WorldWideScience

Sample records for anti-tuberculosis drug resistance

  1. Rapid determination of anti-tuberculosis drug resistance from whole-genome sequences

    KAUST Repository

    Coll, Francesc

    2015-05-27

    Mycobacterium tuberculosis drug resistance (DR) challenges effective tuberculosis disease control. Current molecular tests examine limited numbers of mutations, and although whole genome sequencing approaches could fully characterise DR, data complexity has restricted their clinical application. A library (1,325 mutations) predictive of DR for 15 anti-tuberculosis drugs was compiled and validated for 11 of them using genomic-phenotypic data from 792 strains. A rapid online ‘TB-Profiler’ tool was developed to report DR and strain-type profiles directly from raw sequences. Using our DR mutation library, in silico diagnostic accuracy was superior to some commercial diagnostics and alternative databases. The library will facilitate sequence-based drug-susceptibility testing.

  2. Mycobacterium tuberculosis whole genome sequencing and protein structure modelling provides insights into anti-tuberculosis drug resistance

    KAUST Repository

    Phelan, Jody

    2016-03-23

    Background Combating the spread of drug resistant tuberculosis is a global health priority. Whole genome association studies are being applied to identify genetic determinants of resistance to anti-tuberculosis drugs. Protein structure and interaction modelling are used to understand the functional effects of putative mutations and provide insight into the molecular mechanisms leading to resistance. Methods To investigate the potential utility of these approaches, we analysed the genomes of 144 Mycobacterium tuberculosis clinical isolates from The Special Programme for Research and Training in Tropical Diseases (TDR) collection sourced from 20 countries in four continents. A genome-wide approach was applied to 127 isolates to identify polymorphisms associated with minimum inhibitory concentrations for first-line anti-tuberculosis drugs. In addition, the effect of identified candidate mutations on protein stability and interactions was assessed quantitatively with well-established computational methods. Results The analysis revealed that mutations in the genes rpoB (rifampicin), katG (isoniazid), inhA-promoter (isoniazid), rpsL (streptomycin) and embB (ethambutol) were responsible for the majority of resistance observed. A subset of the mutations identified in rpoB and katG were predicted to affect protein stability. Further, a strong direct correlation was observed between the minimum inhibitory concentration values and the distance of the mutated residues in the three-dimensional structures of rpoB and katG to their respective drugs binding sites. Conclusions Using the TDR resource, we demonstrate the usefulness of whole genome association and convergent evolution approaches to detect known and potentially novel mutations associated with drug resistance. Further, protein structural modelling could provide a means of predicting the impact of polymorphisms on drug efficacy in the absence of phenotypic data. These approaches could ultimately lead to novel resistance

  3. Anti-tuberculosis drug resistance in Sub-Saharan Africa: The case of Uganda

    NARCIS (Netherlands)

    Lukoye, D.

    2015-01-01

    This thesis reports findings of six studies including two tuberculosis (TB) drug resistance surveys, a comparative study of HIV infection rates among patients enrolled in the survey and those under routine TB/HIV surveillance, two TB molecular epidemiological analyses and a systematic review and met

  4. Clinical Study of Drug-resistant Pulmonary Tuberculosis Treated by Combination of Anti-Tuberculosis Chemicals and Compound Astragalus Capsule(复方黄芪胶囊)

    Institute of Scientific and Technical Information of China (English)

    姜艳; 李新; 于志勇; 尹红义; 韩玉庆

    2004-01-01

    Objective: To observe and evaluate the therapeutic effect of anti-tuberculosis (anti-TB) chemicals and Compound Astragalus Capsule (CAC) in combinedly treating drug resistant pulmonary tuberculosis (DR-TB). Methods: Ninety-two patients with DR-TB were equally randomized into the treated group (treated with combination therapy) and the control group (treated with anti-TB chemicals alone). The therapeutic course for both groups was 18 months. Therapeutic effects between the two groups were compared at the end of the therapeutic course. Sputum bacterial negative rate, focal absorption effective rate, cavity closing rate, 10-day symptom improving rate, the incidence of adverse reaction and 2-year bacteriological recurrence rate between the two groups were compared. Results: In the treated group, the sputum bacterial negative conversion rate was 84. 8%, focal absorption effective rate 91.3 %, cavity closing rate 58. 7 % and 10-day symptom improving rate 54.4%, while in the control group, the corresponding rates were 65.2%,73.9 %, 37. 0% and 26.1%, respectively. Comparison between the groups showed significant difference in all the parameters ( P<0.05, P<0.05, P<0.05 and P<0.01 ). The incidence of adverse reaction and 2year bacteriological recurrence rate in the treated group were 23.9 % and 2.6 % respectively, while those in the control group 50.0% and 16.7%, which were higher than the former group with significant difference ( P<0.01 and P<0.05, respectively). Conclusion: The therapeutic effect of combined treatment with antiTB and CAC is superior to that of treatment with anti-TB chemicals alone, and the Chinese herbal medicine showed an adverse reaction alleviating effect, which provides a new therapy for DR-TB, and therefore, it is worth spreading in clinical practice.

  5. Hematological and liver toxicity of anti-tuberculosis drugs

    Science.gov (United States)

    Mirlohi, Maryam-Sadat; Ekrami, Alireza; Shirali, Saeed; Ghobeishavi, Mehdi; Pourmotahari, Fatemeh

    2016-01-01

    Introduction Tuberculosis (TB) is a major global health problem, and anti-tuberculosis drugs can cause severe adverse reactions. The aim of this study was to determine hematological and biochemical changes and associated risk factors in smear positive pulmonary tuberculosis patients undergoing treatment with standard protocols. Methods In a descriptive study, a total of 40 tuberculosis patients aged between 15–60 years were collected from hospitals in Khuzestan Province (Iran) from March 2013 to March 2014. The patients were treated with drugs (isoniazid, rifampicin, ethambutol, and pyrazinamide) during the initial two months, followed by isoniazid and rifampicin for the next four to six months. Activities of liver enzymes (ALT, AST, and ALP) and hematological parameters were recorded before and after treatment. Data were analyzed using paired samples t-test and Wilcoxon test by SPSS 16. Results After using drug treatments, hematological parameters (RBC, Hb, HCT, MCV, MCH, and MCHC), except platelet count, were changed significantly (p ≤ 0.001). Liver enzyme activities (ALT, AST, and ALP) were decreased significantly (p ≤ 0.001) after treatment. Conclusion In this study, changes of hematological and biochemical parameters have been observed in patients with pulmonary tuberculosis. It can be concluded that the anti-tuberculosis treatment is associated with changes of hematological parameters and liver enzymes.

  6. 抗痨颗粒对耐多药结核分枝杆菌蛋白质组学的影响%Effect of Anti-tuberculosis Particles on Proteomics of Drug-resistant Mycobacterium Tuberculosis

    Institute of Scientific and Technical Information of China (English)

    李建国; 刘湘花; 汤红琴; 董修兵; 李宁宁

    2012-01-01

    目的:应用蛋白质组学的双向电泳技术,比较分析抗痨颗粒提取物作用前后耐多药结核分枝杆菌的全菌蛋白表达差异,揭示药物作用机制.方法:临床耐多药结核分枝杆菌接种在7H9添加OADC液体培养基中37℃培养6~8d,细菌密度为1×108/mL~2 × 108/mL.抗痨颗粒浸提物的最低抑菌浓度(MIC)为0.638 8 g·L-1.加到液体培养基中,作用20 h,终浓度为相当于生药0.255 6 g·mL-1.局部内环境与外部环境完全隔离下,采用双向凝胶电泳分离全菌总蛋白,得到差异表达的蛋白质点进行分析比对.结果:耐多药结核分枝杆菌用药前后,发现了8个差异斑点,确定其中2个蛋白质为:硫代硫酸硫转移酶( thiosulfate sulfurtransferase)和假定蛋白Rv0634A.结论:揭示了抗痨颗粒对耐多药结核分枝杆菌的翻译,结构组成,氨基酸代谢,氰化物和H2S的解毒以及硫和铁转移等各方面均有一定影响,从而破坏结核分枝杆菌的生活能力,从而达到抑制结核分枝杆菌的目的.%Objective; To reveal the mechanism of drug action to compare and analyze of the effect of anti-tuberculosis particles extract on multi-drug resistant-mycobacterium tuberculosis proteomics to reveal the mechanism of drug action. Method; The clinical mycobacterium tuberculosis with multidrug resistance was added in Middlebrook 7H9 OADC liquid medium at 37 ℃ for 6-8 d, when the bacterial density researched 1 × l08/mL-2 × l08/mL, the minimum inhibitory concentration ( MIC) of anti-tuberculosis particulate extracts was 0. 638 8 g · L-1 , the final concentration was equivalent to 0. 255 6 g · mL . Local environment and external environment was completely isolated, two-dimensional gel electrophoresis separation of whole cell total protein was used to analyze differentially expressed protein spots. Result; Before and after treatment by anti-tuberculosis particles extract, multidrug-resistant mycobacterium tuberculosis showed eight

  7. Synergism between ethanolic extract of propolis (EEP) and anti-tuberculosis drugs on growth of mycobacteria.

    Science.gov (United States)

    Scheller, S; Dworniczak, S; Waldemar-Klimmek, K; Rajca, M; Tomczyk, A; Shani, J

    1999-01-01

    Ethanolic extract of propolis exerts a strong anti-bacterial activity, in addition to antifungal, antiviral and antiprotozoal properties. In previous studies from these laboratories we have demonstrated that the intensity of the bactericidal activity of EEP is correlated with the virulence of the mycobacteria tested, and that EEP has a synergistic effect with antibiotics on growth of staphylococcus aureus. In the present study we investigated whether the same synergism and correlation exists between EEP and some anti-tuberculosis drugs on tuberculosis mycobacteria with different degrees of virulence. Six standard strains and 11 wild strains of mycobacteria were exposed for 30 days to EEP, with or without streptomycin, rifamycin, isoniazid or ethambutol. Out of the 17 strains, 8 were resistant to at least two standard antibiotics, and were considered "multi-resistant strains". The rest were either susceptible or resistant to only one of the antimycobacterial drugs. Antagonism was recorded only in one case, when Staphylococcus aureus were treated with a mixture of EEP and ethambutol, suggesting that a chemical bond could have been formed between this anti-tuberculosis antibiotic and one of the active components of the ethanol extract of propolis.

  8. Drug-induced complications of anti-tuberculosis drugs in HIV patients

    Directory of Open Access Journals (Sweden)

    Rasoulinejad M

    2011-01-01

    Full Text Available "n 800x600 Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 st1":*{behavior:url(#ieooui } /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman","serif";} Background: Tuberculosis with high prevalence in HIV/AIDS patients is the main reason for morbidity and mortality in these patients. About one-third of patients with HIV infection have concomitant tuberculosis. Lack of appropriate infection control on many social and economic communities will impose. Comprehensive study on the effects of anti-tuberculosis drugs in patients with HIV infecting less done, also due to the importance of reducing morbidity and mortality, reduce the cost of disease, identifying drug pharmacokinetics, the importance of completing treatment tuberculosis, this study was performed to evaluate the effects of anti- tuberculosis drugs on HIV infection and to identify the drug pharmacokinetics and so more complete tuberculosis treatment."n"nMethods: A historical cohort study was performed on patients referring to the research center for HIV/AIDS, consultation center, department of infection diseases of Imam Khomeini Hospital in Tehran, Iran. A total number of 75 cases with HIV negative versus HIV positive patients with pulmonary tuberculosis and positive sputum smear in accordance with inclusion and exclusion criteria were selected."n"nResults: In this study, the frequency of peripheral neuropathy 27(73%, arthralgia 31(83.8%, vomiting 18(48.6%, headache 26(70.3%, dizziness 20(54.1%, renal toxicity 4(10.8% and of skin rash 10(27% in patients with HIV virus infection were significantly more than HIV- negative patients. Hepatotoxicity, fever and

  9. Silymarin protects liver against toxic effects of anti-tuberculosis drugs in experimental animals

    Directory of Open Access Journals (Sweden)

    Izzettin Fikret V

    2008-07-01

    Full Text Available Abstract Background The first line anti-tuberculosis drugs isoniazid (INH, rifampicin (RIF and pyrazinamide (PZA continues to be the effective drugs in the treatment of tuberculosis, however, the use of these drugs is associated with toxic reactions in tissues, particularly in the liver, leading to hepatitis. Silymarin, a standard plant extract with strong antioxidant activity obtained from S. marianum, is known to be an effective agent for liver protection and liver regeneration. The aim of this study was to investigate the protective actions of silymarin against hepatotoxicity caused by different combinations of anti-tuberculosis drugs. Methods Male Wistar albino rats weighing 250–300 g were used to form 6 study groups, each group consisting of 10 rats. Animals were treated with intra-peritoneal injection of isoniazid (50 mg/kg and rifampicin (100 mg/kg; and intra-gastric administration of pyrazinamid (350 mg/kg and silymarin (200 mg/kg. Hepatotoxicity was induced by a combination of drugs with INH+RIF and INH+RIF+PZA. Hepatoprotective effect of silymarin was investigated by co-administration of silymarin together with the drugs. Serum biochemical tests for liver functions and histopathological examination of livers were carried out to demonstrate the protection of liver against anti-tuberculosis drugs by silymarin. Results Treatment of rats with INH+RIF or INH+RIF+PZA induced hepatotoxicity as evidenced by biochemical measurements: serum alanine aminotransferase (ALT, aspartate aminotransferase (AST and alkaline phosphatase (ALP activities and the levels of total bilirubin were elevated, and the levels of albumin and total protein were decreased in drugs-treated animals. Histopathological changes were also observed in livers of animals that received drugs. Simultaneous administration of silymarin significantly decreased the biochemical and histological changes induced by the drugs. Conclusion The active components of silymarin had

  10. Adequacy of anti-tuberculosis drug prescriptions in Viet Nam

    DEFF Research Database (Denmark)

    Hoa, N B; Lauritsen, J M; Rieder, H L

    2012-01-01

    SETTING: National Tuberculosis Program, Viet Nam, 2008. OBJECTIVES: To determine drug prescription adherence to national guidelines, to examine factors associated with an erroneous dosage of rifampin (RMP) and to evaluate the impact of an insufficient RMP dosage on treatment outcome. METHODS: A r...

  11. A population-based case-control study of the safety of oral anti-tuberculosis drug treatment during pregnancy

    DEFF Research Database (Denmark)

    Czeizel, A.E.; Rockenbauer, M.; Olsen, J.

    2001-01-01

    OBJECTIVE: To study the human teratogenic potential of isoniazid and other anti-tuberculosis drug treatment during pregnancy. DESIGN AND SETTING: Cases from a large population-based dataset at the Hungarian Case-Control Surveillance of Congenital Abnormalities, and controls from the National Birth...... Registry, between 1980 and 1996. Information on all oral anti-tuberculosis drug treatments during pregnancy was medically recorded. STUDY PARTICIPANTS: Women who had newborns or fetuses with congenital abnormalities (case group), and women who had babies with no congenital abnormality (control group). MAIN...

  12. Sale of anti-tuberculosis drugs through private pharmacies: a cross sectional study in Kerala, India.

    Directory of Open Access Journals (Sweden)

    Binoo Divakaran

    2011-03-01

    Full Text Available

    Background: Private health care providers are largely the first point of contact for Tuberculosis (TB patients, who either undergo treatment from private practitioners or buy medicines on their own from private pharmacies. Aims: This study assessed the availability, sale and magnitude of anti-tuberculosis drugs dispensing through private pharmacies.

