutical Sciences, Université des Montagnes, Bangangté, 7Department of Communications, Africa Disease Intelligence and Surveillance, Communication and Response Institute, Yaoundé, Cameroon; 8Department of Biotechnology, Haldia Institute of Technology, Haldia, India Background and aims: Aspergillus terreus Thom is a pathogen of public health and agricultural importance for its seamless abilities to expand its ecological niche. The aim of this study was holistically to investigate A. terreus morphological and immunoadaptations and their implication in antifungal resistance and proliferation during infection.Materials and methods: In-depth unstructured mining of relevant peer-reviewed literature was performed for A. terreus morphological, immune, resistance, and genetic diversity based on the sequenced calmodulin-like gene.Results: Accessory conidia and phialidic conidia produced by A. terreus confer discrete antifungal resistance that ensures survivability during therapies. Interestingly, by producing unique metabolites such as Asp–melanin and terretonin, A. terreus is capable of hijacking macrophages and scavenging iron, respectively. As such, A. terreus has established a rare mechanism to mitigate

  5. Epidemiology of antifungal resistance in human pathogenic yeasts: current viewpoint and practical recommendations for management.

    Science.gov (United States)

    Farmakiotis, Dimitrios; Kontoyiannis, Dimitrios P

    2017-09-01

    In this review, we describe the epidemiology and clinical significance of resistance in Candida spp. and other non-Cryptococcus yeasts. The rise in echinocandin resistance, azole resistance and cross-resistance to two or more antifungal classes [multidrug resistance (MDR)] has been a worrisome trend, mainly in US large tertiary and oncology centres, particularly as it relates to Candida glabrata. Candida kefyr is also a concern as it can be resistant to echinocandins and polyenes, especially in patients with haematological malignancies. Lately, Candida auris has drawn a lot of attention: this uncommon Candida spp. is the first globally emerging fungal pathogen that exhibits MDR and strong potential for nosocomial transmission. Its almost simultaneous spread in four continents could be indicative of increasing selection pressures from the use of antifungal agents. Echinocandin non-susceptibility is also common among non-Candida, non-Cryptococcus yeasts. As Candida resistance patterns reflect, in part, institutional practices of antifungal administration, the benefits of antifungal stewardship protocols are increasingly recognised and endorsed in recent guidelines. Development of rapid diagnostic methods for detecting or ruling out the presence of candidaemia and antifungal resistance, as well as discovery of novel antifungals, are key priorities in medical mycology research. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  6. Drug-resistant tuberculosis

    African Journals Online (AJOL)

    The epidemic of drug-resistant tuberculosis. (DR-TB) is a public health emergency that threatens to destabilise global TB control. Although TB incidence and mortality are decreasing in several parts of the world, the overall prevalence of multidrug-resistant tuberculosis (MDR-TB) is increasing in many high-burden countries, ...

  7. Antifungal activity of terrestrial Streptomyces rochei strain HF391 against clinical azole -resistant Aspergillus fumigatus

    Science.gov (United States)

    Hadizadeh, S; Forootanfar, H; Shahidi Bonjar, GH; Falahati Nejad, M; Karamy Robati, A; Ayatollahi Mousavi, SA; Amirporrostami, S

    2015-01-01

    Background and Purpose: Actinomycetes have been discovered as source of antifungal compounds that are currently in clinical use. Invasive aspergillosis (IA) due to Aspergillus fumigatus has been identified as individual drug-resistant Aspergillus spp. to be an emerging pathogen opportunities a global scale. This paper described the antifungal activity of one terrestrial actinomycete against the clinically isolated azole-resistant A. fumigatus. Materials and Methods: Soil samples were collected from various locations of Kerman, Iran. Thereafter, the actinomycetes were isolated using starch-casein-nitrate-agar medium and the most efficient actinomycetes (capable of inhibiting A. fumigatus) were screened using agar block method. In the next step, the selected actinomycete was cultivated in starch-casein- broth medium and the inhibitory activity of the obtained culture broth was evaluated using agar well diffusion method. Results: The selected actinomycete, identified as Streptomyces rochei strain HF391, could suppress the growth of A. fumigatus isolates which was isolated from the clinical samples of patients treated with azoles. This strain showed higher inhibition zones on agar diffusion assay which was more than 15 mm. Conclusion: The obtained results of the present study introduced Streptomyces rochei strain HF391 as terrestrial actinomycete that can inhibit the growth of clinically isolated A. fumigatus. PMID:28680984

  8. Susceptibility of Selected Multi-Drug Resistant Clinical Isolates to ...

    African Journals Online (AJOL)

    2018-03-01

    Mar 1, 2018 ... pharmacological potentials that could show efficiency in the treatment of bacterial infections. Keywords: Carpolobia lutea, antifungal, antibacterial, multi-drug ..... Antimicrobial Resistance 2016;7: 41-144. 21. Yoon Y, Kim J, Sohn J, Yang K, Kim M. Role of piperacillin/tazobactam as a carbapenem-sparing.

  9. Quantitative and qualitative analysis of the antifungal activity of allicin alone and in combination with antifungal drugs.

    Directory of Open Access Journals (Sweden)

    Young-Sun Kim

    Full Text Available The antifungal activity of allicin and its synergistic effects with the antifungal agents flucytosine and amphotericin B (AmB were investigated in Candida albicans (C. albicans. C. albicans was treated with different conditions of compounds alone and in combination (allicin, AmB, flucytosine, allicin + AmB, allicin + flucytosine, allicin + AmB + flucytosine. After a 24-hour treatment, cells were examined by scanning electron microscopy (SEM and atomic force microscopy (AFM to measure morphological and biophysical properties associated with cell death. The clearing assay was conducted to confirm the effects of allicin. The viability of C. albicans treated by allicin alone or with one antifungal drug (AmB, flucytosine in addition was more than 40% after a 24-hr treatment, but the viability of groups treated with combinations of more than two drugs was less than 32%. When the cells were treated with allicin alone or one type of drug, the morphology of the cells did not change noticeably, but when cells were treated with combinations of drugs, there were noticeable morphological changes. In particular, cells treated with allicin + AmB had significant membrane damage (burst or collapsed membranes. Classification of cells according to their cell death phase (CDP allowed us to determine the relationship between cell viability and treatment conditions in detail. The adhesive force was decreased by the treatment in all groups compare to the control. Cells treated with AmB + allicin had a greater adhesive force than cells treated with AmB alone because of the secretion of molecules due to collapsed membranes. All cells treated with allicin or drugs were softer than the control cells. These results suggest that allicin can reduce MIC of AmB while keeping the same efficacy.

  10. Flow cytometry susceptibility testing for conventional antifungal drugs and Comparison with the NCCLS Broth Macrodilution Test

    Directory of Open Access Journals (Sweden)

    M.J. Najafzadeh

    2009-08-01

    Full Text Available Introduction: During the last decade, the incidence of fungal infection has been increased in many countries. Because of the advent of resistant to antifungal agents, determination of an efficient strategic plan for treatment of fungal disease is an important issue in clinical mycology. Many methods have been introduced and developed for determination of invitro susceptibility tests. During the recent years, flow cytometry has developed to solving the problem and many papers have documented the usefulness of this technique. Materials and methods: As the first step, the invitro susceptibility of standard PTCC (Persian Type of Culture Collection strain and some clinical isolates of Candida consisting of Candida albicans, C. dubliniensis, C. glabrata, C. kefyer and C. parapsilosis were evaluated by macrodilution broth method according to NCCLS (National Committee for Clinical Laboratory Standards guidelines and flow cytometry susceptibility test. Results:  The data indicated that macro dilution broth methods and flow cytometry have the same results in determination of MIC (Minimum Inhibitory Concentration for amphotericin B, clotrimazole, fluconazole, ketoconazole and miconazole in C. albicans PTCC 5027 as well as clinical Candida isolates, such as C.albicans, C.dubliniensis, C.glabrata C.kefyr, and C.parapsilosis. Discussion: Comparing the results obtained by macrodilution broth and flow cytometry methods revealed that flow cytometry was faster. It is suggested that flow cytometry susceptibility test can be used as a powerful tool for determination of MIC and administration of the best antifungal drug in treatment of patients with Candida infections.

  11. Kinetically Controlled Drug Resistance

    DEFF Research Database (Denmark)

    Sun, Xin E.; Hansen, Bjarne Gram; Hedstrom, Lizbeth

    2011-01-01

    The filamentous fungus Penicillium brevicompactum produces the immunosuppressive drug mycophenolic acid (MPA), which is a potent inhibitor of eukaryotic IMP dehydrogenases (IMPDHs). IMPDH catalyzes the conversion of IMP to XMP via a covalent enzyme intermediate, E-XMP*; MPA inhibits by trapping E...... of resistance is not apparent. Here, we show that, unlike MPA-sensitive IMPDHs, formation of E-XMP* is rate-limiting for both PbIMPDH-A and PbIMPDH-B. Therefore, MPA resistance derives from the failure to accumulate the drug-sensitive intermediate....

  12. Drug resistance in malaria

    Directory of Open Access Journals (Sweden)

    S C Parija

    2011-01-01

    Full Text Available Antimalarial chemotherapy is an important component of all malaria control programmes throughout the world. This is especially so in light of the fact that there are no antimalarial vaccines which are available for clinical use at present. Emergence and spread of malaria parasites which are resistant to many of the available antimalarials today is, therefore, a major cause for concern. Till date, resistance to all groups of antimalarials excluding artemisinin has been reported. In recent years, in vitro resistance to even artemisinin has been described. While resistance to antibacterial agents has come to prominence as a clinical problem in recent years, antiparasitic resistance in general and antimalarial resistance in particular has not received much attention, especially in the Indian scenario. The present review deals with commonly used antimalarial drugs and the mechanisms of resistance to them. Various methods of detecting antimalarial resistance and avoiding the same have also been dealt with. Newer parasite targets which can be used in developing newer antimalarial agents and antimalarials obtained from plants have also been mentioned.

  13. Adverse events of modern antifungal drugs during treatment of invasive fungal infections

    Directory of Open Access Journals (Sweden)

    N. V. Dmitrieva

    2013-01-01

    Full Text Available Characteristics of adverse events of modern antimycotics by organ systems and comparative frequency between different medicines and their groups are presented. The examples of incompatibility of antifungal drugs with other pharmacological groups are discussed. Records of adverse events and drug compatibility will allow the practitioner to prevent and timely cure possible complications, should they arise.

  14. Investigation of the antifungal potential of linalool against clinical isolates of fluconazole resistant Trichophyton rubrum.

    Science.gov (United States)

    de Oliveira Lima, M I; Araújo de Medeiros, A C; Souza Silva, K V; Cardoso, G N; de Oliveira Lima, E; de Oliveira Pereira, F

    2017-06-01

    The aim of this study was to investigate the activity of the monoterpene linalool against clinical isolates of Trichophyton rubrum. Initially, a sensitivity assay for commercial antifungals with solid disks in diffusion medium was performed. Minimum inhibitory concentration (MIC) of linalool and ketoconazole (positive control) were determined by microdilution in RPMI 1640 medium (CLSI M38-A2). We then evaluated the action of linalool and ketoconazole at different concentrations (1/2MIC, MIC and 2×MIC) on mycelial growth (radial mycelial growth), conidia production and conidia germination using a hemacytometer. The effects on cell membrane (release of intracellular material) were also investigated. Finally, changes in fungal morphology as induced by the test drugs were analyzed. Based on the sensitivity tests, the fungal strains showed resistance to 5-fluorocytosine and fluconazole. The linalool MIC values ranged from 256μg/mL to 512μg/mL, whereas ketoconazole showed values of 4μg/mL to 8μg/mL. For the LM 305 strain, the test drugs showed the following MIC values: linalool 256μg/mL and ketoconazole 8μg/mL. The mycelial growth of T. rubrum LM 305 was inhibited by linalool (2×MIC) and ketoconazole (1/2MIC, MIC, 2×MIC), in 7 days of treatment (PLinalool also caused leakage of intracellular material (Plinalool and ketoconazole to induce micro-morphological changes, forming abnormal, wide, short and crooked hyphae. Based on these results, we conclude that linalool presents as an antifungal agent with anti-Trichophyton rubrum potential, an important dermatophytosis agent. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  15. Drug resistance in cancer cells

    National Research Council Canada - National Science Library

    Mehta, Kapil, Dr; Siddik, Zahid H

    2009-01-01

    ... from disappointment with the drug resistance reversal strategies that were carried out in the 1990s using pump inhibitors to block drug resistance mediated by P-glycoprotein, product of the MDR-1 gene. However, if one takes the larger definition - multidrug resistance as simultaneous resistance to multiple structurally unrelated anticancer therapies - its...

  16. Usefulness of intraventricular infusion of antifungal drugs through Ommaya reservoirs for cryptococcal meningitis treatment.

    Science.gov (United States)

    Nakama, Tatsuya; Yamashita, Satoshi; Hirahara, Tomoo; Okamoto, Sadahisa; Honda, Shoji; Watanabe, Masaki; Kimura, En; Uchino, Makoto; Yano, Shigetoshi; Kuratsu, Jun-ichi; Ando, Yukio

    2015-11-15

    Cryptococcal meningitis is a severe infection among immunosuppressed individuals, with a high mortality rate. Although amphotericin B is the first-choice drug for treatment, its use is restricted when adverse effects are clinically problematic. The usefulness of intraventricular infusion of antifungal drugs through Ommaya reservoirs for cryptococcal meningitis treatment has been unconfirmed. We evaluated the efficacy of intraventricular infusion of amphotericin B through Ommaya reservoirs. We retrospectively analyzed 10 consecutive patients with cryptococcal meningitis who were refractory to systemic administration of antifungal drugs. Fever or nausea occurred in most patients. However, no patient complained of serious complications such as renal toxicity. Seven patients recovered completely or partially, whereas three patients died. To establish the efficacy of the intraventricular infusion of antifungal drugs through Ommaya reservoirs for cryptococcal meningitis, a prospective investigation should be designed to compare those treated according to the updated guidelines and those treated with antifungal drugs through the Ommaya reservoirs. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Genetic engineering of crop plants for fungal resistance: role of antifungal genes.

    Science.gov (United States)

    Ceasar, S Antony; Ignacimuthu, S

    2012-06-01

    Fungal diseases damage crop plants and affect agricultural production. Transgenic plants have been produced by inserting antifungal genes to confer resistance against fungal pathogens. Genes of fungal cell wall-degrading enzymes, such as chitinase and glucanase, are frequently used to produce fungal-resistant transgenic crop plants. In this review, we summarize the details of various transformation studies to develop fungal resistance in crop plants.

  18. Development of fluconazole resistance in a series of Candida parapsilosis isolates from a persistent candidemia patient with prolonged antifungal therapy.

    Science.gov (United States)

    Zhang, Li; Xiao, Meng; Watts, Matthew R; Wang, He; Fan, Xin; Kong, Fanrong; Xu, Ying-Chun

    2015-08-18

    Candida parapsilosis was the most common species causing candidemia in the 2010 China Hospital Invasive Fungal Surveillance Net (CHIF-NET) database. Compared to Candida albicans, the description of azole resistance and mechanisms in C. parapsilosis is very limited. We report a patient with C. parapsilosis candidemia over several months, due to a probable intravascular source, who developed fluconazole resistance after prolonged treatment. An 82 year-old male had a hospital admission of approximately 1.5 years duration. He was initially admitted with acute pancreatitis. Prior to succumbing to the illness, he developed candidemia and treated with three antifungal drugs for nearly 5 months, at suboptimal doses and without source control. Following treatment, 6 blood cultures were still positive for C. parapsilosis. The last 2 strains were resistant to fluconazole (MICs 32 μg/mL) and intermediate to voriconazole (MICs 0.5 μg/mL). Microsatellite multilocus analysis indicated that the 6 isolates from the patient belonged to a single genotype. The first 4 isolates were susceptible to fluconazole (MICs 2 μg/mL) and voriconazole (MICs 0.015-0.03 μg/mL), which were slightly higher than susceptible control strains from other patients. Overexpression of MDR1 genes were detected in the two resistant isolates, and this was associated with a homozygous mutation in MRR1 genes (T2957C /T2957C), with the amino acid exchange L986P. This case corroborates that the resistant C. parapsilosis isolates can emerge in the setting of complicated infections and the extensive use of antifungal agents, emphasizing the need for standardizing and improving the antifungal treatment as well as source control in the treatment of infection diseases.

  19. [Genotyping of Vaginal Candida glabrata Isolates Using Microsatellite Marker Analysis and DNA Sequencing to Identify Mutations Associated with Antifungal Resistance].

    Science.gov (United States)

    Döğen, Aylin; Durukan, Hüseyin; Güzel, Ahmet Barış; Oksüz, Zehra; Kaplan, Engin; Serin, Mehmet Sami; Serin, Ayşe; Emekdaş, Gürol; Aslan, Gönül; Tezcan, Seda; Kalkancı, Ayşe; Ilkit, Macit

    2013-01-01

    Vulvovaginal candidosis is the second most common cause of vaginitis (17-39%) after bacterial vaginosis (22-50%). Since the diagnosis of vulvovaginal candidosis mainly depends on clinical findings without mycologic confirmatory tests and treated empirically, the actual incidence rate of vulvovaginal candidosis is unknown. Approximately 70-90% of vulvovaginal candidosis cases are caused by Candida albicans, however the increasing incidence of C.glabrata infections and its reduced susceptibility to azole drug therapy have generated increasing attention. The epidemiology and population structure of vulvovaginal candidosis due to C.glabrata are poorly characterized. This study was aimed to genotype the C.glabrata strains isolated from vaginal samples in Cukurova region, Turkey by microsatellite markers, to investigate the antifungal susceptibility profiles of the strains and to determine the molecular mechanisms leading to phenotypical azole resistance. A total of 34 unrelated vaginal C.glabrata strains isolated from patients with acute (n= 11) and recurrent (n= 14) vulvovaginal candidosis, control group (n= 9) without vaginitis symptoms, and a reference strain of C.glabrata CBS 138 (ATCC 2001) were included in the study. These isolates were genotyped using multiple-locus variable number tandem repeat analysis of three microsatellite markers (RPM2, MTI, and Cg6). Analysis of microsatellite markers was performed by fragment size determination of RPM2, MTI, and Cg6 PCR products through capillary electrophoresis. For each of the evaluated strains, DNA sequence analysis was performed for one gene (CgERG11) and four loci (CgPDR1, NTM1, TRP1, and URA3) to detect mutations possibly associated with antifungal resistance in each strain. In vitro susceptibility profiles of the strains to 13 antifungals and boric acid were determined according to CLSI document M27-A3 to investigate possible relationships between detected mutations and phenotypic resistance. C.glabrata CBS 138

  20. Rapid identification of antifungal compounds against Exserohilum rostratum using high throughput drug repurposing screens.

    Directory of Open Access Journals (Sweden)

    Wei Sun

    Full Text Available A recent large outbreak of fungal infections by Exserohilum rostratum from contaminated compounding solutions has highlighted the need to rapidly screen available pharmaceuticals that could be useful in therapy. The present study utilized two newly-developed high throughput assays to screen approved drugs and pharmaceutically active compounds for identification of potential antifungal agents. Several known drugs were found that have potent effects against E. rostratum including the triazole antifungal posaconazole. Posaconazole is likely to be effective against infections involving septic joints and may provide an alternative for refractory central nervous system infections. The anti-E. rostratum activities of several other drugs including bithionol (an anti-parasitic drug, tacrolimus (an immunosuppressive agent and floxuridine (an antimetabolite were also identified from the drug repurposing screens. In addition, activities of other potential antifungal agents against E. rostratum were excluded, which may avoid unnecessary therapeutic trials and reveals the limited therapeutic alternatives for this outbreak. In summary, this study has demonstrated that drug repurposing screens can be quickly conducted within a useful time-frame. This would allow clinical implementation of identified alternative therapeutics and should be considered as part of the initial public health response to new outbreaks or rapidly-emerging microbial pathogens.

  1. Transgenic maize plants expressing the Totivirus antifungal protein, KP4, are highly resistant to corn smut.

    Science.gov (United States)

    Allen, Aron; Islamovic, Emir; Kaur, Jagdeep; Gold, Scott; Shah, Dilip; Smith, Thomas J

    2011-10-01

    The corn smut fungus, Ustilago maydis, is a global pathogen responsible for extensive agricultural losses. Control of corn smut using traditional breeding has met with limited success because natural resistance to U. maydis is organ specific and involves numerous maize genes. Here, we present a transgenic approach by constitutively expressing the Totivirus antifungal protein KP4, in maize. Transgenic maize plants expressed high levels of KP4 with no apparent negative impact on plant development and displayed robust resistance to U. maydis challenges to both the stem and ear tissues in the greenhouse. More broadly, these results demonstrate that a high level of organ independent fungal resistance can be afforded by transgenic expression of this family of antifungal proteins. © 2011 The Authors. Plant Biotechnology Journal © 2011 Society for Experimental Biology, Association of Applied Biologists and Blackwell Publishing Ltd.

  2. Phenotypic switching of Candida guilliermondii is associated with pseudohyphae formation and antifungal resistance.

    Science.gov (United States)

    Lastauskienė, Eglė; Čeputytė, Jolita; Girkontaitė, Irutė; Zinkevičienė, Auksė

    2015-04-01

    Switching between two cell types in fungi is called phenotypic switching, and it is commonly observed in pathogenic yeast. Candida lusitaniae undergoes antifungal resistance-associated phenotypic switching and results in three colony colors: light brown, brown and dark brown. In this study, we included C. lusitaniae as control. This study had two objectives. First, we wanted to evaluate whether also a prevalent human pathogen C. guilliermondii can undergo phenotypic switching. Second, our aim was to determine whether switching can change yeasts susceptibility to antifungals. Yeast suspension (1 × 10(3)-5 × 10(3) c.f.u./ml) was plated on the YPD medium containing 1 mM CuSO4. Colonies exhibiting the original and variant phenotypes were counted and converted to percentage of the population. Minimum inhibitory concentrations of amphotericin B, formic acid and acetic acid for the cells from random colonies of the different phenotypes were determined by microdilution method. After 5 days of incubation, C. guilliermondii switched spontaneously and reversibly among two phenotypes distinguishable on CuSO4 containing agar, white and dark brown. Phenotypes occurred with greater frequency (10(-1)-10(-2)) than spontaneous mutations and were reversible, fulfilling the two phenotypic switching criteria. The study showed that phenotypic switching was associated with filamentation and affected antifungal resistance. Resistance to amphotericin B increased tenfold and was associated with C. lusitaniae dark brown phenotype. C. guilliermondii colonies with brown phenotype displayed 20 and 2 times higher resistance to amphotericin B and acetic acid, respectively.

  3. Lamisil, a potent alternative antifungal drug for otomycosis

    Directory of Open Access Journals (Sweden)

    Ali Zarei Mahmoudabadi

    2015-01-01

    Results: Out of 23 isolates of Aspergillus, Candida 4(17.4% and 1(4.4% were resistant to nystatin and miconazole, respectively. In addition, all tested organisms were sensitive to clotrimazole and terbinafine. Statistical analysis has shown that there are no significant differences on the effects of clotrimazole, miconazole and, terbinafine on saprophytic (environmental and pathogenic isolates of A. niger, A. flavus, and A. terreus (P value= 0.85. In addition, all tested organisms were found to be highly susceptible to terbinafine (P< 0.04. Conclusion: This is a new approach for the possible use of Lamisil for the treatment of otomycosis.

  4. Regulatory circuitry governing fungal development, drug resistance, and disease.

    Science.gov (United States)

    Shapiro, Rebecca S; Robbins, Nicole; Cowen, Leah E

    2011-06-01

    Pathogenic fungi have become a leading cause of human mortality due to the increasing frequency of fungal infections in immunocompromised populations and the limited armamentarium of clinically useful antifungal drugs. Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus are the leading causes of opportunistic fungal infections. In these diverse pathogenic fungi, complex signal transduction cascades are critical for sensing environmental changes and mediating appropriate cellular responses. For C. albicans, several environmental cues regulate a morphogenetic switch from yeast to filamentous growth, a reversible transition important for virulence. Many of the signaling cascades regulating morphogenesis are also required for cells to adapt and survive the cellular stresses imposed by antifungal drugs. Many of these signaling networks are conserved in C. neoformans and A. fumigatus, which undergo distinct morphogenetic programs during specific phases of their life cycles. Furthermore, the key mechanisms of fungal drug resistance, including alterations of the drug target, overexpression of drug efflux transporters, and alteration of cellular stress responses, are conserved between these species. This review focuses on the circuitry regulating fungal morphogenesis and drug resistance and the impact of these pathways on virulence. Although the three human-pathogenic fungi highlighted in this review are those most frequently encountered in the clinic, they represent a minute fraction of fungal diversity. Exploration of the conservation and divergence of core signal transduction pathways across C. albicans, C. neoformans, and A. fumigatus provides a foundation for the study of a broader diversity of pathogenic fungi and a platform for the development of new therapeutic strategies for fungal disease.

  5. Drug-resistant spinal tuberculosis

    Directory of Open Access Journals (Sweden)

    Anil K Jain

    2018-01-01

    Full Text Available Drug-resistant spinal tuberculosis (TB is an emerging health problem in both developing and developed countries. In this review article, we aim to define management protocols for suspicion, diagnosis, and treatment of such patients. Spinal TB is a deep-seated paucibacillary lesion, and the demonstration of acid-fast bacilli on Ziehl-Neelsen staining is possible only in 10%–30% of cases. Drug resistance is suspected in patients showing the failure of clinicoradiological improvement or appearance of a fresh lesion of osteoarticular TB while on anti tubercular therapy (ATT for a minimum period of 5 months. The conventional culture of Mycobacterium tuberculosis remains the gold standard for both bacteriological diagnosis and drug sensitivity testing (DST; however, the high turn around time of 2–6 weeks for detection with added 3 weeks for DST is a major limitation. To overcome this problem, rapid culture methods and molecular methods have been introduced. From a public health perspective, reducing the period between diagnosis and treatment initiation has direct benefits for both the patient and the community. For all patients of drug-resistant spinal TB, a complete Drug-O-Gram should be prepared which includes details of all drugs, their doses, and duration. Patients with confirmed multidrug-resistant TB strains should receive a regimen with at least five effective drugs, including pyrazinamide and one injectable. Patients with resistance to additional antitubercular drugs should receive individualized ATT as per their DST results.

  6. Drug-resistant Spinal Tuberculosis.

    Science.gov (United States)

    Jain, Anil K; Jaggi, Karan Raj; Bhayana, Himanshu; Saha, Rumpa

    2018-01-01

    Drug-resistant spinal tuberculosis (TB) is an emerging health problem in both developing and developed countries. In this review article, we aim to define management protocols for suspicion, diagnosis, and treatment of such patients. Spinal TB is a deep-seated paucibacillary lesion, and the demonstration of acid-fast bacilli on Ziehl-Neelsen staining is possible only in 10%-30% of cases. Drug resistance is suspected in patients showing the failure of clinicoradiological improvement or appearance of a fresh lesion of osteoarticular TB while on anti tubercular therapy (ATT) for a minimum period of 5 months. The conventional culture of Mycobacterium tuberculosis remains the gold standard for both bacteriological diagnosis and drug sensitivity testing (DST); however, the high turn around time of 2-6 weeks for detection with added 3 weeks for DST is a major limitation. To overcome this problem, rapid culture methods and molecular methods have been introduced. From a public health perspective, reducing the period between diagnosis and treatment initiation has direct benefits for both the patient and the community. For all patients of drug-resistant spinal TB, a complete Drug-O-Gram should be prepared which includes details of all drugs, their doses, and duration. Patients with confirmed multidrug-resistant TB strains should receive a regimen with at least five effective drugs, including pyrazinamide and one injectable. Patients with resistance to additional antitubercular drugs should receive individualized ATT as per their DST results.

  7. In vitro inhibitory effects of farnesol and interactions between farnesol and antifungals against biofilms of Candida albicans resistant strains.

    Science.gov (United States)

    Xia, Jinping; Qian, Fang; Xu, Wenqian; Zhang, Zhenzhen; Wei, Xin

    2017-04-01

    Antifungal resistance is a serious problem in clinical infections. Farnesol, which is a potential antifungal agent against biofilms formed by Candida albicans resistant strains (a fluconazole-resistant isolate derived from SC5314 and two clinical Candida resistant isolates), was investigated in this study. The inhibitory effects of farnesol on biofilms were examined by XTT assay. The morphological changes and biofilm thicknesses were analyzed by scanning electron microscopy and confocal laser scanning microscopy, respectively. Additionally, the checkerboard microdilution method was used to investigate the interactions between farnesol and antifungals (fluconazole, amphotericin B, caspofungin, itraconazole, terbinafine and 5-flurocytosine) against biofilms. The results showed decreased SMICs of farnesol and thinner biofilms in the farnesol-treated groups, indicating that farnesol inhibited the development of biofilms formed by the resistant strain. Furthermore, there were synergistic effects between farnesol and fluconazole/5-flurocytosine, while there were antagonistic effects between farnesol and terbinafine/itraconazole, respectively, on the biofilms formed by the resistant strains.

  8. Is antifungal resistance a cause for treatment failure in dermatophytosis: A study focused on tinea corporis and cruris from a tertiary centre?

    Directory of Open Access Journals (Sweden)

    Kabir Sardana

    2018-01-01

    Full Text Available Background: Dermatophytoses are one of the most common skin diseases that have been largely simple to treat. However, in recent years, these infections have become recalcitrant to treatment which can possibly be due to antifungal resistance. Aim: To analyze the resistance pattern of patients with recalcitrant dermatophytoses. Materials and Methods: A cross-sectional evaluation was undertaken of 40 consecutive patients with recalcitrant tinea corporis/cruris/both who had taken systemic antifungal treatment and did not respond completely to therapy or had recurrent lesion within 1 month of stopping the therapy. Terbinafine, fluconazole, itraconazole, ketoconazole, amphotericin B, and voriconazole were the antifungals tested using broth microdilution assay for antifungal susceptibility testing of dermatophytes, and MIC50, 90 values were recorded. Results: KOH mount was positive in 18 (45% patients, culture was positive in 28 (70% patients. Trichophyton mentagrophytes (35% and T. rubrum (27.5% were the predominant isolates. Overall, activity of terbinafine and itraconazole were significantly higher than the other drugs tested. For terbinafine, both T. mentagrophytes and T. rubrum were inhibited at MIC90of 0.125 μg/ml. Itraconazole-inhibited T. mentagrophytes and T. rubrum at MIC90of 0.0625 and 0.25 μg/ml, respectively. All isolates had reduced susceptibility to fluconazole. Conclusion: While MIC seen were higher than western data, in-vitro resistance (>1 μg/ml to antifungals was not seen and probably may not be a cause of treatment failure. Possibly, treatment failure lies in the intricate host fungal interaction and virulence of species which help it to evade host immune response.

  9. Posttreatment Antifungal Resistance among Colonizing Candida Isolates in Candidemia Patients

    DEFF Research Database (Denmark)

    Jensen, R H; Johansen, H K; Søes, L M

    2015-01-01

    The prevalence of intrinsic and acquired resistance among colonizing Candida isolates from patients after candidemia was investigated systematically in a 1-year nationwide study. Patients were treated at the discretion of the treating physician. Oral swabs were obtained after treatment. Species...... distributions and MIC data were investigated for blood and posttreatment oral isolates from patients exposed to either azoles or echinocandins for assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and internal...

  10. 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.

    Directory of Open Access Journals (Sweden)

    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.

  11. Antimicrobial (Drug) Resistance

    Science.gov (United States)

    ... causes of resistance. Learn more about research and investigations currently underway . Clinical Research Clinical research projects related ... Interest for NIAID’s Small Business Program Division of AIDS High-Priority Areas of Interest Division of Allergy, ...

  12. A case of Candida famata sepsis in a very low birth weight infant successfully treated with fluconazole following antifungal susceptibility testing

    Directory of Open Access Journals (Sweden)

    Shilpee Raturi

    2015-01-01

    This case report highlights the growing number of cases arising due to nonalbicans Candida infections in the neonatal intensive care units and the usefulness of antifungal susceptibility testing in deciding optimal antifungal therapy and preventing the emergence of drug resistance.

  13. Computational Studies of Drug Resistance

    DEFF Research Database (Denmark)

    da Silva Martins, João Miguel

    Drug resistance has been an increasing problem in patient treatment and drug development. Starting in the last century and becoming a major worry in the medical and scienti c communities in the early part of the current millennium, major research must be performed to address the issues of viral...... is of the utmost importance in developing better and less resistance-inducing drugs. A drug's in uence can be characterized in many diff erent ways, however, and the approaches I take in this work re ect those same different in uences. This is what I try to achieve in this work, through seemingly unrelated...... approaches that come together in the study of drug's and their in uence on proteins and vice-versa. In part I, I aim to understand through combined theoretical ensemble analysis and free energy calculations the e ects mutations have over the binding anity and function of the M2 proton channel. This research...

  14. Extracellular DNA Release Acts as an Antifungal Resistance Mechanism in Mature Aspergillus fumigatus Biofilms

    Science.gov (United States)

    Rajendran, Ranjith; Williams, Craig; Lappin, David F.; Millington, Owain; Martins, Margarida

    2013-01-01

    Aspergillus fumigatus has been shown to form biofilms that are associated with adaptive antifungal resistance mechanisms. These include multidrug efflux pumps, heat shock proteins, and extracellular matrix (ECM). ECM is a key structural and protective component of microbial biofilms and in bacteria has been shown to contain extracellular DNA (eDNA). We therefore hypothesized that A. fumigatus biofilms also possess eDNA as part of the ECM, conferring a functional role. Fluorescence microscopy and quantitative PCR analyses demonstrated the presence of eDNA, which was released phase dependently (8 autolysis, were significantly upregulated as the biofilm matured and that inhibition of chitinases affected biofilm growth and stability, indicating mechanistically that autolysis was possibly involved. Finally, using checkerboard assays, it was shown that combinational treatment of biofilms with DNase plus amphotericin B and caspofungin significantly improved antifungal susceptibility. Collectively, these data show that eDNA is an important structural component of A. fumigatus ECM that is released through autolysis, which is important for protection from environmental stresses, including antifungal therapy. PMID:23314962

  15. A novel hydroxyproline rich glycopeptide from pericarp of Datura stramonium: proficiently eradicate the biofilm of antifungals resistant Candida albicans.

    Science.gov (United States)

    Mandal, Santi M

    2012-01-01

    The increasing threats of multidrug resistant fungal pathogens, several studies have been focused to identify novel antifungal plant peptides with unique characteristics. Plants have been defending themselves against fungal infection by generating effective antifungal molecules. Here, a novel antifungal peptide with molecular mass of 4.0 kDa was purified from the pericarp of D. stramonium using reversed phase chromatography system after acetic acid extraction. Presence of sugar moieties (-GlcNAc-) in the peptide have been confirmed using thin layer chromatographic (TLC), CD polarimeter, and MALDI MS analysis. Complete amino acid sequences of this peptide by PSD MALDI MS analysis revealed to contain hydroxyproline in the centre of two cysteine residues. After sequencing "TFPKCAPTRhyPhy PGPKhyPCDINNFKSKFWHIWRA-(GlcNAc-)Asn" peptide named as "datucin." Antifungal sensitivity of datucin have been performed for both planktonic cells and biofilm phenotype ofa multidrug resistant clinical isolates, C. albicans and showed a MIC and MBEC values of 1 microM and 2 microM, respectively. Hence, D. stramonium offers a potential source of novel antifungal peptide datucin with possible utility in antifungal chemotherapy.

  16. The role of the multidisciplinary team in antifungal stewardship

    NARCIS (Netherlands)

    Agrawal, S.; Barnes, R.; Bruggemann, R.J.; Rautemaa-Richardson, R.; Warris, A.

    2016-01-01

    There are a variety of challenges faced in the management of invasive fungal diseases (IFD), including high case-fatality rates, high cost of antifungal drugs and development of antifungal resistance. The diagnostic challenges and poor outcomes associated with IFD have resulted in excessive

  17. Spectrophotometric reading of EUCAST antifungal susceptibility testing of Aspergillus fumigatus

    NARCIS (Netherlands)

    Meletiadis, J.; Mortensen, K.L.; Verweij, P.E.; Mouton, J.W.; Arendrup, M.C.

    2017-01-01

    OBJECTIVES: Given the increasing number of antifungal drugs and the emergence of resistant Aspergillus isolates, objective, automated and high-throughput antifungal susceptibility testing is important. The EUCAST E.Def 9.3 reference method for MIC determination of Aspergillus species relies on

  18. Extensively Drug-Resistant TB

    Centers for Disease Control (CDC) Podcasts

    2016-12-16

    Dr. Charlotte Kvasnovsky, a surgery resident and Ph.D. candidate in biostatistics, discusses various types of drug resistance in TB patients in South Africa.  Created: 12/16/2016 by National Center for Emerging and Zoonotic Infectious Diseases (NCEZID).   Date Released: 12/16/2016.

  19. Initial drug resistance in India

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. Initial drug resistance in India. There is gradual increase in primary MDR all over India : Pondi= Pondicherry 1985; Bangalore =1986; Jaipur = 1991; Jaipur =2000. Overall the MDR is less than 3% (TRC studies).

  20. Drug-resistant Escherichia coli, Rural Idaho

    OpenAIRE

    Hannah, Elizabeth L.; Angulo, Frederick J.; Johnson, James R.; Haddadin, Bassam; Williamson, Jacquelyn; Samore, Matthew H.

    2005-01-01

    Stool carriage of drug-resistant Escherichia coli in home-living residents of a rural community was examined. Carriage of nalidixic acid–resistant E. coli was associated with recent use of antimicrobial agents in the household. Household clustering of drug-resistant E. coli was observed. Most carriers of drug-resistant E. coli lacked conventional risk factors.

  1. Antifungal susceptibility of clinical and environmental isolates of Cryptococcus neoformans to four antifungal drugs determined by two techniques.

    Science.gov (United States)

    Moraes, E M P; Prímola, N S; Hamdan, Júnia Soares

    2003-06-01

    A total of 64 Cryptococcus neoformans strains, including clinical and environmental Brazilian isolates var. neoformans and var. gattii, were tested for susceptibility to amphotericin B, 5-flucytosine, fluconazole and itraconazole. The tests were performed according to the recommendations of National Committee of Clinical Laboratory Standards and the method of macrodilution in liquid medium of Shadomy et al. [Manual de Microbiologia Clínica, 4th ed. Buenos Aires: Editorial Medica Panamericana, 1987: 1229-38]. For most drugs there was a significant difference between the readings taken at 24 and 48 h with both methods. When the minimum inhibitory concentrations obtained by the two techniques were compared, significant differences were observed for amphotericin B and fluconazole. Overall, differences in drug susceptibility with respect to the origin of the isolates or the variety of the fungus were not observed. As an exception, the gattii variety exhibited a high resistance rate to amphotericin B when the technique of Shadomy et al. was applied, a fact possibly related to the greater difficulty for treatment of the disease caused by this fungal variety.

  2. Spectrophotometric and spectroscopic studies on charge transfer complexes of the antifungal drug clotrimazole

    Directory of Open Access Journals (Sweden)

    Nasrin Banu Shaikh Ismail

    2017-09-01

    Full Text Available Clotrimazole (CLZ is an imidazole derivative that is therapeutically used as an antifungal drug. The routine control analysis of CLZ requires rapid, reliable, accurate and precise methods for the quantification of the drug in its pharmaceutical formulations. Spectrophotometric methods are presented for the determination of the antifungal agent that are based on the charge transfer complexation reaction of CLZ with the π-acceptors tetracyanoethylene (TCE and 7,7′,8,8′-tetracyanoquinodimethane (TCNQ. The formation of coloured complexes was quantitated at 396 nm and 842 nm for CLZ-TCE and CLZ-TCNQ, respectively, which enabled the development of simple and accurate spectrophotometric methods for the analysis of CLZ in pure drug substances and its pharmaceutical products. Under the optimum reaction conditions, linear relationships with appreciable correlation coefficients (0.9985–0.9994 were found between the absorbance at the relevant maxima and the concentrations of CLZ in the range of 5.00–35.00 μg mL−1 for CLZ-TCE and 1.00–25.00 μg mL−1 for CLZ-TCNQ. The molar absorptivities and Sandell's sensitivity values were also statistically evaluated. The proposed methods were successfully applied to analyze CLZ in topical creams and sterile solutions with mean recovery percentages in the range of 99.60–100.20%, which indicated no interference from the inactive ingredients. Furthermore, the charge transfer complexes of CLZ were also characterized by FT-IR spectroscopy.

  3. Epidemiology and antifungal resistance in invasive Aspergillosis according to primary disease: review of the literature.

    Science.gov (United States)

    Mayr, A; Lass-Flörl, Cornelia

    2011-04-28

    Aspergilli, less susceptible to antifungals emerge and resistance to azoles have been found mainly in Aspergillus fumigatus; this has launched a new phase in handling aspergillosis. Resistant strains have currently been reported from Belgium, Canada, China, Denmark, France, Norway, Spain, Sweden, The Netherlands, UK and the USA. Centres in the UK (Manchester) and The Netherlands (Nijmegen) have described particularly high frequencies (15 and 10% respectively), and a significant increase in azole resistance in recent years. The reason of this high incidence may be due to long term azole therapy in patients with chronic aspergillosis in Manchester, and due to high use of agricultural azoles in Nijmegen. The primary underlying mechanism of resistance is as a result of alterations in the cyp51A target gene, with a variety of mutations found in clinical isolates and one genotype identified in the environmental (LH98). Reports on well documented in vitro and in vivo resistance to echinocandins are rare for Aspergillus species and resistance may be under-diagnosed as susceptibility testing is less frequently performed due to technical reasons.

  4. Novel Antifungal Compounds Discovered in Medicines for Malaria Venture's Malaria Box.

    Science.gov (United States)

    Jung, Eric H; Meyers, David J; Bosch, Jürgen; Casadevall, Arturo

    2018-01-01

    Similarities in fungal and animal cells make antifungal discovery efforts more difficult than those for other classes of antimicrobial drugs. Currently, there are only three major classes of antifungal drugs used for the treatment of systemic fungal diseases: polyenes, azoles, and echinocandins. Even in situations where the offending fungal organism is susceptible to the available drugs, treatment courses can be lengthy and unsatisfactory, since eradication of infection is often very difficult, especially in individuals with impaired immunity. Consequently, there is a need for new and more effective antifungal drugs. We have identified compounds with significant antifungal activity in the Malaria Box (Medicines for Malaria Ventures, Geneva, Switzerland) that have higher efficacy than some of the currently used antifungal drugs. Our best candidate, MMV665943 (IUPAC name 4-[6-[[2-(4-aminophenyl)-3H-benzimidazol-5-yl]methyl]-1H-benzimidazol-2-yl]aniline), here referred to as DM262, showed 16- to 32-fold-higher activity than fluconazole against Cryptococcus neoformans . There was also significant antifungal activity in other fungal species with known antifungal resistance, such as Lomentospora prolificans and Cryptococcus gattii . Antifungal activity was also observed against a common fungus, Candida albicans . These results are important because they offer a potentially new class of antifungal drugs and the repurposing of currently available therapeutics. IMPORTANCE Much like the recent increase in drug-resistant bacteria, there is a rise in antifungal-resistant strains of pathogenic fungi. There is a need for novel and more potent antifungal therapeutics. Consequently, we investigated a mixed library of drug-like and probe-like compounds with activity in Plasmodium spp. for activity against two common fungal pathogens, Cryptococcus neoformans and Candida albicans , along with two less common pathogenic species, Lomentospora prolificans and Cryptococcus gattii . We

  5. Increased chitin biosynthesis contributes to the resistance of Penicillium polonicum against the antifungal protein PgAFP.

    Science.gov (United States)

    Delgado, Josué; Owens, Rebecca A; Doyle, Sean; Asensio, Miguel A; Núñez, Félix

    2016-01-01

    Antifungal proteins from molds have been proposed as a valuable tool against unwanted molds, but the resistance of some fungi limits their use. Resistance to antimicrobial peptides has been suggested to be due to lack of interaction with the mold or to a successful response. The antifungal protein PgAFP produced by Penicillium chrysogenum inhibits the growth of various ascomycetes, but not Penicillium polonicum. To study the basis for resistance to this antifungal protein, localization of PgAFP and metabolic, structural, and morphological changes were investigated in P. polonicum. PgAFP bound the outer layer of P. polonicum but not regenerated chitin, suggesting an interaction with specific molecules. Comparative two-dimensional gel electrophoresis (2D-PAGE) and comparative quantitative proteomics revealed changes in the relative abundance of several proteins from ribosome, spliceosome, metabolic, and biosynthesis of secondary metabolite pathways. The proteome changes and an altered permeability reveal an active reaction of P. polonicum to PgAFP. The successful response of the resistant mold seems to be based on the higher abundance of protein Rho GTPase Rho1 that would lead to the increased chitin deposition via cell wall integrity (CWI) signaling pathway. Thus, combined treatment with chitinases could provide a complementary means to combat resistance to antifungal proteins.

  6. Natural and synthetic peptides with antifungal activity.

    Science.gov (United States)

    Ciociola, Tecla; Giovati, Laura; Conti, Stefania; Magliani, Walter; Santinoli, Claudia; Polonelli, Luciano

    2016-08-01

    In recent years, the increase of invasive fungal infections and the emergence of antifungal resistance stressed the need for new antifungal drugs. Peptides have shown to be good candidates for the development of alternative antimicrobial agents through high-throughput screening, and subsequent optimization according to a rational approach. This review presents a brief overview on antifungal natural peptides of different sources (animals, plants, micro-organisms), peptide fragments derived by proteolytic cleavage of precursor physiological proteins (cryptides), synthetic unnatural peptides and peptide derivatives. Antifungal peptides are schematically reported based on their structure, antifungal spectrum and reported effects. Natural or synthetic peptides and their modified derivatives may represent the basis for new compounds active against fungal infections.

  7. Drug Resistance in Cancer: An Overview

    Science.gov (United States)

    Housman, Genevieve; Byler, Shannon; Heerboth, Sarah; Lapinska, Karolina; Longacre, Mckenna; Snyder, Nicole; Sarkar, Sibaji

    2014-01-01

    Cancers have the ability to develop resistance to traditional therapies, and the increasing prevalence of these drug resistant cancers necessitates further research and treatment development. This paper outlines the current knowledge of mechanisms that promote or enable drug resistance, such as drug inactivation, drug target alteration, drug efflux, DNA damage repair, cell death inhibition, and the epithelial-mesenchymal transition, as well as how inherent tumor cell heterogeneity plays a role in drug resistance. It also describes the epigenetic modifications that can induce drug resistance and considers how such epigenetic factors may contribute to the development of cancer progenitor cells, which are not killed by conventional cancer therapies. Lastly, this review concludes with a discussion on the best treatment options for existing drug resistant cancers, ways to prevent the formation of drug resistant cancers and cancer progenitor cells, and future directions of study. PMID:25198391

  8. DRUG RESISTANCE IN HELICOBACTER PYLORI

    Directory of Open Access Journals (Sweden)

    Júlia Silveira VIANNA

    Full Text Available ABSTRACT Background Helicobacter pylori has a worldwide distribution and is associated with the pathogenesis of various diseases of the digestive system. Treatment to eradicate this microorganism involves the use of a combination of antimicrobials, such as amoxicillin, metronidazole, clarithromycin, and levofloxacin, combined with proton pump inhibitors. Although the current therapy is effective, a high rate of treatment failure has been observed, mainly because of the acquisition of point mutations, one of the major resistance mechanisms developed by H. pylori. This phenomenon is related to frequent and/or inappropriate use of antibiotics. Conclusion This review reported an overview of the resistance to the main drugs used in the treatment of H. pylori, confirming the hypothesis that antibacterial resistance is a highly local phenomenon and genetic characteristics of a given population can influence which therapy is the most appropriate.

  9. Drug Resistance in Visceral Leishmaniasis

    Directory of Open Access Journals (Sweden)

    Helena C. Maltezou

    2010-01-01

    Full Text Available Visceral leishmaniasis remains a public health problem worldwide. This illness was included by the World Health Organization in the list of neglected tropical diseases targeted for elimination by 2015. The widespread emergence of resistance to pentavalent antimonials in India where half cases occur globally and the unavailability of a vaccine in clinical use constitute major obstacles in achieving this goal. The last decade new antileishmanials became available, including the oral agent miltefosine. However, in poor endemic countries their wide use was curtailed because of the high costs, and also due to concerns of toxicity and emergence of resistance. Various mechanisms of antileishmanial resistance were identified recently in field isolates. Their elucidation will boost the design of new drugs and the molecular surveillance of resistance. Combination regimens should be evaluated in large trials. Overall, the development of antileishmanials has been generally slow; new drugs are needed. In order to control visceral leishmaniasis worldwide, treatment advances should become affordable in the poorest countries, where they are needed most.

  10. Progressive development in experimental models of transungual drug delivery of anti-fungal agents.

    Science.gov (United States)

    Thatai, P; Tiwary, A K; Sapra, B

    2016-02-01

    Pre-clinical development comprises of different procedures that relate drug discovery in the laboratory for commencement of human clinical trials. Pre-clinical studies can be designed to recognize a lead candidate from a list to develop the procedure for scale-up, to choose the unsurpassed formulation, to determine the frequency, and duration of exposure; and eventually make the foundation of the anticipated clinical trial design. The foremost aim in the pharmaceutical research and industry is the claim of drug product quality throughout a drug's life cycle. The particulars of the pre-clinical development process for different candidates may vary; however, all have some common features. Typically in vitro, in vivo or ex vivo studies are elements of pre-clinical studies. Human pharmacokinetic in vivo studies are often supposed to serve as the 'gold standard' to assess product performance. On the other hand, when this general assumption is revisited, it appears that in vitro studies are occasionally better than in vivo studies in assessing dosage forms. The present review is compendious of different such models or approaches that can be used for designing and evaluation of formulations for nail delivery with special reference to anti-fungal agents. © 2015 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

  11. A histone deacetylase complex mediates biofilm dispersal and drug resistance in Candida albicans.

    Science.gov (United States)

    Nobile, Clarissa J; Fox, Emily P; Hartooni, Nairi; Mitchell, Kaitlin F; Hnisz, Denes; Andes, David R; Kuchler, Karl; Johnson, Alexander D

    2014-06-10

    Biofilms are resilient, surface-associated communities of cells with specialized properties (e.g., resistance to drugs and mechanical forces) that are distinct from those of suspension (planktonic) cultures. Biofilm formation by the opportunistic human fungal pathogen Candida albicans is medically relevant because C. albicans infections are highly correlated with implanted medical devices, which provide efficient substrates for biofilm formation; moreover, biofilms are inherently resistant to antifungal drugs. Biofilms are also important for C. albicans to colonize diverse niches of the human host. Here, we describe four core members of a conserved histone deacetylase complex in C. albicans (Set3, Hos2, Snt1, and Sif2) and explore the effects of their mutation on biofilm formation. We find that these histone deacetylase complex members are needed for proper biofilm formation, including dispersal of cells from biofilms and multifactorial drug resistance. Our results underscore the importance of the physical properties of biofilms in contributing to drug resistance and dispersal and lay a foundation for new strategies to target biofilm dispersal as a potential antifungal intervention. Through the formation of biofilms--surface-associated communities of cells--microorganisms can establish infections, become drug resistant, and evade the host immune system. Here we investigate how four core members of a conserved histone deacetylase complex mediate biofilm formation by Candida albicans, the major fungal pathogen of humans. We show that this histone deacetylase complex is required for biofilm dispersal, a process through which cells leave the biofilm to establish new infections. We also show that the deacetylase complex mediates biofilm drug resistance. This work provides new insight into how the physical properties of biofilms affect dispersal and drug resistance and suggests new potential antifungal strategies that could be effective against biofilms. Copyright

  12. Identification and Determination of Drug Resistant of Candida species isolated from Hospital Acquired Infections

    Directory of Open Access Journals (Sweden)

    Kambiz Diba

    2015-01-01

    Full Text Available Background & aim: Currently, the use of antifungal azole group and yeasts resistant to these drugs is increasing. The aim of this study was to isolate and identify the yeasts obtained from candidiasis patients and furthermore determining thier antifungal resistance. Methods: In the present descriptive study, infections samples were collected from 256 patients with suspected nosocomial candidiasis, then direct exam and culture were performed. Yeast colonies were identified using phenotypic methods, polymerase chain reaction method and enzyme digestion. Data were analyzed using Descriptive statistical tests. Results: Of sixty isolated yeast, thirty-seven cases of Candida albicans (61.6%, seven cases of C. krusei and C. glabrata (11.6% each, five cases of C. dubliniensis (8.3% and four cases of C. tropicalis (6.6% were indicated. The study showed that the sensitivity of C. albicans and C. cruise species to amphotericin B was negligible in disk diffusion and very sensitve in microdilution. Conclusion: Inspite of the results of antifungal susceptibility test of strains studied did not show high resistance, but screening for drug-resistant Candida isolates in Candida infection by disk diffusion and microdilution methods for new cases of drug resistance is reasonable.

  13. Lemon grass (Cymbopogon citratus essential oil as a potent anti-inflammatory and antifungal drugs

    Directory of Open Access Journals (Sweden)

    Mohamed Nadjib Boukhatem

    2014-09-01

    Full Text Available Background: Volatile oils obtained from lemon grass [Cymbopogon citratus (DC. Stapf, Poaceae family] are used in traditional medicine as remedies for the treatment of various diseases. Aims: In the present study, lemon grass essential oil (LGEO was evaluated for its in vivo topical and oral anti-inflammatory effects, and for its in vitro antifungal activity using both liquid and vapor phases. Methods: The chemical profile of LGEO as determined by gas chromatography–mass spectrometry analysis revealed two major components: geranial (42.2%, and neral (31.5%. The antifungal activity of LGEO was evaluated against several pathogenic yeasts and filamentous fungi using disc diffusion and vapor diffusion methods. Results: LGEO exhibited promising antifungal effect against Candida albicans, C. tropicalis, and Aspergillus niger, with different inhibition zone diameters (IZDs (35–90 mm. IZD increased with increasing oil volume. Significantly, higher anti-Candida activity was observed in the vapor phase. For the evaluation of the anti-inflammatory effect, LGEO (10 mg/kg, administered orally significantly reduced carrageenan-induced paw edema with a similar effect to that observed for oral diclofenac (50 mg/kg, which was used as the positive control. Oral administration of LGEO showed dose-dependent anti-inflammatory activity. In addition, topical application of LGEO in vivo resulted in a potent anti-inflammatory effect, as demonstrated by using the mouse model of croton oil-induced ear edema. To our knowledge, this is the first such report to be published. The topical application of LGEO at doses of 5 and 10 µL/ear significantly reduced acute ear edema induced by croton oil in 62.5 and 75% of the mice, respectively. In addition, histological analysis clearly confirmed that LGEO inhibits the skin inflammatory response in animal models. Conclusion: Results of the present study indicate that LGEO has a noteworthy potential for the development of drugs for

  14. Triazole derivatives with improved in vitro antifungal activity over azole drugs

    Directory of Open Access Journals (Sweden)

    Yu S

    2014-04-01

    Full Text Available Shichong Yu,1,* Xiaoyun Chai,1,* Yanwei Wang,1 Yongbing Cao,2 Jun Zhang,3 Qiuye Wu,1 Dazhi Zhang,1 Yuanying Jiang,2 Tianhua Yan,4 Qingyan Sun11Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China; 2Drug Research Center, School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China; 3Overseas Education Faculty of the Second Military Medical University, Shanghai, People's Republic of China; 4Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China*These authors contributed equally to this workAbstract: A series of triazole antifungal agents with piperidine side chains was designed and synthesized. The results of antifungal tests against eight human pathogenic fungi in vitro showed that all the compounds exhibited moderate-to-excellent activities. Molecular docking between 8d and the active site of Candida albicans CYP51 was provided based on the computational docking results. The triazole interacts with the iron of the heme group. The difluorophenyl group is located in the S3 subsite and its fluorine atom (2-F can form H-bonds with Gly307. The side chain is oriented into the S4 subsite and formed hydrophobic and van der Waals interactions with the amino residues. Moreover, the phenyl group in the side chain interacts with the phenol group of Phe380 through the formation of π–π face-to-edge interactions.Keywords: synthesis, CYP51, molecular docking, azole agents

  15. Quorum sensing and microbial drug resistance.

    Science.gov (United States)

    Chen, Yu-fan; Liu, Shi-yin; Liang, Zhi-bin; Lv, Ming-fa; Zhou, Jia-nuan; Zhang, Lian-hui

    2016-10-20

    Microbial drug resistance has become a serious problem of global concern, and the evolution and regulatory mechanisms of microbial drug resistance has become a hotspot of research in recent years. Recent studies showed that certain microbial resistance mechanisms are regulated by quorum sensing system. Quorum sensing is a ubiquitous cell-cell communication system in the microbial world, which associates with cell density. High-density microbial cells produce sufficient amount of small signal molecules, activating a range of downstream cellular processes including virulence and drug resistance mechanisms, which increases bacterial drug tolerance and causes infections on host organisms. In this review, the general mechanisms of microbial drug resistance and quorum-sensing systems are summarized with a focus on the association of quorum sensing and chemical signaling systems with microbial drug resistance mechanisms, including biofilm formation and drug efflux pump. The potential use of quorum quenching as a new strategy to control microbial resistance is also discussed.

  16. Suppression of Drug Resistance in Dengue Virus

    Science.gov (United States)

    Mateo, Roberto; Nagamine, Claude M.

    2015-01-01

    ABSTRACT Dengue virus is a major human pathogen responsible for 400 million infections yearly. As with other RNA viruses, daunting challenges to antiviral design exist due to the high error rates of RNA-dependent RNA synthesis. Indeed, treatment of dengue virus infection with a nucleoside analog resulted in the expected genetic selection of resistant viruses in tissue culture and in mice. However, when the function of the oligomeric core protein was inhibited, no detectable selection of drug resistance in tissue culture or in mice was detected, despite the presence of drug-resistant variants in the population. Suppressed selection of drug-resistant virus correlated with cooligomerization of the targeted drug-susceptible and drug-resistant core proteins. The concept of “dominant drug targets,” in which inhibition of oligomeric viral assemblages leads to the formation of drug-susceptible chimeras, can therefore be used to prevent the outgrowth of drug resistance during dengue virus infection. PMID:26670386

  17. Antifungal stewardship in a tertiary hospital.

    Science.gov (United States)

    Ramos, Antonio; Pérez-Velilla, Claudia; Asensio, Angel; Ruiz-Antorán, Belén; Folguera, Carlos; Cantero, Mireia; Orden, Beatriz; Muñez, Elena

    2015-01-01

    The inappropriate use of antifungals is an important health problem related to increasing adverse effects, unnecessary cost and promotion of resistant and emerging fungal infections. Despite its relevance, many health institutions assign few resources to improve prescribing practices. To evaluate the efficiency of an antifungal stewardship programme (ASP) centered on restricted antifungal agents. The main activity during the eight-month study was to perform a programmed review of restricted antifungals (lipid formulations of amphotericin B, echinocandins and voriconazole) prescribed in hospitalized patients. In the case of amendable antifungal treatment, a recommendation was included in the electronic medical record. A total of 280 antifungal prescriptions for 262 patients were revised during the study period. The indications were prophylactic in 85 cases (30.4%), pre-emptive in 10 cases (3.5%), empiric in 122 cases (43.6%), and directed in 63 cases (22.5%). A total of 70 prescriptions (25%) in 61 patients were considered to be amendable. In most of these cases, treatment could have been reduced considering the patient's clinical improvement and microbiological results. The most common advice was antifungals change (70%), antifungal withdrawal (21%), removal of one antifungal drug in cases of combined therapy (7%), and switching to oral route (1%). Proposed recommendations were addressed in 28 cases (40%). There was no significant difference in adherence with respect to the type of recommendation (p=0.554). There was a 42% lower use of antifungals during the period of the study compared to that observed during a similar previous period. Mortality among patients who were treated according to the recommendations of the ASP was 17% and in whom treatment was not modified it was 30% (p=0.393). ASPs centered on hospitalized patients may be an efficient strategy to ameliorate antifungal use in hospitals. Copyright © 2014 Revista Iberoamericana de Micología. Published by

  18. Solvates of the antifungal drug griseofulvin: structural, thermochemical and conformational analysis.

    Science.gov (United States)

    Aitipamula, Srinivasulu; Chow, Pui Shan; Tan, Reginald B H

    2014-02-01

    Four solvates of an antifungal drug, griseofulvin (GF), were discovered. All the solvates were characterized by differential scanning calorimetry, thermogravimetric analysis, and their crystal structures were determined by single-crystal X-ray diffraction. The solvents that form the solvates are acetonitrile, nitromethane and nitroethane (2:1 and 1:1). It was found that all the solvates lose the solvent molecules from the crystal lattice between 343 and 383 K, and that the melting point of the desolvated materials matched the melting point of the solvent-free GF (493 K). The conformation of the GF molecule in solvent-free form was found to be significantly different from the conformations found in the solvates. Solution stability studies revealed that the GF-acetonitrile solvate transforms to GF and that GF-nitroethane (1:1) solvate transforms to GF-nitroethane (2:1) solvate. On the other hand, GF-nitromethane and GF-nitroethane (2:1) solvates were found to be stable in solution. Our results highlight the importance of the co-crystallization technique in the pharmaceutical drug development; it not only expands the solid form diversity but also creates new avenues for unraveling novel solvates.

  19. High Virulence and Antifungal Resistance in Clinical Strains of Candida albicans

    Directory of Open Access Journals (Sweden)

    Eric Monroy-Pérez

    2016-01-01

    Full Text Available Antifungal resistance and virulence properties of Candida albicans are a growing health problem worldwide. To study the expression of virulence and azole resistance genes in 39 clinical strains of C. albicans, we used a model of infection of human vaginal epithelial cells with C. albicans strains isolated from Mexican women with vulvovaginal candidiasis (VVC. The strains were identified by PCR amplification of the ITS1 and ITS2 regions of rRNA. The detection and expression of virulence genes and azole resistance genes MDR1 and CDR1 were performed using PCR and RT-PCR, respectively. All strains were sensitive to nystatin and 38 (97.4% and 37 (94.9% were resistant to ketoconazole and fluconazole, respectively. ALS1, SAP4–SAP6, LIP1, LIP2, LIP4, LIP6, LIP7, LIP9, LIP10, and PLB1-PLB2 were present in all strains; SAP1 was identified in 37 (94.8% isolates, HWP1 in 35 (89.7%, ALS3 in 14 (35.8%, and CDR1 in 26 (66.6%. In nearly all of the strains, ALS1, HWP1, SAP4–SAP6, LIP1–LIP10, PLB1, and PLB2 were expressed, whereas CDR1 was expressed in 20 (51.3% and ALS3 in 14 (35.8%. In our in vitro model of infection with C. albicans, the clinical strains showed different expression profiles of virulence genes in association with the azole resistance gene CDR1. The results indicate that the strains that infect Mexican patients suffering from VVC are highly virulent and virtually all are insensitive to azoles.

  20. Antifolate drug resistance: Novel mutations and haplotype ...

    Indian Academy of Sciences (India)

    N P Sarmah

    2017-09-27

    Sep 27, 2017 ... Malaria is a major public health concern in Northeast India with a preponderance of drug-resistant strains. Until recently the partner drug for artemisinin combination therapy (ACT) was sulphadoxine pyrimethamine (SP). Antifolate drug resistance has been associated with the mutations at dihydropteroate ...

  1. Nosocomial Candidiasis: Antifungal Stewardship and the Importance of Rapid Diagnosis.

    Science.gov (United States)

    Pfaller, Michael A; Castanheira, Mariana

    2016-01-01

    Candidemia and other forms of candidiasis are associated with considerable excess mortality and costs. Despite the addition of several new antifungal agents with improved spectrum and potency, the frequency of Candida infection and associated mortality have not decreased in the past two decades. The lack of rapid and sensitive diagnostic tests has led to considerable overuse of antifungal agents resulting in increased costs, selection pressure for resistance, unnecessary drug toxicity, and adverse drug interactions. Both the lack of timely diagnostic tests and emergence of antifungal resistance pose considerable problems for antifungal stewardship. Whereas antifungal stewardship with a focus on nosocomial candidiasis should be able to improve the administration of antifungal therapy in terms of drug selection, proper dose and duration, source control and de-escalation therapy, an important parameter, timeliness of antifungal therapy, remains a victim of slow and insensitive diagnostic tests. Fortunately, new proteomic and molecular diagnostic tools are improving the time to species identification and detection. In this review we will describe the potential impact that rapid diagnostic testing and antifungal stewardship can have on the management of nosocomial candidiasis. © The Author 2015. 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.

  2. Evaluation of Virulence FactorsIn vitro, Resistance to Osmotic Stress and Antifungal Susceptibility ofCandida tropicalisIsolated from the Coastal Environment of Northeast Brazil.

    Science.gov (United States)

    Zuza-Alves, Diana L; de Medeiros, Sayama S T Q; de Souza, Luanda B F C; Silva-Rocha, Walicyranison P; Francisco, Elaine C; de Araújo, Maria C B; Lima-Neto, Reginaldo G; Neves, Rejane P; Melo, Analy S de Azevedo; Chaves, Guilherme M

    2016-01-01

    Several studies have been developed regarding human health risks associated with the recreational use of beaches contaminated with domestic sewage. These wastes contain various micro-organisms, including Candida tropicalis . In this context, the objective of this study was to characterize C. tropicalis isolates from the sandy beach of Ponta Negra, Natal, Rio Grande do Norte, Brazil, regarding the expression of in vitro virulence factors, adaptation to osmotic stress and susceptibility to antifungal drugs. We analyzed 62 environmental isolates and observed a great variation among them for the various virulence factors evaluated. In general, environmental isolates were more adherent to human buccal epithelial cells (HBEC) than C. tropicalis ATCC13803 reference strain, and they also showed increased biofilm production. Most of the isolates presented wrinkled phenotypes on Spider medium (34 isolates, 54.8%). The majority of the isolates also showed higher proteinase production than control strains, but low phospholipase activity. In addition, 35 isolates (56.4%) had high hemolytic activity (hemolysis index > 0.55). With regard to C. tropicalis resistance to osmotic stress, 85.4% of the isolates were able to grow in a liquid medium containing 15% sodium chloride. The strains were highly resistant to the azoles tested (fluconazole, voriconazole and itraconazole). Fifteen strains were resistant to the three azoles tested (24.2%). Some strains were also resistant to amphotericin B (14 isolates; 22.6%), while all of them were susceptible for the echinocandins tested, except for a single strain of intermediate susceptibility to micafungin. Our results demonstrate that C. tropicalis isolated from the sand can fully express virulence attributes and showed a high persistence capacity on the coastal environment; in addition of showing high minimal inhibitory concentrations to several antifungal drugs used in current clinical practice, demonstrating that environmental isolates

  3. Evaluation of Virulence Factors In vitro, Resistance to Osmotic Stress and Antifungal Susceptibility of Candida tropicalis Isolated from the Coastal Environment of Northeast Brazil

    Science.gov (United States)

    Zuza-Alves, Diana L.; de Medeiros, Sayama S. T. Q.; de Souza, Luanda B. F. C.; Silva-Rocha, Walicyranison P.; Francisco, Elaine C.; de Araújo, Maria C. B.; Lima-Neto, Reginaldo G.; Neves, Rejane P.; Melo, Analy S. de Azevedo; Chaves, Guilherme M.

    2016-01-01

    Several studies have been developed regarding human health risks associated with the recreational use of beaches contaminated with domestic sewage. These wastes contain various micro-organisms, including Candida tropicalis. In this context, the objective of this study was to characterize C. tropicalis isolates from the sandy beach of Ponta Negra, Natal, Rio Grande do Norte, Brazil, regarding the expression of in vitro virulence factors, adaptation to osmotic stress and susceptibility to antifungal drugs. We analyzed 62 environmental isolates and observed a great variation among them for the various virulence factors evaluated. In general, environmental isolates were more adherent to human buccal epithelial cells (HBEC) than C. tropicalis ATCC13803 reference strain, and they also showed increased biofilm production. Most of the isolates presented wrinkled phenotypes on Spider medium (34 isolates, 54.8%). The majority of the isolates also showed higher proteinase production than control strains, but low phospholipase activity. In addition, 35 isolates (56.4%) had high hemolytic activity (hemolysis index > 0.55). With regard to C. tropicalis resistance to osmotic stress, 85.4% of the isolates were able to grow in a liquid medium containing 15% sodium chloride. The strains were highly resistant to the azoles tested (fluconazole, voriconazole and itraconazole). Fifteen strains were resistant to the three azoles tested (24.2%). Some strains were also resistant to amphotericin B (14 isolates; 22.6%), while all of them were susceptible for the echinocandins tested, except for a single strain of intermediate susceptibility to micafungin. Our results demonstrate that C. tropicalis isolated from the sand can fully express virulence attributes and showed a high persistence capacity on the coastal environment; in addition of showing high minimal inhibitory concentrations to several antifungal drugs used in current clinical practice, demonstrating that environmental isolates may

  4. Leading Antimicrobial Drug-Resistant Diseases

    Science.gov (United States)

    ... supporting research on several organisms that have developed resistance to antimicrobial drug treatment. The institute manages a research portfolio of grants aimed at the problem of antimicrobial resistance and hospital-acquired infections. Here is a list ...

  5. Drug-resistant tuberculosis in Sindh

    International Nuclear Information System (INIS)

    Almani, S.A.; Memon, N.M.; Qureshi, A.F.

    2002-01-01

    Objective: To assess the prevalence of primary and secondary drug resistance amongst the clinical isolates of M.tuberculosis, to identify risk factors and how to overcome this problem. Design: A case series of 50 indoor patients with sputum smear-positive pulmonary tuberculosis. Place and duration of Study: Department of Medicine, Liaquat University of Medical and Health Sciences Jamshoro, Sindh, (Pakistan) from January 1999 to December 2000. Patients and methods: Four first line anti-tuberculous drugs rifampicine, ethambutol and streptomycin were tested for sensitivity pattern. Results: Twelve (26.66%) were sensitive to all four drugs, 12(26.66%) were resistant to one drug, 14 (31.11%) were resistant to two drugs, 2 (4.44%) were resistant to three drugs, and 5(11.11%) were resistant to all four drugs. Resistance to isoniazid was the most common in 27 cases (60%) with primary resistance in 6(13.33%) and secondary resistance in 21(46.66%), followed by resistance to streptomycin in 17 cases (37.77%) with primary resistance in 5(11.11%) and secondary resistance in 12 (26.66%). Resistance to ethambutol in 10 cases (22.22%) and rifampicine in 11 (24.44%) and all cases were secondary. Similarly multi-drugs resistance (MRD) TB was found in 11(24.44%) isolates. Conclusion: This study showed high prevalence of drug resistance among clinical isolates of M. tuberculosis. Their is a need to establish centers at number of places with adequate facilities for susceptibility testing so that the resistant pattern could be ascertained and treatment regimens tailored accordingly. (author)

  6. Multidrug resistant to extensively drug resistant tuberculosis: What is ...

    Indian Academy of Sciences (India)

    Prakash

    major anti tuberculosis drugs; Isoniazid and Rifampicin with or without resistance to other anti-TB drugs has been termed. MDR-TB. MDR-TB is more difficult to treat than drug- susceptible TB, requiring the use of less effective second line anti tubercular drugs (SLDs) which are often associated with major side effects. 2.

  7. Clinical Management of HIV Drug Resistance

    Science.gov (United States)

    Cortez, Karoll J.; Maldarelli, Frank

    2011-01-01

    Combination antiretroviral therapy for HIV-1 infection has resulted in profound reductions in viremia and is associated with marked improvements in morbidity and mortality. Therapy is not curative, however, and prolonged therapy is complicated by drug toxicity and the emergence of drug resistance. Management of clinical drug resistance requires in depth evaluation, and includes extensive history, physical examination and laboratory studies. Appropriate use of resistance testing provides valuable information useful in constructing regimens for treatment-experienced individuals with viremia during therapy. This review outlines the emergence of drug resistance in vivo, and describes clinical evaluation and therapeutic options of the individual with rebound viremia during therapy. PMID:21994737

  8. Epidemiology, risk factor, species distribution, antifungal resistance and outcome of Candidemia at a single French hospital: a 7-year study.

    Science.gov (United States)

    Tadec, Laurent; Talarmin, Jean-Philippe; Gastinne, Thomas; Bretonnière, Cédric; Miegeville, Michel; Le Pape, Patrice; Morio, Florent

    2016-05-01

    Candidemia remains a major cause of disease worldwide and is associated with a high mortality rate. We conducted a retrospective study of candidemia at Nantes Hospital, France, between 2004 and 2010. A total of 191 episodes (n = 188 patients) were reviewed. Incidence, demographics, risk factors, antifungal management, species identification, in vitro susceptibility and 12 weeks survival were analysed. Global incidence of candidemia was 0.37‰ admissions. Higher incidences were observed in haematology (6.65‰) and intensive care units (2‰). Central venous catheter and antibiotic exposure were the most frequent risk factors (77% and 76% respectively). Candida albicans was the predominant species (51.8%) followed by C. parapsilosis (14.5%), C. glabrata (9.8%), C. tropicalis (9.8%) and C. krusei (4.1%). However, species distribution differed significantly between medical units with frequency of C. tropicalis being higher in haematology compared to other medical units. Fluconazole and caspofungin were the main antifungals given as first-line therapy. Although not significant, 12 weeks mortality rate was 30.9%, being higher for C. tropicalis (44.4%) than for C. parapsilosis (16%). Acquired azole or echinocandin resistance was noted in some isolates, underlining the need for systematic antifungal susceptibility testing in patients with candidemia. These epidemiological findings will be of interest for antifungal stewardship at our hospital. © 2016 Blackwell Verlag GmbH.

  9. Preventing drug resistance in severe influenza

    Science.gov (United States)

    Dobrovolny, Hana; Deecke, Lucas

    2015-03-01

    Severe, long-lasting influenza infections are often caused by new strains of influenza. The long duration of these infections leads to an increased opportunity for the emergence of drug resistant mutants. This is particularly problematic for new strains of influenza since there is often no vaccine, so drug treatment is the first line of defense. One strategy for trying to minimize drug resistance is to apply periodic treatment. During treatment the wild-type virus decreases, but resistant virus might increase; when there is no treatment, wild-type virus will hopefully out-compete the resistant virus, driving down the number of resistant virus. We combine a mathematical model of severe influenza with a model of drug resistance to study emergence of drug resistance during a long-lasting infection. We apply periodic treatment with two types of antivirals: neuraminidase inhibitors, which block release of virions; and adamantanes, which block replication of virions. We compare the efficacy of the two drugs in reducing emergence of drug resistant mutants and examine the effect of treatment frequency on the emergence of drug resistant mutants.

  10. Drug Resistance of Mycobacterium tuberculosis Complex among ...

    African Journals Online (AJOL)

    BACKGROUND: In Burkina Faso, there is no recent data about the level of drug resistance in Mycobacterium tuberculosis strains among newly diagnosed tuberculosis cases. OBJECTIVE: To provide an update of the primary drug resistance of mycobacterium tuberculosis among patients in Burkina faso. METHODS: ...

  11. Tuberculosis drug resistance in the Western Cape

    African Journals Online (AJOL)

    Objectives. Drug resistance is a serious problem in the treatment of tuberculosis and a threat to successful tuberculosis control programmes. Local health workers have expressed concern that the increasing tuberculosis epidemic in the Western Cape is partly attributable to drug resistance. The aim of this study was to ...

  12. [Change in drug resistance of Staphylococcus aureus].

    Science.gov (United States)

    Lin, Yan; Liu, Yan; Luo, Yan-Ping; Liu, Chang-Ting

    2013-11-01

    To analyze the change in drug resistance of Staphylococcus aureus (SAU) in the PLA general hospital from January 2008 to December 2012, and to provide solid evidence to support the rational use of antibiotics for clinical applications. The SAU strains isolated from clinical samples in the hospital were collected and subjected to the Kirby-Bauer disk diffusion test. The results were assessed based on the 2002 American National Committee for Clinical Laboratory Standards (NCCLS) guidelines. SAU strains were mainly isolated from sputum, urine, blood and wound excreta and distributed in penology, neurology wards, orthopedics and surgery ICU wards. Except for glycopeptide drugs, methicillin-resistant Staphylococcus aureus (MRSA) had a higher drug resistance rate than those of the other drugs and had significantly more resistance than methicillin-sensitive Staphylococcus aureus (MSSA) (P resistance, we discovered a gradual increase in drug resistance to fourteen test drugs during the last five years. Drug resistance rate of SAU stayed at a higher level over the last five years; moreover, the detection ratio of MRSA keeps rising year by year. It is crucial for physicians to use antibiotics rationally and monitor the change in drug resistance in a dynamic way.

  13. Combined antiretroviral and anti- tuberculosis drug resistance ...

    African Journals Online (AJOL)

    these epidemics, many challenges remain.[3] Antiretroviral and anti-TB drug resistance pose considerable threats to the control of these epidemics.[4,5]. The breakdown in HIV/TB control within prisons is another emerging threat.[6,7] We describe one of the first reports of combined antiretroviral and anti-TB drug resistance ...

  14. Extensively Drug-Resistant Tuberculosis, Burkina Faso

    OpenAIRE

    Saleri, Nuccia; Badoum, Gisèle; Ouedraogo, Martial; Dembélé, Sary M.; Nacanabo, Rachel; Bonkoungou, Victor; Cirillo, Daniela; Pinsi, Gabriele; Matteelli, Alberto

    2010-01-01

    Because data from countries in Africa are limited, we measured the proportion of extensively drug-resistant (XDR) tuberculosis (TB) cases among TB patients in Burkina Faso for whom retreatment was failing. Of 34 patients with multidrug-resistant TB, 2 had an XDR TB strain. Second-line TB drugs should be strictly controlled to prevent further XDR TB increase.

  15. Reverse Transcriptase Inhibitors Drug Resistance Mutations in Drug ...

    African Journals Online (AJOL)

    Objective: To evaluate the extent of HIV-1 drug resistance among drug naïve Kenyan individuals. Design: Cross-sectional study. Setting: Kenya Medical Research Institute HIV laboratory Nairobi, Kenya. Subjects: A total of seventy eight HIV-1 positive drug naïve subjects randomised from five Kenyan provincial hospitals ...

  16. Minimal inhibitory concentration distributions and epidemiological cutoff values of five antifungal agents against Sporothrix brasiliensis

    OpenAIRE

    Almeida-Paes, Rodrigo; Brito-Santos, Fábio; Figueiredo-Carvalho, Maria Helena Galdino; Machado, Ana Caroline Sá; Oliveira, Manoel Marques Evangelista; Pereira, Sandro Antonio; Gutierrez-Galhardo, Maria Clara; Zancopé-Oliveira, Rosely Maria

    2017-01-01

    BACKGROUND Sporothrix brasiliensis is the most virulent sporotrichosis agent. This species usually responds to antifungal drugs, but therapeutic failure can occur in some patients. Antifungal susceptibility tests have been performed on this species, but no clinical breakpoints (CBPs) are available. In this situation, minimal inhibitory concentration (MIC) distributions and epidemiological cutoff values (ECVs) support the detection of identification of resistant strains. OBJECTIVES To study ...

  17. Spectrophotometric reading of EUCAST antifungal susceptibility testing of Aspergillus fumigatus

    DEFF Research Database (Denmark)

    Meletiadis, J.; Leth Mortensen, K.; Verweij, P. E.

    2017-01-01

    Objectives Given the increasing number of antifungal drugs and the emergence of resistant Aspergillus isolates, objective, automated and high-throughput antifungal susceptibility testing is important. The EUCAST E.Def 9.3 reference method for MIC determination of Aspergillus species relies on vis...

  18. [Susceptibility of Candida albicans blood isolates to 3 antifungal drugs: retrospective study in Rio Grande do Sul, Brazil, 1999-2009].

    Science.gov (United States)

    Mattei, Antonella Souza; Alves, Sydney Hartz; Mario, Débora Alves; Watte, Guilherme; Severo, Cecília Bittencourt; Guazzelli, Luciana da Silva; Oliveira, Flávio de Mattos; Severo, Luiz Carlos

    2013-01-01

    Candidiasis is one of the most important among recurrent invasive yeast infections in patients, thus antifungal treatment becomes a challenge. The aim of this study was to evaluate the in vitro activity of clinical Candida albicans isolates from blood cultures to fluconazole, amphotericin B and anidulafungin, in a hospital from Rio Grande do Sul, Brazil. The susceptibility of 153 isolates to the 3 drugs mentioned was tested according to Clinical and Laboratory Standars Institute. Minimal inhibitory and fungicidal concentrations (MIC, MFC, respectively) of each drug were determined, as well as the epidemiological cutoff value (ECV). All of the isolates were susceptible to anidulafungin, MIC and MFC ≤ 1 μg/ml; however, when compared with ECV, 3% of the isolates exhibited higher values against fluconazole, 96% were susceptible, 3% susceptible dose-dependent, and 1% resistant. Also, it was observed that 21% of the isolates exhibited higher values than ECV. One isolate was resistant to amphotericin B; the other ones, susceptible, based on the MFC; furthermore, 1.5% of the isolates exhibited higher values. C. albicans isolates exhibited more susceptibility to anidulafungin, and 90% of them (MIC90) exhibited the lowest values against amphotericin B. Based on ECV and Pfaller classification, isolates could be resistant to fluconazole, demonstrating the importance of the combination of these parameters. Copyright © 2012 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.

  19. In vitro activities of antifungal drugs against environmental Exophiala isolates and review of the literature.

    Science.gov (United States)

    Gülmez, Dolunay; Doğan, Özlem; Boral, Barış; Döğen, Aylin; İlkit, Macit; de Hoog, G Sybren; Arikan-Akdagli, Sevtap

    2018-04-03

    Exophiala is a genus of black fungi isolated worldwide from environmental and clinical specimens. Data on antifungal susceptibility of Exophiala isolates are limited and the methodology on susceptibility testing is not yet standardized. In this study, we investigated in vitro antifungal susceptibilities of environmental Exophiala isolates. A total of 87 Exophiala isolated from dishwashers or railway ties were included. CLSI M38-A2 microdilution method with modifications was used to determine antifungal susceptibility for fluconazole, voriconazole, posaconazole, itraconazole, amphotericin B, and terbinafine. Minimum inhibitory concentration (MIC) values were determined visually at 48h, 72h, and 96h. MIC-0 endpoint (complete inhibition of growth) was used for amphotericin B and azoles, except fluconazole, for which MIC-2 endpoint (~50% inhibition compared to growth control) was used. Both MIC-0 and MIC-1 (~80% inhibition compared to growth control) results were analysed for terbinafine, to enable comparison with previous studies. Fungal growth was sufficient for determination of MICs at 48h for all isolates except two Exophiala dermatitidis strains. At 72h, most active antifungal agents according to GM MIC were voriconazole and terbinafine, followed by posaconazole, itraconazole, and amphotericin B in rank order of decreasing activity. While amphotericin B displayed adequate in vitro activity despite relatively high MICs, fluconazole showed no meaningful antifungal activity against Exophiala. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  20. Defensins: antifungal lessons from eukaryotes

    Directory of Open Access Journals (Sweden)

    Patrícia M. Silva

    2014-03-01

    Full Text Available Over the last years, antimicrobial peptides (AMPs have been the focus of intense research towards the finding of a viable alternative to current antifungal drugs. Defensins are one of the major families of AMPs and the most represented among all eukaryotic groups, providing an important first line of host defense against pathogenic microorganisms. Several of these cysteine-stabilized peptides present a relevant effect against fungi. Defensins are the AMPs with the broader distribution across all eukaryotic kingdoms, namely, Fungi, Plantæ and Animalia, and were recently shown to have an ancestor in a bacterial organism. As a part of the host defense, defensins act as an important vehicle of information between innate and adaptive immune system and have a role in immunomodulation. This multidimensionality represents a powerful host shield, hard for microorganisms to overcome using single approach resistance strategies. Pathogenic fungi resistance to conventional antimycotic drugs is becoming a major problem. Defensins, as other AMPs, have shown to be an effective alternative to the current antimycotic therapies, demonstrating potential as novel therapeutic agents or drug leads. In this review, we summarize the current knowledge on some eukaryotic defensins with antifungal action. An overview of the main targets in the fungal cell and the mechanism of action of these AMPs (namely, the selectivity for some fungal membrane components are presented. Additionally, recent works on antifungal defensins structure, activity and citotoxicity are also reviewed.

  1. Calcineurin is required for pseudohyphal growth, virulence, and drug resistance in Candida lusitaniae.

    Directory of Open Access Journals (Sweden)

    Jing Zhang

    Full Text Available Candida lusitaniae is an emerging fungal pathogen that infects immunocompromised patients including HIV/AIDS, cancer, and neonatal pediatric patients. Though less prevalent than other Candida species, C. lusitaniae is unique in its ability to develop resistance to amphotericin B. We investigated the role of the calcium-activated protein phosphatase calcineurin in several virulence attributes of C. lusitaniae including pseudohyphal growth, serum survival, and growth at 37°C. We found that calcineurin and Crz1, a C. albicans Crz1 homolog acting as a downstream target of calcineurin, are required for C. lusitaniae pseudohyphal growth, a process for which the underlying mechanism remains largely unknown in C. lusitaniae but hyphal growth is fundamental to C. albicans virulence. We demonstrate that calcineurin is required for cell wall integrity, ER stress response, optimal growth in serum, virulence in a murine systemic infection model, and antifungal drug tolerance in C. lusitaniae. To further examine the potential of targeting the calcineurin signaling cascade for antifungal drug development, we examined the activity of a calcineurin inhibitor FK506 in combination with caspofungin against echinocandin resistant C. lusitaniae clinical isolates. Broth microdilution and drug disk diffusion assays demonstrate that FK506 has synergistic fungicidal activity with caspofungin against echinocandin resistant isolates. Our findings reveal that pseudohyphal growth is controlled by the calcineurin signaling cascade, and highlight the potential use of calcineurin inhibitors and caspofungin for emerging drug-resistant C. lusitaniae infections.

  2. Plasmodium falciparum drug resistance in Angola.

    Science.gov (United States)

    Fançony, Cláudia; Brito, Miguel; Gil, Jose Pedro

    2016-02-09

    Facing chloroquine drug resistance, Angola promptly adopted artemisinin-based combination therapy as the first-line to treat malaria. Currently, the country aims to consolidate malaria control, while preparing for the elimination of the disease, along with others African countries in the region. However, the remarkable capacity of Plasmodium to develop drug resistance represents an alarming threat for those achievements. Herein, the available, but relatively scarce and dispersed, information on malaria drug resistance in Angola, is reviewed and discussed. The review aims to inform but also to encourage future research studies that monitor and update the information on anti-malarial drug efficacy and prevalence of molecular markers of drug resistance, key fields in the context and objectives of elimination.

  3. Mechanisms of Drug Resistance: Daptomycin Resistance

    Science.gov (United States)

    Tran, Truc T.; Munita, Jose M.; Arias, Cesar A.

    2016-01-01

    Daptomycin (DAP) is a cyclic lipopeptide with in vitro activity against a variety of Gram-positive pathogens, including multidrug-resistant organisms. Since its introduction in clinical practice in 2003, DAP has become an important key front-line antibiotic for severe or deep-seated infections caused by Gram-positive organisms. Unfortunately, DAP-resistance (R) has been extensively documented in clinically important organisms such as Staphylococcus aureus, Enterococcus spp, and Streptococcus spp. Studies on the mechanisms of DAP-R in Bacillus subtilis and other Gram-positive bacteria indicate that the genetic pathways of DAP resistance are diverse and complex. However, a common phenomenon emerging from these mechanistic studies is that DAP-R is associated with important adaptive changes in cell wall and cell membrane homeostasis with critical changes in cell physiology. Findings related to these adaptive changes have offered novel insights into the genetics and molecular mechanisms of bacterial cell envelope stress response and the manner in which Gram-positive bacteria cope with the antimicrobial peptide attack and protect vital structures of the cell envelope such as the cell membrane. In this review, we will examine the most recent findings related to the molecular mechanisms of resistance to DAP in relevant Gram-positive pathogens and discuss the clinical implications for therapy against these important bacteria. PMID:26495887

  4. Preventing and managing antiretroviral drug resistance.

    Science.gov (United States)

    Kuritzkes, Daniel R

    2004-05-01

    Development of resistance to antiretroviral drugs (ARVs) is a major impediment to optimum treatment of HIV-1 infection. Although resistance testing can help to select subsequent regimens when virologic failure occurs, cross-resistance, which affects all classes of ARVs, may make it more difficult to achieve optimum control of HIV. We have known for some time that our first choice of antiretroviral therapy offers the best chance to control HIV replication and that initial therapy should be selected with an eye on future options. Potency is the first line of defense against the development of resistance. Other factors that affect resistance development include: tolerability, potential for optimum adherence, and genetic and pharmacologic barriers to development of resistance. If resistance emerges, only a single drug may be affected initially, and a rapid change in ARVs may preserve the efficacy of other components. One cautionary note is that we can no longer assume that a patient's HIV is fully susceptible to all ARVs even in the initial regimen. Transmission of drug-resistant HIV means that the genetic composition may be that of an "experienced" virus with reduced susceptibility to ARVs. Resistance testing at the time of transmission is most likely to reveal this resistance, but over time the dominant genetic pattern may revert to wild-type, and be missed by resistance testing. Because "archived" resistant HIV may emerge quickly once treatment is initiated, we need to keep this in mind when selecting initial therapy.

  5. Measurement and correlation of antifungal drugs solubility in pure supercritical CO{sub 2} using semiempirical models

    Energy Technology Data Exchange (ETDEWEB)

    Yamini, Yadollah, E-mail: yyamini@modares.ac.ir [Department of Chemistry, Faculty of Sciences, Tarbiat Modares University, P.O. Box 14115-175, Tehran (Iran, Islamic Republic of); Moradi, Morteza [Department of Chemistry, Faculty of Sciences, Tarbiat Modares University, P.O. Box 14115-175, Tehran (Iran, Islamic Republic of)

    2011-07-15

    Highlights: > Ketoconazole (KZ) and clotrimazole (CZ) are two antifungal drugs. > The solubilities of KZ and CZ were measured in supercritical CO{sub 2}. > The experimental results were correlated using five density based models. > The heats' of drug-CO{sub 2} solvation and drug vaporization were estimated. - Abstract: In the present study the solubilities of two antifungal drugs of ketoconazole and clotrimazole in supercritical carbon dioxide were measured using a simple static method. The experimental data were measured at (308 to 348) K, over the pressure range of (12.2 to 35.5) MPa. The mole fraction solubilities ranged from 0.2 . 10{sup -6} to 17.45 . 10{sup -5}. In this study five density based models were used to calculate the solubility of drugs in supercritical carbon dioxide. The density based models are Chrastil, modified Chrastil, Bartle, modified Bartle and Mendez-Santiago and Teja (M-T). Interaction parameters for the studied models were obtained and the percentage of average absolute relative deviation (AARD%) in each calculation was displayed. The correlation results showed good agreement with the experimental data. A comparison among the five models revealed that the Bartle and its modified models gave much better correlations of the solubility data with an average absolute relative deviation (AARD%) ranging from 4.8% to 6.2% and from 4.5% to 6.3% for ketoconazole and clotrimazole, respectively. Using the correlation results, the heat of drug-CO{sub 2} solvation and that of drug vaporization was separately approximated in the range of (-22.1 to -26.4 and 88.3 to 125.9) kJ . mol{sup -1}.

  6. Emerging pathogens: Dynamics, mutation and drug resistance

    Energy Technology Data Exchange (ETDEWEB)

    Perelson, A.S.; Goldstein, B.; Korber, B.T. [and others

    1997-10-01

    This is the final report of a one-year, Laboratory Directed Research and Development (LDRD) project at Los Alamos National Laboratory (LANL). The objectives of this project were to develop models of the spread of pathogens, such as HIV-1 and influenza, in humans, and then to use the models to address the possibility of designing appropriate drug therapies that may limit the ability of the pathogen to escape treatment by mutating into a drug resistant form. We have developed a model of drug-resistance to amantidine and rimantadine, the two major antiviral drugs used to treat influenza, and have used the model to suggest treatment strategies during an epidemic.

  7. Melanins Protect Sporothrix brasiliensis and Sporothrix schenckii from the Antifungal Effects of Terbinafine

    OpenAIRE

    Almeida-Paes, Rodrigo; Figueiredo-Carvalho, Maria Helena Galdino; Brito-Santos, F?bio; Almeida-Silva, Fernando; Oliveira, Manoel Marques Evangelista; Zancop?-Oliveira, Rosely Maria

    2016-01-01

    Terbinafine is a recommended therapeutic alternative for patients with sporotrichosis who cannot use itraconazole due to drug interactions or side effects. Melanins are involved in resistance to antifungal drugs and Sporothrix species produce three different types of melanin. Therefore, in this study we evaluated whether Sporothrix melanins impact the efficacy of antifungal drugs. Minimal inhibitory concentrations (MIC) and minimal fungicidal concentrations (MFC) of two Sporothrix brasiliensi...

  8. The In Vitro Efficacy of Essential Oils and Antifungal Drugs Against Prototheca zopfii.

    Science.gov (United States)

    Grzesiak, Barbara; Głowacka, Anna; Krukowski, Henryk; Lisowski, Andrzej; Lassa, Henryka; Sienkiewicz, Monika

    2016-08-01

    The algae of the genus Prototheca are environmental pathogens whose main reservoir is the habitat of cows. They can cause protothecosis in domestic and wild animals, as well as human beings, with the main etiological agents being Prototheca zopfii in animals and Prototheca wickerhamii in humans. The aim of the study was to evaluate the in vitro activity of selected essential oils and antifungal antibiotics against P. zopfii isolates. The material consisted of nine P. zopfii strains isolated from the milk of cows suffering from mastitis. Eight essential oils produced by POLLENA-AROMA, Poland, and nine antifungal agents were tested. The effects of essential oils on P. zopfii were evaluated by microdilution with liquid Sabouraud dextrose broth, and susceptibility to antifungal agents was tested using the disk-diffusion method. All used essential oils inhibited the activity of P. zopfii isolates, with MIC values ranging from 0.2 to 10.5 μl/ml. Cinnamon, clove, and thyme demonstrated the highest activity against the tested P. zopfii strains at concentrations ranging from 0.6 to 1.0 μl/ml. Of the antifungal agents, the tested strains were the most sensitive to nystatin (100 %). The tested essential oils can be used to complement protothecosis therapy in animals and human beings.

  9. mycobacterium tuberculosis genetic diversity and drug resistance ...

    African Journals Online (AJOL)

    East African Medical Journal Vol. 88 No. 12 December 2011. MYCOBACTERIUM TUBERCULOSIS GENETIC DIVERSITY AND DRUG RESISTANCE CONFERRING MUTATIONS. IN THE DEMOCRATIC REPUBLIC OF THE CONGO. L. Fenner, Institute of Social and Preventive Medicine, University of Bern, Switzerland, S.

  10. Pharmacokinetic evaluation of UK-49,858, a metabolically stable triazole antifungal drug, in animals and humans.

    Science.gov (United States)

    Humphrey, M J; Jevons, S; Tarbit, M H

    1985-11-01

    The pharmacokinetic profile of UK-49,858 (fluconazole), a novel triazole antifungal agent which is being developed for oral and intravenous use, was determined in mice, rats, dogs, and humans. Comparative data following oral and intravenous administration showed that bioavailability was essentially complete in all four species. Peak concentrations in plasma of drug normalized to a 1-mg/kg dose level following oral administration, were relatively high: 0.7, 0.6, 1.1, and 1.4 micrograms/ml in mice, rats, dogs, and humans, respectively. The volumes of distribution ranged between 1.1 liter/kg in mice and 0.7 liter/kg in humans, which are approximate to the values for total body water. Whole body autoradiography studies in mice following intravenous administration of [14C]UK-49,858 demonstrated that the drug was evenly distributed throughout the tissues, including the central nervous system and the gastrointestinal tract. Plasma protein binding was low (11 to 12%) in all species. Marked species differences were observed in elimination half-lives, with mean values of 4.8, 4.0, 14, and 22 h in mice, rats, dogs, and humans, respectively. The major route of elimination of the drug was renal clearance, with about 70% of the dose being excreted unchanged in the urine in each species. Studies with [14C]UK-49,858 on metabolism and excretion (intravenous and oral) in mice and dogs showed that about 90% of the dose was recovered as unchanged drug in urine and feces, confirming the metabolic stability of the drug. This pharmacokinetic profile is markedly different from that of imidazole antifungal drugs and undoubtedly contributes to the excellent efficacy of UK-49,858 in vivo.

  11. Emergence of Extensively Drug Resistant Tuberculosis

    Centers for Disease Control (CDC) Podcasts

    2007-03-01

    Extensively drug-resistant tuberculosis (XDR TB) outbreaks have been reported in South Africa, and strains have been identified on 6 continents. Dr. Peter Cegielski, team leader for drug-resistant TB with the Division of Tuberculosis Elimination at CDC, comments on a multinational team's report on this emerging global public health threat.  Created: 3/1/2007 by Emerging Infectious Diseases.   Date Released: 3/26/2007.

  12. Chloroquine sensitizes biofilms of Candida albicans to antifungal azoles

    Directory of Open Access Journals (Sweden)

    Ravikumar Bapurao Shinde

    Full Text Available Biofilms formed by Candida albicans, a human pathogen, are known to be resistant to different antifungal agents. Novel strategies to combat the biofilm associated Candida infections like multiple drug therapy are being explored. In this study, potential of chloroquine to be a partner drug in combination with four antifungal agents, namely fluconazole, voriconazole, amphotericin B, and caspofungin, was explored against biofilms of C. albicans. Activity of various concentrations of chloroquine in combination with a particular antifungal drug was analyzed in a checkerboard format. Growth of biofilm in presence of drugs was analyzed by XTT-assay, in terms of relative metabolic activity compared to that of drug free control. Results obtained by XTT-metabolic assay were confirmed by scanning electron microscopy. The interactions between chloroquine and four antifungal drugs were determined by calculating fractional inhibitory concentration indices. Azole resistance in biofilms was reverted significantly (p < 0.05 in presence of 250 µg/mL of chloroquine, which resulted in inhibition of biofilms at very low concentrations of antifungal drugs. No significant alteration in the sensitivity of biofilms to caspofungin and amphotericin B was evident in combination with chloroquine. This study for the first time indicates that chloroquine potentiates anti-biofilm activity of fluconazole and voriconazole.

  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

    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). 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). 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<0.05). The main finding was that the susceptibilities of FLU-resistant C. albicans to essential oils were higher than those of the FLU-susceptible yeasts. Results of this study indicated that the oils from medicinal plants could be used as potential anti FLU-resistant C. albicans agents.

  14. Local, systemic, demographic, and health-related factors influencing pathogenic yeast spectrum and antifungal drug administration frequency in oral candidiasis: a retrospective study.

    Science.gov (United States)

    Hertel, Moritz; Schmidt-Westhausen, Andrea Maria; Strietzel, Frank-Peter

    2016-09-01

    In order to identify oral candidiasis patients being at risk of carrying potentially drug-resistant Candida, the aim of the study was to detect local, systemic, demographic, and health-related factors influencing (I) yeast spectrum composition and (II) antifungal administration frequency. Additionally, the aim was to investigate (III) species shift occurrence. Data from 798 patients (496 females, 302 males; mean age 59.7) with oral candidiasis diagnosed based on positive clinical and microbial findings (species identification and CFU count) between 2006 and 2011 were retrospectively analyzed using Pearson's chi(2) test and regression analysis. Among 958 isolates, Candida albicans was the most frequently detected (76.8 %). Also, species intrinsically resistant to azoles were frequently isolated (15.8 and 17.7 % of isolates and patients). (I) Infections only caused by C. albicans were significantly associated with the use of inhalation steroids (p = 0.001) and antibiotics (p = 0.04), super-infection of lichen planus (p = 0.002), and the absence of removable dentures (p oral candidiasis remains C. albicans. Nevertheless, therapeutic problems may be caused by the frequent presence of species intrinsically resistant to azoles, especially in patients wearing dentures.

  15. Drug resistance in the mouse cancer clinic

    NARCIS (Netherlands)

    Rottenberg, Sven; Borst, Piet

    2012-01-01

    Drug resistance is one of the most pressing problems in treating cancer patients today. Local and regional disease can usually be adequately treated, but patients eventually die from distant metastases that have become resistant to all available chemotherapy. Although work on cultured tumor cell

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

    Directory of Open Access Journals (Sweden)

    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.

  17. Campylobacter Antimicrobial Drug Resistance among Humans in ...

    African Journals Online (AJOL)

    Background: Though Campylobacter enteritis is a self-limiting disease, antimicrobial agents are recommended for extraintestinal infections and for treating immunocompromised persons. Erythromycin and ciprofloxacin are drugs of choice. The rate of resistance to these drugs is increasing in both developed and developing ...

  18. Drug resistance mutations for surveillance of transmitted HIV-1 drug-resistance: 2009 update.

    Directory of Open Access Journals (Sweden)

    Diane E Bennett

    Full Text Available Programs that monitor local, national, and regional levels of transmitted HIV-1 drug resistance inform treatment guidelines and provide feedback on the success of HIV-1 treatment and prevention programs. To accurately compare transmitted drug resistance rates across geographic regions and times, the World Health Organization has recommended the adoption of a consensus genotypic definition of transmitted HIV-1 drug resistance. In January 2007, we outlined criteria for developing a list of mutations for drug-resistance surveillance and compiled a list of 80 RT and protease mutations meeting these criteria (surveillance drug resistance mutations; SDRMs. Since January 2007, several new drugs have been approved and several new drug-resistance mutations have been identified. In this paper, we follow the same procedures described previously to develop an updated list of SDRMs that are likely to be useful for ongoing and future studies of transmitted drug resistance. The updated SDRM list has 93 mutations including 34 NRTI-resistance mutations at 15 RT positions, 19 NNRTI-resistance mutations at 10 RT positions, and 40 PI-resistance mutations at 18 protease positions.

  19. Profiling evolutionary landscapes underlying drug resistance

    DEFF Research Database (Denmark)

    Hickman, Rachel

    bacterial communities i.e. biofilms or dormant metabolic states. Antibiotic drugs are currently our best medicine to treat (against) bacterial pathogens due to antibiotics unique properties of being small molecules that are soluble and act systemically. These qualities allow for many modern medical......, the work involved in this PhD thesis, examines the evolution of antibiotic resistance in bacterial populations. Two main studies were performed: the first to elucidate the molecular mechanisms of collateral sensitive drug pairs and collateral resistance drug pairs in adaptation of Escherichia coli...

  20. Antifungal activity of Myrtus communis against Malassezia sp. isolated from the skin of patients with pityriasis versicolor.

    Science.gov (United States)

    Barac, Aleksandra; Donadu, Matthew; Usai, Donatella; Spiric, Vesna Tomic; Mazzarello, Vittorio; Zanetti, Stefania; Aleksic, Ema; Stevanovic, Goran; Nikolic, Natasa; Rubino, Salvatore

    2017-11-20

    The increasing incidence of fungal infections and antifungal resistance has prompted the search for novel antifungal drugs and alternative agents. We explored the antifungal activity of Myrtus communis essential oil (EO) against Malassezia sp. isolated from the skin of patients with pityriasis versicolor. These broad-spectrum antimicrobial activities of M. communis EO and its potent inhibiting activity on Malassezia growth deserve further research with aim to considerate this EO as candidate for topical use in treatment of skin diseases.

  1. Streptococcus pneumoniae Drugs Resistance in Acute Rhinosinusitis

    Directory of Open Access Journals (Sweden)

    Chong Jie Hao

    2016-03-01

    Full Text Available Background: Acute rhinosinusitis that usually caused by Streptococcus pneumoniae becomes the reason why patients seek for medical care. Drugs resistance in Streptococcus pneumoniae is increasing worldwide. This study was conducted to determine drugs resistance of Streptococcus pneumonia from acute rhinosinusitis in Dr. Hasan Sadikin General Hospital. Methods: A descriptive laboratory study was conducted in June–October 2014 at the Laboratory of Microbiology Faculty of Medicine Universitas Padjadjaran. The sample was taken using nasopharyngeal swabbing from 100 acute rhinosinusitis patients in Dr. Hasan Sadikin General Hospital and planted on tryptic soy agar containing 5% sheep blood and 5 μg/ml of gentamicin sulphate and then incubated in 5% CO2 incubator at 37°C for 24 hours. The identification of Streptococcus pneumonia was performed by optochin test. The susceptibility test against Streptococcus pneumoniae was done using disk diffusion method.The antibiotic disks were trimethoprim-sulfamethoxazole, oxacillin, levofloxacin, azithromycin, and doxycycline. Results: Out of 100 samples, 8 of them were tested positive for Streptococcus pneumoniae. Three of Streptococcus pneumoniae isolates died with unknown reason after it were stored at -80 .The drugs resistance test showed the resistance of Streptococcus pneumonia to oxacillin, azithromycin and trimethoprim were 6, whereas levofloxacin and doxycycline are 4. Conclusions: Streptococcus pneumonia drugs resistance in acute rhinosinusitis shows the resistance of Streptococcus pneumoniae to oxacillin, azithromycin and trimethoprim are 6, whereas the resistance to levofloxacin and doxycycline are 4.

  2. Role of drug transporters and drug accumulation in the temporal acquisition of drug resistance

    International Nuclear Information System (INIS)

    Hembruff, Stacey L; Laberge, Monique L; Villeneuve, David J; Guo, Baoqing; Veitch, Zachary; Cecchetto, Melanie; Parissenti, Amadeo M

    2008-01-01

    Anthracyclines and taxanes are commonly used in the treatment of breast cancer. However, tumor resistance to these drugs often develops, possibly due to overexpression of drug transporters. It remains unclear whether drug resistance in vitro occurs at clinically relevant doses of chemotherapy drugs and whether both the onset and magnitude of drug resistance can be temporally and causally correlated with the enhanced expression and activity of specific drug transporters. To address these issues, MCF-7 cells were selected for survival in increasing concentrations of doxorubicin (MCF-7 DOX-2 ), epirubicin (MCF-7 EPI ), paclitaxel (MCF-7 TAX-2 ), or docetaxel (MCF-7 TXT ). During selection cells were assessed for drug sensitivity, drug uptake, and the expression of various drug transporters. In all cases, resistance was only achieved when selection reached a specific threshold dose, which was well within the clinical range. A reduction in drug uptake was temporally correlated with the acquisition of drug resistance for all cell lines, but further increases in drug resistance at doses above threshold were unrelated to changes in cellular drug uptake. Elevated expression of one or more drug transporters was seen at or above the threshold dose, but the identity, number, and temporal pattern of drug transporter induction varied with the drug used as selection agent. The pan drug transporter inhibitor cyclosporin A was able to partially or completely restore drug accumulation in the drug-resistant cell lines, but had only partial to no effect on drug sensitivity. The inability of cyclosporin A to restore drug sensitivity suggests the presence of additional mechanisms of drug resistance. This study indicates that drug resistance is achieved in breast tumour cells only upon exposure to concentrations of drug at or above a specific selection dose. While changes in drug accumulation and the expression of drug transporters does occur at the threshold dose, the magnitude of

  3. Role of drug transporters and drug accumulation in the temporal acquisition of drug resistance

    Directory of Open Access Journals (Sweden)

    Veitch Zachary

    2008-11-01

    Full Text Available Abstract Background Anthracyclines and taxanes are commonly used in the treatment of breast cancer. However, tumor resistance to these drugs often develops, possibly due to overexpression of drug transporters. It remains unclear whether drug resistance in vitro occurs at clinically relevant doses of chemotherapy drugs and whether both the onset and magnitude of drug resistance can be temporally and causally correlated with the enhanced expression and activity of specific drug transporters. To address these issues, MCF-7 cells were selected for survival in increasing concentrations of doxorubicin (MCF-7DOX-2, epirubicin (MCF-7EPI, paclitaxel (MCF-7TAX-2, or docetaxel (MCF-7TXT. During selection cells were assessed for drug sensitivity, drug uptake, and the expression of various drug transporters. Results In all cases, resistance was only achieved when selection reached a specific threshold dose, which was well within the clinical range. A reduction in drug uptake was temporally correlated with the acquisition of drug resistance for all cell lines, but further increases in drug resistance at doses above threshold were unrelated to changes in cellular drug uptake. Elevated expression of one or more drug transporters was seen at or above the threshold dose, but the identity, number, and temporal pattern of drug transporter induction varied with the drug used as selection agent. The pan drug transporter inhibitor cyclosporin A was able to partially or completely restore drug accumulation in the drug-resistant cell lines, but had only partial to no effect on drug sensitivity. The inability of cyclosporin A to restore drug sensitivity suggests the presence of additional mechanisms of drug resistance. Conclusion This study indicates that drug resistance is achieved in breast tumour cells only upon exposure to concentrations of drug at or above a specific selection dose. While changes in drug accumulation and the expression of drug transporters does

  4. FKBP12-Dependent Inhibition of Calcineurin Mediates Immunosuppressive Antifungal Drug Action inMalassezia.

    Science.gov (United States)

    Ianiri, Giuseppe; Applen Clancey, Shelly; Lee, Soo Chan; Heitman, Joseph

    2017-10-24

    has adverse side effects and is not recommended for long treatment periods. Calcineurin inhibitors have been proposed as a suitable alternative to treat patients affected by skin lesions caused by Malassezia Although calcineurin inhibitors are well-known as immunosuppressive drugs, they are also characterized by potent antimicrobial activity. In the present study, we investigated the mechanism of action of FK506 (tacrolimus), ascomycin (FK520), and pimecrolimus in M. furfur and M. sympodialis and found that the conserved immunophilin FKBP12 is the target of these drugs with which it forms a complex that directly binds calcineurin and inhibits its signaling activity. We found that FKBP12 is also required for the additive activity of calcineurin inhibitors with fluconazole. Furthermore, the increasing natural occurrence in fungal pathogen populations of mutator strains poses a high risk for the rapid emergence of drug resistance and adaptation to host defense. This led us to generate an engineered hypermutator msh2 Δ mutant strain of M. sympodialis and genetically evaluate mutational events resulting in a substantially increased rate of resistance to FK506 compared to that of the wild type. Our study paves the way for the novel clinical use of calcineurin inhibitors with lower immunosuppressive activity that could be used clinically to treat a broad range of fungal infections, including skin disorders caused by Malassezia . Copyright © 2017 Ianiri et al.

  5. Antimicrobial Drug Resistance and Gonorrhea

    Centers for Disease Control (CDC) Podcasts

    2017-12-26

    Dr. Robert Kirkcaldy, a medical officer at CDC, discusses his article on antimicrobial resistance and gonorrhea.  Created: 12/26/2017 by National Center for Emerging and Zoonotic Infectious Diseases (NCEZID).   Date Released: 12/26/2017.

  6. Antibacterial drug discovery in the resistance era.

    Science.gov (United States)

    Brown, Eric D; Wright, Gerard D

    2016-01-21

    The looming antibiotic-resistance crisis has penetrated the consciousness of clinicians, researchers, policymakers, politicians and the public at large. The evolution and widespread distribution of antibiotic-resistance elements in bacterial pathogens has made diseases that were once easily treatable deadly again. Unfortunately, accompanying the rise in global resistance is a failure in antibacterial drug discovery. Lessons from the history of antibiotic discovery and fresh understanding of antibiotic action and the cell biology of microorganisms have the potential to deliver twenty-first century medicines that are able to control infection in the resistance era.

  7. Current perspective on emergence, diagnosis and drug resistance in Candida auris

    Directory of Open Access Journals (Sweden)

    Sarma S

    2017-06-01

    Full Text Available Smita Sarma, Shalini Upadhyay Department of Microbiology, Medanta – The Medicity, Gurgaon, Haryana, India Abstract: Candida auris is an emerging fungus that presents a serious threat to global health. The organism is difficult to identify using conventional biochemical methods. C. auris has also attracted attention because of its reduced susceptibility to azoles, polyenes, and echinocandins, with a few strains even resistant to all three classes of antifungals. In this review paper we discuss the trends in emergence of C. auris in different parts of the world, associated risk factors, drug resistance, and diagnostic challenges. Strategies for prevention and therapeutic options for such infections is also addressed. Keywords: Candidemia, Candida haemulonii, outbreak, drug resistance

  8. Drug resistance mutations for surveillance of transmitted HIV-1 drug-resistance: 2009 update

    NARCIS (Netherlands)

    D.E. Bennett (Diane); R.J. Camacho (Ricardo Jorge); D. Otelea (Dan); D.R. Kuritzkes (Daniel); H. Fleury (Hervé); M. Kiuchi (Mark); W. Heneine (Walid); R. Kantor (Rami); M.R. Jordan (Michael); J.M. Schapiro (Jonathan); A.M. Vandamme (Anne Mieke); P. Sandstrom (Paul); C.A.B. Boucher (Charles); D.A.M.C. van de Vijver (David); S.Y. Rhee (Soo Yoon); T.F. Liu (Tommy); D. Pillay (Deenan); R.W. Shafer (Robert)

    2009-01-01

    textabstractPrograms that monitor local, national, and regional levels of transmitted HIV-1 drug resistance inform treatment guidelines and provide feedback on the success of HIV-1 treatment and prevention programs. To accurately compare transmitted drug resistance rates across geographic regions

  9. Minority Variants of Drug-Resistant HIV

    Science.gov (United States)

    Gianella, Sara; Richman, Douglas D.

    2010-01-01

    Minor drug-resistant variants exist in every HIV-infected patient. Since these minority variants are usually present at very low levels, they cannot be detected and quantified using conventional genotypic and phenotypic tests. Recently, several assays have been developed to characterize these low-abundance drug-resistant variants in the large genetically complex population present in every HIV-infected individual. The most important issue is, what results generated by these assays can predict clinical or treatment outcomes and might guide patient management in clinical practice. Cutoff-values for the detection of these low-abundance viral variants that predict increased risk of treatment failure should be determined. These thresholds may be specific for each mutation and treatment regimen. In this review we summarize the attributes and limitations of the currently available detection assays and review the existing information about both acquired and transmitted drug resistant minority variants. PMID:20649427

  10. Antifungal susceptibility profiles of 1698 yeast reference strains revealing potential emerging human pathogens.

    Directory of Open Access Journals (Sweden)

    Marie Desnos-Ollivier

    Full Text Available New molecular identification techniques and the increased number of patients with various immune defects or underlying conditions lead to the emergence and/or the description of novel species of human and animal fungal opportunistic pathogens. Antifungal susceptibility provides important information for ecological, epidemiological and therapeutic issues. The aim of this study was to assess the potential risk of the various species based on their antifungal drug resistance, keeping in mind the methodological limitations. Antifungal susceptibility profiles to the five classes of antifungal drugs (polyens, azoles, echinocandins, allylamines and antimetabolites were determined for 1698 yeast reference strains belonging to 992 species (634 Ascomycetes and 358 Basidiomycetes. Interestingly, geometric mean minimum inhibitory concentrations (MICs of all antifungal drugs tested were significantly higher for Basidiomycetes compared to Ascomycetes (p<0.001. Twenty four strains belonging to 23 species of which 19 were Basidiomycetes seem to be intrinsically "resistant" to all drugs. Comparison of the antifungal susceptibility profiles of the 4240 clinical isolates and the 315 reference strains belonging to 53 shared species showed similar results. Even in the absence of demonstrated in vitro/in vivo correlation, knowing the in vitro susceptibility to systemic antifungal agents and the putative intrinsic resistance of yeast species present in the environment is important because they could become opportunistic pathogens.

  11. Mesenchymal change and drug resistance in neuroblastoma.

    Science.gov (United States)

    Naiditch, Jessica A; Jie, Chunfa; Lautz, Timothy B; Yu, Songtao; Clark, Sandra; Voronov, Dimitry; Chu, Fei; Madonna, Mary Beth

    2015-01-01

    Metastatic initiation has many phenotypic similarities to epithelial-to-mesenchymal transition, including loss of cell-cell adhesion, increased invasiveness, and increased cell mobility. We have previously demonstrated that drug resistance is associated with a metastatic phenotype in neuroblastoma (NB). The purpose of this project was to determine if the development of doxorubicin resistance is associated with characteristics of mesenchymal change in human NB cells. Total RNA was isolated from wild type (WT) and doxorubicin-resistant (DoxR) human NB cell lines (SK-N-SH and SK-N-BE(2)C) and analyzed using the Illumina Human HT-12 version 4 Expression BeadChip. Differentially expressed genes (DEGs) were identified. Volcano plots and heat maps were generated. Genes of interest with a fold change in expression >1.5 and an adjusted P change via multiple pathways in the transition to a drug-resistant state. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. reverse transcriptase inhibitors drug resistance mutations in drug ...

    African Journals Online (AJOL)

    2011-01-01

    Jan 1, 2011 ... through put drug resistance testing for the increasing number of infected individuals in order to effectively manage those initiating ART. ACKNoWLEdGEMENTs. To the patient who participated in the study, the Kenya. Medical Research Institute, Centre for Virus HIV. Laboratory division staff for their support.

  13. Requirement for ergosterol in V-ATPase function underlies antifungal activity of azole drugs.

    Directory of Open Access Journals (Sweden)

    Yong-Qiang Zhang

    2010-06-01

    Full Text Available Ergosterol is an important constituent of fungal membranes. Azoles inhibit ergosterol biosynthesis, although the cellular basis for their antifungal activity is not understood. We used multiple approaches to demonstrate a critical requirement for ergosterol in vacuolar H(+-ATPase function, which is known to be essential for fungal virulence. Ergosterol biosynthesis mutants of S. cerevisiae failed to acidify the vacuole and exhibited multiple vma(- phenotypes. Extraction of ergosterol from vacuolar membranes also inactivated V-ATPase without disrupting membrane association of its subdomains. In both S. cerevisiae and the fungal pathogen C. albicans, fluconazole impaired vacuolar acidification, whereas concomitant ergosterol feeding restored V-ATPase function and cell growth. Furthermore, fluconazole exacerbated cytosolic Ca(2+ and H(+ surges triggered by the antimicrobial agent amiodarone, and impaired Ca(2+ sequestration in purified vacuolar vesicles. These findings provide a mechanistic basis for the synergy between azoles and amiodarone observed in vitro. Moreover, we show the clinical potential of this synergy in treatment of systemic fungal infections using a murine model of Candidiasis. In summary, we demonstrate a new regulatory component in fungal V-ATPase function, a novel role for ergosterol in vacuolar ion homeostasis, a plausible cellular mechanism for azole toxicity in fungi, and preliminary in vivo evidence for synergism between two antifungal agents. New insights into the cellular basis of azole toxicity in fungi may broaden therapeutic regimens for patient populations afflicted with systemic fungal infections.

  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. Drug resistance patterns in pulmonary tuberculosis

    International Nuclear Information System (INIS)

    Khoharo, H.K.; Shaikh, I.A.

    2011-01-01

    Objective: To determine the resistance patterns of mycobacterium tuberculosis (MTB) isolates among category I and II patients of pulmonary tuberculosis. Methods: This cross sectional study was conducted at the Department of Medicine, Liaquat University of Medical and Health Sciences Jamshoro, from November 2008 to September 2009. Patients were divided into category I and II. The sputa were collected, stained with Ziehl-Nielsen (Z-N) staining and ultimately inoculated on Lowenstein-Jensen (L-J) media for six weeks. Out of 890 pulmonary tuberculosis (PTB) patients, the growth was obtained in 285 cases. The Drug sensitivity testing (DST) for Isoniazid (INH), Rifampicin (RIF), Ethambutol (EMB) Pyrazinamide (PZA) and Streptomycin (SM) were performed. The data was analyzed on SPSS 10.0. A p-value of <0.05 was taken as significant. Result: Out of 285 cases, 176 (61.75%) were male and 109 (38.24%) female. The mean age was 37 +- 19.90 years. The DST showed drug sensitive and drug resistant isolates in 80 (28.05%) and 205 (71.92%) cases respectively (p=0.001). The drug resistant tuberculosis (DR-TB) rates for individual drugs; INH, RIF, EMB, PZA and SM were 51,22%, 15.4%, 13.33%, 9%12, and 3.85% respectively (p=0.03). The MDR-TB isolates were detected in 120 (42.10%) cases, including 5 (5.88%) in category I and 115 (57.50%) in category II patients (p=0.0001). Conclusion: Drug resistant and multidrug resistant tuberculosis was observed mainly in category II patients. However, primary MDR was also observed in category I patients and reflects dissemination of MDR cases within the community. (author)

  16. Repurposing salicylanilide anthelmintic drugs to combat drug resistant Staphylococcus aureus.

    Directory of Open Access Journals (Sweden)

    Rajmohan Rajamuthiah

    Full Text Available Staphylococcus aureus is a Gram-positive bacterium that has become the leading cause of hospital acquired infections in the US. Repurposing Food and Drug Administration (FDA approved drugs for antimicrobial therapy involves lower risks and costs compared to de novo development of novel antimicrobial agents. In this study, we examined the antimicrobial properties of two commercially available anthelmintic drugs. The FDA approved drug niclosamide and the veterinary drug oxyclozanide displayed strong in vivo and in vitro activity against methicillin resistant S. aureus (minimum inhibitory concentration (MIC: 0.125 and 0.5 μg/ml respectively; minimum effective concentration: ≤ 0.78 μg/ml for both drugs. The two drugs were also effective against another Gram-positive bacteria Enterococcus faecium (MIC 0.25 and 2 μg/ml respectively, but not against the Gram-negative species Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter aerogenes. The in vitro antimicrobial activity of niclosamide and oxyclozanide were determined against methicillin, vancomycin, linezolid or daptomycin resistant S. aureus clinical isolates, with MICs at 0.0625-0.5 and 0.125-2 μg/ml for niclosamide and oxyclozanide respectively. A time-kill study demonstrated that niclosamide is bacteriostatic, whereas oxyclozanide is bactericidal. Interestingly, oxyclozanide permeabilized the bacterial membrane but neither of the anthelmintic drugs exhibited demonstrable toxicity to sheep erythrocytes. Oxyclozanide was non-toxic to HepG2 human liver carcinoma cells within the range of its in vitro MICs but niclosamide displayed toxicity even at low concentrations. These data show that the salicylanilide anthelmintic drugs niclosamide and oxyclozanide are suitable candidates for mechanism of action studies and further clinical evaluation for treatment of staphylococcal infections.

  17. Repurposing salicylanilide anthelmintic drugs to combat drug resistant Staphylococcus aureus.

    Science.gov (United States)

    Rajamuthiah, Rajmohan; Fuchs, Beth Burgwyn; Conery, Annie L; Kim, Wooseong; Jayamani, Elamparithi; Kwon, Bumsup; Ausubel, Frederick M; Mylonakis, Eleftherios

    2015-01-01

    Staphylococcus aureus is a Gram-positive bacterium that has become the leading cause of hospital acquired infections in the US. Repurposing Food and Drug Administration (FDA) approved drugs for antimicrobial therapy involves lower risks and costs compared to de novo development of novel antimicrobial agents. In this study, we examined the antimicrobial properties of two commercially available anthelmintic drugs. The FDA approved drug niclosamide and the veterinary drug oxyclozanide displayed strong in vivo and in vitro activity against methicillin resistant S. aureus (minimum inhibitory concentration (MIC): 0.125 and 0.5 μg/ml respectively; minimum effective concentration: ≤ 0.78 μg/ml for both drugs). The two drugs were also effective against another Gram-positive bacteria Enterococcus faecium (MIC 0.25 and 2 μg/ml respectively), but not against the Gram-negative species Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter aerogenes. The in vitro antimicrobial activity of niclosamide and oxyclozanide were determined against methicillin, vancomycin, linezolid or daptomycin resistant S. aureus clinical isolates, with MICs at 0.0625-0.5 and 0.125-2 μg/ml for niclosamide and oxyclozanide respectively. A time-kill study demonstrated that niclosamide is bacteriostatic, whereas oxyclozanide is bactericidal. Interestingly, oxyclozanide permeabilized the bacterial membrane but neither of the anthelmintic drugs exhibited demonstrable toxicity to sheep erythrocytes. Oxyclozanide was non-toxic to HepG2 human liver carcinoma cells within the range of its in vitro MICs but niclosamide displayed toxicity even at low concentrations. These data show that the salicylanilide anthelmintic drugs niclosamide and oxyclozanide are suitable candidates for mechanism of action studies and further clinical evaluation for treatment of staphylococcal infections.

  18. Multidrug resistant to extensively drug resistant tuberculosis: What is ...

    Indian Academy of Sciences (India)

    Prakash

    reported figure, because the annual risk of tuberculosis and prevalence of acquired multi-drug resistant tuberculosis and tuberculosis with HIV is increasing in India (Narain and Lo 2004). One case of XDR- TB is recently reported from Tuberculosis Research Center, Chennai (Thomas et al. 2007). 7. XDR-TB with HIV/AIDS.

  19. Ultrasound-air-assisted demulsified liquid-liquid microextraction by solidification of a floating organic droplet for determination of three antifungal drugs in water and biological samples.

    Science.gov (United States)

    Ezoddin, Maryam; Shojaie, Mehran; Abdi, Khosrou; Karimi, Mohammad Ali

    2017-03-01

    A novel ultrasound-air-assisted demulsified liquid-liquid microextraction by solidification of a floating organic droplet (UAAD-LLM-SFO) followed by HPLC-UV detection was developed for the analysis of three antifungal drugs in water and biological samples. In this method, 1-dodecanol was used as the extraction solvent. The emulsion was rapidly formed by pulling in and pushing out the mixture of sample solution and extraction solvent for 5 times repeatedly using a 10-mL glass syringe while sonication was performed. Therefore, an organic dispersive solvent required in common microextraction methods was not used in the proposed method. After dispersing, an aliquot of acetonitrile was introduced as a demulsifier solvent into the sample solution to separate two phases. Therefore, some additional steps, such as the centrifugation, ultrasonication, or agitation of the sample solution, are not needed. Parameters influencing the extraction recovery were investigated. The proposed method showed a good linearity for the three antifungal drugs studied with the correlation coefficients (R 2  > 0.9995). The limits of detection (LODs) and the limits of the quantification (LOQs) were between 0.01-0.03 μg L -1 and 0.03-0.08 μg L -1 , respectively. The preconcentration factors (PFs) were in the range of 107-116, respectively. The precisions, as the relative standard deviations (RSDs) (n = 5), for inter-day and intra-day analysis were in the range of 2.1-4.5% and 6.5-8.5%, respectively. This method was successfully applied to determine the three antifungal drugs in tap water and biological samples. The recoveries of antifungal drugs in these samples were 92.4-98.5%. Graphical abstract Ultrasound-air-assisted demulsified liquid-liquid microextraction by solidification of a floating organic droplet for the analysis of three antifungal drugs prior HPLC-UV.