    Methodology: The present cross sectional study was conducted among private pharmacies located along the national highway from Thalassery to Payyannur in the Kannur district of Kerala, India. A total of 38 private pharmacies located along the national highway were included.

    Results: The duration that anti–TB drugs had been on sale showed that 74.3% of pharmacies had started to sell these drugs only less than ten years ago. The majority (82.9% of the private pharmacies received up to 5 prescriptions for anti-TB drugs weekly. Out of the total of 35 pharmacies selling these drugs, 22 (62.9% reported an increase in their sales. Nearly 82% of those pharmacies that reported an increase in the sale of anti-TB drugs were selling these drugs for less than the past ten years.

    Conclusions: The current study shows that a large number of tuberculosis patients are still approaching private pharmacies for anti-tuberculosis drugs. This tendency has to be completely stopped and needs properly planned strategies to encourage private pharmacies to participate actively in the DOTS (Direct Observation Treatment Short course program of the Government, by providing them attractive alternative incentives

  13. Research Progress of the Anti-Tuberculosis Drugs%抗结核药物的研究进展

    Institute of Scientific and Technical Information of China (English)

    耿叶慧; 李子强

    2016-01-01

    目的:为进一步研发新型抗结核药物提供参考。方法通过Science Direct,Wiley,Springer Link等数据库进行文献检索,将近几年文献报道抗结核候选药物进行归纳和总结。结果最低抑菌浓度小于7μmol/L,低毒和高选择性的最有潜力的抗结核候选药物已大量出现。结论抗结核候选药物的开发思路为研发更多新型抗结核药物提供了参考。%Objective To provide a reference for further researching and developping new anti-tuberculosis drugs. Methods Through document retrieval in the databases of Science Direct, Wiley and Springer Link, etc., the literatures about new antitubercular drugs were summarized. Results The most potent anti-tuberculosis drugs with low toxicity, a high selective index and MIC values ﹤ 7 μmol/L were appeared in large numbers. Conclusion The thoughts on the development of anti-tuberculosis drugs provide perspectives on the development of new anti-tuberculosis drugs.

  14. Efficacy and safety of anti-tuberculosis drugs in HIV-positive patients: A prospective study

    Directory of Open Access Journals (Sweden)

    Jigar D Kapadia

    2013-01-01

    Full Text Available Objectives: To assess the efficacy and safety of anti-tuberculosis drugs in HIV-positive patients at a tertiary care teaching hospital. Materials and Methods: As a part of an ongoing study of opportunistic infections (OIs in HIV-positive patients, drug treatment in patients suffering from tuberculosis was assessed to determine its efficacy and safety. Based on prevalence data for last three years, a purposive sampling of study population was carried out in this observational, prospective, single centre study. Tuberculosis (TB was the most common OI observed. The selected patients were followed up for a period of one year to evaluate the clinical course and outcome of OIs, and the efficacy and safety of drugs used was checked. Results: Tuberculosis was observed in 89 out of 134 enrolled patients. These included 79 adults and 10 children. Males (66.2% were commonly affected. Extra pulmonary TB (73% was the most common manifestation with abdominal TB observed in 55 (61.7% patients. All patients were treated in accordance with the Revised National Tuberculosis Control Programme (RNTCP guidelines as recommended by National AIDS Control Organization (NACO, India. Outcome of TB was assessable in 70 patients. Majority (82.8% of the patients were cured, while 12 patients (17.1% died during the course of treatment. A total of 149 ADRs were observed in 67 (75.2% patients. Majority of ADRs (n = 147 were non-serious and did not warrant a change in therapy. Discoloration of urine was the most common ADR observed. Conclusion: TB is the most common opportunistic infection in HIV-positive patients with abdominal TB being the most common manifestation. RNTCP and NACO guidelines are adhered to in these patients. Anti-tuberculosis drugs are well tolerated and effective in majority of the patients.

  15. Incidence, clinical features and impact on anti-tuberculosis treatment of anti-tuberculosis drug induced liver injury (ATLI in China.

    Directory of Open Access Journals (Sweden)

    Penghui Shang

    Full Text Available BACKGROUND: Anti-tuberculosis drug induced liver injury (ATLI is emerging as a significant threat to tuberculosis control in China, though limited data is available about the burden of ATLI at population level. This study aimed to estimate the incidence of ATLI, to better understand its clinical features, and to evaluate its impact on anti-tuberculosis (TB treatment in China. METHODOLOGY/PRINCIPAL FINDINGS: In a population-based prospective study, we monitored 4,304 TB patients receiving directly observed treatment strategy (DOTS treatment, and found that 106 patients developed ATLI with a cumulative incidence of 2.55% (95% Confidence Interval [CI], 2.04%-3.06%. Nausea, vomiting and anorexia were the top three most frequently observed symptoms. There were 35 (33.02% ATLI patients with no symptoms, including 8 with severe hepatotoxicity. Regarding the prognosis of ATLI, 84 cases (79.25% recovered, 18 (16.98% improved, 2 (1.89% failed to respond to the treatment with continued elevation of serum alanine aminotransferase, and 2 (1.89% died as result of ATLI. Of all the ATLI cases, 74 (69.81% cases changed their anti-TB treatment, including 4 (3.77% cases with medication administration change, 21 (19.81% cases with drugs replacement, 54 (50.94% cases with therapy interruption, and 12 (11.32% cases who discontinued therapy. In terms of treatment outcomes, 53 (51.46% cases had TB cured in time, 48 (46.60% cases had therapy prolonged, and 2 (1.94% cases died. Compared with non-ATLI patients, ATLI patients had a 9.25-fold (95%CI, 5.69-15.05 risk of unsuccessful anti-TB treatment outcomes and a 2.11-fold (95%CI, 1.23-3.60 risk of prolonged intensive treatment phase. CONCLUSIONS/SIGNIFICANCE: ATLI could considerably impact the outcomes of anti-TB treatment. Given the incidence of ATLI and the size of TB population in China, the negative impact is substantial. Therefore, more research and efforts are warranted in order to enhance the diagnosis and the

  16. The protective effect of diammonium glycyrrhizinate and polyene phosphatidyl choline on livery damage caused by anti-tuberculosis drugs

    Institute of Scientific and Technical Information of China (English)

    Li Wang

    2016-01-01

    Objective:To study the protective effect of diammonium glycyrrhizinate and polyene phosphatidyl choline on livery damage caused by anti-tuberculosis drugs.Methods:Patients who received initial 2HRS(E)Z/4HR short-range anti-tuberculosis treatment in our hospital from October 2013 to October 2015 were selected and randomly divided into diammonium glycyrrhizinate group (group A) and polyene phosphatidyl choline group (group B), and after 4 weeks of liver protection treatment, serum levels of liver damage marker molecules, stress marker molecules and NF-κB-mediated inflammatory molecules as well as protein expression levels of bile acid metabolism genes were determined.Results: Serum ALT, AST, GGT, ALP, GDH, TBIL, NF-κB, IL-1β, TNF-α and MCP-1 levels of group B were significantly lower than those of group A while HO-1, GSH-Px, SOD, ERK, MEK and SIRT1 levels were significantly higher than those of group A; serum CYP7A1, FXR and SHP protein expression levels of group B were significantly lower than those of group A while BESP protein expression level was significantly higher than that of group A.Conclusion:Polyene phosphatidyl choline has better protective effect on liver damage caused by anti-tuberculosis drugs than diammonium glycyrrhizinate, and the molecular mechanisms of polyene phosphatidyl choline to protect the liver are enhancing the antioxidant effect mediated by HO-1 and SIRT1, inhibiting the inflammatory response mediated by NF-κB and regulating the expression of bile acid metabolism genes.

  17. Natural Compounds from Mexican Medicinal Plants as Potential Drug Leads for Anti-Tuberculosis Drugs

    Directory of Open Access Journals (Sweden)

    ROCIO GÓMEZ-CANSINO

    Full Text Available ABSTRACT In Mexican Traditional Medicine 187 plant species are used in the treatment of respiratory conditions that may be associated with tuberculosis. In this contribution, we review the ethnobotany, chemistry and pharmacology of 63 species whose extracts have been assayed for antimycobacterial activity in vitro. Among these, the most potent is Aristolochia brevipes (MIC= 12.5 µg/mL, followed by Aristolochia taliscana, Citrus sinensis, Chrysactinia mexicana, Persea americana, and Olea europaea (MIC 95%, 50 µg/mL include: Amphipterygium adstringens, Larrea divaricata, and Phoradendron robinsoni. Several active compounds have been identified, the most potent are: Licarin A (isolated from A. taliscana, and 9-amino-9-methoxy-3,4-dihydro-2H-benzo[h]-chromen-2-one (transformation product of 9-methoxytariacuripyrone isolated from Aristolochia brevipes, both with MIC= 3.125 µg/mL, that is 8-fold less potent than the reference drug Rifampicin (MIC= 0.5 µg/mL. Any of the compounds or extracts here reviewed has been studied in clinical trials or with animal models; however, these should be accomplished since several are active against strains resistant to common drugs.

  18. Natural Compounds from Mexican Medicinal Plants as Potential Drug Leads for Anti-Tuberculosis Drugs.

    Science.gov (United States)

    Gómez-Cansino, Rocio; Guzmán-Gutiérrez, Silvia Laura; Campos-Lara, María Guadalupe; Espitia-Pinzón, Clara Ines; Reyes-Chilpa, Ricardo

    2017-02-09

    In Mexican Traditional Medicine 187 plant species are used in the treatment of respiratory conditions that may be associated with tuberculosis. In this contribution, we review the ethnobotany, chemistry and pharmacology of 63 species whose extracts have been assayed for antimycobacterial activity in vitro. Among these, the most potent is Aristolochia brevipes (MIC= 12.5 µg/mL), followed by Aristolochia taliscana, Citrus sinensis, Chrysactinia mexicana, Persea americana, and Olea europaea (MIC 95%, 50 µg/mL) include: Amphipterygium adstringens, Larrea divaricata, and Phoradendron robinsoni. Several active compounds have been identified, the most potent are: Licarin A (isolated from A. taliscana), and 9-amino-9-methoxy-3,4-dihydro-2H-benzo[h]-chromen-2-one (transformation product of 9-methoxytariacuripyrone isolated from Aristolochia brevipes), both with MIC= 3.125 µg/mL, that is 8-fold less potent than the reference drug Rifampicin (MIC= 0.5 µg/mL). Any of the compounds or extracts here reviewed has been studied in clinical trials or with animal models; however, these should be accomplished since several are active against strains resistant to common drugs.

  19. Trends of Mycobacterium bovis Isolation and First-Line Anti-tuberculosis Drug Susceptibility Profile: A Fifteen-Year Laboratory-Based Surveillance.

    Directory of Open Access Journals (Sweden)

    Miriam Bobadilla-del Valle

    2015-09-01

    Full Text Available Mycobacterium tuberculosis causes the majority of tuberculosis (TB cases in humans; however, in developing countries, human TB caused by M. bovis may be frequent but undetected. Human TB caused by M. bovis is considered a zoonosis; transmission is mainly through consumption of unpasteurized dairy products, and it is less frequently attributed to animal-to-human or human-to-human contact. We describe the trends of M. bovis isolation from human samples and first-line drug susceptibility during a 15-year period in a referral laboratory located in a tertiary care hospital in Mexico City.Data on mycobacterial isolates from human clinical samples were retrieved from the laboratory's database for the 2000-2014 period. Susceptibility to first-line drugs: rifampin, isoniazid, streptomycin (STR and ethambutol was determined. We identified 1,165 isolates, 73.7% were M. tuberculosis and 26.2%, M. bovis. Among pulmonary samples, 16.6% were M. bovis. The proportion of M. bovis isolates significantly increased from 7.8% in 2000 to 28.4% in 2014 (X(2trend, p<0.001. Primary STR resistance was higher among M. bovis compared with M. tuberculosis isolates (10.9% vs.3.4%, p<0.001. Secondary multidrug resistance (MDR rates were 38.5% and 34.4% for M. bovis and M. tuberculosis, respectively (p = 0.637. A rising trend of primary STR monoresistance was observed for both species (3.4% in 2000-2004 vs. 7.6% in 2010-2014; p = 0.02.There is a high prevalence and a rising trend of M. bovis isolates in our region. The proportion of pulmonary M. bovis isolates is higher than in previous reports. Additionally, we report high rates of primary anti-tuberculosis resistance and secondary MDR in both M. tuberculosis and M. bovis. This is one of the largest reports on drug susceptibility of M. bovis from human samples and shows a significant proportion of first-line anti-tuberculosis drug resistance.

  20. Amelioration of anti-tuberculosis drug induced oxidative stress in kidneys by Spirulina fusiformis in a rat model.

    Science.gov (United States)

    Martin, Sherry Joseph; Sabina, Evan Prince

    2016-08-01

    Nephrotoxicity is a rare complication caused by anti-tuberculosis therapy-induced oxidative stress. The Cyanobacterium Spirulina fusiformis Voronikhin belonging to Oscillatoriaceae family is used traditionally as a source of antioxidants against oxidative stress. We aimed to investigate the efficacy of S. fusiformis in modifying isoniazid (INH) and rifampicin (RIF)-induced changes in Wistar rat kidneys. Animals were divided into six groups: normal control rats; toxic control (INH & RIF-50 mg/kg b.w./d each; p.o.); INH & RIF + S. fusiformis (400 mg/kg b.w./d); INH & RIF + S. fusiformis (800 mg/kg b.w./d); S. fusiformis (800 mg/kg b.w./d) alone-treated rats; INH & RIF + silymarin (25 mg/kg b.w./d). Study duration was 28 d after which blood and kidneys were analyzed. We also studied the binding and interactions of the transcription factors Liver X Receptor (LXR) and Farnesoid X Receptor (FXR) with INH, RIF, and representative active compounds of S. fusiformis by in silico methods. INH & RIF treatment caused significant (p< 0.05) decrease in antioxidant levels and significant (p< 0.05) increase in the levels of creatinine, urea, and uric acid showing impaired kidney function. Spirulina fusiformis ameliorated these effects in a dose dependent manner. Histological examination of kidneys supported these findings. Results of the in silico analyses showed that selected active components of S. fusiformis interact with LXR and FXR and could be a possible mechanism of action. S. fusiformis rendered protection against anti-tuberculosis drugs-induced oxidative stress in kidney tissues of rats.

  1. Adverse events in healthy individuals and MDR-TB contacts treated with anti-tuberculosis drugs potentially effective for preventing development of MDR-TB: a systematic review.

    Science.gov (United States)

    Langendam, Miranda W; Tiemersma, Edine W; van der Werf, Marieke J; Sandgren, Andreas

    2013-01-01

    A recent systematic review concluded that there is insufficient evidence on the effectiveness to support or reject preventive therapy for treatment of contacts of patients with multidrug resistant tuberculosis (MDR-TB). Whether preventive therapy is favorable depends both on the effectiveness and the adverse events of the drugs used. We performed a systematic review to assess adverse events in healthy individuals and MDR-TB contacts treated with anti-tuberculosis drugs potentially effective for preventing development of MDR-TB. We searched MEDLINE, EMBASE, and other databases (August 2011). Record selection, data extraction, and study quality assessment were done in duplicate. The quality of evidence was assessed using the GRADE approach. Of 6,901 identified references, 20 studies were eligible. Among the 16 studies in healthy volunteers (a total of 87 persons on either levofloxacin, moxifloxacin, ofloxacin, or rifabutin, mostly for 1 week), serious adverse events and treatment discontinuation due to adverse events were rare (MDR-TB contacts, therapy was stopped for 58-100% of the included persons because of the occurrence of adverse events ranging from mild adverse events such as nausea and dizziness to serious events requiring treatment. The quality of the evidence was very low. Although the number of publications and quality of evidence are low, the available evidence suggests that shortly after starting treatment the occurrence of serious adverse events is rare. Mild adverse events occur more frequently and may be of importance because these may provoke treatment interruption.