  20. Characterization of drug resistant Pseudomonas aeruginosa and ...

    African Journals Online (AJOL)

    Lizards as well as some other reptiles have been known to carry pathogenic bacteria organisms as well as drug resistant pathogens. Despite the fact that they remain asymptomatic in many cases, they nevertheless play significant roles in the epidemiology of these pathogens through their dissemination to the public, ...

  1. Antifungal Resistance Patterns in Molds Isolated from Wounds of Combat Related Trauma Patients

    Science.gov (United States)

    2017-10-05

    13. SUPPLEMENTARY NOTES ID Week, San Diego, CA , Oct 5 2017 14. ABSTRACT Background: An outbreak of trauma-related invasive fimgal infections (IFI...surgical debridement. Antifungal susceptibilities (AS) and relation to outcoID Week, San Diego, CA , Oct 5 20 l 7mes are yet to be described. Methods...25 16 ... 2 ... 7/17/13 0.125 • >16 2 >16 A._,,......,. __ 7/1Dl12 0.5 0 . 125 ɘ.0313 0.25 ɘ.0313 7""󈧐 0.25 1 ɘ.031! 1 0 . 125 7/20/12 0.25 1

  2. Population mobility, globalization, and antimicrobial drug resistance.

    Science.gov (United States)

    MacPherson, Douglas W; Gushulak, Brian D; Baine, William B; Bala, Shukal; Gubbins, Paul O; Holtom, Paul; Segarra-Newnham, Marisel

    2009-11-01

    Population mobility is a main factor in globalization of public health threats and risks, specifically distribution of antimicrobial drug-resistant organisms. Drug resistance is a major risk in healthcare settings and is emerging as a problem in community-acquired infections. Traditional health policy approaches have focused on diseases of global public health significance such as tuberculosis, yellow fever, and cholera; however, new diseases and resistant organisms challenge existing approaches. Clinical implications and health policy challenges associated with movement of persons across barriers permeable to products, pathogens, and toxins (e.g., geopolitical borders, patient care environments) are complex. Outcomes are complicated by high numbers of persons who move across disparate and diverse settings of disease threat and risk. Existing policies and processes lack design and capacity to prevent or mitigate adverse health outcomes. We propose an approach to global public health risk management that integrates population factors with effective and timely application of policies and processes.

  3. Death receptor ligands, in particular TRAIL, to overcome drug resistance

    NARCIS (Netherlands)

    de Jong, S; Timmer, T; Heijenbrok, FJ; de Vries, EGE

    2001-01-01

    The efficacy of chemotherapeutic drugs is hampered by the occurrence of intrinsic and acquired drug resistance. A variety of mechanisms cause drug-resistance. A final common factor, however, is the reduced capacity of drug resistant cells to go into apoptosis following treatment with DNA damaging

  4. Effects of Membrane PEGylation on Entry and Location of Antifungal Drug Itraconazole and Their Pharmacological Implications

    DEFF Research Database (Denmark)

    Dzieciuch-Rojek, Monika; Poojari, Chetan; Bednar, Jan

    2017-01-01

    Itraconazole (ITZ) is an antifungal agent used clinically to treat mycotic infections. However, its therapeutic effects are limited by low solubility in aqueous media. Liposome-based delivery systems (LDS) have been proposed as a delivery mechanism for ITZ to alleviate this problem. Furthermore...... of ITZ incorporation into liposomes both with and without PEGylation because it can provide a potential foundation for the rational design of LDS-based systems for delivery of ITZ, using alternate protective polymers or formulations. Here we have combined atomistic simulations, cryo-TEM, Langmuir film...... to its protective properties, PEGylation significantly increases the stability of liposomes that host ITZ. In a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer without PEGylation, ITZ was found to reside inside the lipid bilayer between the glycerol and the double-bond regions of POPC...

  5. In vitro susceptibility of antifungal drugs against Sporothrix brasiliensis recovered from cats with sporotrichosis in Brazil.

    Science.gov (United States)

    Brilhante, Raimunda Sâmia Nogueira; Rodrigues, Anderson Messias; Sidrim, José Júlio Costa; Rocha, Marcos Fábio Gadelha; Pereira, Sandro Antonio; Gremião, Isabella Dib Ferreira; Schubach, Tânia Maria Pacheco; de Camargo, Zoilo Pires

    2016-03-01

    Sporotrichosis is an important subcutaneous mycosis of humans and animals. Classically, the disease is acquired upon traumatic inoculation of Sporothrix propagules from contaminated soil and plant debris. In addition, the direct horizontal transmission of Sporothrix among animals and the resulting zoonotic infection in humans highlight an alternative and efficient rout of transmission through biting and scratching. Sporothrix brasiliensis is the most virulent species of the Sporothrix schenckii complex and is responsible for the long-lasting outbreak of feline sporotrichosis in Brazil. However, antifungal susceptibility data of animal-borne isolates is scarce. Therefore, this study evaluated the in vitro activity of amphotericin B, caspofungin, itraconazole, voriconazole, fluconazole, and ketoconazole against animal-borne isolates of S. brasiliensis. The susceptibility tests were performed through broth microdilution (M38-A2). The results show the relevant activity of itraconazole, amphotericin B, and ketoconazole against S. brasiliensis, with the following MIC ranges: 0.125-2, 0.125-4 and 0.0312-2 μg/ml, respectively. Caspofungin was moderately effective, displaying higher variation in MIC values (0.25-64 μg/ml). Voriconazole (2-64 μg/ml) and fluconazole (62.5-500 μg/ml) showed low activity against S. brasiliensis strains. This study contributed to the characterization of the in vitro antifungal susceptibility of strains of S. brasiliensis recovered from cats with sporotrichosis, which have recently been considered the main source of human infections. © The Author 2015. 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.

  6. Clinicomycological Profile and Antifungal Sensitivity Pattern of Commonly Used Azoles in Dermatophytosis

    Directory of Open Access Journals (Sweden)

    Mahesh Mathur

    2015-06-01

    Conclusions: This study highlighted the increasing resistance of the antifungals, which is responsible for the treatment failure in dermatophye infections. Keywords: antifungal resistance; dermatophyte; epidemiology.

  7. Evaluation of antibacterial, antifungal and modulatory activity of ...

    African Journals Online (AJOL)

    Methods: The tests for the minimum inhibitory concentration and modulation of microbial resistance, with the use of ethanolic and methanolic extracts of Padina Sanctae-cruces combined with drugs of the class of aminoglycosides and antifungal were used to evaluate the activity against the cited microorganisms. Results: ...

  8. Antifungal susceptibility profiles and risk factors of vaginal ...

    African Journals Online (AJOL)

    Antifungal susceptibility results showed a high resistance to fluconazole (82.0%), nystatin (80.0%) and ketoconazole (72.0%), while clotrimazole (50.0%) was the most activeantifungal drug. There was a high prevalence of VC in this study population with previous vaginal infectionbeing important risk factor for reoccurrence.

  9. A rifampicin-resistant (rpoB) mutation in Pseudomonas protegens Pf-5 strain leads to improved antifungal activity and elevated production of secondary metabolites.

    Science.gov (United States)

    Xie, Yali; Liu, Zhengqiang; Zhang, Guoyong; Mo, Xiangtao; Ding, Xuezhi; Xia, Liqiu; Hu, Shengbiao

    2016-10-01

    Ribosome engineering has proven to be a practical method for increasing antibiotic production, and is extensively applied to strain improvement in antibiotic production and activation of silent genes in several prokaryotes. In this study, ribosome engineering was used to improve production of bioactive secondary metabolites produced by Pseudomonas protegens Pf-5. Rifampicin-resistant mutants that bear the H531N in the β-subunit of RNA polymerase showed improved antifungal activity and morphological changes. The production of several secondary metabolites in R55 mutant was significantly improved using high-performance liquid chromatography (HPLC) analysis. Two antibiotics with antifungal activity, 2, 4-diacetylphloroglucinol (Phl) and pyoluteorin (Plt), which may contribute to the improved antifungal activity of the R55 mutant, were identified by mass spectrometer (MS) analysis. Copyright © 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  10. An insight into the drug resistance profile & mechanism of drug resistance in Neisseria gonorrhoeae.

    Science.gov (United States)

    Patel, Achchhe Lal; Chaudhry, Uma; Sachdev, Divya; Sachdeva, Poonam Nagpal; Bala, Manju; Saluja, Daman

    2011-10-01

    Among the aetiological agents of treatable sexually transmitted diseases (STDs), Neissseria gonorrhoeae is considered to be most important because of emerging antibiotic resistant strains that compromise the effectiveness of treatment of the disease - gonorrhoea. In most of the developing countries, treatment of gonorrhoea relies mainly on syndromic management rather than the aetiological based therapy. Gonococcal infections are usually treated with single-dose therapy with an agent found to cure > 95 per cent of cases. Unfortunately during the last few decades, N. gonorrhoeae has developed resistance not only to less expensive antimicrobials such as sulphonamides, penicillin and tetracyclines but also to fluoroquinolones. The resistance trend of N. gonorrhoeae towards these antimicrobials can be categorised into pre-quinolone, quinolone and post-quinolone era. Among the antimicrobials available so far, only the third-generation cephalosporins could be safely recommended as first-line therapy for gonorrhoea globally. However, resistance to oral third-generation cephalosporins has also started emerging in some countries. Therefore, it has become imperative to initiate sustained national and international efforts to reduce infection and misuse of antibiotics so as to prevent further emergence and spread of antimicrobial resistance. It is necessary not only to monitor drug resistance and optimise treatment regimens, but also to gain insight into how gonococcus develops drug resistance. Knowledge of mechanism of resistance would help us to devise methods to prevent the occurrence of drug resistance against existing and new drugs. Such studies could also help in finding out new drug targets in N. gonorrhoeae and also a possibility of identification of new drugs for treating gonorrhoea.

  11. Antituberculosis drug resistance patterns in adults with tuberculous meningitis

    DEFF Research Database (Denmark)

    Senbayrak, Seniha; Ozkutuk, Nuri; Erdem, Hakan

    2015-01-01

    BACKGROUND: Tuberculous meningitis (TBM) caused by Mycobacterium tuberculosis resistant to antituberculosis drugs is an increasingly common clinical problem. This study aimed to evaluate drug resistance profiles of TBM isolates in adult patients in nine European countries involving 32 centers to ...

  12. Comparative study on the effects of two antifungal drugs against Candida albicans by microcalorimetry and transmission electron microscopy

    International Nuclear Information System (INIS)

    Guo, Qing-Lian; Zhang, Juan; Xu, Zi-Qiang; Li, Ran; Jiang, Feng-Lei; Xiao, Qi; Liu, Yi

    2012-01-01

    Highlights: ► Microcalorimetry is a fast, simple method to study the antibiotic property of drugs. ► We noticed that the antibiotic effect of ITZ was slightly better than that of KTZ. ► We perform the TEM to study the morphology changes of C. albicans cells. - Abstract: In this work, a multi-channel thermal activity monitor (TAM 2277) was applied to study the growth metabolism of Candida albicans (C. albicans) in vitro in the absence and presence of different concentrations of ketoconazole (KTZ) and itraconazole (ITZ). The results showed that the half inhibiting concentrations (IC 50 ) of C. albicans by KTZ and ITZ are 73.5 and 66.3 μmol L −1 , respectively. So the antibiotic effect of ITZ was slightly better than that of KTZ. The morphology of C. albicans cells both in the absence and presence of antifungal agents was examined by transmission electron microscopy (TEM). Our research also suggests that microcalorimetry is a fast, simple, non-invasive, non-destructive and more sensitive method, and can be easily performed to study the antibiotic property of different species of drugs on microorganism compared to other biological and clinical methods.

  13. Comparative study on the effects of two antifungal drugs against Candida albicans by microcalorimetry and transmission electron microscopy

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Qing-Lian [Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Zhang, Juan [Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Department of Stomatology, Hubei Provincial Maternal and Child Health Hospital, Wuhan 430070 (China); Xu, Zi-Qiang; Li, Ran [State Key Laboratory of Virology and Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072 (China); Jiang, Feng-Lei, E-mail: fljiang@whu.edu.cn [State Key Laboratory of Virology and Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072 (China); Xiao, Qi, E-mail: qi.xiao@whu.edu.cn [College of Chemistry and Life Science, Guangxi Teachers Education University, Nanning 530001 (China); Liu, Yi [State Key Laboratory of Virology and Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072 (China)

    2012-09-10

    Highlights: Black-Right-Pointing-Pointer Microcalorimetry is a fast, simple method to study the antibiotic property of drugs. Black-Right-Pointing-Pointer We noticed that the antibiotic effect of ITZ was slightly better than that of KTZ. Black-Right-Pointing-Pointer We perform the TEM to study the morphology changes of C. albicans cells. - Abstract: In this work, a multi-channel thermal activity monitor (TAM 2277) was applied to study the growth metabolism of Candida albicans (C. albicans) in vitro in the absence and presence of different concentrations of ketoconazole (KTZ) and itraconazole (ITZ). The results showed that the half inhibiting concentrations (IC{sub 50}) of C. albicans by KTZ and ITZ are 73.5 and 66.3 {mu}mol L{sup -1}, respectively. So the antibiotic effect of ITZ was slightly better than that of KTZ. The morphology of C. albicans cells both in the absence and presence of antifungal agents was examined by transmission electron microscopy (TEM). Our research also suggests that microcalorimetry is a fast, simple, non-invasive, non-destructive and more sensitive method, and can be easily performed to study the antibiotic property of different species of drugs on microorganism compared to other biological and clinical methods.

  14. HIV drug resistance: problems and perspectives

    OpenAIRE

    Pleuni S. Pennings

    2013-01-01

    Access to combination antiretroviral treatment (ART) has improved greatly over recent years. At the end of 2011, more than eight million HIV infected people were receiving antiretroviral therapy in low-income and middle-income countries. ART generally works well in keeping the virus suppressed and the patient healthy. However, treatment only works as long as the virus is not resistant against the drugs used. In the last decades, HIV treatments have become better and better at slowing down the...

  15. The impact of anticoccidial drug resistance on poultry production - a ...

    African Journals Online (AJOL)

    This review, using coccidiosis and anticoccidial drug resistance highlighted the economic impact of drug resistance on livestock industry but also suggested ways of preventing or minimizing drug resistance on the farm. This way, economic loss will be minimized and more protein from animal origin will be made available to ...

  16. Overcoming drug resistance in multi-drug resistant cancers and microorganisms: a conceptual framework.

    Science.gov (United States)

    Avner, Benjamin S; Fialho, Arsenio M; Chakrabarty, Ananda M

    2012-01-01

    Resistance development against multiple drugs is a common feature among many pathogens--including bacteria such as Pseudomonas aeruginosa, viruses, and parasites--and also among cancers. The reasons are two-fold. Most commonly-used rationally-designed small molecule drugs or monoclonal antibodies, as well as antibiotics, strongly inhibit a key single step in the growth and proliferation of the pathogen or cancer cells. The disease agents quickly change or switch off this single target, or activate the efflux mechanisms to pump out the drug, thereby becoming resistant to the drug. A second problem is the way drugs are designed. The pharmaceutical industry chooses to use, by high-throughput screening, compounds that are maximally inhibitory to the key single step in the growth of the pathogen or cancer, thereby promoting selective pressure. An ideal drug would be one that inhibits multiple steps in the disease progression pathways with less stringency in these steps. Low levels of inhibition at multiple steps provide cumulative strong inhibitory effect, but little incentives or ability on the part of the pathogen/cancer to develop resistance. Such intelligent drug design involving multiple less stringent inhibitory steps is beyond the scope of the drug industry and requires evolutionary wisdom commonly possessed by bacteria. This review surveys assessments of the current clinical situation with regard to drug resistance in P. aeruginosa, and examines tools currently employed to limit this trend. We then provide a conceptual framework in which we explore the similarities between multi-drug resistance in pathogens and in cancers. We summarize promising work on anti-cancer drugs derived from the evolutionary wisdom of bacteria such as P. aeruginosa, and how such strategies can be the basis for how to look for candidate protein/peptide antibiotic drugs from bioengineered bugs. Such multi-domain proteins, unlike diffusible antibiotics, are not diffusible because of their

  17. Multidrug Resistant and Extensively Drug Resistant Bacteria: A Study

    Directory of Open Access Journals (Sweden)

    Silpi Basak

    2016-01-01

    Full Text Available Background and Objective. Antimicrobial resistance is now a major challenge to clinicians for treating patients. Hence, this short term study was undertaken to detect the incidence of multidrug-resistant (MDR, extensively drug-resistant (XDR, and pandrug-resistant (PDR bacterial isolates in a tertiary care hospital. Material and Methods. The clinical samples were cultured and bacterial strains were identified in the department of microbiology. The antibiotic susceptibility profile of different bacterial isolates was studied to detect MDR, XDR, and PDR bacteria. Results. The antibiotic susceptibility profile of 1060 bacterial strains was studied. 393 (37.1% bacterial strains were MDR, 146 (13.8% strains were XDR, and no PDR was isolated. All (100% Gram negative bacterial strains were sensitive to colistin whereas all (100% Gram positive bacterial strains were sensitive to vancomycin. Conclusion. Close monitoring of MDR, XDR, or even PDR must be done by all clinical microbiology laboratories to implement effective measures to reduce the menace of antimicrobial resistance.

  18. Efficient click chemistry towards fatty acids containing 1,2,3-triazole: Design and synthesis as potential antifungal drugs for Candida albicans.

    Science.gov (United States)

    Fu, Nina; Wang, Suiliang; Zhang, Yuqian; Zhang, Caixia; Yang, Dongliang; Weng, Lixing; Zhao, Baomin; Wang, Lianhui

    2017-08-18

    Candida is an important opportunistic human fungal pathogen. The cis-2-dodecenoic acid (BDSF) showing in vitro activity of against C. albicans growth, germ-tube germination and biofilm formation has been a potential inhibitor for Candida and other fungi. In this study, facile synthetic strategies toward a novel family of BDSF analogue, 1-alkyl-1H-1,2,3-triazole-4-carboxylic acids (ATCs) was developed. The straightforward synthetic method including converting the commercial available alkyl bromide to alkyl azide, consequently with a typical click chemistry method, copper(II) sulfate and sodium ascorbate as catalyst in water to furnish ATCs with mild to good yields. According to antifungal assay, 1-decyl-4,5-dihydro-1H-1,2,3-triazole-4-carboxylic acid (5d) showed antifungal capability slightly better than BDSF. The 1,2,3-triazole unit played a crucial role for the bioactivity of ATCs was also confirmed when compared with two alkyl-aromatic carboxylic acids. Given its simplicity, high antifungal activity, and wide availability of compounds with halide atoms on the end part of the alkyl chains, the method can be extended to develop more excellent ATC drugs for accomplishing the challenges in future antifungal applications. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  19. Biophysics of Cell Membrane Lipids in Cancer Drug Resistance: Implications for Drug Transport and Drug Delivery with Nanoparticles

    Science.gov (United States)

    Peetla, Chiranjeevi; Vijayaraghavalu, Sivakumar; Labhasetwar, Vinod

    2013-01-01

    In this review, we focus on the biophysics of cell membrane lipids, particularly when cancers develop acquired drug resistance, and how biophysical changes in resistant cell membrane influence drug transport and nanoparticle-mediated drug delivery. Recent advances in membrane lipid research show the varied roles of lipids in regulating membrane P-glycoprotein function, membrane trafficking, apoptotic pathways, drug transport, and endocytic functions, particularly endocytosis, the primary mechanism of cellular uptake of nanoparticle-based drug delivery systems. Since acquired drug resistance alters lipid biosynthesis, understanding the role of lipids in cell membrane biophysics and its effect on drug transport is critical for developing effective therapeutic and drug delivery approaches to overcoming drug resistance. Here we discuss novel strategies for (a) modulating the biophysical properties of membrane lipids of resistant cells to facilitate drug transport and regain endocytic function and (b) developing effective nanoparticles based on their biophysical interactions with membrane lipids to enhance drug delivery and overcome drug resistance. PMID:24055719

  20. Antifungal susceptibility testing for yeasts: how, when and why, according to the new EUCAST guidelines

    Directory of Open Access Journals (Sweden)

    Esther Manso

    2011-03-01

    Full Text Available Antifungal susceptibility testing of yeasts and the development of interpretive breakpoints are nowadays very important topics both for the increasing incidence of invasive mycoses and number of available antifungal drugs and for the appearance of acquired resistance. The Subcommittee on Antifungal Susceptibility Testing (AFST of the European Committee on Antibiotic Susceptibility Testing (EUCAST has recently released both the operative standards to evaluate the fermenting yeasts susceptibility against antimycotic drugs and the breakpoints for infections due to some Candida species and for some of the available antifungals. Antifungal susceptibility testing is mandatory on a routine base for: 1. therapeutic failure, 2. breakthrough fungemias, 3. on yeasts isolated from patients who recently received prophylactic antifungal treatments, and 4. when the deep-seated infection is due to less common yeasts, with an unknown susceptibility pattern. The Medical Mycology Committee (CoSM of the Italian Society of Clinical Microbiologists (AMCLI adopted the interpretive breakpoints of both CLSI and EUCAST. The operating procedure for antifungal susceptibility testing according to EUCAST is supported by the recommendation to use, when clinically necessary, validated commercial methods (Vitek2, Sensititre, E-test. Finally, the CoSM reports the recommendations for a correct management of antifungal susceptibility testing.

  1. Amphotericin B: an antifungal drug in nanoformulations for the treatment of paracoccidioidomycosis

    Directory of Open Access Journals (Sweden)

    Mônica Pereira Garcia

    2013-12-01

    Full Text Available The use of magnetic nanoparticles (MNPs in drug delivery vehicles must address issues such as drugloading capacity, desired release profile, aqueous dispersion stability, biocompatibility with cells and tissue, and retention of magnetic properties after interaction with macromolecules or modification via chemical reactions. Amphotericin B (AmB is still the first choice for the treatment of severe paracoccidioidomycosis, an important systemic fungal infection caused by Paracoccidoides brasiliensis. Unfortunately, AmB causes acute side effects (mainly urinary problems following intravenous administration, which limits its clinical use. The use of magnetic nanoparticles stabilized with biocompatible substances, together with the possibility of their conjugation with drugs has become a new nanotechnological strategy in the treatment of diseases for drug delivery to specific locations, such as the lungs in paracoccidoidiodomycosis. This review provides an overview of the disease, its etiologic agent and treatment with emphasis on the main strategies to improve the use of AmB in nanoformulations.

  2. Exploiting nanotechnology to overcome tumor drug resistance: Challenges and opportunities.

    Science.gov (United States)

    Kirtane, Ameya R; Kalscheuer, Stephen M; Panyam, Jayanth

    2013-11-01

    Tumor cells develop resistance to chemotherapeutic drugs through multiple mechanisms. Overexpression of efflux transporters is an important source of drug resistance. Efflux transporters such as P-glycoprotein reduce intracellular drug accumulation and compromise drug efficacy. Various nanoparticle-based approaches have been investigated to overcome efflux-mediated resistance. These include the use of formulation excipients that inhibit transporter activity and co-delivery of the anticancer drug with a specific inhibitor of transporter function or expression. However, the effectiveness of nanoparticles can be diminished by poor transport in the tumor tissue. Hence, adjunct therapies that improve the intratumoral distribution of nanoparticles may be vital to the successful application of nanotechnology to overcome tumor drug resistance. This review discusses the mechanisms of tumor drug resistance and highlights the opportunities and challenges in the use of nanoparticles to improve the efficacy of anticancer drugs against resistant tumors. © 2013.

  3. Prediction of resistance development against drug combinations by collateral responses to component drugs

    DEFF Research Database (Denmark)

    Munck, Christian; Gumpert, Heidi; Nilsson Wallin, Annika

    2014-01-01

    the genomes of all evolved E. coli lineages, we identified the mutational events that drive the differences in drug resistance levels and found that the degree of resistance development against drug combinations can be understood in terms of collateral sensitivity and resistance that occurred during...... adaptation to the component drugs. Then, using engineered E. coli strains, we confirmed that drug resistance mutations that imposed collateral sensitivity were suppressed in a drug pair growth environment. These results provide a framework for rationally selecting drug combinations that limit resistance...

  4. FKBP12-Dependent Inhibition of Calcineurin Mediates Immunosuppressive Antifungal Drug Action in Malassezia

    Directory of Open Access Journals (Sweden)

    Giuseppe Ianiri

    2017-10-01

    Full Text Available The genus Malassezia includes yeasts that are commonly found on the skin or hair of animals and humans as commensals and are associated with a number of skin disorders. We have previously developed an Agrobacterium tumefaciens transformation system effective for both targeted gene deletion and insertional mutagenesis in Malassezia furfur and M. sympodialis. In the present study, these molecular resources were applied to characterize the immunophilin FKBP12 as the target of tacrolimus (FK506, ascomycin, and pimecrolimus, which are calcineurin inhibitors that are used as alternatives to corticosteroids in the treatment of inflammatory skin disorders such as those associated with Malassezia species. While M. furfur and M. sympodialis showed in vitro sensitivity to these agents, fkb1Δ mutants displayed full resistance to all three of them, confirming that FKBP12 is the target of these calcineurin inhibitors and is essential for their activity. We found that calcineurin inhibitors act additively with fluconazole through an FKBP12-dependent mechanism. Spontaneous M. sympodialis isolates resistant to calcineurin inhibitors had mutations in the gene encoding FKBP12 in regions predicted to affect the interactions between FKBP12 and FK506 based on structural modeling. Due to the presence of homopolymer nucleotide repeats in the gene encoding FKBP12, an msh2Δ hypermutator of M. sympodialis was engineered and exhibited an increase of more than 20-fold in the rate of emergence of resistance to FK506 compared to that of the wild-type strain, with the majority of the mutations found in these repeats.

  5. FKBP12-Dependent Inhibition of Calcineurin Mediates Immunosuppressive Antifungal Drug Action in Malassezia

    Science.gov (United States)

    Ianiri, Giuseppe; Applen Clancey, Shelly; Lee, Soo Chan

    2017-01-01

    ABSTRACT The genus Malassezia includes yeasts that are commonly found on the skin or hair of animals and humans as commensals and are associated with a number of skin disorders. We have previously developed an Agrobacterium tumefaciens transformation system effective for both targeted gene deletion and insertional mutagenesis in Malassezia furfur and M. sympodialis. In the present study, these molecular resources were applied to characterize the immunophilin FKBP12 as the target of tacrolimus (FK506), ascomycin, and pimecrolimus, which are calcineurin inhibitors that are used as alternatives to corticosteroids in the treatment of inflammatory skin disorders such as those associated with Malassezia species. While M. furfur and M. sympodialis showed in vitro sensitivity to these agents, fkb1Δ mutants displayed full resistance to all three of them, confirming that FKBP12 is the target of these calcineurin inhibitors and is essential for their activity. We found that calcineurin inhibitors act additively with fluconazole through an FKBP12-dependent mechanism. Spontaneous M. sympodialis isolates resistant to calcineurin inhibitors had mutations in the gene encoding FKBP12 in regions predicted to affect the interactions between FKBP12 and FK506 based on structural modeling. Due to the presence of homopolymer nucleotide repeats in the gene encoding FKBP12, an msh2Δ hypermutator of M. sympodialis was engineered and exhibited an increase of more than 20-fold in the rate of emergence of resistance to FK506 compared to that of the wild-type strain, with the majority of the mutations found in these repeats. PMID:29066552

  6. My Cousin, My Enemy: quasispecies suppression of drug resistance

    Science.gov (United States)

    Kirkegaard, Karla; van Buuren, Nicholas J; Mateo, Roberto

    2017-01-01

    If a freshly minted genome contains a mutation that confers drug resistance, will it be selected in the presence of the drug? Not necessarily. During viral infections, newly synthesized viral genomes occupy the same cells as parent and other progeny genomes. If the antiviral target is chosen so that the drug-resistant progeny’s growth is dominantly inhibited by the drug-susceptible members of its intracellular family, its outgrowth can be suppressed. Precedent for ‘dominant drug targeting’ as a deliberate approach to suppress the outgrowth of inhibitor-resistant viruses has been established for envelope variants of vesicular stomatitis virus and for capsid variants of poliovirus and dengue virus. Small molecules that stabilize oligomeric assemblages are a promising means to an unfit family to destroy the effectiveness of a newborn drug-resistant relative due to the co-assembly of drug-susceptible and drug-resistant monomers. PMID:27764731

  7. mtct regimen choice, drug resistance and the treatment of hiv

    African Journals Online (AJOL)

    Perinauzl HW Unit, University ofcJu WilWalmTand. MTCT REGIMEN CHOICE, DRUG. RESISTANCE AND THE TREATMENT OF. HIV-I-INFECTED CHILDREN assessing ARV drug resistance. Genotypic assays detect specific point mutations in the HIV genome that are associated with phenotypic resistance. These are most.

  8. Prevalence of drug resistant tuberculosis in Arsi Zone, Ethiopia ...

    African Journals Online (AJOL)

    Background: Wide spread of occurrence of multi-drug resistance tuberculosis is becoming a major challenge to effective tuberculosis control. Thus, it is imperative to monitor the sensitivity of anti-TB drugs regularly. Objective: To determine the prevalence resistance to anti-TB drugs in a well established control program area ...

  9. Predicted levels of HIV drug resistance

    DEFF Research Database (Denmark)

    Cambiano, Valentina; Bertagnolio, Silvia; Jordan, Michael R

    2014-01-01

    -term effects. METHODS: The previously validated HIV Synthesis model was calibrated to South Africa. Resistance was modeled at the level of single mutations, transmission potential, persistence, and effect on drug activity. RESULTS: We estimate 652 000 people (90% uncertainty range: 543 000-744 000) are living...... are maintained, in 20 years' time HIV incidence is projected to have declined by 22% (95% confidence interval, CI -23 to -21%), and the number of people carrying NNRTI resistance to be 2.9-fold higher. If enhancements in diagnosis and retention in care occur, and ART is initiated at CD4 cell count less than 500......  cells/μl, HIV incidence is projected to decline by 36% (95% CI: -37 to -36%) and the number of people with NNRTI resistance to be 4.1-fold higher than currently. Prevalence of people with viral load more than 500  copies/ml carrying NRMV is not projected to differ markedly according to future ART...

  10. Clotrimazole Drug Resistance in Candida glabrata Clinical Isolates Correlates with Increased Expression of the Drug:H(+) Antiporters CgAqr1, CgTpo1_1, CgTpo3, and CgQdr2.

    Science.gov (United States)

    Costa, Catarina; Ribeiro, Jonathan; Miranda, Isabel M; Silva-Dias, Ana; Cavalheiro, Mafalda; Costa-de-Oliveira, Sofia; Rodrigues, Acácio G; Teixeira, Miguel C

    2016-01-01

    For years, antifungal drug resistance in Candida species has been associated to the expression of ATP-Binding Cassette (ABC) multidrug transporters. More recently, a few drug efflux pumps from the Drug:H(+) Antiporter (DHA) family have also been shown to play a role in this process, although to date only the Candida albicans Mdr1 transporter has been demonstrated to be relevant in the clinical acquisition of antifungal drug resistance. This work provides evidence to suggest the involvement of the C. glabrata DHA transporters CgAqr1, CgQdr2, CgTpo1_1, and CgTpo3 in the clinical acquisition of clotrimazole drug resistance. A screening for azole drug resistance in 138 C. glabrata clinical isolates, from patients attending two major Hospitals in Portugal, was performed. Based on this screening, 10 clotrimazole susceptible and 10 clotrimazole resistant isolates were selected for further analysis. The transcript levels of CgAQR1, CgQDR2, CgTPO1_1, and CgTPO3 were found to be significantly up-regulated in resistant isolates when compared to the susceptible ones, with a level of correlation that was found to be similar to that of CgCDR2, an ABC gene known to be involved in the clinical acquisition of resistance. As a proof-of-concept experiment, the CgTPO3 gene was deleted in an azole resistant C. glabrata isolate, exhibiting high levels of expression of this gene. The deletion of CgTPO3 in this isolate was found to lead to decreased resistance to clotrimazole and fluconazole, and increased accumulation of azole drugs, thus suggesting the involvement of this transporter in the manifestation of azole resistance.

  11. Study on drug resistance of mycobacterium tuberculosis in patients with pulmonary tuberculosis by drug resistance gene detecting

    International Nuclear Information System (INIS)

    Wang Wei; Li Hongmin; Wu Xueqiong; Wang Ansheng; Ye Yixiu; Wang Zhongyuan; Liu Jinwei; Chen Hongbing; Lin Minggui; Wang Jinhe; Li Sumei; Jiang Ping; Feng Bai; Chen Dongjing

    2004-01-01

    To investigate drug resistance of mycobacterium tuberculosis in different age group, compare detecting effect of two methods and evaluate their the clinical application value, all of the strains of mycobacterium tuberculosis were tested for resistance to RFP, INH SM PZA and EMB by the absolute concentration method on Lowenstein-Jensen medium and the mutation of the rpoB, katG, rpsL, pncA and embB resistance genes in M. tuberculosis was tested by PCR-SSCP. In youth, middle and old age group, the rate of acquired drug resistance was 89.2%, 85.3% and 67.6% respectively, the gene mutation rate was 76.2%, 81.3% and 63.2% respectively. The rate of acquired drug resistance and multiple drug resistance in youth group was much higher than those in other groups. The gene mutation was correlated with drug resistance level of mycobacterium tuberculosis. The gene mutation rate was higher in strains isolated from high concentration resistance than those in strains isolated from low concentration resistance. The more irregular treatment was longer, the rate of drug resistance was higher. Acquired drug resistance varies in different age group. It suggested that surveillance of drug resistence in different age group should be taken seriously, especially in youth group. PCR - SSCP is a sensitive and specific method for rapid detecting rpoB, katG, rpsL, pncA and embB genes mutations of MTB. (authors)

  12. Transport Deficiency Is the Molecular Basis of Candida albicans Resistance to Antifungal Oligopeptides

    Directory of Open Access Journals (Sweden)

    Marta Schielmann

    2017-11-01

    Full Text Available Oligopeptides incorporating N3-(4-methoxyfumaroyl-L-2,3-diaminopropanoic acid (FMDP, an inhibitor of glucosamine-6-phosphate synthase, exhibited growth inhibitory activity against Candida albicans, with minimal inhibitory concentration values in the 0.05–50 μg mL-1 range. Uptake by the peptide permeases was found to be the main factor limiting an anticandidal activity of these compounds. Di- and tripeptide containing FMDP (F2 and F3 were transported by Ptr2p/Ptr22p peptide transporters (PTR and FMDP-containing hexa-, hepta-, and undecapeptide (F6, F7, and F11 were taken up by the oligopeptide transporters (OPT oligopeptide permeases, preferably by Opt2p/Opt3p. A phenotypic, apparent resistance of C. albicans to FMDP-oligopeptides transported by OPT permeases was triggered by the environmental factors, whereas resistance to those taken up by the PTR system had a genetic basis. Anticandidal activity of longer FMDP-oligopeptides was strongly diminished in minimal media containing easily assimilated ammonium sulfate or L-glutamine as the nitrogen source, both known to downregulate expression of the OPT genes. All FMDP-oligopeptides tested were more active at lower pH and this effect was slightly more remarkable for peptides F6, F7, and F11, compared to F2 and F3. Formation of isolated colonies was observed inside the growth inhibitory zones induced by F2 and F3 but not inside those induced by F6, F7, and F11. The vast majority (98% of those colonies did not originate from truly resistant cells. The true resistance of 2% of isolates was due to the impaired transport of di- and to a lower extent, tripeptides. The resistant cells did not exhibit a lower expression of PTR2, PTR22, or OPT1–3 genes, but mutations in the PTR2 gene resulting in T422H, A320S, D119V, and A320S substitutions in the amino acid sequence of Ptr2p were found.

  13. Simple strategy to assess linezolid exposure in patients with multi-drug-resistant and extensively-drug-resistant tuberculosis

    NARCIS (Netherlands)

    Kamp, Jasper; Bolhuis, Mathieu S.; Tiberi, Simon; Akkerman, Onno W.; Centis, Rosella; de lange, Wiel C.; Kosterink, Jos G.; van der Werf, Tjip S.; Migliori, Giovanni B.; Alffenaar, Jan-Willem C.

    Linezolid is used increasingly for the treatment of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) tuberculosis (TB). However, linezolid can cause severe adverse events, such as peripheral and optical neuropathy or thrombocytopenia related to higher drug exposure. This study aimed

  14. Antituberculous drug resistance in Manitoba from 1980 to 1989.

    Science.gov (United States)

    Long, R; Manfreda, J; Mendella, L; Wolfe, J; Parker, S; Hershfield, E

    1993-01-01

    OBJECTIVES: To estimate the magnitude of antituberculous drug resistance and identify the risk factors for its development in tuberculosis patients in Manitoba over a 10-year period. As well, to examine the clinical course of the patients whose initial or subsequent isolates of Mycobacterium tuberculosis were resistant to one or more drugs. DESIGN: Comparison of drug-resistant and non-drug-resistant cases of tuberculosis. SETTING: Manitoba. PATIENTS: All people with tuberculosis reported to the Central Tuberculosis Registry of Manitoba between Jan. 1, 1980, and Dec. 31, 1989. MAIN OUTCOME MEASURES: Of 1478 cases of active tuberculosis 1086 were culture positive, and drug susceptibility testing was performed in these cases. The clinical course, including outcome of treatment, of all drug-resistant cases was described. RESULTS: Of 1086 culture-positive cases of tuberculosis 77 (7.1%) were drug resistant. Odds ratios suggested that the risk of drug resistance was significantly higher among the immigrants than among the other Canadians. Compared with the other Canadians the risk of drug resistance was 9.9 times greater among the immigrants in whom tuberculosis developed within the first year after arrival in Canada and 5.4 times greater among the immigrants in whom it developed 2 to 5 years after arrival in Canada. Of the 71 patients with drug-resistant disease whose type of resistance was known 62% had never taken antituberculous drugs before and 38% had. Most (91%) of the 77 cases of drug-resistant disease were resistant to first-line drugs, especially isoniazid and streptomycin. Thirty-two (42%) of the 77 cases were resistant to two or more first-line drugs. Of patients with drug-resistant disease a subgroup of 10 had disease that became resistant to several drugs over the 10-year period. The outcome of treatment in these individuals was poor, and they presented a particular public health problem. CONCLUSION: Resistance to one or more first-line antituberculous

  15. Susceptibility of Selected Multi-Drug Resistant Clinical Isolates to ...

    African Journals Online (AJOL)

    2018-03-01

    . ... multi-drug resistance. INTRODUCTION. Antimicrobials are great resorts in the treatment of bacterial infectious diseases (1). However, over the past few decades, these ..... of carbapenem-resistant Enterobacteriaceae from.

  16. Antifungal activity of multifunctional Fe 3O 4-Ag nanocolloids

    Science.gov (United States)

    Chudasama, Bhupendra; Vala, Anjana K.; Andhariya, Nidhi; Upadhyay, R. V.; Mehta, R. V.

    2011-05-01

    In recent years, rapid increase has been observed in the population of microbes that are resistant to conventionally used antibiotics. Antifungal drug therapy is no exception and now resistance to many of the antifungal agents in use has emerged. Therefore, there is an inevitable and urgent medical need for antibiotics with novel antimicrobial mechanisms. Aspergillus glaucus is the potential cause of fatal brain infections and hypersensitivity pneumonitis in immunocompromised patients and leads to death despite aggressive multidrug antifungal therapy. In the present article, we describe the antifungal activity of multifunctional core-shell Fe 3O 4-Ag nanocolloids against A. glaucus isolates. Controlled experiments are also carried out with Ag nanocolloids in order to understand the role of core (Fe 3O 4) in the antifungal action. The minimum inhibitory concentration (MIC) of nanocolloids is determined by the micro-dilution method. MIC of A. glaucus is 2000 μg/mL. The result is quite promising and requires further investigations in order to develop a treatment methodology against this death causing fungus in immunocompromised patients.

  17. Drug-resistant post-neurosurgical nosocomial Acinetobacter ...

    African Journals Online (AJOL)

    The majority of carbapenem-resistant isolates were resistant to at least three other antibiotic classes. The emergence of postsurgical multi-drug resistant Acinetobacter meningitis highlights the importance of implementing preventative strategies towards nosocomial infections. Key words: Acinetobacter baumannii, resistance ...

  18. Multi-drug resistance and molecular pattern of erythromycin and ...

    African Journals Online (AJOL)

    The appearance and dissemination of penicillin resistant and macrolide resistant Streptococcus pneumoniae strains has caused increasing concern worldwide. The aim of this study was to survey drug resistance and genetic characteristics of macrolide and penicillin resistance in S. pneumoniae. This is a cross-sectional ...

  19. 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.

  20. Antifungal susceptibility testing of Aspergillus species complex in the Clinical Laboratory: how to do it, when to do it, and how to interpret it

    Directory of Open Access Journals (Sweden)

    Esther Manso

    2014-12-01

    Full Text Available The emergence of drug resistance in fungal pathogens has a profound impact on human health given limited number of antifungal drugs. Antifungal resistance in Aspergillus spp. infection can be encountered in the antifungal drug-exposed patient due to selection of intrinsically resistant species or isolates with acquired resistance belonging to species that are normally susceptible. Resistance to triazoles is not common in Aspergillus spp., however, triazole resistance in A. fumigatus appears to be increasing in several European countries in recent years and can be clinically relevant. The Clinical and Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing have developed breakpoints and epidemiological cutoff values that are now established for Aspergillus spp. Clinical microbiology laboratories will be employed commercial susceptibility assays, rather than reference broth microdilution methods and comparative studies are particularly important.

  1. The comparative study of antifungal activity of Syzygium aromaticum, Punica granatum and nystatin on Candida albicans; an in vitro study.

    Science.gov (United States)

    Mansourian, A; Boojarpour, N; Ashnagar, S; Momen Beitollahi, J; Shamshiri, A R

    2014-12-01

    Candida species are opportunistic fungi, among which, Candida albicans is the most important species responsible for infections in immunocompromised patients with invasive fungal disease. Resistance of Candida species to antifungal drugs has led scientists to pay more attention to traditional medicine herbs. Due to the limitations in the treatment of fungal diseases such as shortages, high prices, antifungal side effects and drug resistance or reduced susceptibility to fungal drugs we decided to study the antifungal effects of herbal extracts of Syzygium aromaticum and Punica granatum. Twenty-one isolates of oral C. albicans in patients with denture stomatitis referred to prosthesis department, Dental faculty of Tehran University of Medical Sciences were prepared and cultured. Plant extracts were prepared from the herbs market. Tests on patient samples and standard strains 5027ATCC (PTCC10231) yeast C. albicans were performed via well diffusion method. In addition, nystatin and methanol were used as positive and negative control, respectively. Finally, the antifungal effect of extracts using Statistical Repeated measurement ANOVA test was investigated. Both S. aromaticum and P. granatum showed noticeable antifungal activity in well method. Syzygium aromaticum showed better anti candida activity than nystatin (Pgranatum showed good antifungal effects (P-value<0.001). S. aromaticum (inhibition zone diameter: 29.62) showed better antifungal effects than nystatin (inhibition zone diameter: 28.48). Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  2. [Genotyping and drug resistance of methicillin-resistant Staphylococcus aureus].

    Science.gov (United States)

    Yao, Ming; Guan, Lifeng; Jia, Wei; Wang, Linlin; Li, Gang; Wu, Xuejun; Sun, Tao

    2014-10-01

    To investigate the genotype of staphylococcal chromosomal cassette mec (SCCmec) in methicillin-resistant Staphylococcus aureus (MRSA) isolated from burn wards and its current status of drug resistance. One hundred and seventy-nine strains of Staphylococcus aureus were isolated from wound excretion, blood, and sputum samples of patients that were admitted to ICU or public wards of our Department of Burns and Plastic Surgery from September 2012 to September 2013. Among them, 68 strains were from ICU and 111 strains from public wards. The MRSA phenotype of Staphylococcus aureus was detected with cefoxitin K-B disk diffusion method, and the isolation rates of MRSA in ICU and public wards were compared. Genotyping of SCCmec was performed by PCR in strains of MRSA. In the meantime, the identification result of MRSA by K-B method was verified through detecting methicillin-resistant determinant mecA. The antimicrobial resistance of MRSA and methicillin-sensitive Staphylococcus aureus (MSSA) to 23 kinds of commonly used antibiotics in clinic were detected by K-B disk diffusion method. Except for the antibiotics to which the resistant rates of MRSA were 100.0% or 0, the resistant rates of SCCmecIII MRSA and non-SCCmec III MRSA to the rest of antibiotics were compared. Data were processed with Pearson chi-square test or corrected chi-square test. One hundred and forty-eight strains out of the 179 Staphylococcus aureus were identified as MRSA (accounting for 82.7%), among which 62 were originated from ICU and 86 from public wards. The rest 31 strains of Staphylococcus aureus were MSSA, accounting for 17.3%. The percentage of MRSA in the isolated Staphylococcus aureus was 91.2% (62/68) in ICU, which was significantly higher than that in the public wards [77.5% (86/111), χ2 = 5.526, P = 0.019]. PCR detection showed that the 148 strains of MRSA harbored the mecA gene, out of which 106 strains were SCCmec III positive, accounting for 71.6%. The percentages of SCCmec III type MRSA

  3. Loss of C-5 Sterol Desaturase Activity Results in Increased Resistance to Azole and Echinocandin Antifungals in a Clinical Isolate of Candida parapsilosis.

    Science.gov (United States)

    Rybak, Jeffrey M; Dickens, C Michael; Parker, Josie E; Caudle, Kelly E; Manigaba, Kayihura; Whaley, Sarah G; Nishimoto, Andrew T; Luna-Tapia, Arturo; Roy, Sujoy; Zhang, Qing; Barker, Katherine S; Palmer, Glen E; Sutter, Thomas R; Homayouni, Ramin; Wiederhold, Nathan P; Kelly, Steven L; Rogers, P David

    2017-09-01

    Among emerging non- albicans Candida species, Candida parapsilosis is of particular concern as a cause of nosocomial bloodstream infections in neonatal and intensive care unit patients. While fluconazole and echinocandins are considered effective treatments for such infections, recent reports of fluconazole and echinocandin resistance in C. parapsilosis indicate a growing problem. The present study describes a novel mechanism of antifungal resistance in this organism affecting susceptibility to azole and echinocandin antifungals in a clinical isolate obtained from a patient with prosthetic valve endocarditis. Transcriptome analysis indicated differential expression of several genes in the resistant isolate, including upregulation of ergosterol biosynthesis pathway genes ERG2 , ERG5 , ERG6 , ERG11 , ERG24 , ERG25 , and UPC2 Whole-genome sequencing revealed that the resistant isolate possessed an ERG3 mutation resulting in a G111R amino acid substitution. Sterol profiles indicated a reduction in sterol desaturase activity as a result of this mutation. Replacement of both mutant alleles in the resistant isolate with the susceptible isolate's allele restored wild-type susceptibility to all azoles and echinocandins tested. Disruption of ERG3 in the susceptible and resistant isolates resulted in a loss of sterol desaturase activity, high-level azole resistance, and an echinocandin-intermediate to -resistant phenotype. While disruption of ERG3 in C. albicans resulted in azole resistance, echinocandin MICs, while elevated, remained within the susceptible range. This work demonstrates that the G111R substitution in Erg3 is wholly responsible for the altered azole and echinocandin susceptibilities observed in this C. parapsilosis isolate and is the first report of an ERG3 mutation influencing susceptibility to the echinocandins. Copyright © 2017 American Society for Microbiology.

  4. Antifungal activity of multifunctional Fe{sub 3}O{sub 4}-Ag nanocolloids

    Energy Technology Data Exchange (ETDEWEB)

    Chudasama, Bhupendra, E-mail: bnchudasama@thapar.ed [School of Physics and Materials Science, Thapar University, Patiala 147004 (India); Vala, Anjana K.; Andhariya, Nidhi [Department of Physics, Bhavnagar University, Bhavnagar 364022 (India); Upadhyay, R.V. [P.D. Patel Institute of Applied Sciences, Charotar University of Science and Technology, Changa 388421 (India); Mehta, R.V. [Department of Physics, Bhavnagar University, Bhavnagar 364022 (India)

    2011-05-15

    In recent years, rapid increase has been observed in the population of microbes that are resistant to conventionally used antibiotics. Antifungal drug therapy is no exception and now resistance to many of the antifungal agents in use has emerged. Therefore, there is an inevitable and urgent medical need for antibiotics with novel antimicrobial mechanisms. Aspergillus glaucus is the potential cause of fatal brain infections and hypersensitivity pneumonitis in immunocompromised patients and leads to death despite aggressive multidrug antifungal therapy. In the present article, we describe the antifungal activity of multifunctional core-shell Fe{sub 3}O{sub 4}-Ag nanocolloids against A. glaucus isolates. Controlled experiments are also carried out with Ag nanocolloids in order to understand the role of core (Fe{sub 3}O{sub 4}) in the antifungal action. The minimum inhibitory concentration (MIC) of nanocolloids is determined by the micro-dilution method. MIC of A. glaucus is 2000 {mu}g/mL. The result is quite promising and requires further investigations in order to develop a treatment methodology against this death causing fungus in immunocompromised patients. - Research Highlights: Synthesis of Fe{sub 3}O{sub 4}-Ag core-shell nanocolloids. Antifungal activity of Fe{sub 3}O{sub 4}-Ag nanocolloids against Aspergillus glaucus isolates. The MIC value for A. glaucus is 2000 {mu}g/mL. Antifungal activity is better or comparable with most prominent antibiotics.

  5. Targeted cancer therapy; nanotechnology approaches for overcoming drug resistance.

    Science.gov (United States)

    Gao, Yan; Shen, Jacson K; Milane, Lara; Hornicek, Francis J; Amiji, Mansoor M; Duan, Zhenfeng

    2015-01-01

    Recent advances in cancer molecular biology have resulted in parallel and unprecedented progress in the development of targeted cancer therapy. Targeted therapy can provide higher efficacy and lower toxicity than conventional chemotherapy for cancer. However, like traditional chemotherapy, molecularly targeted cancer therapy also faces the challenge of drug resistance. Multiple mechanisms are responsible for chemotherapy resistance in tumors, including over-expression of efflux transporters, somatic alterations of drug targets, deregulation of apoptosis, and numerous pharmacokinetic issues. Nanotechnology based approaches are proving to be efficacious in overcoming drug resistance in cancer. Combination of targeted therapies with nanotechnology approaches is a promising strategy to overcome targeted therapy drug resistance in cancer treatment. This review discusses the mechanisms of targeted drug resistance in cancer and discusses nanotechnology approaches to circumvent this resistance.

  6. Drug Resistance to EGFR Inhibitors in Lung Cancer

    Science.gov (United States)

    Tetsu, Osamu; Hangauer, Matthew J.; Phuchareon, Janyaporn; Eisele, David W.; McCormick, Frank

    2016-01-01

    Background The discovery of mutations in epidermal growth factor receptor (EGFR) has dramatically changed the treatment of patients with non-small cell lung cancer (NSCLC)—the leading cause of cancer death worldwide. EGFR-targeted therapies show considerable promise, but drug resistance has become a substantial issue. Methods We reviewed the literature to provide an overview of the drug resistance to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. Results The mechanisms causing primary, acquired, and persistent drug resistance to TKIs vary. Researchers and clinicians, who have used study findings to develop more effective therapeutic approaches, have found that the sequential use of single agents presents a formidable challenge, suggesting that multi-drug combinations must be considered. Conclusions In the era of precision medicine, oncologists should promptly obtain an accurate diagnosis of drug resistance in each patient to design the most relevant combination therapy to overcome patient-specific drug resistance. PMID:26910730

  7. Effect of radiation decontamination on drug-resistant bacteria

    International Nuclear Information System (INIS)

    Ito, Hitoshi

    2006-01-01

    More than 80% of food poisoning bacteria such as Salmonella are reported as antibiotic-resistant to at least one type antibiotic, and more than 50% as resistant to two or more. For the decontamination of food poisoning bacteria in foods, radiation resistibility on drug-resistant bacteria were investigated compared with drug-sensitive bacteria. Possibility on induction of drug-resistant mutation by radiation treatment was also investigated. For these studies, type strains of Escherichia coli S2, Salmonella enteritidis YK-2 and Staphylococcus aureus H12 were used to induce drug-resistant strains with penicillin G. From the study of radiation sensitivity on the drug-resistant strain induced from E. coli S2, D 10 value was obtained to be 0.20 kGy compared with 0.25 kGy at parent strain. On S. enteritidis YK-2, D 10 value was obtained to be 0.14 kGy at drug-resistant strain compared with 0.16 kGy at parent strain. D 10 value was also obtained to be 0.15 kGy at drug-resistant strain compared with 0.21 kGy at parent strain of St. aureus H12. Many isolates of E. coli 157:H7 or other type of E. coli from meats such as beef were resistant to penicillin G, and looked to be no relationship on radiation resistivities between drug-resistant strains and sensitive strains. On the study of radiation sensitivity on E. coli S2 at plate agars containing antibiotics, higher survival fractions were obtained at higher doses compared with normal plate agar. The reason of higher survival fractions at higher doses on plate agar containing antibiotics should be recovery of high rate of injured cells by the relay of cell division, and drug-resistant strains by mutation are hardly induced by irradiation. (author)

  8. HIV resistance testing and detected drug resistance in Europe

    NARCIS (Netherlands)

    Schultze, Anna; Phillips, Andrew N.; Paredes, Roger; Battegay, Manuel; Rockstroh, Jürgen K.; Machala, Ladislav; Tomazic, Janez; Girard, Pierre M.; Januskevica, Inga; Gronborg-Laut, Kamilla; Lundgren, Jens D.; Cozzi-Lepri, Alessandro; Losso, M.; Kundro, M.; Vetter, N.; Zangerle, R.; Karpov, I.; Vassilenko, A.; Mitsura, V. M.; Paduto, D.; Clumeck, N.; de Wit, S.; Delforge, M.; Florence, E.; Vandekerckhove, L.; Hadziosmanovic, V.; Kostov, K.; Begovac, J.; Machala, L.; Jilich, D.; Sedlacek, D.; Nielsen, J.; Kronborg, G.; Benfield, T.; Larsen, M.; Gerstoft, J.; Katzenstein, T.; Pedersen, C.; Møller, N. F.; Ostergaard, L.; Dragsted, U. B.; Nielsen, L. N.; Zilmer, K.; Smidt, Jelena; Ristola, M.; Katlama, C.; Pradier, C.; Dabis, F.; Neau, D.; Duvivier, C.; Rockstroh, J.; Schmidt, R.; van Lunzen, J.; Degen, O.; Stefan, C.; Bogner, J.; Fatkenheuer, G.; Chkhartishvili, N.; Kosmidis, J.; Gargalianos, P.; Xylomenos, G.; Perdios, J.; Sambatakou, H.; Banhegyi, D.; Gottfredsson, M.; Mulcahy, F.; Yust, I.; Turner, D.; Burke, M.; Shahar, E.; Hassoun, G.; Elinav, H.; Haouzi, M.; Sthoeger, Z. M.; d'Arminio, A.; Esposito, R.; Mazeu, I.; Mussini, C.; Pristera, R.; Mazzotta, F.; Gabbuti, A.; Vullo, V.; Lichtner, M.; Zaccarelli, M.; Reiss, P.; Ormaasen, V.; Maeland, A.; Bruun, J.; Knysz, B.; Gasiorowski, J.; Inglot, M.; Horban, A.; Bakowska, E.; Grzeszczuk, A.; Flisiak, R.; Parczewski, M.; Pynka, M.; Maciejewska, K.; Beniowski, M.; Mularska, E.; Smiatacz, T.; Jablonowska, E.; Malolepsza, E.; Wojcik, K.; Mozer-Lisewska, I.; Doroana, M.; Caldeira, L.; Mansinho, K.; Maltez, F.; Radoi, R.; Oprea, C.; Babes, Victor; Rakhmanova, A.; Trofimora, T.; Khromova, I.; Kuzovatova, E.; Jevtovic, D.; Shunnar, A.; Stanekova, D.; Tomazic, J.; Moreno, S.; Rodriguez, J. M.; Clotet, B.; Jou, A.; Paredes, R.; Tural, C.; Puig, J.; Bravo, I.; Gatell, J. M.; Miro, J. M.; Domingo, P.; Gutierrez, M.; Mateo, G.; Sambeat, M. A.; Laporte, J. M.; Blaxhult, A.; Flamholc, L.; Thalme, A.; Sonnerborg, A.; Ledergerber, B.; Weber, R.; Cavassini, M.; Calmy, A.; Furrer, H.; Battegay, M.; Elzi, L.; Schmid, P.; Kravchenko, E.; Chentsova, N.; Frolov, V.; Kutsyna, G.; Baskakov, I.; Kuznetsova, A.; Kyselyova, G.; Gazzard, B.; Johnson, A. M.; Simons, E.; Edwards, S.; Phillips, A.; Johnson, M. A.; Mocroft, A.; Orkin, C.; Weber, J.; Scullard, G.; Fisher, M.; Leen, C.; Gatell, J.; Monforte, A. d'Arminio; Lundgren, J.; DeWit, S.; Kirk, O.; Grarup, J.; Cozzi-Lepri, A.; Thiebaut, R.; Burger, D.; Peters, L.; Podlekareva, D.; Nielsen, J. E.; Matthews, C.; Fischer, A. H.; Bojesen, A.; Raben, D.; Kristensen, D.; Laut, K. Grønborg; Larsen, J. F.; Grint, D.; Shepherd, L.; Schultze, A.

    2015-01-01

    Objectives: To describe regional differences and trends in resistance testing among individuals experiencing virological failure and the prevalence of detected resistance among those individuals who had a genotypic resistance test done following virological failure. Design: Multinational cohort

  9. Distribution of red blood cell antigens in drug-resistant and drug ...

    African Journals Online (AJOL)

    Frequency distribution of ABO, Rh-Hr, MN, Kell blood group system antigens were studied in 277 TB patients (151-drug-sensitive and 126 drug-resistant) of pulmonary tuberculosis to know whether there was any association between them, and also between drug resistance and sensitiveness. They were compared with 485 ...

  10. Prevalence of drug resistant Mycobacterium tuberculosis among children in China.

    Science.gov (United States)

    Jiao, Wei-wei; Liu, Zhi-guang; Han, Rui; Zhao, Xiu-qin; Dong, Fang; Dong, Hai-yan; Huang, Hai-rong; Li, Qin-jing; Lin, Nan; Song, Wen-qi; Wan, Kang-lin; Shen, A-dong

    2015-05-01

    The available data on the epidemic of drug resistant tuberculosis (TB) among children in China is limited. This study attempted to clarify the drug resistance profiles of clinical strains isolated from children and estimate risk factors related to acquisition of drug resistance. All Mycobacterium tuberculosis strains from children (age children, 159 from adolescents, and 191 from adults) from all over China. Drug susceptibility testing was performed by a proportion method. As a result, the drug resistance and multi-drug resistance (MDR) rates in children were 55% (55/100) and 22% (22/100), respectively. In children with MDR-TB, new cases accounted for 40.9% (9/22). Compared with adults, the drug resistance rates were similar in all subgroups (new cases, previously treated cases and all cases) of children (P > 0.05), except for the lower resistance rate to isoniazid in total cases of children (P = 0.011). Patient related information was included in the MDR-TB association analysis. The treatment history was found to be strongly associated with MDR-TB in all three age groups (P children in China is alarmingly high and similar to that seen in adults. In contrast, in adolescents, the drug resistance rate to most tested drugs was lower than in adults. Primary transmission and inadequate treatment are two equally important factors for the high MDR-TB rate in children. Thus, major efforts in the TB control in children should focus on decreasing the transmission of drug resistant TB and early testing of drug resistance. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Characteristics of Drug Resistant Tuberculosis in Sanatoria of North Korea.

    Science.gov (United States)

    Jung, Jihee; Jegal, Yangjin; Ki, Moran; Shin, Young Jeon; Kim, Cheon Tae; Shim, Tae Sun; Sung, Nackmoon

    2017-07-01

    Although several reports about drug-resistant tuberculosis (TB) in North Korea have been published, a nationwide surveillance on this disease remains to be performed. This study aims to analyze the drug resistance patterns of Mycobacterium tuberculosis among the patients in the sanatoria of North Korea, especially during the period when second-line drugs (SLDs) had not yet been officially supplied to this country. The Eugene Bell Foundation (EBF) transferred 947 sputum specimens obtained from 667 patients from 2007 to 2009 to the Clinical Research Center, Masan National Tuberculosis Hospital (MNTH), South Korea. Four hundred ninety-two patients were culture positive for TB (73.8%). Drug susceptibility test (DST) was performed for the bacilli isolated from 489 patients. Over 3 quarters of the cases (76.9%) were multidrug-resistant (MDR)-TB. Additionally, 2 patients had extremely drug-resistant (XDR)-TB. Very high resistance to first-line drugs and low resistance to fluoroquinolones (FQs) and injectable drugs (IDs) except for streptomycin (S) were detected. A small but significant regional variation in resistance pattern was observed. Big city regions had higher rate of MDR-TB, higher resistance to FQs and IDs than relatively isolated regions. In conclusion, significant number of drug-resistant TB was detected in North Korean sanatoria, and small but significant regional variations in resistance pattern were noticeable. However, the data in this study do not represent the nationwide drug resistance pattern in North Korea. Further large-scale evaluations are necessary to estimate the resistance pattern of TB in North Korea. © 2017 The Korean Academy of Medical Sciences.

  12. Drug-resistance in chronic tuberculosis cases in Southern Nigeria ...

    African Journals Online (AJOL)

    Nigeria has a high burden of tuberculosis but the drug resistant situationwas previously unknown. This report evaluates the firstline drug resistance and associated factors among chronic tuberculosis cases from the tuberculosis control programme in South south and South east zones ofNigeria. Descriptive study of chronic ...

  13. Tuberculosis drug resistance in the Western Cape | Weyer | South ...

    African Journals Online (AJOL)

    Objectives: Drug resistance is a serious problem in the treatment of tuberculosis and a threat to successful tuberculosis control programmes. Local health workers have expressed concern that the increasing tuberculosis epidemic in the Western Cape is partly attributable to drug resistance. The aim of this study was to ...

  14. Multi-drug resistant tuberculosis in Tanzania: Initial description of ...

    African Journals Online (AJOL)

    Background: Drug resistant Tuberculosis is well documented worldwide and is associated with increasing morbidity and mortality complicating Tuberculosis control with increasing costs of managing the disease. Broad. Objective: To describe clinical and laboratory characteristics of multi-drug resistant Tuberculosis ...

  15. Multi drug resistant tuberculosis: a challenge in the management of ...

    African Journals Online (AJOL)

    kemrilib

    Multi drug resistant tuberculosis (MDR-TB) will not usually respond to short course chemotherapy. Unless the individual infected with this bug is treated appropriately, they can continue spreading resistant strains in the community and further fuel the tuberculosis epidemic. Diagnosis requires drug sensitivity testing and the ...

  16. Adaptation and evolution of drug-resistant Mycobacterium tuberculosis

    NARCIS (Netherlands)

    Bergval, I.L.

    2013-01-01

    Many studies have been conducted on drug resistance and the evolution of Mycobacterium tuberculosis. Notwithstanding, many molecular mechanisms facilitating the emergence, adaptation and spread of drug-resistant tuberculosis have yet to be discovered. This thesis reports studies of the adaptive

  17. Conventional versus newer methods for detection of drug resistance ...

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. Conventional versus newer methods for detection of drug resistance in tuberculosis. Classical microbiological methods are well established but are cumbersome and time consuming. Newer rapid methods for rapid detection of drug resistance - microbiological, ...

  18. Early antiretroviral therapy and potent second-line drugs could decrease HIV incidence of drug resistance.

    Science.gov (United States)

    Shen, Mingwang; Xiao, Yanni; Rong, Libin; Meyers, Lauren Ancel; Bellan, Steven E

    2017-06-28

    Early initiation of antiretroviral therapy (ART) reduces the risk of drug-sensitive HIV transmission but may increase the transmission of drug-resistant HIV. We used a mathematical model to estimate the long-term population-level benefits of ART and determine the scenarios under which earlier ART (treatment at 1 year post-infection, on average) could decrease simultaneously both total and drug-resistant HIV incidence (new infections). We constructed an infection-age-structured mathematical model that tracked the transmission rates over the course of infection and modelled the patients' life expectancy as a function of ART initiation timing. We fitted this model to the annual AIDS incidence and death data directly, and to resistance data and demographic data indirectly among men who have sex with men (MSM) in San Francisco. Using counterfactual scenarios, we assessed the impact on total and drug-resistant HIV incidence of ART initiation timing, frequency of acquired drug resistance, and second-line drug effectiveness (defined as the combination of resistance monitoring, biomedical drug efficacy and adherence). Earlier ART initiation could decrease the number of both total and drug-resistant HIV incidence when second-line drug effectiveness is sufficiently high (greater than 80%), but increase the proportion of new infections that are drug resistant. Thus, resistance may paradoxically appear to be increasing while actually decreasing. © 2017 The Author(s).

  19. Minimal inhibitory concentration distributions and epidemiological cutoff values of five antifungal agents against Sporothrix brasiliensis.

    Science.gov (United States)

    Almeida-Paes, Rodrigo; Brito-Santos, Fábio; Figueiredo-Carvalho, Maria Helena Galdino; Machado, Ana Caroline Sá; Oliveira, Manoel Marques Evangelista; Pereira, Sandro Antonio; Gutierrez-Galhardo, Maria Clara; Zancopé-Oliveira, Rosely Maria

    2017-05-01

    Sporothrix brasiliensis is the most virulent sporotrichosis agent. This species usually responds to antifungal drugs, but therapeutic failure can occur in some patients. Antifungal susceptibility tests have been performed on this species, but no clinical breakpoints (CBPs) are available. In this situation, minimal inhibitory concentration (MIC) distributions and epidemiological cutoff values (ECVs) support the detection of identification of resistant strains. To study the MIC distributions of five antifungal drugs against S. brasiliensis and to propose tentative ECVs. MICs of amphotericin B (AMB), itraconazole (ITR), ketoconazole (KET), posaconazole (POS), and terbinafine (TRB) against 335 S. brasiliensis strains were determined by the Clinical and Laboratory Standards Institute broth microdilution method. The proposed ECV, in µg/mL, for AMB, ITR, KET, POS, and TRB were 4.0, 2.0, 1.0, 2.0, and 0.25, respectively. Percentages of wild-type strains in our population for the above antifungal drugs were 98.48, 95.22, 95.33, 100, and 97.67%, respectively. These ECVs will be useful to detect strains with resistance, to define CBPs, and to elaborate specific therapeutic guidelines for S. brasiliensis. Rational use of antifungals is strongly recommended to avoid the emergence of resistant strains and ensure the therapeutic effectiveness of sporotrichosis.

  20. Minimal inhibitory concentration distributions and epidemiological cutoff values of five antifungal agents against Sporothrix brasiliensis

    Directory of Open Access Journals (Sweden)

    Rodrigo Almeida-Paes

    Full Text Available BACKGROUND Sporothrix brasiliensis is the most virulent sporotrichosis agent. This species usually responds to antifungal drugs, but therapeutic failure can occur in some patients. Antifungal susceptibility tests have been performed on this species, but no clinical breakpoints (CBPs are available. In this situation, minimal inhibitory concentration (MIC distributions and epidemiological cutoff values (ECVs support the detection of identification of resistant strains. OBJECTIVES To study the MIC distributions of five antifungal drugs against S. brasiliensis and to propose tentative ECVs. METHODS MICs of amphotericin B (AMB, itraconazole (ITR, ketoconazole (KET, posaconazole (POS, and terbinafine (TRB against 335 S. brasiliensis strains were determined by the Clinical and Laboratory Standards Institute broth microdilution method. FINDINGS The proposed ECV, in µg/mL, for AMB, ITR, KET, POS, and TRB were 4.0, 2.0, 1.0, 2.0, and 0.25, respectively. Percentages of wild-type strains in our population for the above antifungal drugs were 98.48, 95.22, 95.33, 100, and 97.67%, respectively. MAIN CONCLUSIONS These ECVs will be useful to detect strains with resistance, to define CBPs, and to elaborate specific therapeutic guidelines for S. brasiliensis. Rational use of antifungals is strongly recommended to avoid the emergence of resistant strains and ensure the therapeutic effectiveness of sporotrichosis.

  1. Dominant drug targets suppress the emergence of antiviral resistance

    OpenAIRE

    Tanner, Elizabeth J; Liu, Hong-mei; Oberste, M Steven; Pallansch, Mark; Collett, Marc S; Kirkegaard, Karla

    2014-01-01

    eLife digest Treating a viral infection with a drug sometimes has an unwanted side effect?the virus quickly becomes resistant to the drug. Viruses whose genetic information is encoded in molecules of RNA mutate faster than DNA viruses and are particularly good at developing resistance to drugs. This is because the process of copying the RNA is prone to errors, and by chance some of these errors, or mutations, may allow the virus to resist the drug's effects. Treating viral infections with mos...

  2. Diagnosis and Treatment of Drug-Resistant Tuberculosis.

    Science.gov (United States)

    Caminero, José A; Cayla, Joan A; García-García, José-María; García-Pérez, Francisco J; Palacios, Juan J; Ruiz-Manzano, Juan

    2017-09-01

    In the last 2 decades, drug-resistant tuberculosis has become a threat and a challenge to worldwide public health. The diagnosis and treatment of these forms of tuberculosis are much more complex and prognosis clearly worsens as the resistance pattern intensifies. Nevertheless, it is important to remember that with the appropriatesystematic clinical management, most of these patients can be cured. These guidelines itemize the basis for the diagnosis and treatment of all tuberculosis patients, from those infected by strains that are sensitive to all drugs, to those who are extensively drug-resistant. Specific recommendations are given forall cases. The current and future role of new molecular methods for detecting resistance, shorter multi-drug-resistant tuberculosis regimens, and new drugs with activity against Mycobacterium tuberculosis are also addressed. Copyright © 2017 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.

  3. Repurposing and Revival of the Drugs: A New Approach to Combat the Drug Resistant Tuberculosis

    Directory of Open Access Journals (Sweden)

    Divakar Sharma

    2017-12-01

    Full Text Available Emergence of drug resistant tuberculosis like multi drug resistant tuberculosis (MDR-TB, extensively drug-resistant tuberculosis (XDR-TB and totally drug resistant tuberculosis (TDR-TB has created a new challenge to fight against these bad bugs of Mycobacterium tuberculosis. Repurposing and revival of the drugs are the new trends/options to combat these worsen situations of tuberculosis in the antibiotics resistance era or in the situation of global emergency. Bactericidal and synergistic effect of repurposed/revived drugs along with the latest drugs bedaquiline and delamanid used in the treatment of MDR-TB, XDR-TB, and TDR-TB might be the choice for future promising combinatorial chemotherapy against these bad bugs.

  4. Multi drug resistance tuberculosis: pattern seen in last 13 years

    International Nuclear Information System (INIS)

    Iqbal, R.; Shabbir, I.; Munir, K.; Tabassum, M.N.; Khan, S.U.; Khan, M.Z.U.

    2011-01-01

    Background: Drug resistance in tuberculosis is a serious problem throughout the world especially, after the emergence of multi drug resistant TB strains. Objectives: To estimate drug resistance in TB patients and compare it with previous studies to see the changing trends. Materials and Methods: The PMRC Research Centre receives sputum samples from all the leading hospitals of Lahore. This retrospective analysis was done from 1996 to 2008 on the multi drug resistant TB strains that were seen during these years. Five first lines anti tuberculosis drugs were tested on Lowenstein Jensen medium using standard proportion method. Results: A total of 2661 confirmed isolates of Mycobacterium tuberculosis were seen over the past 13 years. Of the total, 2182 were pulmonary and 479 were extra pulmonary specimens. The patients comprised of those with and without history of previous treatment. These specimens were subjected to drug susceptibility testing. Almost half of the patient had some resistance; multiple drug resistance was seen in 12.3% and 23.0% cases without and with history of previous treatment respectively. Overall resistance to rifampicin was 26.4%, isoniazid 24.1% streptomycin 21.6% ethambutol 13.4% and pyrazinamide 28.4% respectively. Statistically significant difference was seen between primary and acquired resistance. When compared with the reports from previous studies from the same area, there was a trend of gradual increase of drug resistance. Conclusions Resistance to anti tuberculosis drugs is high. Policy message. TB Control Program should start 'DOTS Plus' schemes for which drug susceptibility testing facilities should be available for correctly managing the patients. (author)

  5. Quantifying the Determinants of Evolutionary Dynamics Leading to Drug Resistance.

    Directory of Open Access Journals (Sweden)

    Guillaume Chevereau

    Full Text Available The emergence of drug resistant pathogens is a serious public health problem. It is a long-standing goal to predict rates of resistance evolution and design optimal treatment strategies accordingly. To this end, it is crucial to reveal the underlying causes of drug-specific differences in the evolutionary dynamics leading to resistance. However, it remains largely unknown why the rates of resistance evolution via spontaneous mutations and the diversity of mutational paths vary substantially between drugs. Here we comprehensively quantify the distribution of fitness effects (DFE of mutations, a key determinant of evolutionary dynamics, in the presence of eight antibiotics representing the main modes of action. Using precise high-throughput fitness measurements for genome-wide Escherichia coli gene deletion strains, we find that the width of the DFE varies dramatically between antibiotics and, contrary to conventional wisdom, for some drugs the DFE width is lower than in the absence of stress. We show that this previously underappreciated divergence in DFE width among antibiotics is largely caused by their distinct drug-specific dose-response characteristics. Unlike the DFE, the magnitude of the changes in tolerated drug concentration resulting from genome-wide mutations is similar for most drugs but exceptionally small for the antibiotic nitrofurantoin, i.e., mutations generally have considerably smaller resistance effects for nitrofurantoin than for other drugs. A population genetics model predicts that resistance evolution for drugs with this property is severely limited and confined to reproducible mutational paths. We tested this prediction in laboratory evolution experiments using the "morbidostat", a device for evolving bacteria in well-controlled drug environments. Nitrofurantoin resistance indeed evolved extremely slowly via reproducible mutations-an almost paradoxical behavior since this drug causes DNA damage and increases the mutation

  6. Shigella Antimicrobial Drug Resistance Mechanisms, 2004-2014.

    Science.gov (United States)

    Nüesch-Inderbinen, Magdalena; Heini, Nicole; Zurfluh, Katrin; Althaus, Denise; Hächler, Herbert; Stephan, Roger

    2016-06-01

    To determine antimicrobial drug resistance mechanisms of Shigella spp., we analyzed 344 isolates collected in Switzerland during 2004-2014. Overall, 78.5% of isolates were multidrug resistant; 10.5% were ciprofloxacin resistant; and 2% harbored mph(A), a plasmid-mediated gene that confers reduced susceptibility to azithromycin, a last-resort antimicrobial agent for shigellosis.

  7. Plasmid Conjugation in E. coli and Drug Resistance

    African Journals Online (AJOL)

    Prof. Ogunji

    more the copy number of resistance plasmid present in a bacterial cell, the higher the resistant ability of ... amoxicillin, as well as other semi synthetic penicillins, many cephalosporins, carbapenems, aztreonam, ... drugs resistant E. coli to amoxicillin-clavulanic acid and ceftriaxone were also carried out (Hadley, 2002;.

  8. Cytochromes P450 and drug resistance

    NARCIS (Netherlands)

    Doehmer, J.; Goeptar, A R; Vermeulen, N P

    1993-01-01

    Cytochromes P450 are the key enzymes for activating and inactivating many drugs, in particular anticancer drugs. Therefore, individual expression levels of cytochromes P450 may play a crucial role in drug safety and drug efficacy. Overexpression of cytochrome P450 may yield rapid turnover and

  9. Occurrence of transmitted HIV-1 drug resistance among Drug-naïve ...

    African Journals Online (AJOL)

    Occurrence of transmitted HIV-1 drug resistance among Drug-naïve pregnant women in selected HIV-care centres in Ghana. Alexander Martin-Odoom, Theophilus Adiku, Elena Delgado, Margaret Lartey, William K. Ampofo ...

  10. Cancer stem cells and drug resistance: the potential of nanomedicine

    Science.gov (United States)

    Vinogradov, Serguei; Wei, Xin

    2012-01-01

    Properties of the small group of cancer cells called tumor-initiating or cancer stem cells (CSCs) involved in drug resistance, metastasis and relapse of cancers can significantly affect tumor therapy. Importantly, tumor drug resistance seems to be closely related to many intrinsic or acquired properties of CSCs, such as quiescence, specific morphology, DNA repair ability and overexpression of antiapoptotic proteins, drug efflux transporters and detoxifying enzymes. The specific microenvironment (niche) and hypoxic stability provide additional protection against anticancer therapy for CSCs. Thus, CSC-focused therapy is destined to form the core of any effective anticancer strategy. Nanomedicine has great potential in the development of CSC-targeting drugs, controlled drug delivery and release, and the design of novel gene-specific drugs and diagnostic modalities. This review is focused on tumor drug resistance-related properties of CSCs and describes current nanomedicine approaches, which could form the basis of novel combination therapies for eliminating metastatic and CSCs. PMID:22471722

  11. Chalcone derivatives as potential antifungal agents: Synthesis, and antifungal activity

    Directory of Open Access Journals (Sweden)

    Deepa Gupta

    2015-01-01

    Full Text Available Much research has been carried out with the aim to discover the therapeutic values of chalcone derivatives. Chalcones possess wide range of pharmacological activity such as antibacterial, antimalarial, antiprotozoal, antitubercular, anticancer, and antifungal agents etc. The presence of reactive α,β-unsaturated keto group in chalcones is found to be responsible for their biological activity. The rapid developments of resistance to antifungal agents, led to design, and synthesize the new antifungal agents. The derivatives of chalcones were prepared using Claisen-Schmidt condensation scheme with appropriate tetralone and aldehyde derivatives. Ten derivatives were synthesized and were biologically screened for antifungal activity. The newly synthesized derivatives of chalcone showed antifungal activity against fungal species, Microsporum gypseum. The results so obtained were superior or comparable to ketoconazole. It was observed that none of the compounds tested showed positive results for fungi Candida albicans nor against fungi Aspergillus niger. Chalcone derivatives showed inhibitory effect against M. gypseum species of fungus. It was found that among the chalcone derivatives so synthesized, two of them, that is, 4-chloro derivative, and unsubstituted derivative of chalcone showed antifungal activity superior to ketoconazole. Thus, these can be the potential new molecule as antifungal agent.

  12. Alternate efflux pump mechanism may contribute to drug resistance in extensively drug-resistant isolates of Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Akbar Kanji

    2016-01-01

    Conclusion: Our data show an nsSNP in the drrA efflux pump gene that may result in upregulation of drug efflux mechanisms in MTB strains. It is therefore imperative to understand the mechanism of efflux and its role in drug resistance, which will enable the identification of new drug targets and development of new drug regimens to counteract the drug efflux mechanism of MTB.

  13. in vitro surveillance of drug resistant falciparum malaria in north ...

    African Journals Online (AJOL)

    Dr Oboro VO

    ABSTRACT. Background: drug resistant malaria is spreading inexorably to areas with drug sensitive malaria parasites. This study compared the in vitro sensitivities of Plasmodium falciparum fresh parasite isolates, to some standard antimalarial drugs, in Makurdi and Masaka located over 300 km apart, in north central.

  14. Structural and In Vivo Studies on Trehalose-6-Phosphate Synthase from Pathogenic Fungi Provide Insights into Its Catalytic Mechanism, Biological Necessity, and Potential for Novel Antifungal Drug Design

    Energy Technology Data Exchange (ETDEWEB)

    Miao, Yi; Tenor, Jennifer L.; Toffaletti, Dena L.; Maskarinec, Stacey A.; Liu, Jiuyu; Lee, Richard E.; Perfect, John R.; Brennan, Richard G.; Hendrickson, Wayne A.

    2017-07-25

    ABSTRACT

    The disaccharide trehalose is critical to the survival of pathogenic fungi in their human host. Trehalose-6-phosphate synthase (Tps1) catalyzes the first step of trehalose biosynthesis in fungi. Here, we report the first structures of eukaryotic Tps1s in complex with substrates or substrate analogues. The overall structures of Tps1 fromCandida albicansandAspergillus fumigatusare essentially identical and reveal N- and C-terminal Rossmann fold domains that form the glucose-6-phosphate and UDP-glucose substrate binding sites, respectively. These Tps1 structures with substrates or substrate analogues reveal key residues involved in recognition and catalysis. Disruption of these key residues severely impaired Tps1 enzymatic activity. Subsequent cellular analyses also highlight the enzymatic function of Tps1 in thermotolerance, yeast-hypha transition, and biofilm development. These results suggest that Tps1 enzymatic functionality is essential for the fungal stress response and virulence. Furthermore, structures of Tps1 in complex with the nonhydrolyzable inhibitor, validoxylamine A, visualize the transition state and support an internal return-like catalytic mechanism that is generalizable to other GT-B-fold retaining glycosyltransferases. Collectively, our results depict key Tps1-substrate interactions, unveil the enzymatic mechanism of these fungal proteins, and pave the way for high-throughput inhibitor screening buttressed and guided by the current structures and those of high-affinity ligand-Tps1 complexes.

    IMPORTANCEInvasive fungal diseases have emerged as major threats, resulting in more than 1.5 million deaths annually worldwide. This epidemic has been further complicated by increasing resistance to all major classes of antifungal drugs in the clinic. Trehalose biosynthesis is essential for the fungal stress response and virulence. Critically, this biosynthetic pathway is absent in

  15. Antifungal susceptibility of Malassezia furfur, Malassezia sympodialis, and Malassezia globosa to azole drugs and amphotericin B evaluated using a broth microdilution method.

    Science.gov (United States)

    Rojas, Florencia D; Sosa, María de los A; Fernández, Mariana S; Cattana, María E; Córdoba, Susana B; Giusiano, Gustavo E

    2014-08-01

    We studied the in vitro activity of fluconazole (FCZ), ketoconazole (KTZ), miconazole (MCZ), voriconazole (VCZ), itraconazole (ITZ) and amphotericin B (AMB) against the three major pathogenic Malassezia species, M. globosa, M. sympodialis, and M. furfur. Antifungal susceptibilities were determined using the broth microdilution method in accordance with Clinical and Laboratory Standards Institute reference document M27-A3. To support lipid-dependent yeast development, glucose, peptone, ox bile, malt extract, glycerol, and Tween supplements were added to Roswell Park Memorial Institute RPMI 1640 medium. The supplemented medium allowed good growth of all three species studied. The minimal inhibitory concentrations (MICs) were recorded after 72 h of incubation at 32ºC. The three species showed different susceptibility profiles for the drugs tested. Malassezia sympodialis was the most susceptible and M. furfur the least susceptible species. KTZ, ITZ, and VCZ were the most active drugs, showing low variability among isolates of the same species. FCZ, MCZ, and AMB showed high MICs and wide MIC ranges. Differences observed emphasize the need to accurately identify and evaluate antifungal susceptibility of Malassezia species. Further investigations and collaborative studies are essential for correlating in vitro results with clinical outcomes since the existing limited data do not allow definitive conclusions. © The Author 2014. 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.

  16. Drug resistant tuberculosis in prisons in Azerbaijan: case study

    Science.gov (United States)

    Coninx, R; Pfyffer, G E; Mathieu, C; Savina, D; Debacker, M; Jafarov, F; Jabrailov, I; Ismailov, A; Mirzoev, F; de Haller, R; Portaels, F

    1998-01-01

    Objectives: To document the existence of drug resistance in a tuberculosis treatment programme that adheres strictly to the DOTS principles (directly observed treatment, short course) and to determine the extent of drug resistance in a prison setting in one of the republics of the former Soviet Union. Design: Case study. Setting: Central Penitentiary Hospital in Baku, the referral centre for tuberculosis patients from all prisons in Azerbaijan. Subjects: Prisoners with tuberculosis: 28 selected patients not responding clinically or bacteriologically to the standard treatment (group 1) and 38 consecutive patients at admission to the programme (group 2). Main outcome measures: Drug resistance of Mycobacterium tuberculosis strains grown from sputum. Results: All the non-responding patients (group 1) had strains resistant to at least one drug. 25 (89%) of the non-responding patients and nine (24%) of the consecutive patients had M tuberculosis strains resistant to both rifampicin and isoniazid. A further 17 patients in group 2 had strains resistant to one or more first line drugs. Conclusions: Drug resistant M tuberculosis strains are common in prisons in Azerbaijan. Tuberculosis problems tend to be worse in prisons, but prisoners and former prisoners may have an important role in the transmission of tuberculosis, particularly of drug resistant forms, in the community. National programmes to control tuberculosis will have to take into account and address the problems in prisons to ensure their success. Key messages Tuberculosis is an important problem in prisons in Azerbaijan Multidrug resistant tuberculosis was common and an important cause of non-response to standard treatment National tuberculosis control programmes must include prisons and take account of drug resistance Unless WHO recommended treatment protocols are followed the problem of multidrug resistant tuberculosis may result in untreatable tuberculosis which will spread to the general community PMID

  17. Diversity and evolution of drug resistance mechanisms in Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Al-Saeedi M

    2017-10-01

    Full Text Available Mashael Al-Saeedi, Sahal Al-Hajoj Department of Infection and Immunity, Mycobacteriology Research Section, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia Abstract: Despite the efficacy of antibiotics to protect humankind against many deadly pathogens, such as Mycobacterium tuberculosis, nothing can prevent the emergence of drug-resistant strains. Several mechanisms facilitate drug resistance in M. tuberculosis including compensatory evolution, epistasis, clonal interference, cell wall integrity, efflux pumps, and target mimicry. In this study, we present recent findings relevant to these mechanisms, which can enable the discovery of new drug targets and subsequent development of novel drugs for treatment of drug-resistant M. tuberculosis. Keywords: Mycobacterium tuberculosis, antibiotic resistance, compensatory evolution, epistasis, efflux pumps, fitness cost

  18. Long Non-coding RNAs and Drug Resistance.

    Science.gov (United States)

    Pan, Jing-Jing; Xie, Xiao-Juan; Li, Xu; Chen, Wei

    2015-01-01

    Long non-coding RNAs (lncRNAs) are emerging as key players in gene expression that govern cell developmental processes, and thus contributing to diseases, especially cancers. Many studies have suggested that aberrant expression of lncRNAs is responsible for drug resistance, a substantial obstacle for cancer therapy. Drug resistance not only results from individual variations in patients, but also from genetic and epigenetic differences in tumors. It is reported that drug resistance is tightly modulated by lncRNAs which change the stability and translation of mRNAs encoding factors involved in cell survival, proliferation, and drug metabolism. In this review, we summarize recent advances in research on lncRNAs associated with drug resistance and underlying molecular or cellular mechanisms, which may contribute helpful approaches for the development of new therapeutic strategies to overcome treatment failure.

  19. Is selection relevant in the evolutionary emergence of drug resistance?

    OpenAIRE

    Day, Troy; Huijben, Silvie; Read, Andrew F.

    2015-01-01

    The emergence of drug resistant pathogens is often considered a canonical case of evolution by ‘natural’ selection. Here we argue that the strength of selection can be a poor predictor of the rate of resistance emergence. It is possible for a resistant strain to be under negative selection and still emerge in an infection or spread in a population. Measuring the right parameters is a necessary first step towards the development of evidence-based resistance management strategies. We argue that...

  20. Drug resistance analysis of bacterial strains isolated from burn patients.

    Science.gov (United States)

    Wang, L F; Li, J L; Ma, W H; Li, J Y

    2014-01-22

    This study aimed to analyze the spectrum and drug resistance of bacteria isolated from burn patients to provide a reference for rational clinical use of antibiotics. Up to 1914 bacterial strain specimens isolated from burn patients admitted to hospital between 2001 and 2010 were subjected to resistance monitoring by using the K-B paper disk method. Retrospective analysis was performed on drug resistance analysis of burn patients. The top eight bacterium strains according to detection rate. A total of 1355 strains of Gram-negative (G(-)) bacteria and 559 strains of Gram-positive (G(+)) bacteria were detected. The top eight bacterium strains, according to detection rate, were Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Staphylococcus epidermidis, Klebsiella pneumoniae, Enterobacter cloacae, and Enterococcus. Drug resistance rates were higher than 90% in A. baumannii, P. aeruginosa, S. epidermidis, and S. aureus, which accounted for 52.2, 21.7, 27.8, and 33.3%, respectively, of the entire sample. Those with drug resistance rates lower than 30% accounted for 4.3, 30.4, 16.7, and 16.7%, respectively. Multidrug-resistant S. aureus (MRSA) and methicillin-resistant S. epidermidis (MRSE) accounted for 49.2 and 76.4% of the S. epidermis and S. aureus resistance, respectively. Antibacterial drugs that had drug resistance rates to MRSE and MRSA higher than 90% accounted for 38.9 and 72.2%, respectively, whereas those with lower than 30% drug resistance rates accounted for 11.1 and 16.7%, respectively. The burn patients enrolled in the study were mainly infected with G(-) bacteria. These results strongly suggest that clinicians should practice rational use of antibiotics based on drug susceptibility test results.

  1. HIV resistance testing and detected drug resistance in Europe

    DEFF Research Database (Denmark)

    Schultze, Anna; Phillips, Andrew N; Paredes, Roger

    2015-01-01

    OBJECTIVES: To describe regional differences and trends in resistance testing among individuals experiencing virological failure and the prevalence of detected resistance among those individuals who had a genotypic resistance test done following virological failure. DESIGN: Multinational cohort...... study. METHODS: Individuals in EuroSIDA with virological failure (>1 RNA measurement >500 on ART after >6 months on ART) after 1997 were included. Adjusted odds ratios (aORs) for resistance testing following virological failure and aORs for the detection of resistance among those who had a test were...... calculated using logistic regression with generalized estimating equations. RESULTS: Compared to 74.2% of ART-experienced individuals in 1997, only 5.1% showed evidence of virological failure in 2012. The odds of resistance testing declined after 2004 (global P Resistance was detected in 77...

  2. CASAR82A, a pathogen-induced pepper SAR8.2, exhibits an antifungal activity and its overexpression enhances disease resistance and stress tolerance.

    Science.gov (United States)

    Lee, Sung Chul; Hwang, Byung Kook

    2006-05-01

    Pepper SAR8.2 gene (CASAR82A) was previously reported to be locally or systemically induced in pepper plants by biotic and abiotic stresses. In this study, the physiological and molecular functions of the pepper SAR8.2 protein in the plant defense responses were investigated by generating Arabidopsis transgenic lines overexpressing the CASAR82A gene. The transgenic Arabidopsis plants grew faster than the wild-type plants, indicating that the CASAR82A gene was involved in plant development. The ectopic expression of CASAR82A in Arabidopsis was accompanied by the expression of the Arabidopsis pathogenesis-related (PR)-genes including AtPR-1, AtPR-4 and AtPR-5. CASAR82A overexpression enhanced the resistance against infections by Pseudomonas syringae pv. tomato, Fusarium oxysporum f.sp. matthiolae or Botrytis cinerea. The transgenic plants also exhibited increased NaCl and drought tolerance during all growth stages. Moreover, the methyl viologen test showed that the transgenic plants were tolerant to oxidative stress. The purified recombinant CASAR82A protein and crude protein extracts of the transgenic plants exhibited antifungal activity against some phytopathogenic fungi, indicating that the enhanced resistance of the transgenic plants to fungal pathogen infection may be due to the antifungal effect of SAR8.2 protein.

  3. Drug-Resistant Bacteria: On the Edge of a Crisis | NIH MedlinePlus the Magazine

    Science.gov (United States)

    ... drug-resistant bacteria research program. Why are certain bacteria becoming more resistant to drugs? There is a ... a national, even global crisis of drug-resistant bacteria. Why is that? The more we see this ...

  4. DNA origami as a carrier for circumvention of drug resistance.

    Science.gov (United States)

    Jiang, Qiao; Song, Chen; Nangreave, Jeanette; Liu, Xiaowei; Lin, Lin; Qiu, Dengli; Wang, Zhen-Gang; Zou, Guozhang; Liang, Xingjie; Yan, Hao; Ding, Baoquan

    2012-08-15

    Although a multitude of promising anti-cancer drugs have been developed over the past 50 years, effective delivery of the drugs to diseased cells remains a challenge. Recently, nanoparticles have been used as drug delivery vehicles due to their high delivery efficiencies and the possibility to circumvent cellular drug resistance. However, the lack of biocompatibility and inability to engineer spatially addressable surfaces for multi-functional activity remains an obstacle to their widespread use. Here we present a novel drug carrier system based on self-assembled, spatially addressable DNA origami nanostructures that confronts these limitations. Doxorubicin, a well-known anti-cancer drug, was non-covalently attached to DNA origami nanostructures through intercalation. A high level of drug loading efficiency was achieved, and the complex exhibited prominent cytotoxicity not only to regular human breast adenocarcinoma cancer cells (MCF 7), but more importantly to doxorubicin-resistant cancer cells, inducing a remarkable reversal of phenotype resistance. With the DNA origami drug delivery vehicles, the cellular internalization of doxorubicin was increased, which contributed to the significant enhancement of cell-killing activity to doxorubicin-resistant MCF 7 cells. Presumably, the activity of doxorubicin-loaded DNA origami inhibits lysosomal acidification, resulting in cellular redistribution of the drug to action sites. Our results suggest that DNA origami has immense potential as an efficient, biocompatible drug carrier and delivery vehicle in the treatment of cancer.

  5. Mathematical modeling and computational prediction of cancer drug resistance.

    Science.gov (United States)

    Sun, Xiaoqiang; Hu, Bin

    2017-06-23

    Diverse forms of resistance to anticancer drugs can lead to the failure of chemotherapy. Drug resistance is one of the most intractable issues for successfully treating cancer in current clinical practice. Effective clinical approaches that could counter drug resistance by restoring the sensitivity of tumors to the targeted agents are urgently needed. As numerous experimental results on resistance mechanisms have been obtained and a mass of high-throughput data has been accumulated, mathematical modeling and computational predictions using systematic and quantitative approaches have become increasingly important, as they can potentially provide deeper insights into resistance mechanisms, generate novel hypotheses or suggest promising treatment strategies for future testing. In this review, we first briefly summarize the current progress of experimentally revealed resistance mechanisms of targeted therapy, including genetic mechanisms, epigenetic mechanisms, posttranslational mechanisms, cellular mechanisms, microenvironmental mechanisms and pharmacokinetic mechanisms. Subsequently, we list several currently available databases and Web-based tools related to drug sensitivity and resistance. Then, we focus primarily on introducing some state-of-the-art computational methods used in drug resistance studies, including mechanism-based mathematical modeling approaches (e.g. molecular dynamics simulation, kinetic model of molecular networks, ordinary differential equation model of cellular dynamics, stochastic model, partial differential equation model, agent-based model, pharmacokinetic-pharmacodynamic model, etc.) and data-driven prediction methods (e.g. omics data-based conventional screening approach for node biomarkers, static network approach for edge biomarkers and module biomarkers, dynamic network approach for dynamic network biomarkers and dynamic module network biomarkers, etc.). Finally, we discuss several further questions and future directions for the use of

  6. Identification of drug-resistant subpopulations in canine hemangiosarcoma.

    Science.gov (United States)

    Khammanivong, A; Gorden, B H; Frantz, A M; Graef, A J; Dickerson, E B

    2016-09-01

    Canine hemangiosarcoma is a rapidly progressive disease that is poorly responsive to conventional chemotherapy. Despite numerous attempts to advance treatment options and improve outcomes, drug resistance remains a hurdle to successful therapy. To address this problem, we used recently characterized progenitor cell populations derived from canine hemangiosarcoma cell lines and grown as non-adherent spheres to identify potential drug resistance mechanisms as well as drug-resistant cell populations. Cells from sphere-forming cultures displayed enhanced resistance to chemotherapy drugs, expansion of dye-excluding side populations and altered ATP-binding cassette (ABC) transporter expression. Invasion studies demonstrated variability between cell lines as well as between sphere and monolayer cell populations. Collectively, our results suggest that sphere cell populations contain distinct subpopulations of drug-resistant cells that utilize multiple mechanisms to evade cytotoxic drugs. Our approach represents a new tool for the study of drug resistance in hemangiosarcoma, which could alter approaches for treating this disease. © 2014 John Wiley & Sons Ltd.

  7. Antifungal pharmacodynamics: Latin America's perspective.

    Science.gov (United States)

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

    The current increment of invasive fungal infections and the availability of new broad-spectrum antifungal agents has increased the use of these agents by non-expert practitioners, without an impact on mortality. To improve efficacy while minimizing prescription errors and to reduce the high monetary cost to the health systems, the principles of pharmacokinetics (PK) and pharmacodynamics (PD) are necessary. A systematic review of the PD of antifungals agents was performed aiming at the practicing physician without expertise in this field. The initial section of this review focuses on the general concepts of antimicrobial PD. In vitro studies, fungal susceptibility and antifungal serum concentrations are related with different doses and dosing schedules, determining the PD indices and the magnitude required to obtain a specific outcome. Herein the PD of the most used antifungal drug classes in Latin America (polyenes, azoles, and echinocandins) is discussed. Copyright © 2016 Sociedade Brasileira de Infectologia. Published by Elsevier Editora Ltda. All rights reserved.

  8. Antifungal pharmacodynamics: Latin America's perspective

    Directory of Open Access Journals (Sweden)

    Javier M. Gonzalez

    2017-01-01

    Full Text Available The current increment of invasive fungal infections and the availability of new broad-spectrum antifungal agents has increased the use of these agents by non-expert practitioners, without an impact on mortality. To improve efficacy while minimizing prescription errors and to reduce the high monetary cost to the health systems, the principles of pharmacokinetics (PK and pharmacodynamics (PD are necessary. A systematic review of the PD of antifungals agents was performed aiming at the practicing physician without expertise in this field. The initial section of this review focuses on the general concepts of antimicrobial PD. In vitro studies, fungal susceptibility and antifungal serum concentrations are related with different doses and dosing schedules, determining the PD indices and the magnitude required to obtain a specific outcome. Herein the PD of the most used antifungal drug classes in Latin America (polyenes, azoles, and echinocandins is discussed.

  9. Diversity of endophytic fungi from different Verticillium-wilt-resistant Gossypium hirsutum and evaluation of antifungal activity against Verticillium dahliae in vitro.

    Science.gov (United States)

    Li, Zhi-Fang; Wang, Ling-Fei; Feng, Zi-Li; Zhao, Li-Hong; Shi, Yong-Qiang; Zhu, He-Qin

    2014-09-01

    Cotton plants were sampled and ranked according to their resistance to Verticillium wilt. In total, 642 endophytic fungi isolates representing 27 genera were recovered from Gossypium hirsutum root, stem, and leaf tissues, but were not uniformly distributed. More endophytic fungi appeared in the leaf (391) compared with the root (140) and stem (111) sections. However, no significant difference in the abundance of isolated endophytes was found among resistant cotton varieties. Alternaria exhibited the highest colonization frequency (7.9%), followed by Acremonium (6.6%) and Penicillium (4.8%). Unlike tolerant varieties, resistant and susceptible ones had similar endophytic fungal population compositions. In three Verticillium-wilt-resistant cotton varieties, fungal endophytes from the genus Alternaria were most frequently isolated, followed by Gibberella and Penicillium. The maximum concentration of dominant endophytic fungi was observed in leaf tissues (0.1797). The evenness of stem tissue endophytic communities (0.702) was comparatively more uniform than the other two tissues. Eighty endophytic fungi selected from 27 genera were evaluated for their inhibition activity against highly virulent Verticillium dahliae isolate Vd080 in vitro. Thirty-nine isolates exhibited fungistasis against the pathogen at varying degrees. Seven species, having high growth inhibition rates (≥75%), exhibited strong antifungal activity against V. dahliae. The antifungal activity of both volatile and nonvolatile metabolites was also investigated. The nonvolatile substances produced by CEF-818 (Penicillium simplicissimum), CEF-325 (Fusarium solani), CEF-714 (Leptosphaeria sp.), and CEF-642 (Talaromyces flavus) completely inhibited V. dahliae growth. These findings deepen our understanding of cotton-endophyte interactions and provide a platform for screening G. hirsutum endophytes with biocontrol potential.

  10. Aggressive chemotherapy and the selection of drug resistant pathogens.

    Science.gov (United States)

    Huijben, Silvie; Bell, Andrew S; Sim, Derek G; Tomasello, Danielle; Mideo, Nicole; Day, Troy; Read, Andrew F

    2013-09-01

    Drug resistant pathogens are one of the key public health challenges of the 21st century. There is a widespread belief that resistance is best managed by using drugs to rapidly eliminate target pathogens from patients so as to minimize the probability that pathogens acquire resistance de novo. Yet strong drug pressure imposes intense selection in favor of resistance through alleviation of competition with wild-type populations. Aggressive chemotherapy thus generates opposing evolutionary forces which together determine the rate of drug resistance emergence. Identifying treatment regimens which best retard resistance evolution while maximizing health gains and minimizing disease transmission requires empirical analysis of resistance evolution in vivo in conjunction with measures of clinical outcomes and infectiousness. Using rodent malaria in laboratory mice, we found that less aggressive chemotherapeutic regimens substantially reduced the probability of onward transmission of resistance (by >150-fold), without compromising health outcomes. Our experiments suggest that there may be cases where resistance evolution can be managed more effectively with treatment regimens other than those which reduce pathogen burdens as fast as possible.

  11. Aggressive chemotherapy and the selection of drug resistant pathogens.

    Directory of Open Access Journals (Sweden)

    Silvie Huijben

    2013-09-01

    Full Text Available Drug resistant pathogens are one of the key public health challenges of the 21st century. There is a widespread belief that resistance is best managed by using drugs to rapidly eliminate target pathogens from patients so as to minimize the probability that pathogens acquire resistance de novo. Yet strong drug pressure imposes intense selection in favor of resistance through alleviation of competition with wild-type populations. Aggressive chemotherapy thus generates opposing evolutionary forces which together determine the rate of drug resistance emergence. Identifying treatment regimens which best retard resistance evolution while maximizing health gains and minimizing disease transmission requires empirical analysis of resistance evolution in vivo in conjunction with measures of clinical outcomes and infectiousness. Using rodent malaria in laboratory mice, we found that less aggressive chemotherapeutic regimens substantially reduced the probability of onward transmission of resistance (by >150-fold, without compromising health outcomes. Our experiments suggest that there may be cases where resistance evolution can be managed more effectively with treatment regimens other than those which reduce pathogen burdens as fast as possible.

  12. An evaluation of the emergence of drug resistant virus for HIV/AIDS drug treatments.

    Science.gov (United States)

    Chang, Hyuk-Jun

    2015-01-01

    HIV/AIDS drug treatment, such as highly active anti-retroviral therapy (HAART), often fails due to the emergence of drug resistant species. In this paper we investigate a new estimation method for the possibility of emergence of drug resistant mutation. To the best knowledge of the author this work is the first study to try to describe quantitatively the possibility of drug resistance emergence for HIV/AIDS drug treatments. In simulation studies we compare HIV/AIDS treatment methods, such as structured treatment interruption (STI) and improved gradual dosage reduction (iGDR), based on the proposed analysis. From the analysis we can explain why STI treatment often fails and also can show that iGDR is desirable rather than STI particularly in terms of the decrease of the possibility of emergence of drug resistant virus.

  13. ESBL determination and antibacterial drug resistance pattern of ...

    African Journals Online (AJOL)

    ESBL determination and antibacterial drug resistance pattern of Klebsiella Pneumoniae amongst patients at PIMS Islamabad. Jafar Khan, Noor Naz, Naser M AbdEl-Salam, Nayab Nayab, Anum Tabassum, H Hussain, Riaz Ullah ...

  14. HIV-1 Drug Resistance Mutations: Potential Applications for Point-of-Care Genotypic Resistance Testing

    NARCIS (Netherlands)

    Rhee, Soo-Yon; Jordan, Michael R.; Raizes, Elliot; Chua, Arlene; Parkin, Neil; Kantor, Rami; van Zyl, Gert U.; Mukui, Irene; Hosseinipour, Mina C.; Frenkel, Lisa M.; Ndembi, Nicaise; Hamers, Raph L.; Rinke de Wit, Tobias F.; Wallis, Carole L.; Gupta, Ravindra K.; Fokam, Joseph; Zeh, Clement; Schapiro, Jonathan M.; Carmona, Sergio; Katzenstein, David; Tang, Michele; Aghokeng, Avelin F.; de Oliveira, Tulio; Wensing, Annemarie M. J.; Gallant, Joel E.; Wainberg, Mark A.; Richman, Douglas D.; Fitzgibbon, Joseph E.; Schito, Marco; Bertagnolio, Silvia; Yang, Chunfu; Shafer, Robert W.

    2015-01-01

    The increasing prevalence of acquired and transmitted HIV-1 drug resistance is an obstacle to successful antiretroviral therapy (ART) in the low- and middle-income countries (LMICs) hardest hit by the HIV-1 pandemic. Genotypic drug resistance testing could facilitate the choice of initial ART in

  15. HIV-1 drug resistance mutations : Potential applications for point-of-care Genotypic resistance testing

    NARCIS (Netherlands)

    Rhee, Soo Yon; Jordan, Michael R.; Raizes, Elliot; Chua, Arlene; Parkin, Neil; Kantor, Rami; Van Zy, Gert U.; Mukui, Irene; Hosseinipour, Mina C.; Frenkel, Lisa M.; Ndembi, Nicaise; Hamers, Raph L.; De Wit, Tobias F Rinke; Wallis, Carole L.; Gupta, Ravindra K.; Fokam, Joseph; Zeh, Clement; Schapiro, Jonathan M.; Carmona, Sergio; Katzenstein, David; Tang, Michele; Aghokeng, Avelin F.; De Oliveira, Tulio; Wensing, Annemarie M J; Gallant, Joel E.; Wainberg, Mark A.; Richman, Douglas D.; Fitzgibbon, Joseph E.; Schito, Marco; Bertagnolio, Silvia; Yang, Chunfu; Shafer, Robert W.

    2015-01-01

    The increasing prevalence of acquired and transmitted HIV-1 drug resistance is an obstacle to successful antiretroviral therapy (ART) in the low- and middle-income countries (LMICs) hardest hit by the HIV-1 pandemic. Genotypic drug resistance testing could facilitate the choice of initial ART in

  16. Life cycle synchronization is a viral drug resistance mechanism.

    Directory of Open Access Journals (Sweden)

    Iulia A Neagu

    2018-02-01

    Full Text Available Viral infections are one of the major causes of death worldwide, with HIV infection alone resulting in over 1.2 million casualties per year. Antiviral drugs are now being administered for a variety of viral infections, including HIV, hepatitis B and C, and influenza. These therapies target a specific phase of the virus's life cycle, yet their ultimate success depends on a variety of factors, such as adherence to a prescribed regimen and the emergence of viral drug resistance. The epidemiology and evolution of drug resistance have been extensively characterized, and it is generally assumed that drug resistance arises from mutations that alter the virus's susceptibility to the direct action of the drug. In this paper, we consider the possibility that a virus population can evolve towards synchronizing its life cycle with the pattern of drug therapy. The periodicity of the drug treatment could then allow for a virus strain whose life cycle length is a multiple of the dosing interval to replicate only when the concentration of the drug is lowest. This process, referred to as "drug tolerance by synchronization", could allow the virus population to maximize its overall fitness without having to alter drug binding or complete its life cycle in the drug's presence. We use mathematical models and stochastic simulations to show that life cycle synchronization can indeed be a mechanism of viral drug tolerance. We show that this effect is more likely to occur when the variability in both viral life cycle and drug dose timing are low. More generally, we find that in the presence of periodic drug levels, time-averaged calculations of viral fitness do not accurately predict drug levels needed to eradicate infection, even if there is no synchronization. We derive an analytical expression for viral fitness that is sufficient to explain the drug-pattern-dependent survival of strains with any life cycle length. We discuss the implications of these findings for

  17. Drug-Resistant Tuberculosis among Children, China, 2006-2015.

    Science.gov (United States)

    Tao, Ning-Ning; He, Xiao-Chun; Zhang, Xian-Xin; Liu, Yao; Yu, Chun-Bao; Li, Huai-Chen

    2017-11-01

    Microbial drug resistance has become a major public health concern worldwide. To acquire epidemiologic data on drug-resistant tuberculosis (DR TB) among children, a major cause of illness and death for this population, we conducted a retrospective study of 2006-2015 data from 36 TB prevention and control institutions in Shandong Province, China. A total of 14,223 new TB cases, among which children (tuberculosis. Among children with TB, 18.9% had DR TB and 6.9% had multidrug-resistant TB. Over the past decade, the percentage of DR TB; multidrug-resistant TB; and overall first-line drug resistance for isoniazid, rifampin, ethambutol, and streptomycin among children increased significantly (at least 12%). Understanding the long-term trends of DR TB among children can shed light on the performance of TB control programs, thereby contributing to global TB control.

  18. Combined antiretroviral and antituberculosis drug resistance following incarceration

    Directory of Open Access Journals (Sweden)

    Katharine Elizabeth Stott

    2013-09-01

    Full Text Available We describe a case of HIV/tuberculosis (TB co-infection from KwaZulu-Natal, South Africa, characterised by drug resistance in both pathogens. The development of drug resistance was linked temporally to two periods of incarceration. This highlights the urgent need for improved integration of HIV/TB control strategies within prison health systems and within the broader public health framework.

  19. Treatment of tuberculosis in a region with high drug resistance: outcomes, drug resistance amplification and re-infection.

    Science.gov (United States)

    Bonnet, Maryline; Pardini, Manuela; Meacci, Francesca; Orrù, Germano; Yesilkaya, Hasan; Jarosz, Thierry; Andrew, Peter W; Barer, Mike; Checchi, Francesco; Rinder, Heinz; Orefici, Graziella; Rüsch-Gerdes, Sabine; Fattorini, Lanfranco; Oggioni, Marco Rinaldo; Melzer, Juliet; Niemann, Stefan; Varaine, Francis

    2011-01-01

    Emerging antituberculosis drug resistance is a serious threat for tuberculosis (TB) control, especially in Eastern European countries. We combined drug susceptibility results and molecular strain typing data with treatment outcome reports to assess the influence of drug resistance on TB treatment outcomes in a prospective cohort of patients from Abkhazia (Georgia). Patients received individualized treatment regimens based on drug susceptibility testing (DST) results. Definitions for antituberculosis drug resistance and treatment outcomes were in line with current WHO recommendations. First and second line DST, and molecular typing were performed in a supranational laboratory for Mycobacterium tuberculosis (MTB) strains from consecutive sputum smear-positive TB patients at baseline and during treatment. At baseline, MTB strains were fully drug-susceptible in 189/326 (58.0%) of patients. Resistance to at least H or R (PDR-TB) and multidrug-resistance (MDR-TB) were found in 69/326 (21.2%) and 68/326 (20.9%) of strains, respectively. Three MDR-TB strains were also extensively resistant (XDR-TB). During treatment, 3/189 (1.6%) fully susceptible patients at baseline were re-infected with a MDR-TB strain and 2/58 (3.4%) PDR-TB patients became MDR-TB due to resistance amplification. 5/47 (10.6%) MDR- patients became XDR-TB during treatment. Treatment success was observed in 161/189 (85.2%), 54/69 (78.3%) and 22/68 (32.3%) of patients with fully drug susceptible, PDR- and MDR-TB, respectively. Development of ofloxacin resistance was significantly associated with a negative treatment outcome. In Abkhazia, a region with high prevalence of drug resistant TB, the use of individualized MDR-TB treatment regimens resulted in poor treatment outcomes and XDR-TB amplification. Nosocomial transmission of MDR-TB emphasizes the importance of infection control in hospitals.

  20. Discovery of a Novel Dibromoquinoline Compound Exhibiting Potent Antifungal and Antivirulence Activity That Targets Metal Ion Homeostasis.

    Science.gov (United States)

    Mohammad, Haroon; Elghazawy, Nehal H; Eldesouky, Hassan E; Hegazy, Youssef A; Younis, Waleed; Avrimova, Larisa; Hazbun, Tony; Arafa, Reem K; Seleem, Mohamed N

    2018-03-09

    Globally, invasive fungal infections pose a significant challenge to modern human medicine due to the limited number of antifungal drugs and the rise in resistance to current antifungal agents. A vast majority of invasive fungal infections are caused by species of Candida, Cryptococcus, and Aspergillus. Novel antifungal molecules consisting of unexploited chemical scaffolds with a unique mechanism are a pressing need. The present study identifies a dibromoquinoline compound (4b) with broad-spectrum antifungal activity that inhibits the growth of pertinent species of Candida (chiefly C. albicans), Cryptococcus, and Aspergillus at a concentration of as low as 0.5 μg/mL. Furthermore, 4b, at a subinhibitory concentration, interfered with the expression of two key virulence factors (hyphae and biofilm formation) involved in C. albicans pathogenesis. Three yeast deletion strains ( cox17Δ, ssa1Δ, and aft2Δ) related to metal ion homeostasis were found to be highly sensitive to 4b in growth assays, indicating that the compound exerts its antifungal effect through a unique, previously unexploited mechanism. Supplementing the media with either copper or iron ions reversed the strain sensitivity to 4b, further corroborating that the compound targets metal ion homeostasis. 4b's potent antifungal activity was validated in vivo, as the compound enhanced the survival of Caenorhabditis elegans infected with fluconazole-resistant C. albicans. The present study indicates that 4b warrants further investigation as a novel antifungal agent.

  1. Antiretroviral drug resistance: A guide for the southern African clinician

    African Journals Online (AJOL)

    Both private and public sector see a bewildering clinical array of patients taking failing antiretroviral (ARV) regimens. We intend this article to provide a practical guide to help clinicians understand and manage ARV drug resistance in an African context. ARV resistance is a rapidly evolving field, requiring expertise in dealing ...

  2. Towards an understanding of drug resistance in malaria

    DEFF Research Database (Denmark)

    Lemcke, T; Christensen, I T; Jørgensen, Flemming Steen

    1999-01-01

    and structural differences. Based on this analysis the molecular consequences of point mutations known to be involved in drug resistance were discussed. The significance of the most important point mutation causing resistance, S108N, could be explained by the model, whereas the point mutations associated...

  3. Molecular Analysis of Multi-Drug Resistance (MDR) in ...

    African Journals Online (AJOL)

    The recent emergence of multi-drug resistant (MDR) strains of Mycobacterium tuberculosis has become an area of great concern. This occurs as a result of inadequate treatment management of tuberculosis which provides a selective pressure that favours the emergence of resistant mutants with enhanced infectiousness.

  4. Scabies in the age of increasing drug resistance.

    Science.gov (United States)

    Khalil, Samar; Abbas, Ossama; Kibbi, Abdul Ghani; Kurban, Mazen

    2017-11-01

    Scabies is an infestation of the skin by the mite Sarcoptes scabiei. It manifests with pruritic erythematous papules and excoriations, in addition to the pathognomonic burrows. Multiple drugs can be used for treatment, but resistance to conventional therapy is increasing throughout the years. This paper will review the mechanisms of resistance proposed in the literature and some of the potential solutions to this problem.

  5. Scabies in the age of increasing drug resistance

    OpenAIRE

    Khalil, Samar; Abbas, Ossama; Kibbi, Abdul Ghani; Kurban, Mazen

    2017-01-01

    Scabies is an infestation of the skin by the mite Sarcoptes scabiei. It manifests with pruritic erythematous papules and excoriations, in addition to the pathognomonic burrows. Multiple drugs can be used for treatment, but resistance to conventional therapy is increasing throughout the years. This paper will review the mechanisms of resistance proposed in the literature and some of the potential solutions to this problem.

  6. Drug resistant Proteus mirabilis and Proteus vulgaris isolated from ...

    African Journals Online (AJOL)

    Proteus mirabilis and Proteus vulgaris are pathogens often associated with drug resistance traits. They are of public health importance with zoonotic status. They have been globally associated with humans and poultry infections. Multidrug resistant strains of these organisms are routinely isolated from organs samples from ...

  7. Options for modulation of drug resistance in ovarian cancer

    NARCIS (Netherlands)

    Arts, HJG; Van der Zee, AGJ; De Jong, S; De Vries, EGE

    2000-01-01

    The objective of this paper is to present an update of mechanisms responsible for drug resistance in ovarian cancer and the possible therapeutic options to modulate this resistance using literature review with emphasis on data acquired in studies comprising ovarian tumor samples. The classic

  8. Characterization of drug resistant Enterobacter species isolated from ...

    African Journals Online (AJOL)

    Enterobacter species are emerging clinical pathogens and they play important roles in the dissemination of drug resistant traits within the food chain due to their intrinsic abilities for resistance to commonly used antibiotics such as cephalosporins. Two Enterobacter cloacae and one Enterobacter hormaechei characterized in ...

  9. Design, synthesis, and evaluation of novel fluoroquinolone-flavonoid hybrids as potent antibiotics against drug-resistant microorganisms.

    Science.gov (United States)

    Xiao, Zhu-Ping; Wang, Xu-Dong; Wang, Peng-Fei; Zhou, Yin; Zhang, Jing-Wen; Zhang, Lei; Zhou, Jiao; Zhou, Sha-Sha; Ouyang, Hui; Lin, Xiao-Yi; Mustapa, Manzira; Reyinbaike, Asaimuguli; Zhu, Hai-Liang

    2014-06-10

    Based on a rationally conceived pharmacophore model to build a multi-target bacterial topoisomerase inhibitor, twenty-one fluoroquinolone-flavonoid hybrids were synthesized. Some obtained hybrids show excellent antibacterial activity against drug-resistant microorganisms with narigenin-ciprofloxacin being the most active, showing 8, 43, 23 and 88 times better activity than ciprofloxacin against Escherichia coli ATCC 35218, Bacillus subtilis ATCC 6633, Staphylococcus aureus ATCC 25923 and Candida albicans ATCC 90873, respectively. Drug accumulation and DNA supercoiling assays of two active analogues revealed potent inhibition of both the DNA gyrase and efflux pump, confirming the desired dual mode of action. Molecular docking study disclosed that the introduced flavonoid moiety not only provides several additional interactions but also does not disturb the binding mode of the floxacin moiety. Our data also demonstrated that development of antifungals is possible from fluoroquinolones modified at C-7 position. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  10. World Health Organization/HIVResNet drug resistance laboratory strategy

    NARCIS (Netherlands)

    Bertognolio, Silvio; Derdelinckx, Inge; Parker, Monica; Fitzgibbon, Joseph; Fleury, Herve; Peeters, Martin; Schuurman, Rob; Pillay, Deenan; Morris, Lynn; Tanuri, Amilcar; Gershy-Damet, Guy-Michel; Nkengasong, John; Gilks, Charles F.; Sutherland, Donald; Sandstrom, Paul

    2008-01-01

    With rapidly increasing access to antiretroviral drugs globally, HIV drug resistance (HIVDR) has become a significant public health issue, This requires a coordinated and collaborative response from country level to international level to assess the extent of HIVDR and the establishment of efficient

  11. 2017 update of the drug resistance mutations in HIV-1

    NARCIS (Netherlands)

    Wensing, Annemarie M.; Calvez, Vincent; Günthard, Huldrych F.; Johnson, Victoria A.; Paredes, Roger; Pillay, Deenan; Shafer, Robert W.; Richman, Douglas D.

    2016-01-01

    The 2017 edition of the IAS–USA drug resistance mutations list updates the figures last published in November 2015. The mutations listed are those that have been identified by specific criteria for evidence and drugs described. The figures are designed to assist practitioners in identifying key

  12. mtct regimen choice, drug resistance and the treatment of hiv

    African Journals Online (AJOL)

    drug-resistant variants may become selected as long as the drug is administered. There has been some concern that the use of ARV monotherapy for the prevention of MTCT, including ... potential implications for perinatal transmission, the choice of ... transmission rate using this regimen, short-term treatment with dual ...

  13. Incidence microbiological profile and drug resistance pattern of ...

    African Journals Online (AJOL)

    Klebsiella was the most commonest uropathogen found in our study followed by Enterococcus , E.coli and Pseudomonas. E.coli and Pseudomonas showed high rates of drug resistance. Nitrofurantoin and Amikacin was the most effective drugs for majority of the isolates. Hence routine monitoring and screening for ASB in ...

  14. Multidrug-Resistant Candida: Epidemiology, Molecular Mechanisms, and Treatment.

    Science.gov (United States)

    Arendrup, Maiken Cavling; Patterson, Thomas F

    2017-08-15

    Invasive Candida infections remain an important cause of morbidity and mortality, especially in hospitalized and immunocompromised or critically ill patients. A limited number of antifungal agents from only a few drug classes are available to treat patients with these serious infections. Resistance can be either intrinsic or acquired. Resistance mechanisms are not exchanged between Candida; thus, acquired resistance either emerges in response to an antifungal selection pressure in the individual patient or, more rarely, occur due to horizontal transmission of resistant strains between patients. Although multidrug resistance is uncommon, increasing reports of multidrug resistance to the azoles, echinocandins, and polyenes have occurred in several Candida species, most notably Candida glabrata and more recently Candida auris. Drivers are overall antifungal use, subtherapeutic drug levels at sites of infection/colonization, drug sequestration in the biofilm matrix, and, in the setting of outbreaks, suboptimal infection control. Moreover, recent research suggests that DNA mismatch repair gene mutations may facilitate acquisition of resistance mutations in C. glabrata specifically. Diagnosis of antifungal-resistant Candida infections is critical to the successful management of patients with these infections. Reduction of unnecessary use of antifungals via antifungal stewardship is critical to limit multidrug resistance emergence. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  15. Troglitazone reverses the multiple drug resistance phenotype in cancer cells

    Directory of Open Access Journals (Sweden)

    Gerald F Davies

    2009-03-01

    Full Text Available Gerald F Davies1, Bernhard HJ Juurlink2, Troy AA Harkness11Department of Anatomy and Cell Biology, College of Medicine, University of Saskatchewan, Saskatoon, Canada; 2College of Medicine, Alfaisal University, Riyadh, Kingdom of Saudi ArabiaAbstract: A major problem in treating cancer is the development of drug resistance. We previously demonstrated doxorubicin (DOX resistance in K562 human leukemia cells that was associated with upregulation of glyoxalase 1 (GLO-1 and histone H3 expression. The thiazolidinedione troglitazone (TRG downregulated GLO-1 expression and further upregulated histone H3 expression and post-translational modifications in these cells, leading to a regained sensitivity to DOX. Given the pleiotropic effects of epigenetic changes in cancer development, we hypothesized that TRG may downregulate the multiple drug resistance (MDR phenotype in a variety of cancer cells. To test this, MCF7 human breast cancer cells and K562 cells were cultured in the presence of low-dose DOX to establish DOX-resistant cell lines (K562/DOX and MCF7/DOX. The MDR phenotype was confirmed by Western blot analysis of the 170 kDa P-glycoprotein (Pgp drug efflux pump multiple drug resistance protein 1 (MDR-1, and the breast cancer resistance protein (BCRP. TRG markedly decreased expression of both MDR-1 and BCRP in these cells, resulting in sensitivity to DOX. Silencing of MDR-1 expression also sensitized MCF7/DOX cells to DOX. Use of the specific and irreversible peroxisome proliferator-activated receptor gamma (PPARγ inhibitor GW9662 in the nanomolar range not only demonstrated that the action of TRG on MCF/DOX was PPARγ-independent, but indicated that PPARγ may play a role in the MDR phenotype, which is antagonized by TRG. We conclude that TRG is potentially a useful adjunct therapy in chemoresistant cancers. Keywords: chemotherapy, doxorubicin, breast cancer resistance protein-1, multiple drug resistance, multiple drug resistance protein 1

  16. Oncolytic Virotherapy Targeting Lung Cancer Drug Resistance

    Science.gov (United States)

    2013-08-01

    resistant phenotype. Because cisplatin is highly mutagenic, it has an ability to quickly induce genetic changes in cancer cells usually resulting in... Mendelian selection and generation of cells that acquire a permanent resistant phenotype (8). We initially exposed both KLN205 and LLC1 to increasing...multiple epigenetic and genetic changes. Pharmacological reviews 64:706-721. 9. Siegel, R., D. Naishadham, and A. Jemal. 2013. Cancer statistics, 2013

  17. Antifungal susceptibility testing of Candida in the Clinical Laboratory: how to do it, when to do it, and how to interpret it

    Directory of Open Access Journals (Sweden)

    Esther Manso

    2014-06-01

    Full Text Available Significant changes in the management of fungaemia have occurred in the last decade with increased use of fluconazole prophylaxis, of empirical treatment and of echinocandins as first-line agents for documented disease. The emergence of drug resistance in fungal pathogens has a profound impact on human health given limited number of antifungal drugs. Antifungal resistance in Candida may be either intrinsic or acquired and may be encountered in the antifungal drug exposed but also the antifungal drug naïve patient The variation in resistance rates between centers emphasizes that it is essential to have knowledge of the local Candida species distribution and antifungal resistance rates to guide initial therapy for Candida BSI. Moreover, all Candida isolates from blood and normally sterile sites should be identified to the species level. The Clinical and Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing have developed breakpoints and epidemiological cutoff values that are now established for Candida spp. Clinical microbiology laboratories will be employed commercial susceptibility assays, rather than reference broth microdilution methods and comparative studies are particularly important. Vitek 2®, Etest® and Sensititre YeastOne® provided a high degree of essential agreement and comparable sensitivity and specificity to BMD-RPMI for identifying resistance to azole and echinocandins in Candida spp.

  18. Research Highlights: Helping Adolescents Resist Drugs

    National Research Council Canada - National Science Library

    2000-01-01

    Project ALERT departs boldly from prevention models of the 196Os and 197Os, which emphasized informing adolescents about the long-term consequences of drug use or building their decisionmaking skills...

  19. A study on Prevalence of Drug Resistance in Drug Default ...

    African Journals Online (AJOL)

    ), and particularly multidrug-resistant TB (MDR-TB), has become a significant public health problem in a number of countries and an obstacle to effective global TB control. Method: This is a prospective randomized cross sectional study to ...

  20. Challenges of drug resistance in the management of pancreatic cancer.

    LENUS (Irish Health Repository)

    Sheikh, Rizwan

    2012-02-01

    The current treatment of choice for metastatic pancreatic cancer involves single-agent gemcitabine or a combination of gemcitabine with capecitabine or erlotinib (a tyrosine kinase inhibitor). Only 25–30% of patients respond to this treatment and patients who do respond initially ultimately exhibit disease progression. Median survival for pancreatic cancer patients has reached a plateau due to inherent and acquired resistance to these agents. Key molecular factors implicated in this resistance include: deficiencies in drug uptake, alteration of drug targets, activation of DNA repair pathways, resistance to apoptosis and the contribution of the tumor microenvironment. Moreover, for newer agents including tyrosine kinase inhibitors, overexpression of signaling proteins, mutations in kinase domains, activation of alternative pathways, mutations of genes downstream of the target and\\/or amplification of the target represent key challenges for treatment efficacy. Here we will review the contribution of known mechanisms and markers of resistance to key pancreatic cancer drug treatments.