  2. Hepatitis B or hepatitis C co-infection in individuals infected with human immunodeficiency virus and effect of anti-tuberculosis drugs on liver function

    Directory of Open Access Journals (Sweden)

    Padmapriyadarsini C

    2006-01-01

    Full Text Available Background: Tuberculosis (TB and hepatitis are the two common co-infections in patients infected with human immunodeficiency virus (HIV. Anti-tuberculosis treatment (ATT may have an effect on the liver enzymes in these co-infected HIV patients. Aims: To determine the prevalence of Hepatitis B and C virus coinfection in HIV infected patients in Tamilnadu and assess effects of anti-tuberculosis drugs on their liver function. Settings: HIV positive subjects referred to the Tuberculosis Research Centre, Chennai Materials and Methods: All HIV infected patients referred to the Tuberculosis Research centre, from March 2000 to May 2004, were screened for Hepatitis B surface antigen (HBsAg & Hepatitis C virus (HCV antibodies by enzyme linked immunoabsorbent assay (ELISA. HIV infection was confirmed using two rapid tests and one ELISA. Patients were given either short- course anti-tuberculosis treatment or preventive therapy for tuberculosis, depending on the presence or absence of active TB, if their baseline liver functions were within normal limits. None of these patients were on antiretroviral therapy during the study period. Statistical Analysis: Paired t-test was used to find the significance between baseline and end of treatment liver enzymes levels, while logistic regression was done for assessing various associations. Results: Of the 951 HIV-infected patients, 61 patients (6.4% were HBsAg positive, 20 (2.1% had demonstrable anti HCV antibodies in their blood. Serial estimation of liver enzymes in 140 HIV patients (81 being co-infected with either HBV or HCV showed that 95% did not develop any liver toxicity while they were on anti-tuberculosis treatment or prophylaxis. Conclusions: The prevalence of hepatitis B and C coinfection was fairly high in this largely heterosexually infected population supporting the use of more careful screening for these viruses in HIV positive persons in this region. Anti-tuberculosis therapy as well as TB preventive

  3. Clinical significance of 2 h plasma concentrations of first-line anti-tuberculosis drugs

    DEFF Research Database (Denmark)

    Prahl, Julie B; Johansen, Isik S; Cohen, Arieh S;

    2014-01-01

    OBJECTIVES: To study 2 h plasma concentrations of the first-line tuberculosis drugs isoniazid, rifampicin, ethambutol and pyrazinamide in a cohort of patients with tuberculosis in Denmark and to determine the relationship between the concentrations and the clinical outcome. METHODS: After 6......-207 days of treatment (median 34 days) 2 h blood samples were collected from 32 patients with active tuberculosis and from three patients receiving prophylactic treatment. Plasma concentrations were determined using LC-MS/MS. Normal ranges were obtained from the literature. Clinical charts were reviewed...... failure occurred more frequently when the concentrations of isoniazid and rifampicin were both below the normal ranges (P = 0.013) and even more frequently when they were below the median 2 h drug concentrations obtained in the study (P = 0.005). CONCLUSIONS: At 2 h, plasma concentrations of isoniazid...

  4. Computational medicinal chemistry for rational drug design: Identification of novel chemical structures with potential anti-tuberculosis activity.

    Science.gov (United States)

    Koseki, Yuji; Aoki, Shunsuke

    2014-01-01

    Tuberculosis (TB) is caused by the bacterium Mycobacterium tuberculosis and is a common infectious disease with high mortality and morbidity. The increasing prevalence of drug-resistant strains of TB presents a major public health problem. Due to the lack of effective drugs to treat these drug-resistant strains, the discovery or development of novel anti-TB drugs is important. Computer-aided drug design has become an established strategy for the identification of novel active chemicals through a combination of several drug design tools. In this review, we summarise the current chemotherapy for TB, describe attractive target proteins for the development of antibiotics against TB, and detail several computational drug design strategies that may contribute to the further identification of active chemicals for the treatment of not only TB but also other diseases.

  5. Development of a Nafion/MWCNT-SPCE-Based Portable Sensor for the Voltammetric Analysis of the Anti-Tuberculosis Drug Ethambutol

    Directory of Open Access Journals (Sweden)

    Rosa A. S. Couto

    2016-06-01

    Full Text Available Herein we describe the development, characterization and application of an electrochemical sensor based on the use of Nafion/MWCNT-modified screen-printed carbon electrodes (SPCEs for the voltammetric detection of the anti-tuberculosis (anti-TB drug ethambutol (ETB. The electrochemical behaviour of the drug at the surface of the developed Nafion/MWCNT-SPCEs was studied through cyclic voltammetry (CV and square wave voltammetry (SWV techniques. Electrochemical impedance spectroscopy (EIS and scanning electron microscopy (SEM were employed to characterize the modified surface of the electrodes. Results showed that, compared to both unmodified and MWCNTs-modified SPCEs, negatively charged Nafion/MWCNT-SPCEs remarkably enhanced the electrochemical sensitivity and selectivity for ETB due to the synergistic effect of the electrostatic interaction between cationic ETB molecules and negatively charged Nafion polymer and the inherent electrocatalytic properties of both MWCNTs and Nafion. Nafion/MWCNT-SPCEs provided excellent biocompatibility, good electrical conductivity, low electrochemical interferences and a high signal-to-noise ratio, providing excellent performance towards ETB quantification in microvolumes of human urine and human blood serum samples. The outcomes of this paper confirm that the Nafion/MWCNT-SPCE-based device could be a potential candidate for the development of a low-cost, yet reliable and efficient electrochemical portable sensor for the low-level detection of this antimycobacterial drug in biological samples.

  6. Polymeric emulsion and crosslink-mediated synthesis of super-stable nanoparticles as sustained-release anti-tuberculosis drug carriers.

    Science.gov (United States)

    Choonara, Yahya E; Pillay, Viness; Ndesendo, Valence M K; du Toit, Lisa C; Kumar, Pradeep; Khan, Riaz A; Murphy, Caragh S; Jarvis, Debbie-Leigh

    2011-10-15

    This study focused on evaluating four emulsion-based processing strategies for polymeric nanoparticle synthesis to explicate the mechanisms of nanoparticle formation and the influence on achieving sustained-release of two anti-tuberculosis drugs, isoniazid and rifampicin. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles were formulated with and without sorbitan mono-oleate as a stabilizer using emulsion-solvent-surfactant-evaporation (ESSE) and emulsion-solvent-evaporation (ESE) approaches. An alginate solution gelled by ionic crosslinking with calcium chloride was employed to prepare alginate hydrogel nanoparticles via reverse-emulsion-cationic-gelification (RECG) and reverse-emulsion-surfactant-cationic-gelification (RESCG) approaches. In vitro drug release analysis was performed. The size, zeta potential and morphology of the nanoparticles were analyzed. Molecular mechanics energy relationships (MMER) were employed to explore the spatial disposition of alginate and PLGA with respect to the emulsifying profile of sorbitan monooleate and to corroborate the experimental findings. Results revealed that particle size of the PLGA nanoparticles was influenced by the stabilizer concentration. Nanoparticles synthesized by the ESSE approach had smaller sizes of 240±8.7 nm and 195.5±5.4 nm for rifampicin- and isoniazid-loaded nanoparticles, respectively. This was a substantial size reduction from nanoparticles generated by the ESE approach (>1000 nm). The RESCG approach produced stable and higher nanoparticle yields with desirable size (277±1.0 nm; 289±1.2 nm), a low polydispersity index (27.1±0.3 mV; 28.5±0.5 mV) and drug entrapment efficiency of 73% and 75% for isoniazid and rifampicin, respectively. Drug release from the ESSE and RESCG synthesized nanoparticles displayed desirable release of the two anti-TB drugs with sustained zero-order kinetics over a period of 8h. MMER supported the mechanisms of nanoparticle formation with a sphericalized interlaced network

  7. Dual channel real-time PCR melting curve analysis-based assay for detecting of anti-tuberculosis drug-resistant mutations in Mycobacterium tuberculosis%双通道实时荧光PCR熔解曲线法检测结核分枝杆菌药物耐药相关基因突变

    Institute of Scientific and Technical Information of China (English)

    柳清云; 罗涛; 李静; 梅建; 高谦

    2013-01-01

    目的 基于双标记荧光探针熔解曲线分析技术,建立一种利用实时荧光PCR快速检测结核分枝杆菌耐药突变的方法.方法 根据结核分枝杆菌一线药物常见耐药突变位点(包括rpoB 81 bp耐药决定区、inhA启动子、katG315、ahpC启动子以及embB306)设计6条荧光双标记探针和对应引物,通过PCR扩增耐药突变位点所在基因片段,在扩增完成后通过熔解曲线检测分析实现对耐药突变的快速检测.通过对2008年上海市疾控中心收集的76株临床耐多药(MDR)菌株进行检测,验证本方法的敏感度和特异度.结果 本方法成功从76株MDR菌株中检测出相关耐药突变,各种突变对应ATm值范围为1.8~14.4℃.将检测结果和测序结果对比表明该方法检测敏感度和特异度都为100%(rpoB,80/80:inhA,7/7;katG315,59/59;ahpC,8/8;embB306,27/27).本方法可以成功从最低浓度为100拷贝/μl的结核分枝杆菌DNA样本中准确地检测耐药突变.结论 双通道实时荧光PCR熔解曲线法可以快速灵敏地检测结核分枝杆菌常见耐药突变.该方法具有检测迅速准确、结果易判读、交叉污染概率低等特点,可用于快速检测临床结核耐药相关的基因突变,并对结核耐药情况进行评估.%Objective Based on dual channel melting curve analysis-based assay,we developed a method to rapidly detect the drug-resistant mutations in Mycobacterium tuberculosis through real-time PCR.Methods According to the common first-line drug-resistant mutations of Mycobacterium tuberculosis,we designed six dual-labeled fluorescence probes to rapidly detect the drug-resistant mutations through realtime PCR melting curve after amplifications of drug-resistant related gene region of DNA.The targets include rpoB 81 bp core region,katG315,inhA promoter,ahpC promoter and embB306.To validate the sensitivity and specificity of our method,we performed real-time PCR assays to detect drug-resistant mutations in 76

  8. Drug Resistance

    Science.gov (United States)

    HIV Treatment Drug Resistance (Last updated 3/2/2017; last reviewed 3/2/2017) Key Points As HIV multiplies in the ... the risk of drug resistance. What is HIV drug resistance? Once a person becomes infected with HIV, ...

  9. Reinforcing the membrane-mediated mechanism of action of the anti-tuberculosis candidate drug thioridazine with molecular simulations

    DEFF Research Database (Denmark)

    Kopec, Wojciech; Khandelia, Himanshu

    2014-01-01

    mechanisms of action, the cell membrane-mediated one is peculiarly tempting due to the distinctive feature of phenothiazine drug family to accumulate in selected body tissues. In this study, we employ long-scale molecular dynamics simulations to investigate the interactions of three different concentrations......Thioridazine is a well-known dopamine-antagonist drug with a wide range of pharmacological properties ranging from neuroleptic to antimicrobial and even anticancer activity. Thioridazine is a critical component of a promising multi-drug therapy against M. tuberculosis. Amongst the various proposed...... for the negatively charged bilayer. We show that the origin of such changes is the drug induced decrease of the interfacial tension, which ultimately leads to the significant membrane expansion. Our findings support the hypothesis that the phenothiazines therapeutic activity may arise from the drug...

  10. Reinforcing the membrane-mediated mechanism of action of the anti-tuberculosis candidate drug thioridazine with molecular simulations

    Science.gov (United States)

    Kopec, Wojciech; Khandelia, Himanshu

    2014-02-01

    Thioridazine is a well-known dopamine-antagonist drug with a wide range of pharmacological properties ranging from neuroleptic to antimicrobial and even anticancer activity. Thioridazine is a critical component of a promising multi-drug therapy against M. tuberculosis. Amongst the various proposed mechanisms of action, the cell membrane-mediated one is peculiarly tempting due to the distinctive feature of phenothiazine drug family to accumulate in selected body tissues. In this study, we employ long-scale molecular dynamics simulations to investigate the interactions of three different concentrations of thioridazine with zwitterionic and negatively charged model lipid membranes. Thioridazine partitions into the interfacial region of membranes and modifies their structural and dynamic properties, however dissimilarly so at the highest membrane-occurring concentration, that appears to be obtainable only for the negatively charged bilayer. We show that the origin of such changes is the drug induced decrease of the interfacial tension, which ultimately leads to the significant membrane expansion. Our findings support the hypothesis that the phenothiazines therapeutic activity may arise from the drug-membrane interactions, and reinforce the wider, emerging view of action of many small, bioactive compounds.

  11. Development of a prediction system for anti-tuberculosis drug-induced liver injury in Japanese patients

    Science.gov (United States)

    Mushiroda, Taisei; Yanai, Hideki; Yoshiyama, Takashi; Sasaki, Yuka; Okumura, Masao; Ogata, Hideo; Tokunaga, Katsushi

    2016-01-01

    Drug-induced liver injury (DILI) is a common adverse drug reaction in patients receiving antituberculosis (anti-TB) treatment. Among the anti-TB agents, isoniazid (INH) is the primary drug that causes hepatotoxicity in TB patients with DILI. Previous reports in several populations have consistently demonstrated an association between polymorphisms in the N-acetyltransferase 2 (NAT2) gene, which is responsible for INH hepatic metabolism, and a risk of DILI in TB patients. In this study, the genetic and baseline clinical data from 366 Japanese patients with TB (73 patients with DILI and 293 without DILI) were used to develop a system to predict DILI risk due to anti-TB agents. The distribution of the NAT2 acetylator status among the TB patients with DILI was 31 (42.5%), 29 (39.7%), and 13 (17.8%) for rapid, intermediate, and slow acetylators, respectively. A significant association was observed between NAT2 slow acetylators and DILI risk (odds ratio 4.32, 95% confidence interval 1.93–9.66, P value=5.56×10−4). A logistic regression model based on age and NAT2 genotype revealed that the area under the curve for the receiver-operating characteristic curve was 0.717. The findings demonstrated that slow NAT2 acetylator status is a significant predictor of the risk of DILI by anti-TB agents, and a personalized anti-TB treatment approach may aid in making treatment decisions and reducing the incidence of DILI. PMID:27340556

  12. Evaluation of macrolides for possible use against multidrug-resistant Mycobacterium tuberculosis

    NARCIS (Netherlands)

    van der Paardt, Anne-Fleur; Wilffert, Bob; Akkerman, Onno W.; de Lange, Wiel C. M.; van Soolingen, Dick; Sinha, Bhanu; van der Werf, Tjip S.; Kosterink, Jos G. W.; Alffenaar, Jan-Willem C.