  1. Determination of antifungal susceptibility patterns among the clinical isolates of Candida species

    Directory of Open Access Journals (Sweden)

    Kamiar Zomorodian

    2011-01-01

    Full Text Available Context: Candida species are opportunistic yeasts that cause infections ranging from simple dermatosis to potentially life-threatening fungemia. The emergence of resistance to antifungal drugs has been increased in the past two decades. Aim: the present study we determined to find out the susceptibility profiles of clinical isolates of Candida species against four antifungal drugs, including amphotericin B, ketoconazole, fluconazole and itraconazole. Materials and Methods: Antifungal susceptibility testing of the yeasts was done in accordance with the proposed guidelines for antifungal disk diffusion susceptibility testing of yeasts based on the CLSI document M44-A. Results: A total of 206 yeast isolates were assessed. Among the evaluated Candida species, the highest rates of resistance to ketoconazole were seen in Candida glabrata (16.6% and Candida albicans (3.2%. Susceptibility and intermediate response to fluconazole were seen in 96.6% and 3.4% of the Candida isolates, respectively. A total of 19 (9.2% yeast isolates showed petite phenomenon including 11 C. glabrata, 3 C. albicans, 2 Candida dubliniensis and one isolate of each Candida krusei and Candida parapsilosis. Conclusion: The high number of petite mutation in the isolated yeasts should be seriously considered since it may be one of the reasons of antifungal treatment failure.

  2. Developing artemisinin based drug combinations for the treatment of drug resistant falciparum malaria: A review

    Directory of Open Access Journals (Sweden)

    Olliaro P

    2004-01-01

    Full Text Available The emergence and spread of drug resistant malaria represents a considerable challenge to controlling malaria. To date, malaria control has relied heavily on a comparatively small number of chemically related drugs, belonging to either the quinoline or the antifolate groups. Only recently have the artemisinin derivatives been used but mostly in south east Asia. Experience has shown that resistance eventually curtails the life-span of antimalarial drugs. Controlling resistance is key to ensuring that the investment put into developing new antimalarial drugs is not wasted. Current efforts focus on research into new compounds with novel mechanisms of action, and on measures to prevent or delay resistance when drugs are introduced. Drug discovery and development are long, risky and costly ventures. Antimalarial drug development has traditionally been slow but now various private and public institutions are at work to discover and develop new compounds. Today, the antimalarial development pipeline is looking reasonably healthy. Most development relies on the quinoline, antifolate and artemisinin compounds. There is a pressing need to have effective, easy to use, affordable drugs that will last a long time. Drug combinations that have independent modes of action are seen as a way of enhancing efficacy while ensuring mutual protection against resistance. Most research work has focused on the use of artesunate combined with currently used standard drugs, namely, mefloquine, amodiaquine, sulfadoxine/pyrimethamine, and chloroquine. There is clear evidence that combinations improve efficacy without increasing toxicity. However, the absolute cure rates that are achieved by combinations vary widely and depend on the level of resistance of the standard drug. From these studies, further work is underway to produce fixed dose combinations that will be packaged in blister packs. This review will summarise current antimalarial drug developments and outline recent

  3. The role of drug susceptibility testing in controlling drug resistant tuberculosis: Challenges and possibilities

    Directory of Open Access Journals (Sweden)

    Sven Hoffner

    2015-01-01

    Conclusions: Reliable and timely detection of drug-resistant TB is needed, which is best achieved with molecular assays. In this author's opinion, rapid detection of resistance to isoniazid should be included with rifampicin resistance examination. In MDR, timely detection of the XDR defining agents and PZA is urgently needed. Development and validation of such tests should be a priority, as well as establishing QMS for the implementation and routine use of molecular rapid diagnostics. Each country should develop national diagnostic algorithms for how, when and where rapid molecular assays should be used for early detection of drug-resistant TB.

  4. AMDD: Antimicrobial Drug Database

    OpenAIRE

    Danishuddin, Mohd; Kaushal, Lalima; Hassan Baig, Mohd; Khan, Asad U.

    2012-01-01

    Drug resistance is one of the major concerns for antimicrobial chemotherapy against any particular target. Knowledge of the primary structure of antimicrobial agents and their activities is essential for rational drug design. Thus, we developed a comprehensive database, anti microbial drug database (AMDD), of known synthetic antibacterial and antifungal compounds that were extracted from the available literature and other chemical databases, e.g., PubChem, PubChem BioAssay and ZINC, etc. The ...

  5. ‘A‘ole Drugs! Cultural Practices and Drug Resistance of Rural Hawaiian Youth

    Science.gov (United States)

    PO‘A-KEKUAWELA, KA‘OHINANI; OKAMOTO, SCOTT K.; NEBRE, LA RISA H.; HELM, SUSANA; CHIN, CORALEE I. H.

    2009-01-01

    This qualitative study examined how Native Hawaiian youth from rural communities utilized cultural practices to promote drug resistance and/or abstinence. Forty-seven students from 5 different middle schools participated in gender specific focus groups that focused on the cultural and environmental contexts of drug use for Native Hawaiian youth. The findings described culturally specific activities that participants used in drug related problem situations. The findings also suggested that those youth with higher levels of enculturation were able to resist drugs more effectively than those youth who were disconnected from their culture. The implications of these findings for social work practice are discussed. PMID:20352019

  6. Transgenic expression of gallerimycin, a novel antifungal insect defensin from the greater wax moth Galleria mellonella, confers resistance to pathogenic fungi in tobacco.

    Science.gov (United States)

    Langen, Gregor; Imani, Jafargholi; Altincicek, Boran; Kieseritzky, Gernot; Kogel, Karl-Heinz; Vilcinskas, Andreas

    2006-05-01

    A cDNA encoding gallerimycin, a novel antifungal peptide from the greater wax moth Galleria mellonella, was isolated from a cDNA library of genes expressed during innate immune response in the caterpillars. Upon ectopic expression of gallerimycin in tobacco, using Agrobacterium tumefaciens as a vector, gallerimycin conferred resistance to the fungal pathogens Erysiphe cichoracearum and Sclerotinia minor. Quantification of gallerimycin mRNA in transgenic tobacco by real-time PCR confirmed transgenic expression under control of the inducible mannopine synthase promoter. Leaf sap and intercellular washing fluid from transgenic tobacco inhibited in vitro germination and growth of the fungal pathogens, demonstrating that gallerimycin is secreted into intercellular spaces. The feasibility of the use of gallerimycin to counteract fungal diseases in crop plants is discussed.

  7. Establishing Drug Resistance in Microorganisms by Mass Spectrometry

    Science.gov (United States)

    Demirev, Plamen A.; Hagan, Nathan S.; Antoine, Miquel D.; Lin, Jeffrey S.; Feldman, Andrew B.

    2013-08-01

    A rapid method to determine drug resistance in bacteria based on mass spectrometry is presented. In it, a mass spectrum of an intact microorganism grown in drug-containing stable isotope-labeled media is compared with a mass spectrum of the intact microorganism grown in non-labeled media without the drug present. Drug resistance is determined by predicting characteristic mass shifts of one or more microorganism biomarkers using bioinformatics algorithms. Observing such characteristic mass shifts indicates that the microorganism is viable even in the presence of the drug, thus incorporating the isotopic label into characteristic biomarker molecules. The performance of the method is illustrated on the example of intact E. coli, grown in control (unlabeled) and 13C-labeled media, and analyzed by MALDI TOF MS. Algorithms for data analysis are presented as well.

  8. Efflux Pump-mediated Drug Resistance in Burkholderia

    Directory of Open Access Journals (Sweden)

    Nicole L Podnecky

    2015-04-01

    Full Text Available Several members of the genus Burkholderia are prominent pathogens. Infections caused by these bacteria are difficult to treat because of significant antibiotic resistance. Virtually all Burkholderia species are also resistant to polymyxin, prohibiting use of drugs like colistin that are available for treatment of infections caused by most other drug resistant Gram-negative bacteria. Despite clinical significance and antibiotic resistance of Burkholderia species, characterization of efflux pumps lags behind other non-enteric Gram-negative pathogens such as Acinetobacter baumannii and Pseudomonas aeruginosa. Although efflux pumps have been described in several Burkholderia species, they have been best studied in B. cenocepacia and B. pseudomallei. As in other non-enteric Gram-negatives, efflux pumps of the resistance nodulation cell division (RND family are the clinically most significant efflux systems in these two species. Several efflux pumps were described in B. cenocepacia, which when expressed confer resistance to clinically significant antibiotics, including aminoglycosides, chloramphenicol, fluoroquinolones, and tetracyclines. Three RND pumps have been characterized in B. pseudomallei, two of which confer either intrinsic or acquired resistance to aminoglycosides, macrolides, chloramphenicol, fluoroquinolones, tetracyclines, trimethoprim, and in some instances trimethoprim+sulfamethoxazole. Several strains of the host-adapted B. mallei, a clone of B. pseudomallei, lack AmrAB-OprA and are therefore aminoglycoside and macrolide susceptible. B. thailandensis is closely related to B. pseudomallei, but non-pathogenic to humans. Its pump repertoire and ensuing drug resistance profile parallels that of B. pseudomallei. An efflux pump in B. vietnamiensis plays a significant role in acquired aminoglycoside resistance. Summarily, efflux pumps are significant players in Burkholderia drug resistance.

  9. Drug efflux proteins in multidrug resistant bacteria

    NARCIS (Netherlands)

    vanVeen, HW; Konings, WN

    Bacteria contain an array of transport proteins in their cytoplasmic membrane. Many of these proteins play an important role in conferring resistance to toxic compounds. The multidrug efflux systems encountered in prokaryotic cells are very similar to those observed in eukaryotic cells. Therefore, a

  10. characterization of drug resistant pseudomonas aeruginosa and ...

    African Journals Online (AJOL)

    their dissemination to the public, sometimes through the food chain. Four multidrug resistant Gram negative pathogens including: 2 Pseudomonas aeruginosa and 2 Proteus mirabilis characterized in this study were isolated from lizards captured from some poultry houses in Ibadan Oyo State, Nigeria. The four isolates were ...

  11. Insulin resistance induced by antiretroviral drugs: Current ...

    African Journals Online (AJOL)

    Treatment with highly active antiretroviral therapy (HAART) has improved the prognosis of patients with AIDS, but it has also increased the incidence of various metabolic disorders, in particular insulin resistance accompanied by dyslipidaemia, hyperglycaemia and lipodystrophy. This is often accompanied by frank type 2 ...

  12. Will Drug Resistance against Dolutegravir in Initial Therapy Ever Occur?

    Directory of Open Access Journals (Sweden)

    Mark eWainberg

    2015-04-01

    Full Text Available Dolutegravir (DTG is a second-generation integrase strand transfer inhibitor (INSTI and INSTIs are the latest class of potent anti-HIV drugs. Compared to the first generation INSTIs, raltegravir (RAL and elvitegravir (EVG, DTG shows a limited cross-resistance profile. More interestingly, clinical resistance mutations to DTG in treatment-naive patents have not been observed to this date. This review summarizes recent studies on resistance mutations to DTG and on our understanding of the mechanisms of resistance to DTG as well as future directions for research.

  13. Partner-Drug Resistance and Population Substructuring of Artemisinin-Resistant Plasmodium falciparum in Cambodia.

    Science.gov (United States)

    Parobek, Christian M; Parr, Jonathan B; Brazeau, Nicholas F; Lon, Chanthap; Chaorattanakawee, Suwanna; Gosi, Panita; Barnett, Eric J; Norris, Lauren D; Meshnick, Steven R; Spring, Michele D; Lanteri, Charlotte A; Bailey, Jeffrey A; Saunders, David L; Lin, Jessica T; Juliano, Jonathan J

    2017-06-01

    Plasmodium falciparum in western Cambodia has developed resistance to artemisinin and its partner drugs, causing frequent treatment failure. Understanding this evolution can inform the deployment of new therapies. We investigated the genetic architecture of 78 falciparum isolates using whole-genome sequencing, correlating results to in vivo and ex vivo drug resistance and exploring the relationship between population structure, demographic history, and partner drug resistance. Principle component analysis, network analysis and demographic inference identified a diverse central population with three clusters of clonally expanding parasite populations, each associated with specific K13 artemisinin resistance alleles and partner drug resistance profiles which were consistent with the sequential deployment of artemisinin combination therapies in the region. One cluster displayed ex vivo piperaquine resistance and mefloquine sensitivity with a high rate of in vivo failure of dihydroartemisinin-piperaquine. Another cluster displayed ex vivo mefloquine resistance and piperaquine sensitivity with high in vivo efficacy of dihydroartemisinin-piperaquine. The final cluster was clonal and displayed intermediate sensitivity to both drugs. Variations in recently described piperaquine resistance markers did not explain the difference in mean IC90 or clinical failures between the high and intermediate piperaquine resistance groups, suggesting additional loci may be involved in resistance. The results highlight an important role for partner drug resistance in shaping the P. falciparum genetic landscape in Southeast Asia and suggest that further work is needed to evaluate for other mutations that drive piperaquine resistance. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  14. mycobacterium tuberculosis genetic diversity and drug resistance ...

    African Journals Online (AJOL)

    2011-12-12

    Dec 12, 2011 ... (17) at the TB reference laboratory in Kinshasa. Standard phenotypic drug susceptibility testing. (DST) for isoniazid and rifampicin were performed by proportion method according to international guidelines (17). Molecular investigations: DNA was extracted from subcultures according to standard laboratory.

  15. Nationwide surveillance of drug-resistant tuberculosis in The Netherlands: rates, risk factors and treatment outcome

    NARCIS (Netherlands)

    Lambregts-van Weezenbeek, C. S.; Jansen, H. M.; Nagelkerke, N. J.; van Klingeren, B.; Veen, J.

    1998-01-01

    The Netherlands, 1993 and 1994. To determine 1) rates of drug resistance in relation to nationality and country of birth, 2) risk factors for drug resistance, 3) treatment outcome of drug-resistant cases, and 4) rates of primary and acquired drug resistance. Retrospective study of all cases notified

  16. Nanoparticles: Alternatives Against Drug-Resistant Pathogenic Microbes

    Directory of Open Access Journals (Sweden)

    Gudepalya Renukaiah Rudramurthy

    2016-06-01

    Full Text Available Antimicrobial substances may be synthetic, semisynthetic, or of natural origin (i.e., from plants and animals. Antimicrobials are considered “miracle drugs” and can determine if an infected patient/animal recovers or dies. However, the misuse of antimicrobials has led to the development of multi-drug-resistant bacteria, which is one of the greatest challenges for healthcare practitioners and is a significant global threat. The major concern with the development of antimicrobial resistance is the spread of resistant organisms. The replacement of conventional antimicrobials by new technology to counteract antimicrobial resistance is ongoing. Nanotechnology-driven innovations provide hope for patients and practitioners in overcoming the problem of drug resistance. Nanomaterials have tremendous potential in both the medical and veterinary fields. Several nanostructures comprising metallic particles have been developed to counteract microbial pathogens. The effectiveness of nanoparticles (NPs depends on the interaction between the microorganism and the NPs. The development of effective nanomaterials requires in-depth knowledge of the physicochemical properties of NPs and the biological aspects of microorganisms. However, the risks associated with using NPs in healthcare need to be addressed. The present review highlights the antimicrobial effects of various nanomaterials and their potential advantages, drawbacks, or side effects. In addition, this comprehensive information may be useful in the discovery of broad-spectrum antimicrobial drugs for use against multi-drug-resistant microbial pathogens in the near future.

  17. Initial resistance to antituberculosis drugs in Yaounde, Cameroon in 1995.

    Science.gov (United States)

    Bercion, R; Kuaban, C

    1997-04-01

    Tuberculosis centre of Hôpital Jamot, Yaounde, Cameroon, the sole referral and tuberculosis treatment facility for Yaounde and its surroundings. To identify Mycobacterium tuberculosis complex strains responsible for pulmonary tuberculosis in Yaounde, determine the prevalence of initial resistance to the main antituberculosis drugs and compare this prevalence in human immunodeficiency virus (HIV) positive and HIV-negative patients. In total, 576 consecutive and previously untreated adult patients admitted with sputum smear positive pulmonary tuberculosis to the tuberculosis centre from July 1994 to December 1995 were included in the study. Sputum specimens collected from each eligible patient were cultured on Löwenstein-Jensen and Coletsos media. Identification of the cultured strains was based on their cultural aspects and standard biochemical tests. The susceptibility of isolates to the major antituberculosis drugs was tested using the indirect proportion method. HIV testing was done using two ELISAs and confirmed by Western blot. Growth of M. tuberculosis complex strains was obtained from specimens of 516 (89.6%) of the 576 patients: 53 (10.3%) were identified as M. africanum and 463 (89.7%) as M. tuberculosis. Of the 516 patients with culture positive specimens, 92 (17.8%) were HIV-positive. Of the 516 strains isolated, 164 (31.8%) were resistant to at least one drug. The pattern of resistance was noted as 25% to one drug, 5.8% to two drugs and 1% to three or more drugs. Initial resistance to streptomycine was the most frequent (20.5%), followed by isoniazid (12.4%), thiacetazone (5.6%), rifampicin (0.8%) and ethambutol (0.4%). No significant difference in the rate of initial resistance was observed between HIV-positive and HIV-negative patients. The rate of initial drug resistance of M. tuberculosis in Yaounde is relatively high. There is therefore an urgent need to reestablish a tuberculosis control programme in Cameroon.

  18. Molecular characterisation of drug-resistant Plasmodium falciparum from Thailand

    Directory of Open Access Journals (Sweden)

    Gil José

    2002-10-01

    Full Text Available Abstract Background The increasing levels of Plasmodium falciparum resistance to chloroquine (CQ in Thailand have led to the use of alternative antimalarials, which are at present also becoming ineffective. In this context, any strategies that help improve the surveillance of drug resistance, become crucial in overcoming the problem. Methods In the present study, we have established the in vitro sensitivity to CQ, mefloquine (MF, quinine (QUIN and amodiaquine (AMQ of 52 P. falciparum isolates collected in Thailand, and assessed the prevalence of four putative genetic polymorphisms of drug resistance, pfcrt K76T, pfmdr1 N86Y, pfmdr1 D1042N and pfmdr1 Y1246D, by PCR-RFLP. Results The percentage of isolates resistant to CQ, MF, and AMQ was 96% (50/52, 62% (32/52, and 58% (18/31, respectively, while all parasites were found to be sensitive to QUIN. In addition, 41 (79% of the isolates assayed were resistant simultaneously to more than one drug; 25 to CQ and MF, 9 to CQ and AMQ, and 7 to all three drugs, CQ, MF and AMQ. There were two significant associations between drug sensitivity and presence of particular molecular markers, i CQ resistance / pfcrt 76T (P = 0.001, and ii MF resistance / pfmdr1 86N (P Conclusions i In Thailand, the high levels of CQ pressure have led to strong selection of the pfcrt 76T polymorphism and ii pfmdr1 86N appears to be a good predictor of in vitro MF resistance.

  19. Spread of anti-malarial drug resistance: Mathematical model with implications for ACT drug policies

    Directory of Open Access Journals (Sweden)

    Dondorp Arjen M

    2008-11-01

    Full Text Available Abstract Background Most malaria-endemic countries are implementing a change in anti-malarial drug policy to artemisinin-based combination therapy (ACT. The impact of different drug choices and implementation strategies is uncertain. Data from many epidemiological studies in different levels of malaria endemicity and in areas with the highest prevalence of drug resistance like borders of Thailand are certainly valuable. Formulating an appropriate dynamic data-driven model is a powerful predictive tool for exploring the impact of these strategies quantitatively. Methods A comprehensive model was constructed incorporating important epidemiological and biological factors of human, mosquito, parasite and treatment. The iterative process of developing the model, identifying data needed, and parameterization has been taken to strongly link the model to the empirical evidence. The model provides quantitative measures of outcomes, such as malaria prevalence/incidence and treatment failure, and illustrates the spread of resistance in low and high transmission settings. The model was used to evaluate different anti-malarial policy options focusing on ACT deployment. Results The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and treatment failure is the main force driving the spread of drug resistance. In low transmission settings, ACT slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. In the high transmission settings, however, drug resistance is driven by the proportion of the human population with a residual drug level, which gives resistant parasites some survival advantage. The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with

  20. The role of photodynamic therapy in overcoming cancer drug resistance

    Science.gov (United States)

    Spring, Bryan Q.; Rizvi, Imran; Xu, Nan; Hasan, Tayyaba

    2015-01-01

    Many modalities of cancer therapy induce mechanisms of treatment resistance and escape pathways during chronic treatments, including photodynamic therapy (PDT). It is conceivable that resistance induced by one treatment might be overcome by another treatment. Emerging evidence suggests that the unique mechanisms of tumor cell and microenvironment damage produced by PDT could be utilized to overcome cancer drug resistance, to mitigate the compensatory induction of survival pathways and even to re-sensitize resistant cells to standard therapies. Approaches that capture the unique features of PDT, therefore, offer promising factors for increasing the efficacy of a broad range of therapeutic modalities. Here, we highlight key preclinical findings utilizing PDT to overcome classical drug resistance or escape pathways and thus enhance the efficacy of many pharmaceuticals, possibly explaining the clinical observations of the PDT response to otherwise treatment-resistant diseases. With the development of nanotechnology, it is possible that light activation may be used not only to damage and sensitize tumors but also to enable controlled drug release to inhibit escape pathways that may lead to resistance or cell proliferation. PMID:25856800

  1. Posaconazole exhibits in vitro and in vivo synergistic antifungal activity with caspofungin or FK506 against Candida albicans.

    Directory of Open Access Journals (Sweden)

    Ying-Lien Chen

    Full Text Available The object of this study was to test whether posaconazole, a broad-spectrum antifungal agent inhibiting ergosterol biosynthesis, exhibits synergy with the β-1,3 glucan synthase inhibitor caspofungin or the calcineurin inhibitor FK506 against the human fungal pathogen Candida albicans. Although current drug treatments for Candida infection are often efficacious, the available antifungal armamentarium may not be keeping pace with the increasing incidence of drug resistant strains. The development of drug combinations or novel antifungal drugs to address emerging drug resistance is therefore of general importance. Combination drug therapies are employed to treat patients with HIV, cancer, or tuberculosis, and has considerable promise in the treatment of fungal infections like cryptococcal meningitis and C. albicans infections. Our studies reported here demonstrate that posaconazole exhibits in vitro synergy with caspofungin or FK506 against drug susceptible or resistant C. albicans strains. Furthermore, these combinations also show in vivo synergy against C. albicans strain SC5314 and its derived echinocandin-resistant mutants, which harbor an S645Y mutation in the CaFks1 β-1,3 glucan synthase drug target, suggesting potential therapeutic applicability for these combinations in the future.

  2. Antifungal effects of Allium ascalonicum, Marticaria chamomilla and Stachys lavandulifolia extracts on Candida albicans

    Directory of Open Access Journals (Sweden)

    Moghim Hassan

    2014-01-01

    Full Text Available Introduction: Due to increased risk for opportunistic fungal infections and increasing prevalence of hospital infections caused by pathogenic yeasts and fungus resistance to antifungal drugs, discovery of antifungal compounds with high efficiency is necessary. This study was aimed to evaluate and compare the antifungal activities of Allium ascalonicum, Marticaria chamomilla and Stachys lavandulifolia on Candida albians. Methods: In this study the plants extracts were prepared with macerated method using ethanol 70%. Antifungal activities of the extracts were performed according to microbroth dilution method in 96 well microdilution plates. The amount of Minimum Inhibitory Concentration (MIC and Minimum Fungicidal Concentration (MFC based on counting the number of fungal colonies (CFU were evaluated for each of Allium ascalonicum, Chamomile and Stachys lavandulifolia extracts compared with the control group. Results: MIC of Allium ascalonicum, Marticaria chamomilla and Stachys lavandulifolia were respectively 0.31, 3.75 and 15.13 mg/ml and also MIC50% of Allium ascalonicum, Marticaria chamomilla and Stachys lavandulifolia were respectively 0.93, 10.59 and 41.32 mg/ml and MIC 90% of them were respectively 8.65, 16.88 and 60.55 mg/ml and their MFC were respectively 20, 20 and 65 mg/ml. Conclusion: The results indicate that all three extracts are effective, but Allium ascalonicum possesses the highest antifungal activity on Candida albicans. If clinical trials approve these findings, this plant may represent a new source of antifungal agent for control of Candida albicans.

  3. Enhanced transmission of drug-resistant parasites to mosquitoes following drug treatment in rodent malaria.

    Directory of Open Access Journals (Sweden)

    Andrew S Bell

    Full Text Available The evolution of drug resistant Plasmodium parasites is a major challenge to effective malaria control. In theory, competitive interactions between sensitive parasites and resistant parasites within infections are a major determinant of the rate at which parasite evolution undermines drug efficacy. Competitive suppression of resistant parasites in untreated hosts slows the spread of resistance; competitive release following treatment enhances it. Here we report that for the murine model Plasmodium chabaudi, co-infection with drug-sensitive parasites can prevent the transmission of initially rare resistant parasites to mosquitoes. Removal of drug-sensitive parasites following chemotherapy enabled resistant parasites to transmit to mosquitoes as successfully as sensitive parasites in the absence of treatment. We also show that the genetic composition of gametocyte populations in host venous blood accurately reflects the genetic composition of gametocytes taken up by mosquitoes. Our data demonstrate that, at least for this mouse model, aggressive chemotherapy leads to very effective transmission of highly resistant parasites that are present in an infection, the very parasites which undermine the long term efficacy of front-line drugs.

  4. An investigation of classification algorithms for predicting HIV drug resistance without genotype resistance testing

    CSIR Research Space (South Africa)

    Brandt, P

    2014-01-01

    Full Text Available is limited in low-resource settings. In this paper we investigate machine learning techniques for drug resistance prediction from routine treatment and laboratory data to help clinicians select patients for confirmatory genotype testing. The techniques...

  5. Suppressive drug combinations and their potential to combat antibiotic resistance.

    Science.gov (United States)

    Singh, Nina; Yeh, Pamela J

    2017-11-01

    Antibiotic effectiveness often changes when two or more such drugs are administered simultaneously and unearthing antibiotic combinations with enhanced efficacy (synergy) has been a longstanding clinical goal. However, antibiotic resistance, which undermines individual drugs, threatens such combined treatments. Remarkably, it has emerged that antibiotic combinations whose combined effect is lower than that of at least one of the individual drugs can slow or even reverse the evolution of resistance. We synthesize and review studies of such so-called 'suppressive interactions' in the literature. We examine why these interactions have been largely disregarded in the past, the strategies used to identify them, their mechanistic basis, demonstrations of their potential to reverse the evolution of resistance and arguments for and against using them in clinical treatment. We suggest future directions for research on these interactions, aiming to expand the basic body of knowledge on suppression and to determine the applicability of suppressive interactions in the clinic.

  6. "A'ole" Drugs! Cultural Practices and Drug Resistance of Rural Hawai'ian Youths

    Science.gov (United States)

    Po'A-Kekuawela, Ka'Ohinani; Okamoto, Scott K.; Nebre, La Risa H.; Helm, Susana; Chin, Coralee I. H.

    2009-01-01

    This qualitative study examined how Native Hawai'ian youths from rural communities utilized cultural practices to promote drug resistance and/or abstinence. Forty-seven students from five different middle schools participated in gender-specific focus groups that focused on the cultural and environmental contexts of drug use for Native Hawai'ian…

  7. Breast Cancer-Targeted Nuclear Drug Delivery Overcoming Drug Resistance for Breast Cancer Chemotherapy

    Science.gov (United States)

    2010-09-01

    Biotransformation of curcumin through reduction and glucuronidation in mice. Drug  Metab. Dispos. 27, 486–494 (1999). 46 Ireson C, Orr S, Jones DJL et...factor receptor (EGFR), and estrogen receptor (ER) [1,10,12]. Curcumin was also found to down-regulate multi- drug resistance proteins (MDR) and P

  8. Epigenetic Modulation of the Biophysical Properties of Drug-Resistant Cell Lipids to Restore Drug Transport and Endocytic Functions

    OpenAIRE

    Vijayaraghavalu, Sivakumar; Peetla, Chiranjeevi; Lu, Shan; Labhasetwar, Vinod

    2012-01-01

    In our recent studies exploring the biophysical characteristics of resistant cell lipids, and the role they play in drug transport, we demonstrated the difference of drug-resistant breast cancer cells from drug-sensitive cells in lipid composition and biophysical properties, suggesting that cancer cells acquire a drug-resistant phenotype through the alteration of lipid synthesis to inhibit intracellular drug transport to protect from cytotoxic effect. In cancer cells, epigenetic changes (e.g....

  9. RESISTANCE TO ANTIPLATELET DRUGS IN PATIENTS WITH ISCHEMIC HEART DISEASE

    Directory of Open Access Journals (Sweden)

    D. H. Aynetdinova

    2007-01-01

    Full Text Available The clinical, cell and genetic factors are distinguished among reasons for resistance to antiplatelet drugs. There are many methods to detect sensitivity to antiplatelet drugs, but they all have disadvantages. Moreover, there is no unified approach for interpretation of received results, and no recommendations for their practical use. It is necessary to work out unified procedure to assess platelet function, to define indications for its usage and to work out unified criteria of resistance. Individualized approach and each patient’s peculiarities consideration are essential when prescribing antiplatelet therapy.

  10. Extensively drug-resistant tuberculosis (XDR-TB) in Morocco.

    Science.gov (United States)

    Ennassiri, Wifak; Jaouhari, Sanae; Cherki, Wafa; Charof, Reda; Filali-Maltouf, Abdelkarim; Lahlou, Ouafae

    2017-12-01

    Extensively drug-resistant tuberculosis (XDR-TB) has recently been identified as a major global health threat. The aim of this study was to evaluate the presence of XDR-TB among Mycobacterium tuberculosis isolates in Morocco and its association with demographic, clinical and epidemiological features. A total of 524 patients from the Moroccan National Tuberculosis Reference Laboratory, representative of all of the geographic regions, were subject to first-line drug susceptibility testing (DST). Subsequently, 155 isolates found to be multidrug-resistant tuberculosis (MDR-TB) underwent second-line DST. Moreover, to enhance our understanding of the genetic basis of these drug-resistant strains, drug resistance-associated mutations were investigated in isolates either identified as pre-XDR- and XDR-TB or suspected resistant using the GenoType ® MTBDRsl V1.0 assay. In this study, 4 (2.6%) XDR-TB and 18 (11.6%) pre-XDR-TB isolates were identified. Agreement between the MTBDRsl assay results and phenotypic DST was 95.2% for ofloxacin, 81.0% for kanamycin and 95.2% for amikacin. To the best of our knowledge, this is the first study to evaluate the frequency of XDR-TB in Morocco. These results highlight the need to reinforce the TB management policy in Morocco with regard to control and detection strategies in order to prevent further spread of XDR-TB isolates. Copyright © 2017. Published by Elsevier Ltd.

  11. Scabies in the age of increasing drug resistance

    Science.gov (United States)

    Khalil, Samar; Abbas, Ossama; Kibbi, Abdul Ghani; Kurban, Mazen

    2017-01-01

    Scabies is an infestation of the skin by the mite Sarcoptes scabiei. It manifests with pruritic erythematous papules and excoriations, in addition to the pathognomonic burrows. Multiple drugs can be used for treatment, but resistance to conventional therapy is increasing throughout the years. This paper will review the mechanisms of resistance proposed in the literature and some of the potential solutions to this problem. PMID:29190303

  12. Scabies in the age of increasing drug resistance.

    Directory of Open Access Journals (Sweden)

    Samar Khalil

    2017-11-01

    Full Text Available Scabies is an infestation of the skin by the mite Sarcoptes scabiei. It manifests with pruritic erythematous papules and excoriations, in addition to the pathognomonic burrows. Multiple drugs can be used for treatment, but resistance to conventional therapy is increasing throughout the years. This paper will review the mechanisms of resistance proposed in the literature and some of the potential solutions to this problem.

  13. Skin conditions: emerging drug-resistant skin infections and infestations.

    Science.gov (United States)

    Zuniga, Ramiro; Nguyen, Tam

    2013-04-01

    Methicillin-resistant Staphylococcus aureus (MRSA) skin infections are increasingly common. Automated microbiology systems are now available to detect MRSA and to determine antibiotic resistance patterns. Abscesses should be drained and antibiotics administered, with systemic antibiotics used to manage more severe infections. Until sensitivities are known and depending on local resistance rates, clindamycin is an option for empiric management of stable patients without bacteremia. For patients who are more ill, linezolid and vancomycin are alternatives, the latter being first-line treatment for children hospitalized with MRSA skin infections. Drug resistance also occurs in head lice management. Although topical permethrin is still the first-line drug management, its effectiveness has decreased due to permethrin-resistant strains. Patients who do not benefit from 2 applications of permethrin can be treated with topical malathion or topical ivermectin. Though not approved by the Food and Drug Administration (FDA) for treating head lice, oral ivermectin is sometimes used for difficult-to-treat cases. Permethrin is also the first-line management for scabies, though there is a concern that permethrin-resistant scabies may soon occur. For patients with scabies who do not benefit from topical treatment, oral ivermectin is recommended by the Centers for Disease Control and Prevention, although it is not approved by the FDA for this purpose. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.

  14. Melanins Protect Sporothrix brasiliensis and Sporothrix schenckii from the Antifungal Effects of Terbinafine.

    Directory of Open Access Journals (Sweden)

    Rodrigo Almeida-Paes

    Full Text Available Terbinafine is a recommended therapeutic alternative for patients with sporotrichosis who cannot use itraconazole due to drug interactions or side effects. Melanins are involved in resistance to antifungal drugs and Sporothrix species produce three different types of melanin. Therefore, in this study we evaluated whether Sporothrix melanins impact the efficacy of antifungal drugs. Minimal inhibitory concentrations (MIC and minimal fungicidal concentrations (MFC of two Sporothrix brasiliensis and four Sporothrix schenckii strains grown in the presence of the melanin precursors L-DOPA and L-tyrosine were similar to the MIC determined by the CLSI standard protocol for S. schenckii susceptibility to amphotericin B, ketoconazole, itraconazole or terbinafine. When MICs were determined in the presence of inhibitors to three pathways of melanin synthesis, we observed, in four strains, an increase in terbinafine susceptibility in the presence of tricyclazole, a DHN-melanin inhibitor. In addition, one S. schenckii strain grown in the presence of L-DOPA had a higher MFC value when compared to the control. Growth curves in presence of 2×MIC concentrations of terbinafine showed that pyomelanin and, to a lesser extent, eumelanin were able to protect the fungi against the fungicidal effect of this antifungal drug. Our results suggest that melanin protects the major pathogenic species of the Sporothrix complex from the effects of terbinafine and that the development of new antifungal drugs targeting melanin synthesis may improve sporotrichosis therapies.

  15. Melanins Protect Sporothrix brasiliensis and Sporothrix schenckii from the Antifungal Effects of Terbinafine.

    Science.gov (United States)

    Almeida-Paes, Rodrigo; Figueiredo-Carvalho, Maria Helena Galdino; Brito-Santos, Fábio; Almeida-Silva, Fernando; Oliveira, Manoel Marques Evangelista; Zancopé-Oliveira, Rosely Maria

    2016-01-01

    Terbinafine is a recommended therapeutic alternative for patients with sporotrichosis who cannot use itraconazole due to drug interactions or side effects. Melanins are involved in resistance to antifungal drugs and Sporothrix species produce three different types of melanin. Therefore, in this study we evaluated whether Sporothrix melanins impact the efficacy of antifungal drugs. Minimal inhibitory concentrations (MIC) and minimal fungicidal concentrations (MFC) of two Sporothrix brasiliensis and four Sporothrix schenckii strains grown in the presence of the melanin precursors L-DOPA and L-tyrosine were similar to the MIC determined by the CLSI standard protocol for S. schenckii susceptibility to amphotericin B, ketoconazole, itraconazole or terbinafine. When MICs were determined in the presence of inhibitors to three pathways of melanin synthesis, we observed, in four strains, an increase in terbinafine susceptibility in the presence of tricyclazole, a DHN-melanin inhibitor. In addition, one S. schenckii strain grown in the presence of L-DOPA had a higher MFC value when compared to the control. Growth curves in presence of 2×MIC concentrations of terbinafine showed that pyomelanin and, to a lesser extent, eumelanin were able to protect the fungi against the fungicidal effect of this antifungal drug. Our results suggest that melanin protects the major pathogenic species of the Sporothrix complex from the effects of terbinafine and that the development of new antifungal drugs targeting melanin synthesis may improve sporotrichosis therapies.

  16. Metabolism and resistance of Fusarium spp. to the manzamine alkaloids via a putative retro pictet-spengler reaction and utility of the rational design of antimalarial and antifungal agents.

    Science.gov (United States)

    Kasanah, Noer; Farr, Lorelei Lucas; Gholipour, Abbas; Wedge, David E; Hamann, Mark T

    2014-08-01

    As a part of our continuing investigation of the manzamine alkaloids we studied the in vitro activity of the β-carboline containing manzamine alkaloids against Fusarium solani, Fusarium oxysporium, and Fusarium proliferatum by employing several bioassay techniques including one-dimensional direct bioautography, dilution, and plate susceptibility, and microtiter broth assays. In addition, we also studied the metabolism of the manzamine alkaloids by Fusarium spp. in order to facilitate the redesign of the compounds to prevent resistance of Fusarium spp. through metabolism. The present research reveals that the manzamine alkaloids are inactive against Fusarium spp. and the fungi transform manzamines via hydrolysis, reduction, and a retro Pictet-Spengler reaction. This is the first report to demonstrate an enzymatically retro Pictet-Spengler reaction. The results of this study reveal the utility of the rational design of metabolically stable antifungal agents from this class and the development of manzamine alkaloids as antimalarial drugs through the utilization of Fusarium's metabolic products to reconstruct the molecule.

  17. A Hybrid Drug Limits Resistance by Evading the Action of the Multiple Antibiotic Resistance Pathway.

    Science.gov (United States)

    Wang, Kathy K; Stone, Laura K; Lieberman, Tami D; Shavit, Michal; Baasov, Timor; Kishony, Roy

    2016-02-01

    Hybrid drugs are a promising strategy to address the growing problem of drug resistance, but the mechanism by which they modulate the evolution of resistance is poorly understood. Integrating high-throughput resistance measurements and genomic sequencing, we compared Escherichia coli populations evolved in a hybrid antibiotic that links ciprofloxacin and neomycin B with populations evolved in combinations of the component drugs. We find that populations evolved in the hybrid gain less resistance than those evolved in an equimolar mixture of the hybrid's components, in part because the hybrid evades resistance mediated by the multiple antibiotic resistance (mar) operon. Furthermore, we find that the ciprofloxacin moiety of the hybrid inhibits bacterial growth whereas the neomycin B moiety diminishes the effectiveness of mar activation. More generally, comparing the phenotypic and genotypic paths to resistance across different drug treatments can pinpoint unique properties of new compounds that limit the emergence of resistance. © The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  18. Effect and Safety of Shihogyejitang for Drug Resistant Childhood Epilepsy

    Directory of Open Access Journals (Sweden)

    Jinsoo Lee

    2016-01-01

    Full Text Available Objective. Herbal medicine has been widely used to treat drug resistant epilepsy. Shihogyejitang (SGT has been commonly used to treat epilepsy. We investigated the effect and safety of SGT in children with drug resistant epilepsy. Design. We reviewed medical records of 54 patients with epilepsy, who failed to respond to at least two antiepileptic drugs and have been treated with SGT between April 2006 and June 2014 at the Department of Pediatric Neurology, I-Tomato Hospital, Korea. Effect was measured by the response rate, seizure-free rate, and retention rate at six months. We also checked adverse events, change in antiepileptic drugs use, and the variables related to the outcome. Results. Intent-to-treat analysis showed that, after six months, 44.4% showed a >50% seizure reduction, 24.1% including seizure-free, respectively, and 53.7% remained on SGT. Two adverse events were reported, mild skin rash and fever. Focal seizure type presented significantly more positive responses when compared with other seizure types at six months (p=0.0284, Fisher’s exact test. Conclusion. SGT is an effective treatment with excellent tolerability for drug resistant epilepsy patients. Our data provide evidence that SGT may be used as alternative treatment option when antiepileptic drug does not work in epilepsy children.

  19. Lenghty reverse poly(butylene oxide)-poly(ethylene oxide)-poly(butylene oxide) polymeric micelles and gels for sustained release of antifungal drugs.

    Science.gov (United States)

    Figueroa-Ochoa, Edgar B; Villar-Alvarez, Eva M; Cambón, Adriana; Mistry, Dharmista; Llovo, José; Attwood, David; Barbosa, Silvia; Soltero, J F Armando; Taboada, Pablo

    2016-08-20

    In this work, we present a detailed study of the potential application of polymeric micelles and gels of four different reverse triblock poly(butylene oxide)-poly(ethylene oxide)-poly(butylene oxide) copolymers (BOnEOmBOn, where n denotes the respective block lengths), specifically BO8EO90BO8, BO14EO378BO14, BO20EO411BO20 and BO21EO385BO21, as effective drug transport nanocarriers. In particular, we tested the use of this kind of polymeric nanostructures as reservoirs for the sustained delivery of the antifungals griseofulvin and fluconazole for oral and topical administration. Polymeric micelles and gels formed by these copolymers were shown to solubilize important amounts of these two drugs and to have a good stability in physiologically relevant conditions for oral or topical administration. These polymeric micellar nanocarriers were able to release drugs in a sustained manner, being the release rate slower as the copolymer chain hydrophobicity increased. Different sustained drug release profiles were observed depending on the medium conditions. Gel nanocarriers were shown to display longer sustained release rates than micellar formulations, with the existence of a pulsatile-like release mode under certain solution conditions as a result of their inner network structure. Certain bioadhesive properties were observed for the polymeric physical gels, being moderately tuned by the length and hydrophobicity of the polymeric chains. Furthermore, polymeric gels and micelles showed activity against the yeast Candida albicans and the mould demartophytes (Trichophyton rubrum and Microsporum canis) and, thus, may be useful for the treatment of different cutaneous fungal infections. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Collateral Resistance and Sensitivity Modulate Evolution of High-Level Resistance to Drug Combination Treatment in Staphylococcus aureus

    DEFF Research Database (Denmark)

    de Evgrafov, Mari Cristina Rodriguez; Gumpert, Heidi; Munck, Christian

    2015-01-01

    -type levels. All drug combinations, irrespective of interaction types, effectively limited resistance evolution compared with monotreatment. Cross-resistance and collateral sensitivity were found to be important factors in the extent of resistance evolution toward a combination. Comparative genomic analyses...

  1. Emerging drug -resistance and guidelines for treatment of malaria

    International Nuclear Information System (INIS)

    Khan, M.A.; Smego Jr, R.A.; Razi, S.T.; Beg, M.A.

    2004-01-01

    The increasing prevalence of multi-resistant Plasmodium falciparum malaria worldwide is a serious public health threat to the global control of malaria, especially in poor countries like Pakistan. In many countries chloroquine-resistance is a huge problem, accounting for more than 90% of malaria cases. In Pakistan, resistance to chloroquine is on the rise and reported in up to 16- 62% of Plasmodium falciparum. Four to 25% of Plasmodium falciparum also reported to be resistant to sulfadoxine-pyrimethamine and several cases of delayed parasite clearance have been observed in patients with Plasmodium falciparum malaria treated with quinine. In this article we have introduced the concept of artemisinin- based combination therapy (ACT) and emphasize the use of empiric combination therapy for all patients with Plasmodium falciparum malaria to prevent development of drug resistance and to obtain additive and synergistic killing of parasite. (author)

  2. Drug accumulation in the presence of the multidrug resistance pump

    DEFF Research Database (Denmark)

    Ayesh, S; Litman, Thomas; Stein, W D

    1997-01-01

    We studied the interaction between the multidrug transporter, P-glycoprotein, and two compounds that interact with it: vinblastine, a classical substrate of the pump, and verapamil, a classical reverser. Steady-state levels of accumulation of these two drugs were determined in a multidrug resistant...

  3. Laboratory methods for diagnosis and detection of drug resistant ...

    African Journals Online (AJOL)

    Data source: Published series of peer reviewed journals and manuals written on laboratory methods that are currently used for diagnosis and detection of drug resistance of Mycobacterium tuberculosis complex were reviewed using the index medicus, pubmed and medline search. Conventional bacteriological microscopy ...

  4. Multi-Drug Resistance 1 Genetic Polymorphisms Gene Expression ...

    African Journals Online (AJOL)

    Although anthracycline-based chemotherapy is a crucial treatment for breast cancer, its outcome is limited by the multidrug resistance MDR. Overexpression of P-glycoprotein (Pgp), a transmembrane active efflux transporter of various drugs and carcinogenic substrate, may result in MDR. The impact of MDR1 ...

  5. Extracting causal relations on HIV drug resistance from literature

    NARCIS (Netherlands)

    Q.C. Bui; B.O. Nualláin (Breanndán); C.A.B. Boucher (Charles); P.M.A. Sloot (Peter)

    2010-01-01

    textabstractBackground: In HIV treatment it is critical to have up-to-date resistance data of applicable drugs since HIV has a very high rate of mutation. These data are made available through scientific publications and must be extracted manually by experts in order to be used by virologists and

  6. Alcohol and Other Drug Resistance Strategies Employed by Rural Adolescents

    Science.gov (United States)

    Pettigrew, Jonathan; Miller-Day, Michelle; Krieger, Janice; Hecht, Michael L.

    2011-01-01

    This study seeks to identify how rural adolescents make health decisions and utilize communication strategies to resist influence attempts in offers of alcohol, tobacco, and other drugs (ATOD). Semi-structured interviews were conducted with 113 adolescents from rural school districts to solicit information on ATOD norms, past ATOD experiences, and…

  7. The screening of multi-drug resistance (MDR) susceptibilities of ...

    African Journals Online (AJOL)

    The screening of multi-drug resistance (MDR) susceptibilities of Staphylococcus aureus and Staphylococcus epidermidis to methicillin and vancomycin in teaching hospitals in Nigeria. ... The antibiotics susceptibility patterns were determined both by overnight broth-micro-dilution and agar disk diffusion methods. Results: ...

  8. Diversity of Urinary Tract Pathogens and Drug Resistant Isolates of ...

    African Journals Online (AJOL)

    Purpose: This paper was mainly aimed to investigate drug resistance of the various urinary tract infection (UTI) pathogens from patients of different gender and age groups of Pakistanis. Method: For these purposes, urine samples of 109 patients were analyzed. Samples were screened on CLED agar. Antimicrobial ...

  9. HIV infection and mycobacterium tuberculosis drug-resistance ...

    African Journals Online (AJOL)

    The aim of this study was to compare the drug-resistance patterns of Mycobacterium tuberculosis strains among pulmonary tuberculosis patients, according to their HIV serostatus, in Burkina Faso. Tuberculosis (TB) patients were classified in new and previously treated cases by using a structured questionnaire.

  10. Drug resistance patterns of bacterial isolates from infected wounds ...

    African Journals Online (AJOL)

    unhcc

    Conclusions: High frequency of mono and multi-drug resistant bacterial pathogens were documented. Thus, an alternative method to the causative agent and antimicrobial susceptibility testing surveillance in areas where there is no culture facility is needed to assist health professionals for the selection of appropriate ...

  11. Isolation rate and drug resistance patterns of Shigella species ...

    African Journals Online (AJOL)

    High prevalence of Shigella spp. with multiple antibiotic resistance isolates were observed in this study. Ciprofloxacin may be used as a drug of choice for empirical treatment for Shigella infections. Regular, systematic monitoring of diarrheal cases is also needed to identify changes in the prevalence and antimicrobial ...

  12. Extracting causal relations on HIV drug resistance from literature

    NARCIS (Netherlands)

    Bui, Q.C.; Ó Nualláin, B.; Boucher, C.A.; Sloot, P.M.A.

    2010-01-01

    Background: In HIV treatment it is critical to have up-to-date resistance data of applicable drugs since HIV has a very high rate of mutation. These data are made available through scientific publications and must be extracted manually by experts in order to be used by virologists and medical

  13. Use of hop extract as antifungal ingredient for bread making and selection of autochthonous resistant starters for sourdough fermentation.

    Science.gov (United States)

    Nionelli, Luana; Pontonio, Erica; Gobbetti, Marco; Rizzello, Carlo Giuseppe

    2018-02-02

    Aiming at meeting the consumers' demand in terms of bio-preservation, the potential of the combination of the lactic acid bacteria fermentation and the addition of hop extract as natural preservative in breadmaking, was exploited. The antifungal properties of a hop (Humulus lupulus) extract were investigated, showing a significant inhibition of the hyphal growth of Aspergillus parasiticus, Penicillium carneum, Penicillium polonicum, Penicillium paneum, Penicillium chermesinum, Aspergillus niger, Penicillium roqueforti. Lactic acid bacteria belonging to species of Enterococcus feacium, Lactobacillus plantarum, Lactobacillus brevis, Lactobacillus helveticus, Lactobacillus curvatus, Pediococcus pentosaceus, and Pediococcus acidilactici were isolated from hop and subjected to selection based on kinetics of growth and acidification. The sourdough (hS) enriched with hop extract (hE), started with three selected strains, had phenols concentration and antioxidant activity higher than those obtained in the same condition but without the hE. Hop-sourdough used in breadmaking delayed the fungal growth (14 days), giving a bread characterized by free aminoacids concentration, antioxidant and phytase activities higher than bread started only with baker's yeast, with or without the addition of hE. Specific volume and cell-total area of the bread containing hE improved, and its sensory profile was characterized by typical sourdough attributes, and a moderate bitter/herbaceous perception.

  14. Epigenetic modulation of the biophysical properties of drug-resistant cell lipids to restore drug transport and endocytic functions.

    Science.gov (United States)

    Vijayaraghavalu, Sivakumar; Peetla, Chiranjeevi; Lu, Shan; Labhasetwar, Vinod

    2012-09-04

    In our recent studies exploring the biophysical characteristics of resistant cell lipids, and the role they play in drug transport, we demonstrated the difference of drug-resistant breast cancer cells from drug-sensitive cells in lipid composition and biophysical properties, suggesting that cancer cells acquire a drug-resistant phenotype through the alteration of lipid synthesis to inhibit intracellular drug transport to protect from cytotoxic effect. In cancer cells, epigenetic changes (e.g., DNA hypermethylation) are essential to maintain this drug-resistant phenotype. Thus, altered lipid synthesis may be linked to epigenetic mechanisms of drug resistance. We hypothesize that reversing DNA hypermethylation in resistant cells with an epigenetic drug could alter lipid synthesis, changing the cell membrane's biophysical properties to facilitate drug delivery to overcome drug resistance. Herein we show that treating drug-resistant breast cancer cells (MCF-7/ADR) with the epigenetic drug 5-aza-2'-deoxycytidine (decitabine) significantly alters cell lipid composition and biophysical properties, causing the resistant cells to acquire biophysical characteristics similar to those of sensitive cell (MCF-7) lipids. Following decitabine treatment, resistant cells demonstrated increased sphingomyelinase activity, resulting in a decreased sphingomyelin level that influenced lipid domain structures, increased membrane fluidity, and reduced P-glycoprotein expression. Changes in the biophysical characteristics of resistant cell lipids facilitated doxorubicin transport and restored endocytic function for drug delivery with a lipid-encapsulated form of doxorubicin, enhancing the drug efficacy. In conclusion, we have established a new mechanism for efficacy of an epigenetic drug, mediated through changes in lipid composition and biophysical properties, in reversing cancer drug resistance.

  15. In Vitro Antifungal Susceptibility of Oral Candida Isolates from Patients Suffering from Caries and Chronic Periodontitis.

    Science.gov (United States)

    De-la-Torre, Janire; Ortiz-Samperio, María Esther; Marcos-Arias, Cristina; Marichalar-Mendia, Xabier; Eraso, Elena; Echebarria-Goicouria, María Ángeles; Aguirre-Urizar, José Manuel; Quindós, Guillermo

    2017-06-01

    Caries and chronic periodontitis are common oral diseases where a higher Candida colonization is reported. Antifungal agents could be adjuvant drugs for the therapy of both clinical conditions. The aim of the current study has been to evaluate the in vitro activities of conventional and new antifungal drugs against oral Candida isolates from patients suffering from caries and/or chronic periodontitis. In vitro activities of amphotericin B, fluconazole, itraconazole, miconazole, nystatin, posaconazole and voriconazole against 126 oral Candida isolates (75 Candida albicans, 18 Candida parapsilosis, 11 Candida dubliniensis, six Candida guilliermondii, five Candida lipolytica, five Candida glabrata, four Candida tropicalis and two Candida krusei) from 61 patients were tested by the CLSI M27-A3 method. Most antifungal drugs were highly active, and resistance was observed in less than 5% of tested isolates. Miconazole was the most active antifungal drug, being more than 98% of isolates susceptible. Fluconazole, itraconazole, and the new triazoles, posaconazole and voriconazole, were also very active. Miconazole, fluconazole and voriconazole have excellent in vitro activities against all Candida isolates and could represent suitable treatment for a hypothetically adjunctive therapy of caries and chronic periodontitis.

  16. Potential risk for drug resistance globalization at the Hajj.

    Science.gov (United States)

    Al-Tawfiq, J A; Memish, Z A

    2015-02-01

    Antibiotics were once considered the miracle cure for infectious diseases. The tragedy would be the loss of these miracles as we witness increased antibiotic resistance throughout the world. One of the concerns during mass gatherings is the transmission of antibiotic resistance. Hajj is one of the most common recurring mass gatherings, attracting millions of people from around the world. The transmission of drug-resistant organisms during the Hajj is not well described. In the current review, we summarize the available literature on the transmission and acquisition of antibiotic resistance during the Hajj and present possible solutions. Copyright © 2014 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  17. Antifungal activity of topical microemulsion containing a thiophene derivative

    Directory of Open Access Journals (Sweden)

    Geovani Pereira Guimarães

    2014-06-01

    Full Text Available Fungal infections have become a major problem of worldwide concern. Yeasts belonging to the Candida genus and the pathogenic fungus Cryptococcus neoformans are responsible for different clinical manifestations, especially in immunocompromised patients. Antifungal therapies are currently based on a few chemotherapeutic agents that have problems related to effectiveness and resistance profiles. Microemulsions are isotropic, thermodynamically stable transparent systems of oil, water and surfactant that can improve the solubilization of lipophilic drugs. Taking into account the need for more effective and less toxic drugs along with the potential of thiophene derivatives as inhibitors of pathogenic fungi growth, this study aimed to evaluate the antifungal activity of a thiophene derivative (5CN05 embedded in a microemulsion (ME. The minimum inhibitory concentration (MIC was determined using the microdilution method using amphotericin B as a control. The formulations tested (ME- blank and ME-5CN05 showed physico-chemical properties that would allow their use by the topical route. 5CN05 as such exhibited moderate or weak antifungal activity against Candida species (MIC = 270-540 µg.mL-1 and good activity against C. neoformans (MIC = 17 µg.mL-1. Candida species were susceptible to ME-5CN05 (70-140 µg.mL-1, but C. neoformans was much more, presenting a MIC value of 2.2 µg.mL-1. The results of this work proved promising for the pharmaceutical industry, because they suggest an alternative therapy against C. neoformans.

  18. Drug resistance following irradiation of RIF-1 tumors: Influence of the interval between irradiation and drug treatment

    International Nuclear Information System (INIS)

    Hopwood, L.E.; Davies, B.M.; Moulder, J.E.

    1990-01-01

    RIF-1 tumors contain a small number of cells (1 to 100 per 10(6) cells) that are resistant to 5-fluorouracil, methotrexate, or adriamycin. The frequency of drug-resistant cells among individual untreated tumors is highly variable. Radiation, delivered in vivo at doses of 3 to 12 Gy, increases the frequency of methotrexate- and 5-fluorouracil-resistant cells, but not the frequency of adriamycin-resistant cells. The magnitude of induction of 5-fluorouracil and methotrexate resistance shows a complex dependence on the radiation dose and on the interval between irradiation and assessment of drug resistance. For a dose of 3 Gy, induced 5-fluorouracil and methotrexate resistance is seen only after an interval of 5 to 7 days, whereas for a dose of 12 Gy, high levels of induced resistance are observed 1 to 3 days after irradiation. The maximum absolute risk for induction of resistance is 4 per 10(4) cells per Gy for methotrexate, and 3 per 10(6) cells per Gy for 5-fluorouracil. These results indicate that tumor hypoxia may play a role in the increased levels of drug resistance seen after irradiation, and that both genetic and environmental factors may influence radiation-induction of drug resistance. These studies provide essential data for models of the development of tumor drug resistance, and imply that some of the drug resistance seen when chemotherapy follows radiotherapy may be caused by radiation-induced drug resistance

  19. Modeling HIV-1 drug resistance as episodic directional selection.

    Directory of Open Access Journals (Sweden)

    Ben Murrell

    Full Text Available The evolution of substitutions conferring drug resistance to HIV-1 is both episodic, occurring when patients are on antiretroviral therapy, and strongly directional, with site-specific resistant residues increasing in frequency over time. While methods exist to detect episodic diversifying selection and continuous directional selection, no evolutionary model combining these two properties has been proposed. We present two models of episodic directional selection (MEDS and EDEPS which allow the a priori specification of lineages expected to have undergone directional selection. The models infer the sites and target residues that were likely subject to directional selection, using either codon or protein sequences. Compared to its null model of episodic diversifying selection, MEDS provides a superior fit to most sites known to be involved in drug resistance, and neither one test for episodic diversifying selection nor another for constant directional selection are able to detect as many true positives as MEDS and EDEPS while maintaining acceptable levels of false positives. This suggests that episodic directional selection is a better description of the process driving the evolution of drug resistance.

  20. HIV Drug-Resistant Patient Information Management, Analysis, and Interpretation.

    Science.gov (United States)

    Singh, Yashik; Mars, Maurice

    2012-06-07

    The science of information systems, management, and interpretation plays an important part in the continuity of care of patients. This is becoming more evident in the treatment of human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS), the leading cause of death in sub-Saharan Africa. The high replication rates, selective pressure, and initial infection by resistant strains of HIV infer that drug resistance will inevitably become an important health care concern. This paper describes proposed research with the aim of developing a physician-administered, artificial intelligence-based decision support system tool to facilitate the management of patients on antiretroviral therapy. This tool will consist of (1) an artificial intelligence computer program that will determine HIV drug resistance information from genomic analysis; (2) a machine-learning algorithm that can predict future CD4 count information given a genomic sequence; and (3) the integration of these tools into an electronic medical record for storage and management. The aim of the project is to create an electronic tool that assists clinicians in managing and interpreting patient information in order to determine the optimal therapy for drug-resistant HIV patients.

  1. Molecular Basis for Drug Resistance in HIV-1 Protease

    Directory of Open Access Journals (Sweden)

    Celia A. Schiffer

    2010-11-01

    Full Text Available HIV-1 protease is one of the major antiviral targets in the treatment of patients infected with HIV-1. The nine FDA approved HIV-1 protease inhibitors were developed with extensive use of structure-based drug design, thus the atomic details of how the inhibitors bind are well characterized. From this structural understanding the molecular basis for drug resistance in HIV-1 protease can be elucidated. Selected mutations in response to therapy and diversity between clades in HIV-1 protease have altered the shape of the active site, potentially altered the dynamics and even altered the sequence of the cleavage sites in the Gag polyprotein. All of these interdependent changes act in synergy to confer drug resistance while simultaneously maintaining the fitness of the virus. New strategies, such as incorporation of the substrate envelope constraint to design robust inhibitors that incorporate details of HIV-1 protease’s function and decrease the probability of drug resistance, are necessary to continue to effectively target this key protein in HIV-1 life cycle.

  2. Emerging drugs and vaccines for candidemia.

    Science.gov (United States)

    Moriyama, Brad; Gordon, Lori A; McCarthy, Matthew; Henning, Stacey A; Walsh, Thomas J; Penzak, Scott R

    2014-12-01

    Candidemia and other forms of invasive candidiasis are important causes of morbidity and mortality. The evolving challenge of antimicrobial resistance among fungal pathogens continues to highlight the need for potent, new antifungal agents. MEDLINE, EMBASE, Scopus and Web of Science searches (up to January 2014) of the English-language literature were performed with the keywords 'Candida' or 'Candidemia' or 'Candidiasis' and terms describing investigational drugs with activity against Candida spp. Conference abstracts and the bibliographies of pertinent articles were also reviewed for relevant reports. ClinicalTrials.gov was searched for relevant clinical trials. Currently available antifungal agents for the treatment of candidemia are summarised. Investigational antifungal agents with potential activity against Candida bloodstream infections and other forms of invasive candidiasis and vaccines for prevention of Candida infections are also reviewed as are selected antifungal agents no longer in development. Antifungal agents currently in clinical trials include isavuconazole, albaconazole, SCY-078, VT-1161 and T-2307. Further data are needed to determine the role of these compounds in the treatment of candidemia and other forms of invasive candidiasis. The progressive reduction in antimicrobial drug development may result in a decline in antifungal drug discovery. Still, there remains a critical need for new antifungal agents to treat and prevent invasive candidiasis and other life-threatening mycoses. © 2014 Blackwell Verlag GmbH.

  3. Resistance patterns and trends of extensively drug-resistant tuberculosis: 5-year experience

    Directory of Open Access Journals (Sweden)

    Amresh Kumar Singh

    2013-12-01

    Full Text Available Objective:Extensively drug-resistant tuberculosis (XDR-TB strains were emerged when multidrug-resistant TB (MDR- TB was inadequately treated. Inadequate treatment of MDR-TB cases may result in additional resistance especially non-XDR-TB and then XDR-TB. The aim of this study was to know the prevalence, resistance patterns and trends of the XDR-TB strains among the MDR-TB at a tertiary care hospital in Lucknow, India Methods: A total of 430 Mycobacterium isolates were underwent NAP test and TB MPT64 Ag test for the identification of Mycobacterium tuberculosis complex (MTBC. Drug-susceptibility test (DST was performed over MTBC for the first line drugs by 1% proportion method (Bactec and for the second-line drugs by 1% proportion method (Lowenstein- Jensen media. The XDR-TB status was further confirmed by line probe assay (GenoType® MTBDRsl assay. Results: Among the 430 isolates of mycobacterium, 365 (84.9% were MTBC and 139 (38.1% were MDR-TB respectively. Further 97 MDR-TB from “highly suspected drug resistant-TB (DR-TB” cases among MDR-TB were tested with second line drugs in which 15 (15.5% XDR-TB and 82 (84.5% were non-XDR-TB. Regarding XDR-TB status, using the 1% proportion method a 100% agreement was seen with the GenoType® MTBDRsl assay. Resistance patterns of XDR-TB were as; 10/15 (66.7% as isoniazid + rifampicin + ciprofloxacin + amikacin resistance and 5/15 (33.3% as isoniazid + rifampicin + ciprofloxacin + amikacin + kanamycin resistance. Conclusion:The prevalence of XDR-TB was 15.5% among MDR-TB. Hence laboratory testing of “highly suspected drug resistant-TB” isolates should be done for both first and second line drugs simultaneously especially in developing countries.J Microbiol Infect Dis 2013;3(4: 169-175

  4. Drug resistance patterns of acinetobacter baumannii in makkah, saudi arabia

    International Nuclear Information System (INIS)

    Khan, M.A.; Ashshi, A.M.; Mahomed, M.F.

    2012-01-01

    Background: Acinetobacter baumannii causes infections of respiratory, urinary tract, blood stream and surgical sites. Its clinical significance has increased due to its rapidly developing resistance to major groups of antibiotics used for its treatment. There is limited data available on antimicrobial susceptibility of A. baumannii from Saudi Arabia. Objectives: To determine the patterns of drug resistance of Acinetobacter baumannii and predisposing factors for its acquisition.Subjects and Methods: In this descriptive study, 72 hospitalized patients infected with A baumannii were studied. The clinical and demographic data of the patients were collected using a predesigned questionnaire. Isolation and identification of A.baumannii from all clinical specimens were done using standard microbiological methods. Antibiotic susce ptibility testing was performed by disk diffusion method recommended by Clinical Laboratory Standards Institute. Results: Majority of the isolates (61.1%) were from respiratory tract infections. A.baumannii isolates showed high drug resistance to piperacil lin (93.1%), aztreonam (80.5%), ticarcillin, ampicillin, and tetracycline (76.4%, each) and cefotaxime (75%). Only amikacin showed low rate of resistance compared to other antibiotics (40.3%). About 36% patients had some underlying diseases with diabetes mellitus (11%) being the predominant underlying disease. Conclusions: High antimicrobial resistance to commonly used antibiotics was seen against A.baumannii isolates. Only amikacin was most effective against it. (author)

  5. Multi drug resistant tuberculosis presenting as anterior mediastinal mass

    Directory of Open Access Journals (Sweden)

    Parmarth Chandane

    2016-01-01

    Full Text Available Enlargement of the mediastinal lymphatic glands is a common presentation of intrathoracic tuberculosis (TB in children. However, usually, the mediastinal TB nodes enlarge to 2.8 ± 1.0 cm. In this report, we describe a case of anterior mediastinal lymphnode TB seen as huge mass (7 cm on computed tomography (CT thorax without respiratory or food pipe compromise despite anterior mediastinum being an enclosed space. CT guided biopsy of the mass cultured Mycobacterium TB complex which was resistant to isoniazide, rifampicin, streptomycin ofloxacin, moxifloxacin, and pyrazinamide. Hence, we report primary multi drug resistant TB presenting as anterior mediastinal mass as a rare case report.

  6. Personalized Cancer Medicine: Molecular Diagnostics, Predictive biomarkers, and Drug Resistance

    Science.gov (United States)

    Gonzalez de Castro, D; Clarke, P A; Al-Lazikani, B; Workman, P

    2013-01-01

    The progressive elucidation of the molecular pathogenesis of cancer has fueled the rational development of targeted drugs for patient populations stratified by genetic characteristics. Here we discuss general challenges relating to molecular diagnostics and describe predictive biomarkers for personalized cancer medicine. We also highlight resistance mechanisms for epidermal growth factor receptor (EGFR) kinase inhibitors in lung cancer. We envisage a future requiring the use of longitudinal genome sequencing and other omics technologies alongside combinatorial treatment to overcome cellular and molecular heterogeneity and prevent resistance caused by clonal evolution. PMID:23361103

  7. Systematic drug screening reveals specific vulnerabilities and co-resistance patterns in endocrine-resistant breast cancer

    International Nuclear Information System (INIS)

    Kangaspeska, Sara; Hultsch, Susanne; Jaiswal, Alok; Edgren, Henrik; Mpindi, John-Patrick; Eldfors, Samuli; Brück, Oscar; Aittokallio, Tero; Kallioniemi, Olli

    2016-01-01

    The estrogen receptor (ER) inhibitor tamoxifen reduces breast cancer mortality by 31 % and has served as the standard treatment for ER-positive breast cancers for decades. However, 50 % of advanced ER-positive cancers display de novo resistance to tamoxifen, and acquired resistance evolves in 40 % of patients who initially respond. Mechanisms underlying resistance development remain poorly understood and new therapeutic opportunities are urgently needed. Here, we report the generation and characterization of seven tamoxifen-resistant breast cancer cell lines from four parental strains. Using high throughput drug sensitivity and resistance testing (DSRT) with 279 approved and investigational oncology drugs, exome-sequencing and network analysis, we for the first time, systematically determine the drug response profiles specific to tamoxifen resistance. We discovered emerging vulnerabilities towards specific drugs, such as ERK1/2-, proteasome- and BCL-family inhibitors as the cells became tamoxifen-resistant. Co-resistance to other drugs such as the survivin inhibitor YM155 and the chemotherapeutic agent paclitaxel also occurred. This study indicates that multiple molecular mechanisms dictate endocrine resistance, resulting in unexpected vulnerabilities to initially ineffective drugs, as well as in emerging co-resistances. Thus, combatting drug-resistant tumors will require patient-tailored strategies in order to identify new drug vulnerabilities, and to understand the associated co-resistance patterns. The online version of this article (doi:10.1186/s12885-016-2452-5) contains supplementary material, which is available to authorized users

  8. Mathematical models of tumor heterogeneity and drug resistance

    Science.gov (United States)

    Greene, James

    In this dissertation we develop mathematical models of tumor heterogeneity and drug resistance in cancer chemotherapy. Resistance to chemotherapy is one of the major causes of the failure of cancer treatment. Furthermore, recent experimental evidence suggests that drug resistance is a complex biological phenomena, with many influences that interact nonlinearly. Here we study the influence of such heterogeneity on treatment outcomes, both in general frameworks and under specific mechanisms. We begin by developing a mathematical framework for describing multi-drug resistance to cancer. Heterogeneity is reflected by a continuous parameter, which can either describe a single resistance mechanism (such as the expression of P-gp in the cellular membrane) or can account for the cumulative effect of several mechanisms and factors. The model is written as a system of integro-differential equations, structured by the continuous "trait," and includes density effects as well as mutations. We study the limiting behavior of the model, both analytically and numerically, and apply it to study treatment protocols. We next study a specific mechanism of tumor heterogeneity and its influence on cell growth: the cell-cycle. We derive two novel mathematical models, a stochastic agent-based model and an integro-differential equation model, each of which describes the growth of cancer cells as a dynamic transition between proliferative and quiescent states. By examining the role all parameters play in the evolution of intrinsic tumor heterogeneity, and the sensitivity of the population growth to parameter values, we show that the cell-cycle length has the most significant effect on the growth dynamics. In addition, we demonstrate that the agent-based model can be approximated well by the more computationally efficient integro-differential equations, when the number of cells is large. The model is closely tied to experimental data of cell growth, and includes a novel implementation of

  9. Mycobacterium tuberculosis drug-resistance in previously treated ...

    African Journals Online (AJOL)

    Keywords: Burkina faso, drug resistance, Ouagadougou, tuberculosis. Résumé. Arrière-plan: Tuberculose pharmacorésistance devient commun en Afrique; Toutefois, très peu de données est disponibles au Burkina Faso. L'objectif de cette étude est pour évaluer la résistance acquise de Mycobacterium tuberculosis ...

  10. Extracting causal relations on HIV drug resistance from literature.

    Science.gov (United States)

    Bui, Quoc-Chinh; Nualláin, Breanndán O; Boucher, Charles A; Sloot, Peter M A

    2010-02-23

    In HIV treatment it is critical to have up-to-date resistance data of applicable drugs since HIV has a very high rate of mutation. These data are made available through scientific publications and must be extracted manually by experts in order to be used by virologists and medical doctors. Therefore there is an urgent need for a tool that partially automates this process and is able to retrieve relations between drugs and virus mutations from literature. In this work we present a novel method to extract and combine relationships between HIV drugs and mutations in viral genomes. Our extraction method is based on natural language processing (NLP) which produces grammatical relations and applies a set of rules to these relations. We applied our method to a relevant set of PubMed abstracts and obtained 2,434 extracted relations with an estimated performance of 84% for F-score. We then combined the extracted relations using logistic regression to generate resistance values for each pair. The results of this relation combination show more than 85% agreement with the Stanford HIVDB for the ten most frequently occurring mutations. The system is used in 5 hospitals from the Virolab project http://www.virolab.org to preselect the most relevant novel resistance data from literature and present those to virologists and medical doctors for further evaluation. The proposed relation extraction and combination method has a good performance on extracting HIV drug resistance data. It can be used in large-scale relation extraction experiments. The developed methods can also be applied to extract other type of relations such as gene-protein, gene-disease, and disease-mutation.

  11. Surgical management of cavernous malformations coursing with drug resistant epilepsy

    OpenAIRE

    Mario Arturo Alonso-Vanegas; Jose Miguel eCisneros-Franco; Taisuke eOtsuki

    2012-01-01

    Cerebral cavernous malformations (CM) are dynamic lesions characterized by continuous size changes and repeated bleeding. When involving cortical tissue, CM pose a significant risk for the development of drug-resistant epilepsy, which is thought to be result of an altered neuronal network caused by the lesion itself and its blood degradation products. Preoperative evaluation should comprise a complete seizure history, neurological examination, epilepsy-oriented MRI, EEG, video-EEG, completed ...

  12. The Hsp90 co-chaperones Sti1, Aha1, and P23 regulate adaptive responses to antifungal azoles

    Directory of Open Access Journals (Sweden)

    Xiaokui Gu

    2016-10-01

    Full Text Available Heat Shock Protein 90 (Hsp90 is essential for tumor progression in humans and drug resistance in fungi. However, the roles of its many co-chaperones in antifungal resistance are unknown. In this study, by susceptibility test of Neurospora crassa mutants lacking each of 18 Hsp90/Calcineurin system member genes (including 8 Hsp90 co-chaperone genes to antifungal drugs and other stresses, we demonstrate that the Hsp90 co-chaperones Sti1 (Hop1 in yeast, Aha1, and P23 (Sba1 in yeast were required for the basal resistance to antifungal azoles and heat stress. Deletion of any of them resulted in hypersensitivity to azoles and heat. Liquid chromatography–mass spectrometry (LC-MS analysis showed that the toxic sterols eburicol and 14α-methyl-3,6-diol were significantly accumulated in the sti1 and p23 deletion mutants after ketoconazole treatment, which has been shown before to led to cell membrane stress. At the transcriptional level, Aha1, Sti1, and P23 positively regulate responses to ketoconazole stress by erg11 and erg6, key genes in the ergosterol biosynthetic pathway. Aha1, Sti1, and P23 are highly conserved in fungi, and sti1 and p23 deletion also increased the susceptibility to azoles in Fusarium verticillioides. These results indicate that Hsp90-cochaperones Aha1, Sti1, and P23 are critical for the basal azole resistance and could be potential targets for developing new antifungal agents.

  13. Screening of antifungal azole drugs and agrochemicals with an adapted alamarBlue-based assay demonstrates antibacterial activity of croconazole against Mycobacterium ulcerans.

    Science.gov (United States)

    Scherr, Nicole; Röltgen, Katharina; Witschel, Matthias; Pluschke, Gerd

    2012-12-01

    An alamarBlue-based growth inhibition assay has been adapted for the thermosensitive and slow-growing pathogen Mycobacterium ulcerans. The standardized test procedure enables medium-throughput screening of preselected compound libraries. Testing of a set of 48 azoles with known antifungal activity led to the identification of an imidazole antifungal displaying an inhibitory dose (ID) of 9 μM for M. ulcerans.

  14. The cost of multiple drug resistance in Pseudomonas aeruginosa.

    Science.gov (United States)

    Ward, H; Perron, G G; Maclean, R C

    2009-05-01

    The spread of bacterial antibiotic resistance mutations is thought to be constrained by their pleiotropic fitness costs. Here we investigate the fitness costs of resistance in the context of the evolution of multiple drug resistance (MDR), by measuring the cost of acquiring streptomycin resistance mutations (StrepR) in independent strains of the bacterium Pseudomonas aeruginosa carrying different rifampicin resistance (RifR) mutations. In the absence of antibiotics, StrepR mutations are associated with similar fitness costs in different RifR genetic backgrounds. The cost of StrepR mutations is greater in a rifampicin-sensitive (RifS) background, directly demonstrating antagonistic epistasis between resistance mutations. In the presence of rifampicin, StrepR mutations have contrasting effects in different RifR backgrounds: StrepR mutations have no detectable costs in some RifR backgrounds and massive fitness costs in others. Our results clearly demonstrate the importance of epistasis and genotype-by-environment interactions for the evolution of MDR.

  15. Investigational drugs to treat methicillin-resistant Staphylococcus aureus

    Science.gov (United States)

    Vuong, Cuong; Yeh, Anthony J; Cheung, Gordon YC; Otto, Michael

    2016-01-01

    Introduction Staphylococcus aureus remains one of the leading causes of morbidity and mortality worldwide. This is to a large extent due to antibiotic-resistant strains, in particular methicillin-resistant S. aureus (MRSA). While the toll of invasive MRSA infections appears to decrease in U.S. hospitals, the rate of community-associated MRSA infections remains constant and there is a surge of MRSA in many other countries. This situation calls for continuing if not increased efforts to find novel strategies to combat MRSA infections. Areas covered This review will provide an overview of current investigational antibiotics in clinical development (up to phase II), and of therapeutic antibodies and alternative drugs against S. aureus in preclinical and clinical development, including a short description of the mechanism of action and a presentation of microbiological and clinical data. Expert opinion Increased recent antibiotic development efforts and results from pathogenesis research have led to several new antibiotics and alternative drugs, as well as a more informed selection of targets for vaccination efforts against MRSA. This developing portfolio of novel anti-staphylococcal drugs will hopefully provide us with additional and more efficient ways to combat MRSA infections in the near future and prevent us from running out of treatment options, even if new resistances arise. PMID:26536498

  16. Species distribution & antifungal susceptibility pattern of oropharyngeal Candida isolates from human immunodeficiency virus infected individuals

    Directory of Open Access Journals (Sweden)

    Partha Pratim Das

    2016-01-01

    Results: From the 59 culture positive HIV seropositive cases, 61 Candida isolates were recovered; Candidaalbicans (n=47, 77.0%, C. dubliniensis (n=9, 14.7%, C. parapsilosis (n=2, 3.2%, C. glabrata (n=2, 3.2%, and C. famata (n=1, 1.6%. Candida colonization in HIV-seropositive individuals was significantly higher than that of HIV-seronegative (control group. Antifungal susceptibility testing revealed (n=6, 9.3% C. albicans isolates resistant to voriconazole and fluconazole by disk-diffusion method whereas no resistance was seen by Fungitest method. Interpretation & conclusions: C. albicans was the commonest Candida species infecting or colonizing HIV seropositive individuals. Oropharyngeal Candida isolates had high level susceptibility to all the major antifungals commonly in use. Increased level of immunosuppression in HIV-seropositives and drug resistance of non-albicans Candida species makes identification and susceptibility testing of Candida species necessary in different geographical areas of the country.

  17. Mechanisms of first-line antimicrobial resistance in multi-drug and extensively drug resistant strains of Mycobacterium tuberculosis in KwaZulu-Natal, South Africa

    Directory of Open Access Journals (Sweden)

    Navisha Dookie

    2016-10-01

    Full Text Available Abstract Background In South Africa, drug resistant tuberculosis is a major public health crisis in the face of the colossal HIV pandemic. Methods In an attempt to understand the distribution of drug resistance in our setting, we analysed the rpoB, katG, inhA, pncA and embB genes associated with resistance to key drugs used in the treatment of tuberculosis in clinical isolates of Mycobacterium tuberculosis in the KwaZulu-Natal province. Results Classical mutations were detected in the katG, inhA and embB genes associated with resistance to isoniazid and ethambutol. Diverse mutations were recorded in the multidrug resistant (MDR and extensively drug resistant (XDR isolates for the rpoB and pncA gene associated with resistance to rifampicin and pyrazinamide. Conclusions M.tuberculosis strains circulating in our setting display a combination of previously observed mutations, each mediating resistance to a different drug. The MDR and XDR TB isolates analysed in this study displayed classical mutations linked to INH and EMB resistance, whilst diverse mutations were linked to RIF and PZA resistance. The similarity of the XDR strains confirms reports of the clonality of the XDR epidemic. The successful dissemination of the drug resistant strains in the province underscores the need for rapid diagnostics to effectively diagnose drug resistance and guide treatment.

  18. HIV subtype and drug resistance patterns among drug naïve ...

    African Journals Online (AJOL)

    SERVER

    2007-08-20

    Aug 20, 2007 ... To determine HIV-1 subtypes and antiretroviral drug resistance mutations for 16 infected, pregnant women in Jos, Nigeria, part of pol (1040 bp) was amplified from patient PBMC DNA, sequenced and analyzed. Eight of the samples were subtype G, three were CRF02_AG and 2 were unique recombinant.

  19. Changing prevalence and resistance patterns in children with drug-resistant tuberculosis in Mumbai.

    Science.gov (United States)

    Shah, Ira; Shah, Forum

    2017-05-01

    The prevalence of drug-resistant (DR) tuberculosis (TB) in children is increasing. Although, in India, multi-drug-resistant (MDR) TB rates have been relatively stable, the number of children with pre-extensively drug-resistant and extensively drug-resistant (XDR) TB is increasing. To determine whether the prevalence of DR TB in children in Mumbai is changing and to study the evolving patterns of resistance. A retrospective study was undertaken in 1311 paediatric patients referred between April 2007 and March 2013 to the Paediatric TB clinic at B. J. Wadia Hospital for Children, Mumbai. Children were defined as having DR TB on the basis of drug susceptibility testing (DST) of Mycobacterium tuberculosis grown on culture of body fluids (in the case of extra pulmonary TB) or from gastric lavage/bronchi-alveolar lavage/sputum in patients with pulmonary TB or from DST of the contacts. The prevalence of DR TB was calculated and the type of DR was evaluated yearly and in the pre-2010 and post-2010 eras. The overall prevalence of DR TB was 86 (6.6%) with an increase from 23 (5.6%) patients pre-2010 to 63 (7%) post-2010 (P = 0.40). Nine (10.4%) patients were diagnosed on the basis of contact with a parent with DR TB. Overall fluoroquinolone resistance increased from 9 (39.1%) pre-2010 to 59 (93.7%) post-2010 (P = 0.0001): moxifloxacin resistance increased from 2 (8.7%) to 29 (46%) (P = 0.0018) and ofloxacin resistance increased from 7 (30.4%) to 30 (47.6%) (P = 0.14). Ethionamide resistance also increased from 6 (26.1%) to 31 (49.2%) (P = 0.04), aminoglycoside resistance was one (4.3%) pre-2010 and 12 (19%) post-2010 (P = 0.17) and resistance remained virtually the same for both amikacin [0 pre-2010 and 6 (9.5%) after 2010] and kanamycin [one (4.3%) pre- and 6 (9.5%) post-2010]. Of the first-line drugs, resistance remained the same for isoniazid [23 (100%) to 61 (96.8%)], rifampicin [22 (95.7%) to 51 (80.9%),P = 0.17], pyrazinamide [15 (65.2%) to

  20. Molecular biological studies on the human radioresistance and drug resistance

    International Nuclear Information System (INIS)

    Kim, Chang Min; Hong, Weon Seon

    1992-04-01

    We irradiated the MKN45 and PC14 cell lines with 500 rads and also established the adriamycin-resistant and cis-platinum resistant cell line. The genomic DNA and total RNA were extracted and subjected to the Southern and Northern analysis using various probes including heat shock protein 70, MDR1, fos, TGFb etc. The mRNA transcript was increased 1 hour after the irradiation and sustained during the 48 hours and returned to the level of pre-irradiation. No significant change was observed with the drug resistant cell lines at the level of gene dosage. We suggest that the marked increase of the hsp70 transcript is very important finding and is believed to be a good candidate for the modulation of the cellular response to irradiation and the radioresistance. (Author)

  1. Catalysis and Sulfa Drug Resistance in Dihydropteroate Synthase

    Energy Technology Data Exchange (ETDEWEB)

    Yun, Mi-Kyung; Wu, Yinan; Li, Zhenmei; Zhao, Ying; Waddell, M. Brett; Ferreira, Antonio M.; Lee, Richard E.; Bashford, Donald; White, Stephen W. (SJCH)

    2013-04-08

    The sulfonamide antibiotics inhibit dihydropteroate synthase (DHPS), a key enzyme in the folate pathway of bacteria and primitive eukaryotes. However, resistance mutations have severely compromised the usefulness of these drugs. We report structural, computational, and mutagenesis studies on the catalytic and resistance mechanisms of DHPS. By performing the enzyme-catalyzed reaction in crystalline DHPS, we have structurally characterized key intermediates along the reaction pathway. Results support an S{sub N}1 reaction mechanism via formation of a novel cationic pterin intermediate. We also show that two conserved loops generate a substructure during catalysis that creates a specific binding pocket for p-aminobenzoic acid, one of the two DHPS substrates. This substructure, together with the pterin-binding pocket, explains the roles of the conserved active-site residues and reveals how sulfonamide resistance arises.

  2. HIV-1 Drug Resistance Mutations: Potential Applications for Point-of-Care Genotypic Resistance Testing.

    Directory of Open Access Journals (Sweden)

    Soo-Yon Rhee

    Full Text Available The increasing prevalence of acquired and transmitted HIV-1 drug resistance is an obstacle to successful antiretroviral therapy (ART in the low- and middle-income countries (LMICs hardest hit by the HIV-1 pandemic. Genotypic drug resistance testing could facilitate the choice of initial ART in areas with rising transmitted drug resistance (TDR and enable care-providers to determine which individuals with virological failure (VF on a first- or second-line ART regimen require a change in treatment. An inexpensive near point-of-care (POC genotypic resistance test would be useful in settings where the resources, capacity, and infrastructure to perform standard genotypic drug resistance testing are limited. Such a test would be particularly useful in conjunction with the POC HIV-1 viral load tests that are currently being introduced in LMICs. A POC genotypic resistance test is likely to involve the use of allele-specific point mutation assays for detecting drug-resistance mutations (DRMs. This study proposes that two major nucleoside reverse transcriptase inhibitor (NRTI-associated DRMs (M184V and K65R and four major NNRTI-associated DRMs (K103N, Y181C, G190A, and V106M would be the most useful for POC genotypic resistance testing in LMIC settings. One or more of these six DRMs was present in 61.2% of analyzed virus sequences from ART-naïve individuals with intermediate or high-level TDR and 98.8% of analyzed virus sequences from individuals on a first-line NRTI/NNRTI-containing regimen with intermediate or high-level acquired drug resistance. The detection of one or more of these DRMs in an ART-naïve individual or in a individual with VF on a first-line NRTI/NNRTI-containing regimen may be considered an indication for a protease inhibitor (PI-containing regimen or closer virological monitoring based on cost-effectiveness or country policy.

  3. Definition of drug resistance of Mycobacterium tuberculosis to antituberculosis drugs in patients with multidrugresistant tuberculosis and TB with extremely drug resistant depending on the case of the disease

    Directory of Open Access Journals (Sweden)

    Kryzhanovsky D.G.

    2014-11-01

    Full Text Available There was studied the profile of drug resistance to the main (I line and reserve (II line antituberculosis drugs in patients with MDR and XDR tuberculosis, depending of the case of the disease. According to the randomized retrospective research 200 patients with MDR and XDR tuberculosis, who received treatment in the clinic of hospital Municipal institution «Dnipropetrovsk rigional clinical association «Phthisiology» Dnipropetrovsk regional Council» during the period 2010 – 2012 were involved. Data about patients contained the data on a case of the disease and the results of the test of drug sensitivity to MBT. XDR – TB was revealed in 7.5% of patients with MDR tuberculosis. In patients with MDR tuberculosis as compared with patients with XDR tuberculosis «new cases» were diagnosed in 19.5% against 18.5% (p <0.05. In patients with MDR tuberculosis and with XDR tuberculosis resistance to the antituberculosis drug more commonly developed to S - 88.5%, E - 55% and Z - 24%. The presence of MDR-TB and XDR-TB prevails in patients, who underwent previous courses of treatment with anti-TB drugs in case history as compared with patients with «new cases» of treatment. The development of resistance to anti-TB drugs depends on the availability of these drugs in the previous treatment regimens.

  4. Antifungal activity of essential oils of Origanum vulgare and Rosmarinus officinalis against three Candida albicans strains

    Directory of Open Access Journals (Sweden)

    Delić Dafina N.

    2013-01-01

    Full Text Available Due to general growing resistance and side effects to common antifungal drugs nowadays, there have been many studies reported on the use of herbal essential oils as antifungal agents in recent years. In this study, essential oils of Origanum vulgare and Rosmarinus officinalis (Lamiaceae were examined for their in vitro antifungal activity against three Candida albicans strains (laboratory - CAL, human pulmonary - CAH, and reference ATCC10231-CAR in comparison to Nystatin (0.30 mg/ml and Fluconazole (2 mg/ml as standard antifungal agents. The antifungal activity was evaluated by comparing inhibition zone diameters obtained both by disc-and well-diffusion assays, as well as by comparing MIC and MBC values detected by microdilution assay. Diffusion test results revealed stronger antifungal effect of O. vulgare against all analyzed C. albicans strains identifying CAL strain as the most susceptible one. Inhibition zones ranged from 12.65 to 25.10 mm depending on the concentrations applied. The highest concentrations of Rosemary essential oil (5.00 mg/ml demonstrated activity against two strains: CAL and CAR ATCC 10231 in both diffusion assays applied, while no antifungal activity was recorded against CAH isolate. Microdilution assay showed that both oils demonstrated the same MIC values for all tested strains (0.11 mg/ml, except MIC value against ATCC strain (0.23 mg/ml obtained for Rosemary essential oil. The obtained results indicated that oregano and rosemary essential oils might be highly effective in the natural prevention treatment of candidiasis, although toxicity assays should be previously preformed. [Projekat Ministarstva nauke Republike Srbije, br. 172058

  5. 75 FR 33317 - Antibacterial Resistance and Diagnostic Device and Drug Development Research for Bacterial...

    Science.gov (United States)

    2010-06-11

    ... scientific and potential research issues in antibacterial drug resistance, rapid diagnostic device... antibacterial drug resistance, mechanisms of resistance, epidemiology of resistance, and issues in the..., 2010, from 8 a.m. to 5 p.m. Location: The public workshop will be held at the Crowne Plaza Hotel, 8777...

  6. Antifungal effect of Echinophora platyloba on expression of CDR1 and CDR2 genes in fluconazole-resistant Candida albicans.

    Science.gov (United States)

    Khajeh, Elias; Hosseini Shokouh, Seyed Javad; Rajabibazl, Masoumeh; Roudbary, Maryam; Rafiei, Sajad; Aslani, Peyman; Farahnejad, Zohreh

    2016-01-01

    Several studies examined the effect of the Echinophora platyloba extract in treatment of azole-resistant Candida albicans clinical isolates. We investigated the effect of E. platyloba extract on expression of CDR1 and CDR2 genes in fluconazole-resistant clinical isolates of C. albicans using real-time PCR. The crude extract of E. platyloba was obtained using percolation method. Using serial dilution method, different concentrations of extract were achieved. Two hundred microlitres of fungal suspension (10(6) CFU/ml) was added to the media and cultured with different concentrations and then incubated at 37 °C for 48 h. The concentration of extract in the first tube, which inhibited the growth of C. albicans, was recorded as the Minimal Inhibitory Concentration (MIC). In order to analyse the expression of CDR1 and CDR2 genes, RNA was extracted from C. albicans isolates before and after treatment with MIC of E. platyloba using glass beads and the denaturing buffer agents in an RNase-free environment and then the cDNA was synthesised and used for real-time PCR assay. Twenty of total of 148 isolates were resistant to fluconazole. The MIC and MFC for the alcoholic extract of E. Platyloba were 64 mg/ml and 128 mg/ml, respectively. Real-time PCR results revealed that the mRNA levels of CDR1 and CDR2 genes significantly declined after incubation with E. Platyloba (both p values Candida species.

  7. Candida albicans AGE3, the ortholog of the S. cerevisiae ARF-GAP-encoding gene GCS1, is required for hyphal growth and drug resistance.

    Directory of Open Access Journals (Sweden)

    Thomas Lettner

    Full Text Available BACKGROUND: Hyphal growth and multidrug resistance of C. albicans are important features for virulence and antifungal therapy of this pathogenic fungus. METHODOLOGY/PRINCIPAL FINDINGS: Here we show by phenotypic complementation analysis that the C. albicans gene AGE3 is the functional ortholog of the yeast ARF-GAP-encoding gene GCS1. The finding that the gene is required for efficient endocytosis points to an important functional role of Age3p in endosomal compartments. Most C. albicans age3Delta mutant cells which grew as cell clusters under yeast growth conditions showed defects in filamentation under different hyphal growth conditions and were almost completely disabled for invasive filamentous growth. Under hyphal growth conditions only a fraction of age3Delta cells shows a wild-type-like polarization pattern of the actin cytoskeleton and lipid rafts. Moreover, age3Delta cells were highly susceptible to several unrelated toxic compounds including antifungal azole drugs. Irrespective of the AGE3 genotype, C-terminal fusions of GFP to the drug efflux pumps Cdr1p and Mdr1p were predominantly localized in the plasma membrane. Moreover, the plasma membranes of wild-type and age3Delta mutant cells contained similar amounts of Cdr1p, Cdr2p and Mdr1p. CONCLUSIONS/SIGNIFICANCE: The results indicate that the defect in sustaining filament elongation is probably caused by the failure of age3Delta cells to polarize the actin cytoskeleton and possibly of inefficient endocytosis. The high susceptibility of age3Delta cells to azoles is not caused by inefficient transport of efflux pumps to the cell membrane. A possible role of a vacuolar defect of age3Delta cells in drug susceptibility is proposed and discussed. In conclusion, our study shows that the ARF-GAP Age3p is required for hyphal growth which is an important virulence factor of C. albicans and essential for detoxification of azole drugs which are routinely used for antifungal therapy. Thus, it

  8. 21 CFR 866.3950 - In vitro human immunodeficiency virus (HIV) drug resistance genotype assay.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false In vitro human immunodeficiency virus (HIV) drug... Serological Reagents § 866.3950 In vitro human immunodeficiency virus (HIV) drug resistance genotype assay. (a) Identification. The in vitro HIV drug resistance genotype assay is a device that consists of nucleic acid reagent...

  9. Evaluation of semisolid agar method for antifungal susceptibility test of T. rubrum

    Directory of Open Access Journals (Sweden)

    Sultana Razia

    2016-08-01

    Full Text Available Background: With increasing fungal disease many newer antifungal drugs are available with different spectrum of activ­ity. Antifungal susceptibility test will help clinicians for selection of effective drug and thereby treatment of patient. Objective: The study was undertaken to perform a simple screening drug susceptibility test of T. rnbrum by Semi Solid Agar Antifungal Susceptibility (SAAS Method: Perfonnance of susceptibility method was assessed by comparing the MICs of three commonly prescribed antifungal agents namely- tluconazole (FCZ, itraconazole (ITZ and terbinafine (TER to the CLSI (Clinical and Laboratory Standard Institute recommended M-38, a broth microdilution method. Results: In SAAS method, among twenty nine T. rubrum, twenty five (86.2% were susceptible (MIC range 0.5-64 µg/ml to Fluconazole (FCZ and four (13.7% were resistant (MIC value >64 µg/ml. In broth microdilution method, among twenty nine T. rubrum, twenty six (89.6% were susceptible (MIC range 0.3-64 µg/ml to FCZ and three (10.3% were resistant (MIC value >64 µg/ml. In case of both ITZ and TER, all were susceptible (MIC range 0.3-64 µg/ml to both methods. The SAAS method demonstrated the susceptibility pattern of T. rubrum against FCZ, ITZ and TER usually within 72 to 96 hours after organism isolation and results were concordance with the results of CLSI broth microdilution method. Conclusion: Though it is a newer method with proper standardization of the test method, SAAS method is simple and easily applicable screening method for susceptibility testing of antifungal agents against dermatophytes in any microbiology laboratories.

  10. Repurposing Clinical Molecule Ebselen to Combat Drug Resistant Pathogens.

    Directory of Open Access Journals (Sweden)

    Shankar Thangamani

    Full Text Available Without a doubt, our current antimicrobials are losing the battle in the fight against newly-emerged multidrug-resistant pathogens. There is a pressing, unmet need for novel antimicrobials and novel approaches to develop them; however, it is becoming increasingly difficult and costly to develop new antimicrobials. One strategy to reduce the time and cost associated with antimicrobial innovation is drug repurposing, which is to find new applications outside the scope of the original medical indication of the drug. Ebselen, an organoselenium clinical molecule, possesses potent antimicrobial activity against clinical multidrug-resistant Gram-positive pathogens, including Staphylococcus, Streptococcus, and Enterococcus, but not against Gram-negative pathogens. Moreover, the activity of ebselen against Gram-positive pathogens exceeded those activities determined for vancomycin and linezolid, drugs of choice for treatment of Enterococcus and Staphylococcus infections. The minimum inhibitory concentrations of ebselen at which 90% of clinical isolates of Enterococcus and Staphylococcus were inhibited (MIC90 were found to be 0.5 and 0.25 mg/L, respectively. Ebselen showed significant clearance of intracellular methicillin-resistant S. aureus (MRSA in comparison to vancomycin and linezolid. We demonstrated that ebselen inhibits the bacterial translation process without affecting mitochondrial biogenesis. Additionally, ebselen was found to exhibit excellent activity in vivo in a Caenorhabditis elegans MRSA-infected whole animal model. Finally, ebselen showed synergistic activities with conventional antimicrobials against MRSA. Taken together, our results demonstrate that ebselen, with its potent antimicrobial activity and safety profiles, can be potentially used to treat multidrug resistant Gram-positive bacterial infections alone or in combination with other antibiotics and should be further clinically evaluated.

  11. Susceptibilidad "in vitro" de cepas de Cryptococcus a 5 drogas antifungicas "In vitro" susceptibility of Cryptococcus strains to 5 antifungal drugs

    Directory of Open Access Journals (Sweden)

    A. J. Bava

    1989-10-01

    Full Text Available Se estudió la susceptibilidad "in vitro" de 24 cepas de 3 especies del género Cryptococcus a 5 drogas antifúngicas (anfotericina B, 5 fluorocitosina, ketoconazol, itraconazol y miconazol. Las mismas se agruparon según su especie, variedad y origen de aislamiento. Para determinar la concentración inhibitoria mínima (C.I.M. de cada droga se empleó el método de dilución en agar con el medio básico nitrogenado para levaduras, adicionado de glucosa. Se obtuvo además la media geométrica de estos valores para cada grupo y se comparó cada uno de ellos. Los resultados obtenidos fueron homogéneos con la sola excepción de las cepas de Cryptococcus sp (no neoformans, en las cuales se detectaron elevados valores de C.I.M. para la 5 fluorocitosina.A comparative study of the "in vitro" susceptibility of 24 Cryptococcus strains to 5 antifungal drugs (amphotericin B, 5 fluorocytosine, miconazole, itraconazole and ketoconazole, was carried out. These strains were grouped according to species, varieties and isolation's origins. The minimum inhibitory concentration (M.I.C. was determinated by the agar dilution technique in yeast nitrogen base agar with dextrose. The mean geometrical of the M.I.C. values of each group was compared with the others. The results obtained were homogeneous with the only exception of the "non neoformans" strains, in which, higher M.I.C. to 5 fluorocytosine values were detected.

  12. "DRUG RESISTANCE PATTERN IN ISOLATED BACTERIA FROM BLOOD CULTURES"

    Directory of Open Access Journals (Sweden)

    A. Sobhani

    2004-05-01

    Full Text Available Bacteremia is an important infectious disease which may lead to death. Common bacteria and pattern of antibiotic resistance in different communities are different and understanding these differences is important. In the present study, relative frequency and pattern of drug resistance have been examined in bacteria isolated from blood cultures in Razi Hospital laboratory. The method of the study was descriptive. Data collection was carried out retrospectively. Total sample consisted of 311 positive blood cultures from 1999 to 2001. Variables under study were bacterial strains, antibiotics examined in antibiogram, microbial resistance, and patients' age and sex. The most common isolated bacteria were Salmonella typhi (22.2% and the least common ones were Citrobacter (1.6%. The highest antibiotic resistance was seen against amoxicillin (88.4%. The proportion of males to females was1: 1/1 and the most common age group was 15-44 (47.3%. Common bacteria and pattern of antibiotic resistance were different in some areas and this subject requires further studies in the future.

  13. Analysis of metal and biocides resistance genes in drug resistance and susceptible Salmonella enterica from food animals

    Science.gov (United States)

    Background Generally drug resistant bacteria carry antibiotic resistance genes and heavy metal and biocide resistance genes on large conjugative plasmids. The presence of these metal and biocide resistance genes in susceptible bacteria are not assessed comprehensively. Hence, WGS data of susceptib...

  14. Candidate genes for cross-resistance against DNA-damaging drugs

    DEFF Research Database (Denmark)

    Wittig, Rainer; Nessling, Michelle; Will, Rainer D

    2002-01-01

    Drug resistance of tumor cells leads to major drawbacks in the treatment of cancer. To identify candidate genes for drug resistance, we compared the expression patterns of the drug-sensitive human malignant melanoma cell line MeWo and three derived sublines with acquired resistance to the DNA...... as several apoptosis-related genes, in particular STK17A and CRYAB. As MPP1 and CRYAB are also among the 14 genes differentially expressed in all three of the drug-resistant sublines, they represent the strongest candidates for resistance against DNA-damaging drugs....

  15. Using drug exposure for predicting drug resistance - A data-driven genotypic interpretation tool.

    Directory of Open Access Journals (Sweden)

    Alejandro Pironti

    Full Text Available Antiretroviral treatment history and past HIV-1 genotypes have been shown to be useful predictors for the success of antiretroviral therapy. However, this information may be unavailable or inaccurate, particularly for patients with multiple treatment lines often attending different clinics. We trained statistical models for predicting drug exposure from current HIV-1 genotype. These models were trained on 63,742 HIV-1 nucleotide sequences derived from patients with known therapeutic history, and on 6,836 genotype-phenotype pairs (GPPs. The mean performance regarding prediction of drug exposure on two test sets was 0.78 and 0.76 (ROC-AUC, respectively. The mean correlation to phenotypic resistance in GPPs was 0.51 (PhenoSense and 0.46 (Antivirogram. Performance on prediction of therapy-success on two test sets based on genetic susceptibility scores was 0.71 and 0.63 (ROC-AUC, respectively. Compared to geno2pheno[resistance], our novel models display a similar or superior performance. Our models are freely available on the internet via www.geno2pheno.org. They can be used for inferring which drug compounds have previously been used by an HIV-1-infected patient, for predicting drug resistance, and for selecting an optimal antiretroviral therapy. Our data-driven models can be periodically retrained without expert intervention as clinical HIV-1 databases are updated and therefore reduce our dependency on hard-to-obtain GPPs.

  16. Transferable and non-transferable drug resistance in enteric bacteria from hospital and from general practice

    DEFF Research Database (Denmark)

    Møller, JK; Bak, AL; Bülow, P

    1976-01-01

    Drug resistance to 8 different antibiotics in Enterobacteriaceae isolated from different hospitals and two groups of general practitioners was studied. Escherichia coli dominated among the 632 strains investigated. Drug resistance was found in 62% of the 512 hospital strains and in 38% of the 120...... strains from general practice. Multiple resistance was common especially in strains from hospital. R factors was found in 23% of the 317 drug-resistant strains from hospital and in 11% of the 46 drug-resistant strains from general practice. Resistance to streptomycin, sulphonamide and tetracycline either...

  17. Evaluation of antifungal activity of standardized extract of Salvia rhytidea Benth. (Lamiaceae) against various Candida isolates.

    Science.gov (United States)

    Salari, S; Bakhshi, T; Sharififar, F; Naseri, A; Ghasemi Nejad Almani, P

    2016-12-01

    Salvia species have long been described in traditional medicine for various indications. Owing to the widespread use of this genus by ethnic populations, especially for various infections ranging from skin disease to gastrointestinal disorders, we were encouraged to determine whether Salvia rhytidea could be effective against fungal infections. Given the increased incidence of candidiasis in the past decade, limits on the use of antifungal drugs, emergence of azole-resistant Candida species and increased incidence of treatment failures, it is necessary to identify a novel agent with antifungal properties. Aim of the study was to evaluate the antifungal properties of S. rhytidea against various Candida isolates. In this study, at first rosmarinic acid content of plant extract was determined. A total of 96 Candida isolates were tested, including the following species: Candida albicans (n=42), Candida glabrata (n=16), Candida tropicalis (n=11), Candida krusei (n=9), Candida parapsilosis (n=9), Candida lusitaniae (n=7) and Candida guilliermondii (n=2). The in vitro antifungal activity of methanolic extracts of S. rhytidea Benth. was evaluated against Candida isolates and compared with that of the standard antifungal drug nystatin by using a broth microdilution method, according to CLSI. Phytochemical screening results showed that the methanolic extract of S. rhytidea Benth. was rich in flavonoids and tannins. The minimal inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) values of S. rhytidea Benth. ranged from 3.125 to>100μg/ml and 6.25 to>100μg/ml respectively. The growth inhibition value displayed that C. tropicalis, C. krusei and C. albicans isolates were most susceptible to S. rhytidea. Findings show that S. rhytidea possesses an antifungal effect against Candida isolates. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  18. Accelerating resistance, inadequate antibacterial drug pipelines and international responses.

    Science.gov (United States)

    Theuretzbacher, Ursula

    2012-04-01

    The pandemic of multidrug-resistant (MDR) pathogens and their continuing spread is beyond dispute. In contrast to the past, today's antibacterial research and development (R&D) pipelines are nearly dry, failing to provide the flow of novel antibiotics required to match the clinical challenges of the multidrug resistance (MDR) crisis. Concerned over the rapidly worsening potential global healthcare crisis caused by MDR bacteria and the lack of robust drug pipelines, several multinational campaigns have issued policy recommendations and have initiated broad discussion with a goal of stimulating the development of novel antibacterial drugs and technologies. These activities have resulted in intensified co-operation between the USA and the EU. The recently announced extensive 'Action plan against the rising threats from antimicrobial resistance' substantially ramps up action within the EU. In recognising the potential crisis caused by MDR and the limited treatment options, the European Commission decided on an unprecedented approach to drive the search for novel antibiotics by integrating the pharmaceutical industry, the research capacities of universities and small companies supported by public funding along with pricing/reimbursement and regulatory bodies. The European Commission has shown leadership and put action plans in place. Only the future will tell whether these initiatives will help curb the impact of the MDR pandemic. Copyright © 2012 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

  19. Interactions between antifungal and antiretroviral agents.

    Science.gov (United States)

    Hughes, Christine A; Foisy, Michelle; Tseng, Alice

    2010-09-01

    Since the advent of combination antiretroviral therapy, the incidence of opportunistic infections has declined and the life expectancy of HIV-infected people has significantly increased. However, opportunistic infections, including fungal diseases, remain a leading cause of hospitalizations and mortality in HIV-infected people. With the availability of several new antiretroviral and antifungal agents, drug-drug interactions emerge as a potential safety concern. Relevant literature was identified using a Medline search of articles published up to March 2010 and a review of conference abstracts. Search terms included HIV, antifungal agents and drug interactions. Original papers and relevant citations were considered for this review. Readers will gain an understanding of the pharmacokinetic properties of antiretroviral and antifungal agents, and insight into significant drug-drug interactions which may require dosage adjustments or a change in therapy. Azole antifungal drugs, with the exception of fluconazole, pose the greatest risk of two-way interactions with antiretroviral drugs through CYP450 enzymes effects. Limited studies suggest the risk of interactions between antiretroviral drugs and echinocandins is much lower. The combination of tenofovir and amphotericin B should be used with caution and close monitoring of renal function is required.

  20. [Tiagabine in drug-resistant epilepsy in children: preliminary study].

    Science.gov (United States)

    Wendorff, J; Popielarczyk, M; Zubiel, M; Sokołowska, D

    2000-01-01

    The aim of the study was the presentation of our preliminary experiences and the data concerning the efficacy and safety of tiagabine in patients below the 12-th year of life. 4 cases of drug--resistant epilepsy--with partial complex attacks in 3 and simple in 1 (frontal epilepsy from supplementary motor area) with multiple seizures in the day were the subject of the study. Tiagabine add-one therapy to CBZ or to VPA was used. Initial period--the dose titration lasted 4 weeks. The stable dosis period amounted to 5 months. The effective dosis of tiagabine was 1 mg/kg/day. In 1 case the seizures completely disappeared and in 3 the frequency decreased to 2-4 times in comparison to frequency per day before the treatment. There were not any side-effects reported which would be the cause of the drug discontinuation. Tiagabine appeared to be an effective and safe drug in resistant epilepsy in children below 12 years of age.

  1. From multidrug-resistant to extensively drug-resistant tuberculosis in Lisbon, Portugal: the stepwise mode of resistance acquisition.

    Science.gov (United States)

    Perdigão, João; Macedo, Rita; Silva, Carla; Machado, Diana; Couto, Isabel; Viveiros, Miguel; Jordao, Luisa; Portugal, Isabel

    2013-01-01

    The development and transmission of extensively drug-resistant (XDR) tuberculosis (TB) constitutes a serious threat to the effective control of TB in several countries. Here, in an attempt to further elucidate the dynamics of the acquisition of resistance to second-line drugs and investigate an eventual role for eis promoter mutations in aminoglycoside resistance, we have studied a set of multidrug-resistant (MDR)/XDR-TB isolates circulating in Lisbon, Portugal. Forty-four MDR-TB or XDR-TB isolates were genotyped and screened for mutations in genes associated with second-line drug resistance, namely tlyA, gyrA, rrs and eis. The most prevalent mutations found in each gene were Ins755GT in tlyA, A1401G in rrs, G-10A in eis and S91P in gyrA. Additionally, two genetic clusters were found in this study: Lisboa3 and Q1. The characteristic mutational profile found among recent XDR-TB circulating in Lisbon was also found in MDR-TB strains isolated in the 1990s. Also investigated was the resistance level conferred by eis G-10A mutations, revealing that eis G-10A mutations may result in amikacin resistance undetectable by widely used phenotypic assays. The analysis of the distribution of the mutations found by genetic clustering showed that in the Q1 cluster, two mutations, gyrA D94A and rrs A1401G, were enough to ensure development of XDR-TB from an MDR strain. Moreover, in the Lisboa3 cluster it was possible to elaborate a model in which the development of low-level kanamycin resistance was at the origin of the emergence of XDR-TB strains that can be discriminated by tlyA mutations.

  2. Persistence of Transmitted Drug Resistance among Subjects with Primary Human Immunodeficiency Virus Infection▿

    Science.gov (United States)

    Little, Susan J.; Frost, Simon D. W.; Wong, Joseph K.; Smith, Davey M.; Pond, Sergei L. Kosakovsky; Ignacio, Caroline C.; Parkin, Neil T.; Petropoulos, Christos J.; Richman, Douglas D.

    2008-01-01

    Following interruption of antiretroviral therapy among individuals with acquired drug resistance, preexisting drug-sensitive virus emerges relatively rapidly. In contrast, wild-type virus is not archived in individuals infected with drug-resistant human immunodeficiency virus (HIV) and thus cannot emerge rapidly in the absence of selective drug pressure. Fourteen recently HIV-infected patients with transmitted drug-resistant virus were followed for a median of 2.1 years after the estimated date of infection (EDI) without receiving antiretroviral therapy. HIV drug resistance and pol replication capacity (RC) in longitudinal plasma samples were assayed. Resistance mutations were characterized as pure populations or mixtures. The mean time to first detection of a mixture of wild-type and drug-resistant viruses was 96 weeks (1.8 years) (95% confidence interval, 48 to 192 weeks) after the EDI. The median time to loss of detectable drug resistance using population-based assays ranged from 4.1 years (conservative estimate) to longer than the lifetime of the individual (less conservative estimate). The transmission of drug-resistant virus was not associated with virus with reduced RC. Sexual transmission of HIV selects for highly fit drug-resistant variants that persist for years. The prolonged persistence of transmitted drug resistance strongly supports the routine use of HIV resistance genotyping for all newly diagnosed individuals. PMID:18353964

  3. Antimicrobial drug resistance: "Prediction is very difficult, especially about the future".

    Science.gov (United States)

    Courvalin, Patrice

    2005-10-01

    Evolution of bacteria towards resistance to antimicrobial drugs, including multidrug resistance, is unavoidable because it represents a particular aspect of the general evolution of bacteria that is unstoppable. Therefore, the only means of dealing with this situation is to delay the emergence and subsequent dissemination of resistant bacteria or resistance genes. Resistance to antimicrobial drugs in bacteria can result from mutations in housekeeping structural or regulatory genes. Alternatively, resistance can result from the horizontal acquisition of foreign genetic information. The 2 phenomena are not mutually exclusive and can be associated in the emergence and more efficient spread of resistance. This review discusses the predictable future of the relationship between antimicrobial drugs and bacteria.

  4. Risk Factors for Acquisition of Drug Resistance during Multidrug-Resistant Tuberculosis Treatment, Arkhangelsk Oblast, Russia, 2005–2010

    Science.gov (United States)

    Ershova, Julia; Vlasova, Natalia; Nikishova, Elena; Tarasova, Irina; Eliseev, Platon; Maryandyshev, Andrey O.; Shemyakin, Igor G.; Kurbatova, Ekaterina; Cegielski, J. Peter

    2015-01-01

    Acquired resistance to antituberculosis drugs decreases effective treatment options and the likelihood of treatment success. We identified risk factors for acquisition of drug resistance during treatment for multidrug-resistant tuberculosis (MDR TB) and evaluated the effect on treatment outcomes. Data were collected prospectively from adults from Arkhangelsk Oblast, Russia, who had pulmonary MDR TB during 2005–2008. Acquisition of resistance to capreomycin and of extensively drug-resistant TB were more likely among patients who received 3 effective drugs (9.4% vs. 0% and 8.6% vs. 0.8%, respectively). Poor outcomes were more likely among patients with acquired capreomycin resistance (100% vs. 25.9%), acquired ofloxacin resistance (83.6% vs. 22.7%), or acquired extensive drug resistance (100% vs. 24.4%). To prevent acquired drug resistance and poor outcomes, baseline susceptibility to first- and second-line drugs should be determined quickly, and treatment should be adjusted to contain >3 effective drugs. PMID:25988954

  5. Rapid diagnosis of tuberculosis. Detection of drug resistance mechanisms.

    Science.gov (United States)

    Viñuelas-Bayón, Jesús; Vitoria, María Asunción; Samper, Sofía

    2017-10-01

    Tuberculosis is still a serious public health problem, with 10.8 million new cases and 1.8 million deaths worldwide in 2015. The diversity among members of the Mycobacterium tuberculosis complex, the causal agent of tuberculosis, is conducive to the design of different methods for rapid diagnosis. Mutations in the genes involved in resistance mechanisms enable the bacteria to elude the treatment. We have reviewed the methods for the rapid diagnosis of M. tuberculosis complex and the detection of susceptibility to drugs, both of which are necessary to prevent the onset of new resistance and to establish early, appropriate treatment. Copyright © 2017 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  6. Low-level quinolone-resistance in multi-drug resistant typhoid

    International Nuclear Information System (INIS)

    Mirza, S.H.; Khan, M.A.

    2008-01-01

    To find out the frequency of low-level quinolone-resistance in Multi-Drug Resistant (MDR) typhoid using nalidixic acid screening disc. Blood was obtained from suspected cases of typhoid fever and cultured in to BacT/ALERT. The positive blood cultures bottles were subcultured. The isolates were identified by colony morphology and biochemical tests using API-20E galleries. Susceptibility testing of isolates was done by modified Kirby-Bauer disc diffusion method on Muellar Hinton Agar. For the isolates, which were resistant to nalidixic acid by disc diffusion method, Minimal Inhibitory Concentrations (MICs) of ciprofloxacin and nalidixic acid were determined by using the E-test strips. Disc diffusion susceptibility tests and MICs were interpreted according to the guidelines provided by National Committee for Control Laboratory Standard (NCCLS). A total of 21(65.5%) out of 32 isolates of Salmonellae were nalidixic acid-resistant by disk diffusion method. All the nalidixic acid-resistant isolates by disc diffusion method were confirmed by MICs for both ciprofloxacin and nalidixic acid. All the nalidixic acid-resistant isolates had a ciprofloxacin MIC of 0.25-1 microg/ml (reduced susceptibility) and nalidixic acid MICs > 32 microg (resistant). Out of all Salmonella isolates, 24 (75%) were found to be MDR, and all were S. typbi. Low-level quinolone-resistance in typhoid was high in this small series. Screening for nalidixic acid resistance with a 30 microg nalidixic acid disk is a reliable and cost-effective method to detect low-level fluoroquinolone resistance, especially in the developing countries. (author)

  7. Consensus drug resistance mutations for epidemiological surveillance: basic principles and potential controversies

    OpenAIRE

    Shafer, Robert W; Rhee, Soo-Yon; Bennett, Diane E

    2008-01-01

    Programmes that monitor local, national and regional levels of transmitted HIV-1 drug resistance inform treatment guidelines and provide feedback on the success of HIV-1 treatment and prevention programmes. The World Health Organization (WHO) has established a global programme for genotypic surveillance of HIV-1 drug resistance and has recommended the adoption of a consensus definition of genotypic drug resistance. Such a definition is necessary to accurately compare transmitted drug resistan...

  8. Treatment Options for Carbapenem-Resistant and Extensively Drug-Resistant Acinetobacter baumannii Infections

    Science.gov (United States)

    Viehman, J. Alexander; Nguyen, Minh-Hong; Doi, Yohei

    2014-01-01

    Acinetobacter baumannii is a leading cause of healthcare-associated infections worldwide. Due to various intrinsic and acquired mechanisms of resistance, most β-lactam agents are not effective against many strains, and carbapenems have played an important role in therapy. Recent trends show many infections are caused by carbapenem-resistant, or even extensively drug-resistant (XDR) strains, for which effective therapy is not well established. Evidence to date suggests that colistin constitutes the backbone of therapy, but the unique pharmacokinetic properties of colistin have led many to suggest the use of combination antimicrobial therapy. However, the combination of agents and dosing regimens that delivers the best clinical efficacy while minimizing toxicity is yet to be defined. Carbapenems, sulbactam, rifampin and tigecycline have been the most studied in the context of combination therapy. Most data regarding therapy for invasive, resistant A. baumannii infections come from uncontrolled case series and retrospective analyses, though some clinical trials have been completed and others are underway. Early institution of appropriate antimicrobial therapy is shown to consistently improve survival of patients with carbapenem-resistant and XDR A. baumannii infection, but the choice of empiric therapy in these infections remains an open question. This review summarizes the most current knowledge regarding the epidemiology, mechanisms of resistance, and treatment considerations of carbapenem-resistant and XDR A. baumannii. PMID:25091170

  9. Deciphering an outbreak of drug-resistant Mycobacterium tuberculosis.

    Science.gov (United States)

    Dahle, Ulf R; Sandven, Per; Heldal, Einar; Mannsaaker, Turid; Caugant, Dominique A

    2003-01-01

    There have been ample warnings that multidrug-resistant (MDR) tuberculosis (TB) will continue to emerge if countries do not strengthen their control of TB. In low-incidence European countries, however, these warnings have been substantiated mainly by outbreaks in association with human immunodeficiency virus (HIV)-positive patients. The aim of this study was to investigate an outbreak of infection with MDR and drug-resistant Mycobacterium tuberculosis that was diagnosed among 20 HIV-negative patients living in Norway. Of these, 19 were immigrants from East Africa and one was an ethnic Norwegian. We wanted to find out if transmission had taken place in Norway or abroad and to identify the genetic basis of drug resistance. The strains were analyzed by IS6110 restriction fragment length polymorphism, antibiotic susceptibility tests, spoligotyping, reverse hybridization to regions of the rpoB gene, and sequencing of the katG gene. Epidemiological links between the patients were mapped, and the strains were compared to those isolated in 36 other countries and regions. All strains were resistant to isoniazid and carried Ala234Gly, Ser315Thr, and Arg463Leu substitutions in the katG gene. Eleven strains were MDR and carried a Ser531Leu substitution in the rpoB gene. MDR was acquired in the index patient after arrival in Norway. Links were found among 14 patients. The strain was imported from Somalia but acquired MDR and was transmitted in Norway. This demonstrated that MDR strains are not necessarily imported from high-incidence countries and can be highly communicable. The outbreak underscores a deficiency in the TB control measures employed in many countries and challenges the adequacy of the policy of screening immigrants for TB only on arrival.

  10. Role of integrated cancer nanomedicine in overcoming drug resistance.

    Science.gov (United States)

    Iyer, Arun K; Singh, Amit; Ganta, Srinivas; Amiji, Mansoor M

    2013-11-01

    Cancer remains a major killer of mankind. Failure of conventional chemotherapy has resulted in recurrence and development of virulent multi drug resistant (MDR) phenotypes adding to the complexity and diversity of this deadly disease. Apart from displaying classical physiological abnormalities and aberrant blood flow behavior, MDR cancers exhibit several distinctive features such as higher apoptotic threshold, aerobic glycolysis, regions of hypoxia, and elevated activity of drug-efflux transporters. MDR transporters play a pivotal role in protecting the cancer stem cells (CSCs) from chemotherapy. It is speculated that CSCs are instrumental in reviving tumors after the chemo and radiotherapy. In this regard, multifunctional nanoparticles that can integrate various key components such as drugs, genes, imaging agents and targeting ligands using unique delivery platforms would be more efficient in treating MDR cancers. This review presents some of the important principles involved in development of MDR and novel methods of treating cancers using multifunctional-targeted nanoparticles. Illustrative examples of nanoparticles engineered for drug/gene combination delivery and stimuli responsive nanoparticle systems for cancer therapy are also discussed. © 2013.

  11. Identification of New Drug Targets in Multi-Drug Resistant Bacterial Infections

    Science.gov (United States)

    2012-10-01

    plants (12), and the chorismate pathway is absent in humans. Therefore, our hypothesis is that these proteins are potential therapeutic targets in...Tyr, and other aromatic compounds (e.g. folate, alkaloids ) (13, 14). Although PSCVT has been previously suggested as a drug target for antibacterials...most research in this field has concentrated on Plasmodium falciparum (antimalarials) and glyphosate resistant plants (12, 15, 16

  12. HIV subtype and drug resistance patterns among drug naïve ...

    African Journals Online (AJOL)

    In the 14 drug-naïve subjects, no primary resistance-associated mutations were found, but secondary mutations were identified in 7 different codons of the gene coding for protease: PR K20I, M36I, L63A/P/V, V82I, L10M/I and I93L. In addition, the K238R mutation was identified in the reverse transcriptase gene of 3 viruses.

  13. Detection of First-Line Drug Resistance Mutations and Drug-Protein Interaction Dynamics from Tuberculosis Patients in South India.

    Science.gov (United States)

    Nachappa, Somanna Ajjamada; Neelambike, Sumana M; Amruthavalli, Chokkanna; Ramachandra, Nallur B

    2017-08-16

    Diagnosis of drug-resistant tuberculosis predominantly relies on culture-based drug susceptibility testing, which take weeks to produce a result and a more time-efficient alternative method is multiplex allele-specific PCR (MAS-PCR). Also, understanding the role of mutations in causing resistance helps better drug designing. To evaluate the ability of MAS-PCR in the detection of drug resistance and to understand the mechanism of interaction of drugs with mutant proteins in Mycobacterium tuberculosis. Detection of drug-resistant mutations using MAS-PCR and validation through DNA sequencing. MAS-PCR targeted five loci on three genes, katG 315 and inhA -15 for the drug isoniazid (INH), and rpoB 516, 526, and 531 for rifampicin (RIF). Furthermore, the sequence data were analyzed to study the effect on interaction of the anti-TB drug molecule with the target protein using in silico docking. We identified drug-resistant mutations in 8 out of 114 isolates with 2 of them as multidrug-resistant TB using MAS-PCR. DNA sequencing confirmed only six of these, recording a sensitivity of 85.7% and specificity of 99.3% for MAS-PCR. Molecular docking showed estimated free energy of binding (ΔG) being higher for RIF binding with RpoB S531L mutant. Codon 315 in KatG does not directly interact with INH but blocks the drug access to active site. We propose DNA sequencing-based drug resistance detection for TB, which is more accurate than MAS-PCR. Understanding the action of resistant mutations in disrupting the normal drug-protein interaction aids in designing effective drug alternatives.

  14. Extensively and Pre-Extensively Drug Resistant Tuberculosis in Clinical Isolates of Multi-Drug Resistant Tuberculosis Using Classical Second Line Drugs (Levofloxacin and Amikacin)

    International Nuclear Information System (INIS)

    Mirza, I. A.; Khan, F. A.; Khan, K. A.; Satti, L.; Ghafoor, T.; Fayyaz, M.

    2015-01-01

    Objective:To find out the frequency of Extensively Drug Resistant (XDR) and pre-XDR tuberculosis in clinical isolates of Multi-Drug Resistant (MDR) Tuberculosis (TB) by determining the susceptibilities against Levofloxacin and Amikacin (classical second line antituberculosis drugs). Study Design: A descriptive cross-sectional study. Place and Duration of Study: Microbiology Department, Armed Forces Institute of Pathology (AFIP), Rawalpindi, from September 2011 to August 2013. Methodology: Amikacin (AK) and Levofloxacin (LEVO) were obtained in chemically pure form from Sigma (Taufkirchen, Germany). The breakpoint concentration used for AK was 1.0 micro g/ml and for LEVO 2.0 micro g/ml. Mycobacterial Growth Indicator Tube (MGIT) 960 system was used to carry out drug susceptibility testing as per recommended protocol. Results: A total of 3 MDR-TB isolates (3 percentage) turned out to be XDR-TB based upon simultaneous resistance to injectable second line antituberculosis drug AK and one of the fluoro-quinolones (LEVO). A total of 24 MDR-TB isolates (24 percentage) were found to be pre-XDR based upon resistance to LEVO alone. Treatment status record of patients with XDR and pre-XDRTB isolates revealed that majority of patients had received fluoroquinolones (FQs) during the course of treatment. Conclusion: XDR-TB has started to emerge in MDR-TB isolates in our set up. The worrying sign is the high frequency of pre-XDR tuberculosis. Urgent steps need to be taken to stem the tide of pre-XDR-TB in our population. It is thus recommended to develop facilities to carry out drug susceptibility testing to monitor the status of pre-XDR and XDR-TB in our population. (author)

  15. Liquid and vapour-phase antifungal activities of essential oils against Candida albicans and non-albicans Candida.

    Science.gov (United States)

    Mandras, Narcisa; Nostro, Antonia; Roana, Janira; Scalas, Daniela; Banche, Giuliana; Ghisetti, Valeria; Del Re, Simonetta; Fucale, Giacomo; Cuffini, Anna Maria; Tullio, Vivian

    2016-08-30

    The management of Candida infections faces many problems, such as a limited number of antifungal drugs, toxicity, resistance of Candida to commonly antifungal drugs, relapse of Candida infections, and the high cost of antifungal drugs. Though azole antifungal agents and derivatives continue to dominate as drugs of choice against Candida infections, there are many available data referring to the anticandidal activity of essential oils. Since we have previous observed a good antimicrobial activity of some essential oils against filamentous fungi, the aim of this study was to extend the research to evaluate the activity of the same oils on Candida albicans, C.glabrata and C.tropicalis clinical strains, as well as the effects of related components. Essential oils selection was based both on ethnomedicinal use and on proved antibacterial and/or antifungal activity of some of these oils. Fluconazole and voriconazole were used as reference drugs. The minimum inhibitory concentration (MIC) and the minimal fungicidal concentration (MFC) of essential oils (thyme red, fennel, clove, pine, sage, lemon balm, and lavender) and their major components were investigated by the broth microdilution method (BM) and the vapour contact assay (VC). Using BM, pine oil showed the best activity against all strains tested, though C.albicans was more susceptible than C.glabrata and C.tropicalis (MIC50-MIC90 = 0.06 %, v/v). On the contrary, sage oil displayed a weak activity (MIC50-MIC90 = 1 %, v/v). Thyme red oil (MIC50-MIC90 ≤ 0.0038 %, v/v for C.albicans and C.tropicalis, and 0.0078- Candida spp., including fluconazole/voriconazole resistant strains. These data encourage adequately controlled and randomized clinical investigations. The use in vapour phase could have additional advantages without requiring direct contact, resulting in easy of environmental application such as in hospital, and/or in school.