    2015-01-01

    Multidrug-resistant tuberculosis (MDR-TB) is a major global health problem. The loss of susceptibility to an increasing number of drugs behoves us to consider the evaluation of non-traditional anti-tuberculosis drugs. Clarithromycin, a macrolide antibiotic, is defined as a group 5 anti-tuberculosis

  13. Reagent Precoated Targets for Rapid In-Tissue Derivatization of the Anti-Tuberculosis Drug Isoniazid Followed by MALDI Imaging Mass Spectrometry

    Science.gov (United States)

    Manier, M. Lisa; Reyzer, Michelle L.; Goh, Anne; Dartois, Veronique; Via, Laura E.; Barry, Clifton E.; Caprioli, Richard M.

    2011-08-01

    Isoniazid (INH) is an important component of front-line anti-tuberculosis therapy with good serum pharmacokinetics but unknown ability to penetrate tuberculous lesions. However, endogenous background interferences hinder our ability to directly analyze INH in tissues. Chemical derivatization has been successfully used to measure isoniazid directly from tissue samples using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS). MALDI targets were pretreated with trans-cinnamaldehyde (CA) prior to mounting tissue slices. Isoniazid present in the tissues was efficiently derivatized and the INH-CA product measured by MS/MS. Precoating of MALDI targets allows the tissues to be directly thaw-mounted and derivatized, thus simplifying the preparation. A time-course series of tissues from tuberculosis infected/INH dosed animals were assayed and the MALDI MS/MS response correlates well with the amount of INH determined to be in the tissues by high-performance liquid chromatography (HPLC)-MS/MS.

  14. 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 f

  15. NAT2 variants are associated with drug-induced liver injury caused by anti-tuberculosis drugs in Indonesian patients with tuberculosis.

    Science.gov (United States)

    Yuliwulandari, Rika; Susilowati, Retno Wilujeng; Wicaksono, Britanto Dani; Viyati, Kencono; Prayuni, Kinasih; Razari, Intan; Kristin, Erna; Syafrizal; Subagyo; Sri Diana, Eva; Setiawati, Suci; Ariyani, Aziza; Mahasirimongkol, Surakameth; Yanai, Hideki; Mushiroda, Taisei; Tokunaga, Katsushi

    2016-06-01

    Drug-induced liver injury (DILI) is the most common adverse drug reaction in the treatment of tuberculosis (TB). Several studies showed that patients with TB and the slow-acetylator phenotype caused by NAT2 variants are highly susceptible to DILI caused by anti-TB drugs, hereafter designated AT-DILI. However, the role of NAT2 variants in AT-DILI has never been assessed for an Indonesian population. We recruited 50 patients with TB and AT-DILI and 191 patients with TB but without AT-DILI; we then used direct DNA sequencing to assess single-nucleotide polymorphisms in the coding region of NAT2. NAT2*6A was significantly associated with susceptibility to AT-DILI (P=7.7 × 10(-4), odds ratio (OR)=4.75 (1.8-12.55)). Moreover, patients with TB and the NAT2-associated slow-acetylator phenotype showed higher risk of AT-DILI than patients with the rapid- or intermediate-acetylator phenotypes (P=1.7 × 10(-4), OR=3.45 (1.79-6.67)). In conclusion, this study confirms the significance of the association between slow-acetylator NAT2 variants and susceptibility to AT-DILI in an Indonesian population.

  16. Thymopentin Combined with Anti -tuberculosis Drugs Therapy and Different Risk Factors for Recur-rence of Pulmonary Tuberculosis Parient%胸腺五肽联合化疗与肺结核复发的危险因素

    Institute of Scientific and Technical Information of China (English)

    李奎; 江自成; 杨才勇; 刘胜昔; 方坚

    2016-01-01

    Objective To investigate thymopentin combined with anti -tuberculosis drugs therapy and the risk factors for recurrence of pulmo-nary tuberculosis parient.Methods A total of 428 patients receiving anti -tuberculosis therapy in our hospital from January 2004 to December 2011 were enrol ed in this study to review the clinical characteristics,radiology features and treatment,ten parameters contributing to the recurrence were ana-lyzed.Results Nineteen patients (4.43%)had recurrence.Of the 19 patients,12 patients had early recurrence and 7 patients had the late one.High bacterial loads and cavitations disease were risk factors for early recurrence while higher age and diabetes mel itus were risk factor for the late recur-rence.Conclusions The identification of significant risk factors for recurrence may enable bet er selection of treatment options.%目的:探讨胸腺五肽联合抗结核治疗与肺结核复发的相关性及危险因素。方法分析2004年1月至2011年12月收治的428例经细菌学证实为肺结核的病例,经随访2年以上,选择10项临床、放射及治疗等指标分析对早/晚复发的影响。结果全组有19例复发,复发率为4.43%,早期复发(小于等于1年)12例,晚期复发(大于1年)7例。胸肽腺联合标准一线抗结核药物的早期复发率为1.77%,晚期复发率为1.18%。高细菌学含量和空洞是早期复发的危险因素,而年龄和糖尿病则是晚期复发的危险因素。结论辨别肺结核复发的危险因素对于选择治疗方案有积极的意义。

  17. Metabolism of the anti-tuberculosis drug ethionamide by mouse and human FMO1, FMO2 and FMO3 and mouse and human lung microsomes.

    Science.gov (United States)

    Henderson, Marilyn C; Siddens, Lisbeth K; Morré, Jeffrey T; Krueger, Sharon K; Williams, David E

    2008-12-15

    Tuberculosis (TB) results from infection with Mycobacterium tuberculosis and remains endemic throughout the world with one-third of the world's population infected. The prevalence of multi-drug resistant strains necessitates the use of more toxic second-line drugs such as ethionamide (ETA), a pro-drug requiring bioactivation to exert toxicity. M. tuberculosis possesses a flavin monooxygenase (EtaA) that oxygenates ETA first to the sulfoxide and then to 2-ethyl-4-amidopyridine, presumably through a second oxygenation involving sulfinic acid. ETA is also a substrate for mammalian flavin-containing monooxygenases (FMOs). We examined activity of expressed human and mouse FMOs toward ETA, as well as liver and lung microsomes. All FMOs converted ETA to the S-oxide (ETASO), the first step in bioactivation. Compared to M. tuberculosis, the second S-oxygenation to the sulfinic acid is slow. Mouse liver and lung microsomes, as well as human lung microsomes from an individual expressing active FMO, oxygenated ETA in the same manner as expressed FMOs, confirming this reaction functions in the major target organs for therapeutics (lung) and toxicity (liver). Inhibition by thiourea, and lack of inhibition by SKF-525A, confirm ETASO formation is primarily via FMO, particularly in lung. ETASO production was attenuated in a concentration-dependent manner by glutathione. FMO3 in human liver may contribute to the toxicity and/or affect efficacy of ETA administration. Additionally, there may be therapeutic implications of efficacy and toxicity in human lung based on the FMO2 genetic polymorphism, though further studies are needed to confirm that suggestion.

  18. The timing of death in patients with tuberculosis who die during anti-tuberculosis treatment in Andhra Pradesh, South India

    Directory of Open Access Journals (Sweden)

    Jonnalagada Subbanna

    2011-12-01

    Full Text Available Abstract Background India has 2.0 million estimated tuberculosis (TB cases per annum with an estimated 280,000 TB-related deaths per year. Understanding when in the course of TB treatment patients die is important for determining the type of intervention to be offered and crucially when this intervention should be given. The objectives of the current study were to determine in a large cohort of TB patients in India:- i treatment outcomes including the number who died while on treatment, ii the month of death and iii characteristics associated with "early" death, occurring in the initial 8 weeks of treatment. Methods This was a retrospective study in 16 selected Designated Microscopy Centres (DMCs in Hyderabad, Krishna and Adilabad districts of Andhra Pradesh, South India. A review was performed of treatment cards and medical records of all TB patients (adults and children registered and placed on standardized anti-tuberculosis treatment from January 2005 to September 2009. Results There were 8,240 TB patients (5183 males of whom 492 (6% were known to have died during treatment. Case-fatality was higher in those previously treated (12% and lower in those with extra-pulmonary TB (2%. There was an even distribution of deaths during anti-tuberculosis treatment, with 28% of all patients dying in the first 8 weeks of treatment. Increasing age and new as compared to recurrent TB disease were significantly associated with "early death". Conclusion In this large cohort of TB patients, deaths occurred with an even frequency throughout anti-TB treatment. Reasons may relate to i the treatment of the disease itself, raising concerns about drug adherence, quality of anti-tuberculosis drugs or the presence of undetected drug resistance and ii co-morbidities, such as HIV/AIDS and diabetes mellitus, which are known to influence mortality. More research in this area from prospective and retrospective studies is needed.

  19. Analysis of Related Factors of Liver Damage Caused by Anti Tuberculosis Drugs%抗结核药物致肝损害的相关因素分析

    Institute of Scientific and Technical Information of China (English)

    陈雨燕; 李丹; 林秀华; 陈晓红; 林剑东; 刘建清

    2014-01-01

    目的:探讨抗结核药物致肝损害的相关因素。方法:回顾性分析本院自2010年1月-2013年8月收治的1538例结核病患者的临床资料,分析抗结核药物致肝损害的因素,其中包括患者的性别、年龄、种族、糖尿病史、饮酒史、HBsAg、结核类型以及肝炎史等方面。结果:本组1538例患者中,发生轻度肝损伤154例(10.01%),中度肝损伤45例(2.93%),重度肝损伤25例(1.63%),总损伤224例(14.56%)。HBsAg呈现阳性的患者发生肝损伤的几率明显高于阴性者,有糖尿病史和肝炎史患者发生肝损伤几率明显高于无糖尿病史和肝炎史,有饮酒史的患者发生药物性肝损伤的几率要明显高于无饮酒史患者,进行过预防性保肝治疗的患者其患病率明显低于没有进行过治疗的患者,营养状况的好坏也与患者患病的几率有关,差异有统计学意义(P<0.05)。结论:在进行抗结核药物治疗时,应充分了解患者的病情、病史等,选择对患者危害性较小的抗结核药物,并采取适当的护肝措施,以尽可能减少药物性肝损害的发生,保证抗结核治疗的顺利进行。%Objective:To investigate the related factors liver damage caused by anti tuberculosis drugs. Method:The clinical data of 1538 tuberculosis patients in our hospital from January 2010 to August 2013 were retrospectively analyzed,the factors of liver damage caused by anti tuberculosis drugs were analyzed,including gender, age,race,diabetes history,drinking history,HbsAg,tuberculosis type and hepatitis history etc of patients. Result:In 1538 patients,the occurrence of mild liver injury in 154 cases(10.01%),45 cases of moderate liver injury (2.93%),severe liver injury in 25 cases(1.63%),the total injury in 224 cases(14.56%).The probability of occurrence of liver injury in HBsAg positive patients was significantly higher than that of negative,the probability of occurrence of

  20. Meta Analysis on Chinese Patent Medicine in Prevention and Cure of Hepatic Lesion Caused by Anti-tuberculosis Drugs%中医成方防治抗结核药物致肝损害的Meta分析

    Institute of Scientific and Technical Information of China (English)

    魏华

    2012-01-01

    目的:系统评价中医成方防治抗结核药致肝损害的疗效和安全性.方法:电子检索2000年1月到2011年7月的Medline、Embase、Cochrane library、中国生物医学光盘数据库,万方、维普数据库,并手工检索相关文献,纳入治疗组为中医成方,对照组为常规保肝治疗,逐个对其进行质量评价和资料提取,用RevMan 4.2软件进行Meta分析.结果:最终纳入6个半随机对照试验,共372例患者,纳入研究质量均为C级.中医成方组肝功正常率优于常规l保肝治疗(P<0.01,OR-13.50,95%CI 6.89~26.46);未发现严重不良反应.结论:中医成方防治肝损害效果优于常规保肝治疗,且无明显不良反应.但由于纳入研究的方法学质量较低、观察时间较短,且存在中西医结合诊断不标准、中药使用不规范等问题,可能影响评价结果,尚需更多高质量、长周期、中西医结合规范化研究以系统评价其疗效.%Objective: To evaluate systemically the efficacy and safety of Chinese patent medicine in prevention and cure hepatic lesion caused by anti-tuberculosis drugs. Method :Medline, Embase, Cochrane Library, CBM, VIP and WanFang data from 2000 to May, 2011 were searched online and the literatures published or not were manually retrieved. The papers on Chinese patent medicine were divided into treatment group while routine treatment were in control group, all were undergoing the quality analysis and information extraction. RevMan 4.2 was used for data analysis. Finally six Quasi-randomized control trials involving 372 patients were recruited. Methodological qualities were all graded C. Result: After 1-6 months' treatment, normal rate of liver function in Chinese patent medicine group were higher than in routine treatment (P <0.01, OR=13.50, 95% CI 6.89-26.46) without serious side effects. Conclusion: Chinese patent medicine is better than routine treatment in prevention and cure hepatic lesion caused by anti-tuberculosis drugs

  1. 抗结核药物性肝损伤临床危险因素分析%Analysis of clinical risk factors associated with anti-tuberculosis drug-inducing liver injury

    Institute of Scientific and Technical Information of China (English)

    卫安娜; 方怡; 梁国添; 余燕华; 邝浩斌; 温文沛

    2015-01-01

    Objective To analyze the clinical risk factors associated with anti-tuberculosis drug-inducing liv-er injury (ATLI). Methods From 2013 January to 2014 July, a total of 100 pulmonary tuberculosis patients com-plicated with ATLI were enrolled as the case group, and 100 patients only with pulmonary tuberculosis were randomly selected as the control group. The retrospective case-control study and multivariate logistic regression were used to an-alyze the risk factor associated with liver injury caused by anti-tuberculosis therapy. The factors for analysis included initial/ retreated pulmonary tuberculosis cases, range, sputum smear positive, whether complicated with extra pulmo-nary tuberculosis lesions, hepatitis B surface antigen carriers, alcohol abuse, history of hepatitis diseases besides hepatitis B, diabetes, heart function incomplete, respiratory failure, hypoproteinemia, and anemia. Results The results of multivariate logistic regression analysis showed that the risk factors included hepatitis B surface antigen car-riers (OR = 3. 113, P = 0. 005), history of alcoholism (OR = 3. 427, P = 0. 008), history of the other hepatitis dis-eases besides hepatitis B (OR = 2. 359, P = 0. 032), respiratory failure (OR = 1. 622, P = 0. 045), cardiac func-tional insufficiency (OR = 1. 700, P = 0. 015), hypoproteinemia ( OR = 1. 860, P = 0. 012) and anemia ( OR =1. 718, P = 0. 014). Conclusion The risk factors for liver injury caused by anti tuberculosis drugs include hepatitis B surface antigen carriers, history of alcoholism, history of hepatitis diseases besides hepatitis B, respiratory failure, cardiac functional insufficiency, hypoproteinemia and anemia.%目的:分析肺结核化疗中发生抗结核药物性肝损伤(ATLI)的临床危险因素。方法收集2013年1月到2014年7月期间在我院住院治疗的肺结核合并抗结核药物性肝损伤病例100例为观察组,随机抽取同一时间段在我院住院治疗的肺结核无合并抗

  2. Pediatric tuberculous meningitis: Model-based approach to determining optimal doses of the anti-tuberculosis drugs rifampin and levofloxacin for children.

    Science.gov (United States)

    Savic, R M; Ruslami, R; Hibma, J E; Hesseling, A; Ramachandran, G; Ganiem, A R; Swaminathan, S; McIlleron, H; Gupta, A; Thakur, K; van Crevel, R; Aarnoutse, R; Dooley, K E

    2015-12-01

    Pediatric tuberculous meningitis (TBM) is a highly morbid, often fatal disease. Standard treatment includes isoniazid, rifampin, pyrazinamide, and ethambutol. Current rifampin dosing achieves low cerebrospinal fluid (CSF) concentrations, and CSF penetration of ethambutol is poor. In adult trials, higher-dose rifampin and/or a fluoroquinolone reduced mortality and disability. To estimate optimal dosing of rifampin and levofloxacin for children, we compiled plasma and CSF pharmacokinetic (PK) and outcomes data from adult TBM trials plus plasma PK data from children. A population PK/pharmacodynamic (PD) model using adult data defined rifampin target exposures (plasma area under the curve (AUC)0-24 = 92 mg*h/L). Levofloxacin targets and rifampin pediatric drug disposition information were literature-derived. To attain target rifampin exposures, children require daily doses of at least 30 mg/kg orally or 15 mg/kg intravenously (i.v.). From our pediatric population PK model, oral levofloxacin doses needed to attain exposure targets were 19-33 mg/kg. Our results provide data-driven guidance to maximize pediatric TBM treatment while we await definitive trial results.

  3. First insights into circulating Mycobacterium tuberculosis complex lineages and drug resistance in Guinea.

    Science.gov (United States)

    Ejo, Mebrat; Gehre, Florian; Barry, Mamadou Dian; Sow, Oumou; Bah, Nene Mamata; Camara, Mory; Bah, Boubacar; Uwizeye, Cecile; Nduwamahoro, Elie; Fissette, Kristina; De Rijk, Pim; Merle, Corinne; Olliaro, Piero; Burgos, Marcos; Lienhardt, Christian; Rigouts, Leen; de Jong, Bouke C

    2015-07-01

    In this study we assessed first-line anti-tuberculosis drug resistance and the genotypic distribution of Mycobacterium tuberculosis complex (MTBC) isolates that had been collected from consecutive new tuberculosis patients enrolled in two clinical trials conducted in Guinea between 2005 and 2010. Among the total 359 MTBC strains that were analyzed in this study, 22.8% were resistant to at least one of the first line anti-tuberculosis drugs, including 2.5% multidrug resistance and 17.5% isoniazid resistance, with or without other drugs. In addition, further characterization of isolates from a subset of the two trials (n = 184) revealed a total of 80 different spoligotype patterns, 29 "orphan" and 51 shared patterns. We identified the six major MTBC lineages of human relevance, with predominance of the Euro-American lineage. In total, 132 (71.7%) of the strains were genotypically clustered, and further analysis (using the DESTUS model) suggesting significantly faster spread of LAM10_CAM family (p = 0.00016). In conclusion, our findings provide a first insight into drug resistance and the population structure of the MTBC in Guinea, with relevance for public health scientists in tuberculosis control programs.

  4. Effect of Diet Intervention on Hyperuricemia Induced by Anti-tuberculosis Drugs%饮食干预对抗结核药物性高尿酸血症的影响

    Institute of Scientific and Technical Information of China (English)

    陈敏

    2014-01-01

    [Objective] To analyze the effect of diet intervention on the increased uric acid level in serum leading to withdrawal caused by anti-tuberculosis drug pyrazinamide and its significance .[Methods]The control study was used .The tuberculosis patients with the increased uric acid level in serum caused by pyrazinamide were divided into two groups .To-tally 112 outpatients in the tuberculosis department of our hospital from 2007 to 2008 were taken as intervention group , while 110 patients treated in tuberculosis prevention and control department of the center for disease control in Changning district from 2006 to 2007 were taken as control group .The intervention group received anti-tuberculosis treatment and simple diet intervention without other medicines to control serum urinary acid .Family members sustained the work of diet intervention effectively .The main methods of diet intervention included drinking more water ,keeping warm and alkalizing urine ,etc .The control group needed no dietary requirements .The change of serum uric acid level and withdrawal rate in two groups were observed and compared .[Results] The withdrawal rate in intervention group during chemotherapy process was 6 .25% (7/112) which was obviously lower than that in control group (76 .36% ,84/110) ,and there was sig-nificant difference between two groups ( P<0 .05) .Compared with control groups ,the increased uric acid value in inter-vention group at the end of treatment after one month and two months deceased by 7% and above 10% ,respectively .[Conclusion]Diet intervention can effectively control the increased uric acid level in serum caused by pyrazinamide and largely reduce the withdrawal in chemotherapy process .Therefore ,it has good clinical significance .%[目的]分析饮食干预对抗结核药物吡嗪酰胺引起血尿酸水平升高而导致停药的影响及意义。[方法]采用对照研究,将服用吡嗪酰胺等引起血尿酸增高的结核患者分为两组,2007~2008

  5. A Study of the Timing of Death in Patients with Tuberculosis Who Die During Anti-Tuberculosis Treatment

    Directory of Open Access Journals (Sweden)

    Bhavik Patel

    2016-06-01

    Full Text Available Introduction: India has 2.0 million estimated tuberculosis (TB cases per annum with an estimated 280,000 TB related deaths per year. Understanding when in the course of TB treatment patients die is important for determining the type of intervention to be offered and crucially when this intervention should be given. The objectives of the current study were to determine in a large cohort of TB patients in India: - i treatment outcomes including the number who died while on treatment, ii the month of death and iii characteristics associated with and ldquo;early and rdquo; death, occurring in the initial 8 weeks of treatment. Methodology: This was a retrospective study in C.U.Shah Medical College and Hospital in Surendranagar, Gujarat India. A review was performed of treatment cards and medical records of all TB patients (adults and children registered and placed on standardized anti-tuberculosis treatment from January 2007 to April 2012. Results: There were 376 TB patients of whom 41 (11% were known to have died during treatment. Case-fatality was higher in those previously treated (24% and lower in those with extra-pulmonary TB (1%.Most of deaths during anti-tuberculosis treatment were early, with 66% of all patients dying in the first 8 weeks of treatment. Increasing age and new as compared to recurrent TB disease were significantly associated with and ldquo;early death and rdquo;. In this large cohort of TB patients, Most of deaths occurred early after starting anti-TB treatment. Reasons may relate to i the treatment of the disease itself, raising concerns about drug adherence, quality of anti-tuberculosis drugs or the presence of undetected drug resistance and ii co-morbidities, such as HIV/ AIDS and diabetes mellitus, which are known to influence mortality. iii Late stage presentation by patients themselves. More research in this area from prospective and retrospective studies is needed. [Natl J Med Res 2016; 6(2.000: 186-190

  6. Comparative evaluation of the Nitrate Reductase Assay and the Resazurin Microtitre Assay for drug susceptibility testing of Mycobacterium tuberculosis against first line anti-tuberculosis drugs Avaliação comparative dos métodos Nitrato Redutase e Microdiluição com Resazurina para testar a sensibilidade do Mycobacterium tuberculosis frente aos anti-tuberculosos de primeira linha

    Directory of Open Access Journals (Sweden)

    Karine O. Sanchotene

    2008-03-01

    Full Text Available Tuberculosis remains as a serious infection disease of worldwide distribution, with high morbidity and mortality, mainly in low socio-economic condition countries. The state of emergency of tuberculosis caused by the resistant and multidrug-resistant (MDR strains, became the main threat to the tuberculosis treatment and control programs. A fast detection method for the resistant strains will allow the implementation of an adequate treatment and contribute for controlling the dissemination of these resistant strains. This study evaluated the performance of the nitrate reductase assay in solid (NRA-LJ and liquid (NRA-7H9 media, to determine the susceptibility to first line anti-tuberculosis drugs: isoniazid (INH, rifampicin (RMP, ethambutol (EMB and streptomycin (SMR. Both methods NRA-LJ and NRA-7H9 were evaluated among 18 strains with a known susceptibility profile. The resazurin microtiter assay (REMA was performed as a reference method. One hundred percent of accordance was observed between NRA-7H9 and REMA for the four tested drugs. When the NRA-LJ method was compared to REMA, the sensitivity and the specificity to INH, RMP, EMB and SMR were 100%, 100 %, 85.7%, 76.9% and 80%, 100%, 75% and 80%, respectively. From the 57 clinical isolates of M. tuberculosis evaluated by NRA-7H9 and REMA, 56 (98.2% were sensitive to all antibiotics tested (INH, RMP, EMB and SMR by the NRA-7H9 method, while three of these strains were resistant to INH by REMA. One strain showed resistance to INH and RMP for both methods, and MIC of 1.0 µg/ml to INH for both methods, while MIC of 1.0 and 2.0 µg/ml to RMP for REMA and NRA-7H9, respectively. The three assays showed a high level of agreement for rapid detection of rifampicin and isoniazid resistance. Regarding rapidness, the detection of color change in the NRA method is within instants as compared to the overnight incubation required for the REMA test. NRA might represent an inexpensive and alternative assay for

  7. Chemical constituents and anti-tuberculosis activity of ink extracts of cuttlefish, Sepiella inermis

    Directory of Open Access Journals (Sweden)

    Muthusamy Ravichandiran

    2013-11-01

    Full Text Available Objective: To study the chemical constituents and the anti-tuberculosis activity of methanol and chloroform ink extracts of Sepiella inermis. Methods: Pulverized ink powder was extracted separately with chloroform and methanol. Chemical analysis was carried out by UV-VIS spectrophotometer, FT-IR and GC-MS. Crude extracts were tested in vitro for their activity against Mycobacterium tuberculosis using Lowenstein Jensen (L-J medium. Activity in L-J medium was assessed by mean reduction in number of colonies on extract containing bottles as compared to extract free controls. Results: GC-MS of methanol extract revealed four compounds viz. hexadecanoic acid, 9, 12- octadecadienoic acid, 9-octadecenoic acid and octadecanoic acid. The chloroform extract containing fourteen compounds. The methanol extract exhibited anti-tuberculosis activity in L-J medium at 64 µg/mL with the observed inhibition of 14 CFU. Chloroform extract displayed a weak activity against Mycobacterium tuberculosis. Conclusions: This investigation showed the methanol extract exhibited significant activity against Mycobacterium tuberculosis than chloroform extract. Since ink of sepia is available abundantly as a waste material, further studies aimed at isolation and efficacy of active substances pave the way for new anti-tuberculosis drugs.

  8. Chemical constituents and anti-tuberculosis activity of ink extracts of cuttlefish, Sepiella inermis

    Institute of Scientific and Technical Information of China (English)

    Muthusamy Ravichandiran; Selvam Thiripurasalini; Vaithilingam Ravitchandirane; Srinivasa Gopalane; Chelladurai Stella

    2013-01-01

    Objective: To study the chemical constituents and the anti-tuberculosis activity of methanol and chloroform ink extracts of Sepiella inermis.Methods:Chemical analysis was carried out by UV-VIS spectrophotometer, FT-IR and GC-MS. Crude extracts Pulverized ink powder was extracted separately with chloroform and methanol. were tested in vitro for their activity against Mycobacterium tuberculosis using Lowenstein Jensen (L-J) medium. Activity in L-J medium was assessed by mean reduction in number of colonies on extract containing bottles as compared to extract free controls.Results:octadecadienoic acid, 9-octadecenoic acid and octadecanoic acid. The chloroform extract GC-MS of methanol extract revealed four compounds viz. hexadecanoic acid, 9, 12-containing fourteen compounds. The methanol extract exhibited anti-tuberculosis activity in L-J medium at 64 µg/mL with the observed inhibition of 14 CFU. Chloroform extract displayed a weak activity against Mycobacterium tuberculosis.Conclusions:Mycobacterium tuberculosis than chloroform extract. Since ink of sepia is available abundantly as This investigation showed the methanol extract exhibited significant activity against a waste material, further studies aimed at isolation and efficacy of active substances pave the way for new anti-tuberculosis drugs.

  9. Clinical implications of molecular drug resistance testing for Mycobacterium tuberculosis: a TBNET/RESIST-TB consensus statement.

    Science.gov (United States)

    Domínguez, J; Boettger, E C; Cirillo, D; Cobelens, F; Eisenach, K D; Gagneux, S; Hillemann, D; Horsburgh, R; Molina-Moya, B; Niemann, S; Tortoli, E; Whitelaw, A; Lange, C

    2016-01-01

    The emergence of drug-resistant strains of Mycobacterium tuberculosis is a challenge to global tuberculosis (TB) control. Although culture-based methods have been regarded as the gold standard for drug susceptibility testing (DST), molecular methods provide rapid information on mutations in the M. tuberculosis genome associated with resistance to anti-tuberculosis drugs. We ascertained consensus on the use of the results of molecular DST for clinical treatment decisions in TB patients. This document has been developed by TBNET and RESIST-TB groups to reach a consensus about reporting standards in the clinical use of molecular DST results. Review of the available literature and the search for evidence included hand-searching journals and searching electronic databases. The panel identified single nucleotide mutations in genomic regions of M. tuberculosis coding for katG, inhA, rpoB, embB, rrs, rpsL and gyrA that are likely related to drug resistance in vivo. Identification of any of these mutations in clinical isolates of M. tuberculosis has implications for the management of TB patients, pending the results of in vitro DST. However, false-positive and false-negative results in detecting resistance-associated mutations in drugs for which there is poor or unproven correlation between phenotypic and clinical drug resistance complicate the interpretation. Reports of molecular DST results should therefore include specific information on the mutations identified and provide guidance for clinicians on interpretation and on the choice of the appropriate initial drug regimen.

  10. Study on polymorphisms of genes with susceptibility to drug induced liver injury in a cohort receiving anti-tuberculosis treatment%抗结核治疗队列人群药物性肝损害的感基因多态性研究

    Institute of Scientific and Technical Information of China (English)

    陈茹; 王晶; 唐少文; 吕晓珍; 张渊; 武珊珊; 夏愔愔; 詹思延

    2016-01-01

    Objective To investigate the association between the polymorphisms of genes involving in drug metabolism and transport as well as immunological reaction and the risk of anti-tuberculosis drug-induced liver injury (ATLI) in Chinese.Methods This 1∶4 matched casecontrol study was conducted by using the data from a cohort study of Anti-tuberculosis Drugs Induced Adverse Reactions in National Tuberculosis Prevention and Control Progtam of China.Genes involving in three phase of drug metabolism and transport as well as related immunological reaction were chosen and single nucleotide polymorphisms (SNPs) were genotyped by TaqMan allele discrimination technology.Lasso regression and multivariate conditional logistic regression analysis were used to select susceptible genes.Results A total of 33 genes with 75 SNPs were tested.The combined results of Lasso and regression logistic regression analysis showed that genetic polymorphism of SLCO1BI rs4149014,HSPA1L rs2227956,STAT3 rs1053023 and IL-6 rs2066992 were significantly associated with the risk of ATLI (P<0.05).Conclusion SLCO1B1,HSPA1L,STAT3 and IL-6 might be the susceptibility genes of drug induced liver injury in patients receiving anti-tuberculosis treatment.%目的 探索药物代谢、转运和免疫反应基因多态性与中国人群抗结核药致肝损害的关联.方法 利用“中国结核病防治规划抗结核病药品不良反应研究”的人群资料和样本,构建1∶4巢式病例对照研究,选择与抗结核药物所致肝损害相关的三相代谢基因以及相关免疫基因,采用TaqMan分型技术检测基因单核苷酸多态性(SNP),结合Lasso回归和多因素条件logistic回归筛选易感基因.结果 共检测33个基因的75个SNP位点,Lasso回归和logistic回归的合并分析显示,SLCO1B1 rs4149014、HSPAIL rs2227956、STAT3 rs1053023和IL-6 rs2066992基因多态性与抗结核药致肝损害的关联有统计学意义(P<0.05).结论 SLCOIB1、HSPAlL、STAT3和IL-6基因

  11. Highly successful treatment outcome of multidrug-resistant tuberculosis in the Netherlands, 2000-2009

    NARCIS (Netherlands)

    van Altena, R.; de Vries, G.; Haar, C. H.; de Lange, W. C. M.; Magis-Escurra, C.; van den Hof, S.; van Soolingen, D.; Boeree, M. J.; van der Werf, T. S.