  16. Overcoming drug resistance in hormone- and drug-refractory prostate cancer cell line, PC-3 by docetaxel and gossypol combination.

    Science.gov (United States)

    Cengiz, Ercument; Karaca, Burcak; Kucukzeybek, Yuksel; Gorumlu, Gurbuz; Gul, Mustafa K; Erten, Cigdem; Atmaca, Harika; Uzunoglu, Selim; Karabulut, Bulent; Sanli, Ulus A; Uslu, Ruchan

    2010-03-01

    Drug resistance is a significant challenge of daily oncology practice. Docetaxel and gossypol both have antitumoral activity in hormone-refractory prostate cancer (HRPC). Our results revealed that docetaxel and gossypol were synergistically cytotoxic and apoptotic in PC-3 cells in a dose- and time-dependent manner. We further investigated the expression profiles of genes involved in drug resistance and metabolism with a Human Cancer Drug Resistance and Metabolism PCR Array (SuperArray). Six of the 84 genes that are known to regulate drug resistance, metabolism, cell cycle, DNA repair and oncogenesis were downregulated >or=3-fold change by the combination treatment. These results may be important in devising mechanism-based and targeted therapeutic strategies for prostate cancer, especially in devising combination therapy for drug resistant prostate cancers.

  17. Ion channels and transporters in the development of drug resistance in cancer cells

    DEFF Research Database (Denmark)

    Hoffmann, Else Kay; Lambert, Ian Henry

    2014-01-01

    Multi-drug resistance (MDR) to chemotherapy is the major challenge in the treatment of cancer. MDR can develop by numerous mechanisms including decreased drug uptake, increased drug efflux and the failure to undergo drug-induced apoptosis. Evasion of drug-induced apoptosis through modulation of ion...

  18. The Culturable Soil Antibiotic Resistome: A Community of Multi-Drug Resistant Bacteria

    OpenAIRE

    Walsh, Fiona; Duffy, Brion

    2013-01-01

    Understanding the soil bacterial resistome is essential to understanding the evolution and development of antibiotic resistance, and its spread between species and biomes. We have identified and characterized multi-drug resistance (MDR) mechanisms in the culturable soil antibiotic resistome and linked the resistance profiles to bacterial species. We isolated 412 antibiotic resistant bacteria from agricultural, urban and pristine soils. All isolates were multi-drug resistant, of which greater ...

  19. Nucleoside Derived Antibiotics to Fight Microbial Drug Resistance: New Utilities for an Established Class of Drugs?

    Science.gov (United States)

    Serpi, Michaela; Ferrari, Valentina; Pertusati, Fabrizio

    2016-12-08

    Novel antibiotics are urgently needed to combat the rise of infections due to drug-resistant microorganisms. Numerous natural nucleosides and their synthetically modified analogues have been reported to have moderate to good antibiotic activity against different bacterial and fungal strains. Nucleoside-based compounds target several crucial processes of bacterial and fungal cells such as nucleoside metabolism and cell wall, nucleic acid, and protein biosynthesis. Nucleoside analogues have also been shown to target many other bacterial and fungal cellular processes although these are not well characterized and may therefore represent opportunities to discover new drugs with unique mechanisms of action. In this Perspective, we demonstrate that nucleoside analogues, cornerstones of anticancer and antiviral treatments, also have great potential to be repurposed as antibiotics so that an old drug can learn new tricks.

  20. Incidence of multidrug-resistant, extensively drug-resistant and pan-drug-resistant bacteria in children hospitalized at Dr. Hasan Sadikin general hospital Bandung Indonesia

    Science.gov (United States)

    Adrizain, R.; Suryaningrat, F.; Alam, A.; Setiabudi, D.

    2018-03-01

    Antibiotic resistance has become a global issue, with 700,000 deaths attributable to multidrug-resistance (MDR) occurring each year. Centers for Disease Control and Prevention (CDC) show rapidly increasing rates of infection due to antibiotic-resistant bacteria. The aim of the study isto describe the incidence of MDR, extensively drug-resistant (XDR) and pan drug-resistant (PDR) in Enterococcus spp., Staphylococcus aureus, K. pneumonia, Acinetobacter baumanii, P. aeruginosin, and Enterobacter spp. (ESKAPE) pathogens in children admitted to Dr. Hasan Sadikin Hospital. All pediatric patients having blood culture drawn from January 2015 to December 2016 were retrospectively studied. Data include the number of drawn blood culture, number of positive results, type of bacteria, sensitivity pattern. International standard definitions for acquired resistance by ECDC and CDC was used as definitions for MDR, XDR and PDR bacteria. From January 2015 to December 2016, 299 from 2.542 (11.7%) blood culture was positive, with Staphylococcus aureus, Enterococcus spp., Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter spp., respectively 5, 6, 24, 5, 20 with total 60 (20%). The MDR and XDR pathogen found were 47 and 13 patients, respectively.

  1. Crystal Structure of the New Investigational Drug Candidate VT-1598 in Complex with Aspergillus fumigatus Sterol 14α-Demethylase Provides Insights into Its Broad-Spectrum Antifungal Activity

    Energy Technology Data Exchange (ETDEWEB)

    Hargrove, Tatiana Y.; Garvey, Edward P.; Hoekstra, William J.; Yates, Christopher M.; Wawrzak, Zdzislaw; Rachakonda, Girish; Villalta, Fernando; Lepesheva, Galina I.

    2017-05-01

    ABSTRACT

    Within the past few decades, the incidence and complexity of human fungal infections have increased, and therefore, the need for safer and more efficient, broad-spectrum antifungal agents is high. In the study described here, we characterized the new tetrazole-based drug candidate VT-1598 as an inhibitor of sterol 14α-demethylase (CYP51B) from the filamentous fungusAspergillus fumigatus. VT-1598 displayed a high affinity of binding to the enzyme in solution (dissociation constant, 13 ± 1 nM) and in the reconstituted enzymatic reaction was revealed to have an inhibitory potency stronger than the potencies of all other simultaneously tested antifungal drugs, including fluconazole, voriconazole, ketoconazole, and posaconazole. The X-ray structure of the VT-1598/A. fumigatusCYP51 complex was determined and depicts the distinctive binding mode of the inhibitor in the enzyme active site, suggesting the molecular basis of the improved drug potency and broad-spectrum antifungal activity. These data show the formation of an optimized hydrogen bond between the phenoxymethyl oxygen of VT-1598 and the imidazole ring nitrogen of His374, the CYP51 residue that is highly conserved across fungal pathogens and fungus specific. Comparative structural analysis ofA. fumigatusCYP51/voriconazole andCandida albicansCYP51/VT-1161 complexes supports the role of H bonding in fungal CYP51/inhibitor complexes and emphasizes the importance of an optimal distance between this interaction and the inhibitor-heme iron interaction. Cellular experiments using twoA. fumigatusstrains (strains 32820 and 1022) displayed a direct

  2. Mycobacteria: laboratory methods for testing drug sensitivity and resistance

    Science.gov (United States)

    Canetti, G.; Froman, S.; Grosset, J.; Hauduroy, P.; Langerová, Miloslava; Mahler, H. T.; Meissner, Gertrud; Mitchison, D. A.; Šula, L.

    1963-01-01

    In its seventh report, published in 1960, the WHO Expert Committee on Tuberculosis “noted the need for international standards for the definition and determination of drug resistance which will permit comparisons to be made from one area to another, and recommended that the World Health Organization take appropriate steps to establish such standards”.10 Acting on this recommendation, WHO took the first step towards standardization by convening in Geneva, in December 1961, an informal international meeting of specialists in the bacteriology of tuberculosis. At this meeting an attempt was made to formulate prerequisites for reliable sensitivity tests and to specify the technical procedures for them. The first part of the present paper is a joint contribution by the participants in the meeting, summarizing the general conclusions reached and recommendations made with regard to tests of sensitivity to the three main antituberculosis drugs—isoniazid, streptomycin and p-aminosalicylic acid. The other three parts describe, in turn, three different tests for determining drug sensitivity—the absolute-concentration method, the resistance-ratio method and the proportion method—that are generally considered to give reasonably accurate results. PMID:14102034

  3. Surgical management of cavernous malformations coursing with drug resistant epilepsy

    Directory of Open Access Journals (Sweden)

    Mario Arturo Alonso-Vanegas

    2012-01-01

    Full Text Available Cerebral cavernous malformations (CM are dynamic lesions characterized by continuous size changes and repeated bleeding. When involving cortical tissue, CM pose a significant risk for the development of drug-resistant epilepsy, which is thought to be result of an altered neuronal network caused by the lesion itself and its blood degradation products. Preoperative evaluation should comprise a complete seizure history, neurological examination, epilepsy-oriented MRI, EEG, video-EEG, completed with SPECT, PET, functional MRI and/or invasive monitoring as needed. Radiosurgery shows variable rates of seizure freedom and a high incidence of complications, thus microsurgical resection remains the optimal treatment for CM coursing with drug-resistant epilepsy.Two thirds of patients reach Engel I class at three-year follow-up, regardless of lobar location. Those with secondarily generalized seizures, a higher seizure frequency, and generalized abnormalities on preoperative or postoperative EEG, show poorer outcomes, while factors such as gender, duration of epilepsy, lesion size, age, bleeding at the time of surgery, do not correlate consistently with seizure outcome. Electrocorticography and a meticulous removal of all cortical hemosiderin –beyond pure lesionectomy– reduce the risk of symptomatic recurrences.

  4. Emergence of fluoroquinolone resistance among drug resistant tuberculosis patients at a tertiary care facility in Karachi, Pakistan.

    Science.gov (United States)

    Zaidi, Syed Mohammad Asad; Haseeb, Abdul; Habib, Shifa Salman; Malik, Amyn; Khowaja, Saira; SaifUllah, Nausheen; Rizvi, Nadeem

    2017-07-25

    Pakistan is classified as one of the high multi-drug resistant tuberculosis (MDR-TB) burden countries. A poorly regulated private sector, over-prescription of antibiotics and self-medication has led to augmented rates of drug-resistance in the country. Pakistan's first national anti-tuberculosis drug resistance survey identified high prevalence of fluoroquinolone resistance among MDR-TB patients. Further institutional evidence of fluoroquinolone drug-resistance can support re-evaluation of treatment regimens as well as invigorate efforts to control antibiotic resistance in the country. In this study, data for drug-susceptibility testing (DST) was retrospectively analyzed for a total of 133 patients receiving MDR-TB treatment at the Chest Department of Jinnah Postgraduate Medical Center, Karachi, Pakistan. Frequency analyses for resistance patterns was carried out and association of fluoroquinolone (ofloxacin) resistance with demographics and past TB treatment category were assessed. Within first-line drugs, resistance to isoniazid was detected in 97.7% of cases, followed by rifampicin (96.9%), pyrazinamide (86.4%), ethambutol (69.2%) and streptomycin (64.6%). Within second-line drugs, ofloxacin resistance was detected in 34.6% of cases. Resistance to ethionamide and amikacin was 2.3% and 1.6%, respectively. Combined resistance of oflaxacin and isoniazid was detected in 33.9% of cases. Age, gender and past TB treatment category were not significantly associated with resistance to ofloxacin. Fluoroquinolone resistance was observed in an alarmingly high proportion of MDR-TB cases. Our results suggest caution in their use for empirical management of MDR-TB cases and recommended treatment regimens for MDR-TB may require re-evaluation. Greater engagement of private providers and stringent pharmacy regulations are urgently required.

  5. Multidrug-resistant and extensively drug-resistant tuberculosis: a review of current concepts and future challenges.

    Science.gov (United States)

    Günther, Gunar

    2014-06-01

    Multidrug-resistant and extensively drug-resistant tuberculosis are recent global health issues, which makes tuberculosis - after the success of short course treatment during the second half of the last century - a major health challenge. Globalisation, health inequalities, competing economic interests and political instability contribute substantially to the spread of drug-resistant strains, which are associated with high rates of morbidity and mortality. Issues such as increasing transmission of drug-resistant strains, poor diagnostic coverage and a lengthy, toxic treatment need to be overcome by innovative approaches to tuberculosis control, prevention, diagnostics and treatment. This review addresses recent developments and future concepts. © 2014 Royal College of Physicians.

  6. Antifungal activity of crude extracts of Gladiolus dalenii van Geel ...

    African Journals Online (AJOL)

    Bulb extracts of Gladiolus dalenii reportedly used in the treatment of fungal infections in HIV/AIDS patients in the Lake Victoria region were tested for antifungal activity using the disc diffusion assay technique. Commercially used antifungal drugs, Ketaconazole and Griseofulvin (Cosmos Pharmaceuticals) were used as ...

  7. Combinations against combinations: associations of anti-HIV 1 reverse transcriptase drugs challenged by constellations of drug resistance mutations.

    Science.gov (United States)

    Maga, Giovanni; Spadari, Silvio

    2002-02-01

    The reverse transcriptase inhibitors still represent the majority of the clinically used anti-HIV drugs and constitute the main backbone of currently employed combinatorial regimens. A major obstacle to successfull chemotherapic eradication of HIV is the emergence of viral strains resistant to the drugs in use. Counteracting the emergence of resistance necessitates alternating the panel of agents employed. In order to rationally design alternative drug combinations, physicians not only must know the genotype of the emerging viral strains, but should also be able to correlate it with its resistant phenotype. However, resistant viral strains usually carry multiple mutations, whose reciprocal influences on the overall level of resistance are largely unknown. Moreover, the choice of agents to be combined must take in account drug-drug interactions and adverse metabolic effects. This review will outline the main pharmacological and clinical features of the currently utilised anti-reverse transcriptase drugs, as well as the correspondent resistance profiles selected during therapy. A major focus will be on the reciprocal influence of drug associations on their own metabolism as well as on the interacting effects of the selected combinations of drug resistance mutations.

  8. The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump

    NARCIS (Netherlands)

    Zaman, G. J.; Flens, M. J.; van Leusden, M. R.; de Haas, M.; Mülder, H. S.; Lankelma, J.; Pinedo, H. M.; Scheper, R. J.; Baas, F.; Broxterman, H. J.

    1994-01-01

    The multidrug-resistance associated protein MRP is a 180- to 195-kDa membrane protein associated with resistance of human tumor cells to cytotoxic drugs. We have investigated how MRP confers drug resistance in SW-1573 human lung carcinoma cells by generating a subline stably transfected with an

  9. Drug resistance and genetic diversity of Plasmodium falciparum parasites from Suriname

    NARCIS (Netherlands)

    Peek, Ron; van Gool, Tom; Panchoe, Daynand; Greve, Sophie; Bus, Ellen; Resida, Lesley

    2005-01-01

    Plasmodium falciparum in Suriname was studied for the presence of drug resistance and genetic variation in blood samples of 86 patients with symptomatic malaria. Drug resistance was predicted by determining point mutations in the chloroquine resistance marker of the P. falciparum chloroquine

  10. Drug Resistance versus Spiritual Resistance: A Comparative Analysis from the Perspective of Spiritual Health

    Directory of Open Access Journals (Sweden)

    Mohammad Baqer Mohammadi Laini

    2014-12-01

    Full Text Available Background and Objectives: Taking into account a few principles concerning human being, it becomes plausible that the human spirit would also have a similar reaction to spiritual “medicine” provided to it. In order to better understand how this is possible, we must consider the means by which the human spirit becomes resistant to spiritual remedies and compare them with the resistance developed by the body against physical drugs. As such, this research aimed at creating a comparative analysis between the elements that cause the human spirit to become resistant against spiritual remedies in comparison to the body’s resistance against physical treatments (e.g. drugs and other physical treatment. Methods: The research at hand highlights the conclusions of an overall study of the Holy Quran, books of Islamic narration, and extensive Internet research concerning this subject. With these resources, the various aspects of the spirit’s resistance against spiritual remedies were discussed in detail. Results: According to Holy Quran and Islamic narrations: Based on the expectations which God has of man, his heart (i.e. spirit has the potential to fall under one of two categories – positive or negative. An afflicted heart may at times, like an afflicted body, become resistant against a remedy designed to cure it. In both cases of physical or metaphysical resistance, the underlying element that causes this resistance as well as the symptoms which accompany it are similar to one another. Having considered the teachings found in religious texts, this research discovered the underlying causes of spiritual resistance, and outlined some solutions which can prevent this issue from arising in the first place. Conclusion: Based on the standards of health and spiritual wellbeing as outlined in Holy Quran, it is said that some hearts are unhealthy and require treatment and healing. In Holy Quran, there is also no doubt in it, guidance to the God wary

  11. Gene expression analysis of two extensively drug-resistant tuberculosis isolates show that two-component response systems enhance drug resistance.

    Science.gov (United States)

    Yu, Guohua; Cui, Zhenling; Sun, Xian; Peng, Jinfu; Jiang, Jun; Wu, Wei; Huang, Wenhua; Chu, Kaili; Zhang, Lu; Ge, Baoxue; Li, Yao

    2015-05-01

    Global analysis of expression profiles using DNA microarrays was performed between a reference strain H37Rv and two clinical extensively drug-resistant isolates in response to three anti-tuberculosis drug exposures (isoniazid, capreomycin, and rifampicin). A deep analysis was then conducted using a combination of genome sequences of the resistant isolates, resistance information, and related public microarray data. Certain known resistance-associated gene sets were significantly overrepresented in upregulated genes in the resistant isolates relative to that observed in H37Rv, which suggested a link between resistance and expression levels of particular genes. In addition, isoniazid and capreomycin response genes, but not rifampicin, either obtained from published works or our data, were highly consistent with the differentially expressed genes of resistant isolates compared to those of H37Rv, indicating a strong association between drug resistance of the isolates and genes differentially regulated by isoniazid and capreomycin exposures. Based on these results, 92 genes of the studied isolates were identified as candidate resistance genes, 10 of which are known resistance-related genes. Regulatory network analysis of candidate resistance genes using published networks and literature mining showed that three two-component regulatory systems and regulator CRP play significant roles in the resistance of the isolates by mediating the production of essential envelope components. Finally, drug sensitivity testing indicated strong correlations between expression levels of these regulatory genes and sensitivity to multiple anti-tuberculosis drugs in Mycobacterium tuberculosis. These findings may provide novel insights into the mechanism underlying the emergence and development of drug resistance in resistant tuberculosis isolates and useful clues for further studies on this issue. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Epidemiology and antifungal susceptibility of Candida species in a tertiary care hospital, Kolkata, India

    Directory of Open Access Journals (Sweden)

    Partha Bhattacharjee

    2016-06-01

    Conclusion: Species-level identification of Candida and their antifungal sensitivity testing should to be performed to achieve better clinical result and to select an appropriate and effective antifungal therapy. High resistance to antifungal agents is an alarming sign to the healthcare professionals.

  13. New-Onset Psychosis in a Multi-Drug Resistant Tuberculosis Patient ...

    African Journals Online (AJOL)

    Drug-resistant tuberculosis poses a serious challenge to global control of TB. These forms of TB do not respond to the standard six-month treatment; it can take two years or more to treat with category IV drugs that are less potent, more toxic and much more expensive. Treatment of multi-drug resistant tuberculosis is still ...

  14. A meta-analysis of Drug resistant Tuberculosis in Sub-Saharan Africa

    African Journals Online (AJOL)

    Background: In Sub-Saharan Africa, the fight against tuberculosis (TB) has encountered a great challenge because of the emergence of drug resistant TB strains and the high prevalence of HIV infection. The aim of this meta-analysis was to determine the association of drug-resistant TB with anti-TB drug treatment history ...

  15. Role of Breast Cancer Resistance Protein (BCRP/ABCG2) in Cancer Drug Resistance

    Science.gov (United States)

    Natarajan, Karthika; Xie, Yi; Baer, Maria R.; Ross, Douglas D.

    2012-01-01

    Since cloning of the ATP-binding cassette (ABC) family member breast cancer resistance protein (BCRP/ABCG2) and its characterization as a multidrug resistance efflux transporter in 1998, BCRP has been the subject of more than two thousand scholarly articles. In normal tissues, BCRP functions as a defense mechanism against toxins and xenobiotics, with expression in the gut, bile canaliculi, placenta, blood-testis and blood-brain barriers facilitating excretion and limiting absorption of potentially toxic substrate molecules, including many cancer chemotherapeutic drugs. BCRP also plays a key role in heme and folate homeostasis, which may help normal cells survive under conditions of hypoxia. BCRP expression appears to be a characteristic of certain normal tissue stem cells termed “side population cells,” which are identified on flow cytometric analysis by their ability to exclude Hoechst 33342, a BCRP substrate fluorescent dye. Hence, BCRP expression may contribute to the natural resistance and longevity of these normal stem cells. Malignant tissues can exploit the properties of BCRP to survive hypoxia and to evade exposure to chemotherapeutic drugs. Evidence is mounting that many cancers display subpopulations of stem cells that are responsible for tumor self-renewal. Such stem cells frequently manifest the “side population” phenotype characterized by expression of BCRP and other ABC transporters. Along with other factors, these transporters may contribute to the inherent resistance of these neoplasms and their failure to be cured. PMID:22248732

  16. Drug Resistance in Malaria: Investigation of Mechanisms and Patterns of Drug Resistance and Cross Resistance in Malaria.

    Science.gov (United States)

    1987-10-19

    patients with G6PD deficiency . Furthermore, the increase in fer- riheme may mediate the selective toxicity of menadione for Plasmodium falciparum...may account for the resistance to malaria afforded by G6PD deficiency ." Next, we focused on the process of FP detoxification. Initially, we searched

  17. Childhood Idiopathic Steroid Resistant Nephrotic Syndrome, Different Drugs and Outcome

    International Nuclear Information System (INIS)

    Shah, S. S. H.; Hafeez, F.

    2016-01-01

    Background: The management of steroid resistant nephrotic syndrome (SRNS) is quite difficult in paediatric patients. Not only the remission is difficult but also these patients are at risk of progression to end stage renal disease (ESRD). The goal of treatment is either to achieve complete remission or even partial remission as it is the most important predictor of disease outcome. Methods: This study was conducted at The Children Hospital, Lahore from February 2014 to May 2015. The SRNS patients of either sex between ages of 1-12 years were included with histology showing mesangioproliferative glomerulonephritis (MesangioPGN), focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD). Patients were given different immunosuppressant drugs and steroid 30 mg/m/sup 2/ alternate day therapy on case to case basis and kept on regular follow up to check for response and adverse effects. Results: Total of 105 patients included, 63 (60 percent) male and 42 (40 percent) female patients. The age ranges from 1.08 to 12 years, mean age of 6.53 years and SD of ±3.17. Tacrolimus was the most common drug used 43 (41 percent) patients followed by cyclosporine in 38 (36.2 percent) patients, while Mycophenolate mofetil (MMF) was prescribed in 21 (20 percent) patients. Complete response was in 96 (91.4 percent) initially while partial response was seen in 8 (7.6 percent) patients. On follow up, 92 (87.6 percent) patients showed complete response and partial response was in 5 (4.7 percent) patients. Cushingoid features and hypertrichosis were the most common adverse effect seen. Conclusion: Steroid resistant nephrotic syndrome can be managed well with various immunosuppressant drugs and steroids but treatment should be individualized according to clinical presentation, disease histology and cost/social factors. (author)

  18. Childhood Idiopathic Steroid Resistant Nephrotic Syndrome, Different Drugs And Outcome.

    Science.gov (United States)

    Hussain Shah, Syed Sajid; Hafeez, Farkhanda

    2016-01-01

    The management of steroid resistant nephrotic syndrome (SRNS) is quite difficult in paediatric patients. Not only the remission is difficult but also these patients are at risk of progression to end stage renal disease (ESRD). The goal of treatment is either to achieve complete remission or even partial remission as it is the most important predictor of disease outcome. This study was conducted at The Children's Hospital, Lahore from February 2014 to May 2015. The SRNS patients of either sex between ages of 1-12 years were included with histology showing mesangioproliferative glomerulonephritis (MesangioPGN), focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD). Patients were given different immunosuppressant drugs and steroid 30 mg/m2 alternate day therapy on case to case basis and kept on regular follow up to check for response and adverse effects. Total of 105 patients included, 63 (60%) male and 42 (40%) female patients. The age ranges from 1.08 to 12 years, mean age of 6.53 years and SD of ±3.17. Tacrolimus was the most common drug used 43 (41%) patients followed by cyclosporine in 38 (36.2%) patients, while Mycophenolate mofetil (MMF) was prescribed in 21 (20%) patients. Complete response was in 96 (91.4%) initially while partial response was seen in 8 (7.6%) patients. On follow up, 92 (87.6%) patients showed complete response and partial response was in 5 (4.7%) patients. Cushingoid features and hypertrichosis were the most common adverse effect seen. Steroid resistant nephrotic syndrome can be managed well with various immunosuppressant drugs and steroids but treatment should be individualized according to clinical presentation, disease histology and cost/social factors.

  19. Triclosan Derivatives: Towards Potent Inhibitors of Drug-Sensitive and Drug-Resistant Mycobacterium tuberculosis

    Energy Technology Data Exchange (ETDEWEB)

    Freundlich, Joel S.; Wang, Feng; Vilchèze, Catherine; Gulten, Gulcin; Langley, Robert; Schiehser, Guy A.; Jacobus, David P.; Jacobs, Jr., William R.; Sacchettini, James C.; (Einstein); (TAM); (Jacobus)

    2009-06-30

    Isoniazid (INH) is a frontline antitubercular drug that inhibits the enoyl acyl carrier protein reductase InhA. Novel inhibitors of InhA that are not cross-resistant to INH represent a significant goal in antitubercular chemotherapy. The design, synthesis, and biological activity of a series of triclosan-based inhibitors is reported, including their promising efficacy against INH-resistant strains of M. tuberculosis. Triclosan has been previously shown to inhibit InhA, an essential enoyl acyl carrier protein reductase involved in mycolic acid biosynthesis, the inhibition of which leads to the lysis of Mycobacterium tuberculosis. Using a structure-based drug design approach, a series of 5-substituted triclosan derivatives was developed. Two groups of derivatives with alkyl and aryl substituents, respectively, were identified with dramatically enhanced potency against purified InhA. The most efficacious inhibitor displayed an IC{sub 50} value of 21 nM, which was 50-fold more potent than triclosan. X-ray crystal structures of InhA in complex with four triclosan derivatives revealed the structural basis for the inhibitory activity. Six selected triclosan derivatives were tested against isoniazid-sensitive and resistant strains of M. tuberculosis. Among those, the best inhibitor had an MIC value of 4.7 {mu}g mL{sup -1} (13 {mu}M), which represents a tenfold improvement over the bacteriocidal activity of triclosan. A subset of these triclosan analogues was more potent than isoniazid against two isoniazid-resistant M. tuberculosis strains, demonstrating the significant potential for structure-based design in the development of next generation antitubercular drugs.

  20. Antifungal activity of redox-active benzaldehydes that target cellular antioxidation

    Directory of Open Access Journals (Sweden)

    Mahoney Noreen

    2011-05-01

    Full Text Available Abstract Background Disruption of cellular antioxidation systems should be an effective method for control of fungal pathogens. Such disruption can be achieved with redox-active compounds. Natural phenolic compounds can serve as potent redox cyclers that inhibit microbial growth through destabilization of cellular redox homeostasis and/or antioxidation systems. The aim of this study was to identify benzaldehydes that disrupt the fungal antioxidation system. These compounds could then function as chemosensitizing agents in concert with conventional drugs or fungicides to improve antifungal efficacy. Methods Benzaldehydes were tested as natural antifungal agents against strains of Aspergillus fumigatus, A. flavus, A. terreus and Penicillium expansum, fungi that are causative agents of human invasive aspergillosis and/or are mycotoxigenic. The yeast Saccharomyces cerevisiae was also used as a model system for identifying gene targets of benzaldehydes. The efficacy of screened compounds as effective chemosensitizers or as antifungal agents in formulations was tested with methods outlined by the Clinical Laboratory Standards Institute (CLSI. Results Several benzaldehydes are identified having potent antifungal activity. Structure-activity analysis reveals that antifungal activity increases by the presence of an ortho-hydroxyl group in the aromatic ring. Use of deletion mutants in the oxidative stress-response pathway of S. cerevisiae (sod1Δ, sod2Δ, glr1Δ and two mitogen-activated protein kinase (MAPK mutants of A. fumigatus (sakAΔ, mpkCΔ, indicates antifungal activity of the benzaldehydes is through disruption of cellular antioxidation. Certain benzaldehydes, in combination with phenylpyrroles, overcome tolerance of A. fumigatus MAPK mutants to this agent and/or increase sensitivity of fungal pathogens to mitochondrial respiration inhibitory agents. Synergistic chemosensitization greatly lowers minimum inhibitory (MIC or fungicidal (MFC

  1. Species distribution and antifungal susceptibility patterns of Candida isolates from a public tertiary teaching hospital in the Eastern Cape Province, South Africa.

    Science.gov (United States)

    Mnge, P; Okeleye, B I; Vasaikar, S D; Apalata, T

    2017-05-15

    Candida species are the leading cause of invasive fungal infections, and over the past decade there has been an increased isolation of drug resistant Candida species. This study aimed to identify the species distribution of Candida isolates and to determine their unique antifungal susceptibility and resistance patterns. During a cross-sectional study, 209 Candida isolates (recovered from 206 clinical samples) were collected and their species distribution was determined using ChromAgar Candida. The Vitek-2 system (Biomerieux, South Africa) was used to determine minimum inhibitory concentrations (MICs) to azoles (fluconazole, voriconazole), echinocandins (caspofungin, micafungin), polyenes (amphotericin B) and flucytosine. Four species of Candida were isolated, of which C. albicans was the most frequent, isolated in 45.4% (95/209) of the isolates, followed by C. glabrata: 31.1% (65/209). The MICs of the different antifungal drugs varied amongst the species of Candida. From the 130 isolates tested for MICs, 90.77% (112/130) were susceptible to all antifungal drugs and 6.9% (9/130) of the isolates were multi-drug resistant. C. dubliniensis (n=2) isolates were susceptible to all the above mentioned antifungal drugs. There was no significant difference in species distribution amongst clinical specimens and between patients' genders (P>0.05). An increase in MIC values for fluconazole and flucytosine towards the resistance range was observed. To our knowledge, this is the first report on surveillance of Candida species distribution and antifungal susceptibility at a public tertiary teaching hospital in Eastern Cape, South Africa.

  2. Association of streptomycin resistance mutations with level of drug resistance and Mycobacterium tuberculosis genotypes.

    Science.gov (United States)

    Nhu, N T Q; Lan, N T N; Phuong, N T N; Chau, N van V; Farrar, J; Caws, M

    2012-04-01

    To determine 1) the relationship between specific streptomycin (SM) resistance mutations and the minimum inhibitory concentration (MIC), and 2) whether these mutations are preferentially associated with the Beijing genotype in Viet Nam. A total of 131 consecutive Mycobacterium tuberculosis isolates resistant to either isoniazid (INH) or rifampicin (RMP), collected previously, were tested for SM resistance, spoligotyped and sequenced in the rpsL, rrs and gidB genes. The MIC for 50 mutants was also determined. Overall, 116/131 isolates were SM-resistant. The three most frequently occurring mutation sites in rpsL and rrs were at codon 43 of rpsL (72/116, 62.1%), rpsL88 (22/116, 18.9%) and rrs514 (8/116, 6.9%). Mutations in the rrs910 region were found in two isolates (1.7%), and three isolates had mutations in both rpsL and rrs (2.6%). gidB mutations were found in both resistant and susceptible strains. Among SM-resistant isolates resistant to INH/RMP, the Beijing genotype was strongly associated with rpsL43 mutation (aOR 23.6, 95%CI 2.9-193.4, P = 0.002). The median MIC for each mutation was as follows: rpsL43 = 256 μg/ml, rpsL88 = 16 μg/ml, 515 loop = 4 μg/ml, 910 region = 8 μg/ml, and double mutation = 256 μg/ml. We found a strong association between rpsL43 and high drug resistance levels, with all rpsL43 mutants having an MIC >256 μg/ml (P < 0.001).

  3. Impact of treatment heterogeneity on drug resistance and supply chain costs.

    Science.gov (United States)

    Spiliotopoulou, Eirini; Boni, Maciej F; Yadav, Prashant

    2013-09-01

    The efficacy of scarce drugs for many infectious diseases is threatened by the emergence and spread of resistance. Multiple studies show that available drugs should be used in a socially optimal way to contain drug resistance. This paper studies the tradeoff between risk of drug resistance and operational costs when using multiple drugs for a specific disease. Using a model for disease transmission and resistance spread, we show that treatment with multiple drugs, on a population level, results in better resistance-related health outcomes, but more interestingly, the marginal benefit decreases as the number of drugs used increases. We compare this benefit with the corresponding change in procurement and safety stock holding costs that result from higher drug variety in the supply chain. Using a large-scale simulation based on malaria transmission dynamics, we show that disease prevalence seems to be a less important factor when deciding the optimal width of drug assortment, compared to the duration of one episode of the disease and the price of the drug(s) used. Our analysis shows that under a wide variety of scenarios for disease prevalence and drug cost, it is optimal to simultaneously deploy multiple drugs in the population. If the drug price is high, large volume purchasing discounts are available, and disease prevalence is high, it may be optimal to use only one drug. Our model lends insights to policy makers into the socially optimal size of drug assortment for a given context.

  4. Identification of ten KB425796-A congeners from Paenibacillus sp. 530603 using an antifungal assay against Aspergillus fumigatus in combination with micafungin.

    Science.gov (United States)

    Kai, Hirohito; Yamashita, Midori; Takase, Shigehiro; Hashimoto, Michizane; Muramatsu, Hideyuki; Nakamura, Ikuko; Yoshikawa, Koji; Kanasaki, Ryuichi; Ezaki, Masami; Nitta, Kumiko; Watanabe, Masato; Inamura, Noriaki; Fujie, Akihiko

    2013-08-01

    The discovery and characterization of natural congeners is one approach for understanding the relationship between chemical structure and biological function. We recently isolated the novel antifungal metabolite KB425796-A produced by the recently isolated bacterium Paenibacillus sp. 530603. On the basis of morphological changes of Aspergillus fumigatus induced by KB425796-A in combination with micafungin, we developed a highly sensitive screening method for the specific detection of KB425796-A congeners. Using this method, we isolated ten congeners of KB425796-A, named KB425796-B, -C, -D, -E, -F, -G, -H, -I, -J and -K, which exhibited diverse antifungal potencies against A. fumigatus. One of the most potent congeners, KB425796-C, had antifungal activities against several micafungin-resistant infectious fungi. KB425796-C can be a potential drug candidate for treating micafungin-resistant fungal infections.

  5. Time-programmable drug dosing allows the manipulation, suppression and reversal of antibiotic drug resistance in vitro

    Science.gov (United States)

    Yoshida, Mari; Reyes, Sabrina Galiñanes; Tsuda, Soichiro; Horinouchi, Takaaki; Furusawa, Chikara; Cronin, Leroy

    2017-06-01

    Multi-drug strategies have been attempted to prolong the efficacy of existing antibiotics, but with limited success. Here we show that the evolution of multi-drug-resistant Escherichia coli can be manipulated in vitro by administering pairs of antibiotics and switching between them in ON/OFF manner. Using a multiplexed cell culture system, we find that switching between certain combinations of antibiotics completely suppresses the development of resistance to one of the antibiotics. Using this data, we develop a simple deterministic model, which allows us to predict the fate of multi-drug evolution in this system. Furthermore, we are able to reverse established drug resistance based on the model prediction by modulating antibiotic selection stresses. Our results support the idea that the development of antibiotic resistance may be potentially controlled via continuous switching of drugs.

  6. Rationally designed transmembrane peptide mimics of the multidrug transporter protein Cdr1 act as antagonists to selectively block drug efflux and chemosensitize azole-resistant clinical isolates of Candida albicans.

    Science.gov (United States)

    Maurya, Indresh Kumar; Thota, Chaitanya Kumar; Verma, Sachin Dev; Sharma, Jyotsna; Rawal, Manpreet Kaur; Ravikumar, Balaguru; Sen, Sobhan; Chauhan, Neeraj; Lynn, Andrew M; Chauhan, Virander Singh; Prasad, Rajendra

    2013-06-07

    Drug-resistant pathogenic fungi use several families of membrane-embedded transporters to efflux antifungal drugs from the cells. The efflux pump Cdr1 (Candida drug resistance 1) belongs to the ATP-binding cassette (ABC) superfamily of transporters. Cdr1 is one of the most predominant mechanisms of multidrug resistance in azole-resistant (AR) clinical isolates of Candida albicans. Blocking drug efflux represents an attractive approach to combat the multidrug resistance of this opportunistic human pathogen. In this study, we rationally designed and synthesized transmembrane peptide mimics (TMPMs) of Cdr1 protein (Cdr1p) that correspond to each of the 12 transmembrane helices (TMHs) of the two transmembrane domains of the protein to target the primary structure of the Cdr1p. Several FITC-tagged TMPMs specifically bound to Cdr1p and blocked the efflux of entrapped fluorescent dyes from the AR (Gu5) isolate. These TMPMs did not affect the efflux of entrapped fluorescent dye from cells expressing the Cdr1p homologue Cdr2p or from cells expressing a non-ABC transporter Mdr1p. Notably, the time correlation of single photon counting fluorescence measurements confirmed the specific interaction of FITC-tagged TMPMs with their respective TMH. By using mutant variants of Cdr1p, we show that these TMPM antagonists contain the structural information necessary to target their respective TMHs of Cdr1p and specific binding sites that mediate the interactions between the mimics and its respective helix. Additionally, TMPMs that were devoid of any demonstrable hemolytic, cytotoxic, and antifungal activities chemosensitize AR clinical isolates and demonstrate synergy with drugs that further improved the therapeutic potential of fluconazole in vivo.

  7. Molecular Targets Related Drug Resistance Mechanisms in MDR-, XDR-, and TDR-Mycobacterium tuberculosis Strains

    Directory of Open Access Journals (Sweden)

    H. M. Adnan Hameed

    2018-04-01

    Full Text Available Tuberculosis (TB is a formidable infectious disease that remains a major cause of death worldwide today. Escalating application of genomic techniques has expedited the identification of increasing number of mutations associated with drug resistance in Mycobacterium tuberculosis. Unfortunately the prevalence of bacillary resistance becomes alarming in many parts of the world, with the daunting scenarios of multidrug-resistant tuberculosis (MDR-TB, extensively drug-resistant tuberculosis (XDR-TB and total drug-resistant tuberculosis (TDR-TB, due to number of resistance pathways, alongside some apparently obscure ones. Recent advances in the understanding of the molecular/ genetic basis of drug targets and drug resistance mechanisms have been steadily made. Intriguing findings through whole genome sequencing and other molecular approaches facilitate the further understanding of biology and pathology of M. tuberculosis for the development of new therapeutics to meet the immense challenge of global health.

  8. Adaptive and Mutational Resistance: Role of Porins and Efflux Pumps in Drug Resistance

    Science.gov (United States)

    Fernández, Lucía

    2012-01-01

    Summary: The substantial use of antibiotics in the clinic, combined with a dearth of new antibiotic classes, has led to a gradual increase in the resistance of bacterial pathogens to these compounds. Among the various mechanisms by which bacteria endure the action of antibiotics, those affecting influx and efflux are of particular importance, as they limit the interaction of the drug with its intracellular targets and, consequently, its deleterious effects on the cell. This review evaluates the impact of porins and efflux pumps on two major types of resistance, namely, mutational and adaptive types of resistance, both of which are regarded as key phenomena in the global rise of antibiotic resistance among pathogenic microorganisms. In particular, we explain how adaptive and mutational events can dramatically influence the outcome of antibiotic therapy by altering the mechanisms of influx and efflux of antibiotics. The identification of porins and pumps as major resistance markers has opened new possibilities for the development of novel therapeutic strategies directed specifically against these mechanisms. PMID:23034325

  9. Resistance to anti-tuberculosis drugs and practices in drug susceptibility testing in Moldova, 1995-1999.

    Science.gov (United States)

    Crudu, V; Arnadottir, Th; Laticevschi, D

    2003-04-01

    To evaluate practices in initial drug susceptibility testing (DST) in Moldova, anti-tuberculosis drug resistance and the implications for tuberculosis control. Retrospective record review in the national reference laboratory. Of 3463 cases, 57.1% were recorded as 'new' and 24.6% as 'retreatment' cases; previous treatment status was not recorded for 18.3%. Of the 'new' cases, 1655 were correctly classified according to international recommendations and 322 were misclassified. The number of cases increased from 443 in 1995 to 939 in 1999; the proportion of 'retreatment' increased from 17.4% to 35.5%, 'any drug resistance' from 20.3% to 41.6%, and 'multidrug resistance' from 2.7% to 11.2%. In 1998-1999, 'any drug resistance' and 'multidrug resistance' in 800 previously untreated cases were respectively 29.1% and 5.3%, and respectively 61.0% and 21.9% in 521 'retreatment' cases. Of a total of 216 'multidrug-resistant' cases in 1998-1999, 21.8% were reported resistant to ethambutol and 81.5% to streptomycin. Initial specimens for culture are frequently taken late, after the start of treatment, compromising their usefulness for case management or surveillance. Inadequate treatment has led to an increase in the number of cases, the proportion of previously treated cases and the prevalence of drug resistance. In 1998-1999, a high proportion of cases with 'multidrug resistance' were susceptible to ethambutol.

  10. Pleuromutilins: Potent Drugs for Resistant Bugs-Mode of Action and Resistance.

    Science.gov (United States)

    Paukner, Susanne; Riedl, Rosemarie

    2017-01-03

    Pleuromutilins are antibiotics that selectively inhibit bacterial translation and are semisynthetic derivatives of the naturally occurring tricyclic diterpenoid pleuromutilin, which received its name from the pleuromutilin-producing fungus Pleurotus mutilus Tiamulin and valnemulin are two established derivatives in veterinary medicine for oral and intramuscular administration. As these early pleuromutilin drugs were developed at a time when companies focused on major antibacterial classes, such as the β-lactams, and resistance was not regarded as an issue, interest in antibiotic research including pleuromutilins was limited. Over the last decade or so, there has been a resurgence in interest to develop this class for human use. This has resulted in a topical derivative, retapamulin, and additional derivatives in clinical development. The most advanced compound is lefamulin, which is in late-stage development for the intravenous and oral treatment of community-acquired bacterial pneumonia and acute bacterial skin infections. Overall, pleuromutilins and, in particular, lefamulin are characterized by potent activity against Gram-positive and fastidious Gram-negative pathogens as well as against mycoplasmas and intracellular organisms, such as Chlamydia spp. and Legionella pneumophila Pleuromutilins are unaffected by resistance to other major antibiotic classes, such as macrolides, fluoroquinolones, tetracyclines, β-lactam antibiotics, and others. Furthermore, pleuromutilins display very low spontaneous mutation frequencies and slow, stepwise resistance development at sub-MIC in vitro. The potential for resistance development in clinic is predicted to be slow as confirmed by extremely low resistance rates to this class despite the use of pleuromutilins in veterinary medicine for >30 years. Although rare, resistant strains have been identified in human- and livestock-associated environments and as with any antibiotic class, require close monitoring as well as prudent

  11. Drug Resistance to EGFR Inhibitors in Lung Cancer | Office of Cancer Genomics

    Science.gov (United States)

    The discovery of mutations in epidermal growth factor receptor (EGFR) has dramatically changed the treatment of patients with non-small-cell lung cancer (NSCLC), the leading cause of cancer deaths worldwide. EGFR-targeted therapies show considerable promise, but drug resistance has become a substantial issue. We reviewed the literature to provide an overview of the drug resistance to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. The mechanisms causing primary, acquired and persistent drug resistance to TKIs vary.

  12. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome

    OpenAIRE

    Devinsky, O.; Cross, J. H.; Laux, L.; Marsh, E.; Miller, I.; Nabbout, R.; Scheffer, I. E.; Thiele, E. A.; Wright, S.

    2017-01-01

    BACKGROUND: The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome. METHODS: In this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram...

  13. HIV-1 evolution, drug resistance, and host genetics: The Indian scenario

    OpenAIRE

    Shankarkumar, U.; Pawar,Aruna; Ghosh,Kanjaksha

    2009-01-01

    U Shankarkumar, A Pawar, K GhoshNational Institute of Immunohaematology (ICMR), KEM Hospital, Parel, Mumbai, Maharashtra, IndiaAbstract: A regimen with varied side effects and compliance is of paramount importance to prevent viral drug resistance. Most of the drug-resistance studies, as well as interpretation algorithms, are based on sequence data from HIV-1 subtype B viruses. Increased resistance to antiretroviral drugs leads to poor prognosis by restricting treatment optio...

  14. Tuberculosis drug resistance isolates from pulmonary tuberculosis patients, Kassala State, Sudan

    Directory of Open Access Journals (Sweden)

    Fatima A Khalid

    2015-01-01

    This study revealed that high resistance to rifampicin was associated with various point mutations in and out of the RRDR of the rpoB gene. Molecular methods are needed for early detection of TB disease and drug resistance.

  15. Resistance to different classes of drugs is associated with impaired apoptosis in childhood acute lymphoblastic leukemia

    NARCIS (Netherlands)

    A. Holleman (Amy); M.L. den Boer (Monique); K.M. Kazemier (Karin); G.E. Janka-Schaub (Gritta); R. Pieters (Rob)

    2003-01-01

    textabstractResistance of leukemic cells to chemotherapeutic agents is associated with an unfavorable outcome in pediatric acute lymphoblastic leukemia (ALL). To investigate the underlying mechanisms of cellular drug resistance, the activation of various apoptotic parameters in

  16. Inhibition of Propionibacterium acnes lipase activity by the antifungal agent ketoconazole.

    Science.gov (United States)

    Unno, Mizuki; Cho, Otomi; Sugita, Takashi

    2017-01-01

    The common skin disease acne vulgaris is caused by Propionibacterium acnes. A lipase secreted by this microorganism metabolizes sebum and the resulting metabolites evoke inflammation in human skin. The antifungal drug ketoconazole inhibits P. acnes lipase activity. We previously showed that the drug also inhibits the growth of P. acnes. Thus, ketoconazole may serve as an alternative treatment for acne vulgaris, which is important because the number of antibiotic-resistant P. acnes strains has been increasing. © 2017 The Societies and John Wiley & Sons Australia, Ltd.

  17. Accelerating the development of therapeutic strategies for drug-resistant tuberculosis.

    Science.gov (United States)

    Vjecha, Michael J; Tiberi, Simon; Zumla, Alimuddin

    2018-03-23

    Recent progress in the discovery, development and evaluation of new drugs and combination regimens for drug-resistant tuberculosis through greater collaboration between industry, donors and academia provides renewed hope for overcoming the challenges in tuberculosis treatment.

  18. World TB Day 2018: The Challenge of Drug Resistant Tuberculosis.

    Science.gov (United States)

    Gupta-Wright, Ankur; Tomlinson, Gillian S; Rangaka, Molebogeng X; Fletcher, Helen A

    2018-01-01

    On 24th March, the world commemorates the day in 1882 when Dr Robert Koch announced his discovery of Mycobacterium tuberculosis (MTB). Over 130 years later, tuberculosis (TB) continues to affect individuals, communities, and entire health systems and economies. Koch unsuccessfully tried to 'cure' TB, and despite major advances in other areas of medicine, control of TB remains elusive- in 2016 TB was the leading infectious cause of death. The STOP TB partnership and World Health Organization (WHO) have announced their theme for World TB Day 2018 "Wanted: Leaders for a TB-Free World. You can make history. End TB." This theme recognizes that TB is much larger than any one person, institute or discipline of research, and provides an opportunity for us to reflect on the major challenges and consider how we, as a scientific community, can work together and take the lead to address the global crisis of drug-resistant TB (DR-TB).

  19. Nanoantibiotics: strategic assets in the fight against drug- resistant superbugs

    Directory of Open Access Journals (Sweden)

    Khurana C

    2018-03-01

    Full Text Available Chandni Khurana, Bhupendra Chudasama Laboratory of Nanomedicine, School of Physics and Materials Science, Thapar University, Patiala, Punjab, India Abstract: Antimicrobial characteristics of metals reveal that Ag despite its economic constraints remains the most popular antibiotic agent. Antimicrobial characteristics of copper nanoparticles (CNPs are not well understood. To our knowledge, no systematic comparative study on microbial properties of silver nanoparticles (SNPs and CNPs exists. In this article, a comparative study on microbial properties of engineered metal nanoantibiotics against clinically important strains has been attempted. Our results indicate that biocidal activities of CNPs are better than SNPs. Minimum inhibitory concentration (MIC values of CNPs are 10 times lower than the corresponding MICs of SNPs. These improved biocidal activities of CNPs would make it affordable and potent nontraditional antibiotics against which microbes are least susceptible to develop any drug resistance. Keywords: antibiotics, silver, copper, nanoparticles

  20. Pattern of primary tuberculosis drug resistance and associated treatment outcomes in Transnistria, Moldova.

    Science.gov (United States)

    Dolgusev, O; Obevzenco, N; Padalco, O; Pankrushev, S; Ramsay, A; Van den Bergh, R; Manzi, M; Denisiuk, O; Zachariah, R

    2014-10-21

    This cohort study assessed drug susceptibility testing (DST) patterns and associated treatment outcomes from Transnistria, Moldova, from 2009 to 2012. Of 1089 newly registered tuberculosis (TB) patients with available DST results, 556 (51%) had some form of drug resistance, while 369 (34%) had multidrug-resistant TB (MDR-TB). There were four cases of extensively drug-resistant TB. MDR-TB patients had poor treatment success (45%); human immunodeficiency virus positivity and a history of incarceration were associated with an unfavourable treatment outcome. This first study from Trans-nistria shows a high level of drug-resistant TB, which constitutes a major public health problem requiring urgent attention.

  1. An analysis of drug resistance among people living with HIV/AIDS in Shanghai, China.

    Directory of Open Access Journals (Sweden)

    Fengdi Zhang

    Full Text Available Understanding the mechanisms of drug resistance can facilitate better management of antiretroviral therapy, helping to prevent transmission and decrease the morbidity and mortality of people living with HIV/AIDS. However, there is little data about transmitted drug resistance and acquired drug resistance for HIV/AIDS patients in Shanghai.A retrospective cohort study of HIV-infected patients who visited the Department of Infectious Disease from June 2008 to June 2015 was conducted in Shanghai, China. Logistic regression analysis was performed to analyze risk factors for drug resistance among HIV-infected people with virological failure. The related collected factors included patient age, gender, marital status, infection route, baseline CD4 count, antiretroviral therapy regimens, time between HIV diagnosis and initiating antiretroviral therapy. Factors with p<0.1 in the univariate logistic regression test were analyzed by multivariate logistic regression test.There were 575 subjects selected for this study and 369 participated in this research. For the antiretroviral therapy drugs, the rates of transmitted drug resistance and acquired drug resistance were significantly different. The non-nucleoside reverse transcriptase inhibitor (NNRTI had the highest drug resistance rate (transmitted drug resistance, 10.9%; acquired drug resistance, 53.3% and protease inhibitors (PIs had the lowest drug resistance rate (transmitted drug resistance, 1.7%; acquired drug resistance, 2.7%. Logistic regression analysis found no factors that were related to drug resistance except marital status (married status for tenofovir: odds ratio = 6.345, 95% confidence interval = 1.553-25.921, P = 0.010 and the time span between HIV diagnosis and initiating antiretroviral therapy (≤6M for stavudine: odds ratio = 0.271, 95% confidence interval = 0.086-0.850, P = 0.025; ≤6M for didanosine: odds ratio = 0.284, 95% confidence interval = 0.096-0.842, P = 0.023; ≤6M for

  2. Disinfectant-susceptibility of multi-drug-resistant Mycobacterium tuberculosis isolated in Japan

    Directory of Open Access Journals (Sweden)

    Noriko Shinoda

    2016-02-01

    Full Text Available Abstract Background Multi-drug-resistant Mycobacterium tuberculosis has been an important problem in public health around the world. However, limited information about disinfectant-susceptibility of multi-drug-resistant strain of M. tuberculosis was available. Findings We studied susceptibility of several Japanese isolates of multi-drug-resistant M. tuberculosis against disinfectants, which are commonly used in clinical and research laboratories. We selected a laboratory reference strain (H37Rv and eight Japanese isolates, containing five drug-susceptible strains and three multi-drug-resistant strains, and determined profiles of susceptibility against eight disinfectants. The M. tuberculosis strains were distinguished into two groups by the susceptibility profile. There was no relationship between multi-drug-resistance and disinfectant-susceptibility in the M. tuberculosis strains. Cresol soap and oxydol were effective against all strains we tested, regardless of drug resistance. Conclusions Disinfectant-resistance is independent from multi-drug-resistance in M. tuberculosis. Cresol soap and oxydol were effective against all strains we tested, regardless of drug resistance.

  3. Molecular detection methods of resistance to antituberculosis drugs in Mycobacterium tuberculosis.

    Science.gov (United States)

    Brossier, F; Sougakoff, W

    2017-09-01

    Molecular methods predict drug resistance several weeks before phenotypic methods and enable rapid implementation of appropriate therapeutic treatment. We aimed to detail the most representative molecular tools used in routine practice for the rapid detection of resistance to antituberculosis drugs among Mycobacterium tuberculosis strains. The molecular diagnosis of resistance to antituberculosis drugs in clinical samples or from in vitro cultures is based on the detection of the most common mutations in the genes involved in the development of resistance in M. tuberculosis strains (encoding either protein targets of antibiotics, or antibiotic activating enzymes) by commercial molecular kits or by sequencing. Three hypotheses could explain the discrepancies between the genotypic results and the phenotypic drug susceptibility testing results: a low percentage of resistant mutants precluding the detection by genotypic methods on the primary culture; a low level of resistance not detected by phenotypic testing; and other resistance mechanisms not yet characterized. Molecular methods have varying sensitivity with regards to detecting antituberculosis drug resistance; that is why phenotypic susceptibility testing methods are mandatory for detecting antituberculosis drug-resistant isolates that have not been detected by molecular methods. The questionable ability of existing phenotypic and genotypic drug susceptibility testing to properly classify strains as susceptible or resistant, and at what level of resistance, was raised for several antituberculosis agents. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  4. Pharmacokinetics and Pharmacodynamics of Antifungals in Children and their Clinical Implications

    Science.gov (United States)

    Stockmann, Chris; Constance, Jonathan E.; Roberts, Jessica K.; Olson, Jared; Doby, Elizabeth H.; Ampofo, Krow; Stiers, Justin; Spigarelli, Michael G.

    2017-01-01

    Invasive fungal infections are a significant cause of morbidity and mortality in children. Successful management of these systemic infections requires identification of the causative pathogen, appropriate antifungal selection, and optimisation of its pharmacokinetic and pharmacodynamic properties to maximise its antifungal activity and minimise toxicity and the emergence of resistance. This review highlights salient scientific advancements in paediatric antifungal pharmacotherapies and focuses on pharmacokinetic and pharmacodynamic studies that underpin current clinical decision making. Four classes of drugs are widely used in the treatment of invasive fungal infections in children, including the polyenes, triazoles, pyrimidine analogues and echinocandins. Several lipidic formulations of the polyene amphotericin B have substantially reduced the toxicity associated with the traditional amphotericin B formulation. Monotherapy with the pyrimidine analogue flucytosine rapidly promotes the emergence of resistance and cannot be recommended. However, when used in combination with other antifungal agents, therapeutic drug monitoring of flucytosine has been shown to reduce high peak flucytosine concentrations, which are strongly associated with toxicity. The triazoles feature large inter-individual pharmacokinetic variability, although this pattern is less pronounced with fluconazole. In clinical trials, posaconazole was associated with fewer adverse effects than other members of the triazole family, though both posaconazole and itraconazole display erratic absorption that is influenced by gastric pH and the gastric emptying rate. Limited data suggest that the clinical response to therapy may be improved with higher plasma posaconazole and itraconazole concentrations. For voriconazole, pharmacokinetic studies among children have revealed that children require twice the recommended adult dose to achieve comparable blood concentrations. Voriconazole clearance is also affected

  5. The role of compensatory mutations in the emergence of drug resistance.

    Directory of Open Access Journals (Sweden)

    Andreas Handel

    2006-10-01

    Full Text Available Pathogens that evolve resistance to drugs usually have reduced fitness. However, mutations that largely compensate for this reduction in fitness often arise. We investigate how these compensatory mutations affect population-wide resistance emergence as a function of drug treatment. Using a model of gonorrhea transmission dynamics, we obtain generally applicable, qualitative results that show how compensatory mutations lead to more likely and faster resistance emergence. We further show that resistance emergence depends on the level of drug use in a strongly nonlinear fashion. We also discuss what data need to be obtained to allow future quantitative predictions of resistance emergence.

  6. Malaria medicines to address drug resistance and support malaria elimination efforts.

    Science.gov (United States)

    Achan, Jane; Mwesigwa, Julia; Edwin, Chinagozi Precious; D'alessandro, Umberto

    2018-01-01

    Antimalarial drugs are essential weapons to fight malaria and have been used effectively since the 17 th century. However, P.falciparum resistance has been reported to almost all available antimalarial drugs, including artemisinin derivatives, raising concerns that this could jeopardize malaria elimination. Areas covered: In this article, we present a historical perspective of antimalarial drug resistance, review current evidence of resistance to available antimalarial drugs and discuss possible mitigating strategies to address this challenge. Expert commentary: The historical approach to drug resistance has been to change the national treatment policy to an alternative treatment. However, alternatives to artemisinin-based combination treatment are currently extremely limited. Innovative approaches utilizing available schizonticidal drugs such as triple combination therapies or multiple first line treatments could delay the emergence and spread of drug resistance. Transmission blocking drugs like primaquine may play a key role if given to a substantial proportion of malaria infected persons. Deploying antimalarial medicines in mass drug administration or mass screening and treatment campaigns could also contribute to containment efforts by eliminating resistant parasites in some settings. Ultimately, response to drug resistance should also include further investment in the development of new antimalarial drugs.

  7. Genome-wide mutagenesis and multi-drug resistance in American trypanosomes induced by the front-line drug benznidazole

    KAUST Repository

    Campos, Mônica C.

    2017-10-25

    Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects 5–8 million people in Latin America. Although the nitroheterocyclic compound benznidazole has been the front-line drug for several decades, treatment failures are common. Benznidazole is a pro-drug and is bio-activated within the parasite by the mitochondrial nitroreductase TcNTR-1, leading to the generation of reactive metabolites that have trypanocidal activity. To better assess drug action and resistance, we sequenced the genomes of T. cruzi Y strain (35.5 Mb) and three benznidazole-resistant clones derived from a single drug-selected population. This revealed the genome-wide accumulation of mutations in the resistant parasites, in addition to variations in DNA copy-number. We observed mutations in DNA repair genes, linked with increased susceptibility to DNA alkylating and inter-strand cross-linking agents. Stop-codon-generating mutations in TcNTR-1 were associated with cross-resistance to other nitroheterocyclic drugs. Unexpectedly, the clones were also highly resistant to the ergosterol biosynthesis inhibitor posaconazole, a drug proposed for use against T. cruzi infections, in combination with benznidazole. Our findings therefore identify the highly mutagenic activity of benznidazole metabolites in T. cruzi, demonstrate that this can result in multi-drug resistance, and indicate that vigilance will be required if benznidazole is used in combination therapy.

  8. Reaching consensus on drug resistance conferring mutations (Part 1

    Directory of Open Access Journals (Sweden)

    Daniela M Cirillo

    2016-01-01

    A user-friendly interface designed for nonexpert or expert operability.A standardized and validated analysis pipeline for variant analyses of M. tuberculosis next-generation sequencing (NGS data.Access to data beyond the published literature with dynamic and iterative updates of new data generated by global surveillance and clinical trials.A well-developed legal structure to ensure intellectual property rights and data ownership remain with contributors.A structured data-sharing architecture to restrict access to sensitive or unpublished data sets.Metadata standardization using CDISC: supports global, platform-independent data standards that enable information system interoperability.An emphasis on data quality and rigorous, expert curation with multiple quality control checks for whole-genome sequencing and other metadata.Validation of NGS analysis output by an expert committee with grading of resistance conferring mutations based on rigorous statistical standards.Regulatory-compliant analysis pipeline and database architecture. Successful execution of such an extensive database platform requires substantial collaboration from scientists investigating the genetic basis for drug resistance worldwide, and from developers with expertise in database design and implementation.

  9. Extensively drug-resistant bacteria: Which ethical issues?

    Science.gov (United States)

    Vassal, P; Berthelot, P; Chaussinand, J P; Jay, S; de Filippis, J P; Auboyer, C; Renoux, F; Bedoin, D

    2017-09-01

    The increased bacterial resistance to antibiotics has now become a public health concern. How can we preserve the well-being of patients presenting with infections caused by extensively drug-resistant bacteria (EDRBs) and that of their contacts without inducing any loss of chance of survival, all the while living together and controlling the spread of these EDRBs? Terre d'éthique, a French territorial ethics committee, was asked to reflect on this topic by the infection control unit of a French University Hospital as it raises many ethical issues. Patients are at the core of any ethical approach, and respecting their autonomy is fundamental. Patients should be adequately informed to be able to give consent. Indeed, the creation and dissemination of a register (list of names of contacts or infected patients) entails responsibility of the infected person and that of the community. This responsibility leads to an ethical dilemma as protecting the group (the whole population) necessarily means limiting individual freedom. The principle of autonomy should thus be compared with that of solidarity. Is medical confidentiality an obstacle to the sharing of information or lists of names? We did not aim to answer our problematic but merely wanted to show the complexity of EDRB spread in a broader societal and economic context, all the while respecting the rights of patients. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  10. Future technologies for monitoring HIV drug resistance and cure.

    Science.gov (United States)

    Parikh, Urvi M; McCormick, Kevin; van Zyl, Gert; Mellors, John W

    2017-03-01

    Sensitive, scalable and affordable assays are critically needed for monitoring the success of interventions for preventing, treating and attempting to cure HIV infection. This review evaluates current and emerging technologies that are applicable for both surveillance of HIV drug resistance (HIVDR) and characterization of HIV reservoirs that persist despite antiretroviral therapy and are obstacles to curing HIV infection. Next-generation sequencing (NGS) has the potential to be adapted into high-throughput, cost-efficient approaches for HIVDR surveillance and monitoring during continued scale-up of antiretroviral therapy and rollout of preexposure prophylaxis. Similarly, improvements in PCR and NGS are resulting in higher throughput single genome sequencing to detect intact proviruses and to characterize HIV integration sites and clonal expansions of infected cells. Current population genotyping methods for resistance monitoring are high cost and low throughput. NGS, combined with simpler sample collection and storage matrices (e.g. dried blood spots), has considerable potential to broaden global surveillance and patient monitoring for HIVDR. Recent adaptions of NGS to identify integration sites of HIV in the human genome and to characterize the integrated HIV proviruses are likely to facilitate investigations of the impact of experimental 'curative' interventions on HIV reservoirs.