    2015-01-01

    SETTING: Resistance to the two key anti-tuberculosis drugs isoniazid and rifampicin is a characteristic of multidrug-resistant tuberculosis (MDR-TB). MDR-TB is a scourge requiring toxic, prolonged treatment and is associated with poor outcomes. The Netherlands is a country with a long-standing, inte

  12. 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....

  13. Drug resistance and antiretroviral drug development

    OpenAIRE

    Shafer, Robert W.; Jonathan M Schapiro

    2005-01-01

    As more drugs for treating HIV have become available, drug resistance profiles within antiretroviral drug classes have become increasingly important for researchers developing new drugs and for clinicians integrating new drugs into their clinical practice. In vitro passage experiments and comprehensive phenotypic susceptibility testing are used for the pre-clinical evaluation of drug resistance. Clinical studies are required, however, to delineate the full spectrum of mutations responsible fo...

  14. 抗病毒联合抗结核药物在艾滋病合并肺结核患者治疗中应用分析%Analysis of the application of anti-virus combined with anti-tuberculosis drugs in the treatment of acquired immune deficiency syndrome complicated with pulmonary tuberculosis

    Institute of Scientific and Technical Information of China (English)

    贾中毅

    2015-01-01

    Objective:To explore the application effect of anti-virus combined with anti-tuberculosis drugs in the treatment of acquired immune deficiency syndrome complicated with pulmonary tuberculosis.Methods:32 patients with AIDS combined with tuberculosis were selected.They were given AZT+NVP+DDI antiviral regimen and 2H3R3Z3E3/7H3R3 regimen for tuberculosis treatment.We compared the treatment effect.Results:In 23 cases of HIV/AIDS/TB double infections,15 cases were clinically cured;5 cases completed one course;chest X-ray of 3 cases showed focus was absorbed and they continued to take medicine.Compared with before treatment,the CD4+T lymphocyte count at 6 months and 9 months after treatment was significantly improved(P<0.05). Conclusion:The dual anti infection treatment program of anti tuberculosis and anti-virus can effectively control tuberculosis and improve the immunity of HIV patients.%目的:探讨抗病毒联合抗结核药物在艾滋病合并肺结核患者治疗中应用效果。方法:收治艾滋病合并肺结核患者32例,采用AZT+NVP+DDI抗病毒方案治疗及2H3R3Z3E3/7H3R3抗结核方案治疗,比较治疗效果。结果:23例HIV/AIDS/TB双重感染患中,15例临床治愈,5例完成1个疗程,3例胸片提示病灶吸收好转继续服药。治疗6个月、9个月的CD4+T淋巴细胞计数较治疗前均有明显提高(P<0.05)。结论:该抗结核抗病毒双重抗感染治疗方案,可达到有效控制结核病,提高HIV患者免疫力。

  15. Mechanisms of drug action and resistance in Mycobacterium tuberculosis%抗结核药物的作用机制及结核分枝杆菌的耐药机理

    Institute of Scientific and Technical Information of China (English)

    张颖; 徐顺清; 李传友

    2004-01-01

    Tuberculosis (TB) is a global health problem that poses increasing threat with the spread of HIV infection and drug resistant strains of Mycobacterium tuberculosis. Effective control of TB remains a significant challenge despite the availability of chemotherapy and BCG vaccine. The emergence of strains of M. tuberculosis resistant to multiple anti-tuberculosis drugs is increasing due to inadequate compliance to the lengthy TB therapy and presents a significant problem for the treatment. In order to combat the threat of drug resistant tuberculosis and to more effectively control the disease, an understanding of the mechanisms underlying drug resistance is necessary. Mechanisms of action and resistance of major anti-tuberculosis drugs are reviewed in this article. This knowledge could be used for the development of molecular tests for rapid detection of drug resistant strains and for the design of new anti-tuberculosis drugs.%结核病是一个严重的全球性疾病,随着艾滋病病毒及耐药结核菌的出现及播散成为结核病控制的又一个威胁.虽然我们有结核疫苗及抗结核药物.但控制结核病仍是一件很棘手的事情.多重耐药结核菌的不断出现给结核病的治疗带来很大的困难.为有效控制耐药结核病.我们必须了解结核菌的耐药机理.本文讨论了抗结核药物的作用机制及结核菌的耐药机理.结核菌耐药机理的阐明对耐药菌的快速分子诊断及新药的开发有重要的意义.

  16. Clinical and operational value of the extensively drug-resistant tuberculosis definition.

    Science.gov (United States)

    Migliori, G B; Besozzi, G; Girardi, E; Kliiman, K; Lange, C; Toungoussova, O S; Ferrara, G; Cirillo, D M; Gori, A; Matteelli, A; Spanevello, A; Codecasa, L R; Raviglione, M C

    2007-10-01

    Currently, no information is available on the effect of resistance/susceptibility to first-line drugs different from isoniazid and rifampicin in determining the outcome of extensively drug-resistant tuberculosis (XDR-TB) patients, and whether being XDR-TB is a more accurate indicator of poor clinical outcome than being resistant to all first-line anti-tuberculosis (TB) drugs. To investigate this issue, a large series of multidrug-resistant TB (MDR-TB) and XDR-TB cases diagnosed in Estonia, Germany, Italy and the Russian Federation during the period 1999-2006 were analysed. Drug-susceptibility testing for first- and second-line anti-TB drugs, quality assurance and treatment delivery was performed according to World Health Organization recommendations in all study sites. Out of 4,583 culture-positive TB cases analysed, 361 (7.9%) were MDR and 64 (1.4%) were XDR. XDR-TB cases had a relative risk (RR) of 1.58 to have an unfavourable outcome compared with MDR-TB cases resistant to all first-line drugs (isoniazid, rifampicin ethambutol, streptomycin and, when tested, pyrazinamide), and an RR of 2.61 compared with "other" MDR-TB cases (those susceptible to at least one first-line anti-TB drug among ethambutol, pyrazinamide and streptomycin, regardless of resistance to the second-line drugs not defining XDR-TB). The emergence of extensively drug-resistant tuberculosis confirms that problems in tuberculosis management are still present in Europe. While waiting for new tools which will facilitate management of extensively drug-resistant tuberculosis, accessibility to quality diagnostic and treatment services should be urgently ensured and adequate public health policies should be rapidly implemented to prevent further development of drug resistance.

  17. 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.

  18. Multidrug-resistant and extensively drug-resistant tuberculosis in multi-ethnic region, Xinjiang Uygur Autonomous Region, China.

    Directory of Open Access Journals (Sweden)

    Ying-Cheng Qi

    Full Text Available BACKGROUND: The multidrug-resistant (MDR and extensively drug-resistant (XDR tuberculosis (TB has emerged as a global threat. Xinjiang is a multi-ethnic region and suffered second highest incidence of TB in China. However, epidemiological information on MDR and XDR TB is scarcely investigated. METHODOLOGY/PRINCIPAL FINDINGS: A prospective study was conducted to analyze the prevalence of MDR and XDR TB and the differences of drug resistance TB between Chinese Han and other nationalities population at Chest Hospital of Xinjiang Uygur Autonomous Region, China. We performed in vitro drug susceptibility testing of Mycobacterium tuberculosis to first- and second-line anti-tuberculosis drugs for all 1893 culture confirmed positive TB cases that were diagnosed between June 2009 and June 2011. Totally 1117 (59.0%, 95% CI, 56.8%-61.2% clinical isolates were resistant to ≥1 first-line drugs; the prevalence of MDR TB was 13.2% (95% CI, 11.7%-14.7%, of which, 77 (30.8%; 95% CI, 25.0%-36.6% and 31 (12.8%; 95% CI, 8.6%-17.0% isolates were pre-XDR and XDR TB respectively. Among the MDR/XDR TB, Chinese Han patients were significantly less likely to be younger with an odds ratio 0.42 for age 20-29 years and 0.52 for age 40-49 years; P(trend = 0.004, and Chinese Han patients has a lower prevalence of XDR TB (9.6% than all the other nationality (14.9%. CONCLUSIONS/SIGNIFICANCE: The burden of drug resistance TB cases is sizeable, which highlights an urgent need to reinforce the control, detection and treatment strategies for drug resistance TB. However, the difference of MDR and XDR TB between Chinese Han and other nationalities was not observed.

  19. Drug resistance pattern ofMycobacterium tuberculosis isolates from patients of five provinces of Iran

    Institute of Scientific and Technical Information of China (English)

    Mohammad Javad Nasiri; Faranak Rezaei; Samin Zamani; Davod Darban-Sarokhalil; Abbas Ali Imani Fooladi; Hasan Shojaei; Mohammad Mehdi Feizabadi

    2014-01-01

    Objective:To determine the patterns of resistance to first line anti-tuberculosis(TB) drugs among a collection ofMycobacterium tuberculosis(MTB) isolates from5 provinces ofIran. Methods:A total of the6426 clinical specimens from patients suspected of activeTB were collected fromMarch2010 toJune2012.All specimens were subjected for microscopy and culture tests in theTB centers of studies provinces.Drug susceptibility testing to the first line anti-TB drugs for culture positiveMTB was performed onLöwenstein-Jensen(LJ) medium using proportion method.Results:Of6426 clinical specimens,261 were culture positive for mycobacteria, of which252 wereMTB and9 wereMOTT(mycobacteria other than tuberculosis). Of252MTB isolates,211(83.7%) were pan-susceptible and41(16.3%) were resistant to at least one drug.Resistance was most common to streptomycin,30 isolates(12.0%), followed by isoniazid,20 isolates(8.0%), rifampin,15 isolates(6.0%) and ethambutol,14 isolates(5.5%).Sixteen(6.3%)MTB isolates wereMDR.A clear evidence of heterogeneity amongst the5 provinces in the proportions with resistance to one or more drugs was observed [χ² =12.209(4 degrees of freedom),P values =0.0159].Conclusions:The prevalence of drug resistance in this study area underscoring the need for further enforcement ofTB control strategies in theIran.Drug susceptibility testing for allTB cases to provide optimal treatment, establishing advanced diagnostic facilities for rapid detection ofMDR-TB and continuous monitoring of drug resistance are recommended for prevention and control of drug-resistantTB.

  20. Drug-resistant tuberculous meningitis.

    Science.gov (United States)

    Garg, Ravindra K; Jain, Amita; Malhotra, Hardeep S; Agrawal, Avinash; Garg, Rajiv

    2013-06-01

    Drug-resistant tuberculosis, including drug-resistant tuberculous meningitis, is an emerging health problem in many countries. An association with Beijing strains and drug resistance-related mutations, such as mutations in katG and rpoB genes, has been found. The pathology, clinical features and neuroimaging characteristics of drug-resistant tuberculous meningitis are similar to drug-responsive tuberculous meningitis. Detection of mycobacteria in cerebrospinal fluid (CSF) by conventional methods (smear examination or culture) is often difficult. Nucleic acid amplification assays are better methods owing to their rapidity and high sensitivity. The Xpert MTB/RIF assay (Cepheid, CA, USA) is a fully-automated test that has also been found to be effective for CSF samples. Treatment of multidrug-resistant tuberculous meningitis depends on the drug susceptibility pattern of the isolate and/or the previous treatment history of the patient. Second-line drugs with good penetration of the CSF should be preferred. Isoniazid monoresistant disease requires addition of another drug with better CSF penetration. Drug-resistant tuberculous meningitis is associated with a high mortality. HIV infected patients with drug-resistant tuberculous meningitis have severe clinical manifestations with exceptionally high mortality. Prevention of tuberculosis is the key to reduce drug-resistant tuberculous meningitis.

  1. Factors associated with anti-tuberculosis medication adverse effects: a case-control study in Lima, Peru.

    Directory of Open Access Journals (Sweden)

    Kocfa Chung-Delgado

    Full Text Available BACKGROUND: Long-term exposure to anti-tuberculosis medication increases risk of adverse drug reactions and toxicity. The objective of this investigation was to determine factors associated with anti-tuberculosis adverse drug reactions in Lima, Peru, with special emphasis on MDR-TB medication, HIV infection, diabetes, age and tobacco use. METHODOLOGY AND RESULTS: A case-control study was performed using information from Peruvian TB Programme. A case was defined as having reported an anti-TB adverse drug reaction during 2005-2010 with appropriate notification on clinical records. Controls were defined as not having reported a side effect, receiving anti-TB therapy during the same time that the case had appeared. Crude, and age- and sex-adjusted models were calculated using odds ratios (OR and 95% confidence intervals (95%CI. A multivariable model was created to look for independent factors associated with side effect from anti-TB therapy. A total of 720 patients (144 cases and 576 controls were analyzed. In our multivariable model, age, especially those over 40 years (OR = 3.93; 95%CI: 1.65-9.35, overweight/obesity (OR = 2.13; 95%CI: 1.17-3.89, anemia (OR = 2.10; IC95%: 1.13-3.92, MDR-TB medication (OR = 11.1; 95%CI: 6.29-19.6, and smoking (OR = 2.00; 95%CI: 1.03-3.87 were independently associated with adverse drug reactions. CONCLUSIONS: Old age, anemia, MDR-TB medication, overweight/obesity status, and smoking history are independent risk factors associated with anti-tuberculosis adverse drug reactions. Patients with these risk factors should be monitored during the anti-TB therapy. A comprehensive clinical history and additional medical exams, including hematocrit and HIV-ELISA, might be useful to identify these patients.

  2. Alarming levels of drug-resistant tuberculosis in Belarus: results of a survey in Minsk.

    Science.gov (United States)

    Skrahina, Alena; Hurevich, Henadz; Zalutskaya, Aksana; Sahalchyk, Evgeni; Astrauko, Andrei; van Gemert, Wayne; Hoffner, Sven; Rusovich, Valiantsin; Zignol, Matteo

    2012-06-01

    Resistance to anti-tuberculosis (TB) medicines is a major public health threat in most countries of the former Soviet Union. As no representative and quality-assured information on the magnitude of this problem existed in Belarus, a survey was conducted in the capital city of Minsk. Between November 2009 and December 2010, 156 consecutively diagnosed new and 68 previously treated culture-positive TB patients residing in Minsk were enrolled in the survey. Mycobacterium tuberculosis isolates were obtained from each patient and tested for susceptibility to first- and second-line anti-TB drugs. Multidrug-resistant (MDR)-TB was found in 35.3% (95% CI 27.7-42.8) of new patients and 76.5% (95% CI 66.1-86.8) of those previously treated. Overall, nearly one in two patients enrolled had MDR-TB. Extensively drug-resistant TB was reported in 15 of the 107 MDR-TB patients (14.0%, 95% CI 7.3-20.7). Patients 35 yrs. The findings of this survey in Minsk city are alarming and represent the highest proportions of MDR-TB ever recorded in the world. This study greatly contributes to the understanding of the burden of drug-resistant TB in urban areas of Belarus.