  11. Status of drug-resistant tuberculosis in China: A systematic review and meta-analysis.

    Science.gov (United States)

    Zhang, Jingya; Gou, Haimei; Hu, Xuejiao; Hu, Xin; Shang, Mengqiao; Zhou, Juan; Zhou, Yi; Ye, Yuanxin; Song, Xingbo; Lu, Xiaojun; Chen, Xuerong; Ying, Binwu; Wang, Lanlan

    2016-06-01

    We conducted a systematic review and meta-analysis on drug-resistant tuberculosis in China to provide useful data for tuberculosis (TB) surveillance and treatment. Several databases, including PubMed, Embase, and the Chinese Biological Medical Database, were systematically searched between January 1, 1999, and August 31, 2015, using strict inclusion and exclusion criteria. The corresponding drug-resistant TB prevalence between the new and previously treated cases was significantly different in almost all of the economic regions. The Eastern coastal region is the most developed economic region with the lowest total drug-resistant TB prevalence (any drug resistance: 28%; 95% confidence interval [CI], 25%-32%; multidrug resistance: 9%; 95% CI, 8%-12%) and the lowest number of new cases (any drug resistance: 21%; 95% CI, 19%-23%; multidrug resistance: 4%; 95% CI, 3%-5%). The Northwest is the least developed area with the lowest drug-resistant TB prevalence for previously treated cases (any drug resistance: 45%; 95% CI, 36%-55%; multidrug resistance: 17%; 95% CI, 11%-26%). The prevalence (multidrug and first-line drug resistance) exhibited a downward trend from 1996-2014. The extensively drug-resistant prevalence in China was 3% (95% CI, 2%-5%) in this review. Overall, the status of drug-resistant tuberculosis in China is notably grim and exhibits regional epidemiologic characteristics. We are in urgent need of several comprehensive and effective control efforts to reverse this situation. Copyright © 2016 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

  12. Detection of low frequency multi-drug resistance and novel putative maribavir resistance in immunocompromised paediatric patients with cytomegalovirus

    Directory of Open Access Journals (Sweden)

    Charlotte Jane Houldcroft

    2016-09-01

    Full Text Available Human cytomegalovirus (HCMV is a significant pathogen in immunocompromised individuals, with the potential to cause fatal pneumonitis and colitis, as well as increasing the risk of organ rejection in transplant patients. With the advent of new anti-HCMV drugs there is therefore considerable interest in using virus sequence data to monitor emerging resistance to antiviral drugs in HCMV viraemia and disease, including the identification of putative new mutations. We used target-enrichment to deep sequence HCMV DNA from 11 immunosuppressed paediatric patients receiving single or combination anti-HCMV treatment, serially sampled over 1-27 weeks. Changes in consensus sequence and resistance mutations were analysed for three ORFs targeted by anti-HCMV drugs and the frequencies of drug resistance mutations monitored. Targeted-enriched sequencing of clinical material detected mutations occurring at frequencies of 2%. Seven patients showed no evidence of drug resistance mutations. Four patients developed drug resistance mutations a mean of 16 weeks after starting treatment. In two patients, multiple resistance mutations accumulated at frequencies of 20% or less, including putative maribavir and ganciclovir resistance mutations P522Q (UL54 and C480F (UL97. In one patient, resistance was detected 14 days earlier than by PCR. Phylogenetic analysis suggested recombination or superinfection in one patient. Deep sequencing of HCMV enriched from clinical samples excluded resistance in 7 of eleven subjects and identified resistance mutations earlier than conventional PCR-based resistance testing in 2 patients. Detection of multiple low level resistance mutations was associated with poor outcome.

  13. Nuclear export of proteins and drug resistance in cancer.

    Science.gov (United States)

    Turner, Joel G; Dawson, Jana; Sullivan, Daniel M

    2012-04-15

    The intracellular location of a protein is crucial to its normal functioning in a cell. Cancer cells utilize the normal processes of nuclear-cytoplasmic transport through the nuclear pore complex of a cell to effectively evade anti-neoplastic mechanisms. CRM1-mediated export is increased in various cancers. Proteins that are exported in cancer include tumor-suppressive proteins such as retinoblastoma, APC, p53, BRAC1, FOXO proteins, INI1/hSNF5, galectin-3, Bok, nucleophosmin, RASSF2, Merlin, p21(CIP), p27(KIP1), N-WASP/FAK, estradiol receptor and Tob, drug targets topoisomerase I and IIα and BCR-ABL, and the molecular chaperone protein Hsp90. Here, we review in detail the current processes and known structures involved in the export of a protein through the nuclear pore complex. We also discuss the export receptor molecule CRM1 and its binding to the leucine-rich nuclear export signal of the cargo protein and the formation of a nuclear export trimer with RanGTP. The therapeutic potential of various CRM1 inhibitors will be addressed, including leptomycin B, ratjadone, KOS-2464, and specific small molecule inhibitors of CRM1, N-azolylacrylate analogs, FOXO export inhibitors, valtrate, acetoxychavicol acetate, CBS9106, and SINE inhibitors. We will also discuss examples of how drug resistance may be reversed by targeting the exported proteins topoisomerase IIα, BCR-ABL, and galectin-3. As effective and less toxic CRM1 export inhibitors become available, they may be used as both single agents and in combination with current chemotherapeutic drugs. We believe that the future development of low-toxicity, small-molecule CRM1 inhibitors may provide a new approach to treating cancer. Copyright © 2011 Elsevier Inc. All rights reserved.

  14. A Study on the Frequency of Fungal Rhinosinusitis and to Determine the Sensitivity of the Isolates to Antifungal Drugs in Shiraz, Iran 2012-2013

    Directory of Open Access Journals (Sweden)

    Parisa Badiei

    2015-06-01

    Full Text Available Abstract Background: Fungal spores are present in large amounts in the nature which may cause diseases in the susceptible individuals. Fungal rhinosinusitis has been increased during recent decades. This study aims to investigate fungal rhinosinusitis in the patients with chronic needing endoscopic sinus surgery aims and to determine the sensitivity of the isolates to rhin sinusitis antifungal agents. Materials and Methods: In cross sectional study, specimens were obtained in sterile plates containing normal saline. from the suspected cases of chronic rhinosinusitis who had undergone endoscopic sinus surgery. Microscopic experiments and Cultures were done in Sabouraud Dextrose Agar medium. Minimum inhibitory concentration (MIC of the growth of fungi for seven antifungal agents against the isolates was determined using E-Test. Results: In total, specimens from 102 immunocompetent patients were examined. Nine positive specimens were presented, consisting of 3 for Aspergillus fumigatus, 3 for Penicillium, 2 for Aspergillus flavus and 1 for Alternaria. The mean age of the patients was 38 years, with 59 males and 43 females. The isolates were most sensitive to the voriconazole and amphotericin B. Conclusion: Since the prevalence of fungal rhinosinusitis is low, unfortunately, the clinicians are not attentive enough to the condition, and they initiate antifungal therapy if the patients are not responsive to antibiotics. Early diagnosis and suitable treatment can help more efficient management of patients.

  15. Antifungal Activity of Commercial Essential Oils and Biocides against Candida Albicans.

    Science.gov (United States)

    Serra, Elisa; Hidalgo-Bastida, Lilia Araida; Verran, Joanna; Williams, David; Malic, Sladjana

    2018-01-25

    Management of oral candidosis, most frequently caused by Candida albicans , is limited due to the relatively low number of antifungal drugs and the emergence of antifungal tolerance. In this study, the antifungal activity of a range of commercial essential oils, two terpenes, chlorhexidine and triclosan was evaluated against C. albicans in planktonic and biofilm form. In addition, cytotoxicity of the most promising compounds was assessed using murine fibroblasts and expressed as half maximal inhibitory concentrations (IC50). Antifungal activity was determined using a broth microdilution assay. The minimum inhibitory concentration (MIC) was established against planktonic cells cultured in a range of concentrations of the test agents. The minimal biofilm eradication concentration (MBEC) was determined by measuring re-growth of cells after pre-formed biofilm was treated for 24 h with the test agents. All tested commercial essential oils demonstrated anticandidal activity (MICs from 0.06% ( v / v ) to 0.4% ( v / v )) against planktonic cultures, with a noticeable increase in resistance exhibited by biofilms (MBECs > 1.5% ( v / v )). The IC50s of the commercial essential oils were lower than the MICs, while a one hour application of chlorhexidine was not cytotoxic at concentrations lower than the MIC. In conclusion, the tested commercial essential oils exhibit potential as therapeutic agents against C. albicans , although host cell cytotoxicity is a consideration when developing these new treatments.

  16. In vitro antifungal and antibiofilm activities of halogenated quinoline analogues against Candida albicans and Cryptococcus neoformans.

    Science.gov (United States)

    Zuo, Ran; Garrison, Aaron T; Basak, Akash; Zhang, Peilan; Huigens, Robert W; Ding, Yousong

    2016-08-01

    With the increasing prevalence of fungal infections coupled with emerging drug resistance, there is an urgent need for new and effective antifungal agents. Here we report the antifungal activities of 19 diverse halogenated quinoline (HQ) small molecules against Candida albicans and Cryptococcus neoformans. Four HQ analogues inhibited C. albicans growth with a minimum inhibitory concentration (MIC) of 100 nM, whilst 16 analogues effectively inhibited C. neoformans at MICs of 50-780 nM. Remarkably, two HQ analogues eradicated mature C. albicans and C. neoformans biofilms [minimum biofilm eradication concentration (MBEC) = 6.25-62.5 µM]. Several active HQs were found to penetrate into fungal cells, whilst one inactive analogue was unable to, suggesting that HQs elicit their antifungal activities through an intracellular mode of action. HQs are a promising class of small molecules that may be useful in future antifungal treatments. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  17. Antifungal Activity of Commercial Essential Oils and Biocides against Candida Albicans

    Directory of Open Access Journals (Sweden)

    Elisa Serra

    2018-01-01

    Full Text Available Management of oral candidosis, most frequently caused by Candida albicans, is limited due to the relatively low number of antifungal drugs and the emergence of antifungal tolerance. In this study, the antifungal activity of a range of commercial essential oils, two terpenes, chlorhexidine and triclosan was evaluated against C. albicans in planktonic and biofilm form. In addition, cytotoxicity of the most promising compounds was assessed using murine fibroblasts and expressed as half maximal inhibitory concentrations (IC50. Antifungal activity was determined using a broth microdilution assay. The minimum inhibitory concentration (MIC was established against planktonic cells cultured in a range of concentrations of the test agents. The minimal biofilm eradication concentration (MBEC was determined by measuring re-growth of cells after pre-formed biofilm was treated for 24 h with the test agents. All tested commercial essential oils demonstrated anticandidal activity (MICs from 0.06% (v/v to 0.4% (v/v against planktonic cultures, with a noticeable increase in resistance exhibited by biofilms (MBECs > 1.5% (v/v. The IC50s of the commercial essential oils were lower than the MICs, while a one hour application of chlorhexidine was not cytotoxic at concentrations lower than the MIC. In conclusion, the tested commercial essential oils exhibit potential as therapeutic agents against C. albicans, although host cell cytotoxicity is a consideration when developing these new treatments.

  18. Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates.

    Science.gov (United States)

    Straimer, Judith; Gnädig, Nina F; Witkowski, Benoit; Amaratunga, Chanaki; Duru, Valentine; Ramadani, Arba Pramundita; Dacheux, Mélanie; Khim, Nimol; Zhang, Lei; Lam, Stephen; Gregory, Philip D; Urnov, Fyodor D; Mercereau-Puijalon, Odile; Benoit-Vical, Françoise; Fairhurst, Rick M; Ménard, Didier; Fidock, David A

    2015-01-23

    The emergence of artemisinin resistance in Southeast Asia imperils efforts to reduce the global malaria burden. We genetically modified the Plasmodium falciparum K13 locus using zinc-finger nucleases and measured ring-stage survival rates after drug exposure in vitro; these rates correlate with parasite clearance half-lives in artemisinin-treated patients. With isolates from Cambodia, where resistance first emerged, survival rates decreased from 13 to 49% to 0.3 to 2.4% after the removal of K13 mutations. Conversely, survival rates in wild-type parasites increased from ≤0.6% to 2 to 29% after the insertion of K13 mutations. These mutations conferred elevated resistance to recent Cambodian isolates compared with that of reference lines, suggesting a contemporary contribution of additional genetic factors. Our data provide a conclusive rationale for worldwide K13-propeller sequencing to identify and eliminate artemisinin-resistant parasites. Copyright © 2015, American Association for the Advancement of Science.

  19. Smac combined with DDP can inhibit drug resistance of ovarian cancer through regulation of Survivin expression.

    Science.gov (United States)

    Chen, Qi; Zhang, Hong

    2018-02-28

    Ovarian cancer has the highest mortality rate among gynecological malignancies, presenting a major threat to women's life and health. It is essential to study the mechanisms of drug resistance to chemotherapy to identify ways to enhance drug-sensitivity. In recent years, many studies have shown that Smac/DIABLO is closely related to tumor drug resistance. Smac/DIABLO expression is markedly different between drug-resistant and chemo sensitive tumor cells. Up-regulation of Smac/DIABLO has been shown to increase tumor cell chemotherapy sensitivity. We found that Smac, combined with DDP greatly inhibited proliferation of subcutaneous xenografts of ovarian cancer cell line SKOV3/DDP without side effects. Mechanistic studies showed that Smac can inhibit the expression of Survivin, promote cell apoptosis of drug-resistant ovarian cancer cells and reverse the drug resistance.

  20. Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 Protease

    Directory of Open Access Journals (Sweden)

    Ladislau C. Kovari

    2012-05-01

    Full Text Available Designing HIV-1 protease inhibitors that overcome drug-resistance is still a challenging task. In this study, four clinical isolates of multi-drug resistant HIV-1 proteases that exhibit resistance to all the US FDA-approved HIV-1 protease inhibitors and also reduce the substrate recognition ability were examined. A multi-drug resistant HIV-1 protease isolate, MDR 769, was co-crystallized with the p2/NC substrate and the mutated CA/p2 substrate, CA/p2 P1’F. Both substrates display different levels of molecular recognition by the wild-type and multi-drug resistant HIV-1 protease. From the crystal structures, only limited differences can be identified between the wild-type and multi-drug resistant protease. Therefore, a wild-type HIV-1 protease and four multi-drug resistant HIV-1 proteases in complex with the two peptides were modeled based on the crystal structures and examined during a 10 ns-molecular dynamics simulation. The simulation results reveal that the multi-drug resistant HIV-1 proteases require higher desolvation energy to form complexes with the peptides. This result suggests that the desolvation of the HIV-1 protease active site is an important step of protease-ligand complex formation as well as drug resistance. Therefore, desolvation energy could be considered as a parameter in the evaluation of future HIV-1 protease inhibitor candidates.

  1. Association of the mycobacterial interspersed repetitive unit with drug resistance in mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Xian-feng eCheng

    2016-03-01

    Full Text Available BackgroundRecently, Mycobacterial Interspersed Repetitive Unit (MIRU was supposed to be associated with drug resistance in M.tuberculosis (MTB. However, whether the MIRU was related to drug resistance actually was still unknown. This research was conducted to explore that association.MethodsDrug susceptibility testing was used to evaluate the drug resistance of five anti-tuberculosis drug (isoniazid, INH; rifampicin, RFP; streptomycin, SM; ethambutol, EMB; and Paminosalicylicacid, PAS.. We tested the number of the repeat unite of MIRU (Mycobacterial Interspersed Repetitive Unit locus based on PCR of miru-vntr genotyping. Then, through logistic regression, we evaluated the association between fifteen MIRU and the resistance. In addition, we explored the most suitable MIRU locus of identified MIRU loci for drug resistance through multivariate logistic regression.ResultsAmong these fifteen MIRU, we found several MIRU loci could predict the drug resistance well. For example ,ETRB and ETRC could predict INH resistance; MIRU20 was associated with EMB resistance; and QUB11a was a predictive factor of PSA. ConclusionOur results may provide candidate regions for future genetic studies and aid in the prediction for drug resistance of MTB.

  2. Epidemiology and patterns of drug resistance among tuberculosis patients in Northwestern Iran

    Directory of Open Access Journals (Sweden)

    L Sahebi

    2016-01-01

    Full Text Available Background: Multidrug-resistant tuberculosis (MDR-TB has emerged as an important global health concern and is on the rise throughout the world. Objective: The aim of this study was to examine the epidemiology and pattern of TB drug resistance. Methods: In this cross-sectional study, 180 pulmonary TB patients from two Northwestern provinces of Iran were selected. The first and second line drug susceptibility testing was carried out using the 1% proportion method on the Lφwenstein-Jensen medium. Full demographic, environmental and clinical history was evaluated. Results: Prevalence of resistance to any TB drug was 13.8%. Eight (4.4% patients had MDR-TB (2.4% in the province of East Azerbaijan and 9.3% in the province of Ardabil and one patient had extensively drug-resistant TB. Patient resistance to both isoniazid and streptomycin was the most prevalent at a rate of 8.3%. Patients showed the least resistance to ethambutol (2.8%. There was a significant relationship between the previous history of TB drug treatment and TB drug resistance. Migrants from rural to urban areas were in high-risk groups for the occurrence of TB drug resistance. Conclusion: In our study, prevalence of MDR was less than the global average. It is essential to monitor the patients with previous history of TB treatment and migrants by rapid and accurate techniques in terms of drug-resistance odds.

  3. Pan Drug-Resistant Environmental Isolate of Acinetobacter baumannii from Croatia.

    Science.gov (United States)

    Goic-Barisic, Ivana; Seruga Music, Martina; Kovacic, Ana; Tonkic, Marija; Hrenovic, Jasna

    2017-06-01

    Acinetobacter baumannii is an emerging nosocomial pathogen with also emerging resistance to different antibiotics. Multidrug and pan drug-resistant clinical isolates were reported worldwide. Here we report the first evidence of pan drug-resistant environmental isolate of A. baumannii. The isolate was recovered from the effluent of secondary treated municipal wastewater of the City of Zagreb, Croatia. The isolate was resistant to penicillins/β-lactamase inhibitors, carbapenems, fluoroquinolones, aminoglycosides, folate pathway inhibitors, and polymyxins, except intermediately susceptible to minocycline and tigecycline. Intrinsic chromosomally located bla OXA-51-like gene and acquired plasmid-located bla OXA-23-like gene were related to clinical isolates. Pan drug-resistant A. baumannii can occur in natural environments outside of the hospital. Secondary treated municipal wastewater represents a potential epidemiological reservoir of pan drug-resistant A. baumannii and carbapenem resistance gene.

  4. Increasing drug resistance of Mycobacterium tuberculosis in Sinaloa, Mexico, 1997-2005.

    Science.gov (United States)

    Zazueta-Beltran, Jorge; León-Sicairos, Nidia; Muro-Amador, Secundino; Flores-Gaxiola, Adrian; Velazquez-Roman, Jorge; Flores-Villaseñor, Hector; Canizalez-Roman, Adrian

    2011-04-01

    In 1997 the US Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) reported high proportions of drug-resistant Mycobacterium tuberculosis in three Mexican states: Sinaloa, Baja California, and Oaxaca. In 2006, we showed that resistance to anti-tuberculosis drugs remained frequent in Sinaloa. The objectives of this study were to describe drug-resistant tuberculosis (TB) trends and to investigate the probability that patients acquire resistance to first-line anti-TB drugs on recurrence after treatment in Sinaloa. Sputum specimens were collected from patients diagnosed with TB at all the health care institutions of Sinaloa during 1997-2005. Isolates were tested for susceptibility to first-line drugs. Among 671 isolates tested from 1997 to 2002, the overall resistance rate was 34.9% (95% confidence interval (CI) 31.2-38.4) with a 1.2% increase per year (Chi-square=4.258, p=0.03906). The prevalence of multi-drug resistance (MDR) was 17.9% (95% CI 14.9-20.7) with a 1.2% increase per year (Chi-square=8.352, p=0.00385). Of 50 patients registered twice between 1997 and 2005, 15 were fully susceptible at first registration, of whom six (40%) acquired drug resistance. Of 35 cases with any drug resistance at first registration, 21 (60%) came to acquire resistance to at least one other drug. The proportion of drug-resistant TB increased during 1997-2005 in Sinaloa. Major efforts are needed to prevent the further rise and spread of drug-resistant and MDR TB. Copyright © 2011 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  5. The emerging threat of pre-extensively drug-resistant tuberculosis in West Africa: preparing for large-scale tuberculosis research and drug resistance surveillance.

    Science.gov (United States)

    Gehre, Florian; Otu, Jacob; Kendall, Lindsay; Forson, Audrey; Kwara, Awewura; Kudzawu, Samuel; Kehinde, Aderemi O; Adebiyi, Oludele; Salako, Kayode; Baldeh, Ignatius; Jallow, Aisha; Jallow, Mamadou; Dagnra, Anoumou; Dissé, Kodjo; Kadanga, Essosimna A; Idigbe, Emmanuel Oni; Onubogu, Catherine; Onyejepu, Nneka; Gaye-Diallo, Aissatou; Ba-Diallo, Awa; Rabna, Paulo; Mane, Morto; Sanogo, Moumine; Diarra, Bassirou; Dezemon, Zingue; Sanou, Adama; Senghore, Madikay; Kwambana-Adams, Brenda A; Demba, Edward; Faal-Jawara, Tutty; Kumar, Samrat; Tientcheu, Leopold D; Jallow, Adama; Ceesay, Samba; Adetifa, Ifedayo; Jaye, Assan; Pallen, Mark J; D'Alessandro, Umberto; Kampmann, Beate; Adegbola, Richard A; Mboup, Souleymane; Corrah, Tumani; de Jong, Bouke C; Antonio, Martin

    2016-11-03

    Drug-resistant tuberculosis (TB) is a global public health problem. Adequate management requires baseline drug-resistance prevalence data. In West Africa, due to a poor laboratory infrastructure and inadequate capacity, such data are scarce. Therefore, the true extent of drug-resistant TB was hitherto undetermined. In 2008, a new research network, the West African Network of Excellence for Tuberculosis, AIDS and Malaria (WANETAM), was founded, comprising nine study sites from eight West African countries (Burkina Faso, The Gambia, Ghana, Guinea-Bissau, Mali, Nigeria, Senegal and Togo). The goal was to establish Good Clinical Laboratory Practice (GCLP) principles and build capacity in standardised smear microscopy and mycobacterial culture across partnering laboratories to generate the first comprehensive West African drug-resistance data. Following GCLP and laboratory training sessions, TB isolates were collected at sentinel referral sites between 2009-2013 and tested for first- and second-line drug resistance. From the analysis of 974 isolates, an unexpectedly high prevalence of multi-drug-resistant (MDR) strains was found in new (6 %) and retreatment patients (35 %) across all sentinel sites, with the highest prevalence amongst retreatment patients in Bamako, Mali (59 %) and the two Nigerian sites in Ibadan and Lagos (39 % and 66 %). In Lagos, MDR is already spreading actively amongst 32 % of new patients. Pre-extensively drug-resistant (pre-XDR) isolates are present in all sites, with Ghana showing the highest proportion (35 % of MDR). In Ghana and Togo, pre-XDR isolates are circulating amongst new patients. West African drug-resistance prevalence poses a previously underestimated, yet serious public health threat, and our estimates obtained differ significantly from previous World Health Organisation (WHO) estimates. Therefore, our data are reshaping current concepts and are essential in informing WHO and public health strategists to implement urgently

  6. Time-programmable drug dosing allows the manipulation, suppression and reversal of antibiotic drug resistance in vitro

    OpenAIRE

    Yoshida, Mari; Galiñanes Reyes, Sabrina Galiñanes; Tsuda, Soichiro; Horinouchi, Takaaki; Furusawa, Chikara; Cronin, Leroy

    2017-01-01

    Multi-drug strategies have been attempted to prolong the efficacy of existing antibiotics, but with limited success. Here we show that the evolution of multi-drug-resistant Escherichia coli can be manipulated in vitro by administering pairs of antibiotics and switching between them in ON/OFF manner. Using a multiplexed cell culture system, we find that switching between certain combinations of antibiotics completely suppresses the development of resistance to one of the antibiotics. Using thi...

  7. Infectious drug resistance during an outbreak of salmonellosis

    International Nuclear Information System (INIS)

    Botha, P.; Hirsch, S.; Harley, E.; Elisha, G.; Pratt, K.; Bain, A.; Destroo, L.

    1980-01-01

    The sudden acquisition of aminoglycoside resistance among Salmonella group C 1 isolates causing summer diarrhoea raised the possibility of plasmid-mediated resistance. The demonstration of circular DNA species in the resistant, but not in the sensitive salmonellae and the transfer by conjugation of antibiotic resistance to a sensitive strain of Escherichia coli, was consistent with plasmid-mediated resistance

  8. [Mycobacterium tuberculosis drug resistance in HIV patients in Baixada Santista, São Paulo, Brazil].

    Science.gov (United States)

    Rozman, Luciana Martins; Santo, Augusto Hasiak; Rozman, Mauro Abrahão

    2007-05-01

    Since the early 1990s, an increase in Mycobacterium tuberculosis drug resistance has been reported, with high prevalence among HIV+ patients. We evaluated the sensitivity patterns of M. tuberculosis, resistance rate, and predisposing factors among HIV+ patients in Santos, São Vicente, Cubatão, Praia Grande, and Guarujá, São Paulo State, Brazil. The medical charts of 301 patients with positive cultures for M. tuberculosis from 1993 to 2003 were reviewed. Resistance occurred in 57 patients (18.9%), as follows: 32 (10.6%) displayed multidrug-resistant tuberculosis (resistant to at least Rifampicin and Isoniazid); 4 (1.3%) were resistant to two or more drugs; and 21 (7%) were resistant to a single drug. Acquired resistance was observed in 70.1% of cases. Drug resistance was significantly associated with previous tuberculosis treatment, duration of HIV diagnosis, and previous hospitalization. In logistic regression analysis, only previous tuberculosis treatment adjusted by age remained as an independent risk factor (OR = 5.49; 95%CI: 2.60-11.60). Drug resistance to at least one drug in 18.9% and multidrug resistance in 10.6% of cases highlight the relevance of this problem in HIV patients in the Baixada Santista.

  9. Antibacterial and Antifungal Activities of Spices.

    Science.gov (United States)

    Liu, Qing; Meng, Xiao; Li, Ya; Zhao, Cai-Ning; Tang, Guo-Yi; Li, Hua-Bin

    2017-06-16

    Infectious diseases caused by pathogens and food poisoning caused by spoilage microorganisms are threatening human health all over the world. The efficacies of some antimicrobial agents, which are currently used to extend shelf-life and increase the safety of food products in food industry and to inhibit disease-causing microorganisms in medicine, have been weakened by microbial resistance. Therefore, new antimicrobial agents that could overcome this resistance need to be discovered. Many spices-such as clove, oregano, thyme, cinnamon, and cumin-possessed significant antibacterial and antifungal activities against food spoilage bacteria like Bacillus subtilis and Pseudomonas fluorescens , pathogens like Staphylococcus aureus and Vibrio parahaemolyticus, harmful fungi like Aspergillus flavus, even antibiotic resistant microorganisms such as methicillin resistant Staphylococcus aureus. Therefore, spices have a great potential to be developed as new and safe antimicrobial agents. This review summarizes scientific studies on the antibacterial and antifungal activities of several spices and their derivatives.

  10. Toward repurposing ciclopirox as an antibiotic against drug-resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae.

    Directory of Open Access Journals (Sweden)

    Kimberly M Carlson-Banning

    Full Text Available Antibiotic-resistant infections caused by gram-negative bacteria are a major healthcare concern. Repurposing drugs circumvents the time and money limitations associated with developing new antimicrobial agents needed to combat these antibiotic-resistant infections. Here we identified the off-patent antifungal agent, ciclopirox, as a candidate to repurpose for antibiotic use. To test the efficacy of ciclopirox against antibiotic-resistant pathogens, we used a curated collection of Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae clinical isolates that are representative of known antibiotic resistance phenotypes. We found that ciclopirox, at 5-15 µg/ml concentrations, inhibited bacterial growth regardless of the antibiotic resistance status. At these same concentrations, ciclopirox reduced growth of Pseudomonas aeruginosa clinical isolates, but some of these pathogens required higher ciclopirox concentrations to completely block growth. To determine how ciclopirox inhibits bacterial growth, we performed an overexpression screen in E. coli. This screen revealed that galE, which encodes UDP-glucose 4-epimerase, rescued bacterial growth at otherwise restrictive ciclopirox concentrations. We found that ciclopirox does not inhibit epimerization of UDP-galactose by purified E. coli GalE; however, ΔgalU, ΔgalE, ΔrfaI, or ΔrfaB mutant strains all have lower ciclopirox minimum inhibitory concentrations than the parent strain. The galU, galE, rfaI, and rfaB genes all encode enzymes that use UDP-galactose or UDP-glucose for galactose metabolism and lipopolysaccharide (LPS biosynthesis. Indeed, we found that ciclopirox altered LPS composition of an E. coli clinical isolate. Taken together, our data demonstrate that ciclopirox affects galactose metabolism and LPS biosynthesis, two pathways important for bacterial growth and virulence. The lack of any reported fungal resistance to ciclopirox in over twenty years of use in the clinic

  11. Toward repurposing ciclopirox as an antibiotic against drug-resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae.

    Science.gov (United States)

    Carlson-Banning, Kimberly M; Chou, Andrew; Liu, Zhen; Hamill, Richard J; Song, Yongcheng; Zechiedrich, Lynn

    2013-01-01

    Antibiotic-resistant infections caused by gram-negative bacteria are a major healthcare concern. Repurposing drugs circumvents the time and money limitations associated with developing new antimicrobial agents needed to combat these antibiotic-resistant infections. Here we identified the off-patent antifungal agent, ciclopirox, as a candidate to repurpose for antibiotic use. To test the efficacy of ciclopirox against antibiotic-resistant pathogens, we used a curated collection of Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae clinical isolates that are representative of known antibiotic resistance phenotypes. We found that ciclopirox, at 5-15 µg/ml concentrations, inhibited bacterial growth regardless of the antibiotic resistance status. At these same concentrations, ciclopirox reduced growth of Pseudomonas aeruginosa clinical isolates, but some of these pathogens required higher ciclopirox concentrations to completely block growth. To determine how ciclopirox inhibits bacterial growth, we performed an overexpression screen in E. coli. This screen revealed that galE, which encodes UDP-glucose 4-epimerase, rescued bacterial growth at otherwise restrictive ciclopirox concentrations. We found that ciclopirox does not inhibit epimerization of UDP-galactose by purified E. coli GalE; however, ΔgalU, ΔgalE, ΔrfaI, or ΔrfaB mutant strains all have lower ciclopirox minimum inhibitory concentrations than the parent strain. The galU, galE, rfaI, and rfaB genes all encode enzymes that use UDP-galactose or UDP-glucose for galactose metabolism and lipopolysaccharide (LPS) biosynthesis. Indeed, we found that ciclopirox altered LPS composition of an E. coli clinical isolate. Taken together, our data demonstrate that ciclopirox affects galactose metabolism and LPS biosynthesis, two pathways important for bacterial growth and virulence. The lack of any reported fungal resistance to ciclopirox in over twenty years of use in the clinic, its excellent safety

  12. Drug ratio-dependent antagonism: a new category of multidrug resistance and strategies for its circumvention.

    Science.gov (United States)

    Harasym, Troy O; Liboiron, Barry D; Mayer, Lawrence D

    2010-01-01

    A newly identified form of multidrug resistance (MDR) in tumor cells is presented, pertaining to the commonly encountered resistance of cancer cells to anticancer drug combinations at discrete drug:drug ratios. In vitro studies have revealed that whether anticancer drug combinations interact synergistically or antagonistically can depend on the ratio of the combined agents. Failure to control drug ratios in vivo due to uncoordinated pharmacokinetics could therefore lead to drug resistance if tumor cells are exposed to antagonistic drug ratios. Consequently, the most efficacious drug combination may not occur at the typically employed maximum tolerated doses of the combined drugs if this leads to antagonistic ratios in vivo after administration and resistance to therapeutic effects of the drug combination. Our approach to systematically screen a wide range of drug ratios and concentrations and encapsulate the drug combination in a liposomal delivery vehicle at identified synergistic ratios represents a means to mitigate this drug ratio-dependent MDR mechanism. The in vivo efficacy of the improved agents (CombiPlex formulations) is demonstrated and contrasted with the decreased efficacy when drug combinations are exposed to tumor cells in vivo at antagonistic ratios.

  13. Epidemiology of anti-tuberculosis drug resistance in a chinese population: current situation and challenges ahead

    Science.gov (United States)

    2011-01-01

    Background Drug resistance has been a cause of concern for tuberculosis (TB) control in both developed and developing countries. Careful monitoring of the patterns and trends of drug resistance should remain a priority. Methods Strains were collected from 1824 diagnosed sputum smear positive pulmonary TB patients in Jiangsu province of China and then tested for drug susceptibility against rifampicin, isoniazid, ethambutol and streptomycin. The prevalence and patterns of drug resistance in mycobacterium tuberculosis (MTB) isolates were investigated. Multiple logistic regression analysis was performed to identify the risk factors for multidrug resistant (MDR) bacterial infection. The strength of association was estimated by odds ratio (OR) and 95% confidence interval (95% CI). Results The drug susceptibility tests showed that 1077(59.05%) MTB strains were sensitive to all the four antibiotics and the other 747(40.95%) strains were resistant to at least one drug. The proportions of mono-drug resistance were 28.73% for isoniazid, 19.41% for rifampicin, 29.33% for streptomycin, and 13.98% for ethambutol, respectively. The prevalence of MDR-TB was 16.61%, which was significantly different between new cases (7.63%) and those with previous treatment history (33.07%). Geographical variation of drug resistance was observed, where the proportion of MDR-TB among new cases was higher in the central (9.50%) or north part (9.57%) than that in the south area (4.91%) of Jiangsu province. The age of patients was significantly associated with the risk of drug resistance (P control. Prevention and control of drug-resistant TB should be emphasized by the revised DOTS (direct observed therapy, short course) program through prompt case detection, routine and quality-assured drug susceptibility test for patients at high risk of resistance, programmatic treatment with both first and second-line medicines, and systematic treatment observation, with priority for high MDR-TB settings. PMID

  14. Pharmacological synergism of bee venom and melittin with antibiotics and plant secondary metabolites against multi-drug resistant microbial pathogens.

    Science.gov (United States)

    Al-Ani, Issam; Zimmermann, Stefan; Reichling, Jürgen; Wink, Michael

    2015-02-15

    The goal of this study was to investigate the antimicrobial activity of bee venom and its main component, melittin, alone or in two-drug and three-drug combinations with antibiotics (vancomycin, oxacillin, and amikacin) or antimicrobial plant secondary metabolites (carvacrol, benzyl isothiocyanate, the alkaloids sanguinarine and berberine) against drug-sensitive and antibiotic-resistant microbial pathogens. The secondary metabolites were selected corresponding to the molecular targets to which they are directed, being different from those of melittin and the antibiotics. The minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) were evaluated by the standard broth microdilution method, while synergistic or additive interactions were assessed by checkerboard dilution and time-kill curve assays. Bee venom and melittin exhibited a broad spectrum of antibacterial activity against 51 strains of both Gram-positive and Gram-negative bacteria with strong anti-MRSA and anti-VRE activity (MIC values between 6 and 800 µg/ml). Moreover, bee venom and melittin showed significant antifungal activity (MIC values between 30 and 100 µg/ml). Carvacrol displayed bactericidal activity, while BITC exhibited bacteriostatic activity against all MRSA and VRE strains tested (reference strains and clinical isolates), both compounds showed a remarkable fungicidal activity with minimum fungicidal concentration (MFC) values between 30 and 200 µg/ml. The DNA intercalating alkaloid sanguinarine showed bactericidal activity against MRSA NCTC 10442 (MBC 20 µg/ml), while berberine exhibited bacteriostatic activity against MRSA NCTC 10442 (MIC 40 µg/ml). Checkerboard dilution tests mostly revealed synergism of two-drug combinations against all the tested microorganisms with FIC indexes between 0.24 and 0.50, except for rapidly growing mycobacteria in which combinations exerted an additive effect (FICI = 0.75-1). In time-kill assays all three-drug

  15. Primary antiretroviral drug resistance among HIV type 1-infected individuals in Brazil.

    Science.gov (United States)

    Sprinz, Eduardo; Netto, Eduardo M; Patelli, Maria; Lima, J S; Lima, Maria Patelli J S; Furtado, Juvênao J D; da Eira, Margareth; Zajdenverg, Roberto; Madruga, José V; Lewi, David S; Machado, Alcyone A; Pedro, Rogério J; Soares, Marcelo A

    2009-09-01

    Infection with drug-resistant human immunodeficiency virus type 1 (HIV-1) has been documented in all countries that have surveyed for it and may result in an unfavorable response to therapy. The prevalence and characteristics of individuals with transmitted resistance to antiretroviral drugs have been scarcely described in Brazil. We performed antiretroviral resistance testing prior to initiation of therapy in 400 subjects enrolled from 20 centers in 13 Brazilian cities between March and September 2007. Genotyping was conducted using PCR-amplified HIV pol products by automated sequencing, and genotype interpretation was done according to the IAS-USA consensus. Of 400 eligible participants, 387 (95.8%) were successfully tested. Seven percent of antiretroviral-naive patients carried viruses with one or more major mutation associated with drug resistance. The prevalence of these mutations was 1.0% for protease inhibitors, 4.4% for nonnucleoside reverse transcriptase inhibitors, and 1.3% for nucleoside reverse transcriptase inhibitors. The frequency of multidrug resistance among the resistant strains was 13.6%. Among subjects infected with drug-resistant virus, the majority were infected with subtype B viruses (91%). Subjects from the city of São Paulo had higher transmitted resistance mutations compared to the rest of the country. Reporting a partner taking antiretroviral medications was associated with a higher chance of harboring HIV variants with major drug resistance mutations [odds ratio = 2.57 (95% confidence interval, 1.07-6.16); p = 0.014]. Resistance testing in drug-naive individuals identified 7% of subjects with mutations associated with reduced susceptibility to antiretroviral drugs. Continued surveillance of drug-resistant HIV-1 in Brazil is warranted when guidelines for HIV prophylaxis and treatment are updated. Resistance testing among drug-naive patients prior to treatment initiation should be considered, mainly directed at subjects whose partners are

  16. Glucuronidation as a mechanism of intrinsic drug resistance in colon cancer cells: contribution of drug transport proteins

    NARCIS (Netherlands)

    Cummings, Jeffrey; Zelcer, Noam; Allen, John D.; Yao, Denggao; Boyd, Gary; Maliepaard, Mark; Friedberg, Thomas H.; Smyth, John F.; Jodrell, Duncan I.

    2004-01-01

    We have recently shown that drug conjugation catalysed by UDP-glucuronosyltransferases (UGTs) functions as an intrinsic mechanism of resistance to the topoisomerase I inhibitors 7-ethyl-10-hydroxycamptothecin and NU/ICRF 505 in human colon cancer cells and now report on the role of drug transport in

  17. Automated sequence analysis and editing software for HIV drug resistance testing

    NARCIS (Netherlands)

    Struck, Daniel; Wallis, Carole L.; Denisov, Gennady; Lambert, Christine; Servais, Jean-Yves; Viana, Raquel V.; Letsoalo, Esrom; Bronze, Michelle; Aitken, Sue C.; Schuurman, Rob; Stevens, Wendy; Schmit, Jean Claude; Rinke de Wit, Tobias; Perez Bercoff, Danielle

    2012-01-01

    Background: Access to antiretroviral treatment in resource-limited-settings is inevitably paralleled by the emergence of HIV drug resistance. Monitoring treatment efficacy and HIV drugs resistance testing are therefore of increasing importance in resource-limited settings. Yet low-cost technologies

  18. Surveillance of extensively drug-resistant tuberculosis in Europe, 2003-2007.

    NARCIS (Netherlands)

    Devaux, I.; Manissero, D.; Fernandez de la Hoz, K.; Kremer, K.; Soolingen, D. van

    2010-01-01

    This paper describes the results of second-line drug (SLD) susceptibility tests among multidrug-resistant tuberculosis (MDR TB) cases reported in 20 European countries aiming to identify extensively drug-resistant tuberculosis (XDR TB) cases. A project on molecular surveillance of MDR TB cases was

  19. Exploring Culturally Specific Drug Resistance Strategies of Hawaiian Youth in Rural Communities

    Science.gov (United States)

    Okamoto, Scott K.; Po'a-Kekuawela, Ka'ohinani; Chin, Coralee I. H.; Nebre, La Risa H.; Helm, Susana

    2010-01-01

    This qualitative study examined the drug resistance strategies of Hawaiian youth residing in rural communities in Hawai'i. Forty seven youth participated in 14 focus groups which focused on the social and environmental context of drug use for these youth. The findings indicated that there were 47 references to resistance strategies used in drug…

  20. Extremely Drug-Resistant Salmonella enterica Serovar Senftenberg Infections in Patients in Zambia

    DEFF Research Database (Denmark)

    Hendriksen, Rene S.; Joensen, Katrine Grimstrup; Lukwesa-Musyani, Chileshe

    2013-01-01

    Two cases of extremely drug-resistant Salmonella enterica serovar Senftenberg isolated from patients in Zambia were investigated by utilizing MIC determinations and whole-genome sequencing. The isolates were resistant to, and harbored genes toward, nine drug classes, including fluoroquinolones an...... and extended-spectrum cephalosporins, contained two plasmid replicons, and differed by 93 single-nucleotide polymorphisms....

  1. Relationship between National TB program and prevalence of TB drug resistance in Algeria, 1965 to 2013

    Directory of Open Access Journals (Sweden)

    Fadila Boulahbal

    2015-01-01

    The different steps will be presented of the development of the National TB program in Algeria between 1964 and 2014, and in the same way the variations of the prevalence rate of TB drug resistance to demonstrate that the drug resistance surveillance is an acceptable indicator of the performance of TB control program in the country.

  2. Efficacy of verapamil as an adjunctive treatment in children with drug-resistant epilepsy

    DEFF Research Database (Denmark)

    Nicita, Francesco; Spalice, Alberto; Papetti, Laura

    2014-01-01

    Verapamil, a voltage-gated calcium channel blocker, has been occasionally reported to have some effect on reducing seizure frequency in drug-resistant epilepsy or status epilepticus. We aimed to investigate the efficacy of verapamil as add-on treatment in children with drug-resistant epilepsy....

  3. Multi-drug resistant tuberculosis in the Netherlands : Personalised treatment and outcome

    NARCIS (Netherlands)

    van Altena, Richard

    2016-01-01

    Tuberculosis (TB) caused by bacilli that are resistant to the two major drugs, rifampicin and isoniazid is defined as Multi-Drug Resistant TB or MDRTB. MDRTB kills around 50% of people affected around the world. In contrast, treatment results of MDR-TB in the Netherlands (1985-2013) have

  4. Antituberculosis drug resistance in the south of Vietnam: prevalence and trends

    NARCIS (Netherlands)

    Huong, Nguyen T.; Lan, Nguyen T. N.; Cobelens, Frank G. J.; Duong, Bui D.; Co, Nguyen V.; Bosman, Maarten C.; Kim, Sang-Jae; van Soolingen, Dick; Borgdorff, Martien W.

    2006-01-01

    BACKGROUND: There is limited evidence that the DOTS (directly observed therapy, short course) strategy for tuberculosis (TB) control can contain the emergence and spread of drug resistance in the absence of second-line treatment. We compared drug-resistance levels between 1996 and 2001 in the south

  5. Potent Antifungal Activity of Pure Compounds from Traditional Chinese Medicine Extracts against Six Oral Candida Species and the Synergy with Fluconazole against Azole-Resistant Candida albicans

    Directory of Open Access Journals (Sweden)

    Zhimin Yan

    2012-01-01

    Full Text Available This study was designed to evaluate the in vitro antifungal activities of four traditional Chinese medicine (TCM extracts. The inhibitory effects of pseudolaric acid B, gentiopicrin, rhein, and alion were assessed using standard disk diffusion and broth microdilution assays. They were tested against six oral Candida species, Candida albicans, Candida glabrata, Candida tropicalis, Candida krusei, Candida dubliniensis, and Candida guilliermondii, including clinical isolates from HIV-negative, HIV-positive, and Sjögren's syndrome patients. It was found that pseudolaric acid B had the most potent antifungal effect and showed similar antifungal activity to all six Candida spp, and to isolates from HIV-negative, HIV-positive, and Sjögren's syndrome patients. The MIC values ranged from 16 to 128 μg/mL. More interestingly, a synergistic effect of pseudolaric acid B in combination with fluconazole was observed. We suggest that pseudolaric acid B might be a potential therapeutic fungicidal agent in treating oral candidiasis.

  6. Primary drug resistance among pulmonary treatment-naïve tuberculosis patients in Amazonas State, Brazil.

    Science.gov (United States)

    da Silva Garrido, M; Ramasawmy, R; Perez-Porcuna, T M; Zaranza, E; Chrusciak Talhari, A; Martinez-Espinosa, F E; Bührer-Sékula, S

    2014-05-01

    Multidrug-resistant tuberculosis (MDR-TB) is the main indicator of previous treatment in tuberculosis (TB) patients. MDR-TB among treatment-naïve patients indicates infection with drug-resistant Mycobacterium tuberculosis strains, and such cases are considered primary drug-resistant cases. To estimate the prevalence of drug resistance in pulmonary TB (PTB) treatment-naïve patients and to identify the socio-demographic and clinical characteristics of the resistant population. A total of 205 treatment-naïve PTB patients from Manaus, Amazonas State, Brazil, were enrolled. Drug susceptibility testing (DST) was performed on all positive mycobacterial cultures using the 1% proportion method. Positive M. tuberculosis cultures were obtained from only 175 patients for DST. The prevalence of primary MDR-TB was 1.7% (3/175); 14.3% (25/175) of the cultures presented resistance to at least one of the drugs. Resistance to streptomycin, isoniazid, rifampicin and ethambutol was respectively 8.6%, 6.9%, 3.4% and 2.3%. An association between TB patients with resistance to more than one drug and known previous household contact with a TB patient was observed (P= 0.008, OR 6.7, 95%CI 1.2-67.3). Although the prevalence of primary MDR-TB currently is relatively low, it may become a major public health problem if tailored treatment is not provided, as resistance to more than one drug is significantly associated with household contact.

  7. Fitness trade-offs in the evolution of dihydrofolate reductase and drug resistance in Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Marna S Costanzo

    Full Text Available Patterns of emerging drug resistance reflect the underlying adaptive landscapes for specific drugs. In Plasmodium falciparum, the parasite that causes the most serious form of malaria, antifolate drugs inhibit the function of essential enzymes in the folate pathway. However, a handful of mutations in the gene coding for one such enzyme, dihydrofolate reductase, confer drug resistance. Understanding how evolution proceeds from drug susceptibility to drug resistance is critical if new antifolate treatments are to have sustained usefulness.We use a transgenic yeast expression system to build on previous studies that described the adaptive landscape for the antifolate drug pyrimethamine, and we describe the most likely evolutionary trajectories for the evolution of drug resistance to the antifolate chlorcycloguanil. We find that the adaptive landscape for chlorcycloguanil is multi-peaked, not all highly resistant alleles are equally accessible by evolution, and there are both commonalities and differences in adaptive landscapes for chlorcycloguanil and pyrimethamine.Our findings suggest that cross-resistance between drugs targeting the same enzyme reflect the fitness landscapes associated with each particular drug and the position of the genotype on both landscapes. The possible public health implications of these findings are discussed.

  8. Antimalarial Drug Resistance: Literature Review and Activities and Findings of the ICEMR Network.

    Science.gov (United States)

    Cui, Liwang; Mharakurwa, Sungano; Ndiaye, Daouda; Rathod, Pradipsinh K; Rosenthal, Philip J

    2015-09-01

    Antimalarial drugs are key tools for the control and elimination of malaria. Recent decreases in the global malaria burden are likely due, in part, to the deployment of artemisinin-based combination therapies. Therefore, the emergence and potential spread of artemisinin-resistant parasites in southeast Asia and changes in sensitivities to artemisinin partner drugs have raised concerns. In recognition of this urgent threat, the International Centers of Excellence for Malaria Research (ICEMRs) are closely monitoring antimalarial drug efficacy and studying the mechanisms underlying drug resistance. At multiple sentinel sites of the global ICEMR network, research activities include clinical studies to track the efficacies of antimalarial drugs, ex vivo/in vitro assays to measure drug susceptibilities of parasite isolates, and characterization of resistance-mediating parasite polymorphisms. Taken together, these efforts offer an increasingly comprehensive assessment of the efficacies of antimalarial therapies, and enable us to predict the emergence of drug resistance and to guide local antimalarial drug policies. Here we briefly review worldwide antimalarial drug resistance concerns, summarize research activities of the ICEMRs related to drug resistance, and assess the global impacts of the ICEMR programs. © The American Society of Tropical Medicine and Hygiene.

  9. Antifungal susceptibilities and identification of species of the Sporothrix schenckii complex isolated in Brazil.

    Science.gov (United States)

    Ottonelli Stopiglia, Cheila Denise; Magagnin, Cibele Massotti; Castrillón, Mauricio Ramírez; Mendes, Sandra Denise Camargo; Heidrich, Daiane; Valente, Patricia; Scroferneker, Maria Lúcia

    2014-01-01

    Sporotrichosis is a subacute or chronic mycosis caused worldwide by the dimorphic species complex, Sporothrix schenckii. We studied 85 isolates recovered in Brazil to verify their identification and evaluate their in vitro antifungal susceptibility patterns. Based on phenotypic tests (microscopic features, ability to grow at 30°C and 37°C, colony diameters, as well as assimilation of sucrose and raffinose) and molecular assays (amplification of a fragment of the calmodulin gene), the strains were identified as S. schenckii, S. brasiliensis and S. globosa, with a predominance of S. schenckii isolates. There was 37.7% disagreement between the phenotypic and genotypic identification methodologies. In general, terbinafine was the most active drug, followed by ketoconazole and itraconazole, and the less active fluconazole and voriconazole. Five isolates (one S. globosa and four S. schenckii) were found to be itraconazole-resistant strains but, in general, there were no differences in the in vitro antifungal susceptibility profiles among the Sporothrix species.

  10. Pretreatment HIV drug resistance results in virological failure and accumulation of additional resistance mutations in Ugandan children

    NARCIS (Netherlands)

    Kityo, Cissy; Boerma, Ragna S.; Sigaloff, Kim C. E.; Kaudha, Elizabeth; Calis, Job C. J.; Musiime, Victor; Balinda, Sheila; Nakanjako, Rita; Boender, T. Sonia; Mugyenyi, Peter N.; Rinke de Wit, Tobias F.

    2017-01-01

    Background: Pretreatment HIV drug resistance (PDR) can impair virological response to ART, jeopardizing effective treatment for children. Methods: Children aged <12 years initiated first-line ART in Uganda during 2010-11. Baseline and 6 monthly viral load (VL) and genotypic resistance testing if VL.

  11. HIV drug resistance in infants increases with changing prevention of mother-to-child transmission regimens.

    Science.gov (United States)

    Poppe, Lisa K; Chunda-Liyoka, Catherine; Kwon, Eun H; Gondwe, Clement; West, John T; Kankasa, Chipepo; Ndongmo, Clement B; Wood, Charles

    2017-08-24

    The objectives of this study were to determine HIV drug resistance (HIVDR) prevalence in Zambian infants upon diagnosis, and to determine how changing prevention of mother-to-child transmission (PMTCT) drug regimens affect drug resistance. Dried blood spot (DBS) samples from infants in the Lusaka District of Zambia, obtained during routine diagnostic screening, were collected during four different years representing three different PMTCT drug treatment regimens. DNA extracted from dried blood spot samples was used to sequence a 1493 bp region of the reverse transcriptase gene. Sequences were analyzed via the Stanford HIVDRdatabase (http://hivdb.standford.edu) to screen for resistance mutations. HIVDR in infants increased from 21.5 in 2007/2009 to 40.2% in 2014. Nonnucleoside reverse transcriptase inhibitor resistance increased steadily over the sampling period, whereas nucleoside reverse transcriptase inhibitor resistance and dual class resistance both increased more than threefold in 2014. Analysis of drug resistance scores in each group revealed increasing strength of resistance over time. In 2014, children with reported PMTCT exposure, defined as infant prophylaxis and/or maternal treatment, showed a higher prevalence and strength of resistance compared to those with no reported exposure. HIVDR is on the rise in Zambia and presents a serious problem for the successful lifelong treatment of HIV-infected children. PMTCT affects both the prevalence and strength of resistance and further research is needed to determine how to mitigate its role leading to resistance.

  12. Antifungal compounds from cyanobacteria.

    Science.gov (United States)

    Shishido, Tânia K; Humisto, Anu; Jokela, Jouni; Liu, Liwei; Wahlsten, Matti; Tamrakar, Anisha; Fewer, David P; Permi, Perttu; Andreote, Ana P D; Fiore, Marli F; Sivonen, Kaarina

    2015-04-13

    Cyanobacteria are photosynthetic prokaryotes found in a range of environments. They are infamous for the production of toxins, as well as bioactive compounds, which exhibit anticancer, antimicrobial and protease inhibition activities. Cyanobacteria produce a broad range of antifungals belonging to structural classes, such as peptides, polyketides and alkaloids. Here, we tested cyanobacteria from a wide variety of environments for antifungal activity. The potent antifungal macrolide scytophycin was detected in Anabaena sp. HAN21/1, Anabaena cf. cylindrica PH133, Nostoc sp. HAN11/1 and Scytonema sp. HAN3/2. To our knowledge, this is the first description of Anabaena strains that produce scytophycins. We detected antifungal glycolipopeptide hassallidin production in Anabaena spp. BIR JV1 and HAN7/1 and in Nostoc spp. 6sf Calc and CENA 219. These strains were isolated from brackish and freshwater samples collected in Brazil, the Czech Republic and Finland. In addition, three cyanobacterial strains, Fischerella sp. CENA 298, Scytonema hofmanni PCC 7110 and Nostoc sp. N107.3, produced unidentified antifungal compounds that warrant further characterization. Interestingly, all of the strains shown to produce antifungal compounds in this study belong to Nostocales or Stigonematales cyanobacterial orders.

  13. (MRSA) and E. coli Multiple Drug Resistance (MDR)

    African Journals Online (AJOL)

    Background: Staphylococcus aureus, methicillin-resistant and Escherichia coli, multidrug-resistant included in the list of antibiotic-resistant priority pathogens from WHO. As multidrug-resistant bacteria problem is increasing, it is necessary to probe new sources for identifying antimicrobial compounds. Medicinal plants ...

  14. Combination Effect of Antituberculosis Drugs and Ethanolic Extract of Selected Medicinal Plants against Multi-Drug Resistant Mycobacterium tuberculosis Isolates

    Science.gov (United States)

    Fauziyah, Prabasiwi Nur; Sukandar, Elin Yulinah; Ayuningtyas, Dhyan Kusuma

    2017-01-01

    Adverse drug reaction and resistance to antituberculosis drugs remain the causes of tuberculosis therapeutic failure. This research aimed to find the combination effect of standard antituberculosis drugs with Hibiscus sabdariffa L., Kaempferia galanga L., and Piper crocatum N.E. Br against multi-drug resistant (MDR) Mycobacterium tuberculosis isolates. Two MDR strains (i.e., isoniazid/ethambutol resistant and rifampicin/streptomycin resistant) of M. tuberculosis were inoculated in Löwenstein–Jensen medium containing a combination of standard antituberculosis drugs and ethanolic extracts of H. sabdariffa calyces, K. galanga rhizomes, and P. crocatum leaves using various concentration combinations of drug and extract. The colony numbers were observed for 8 weeks. The effect of the combination was analyzed using the proportion method which was calculated by the mean percentage of inhibition reduction in a number of colonies on drug–extract containing medium compared to extract-free control medium. The results showed that all three plant extracts achieved good combination effects with rifampicin against the rifampicin/streptomycin resistant strain. Antagonistic effects were, however, observed with streptomycin, ethambutol and isoniazid, therefore calling for caution when using these plants in combination with antituberculosis treatment. PMID:28335544

  15. Tumor Heterogeneity, Single-Cell Sequencing, and Drug Resistance

    Directory of Open Access Journals (Sweden)

    Felix Schmidt

    2016-06-01

    Full Text Available Tumor heterogeneity has been compared with Darwinian evolution and survival of the fittest. The evolutionary ecosystem of tumors consisting of heterogeneous tumor cell populations represents a considerable challenge to tumor therapy, since all genetically and phenotypically different subpopulations have to be efficiently killed by therapy. Otherwise, even small surviving subpopulations may cause repopulation and refractory tumors. Single-cell sequencing allows for a better understanding of the genomic principles of tumor heterogeneity and represents the basis for more successful tumor treatments. The isolation and sequencing of single tumor cells still represents a considerable technical challenge and consists of three major steps: (1 single cell isolation (e.g., by laser-capture microdissection, fluorescence-activated cell sorting, micromanipulation, whole genome amplification (e.g., with the help of Phi29 DNA polymerase, and transcriptome-wide next generation sequencing technologies (e.g., 454 pyrosequencing, Illumina sequencing, and other systems. Data demonstrating the feasibility of single-cell sequencing for monitoring the emergence of drug-resistant cell clones in patient samples are discussed herein. It is envisioned that single-cell sequencing will be a valuable asset to assist the design of regimens for personalized tumor therapies based on tumor subpopulation-specific genetic alterations in individual patients.

  16. Mitochondrial ROS and cancer drug resistance: Implications for therapy.

    Science.gov (United States)

    Okon, Imoh S; Zou, Ming-Hui

    2015-10-01

    Under physiological conditions, a well-coordinated and balanced redox system exists to ensure that reactive oxygen species (ROS) are appropriately utilized to accomplish specific functions, such as signaling and protein regulation. The influence of ROS within malignant cells, whether for good or bad may depend on several factors, such as tumor and tissue type, disease stage, treatment strategy, as well as duration, specificity and levels of ROS. What then are the known roles of ROS in cancer? Firstly, ROS significantly impacts cancer phenotypes. Secondly, the oxidative ROS property responsible for killing cancer cells, also impact secondary signaling networks. Thirdly, a strong correlation exist between ROS and genetic instability which may promote mutations. Finally, emerging observations suggest a role for mitochondrial ROS in cancer drug resistance, with implications for therapy. The mitochondria is a key regulator of metabolic-redox (meta-redox) alterations within cancer cells. Like a double-edged sword, mitochondrial ROS perturbations in cancer therapy may be beneficial or detrimental. However, harnessing ROS-specific cancer-targeting benefits remain a major challenge. Published by Elsevier Ltd.

  17. Multimodal neuroimaging in presurgical evaluation of drug-resistant epilepsy.

    Science.gov (United States)

    Zhang, Jing; Liu, Weifang; Chen, Hui; Xia, Hong; Zhou, Zhen; Mei, Shanshan; Liu, Qingzhu; Li, Yunlin

    2014-01-01

    Intracranial EEG (icEEG) monitoring is critical in epilepsy surgical planning, but it has limitations. The advances of neuroimaging have made it possible to reveal epileptic abnormalities that could not be identified previously and improve the localization of the seizure focus and the vital cortex. A frequently asked question in the field is whether non-invasive neuroimaging could replace invasive icEEG or reduce the need for icEEG in presurgical evaluation. This review considers promising neuroimaging techniques in epilepsy presurgical assessment in order to address this question. In addition, due to large variations in the accuracies of neuroimaging across epilepsy centers, multicenter neuroimaging studies are reviewed, and there is much need for randomized controlled trials (RCTs) to better reveal the utility of presurgical neuroimaging. The results of multiple studies indicate that non-invasive neuroimaging could not replace invasive icEEG in surgical planning especially in non-lesional or extratemporal lobe epilepsies, but it could reduce the need for icEEG in certain cases. With technical advances, multimodal neuroimaging may play a greater role in presurgical evaluation to reduce the costs and risks of epilepsy surgery, and provide surgical options for more patients with drug-resistant epilepsy.

  18. Resistance to Antibiotics and Antifungal Medicinal Products: Can Complementary and Alternative Medicine Help Solve the Problem in Common Infection Diseases? The Introduction of a Dutch Research Consortium

    Directory of Open Access Journals (Sweden)

    Esther T. Kok

    2015-01-01

    Full Text Available The increase of antibiotic resistance worldwide, rising numbers of deaths and costs associated with this, and the fact that hardly any new antimicrobial drugs have been developed during the last decade have increased the interest in Complementary and Alternative Medicine (CAM therapeutic interventions, if proven safe and effective. Observational studies on clinical CAM practices demonstrate positive effects of treatment of infections with CAM therapies (clinical effects, patient satisfaction in combination with small percentages of antibiotics prescription. However, Cochrane reviews and other studies demonstrate that in most instances the quality of clinical trials on CAM treatment of infections is currently too low to provide sufficient evidence. Therefore a Dutch consortium on (in vitro and clinical scientific research on CAM and antibiotic resistance has been formed. The aim and objective of the consortium is to establish an enduring partnership and to develop expertise to further develop and investigate safe and effective CAM treatments for infectious diseases of humans (and animals. A first ongoing project on the development of safe and effective biobased CAM antimycotics in women with (recurrent vaginal candidiasis infection is introduced.

  19. A Nanolayer Copper Coating for Prevention Nosocomial Multi-Drug Resistant Infections

    Science.gov (United States)

    2016-10-01

    AWARD NUMBER: W81XWH-15-2-0066 TITLE: A Nanolayer Copper Coating for Prevention Nosocomial Multi- drug Resistant Infections PRINCIPAL...SUBTITLE A Nanolayer Copper Coating for Prevention Nosocomial Multi- drug Resistant Infections 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-15-2-0066 5c...for in vitro antimicrobial efficacy and mammalian cell cytotoxicity potential using standardized assays that are approved by the Food and Drug

  20. [Primary resistance of Mycobacterium tuberculosis to anti-tuberculosis drugs in Kinshasa, (DRC)].

    Science.gov (United States)

    Kabedi, M J; Kashongwe, M; Kayembe, J M; Mumba Ngoyi, D; Mampasi, P; Mbaya, P; Fissette, K; Verhaegen, J; Portaels, F; Muyembe-Tamfum, J J

    2007-10-01

    In a descriptive cross-sectional study carried out in Kinshasa between July 2003 and January 2004, we determined the prevalence of the primary resistance of M. tuberculosis to first-line anti-tuberculosis drugs. The antibiogram was performed with the proportion method on 301 isolats from patients who all had a first episode of pulmonary tuberculosis with positive microscopy (TPM+) and who had not received any anti-tuberculosis treatment before. The primary resistance rate reached 43.5%; it reached 31.6% in 1990. The multi-drug-resistance rate (MDR-TB) notified as resistant to both rifamicine and isoniazide rose to 5.3%. This rate of primary resistance is among the highest in Africa. The emergence of the resistant strains and specially the multi-drug-resistant strains (MDR-TB) in Kinshasa requires a regular assessment of these phenomena which threaten seriously the implementation of the national tuberculosis control programme.