  3. Gene chip array for differentiation of mycobacterial species and detection of drug resistance

    Institute of Scientific and Technical Information of China (English)

    SHI Xiao-chun; LIU Xiao-qing; XIE Xiu-li; XU Ying-chun; ZHAO Zhi-xian

    2012-01-01

    Background Gene chip array can differentiate isolated mycobacterial strains using vadous mycobacterium specific probes simultaneously.Gene chip array can evaluate drug resistance to isoniazid and rifampin of tuberculosis strains by detecting drug resistance related gene mutation.This technique has great potential for clinical application.We performed a retrospective study to investigate the capability of gene chip array in the rapid differentiation of species and detection of drug resistance in mycobacterium,and to evaluate its clinical efficacy.Methods We selected 39 patients (54 clinical mycobacterium isolates),used gene chip array to identify the species of these isolates and detect drug resistance to isoniazid and rifampin in Mycobacterium tuberculosis isolates.Meanwhile,these patients' clinical data were analyzed retrospectively.Results Among these 39 patients whose mycopacterium culture were positive,32 patients' isolates were identified as Mycobacterium tubercu/osis, all of them were clinical infection. Seven patients' isolates were identified as non-tuberculosis mycobacterium.Analyzed with their clinical data,only two patients were considered as clinical infection,both of them were diagnosed as hematogenous disseminated Mycobacterium introcellulare infection.The other five patients' isolates were of no clinical significance; their clinical samples were all respiratory specimens.Clinical manifestations of tuberculosis and non-tuberculous mycobacterial infections were similar.Isoniazid resistance was detected in two tuberculosis patients,while rifampin resistance was detected in one tuberculosis patient; there was another patient whose Mycobacterium tuberculosis isolate was resistant to both isoniazid and rifampin (belongs to multidrug resistance tuberculosis).The fact that this patient did not respond to routine anti-tuberculosis chemotherapy also confirmed this result.Conclusions Gene chip array may be a simple,rapid,and reliable method for the

  4. Mechanisms of drug resistance: quinolone resistance.

    Science.gov (United States)

    Hooper, David C; Jacoby, George A

    2015-09-01

    Quinolone antimicrobials are synthetic and widely used in clinical medicine. Resistance emerged with clinical use and became common in some bacterial pathogens. Mechanisms of resistance include two categories of mutation and acquisition of resistance-conferring genes. Resistance mutations in one or both of the two drug target enzymes, DNA gyrase and DNA topoisomerase IV, are commonly in a localized domain of the GyrA and ParE subunits of the respective enzymes and reduce drug binding to the enzyme-DNA complex. Other resistance mutations occur in regulatory genes that control the expression of native efflux pumps localized in the bacterial membrane(s). These pumps have broad substrate profiles that include quinolones as well as other antimicrobials, disinfectants, and dyes. Mutations of both types can accumulate with selection pressure and produce highly resistant strains. Resistance genes acquired on plasmids can confer low-level resistance that promotes the selection of mutational high-level resistance. Plasmid-encoded resistance is due to Qnr proteins that protect the target enzymes from quinolone action, one mutant aminoglycoside-modifying enzyme that also modifies certain quinolones, and mobile efflux pumps. Plasmids with these mechanisms often encode additional antimicrobial resistances and can transfer multidrug resistance that includes quinolones. Thus, the bacterial quinolone resistance armamentarium is large.

  5. A case of isoniazid-resistant miliary tuberculosis in which tuberculous meningitis paradoxically developed despite systemic improvement.

    Science.gov (United States)

    Ikegame, Satoshi; Wakamatsu, Kentaro; Fujita, Masaki; Nakanishi, Yoichi; Harada, Mine; Kajiki, Akira

    2011-10-01

    A 63-year-old man with chronic myelomonocytic leukemia was admitted to our hospital with miliary tuberculosis. He received anti-tuberculosis drugs: isoniazid (INH), rifampicin (RFP), ethambutol (EB), and pyrazinamide (PZA). His condition clearly and immediately improved after the therapy, but he experienced a high fever of about 38°C every day from 1 month after the initiation of the therapy. Drug-induced fever and tumor fever were suspected as causes, but the etiology could not be determined. The tuberculosis was identified as an INH-resistant strain, so INH was stopped and levofloxacin (LVFX) was introduced, with streptomycin (SM), in addition to RFP, EB, and PZA. At 2 months after the initiation of the therapy (about one week after the change in the anti-tuberculosis drug regimen), his spinal fluid was examined, given his complaints of headache and vomiting. The spinal fluid analysis revealed invasion of lymphocytic inflammatory cells and high adenosine deaminase activity; the patient was thus diagnosed with tuberculous meningitis. His condition gradually improved after the changing of the anti-tuberculosis drugs. Thus, to summarize, the tuberculous meningitis had worsened paradoxically despite his systemic improvement, although it was successfully treated by the addition of LVFX and SM. We must keep in mind that a potential cause of fever during anti-tuberculosis therapy may be INH-resistant tuberculous meningitis.

  6. Characterization of RPO B gene for detection of rifampicin drug resistance by SSCP and sequence analysis

    Directory of Open Access Journals (Sweden)

    Negi S

    2009-01-01

    Full Text Available Purpose: Because of the emergence of multidrug-resistant tuberculosis in recent times, the rapid detection of resistance to the first-line anti-tuberculosis drug rifampicin was felt worldwide. Accordingly, this study was conducted to evaluate the diagnostic potential of polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP for checking its utility as a rapid screening test for determination of rifampicin drug resistance. Materials and Methods: A total of 34 isolates of Mycobacterium tuberculosis ( M. tuberculosis (22 rifampicin resistant, 11 rifampicin sensitive and one control H37Rv strains were analysed by PCR-SSCP and DNA sequencing within the 157-bp region of the rpo B gene (Ala 500 -Val 550 . Results: Rifampicin resistance was detected successfully by PCR-SSCP in 20/22(90.90% of rifampicin-resistant strains showing a total of nine different mutations in seven codon positions: codon 513 (CAA→CCA, 516 (GAC→GTC, 507 (GGC→GAC, 526 (CAC→GAC, TAC, 531 (TCG→TTG, TGG, 522 (TCG→TGG and 533 (GTG→CCG. Two rifampicin-resistant strains showed an identical PCR-SSCP pattern with the wild type H37Rv; 77.27% rifampicin-resistant strains showed a single point mutation and 9.09% had no mutation. Three rifampicin-resistant strains showed characteristic double mutations at codon positions 526 and 531. Sensitivity and specificity were calculated as 90.90% and 100%. Conclusions: Rifampicin-resistant genotypes were mainly found in codon positions 516, 526 and 531. PCR-SSCP seems to be an efficacious method of predicting rifampicin resistance and substantially reduces the time required for susceptibility testing from 4 to 6 weeks to a few weeks.

  7. 治疗剂量下4种抗结核药物与Caco-2细胞上P-gp相互作用研究%Initial Study on Interaction between Therapeutic Doses of Four Anti-Tuberculosis Drugs and P-Glycoprotein in Caco-2 Cells

    Institute of Scientific and Technical Information of China (English)

    方平飞; 高维; 李焕德; 刘艺平

    2011-01-01

    目的 研究治疗剂量下4种抗结核药物(异烟肼、左氧氟沙星、乙胺丁醇、吡嗪酰胺)对Caco-2细胞上P-糖蛋白功能、表达及MDR1 mRNA表达的影响,从而解释联合抗痨治疗中不同组合的合理性.方法 采用流式细胞仪测定细胞内罗丹明-123的浓度,考察药物对P-糖蛋白功能的影响,流式细胞术分析药物对Caco-2细胞上P-糖蛋白表达的影响,实时荧光定量PCR技术分析药物对Caco-2细胞MDRI基因mRNA水平表达的影响.结果 含药培养20 d后,异烟肼和乙胺丁醇减少了罗丹明-123在Caco-2细胞内的蓄积(P<0.05),为诱导作用;异烟肼、乙胺丁醇均上调了Caco-2细胞上P-糖蛋白的表达(P<0.05),其P-糖蛋白表达量分别为阴性对照组的3.5和3.8倍;同时上调了Caco-2细胞上MDR1 mRNA的表达(P<0.05),其MDRImRNA的表达量分别为阴性对照组的11.5和11倍.左氧氟沙星增加了罗丹明-123在Caco-2细胞内的蓄积(P<0.05),为抑制作用;下调了Caco-2细胞上P-糖蛋白和MDR1 mRNA的表达(P<0.05),其P-糖蛋白和MDR1 mRNA表达量分别为阴性对照组的50%和32%.而吡嗪酰胺与P-糖蛋白无明显相互作用.结论 治疗剂量的异烟肼和乙胺丁醇为P-糖蛋白的诱导剂,左氧氟沙星为P-糖蛋白的抑制剂,而吡嗪酰胺对P-糖蛋白功能和表达无明显影响.%OBJECTIVE To study the effects of four anti-tuberculosis drugs on the function and expression of P-glycoprotein and the MDR1 mRNA expression, for explaining the rationality of different combination in anti-tuberculosis chemotherapy. METHODS The effect of the drugs on P-glycoprotein function was analyzed using Rh-123 assay. The flow cytometry was used to determine the intracellular Rh-123 concentration and the expression of P-glycoprotein in Caco-2 cells. Real-time fluorescent quantitative polymerase chain reaction was used to measure the expression of MDR1 gene mRNA in Caco-2 cells. RESULTS After the intervention for 20 d, the

  8. Primary drug-resistant tuberculosis in Hanoi, Viet Nam: present status and risk factors.

    Directory of Open Access Journals (Sweden)

    Nguyen Thi Le Hang

    Full Text Available INTRODUCTION: Resistance of Mycobacterium tuberculosis (MTB to anti-tuberculosis (TB drugs presents a serious challenge to TB control worldwide. We investigated the status of drug resistance, including multidrug-resistant (MDR TB, and possible risk factors among newly diagnosed TB patients in Hanoi, the capital of Viet Nam. METHODS: Clinical and epidemiological information was collected from 506 newly diagnosed patients with sputum smear- and culture-positive TB, and 489 (96.6% MTB isolates were subjected to conventional drug susceptibility testing, spoligotyping, and 15-locus variable numbers of tandem repeats typing. Adjusted odds ratios (aORs were calculated to analyze the risk factors for primary drug resistance. RESULTS: Of 489 isolates, 298 (60.9% were sensitive to all drugs tested. Resistance to isoniazid, rifampicin, streptomycin, ethambutol, and MDR accounted for 28.2%, 4.9%, 28.2%, 2.9%, and 4.5%, respectively. Of 24 isolates with rifampicin resistance, 22 (91.7% were MDR and also resistant to streptomycin, except one case. Factors associated with isoniazid resistance included living in old urban areas, presence of the Beijing genotype, and clustered strains [aOR = 2.23, 95% confidence interval (CI 1.15-4.35; 1.91, 1.18-3.10; and 1.69, 1.06-2.69, respectively. The Beijing genotype was also associated with streptomycin resistance (aOR = 2.10, 95% CI 1.29-3.40. Human immunodeficiency virus (HIV coinfection was associated with rifampicin resistance and MDR (aOR = 5.42, 95% CI 2.07-14.14; 6.23, 2.34-16.58, respectively. CONCLUSION: Isoniazid and streptomycin resistance was observed in more than a quarter of TB patients without treatment history in Hanoi. Transmission of isoniazid-resistant TB among younger people should be carefully monitored in urban areas, where Beijing strains and HIV coinfection are prevalent. Choosing an optimal treatment regimen on the basis of the results of drug susceptibility tests and monitoring of treatment

  9. Polyneuropathy, anti-tuberculosis treatment and the role of pyridoxine in the HIV/AIDS era: a systematic review.

    Science.gov (United States)

    van der Watt, J J; Harrison, T B; Benatar, M; Heckmann, J M

    2011-06-01

    Tuberculosis (TB) is increasing in incidence in certain parts of the world, particularly where there is a co-epidemic of human immunodeficiency virus/acquired immune-deficiency syndrome (HIV/AIDS), and it is associated with a significant degree of morbidity and mortality. One of the most common complications of anti-tuberculosis treatment is the development of a painful isoniazid (INH) associated polyneuropathy (PN), which is preventable with adequate pyridoxine supplementation. As PN is also the most frequent neurological complication associated with HIV infection, subjects who are HIV and TB co-infected may be at increased risk of developing PN. In this review, we explore current knowledge of anti-tuberculosis drug associated PN focusing on INH and its relationship to pyridoxine, as well as the additional impact of antiretroviral treatment and TB-HIV co-infection. It is evident that guidelines established for the prevention and treatment of this problem differ between industrialised and developing countries, and that further research is needed to define the optimum dosing of pyridoxine supplementation in populations where there is a significant burden of TB and HIV.

  10. 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.

  11. Bioautography with TLC-MS/NMR for Rapid Discovery of Anti-tuberculosis Lead Compounds from Natural Sources.

    Science.gov (United States)

    Grzelak, Edyta M; Hwang, Changhwa; Cai, Geping; Nam, Joo-Won; Choules, Mary P; Gao, Wei; Lankin, David C; McAlpine, James B; Mulugeta, Surafel G; Napolitano, José G; Suh, Joo-Won; Yang, Seung Hwan; Cheng, Jinhua; Lee, Hanki; Kim, Jin-Yong; Cho, Sang-Hyun; Pauli, Guido F; Franzblau, Scott G; Jaki, Birgit U

    2016-04-08

    While natural products constitute an established source of lead compounds, the classical iterative bioassay-guided isolation process is both time- and labor-intensive and prone to failing to identify active minor constituents. (HP)TLC-bioautography-MS/NMR, which combines cutting-edge microbiological, chromatographic, and spectrometric technologies, was developed to accelerate anti-tuberculosis (TB) drug discovery from natural sources by acquiring structural information at a very early stage of the isolation process. Using the avirulent, bioluminescent Mtb strain mc(2)7000 luxABCDE, three variations of bioautography were evaluated and optimized for sensitivity in detecting anti-TB agents, including established clinical agents and new leads with novel mechanisms of action. Several exemplary applications of this approach to microbial extracts demonstrate its potential as a routine method in anti-TB drug discovery from natural sources.

  12. Preparation, characterization, and in vitro cytotoxicity evaluation of a novel anti-tuberculosis reconstruction implant.

    Directory of Open Access Journals (Sweden)

    JunFeng Dong

    Full Text Available BACKGROUND: Reconstruction materials currently used in clinical for osteoarticular tuberculosis (TB are unsatisfactory due to a variety of reasons. Rifampicin (RFP is a well-known and highly effective first-line anti-tuberculosis (anti-TB drug. Poly-DL-lactide (PDLLA and nano-hydroxyapatite (nHA are two promising materials that have been used both for orthopedic reconstruction and as carriers for drug release. In this study we report the development of a novel anti-TB implant for osteoarticular TB reconstruction using a combination of RFP, PDLLA and nHA. METHODS: RFP, PDLLA and nHA were used as starting materials to produce a novel anti-TB activity implant by the solvent evaporation method. After manufacture, the implant was characterized and its biodegradation and drug release profile were tested. The in vitro cytotoxicity of the implant was also evaluated in pre-osteoblast MC3T3-E1 cells using multiple methodologies. RESULTS: A RFP/PDLLA/nHA composite was successfully synthesized using the solvent evaporation method. The composite has a loose and porous structure with evenly distributed pores. The production process was steady and no chemical reaction occurred as proved by Fourier Transform Infrared Spectroscopy (FTIR and X-Ray Diffraction (XRD. Meanwhile, the composite blocks degraded and released drug for at least 12 weeks. Evaluation of in vitro cytotoxicity in MC3T3-E1 cells verified that the synthesized composite blocks did not affect cell growth and proliferation. CONCLUSION: It is feasible to manufacture a novel bioactive anti-TB RFP/PDLLA/nHA composite by the solvent evaporation method. The composite blocks showed appropriate properties such as degradation, drug release and biosafety to MC3T3-E1 cells. In conclusion, the novel composite blocks may have great potential for clinical applications in repairing bone defects caused by osteoarticular TB.

  13. 14C-urea breath test in patients undergoing anti-tuberculosis therapy

    Institute of Scientific and Technical Information of China (English)

    Sayed Amir Mirbagheri; Amir Ali Sohrabpour; Mehrdad Hasibi; Babak Moghimi; Mehdi Mohamadnejad

    2005-01-01

    AIM: Urea breath test (UBT) is a non-invasive diagnostic test for detecting the presence of Helicobacter pylori(H pylori).In this study we evaluated the effect of anti-tuberculosis therapy on the results of 14C-UBT.METHODS: Patients, with the diagnosis of tuberculosis (TB) who had a positive UBT at the point of starting antiTB therapy, were included. None had a history of peptic ulcer disease or had taken antibiotics, bismuth compounds and/or PPI in the previous month, 14C-UBT was repeated at the end of the second month and the end of treatment period and one month after completion of treatment course.RESULTS: Thirty-five patients (23 males) were enrolled.14C-UBT was negative in all 35 patients (100%) at the end of the second month and remained negative in 30cases (85.7%) at the end of the treatment course. One month after completion of treatment course, UBT remained negative in 13 patients (37.1%).CONCLUSION: Our report underscores the need for caution while interpreting urea breath test results in patients undergoing anti-TB therapy. Furthermore, the combination of drugs used in this study resulted in H pylori eradication in a minority of patients.

  14. Mutation in katG315 is, possibly, a good prognostic marker for treatment with second-line drugs in multi-drug resistant tuberculosis: a preliminary study.

    Science.gov (United States)

    Ahmed, Mohanad M; Mohammed, Suhad H; Nasurallah, Hassan A A

    2013-01-01

    The aim of this study was to explore baseline data, laboratory and molecular analyses to determine if any could serve as potential prognostic marker(s) for treatment response to second line tuberculosis regimens. Of a total number of 50 multi-drug resistant tuberculosis (MDR-TB) patients starting second-line drug MDR-TB treatment in Iraq, only 21 showed treatment adherence and thus, included in this study. Response to treatment was monitored for 11 months by sputum microscopy and culture. We explored baseline data, laboratory and molecular analyses to determine if any could serve as potential prognostic marker(s) for treatment response. Highly significant association (P = 0.019) was detected between mutations in katG315 codon and good response to second-line anti-TB drugs. Spoligotyping and mycobacterial interspersed repetitive unit variable number tandem repeat confirmed that katG315-mutatnt isolates were genotypically unrelated. The katG315 mutation is a potential prognostic marker for treatment response to second-line anti-tuberculosis drugs. One possible explanation of our results is that the katG315-mutants are sensitive to bacterial killing by "oxidative killing.".

  15. Treatment effect of anti-tuberculosis drug-resistance and multi-drug resistance of TB inpatients%柳州市肺结核病人耐药状况与疗效分析

    Institute of Scientific and Technical Information of China (English)

    吕康言; 廖光富

    2006-01-01

    目的了解结核病医院住院病人的耐药及耐多药结核病(MDR-TB)流行情况、流行特点及影响因素.方法对2001年11月至2004年8月在广西龙潭医院住院治疗痰结核菌培养阳性病人用临床流行病学方法进行统计和分析.结果耐药率为26.7%,耐H20.5%,R17.5,S10.7%和E8.3%,MDR-TB13.5%,初始MDR-TB为1.93%,继发MDR-TB为11.1%,MDR-TB死亡率为9.1%.结论耐药及MDR-TB发病率逐年增加,死亡率高,应加强肺结核病人的治疗管理.

  16. Lessons from history of socioeconomic improvements: a new approach to treating multi-drug-resistant tuberculosis.

    Science.gov (United States)

    Holloway, K L; Staub, K; Rühli, F; Henneberg, M

    2014-09-01

    This study investigated the trends in tuberculosis mortality through time in Switzerland. Information on the decline in mortality before chemotherapies were introduced may be useful in developing countries where drug-resistant tuberculosis is now becoming a major problem. Swiss data were collected from historical records and comparative data were obtained from the literature for England and Wales, New York, Japan, Brazil and Sierra Leone. Logistic curves were fitted to examine the rate of decline before introduction of pharmacotherapies and these show that the decline would have continued without the introduction of chemical therapies, including antibiotics. In Switzerland, England and Wales and New York, the decline had occurred long before the introduction of specific anti-tuberculosis agents. In Brazil and Japan, chemical therapy was co-incident with the decline in tuberculosis mortality rates. Overall, it is suggested that the effective control of tuberculosis can be achieved through a combination of chemical interventions, conservative therapy (rest, good nutrition, ventilation, etc.) as well as public health interventions addressing hygiene, nutrition, reducing exposure to infections and educating the population about tuberculosis.

  17. Study on the relationship between the gene polymorphisms of cytochrome P450 1A1 or glutathione transferase P1 and anti-tuberculosis drug-induced liver injury%CYP1 A1和 GSTP1基因多态性与抗结核药物性肝损伤的关系

    Institute of Scientific and Technical Information of China (English)

    贺蕾; 高丽; 史哲; 李世明; 张朋; 郑国颖; 李云; 胡泊; 冯福民

    2015-01-01

    Objective To retrospectively investigate the relationship be-tween the gene polymorphisms of cytochrome P450 1 A1 \\glutathione transferase P1 ( CYP1 A1 or GSTP1 ) and anti -tuberculosis drug -induced liver injury ( ADLI).Methods Total 127 cases and 127 con-trols were collected in 1∶1 match.Their exposure data of data and blood samples were collected. The genotypes were detected by polymerase chain reaction and restriction fragment length polymorphism technique ( PCR -RFLP ) method SPSS 17.0 software was used to do Logistic regression analysis on environmental factors and genotype univariate and multivariate analysis.Results The allele frequencies of gene CYP1 A1 genes in two groups had no statistical difference.While the frequencies of AA, AG and GG genotypes at Ile105 Val site of GSTP1 gene were 55.91%, 32.28%, 11.81% in case group and 70.08%, 26.77%, 3.15%in control group.The analysis demonstrated that the frequencies of GSTP1 gene Ile105 Val genotypes in case group were significantly higher than those in control group ( P<0.05 ) .Univariate Logistic re-gression analysis showed that alcohol was the risk factor of ADLI, and after the regulation of certain factor in multivariate analysis, the GG genotype at Ile105 Val site of GSTP1 gene was still the risk factor of ADLI.Conclusion The polymorphim of Ile105 Val site of GSTP1 gene is correlated with the occur-rence of ADLI and GG carriers are considered as risk population.%目的:分析细胞色素P4501A1(CYP1A1)和谷胱甘肽转移酶P1(GSTP1)基因多态性与抗结核药物性肝损伤( ADLI )的相关性。方法抗结核治疗致肝损伤的结核病患者127例为病例组,127例无肝损伤者为对照组,收集其环境因素暴露资料及静脉血。 CYP1A1基因Msp I位点和GSTP1基因 Ile105 Val位点多态性检测用聚合酶链反应限制性片段长度多态法( PCR-RFLP )。用SPSS 17.0软件对环境因素和基因型进行单因素和多因素条件Logistic

  18. Prevention of hepatotoxicity due to anti tuberculosis treatment: A novel integrative approach

    Institute of Scientific and Technical Information of China (English)

    Meghna R Adhvaryu; Narsimha M Reddy; Bhasker C Vakharia

    2008-01-01

    AIM: To evaluate the ability of Curcuma longa (CL) and Tinospora cordifolia (TC) formulation to prevent anti-tuberculosis (TB) treatment (ATT) induced hepatotoxicity.METHODS: Patients with active TB diagnosis were randomized to a drug control group and a trial group on drugs plus an herbal formulation.Isoniazid,rifampicin,pyrazinamide and ethambutol for first 2 mo followed by continuation phase therapy excluding Pyrazinamide for 4 mo comprised the anti-tuberculous treatment.Curcumin enriched (25%) CL and a hydro-ethanolic extract enriched (50%) TC 1 g each divided in two doses comprised the herbal adjuvant.Hemogram,bilirubin and liver enzymes were tested initially and monthly till the end of study to evaluate the result.RESULTS: Incidence and severity of hepatotoxicity was significantly lower in trial group (incidence: 27/192 vs 2/316,P < 0.0001).Mean aspartate transaminase (AST) (195.93 ± 108.74 vs 85 ± 4.24,P < 0.0001),alanine transaminase (ALT) (75.74 ± 26.54 vs 41 ±1.41,P < 0.0001) and serum bilirubin (5.4 ± 3.38 vs 1.5± 0.42,P < 0.0001).A lesser sputum positivity ratio at the end of 4 wk (10/67 vs 4/137,P = 0.0068) and decreased incidence of poorly resolved parenchymal lesion at the end of the treatment (9/152 vs 2/278,P = 0.0037) was observed.Improved patient compliance was indicated by nil drop-out in trial vs 10/192 in control group (P < 0.0001).CONCLUSION: The herbal formulation prevented hepatotoxicity significantly and improved the disease outcome as well as patient compliance without any toxicity or side effects.

  19. Drug resistance mechanisms and novel drug targets for tuberculosis therapy.

    Science.gov (United States)

    Islam, Md Mahmudul; Hameed, H M Adnan; Mugweru, Julius; Chhotaray, Chiranjibi; Wang, Changwei; Tan, Yaoju; Liu, Jianxiong; Li, Xinjie; Tan, Shouyong; Ojima, Iwao; Yew, Wing Wai; Nuermberger, Eric; Lamichhane, Gyanu; Zhang, Tianyu

    2017-01-20

    Drug-resistant tuberculosis (TB) poses a significant challenge to the successful treatment and control of TB worldwide. Resistance to anti-TB drugs has existed since the beginning of the chemotherapy era. New insights into the resistant mechanisms of anti-TB drugs have been provided. Better understanding of drug resistance mechanisms helps in the development of new tools for the rapid diagnosis of drug-resistant TB. There is also a pressing need in the development of new drugs with novel targets to improve the current treatment of TB and to prevent the emergence of drug resistance in Mycobacterium tuberculosis. This review summarizes the anti-TB drug resistance mechanisms, furnishes some possible novel drug targets in the development of new agents for TB therapy and discusses the usefulness using known targets to develop new anti-TB drugs. Whole genome sequencing is currently an advanced technology to uncover drug resistance mechanisms in M. tuberculosis. However, further research is required to unravel the significance of some newly discovered gene mutations in their contribution to drug resistance.

  20. High isoniazid resistance rates in rifampicin susceptible Mycobacterium tuberculosis pulmonary isolates from Pakistan.

    Directory of Open Access Journals (Sweden)

    Naima Fasih

    Full Text Available BACKGROUND: Rapid new diagnostic methods (including Xpert MTB/RIF assay use rifampicin resistance as a surrogate marker for multidrug resistant tuberculosis. Patients infected with rifampicin susceptible strains are prescribed first line anti-tuberculosis therapy. The roll out of such methods raises a concern that strains with resistance to other first line anti-tuberculosis drugs including isoniazid will be missed and inappropriate treatment given. To evaluate implications of using such methods review of resistance data from high burden settings such as ours is essential. OBJECTIVE: To determine resistance to first line anti-tuberculosis drugs amongst rifampicin susceptible pulmonary Mycobacterium tuberculosis (MTB isolates from Pakistan. MATERIALS AND METHODS: Data of pulmonary Mycobacterium tuberculosis strains isolated in Aga Khan University Hospital (AKUH laboratory (2009-2011 was retrospectively analyzed. Antimicrobial susceptibility profile of rifampicin susceptible isolates was evaluated for resistance to isoniazid, pyrazinamide, ethambutol, and streptomycin. RESULTS: Pulmonary specimens submitted to AKUH from 2009 to 2011 yielded 7738 strains of Mycobacterium tuberculosis. These included 54% (n 4183 rifampicin susceptible and 46% (n: 3555 rifampicin resistant strains. Analysis of rifampicin susceptible strains showed resistance to at least one of the first line drugs in 27% (n:1133 of isolates. Overall isoniazid resistance was 15.5% (n: 649, with an isoniazid mono-resistance rate of 4% (n: 174. Combined resistance to isoniazid, pyrazinamide, and ethambutol was noted in 1% (n: 40, while resistance to isoniazid, pyrazinamide, ethambutol, and streptomycin was observed in 1.7% (n: 70 of strains. CONCLUSIONS: Our data suggests that techniques (including Xpert MTB/RIF assay relying on rifampicin susceptibility as an indicator for initiating first line therapy will not detect patients infected with MTB strains resistant to other first line

  1. Transmission pattern of drug-resistant tuberculosis and its implication for tuberculosis control in eastern rural China.

    Directory of Open Access Journals (Sweden)

    Yi Hu

    Full Text Available OBJECTIVE: Transmission patterns of drug-resistant Mycobacterium tuberculosis (MTB may be influenced by differences in socio-demographics, local tuberculosis (TB endemicity and efficaciousness of TB control programs. This study aimed to investigate the impact of DOTS on the transmission of drug-resistant TB in eastern rural China. METHODS: We conducted a cross-sectional study of all patients diagnosed with drug-resistant TB over a one-year period in two rural Chinese counties with varying lengths of DOTS implementation. Counties included Deqing, with over 11 years' DOTS implementation and Guanyun, where DOTS was introduced 1 year prior to start of this study. We combined demographic, clinical and epidemiologic information with IS6110-based restricted fragment length polymorphism (RFLP and Spoligotyping analysis of MTB isolates. In addition, we conducted DNA sequencing of resistance determining regions to first-line anti-tuberculosis agents. RESULTS: Of the 223 drug-resistant isolates, 73(32.7% isolates were identified with clustered IS6110RFLP patterns. The clustering proportion among total drug-resistant TB was higher in Guanyun than Deqing (26/101.vs.47/122; p,0.04, but not significantly different among the 53 multidrug-resistant isolates (10/18.vs.24/35; p,0.35. Patients with cavitary had increased risk of clustering in both counties. In Guanyun, patients with positive smear test or previous treatment history had a higher clustering proportion. Beijing genotype and isolates resistant to isoniazid and/or rifampicin were more likely to be clustered. Of the 73 patients with clustered drug-resistant isolates, 71.2% lived in the same or neighboring villages. Epidemiological link (household and social contact was confirmed in 12.3% of the clustered isolates. CONCLUSION: Transmission of drug-resistant TB in eastern rural China is characterized by small clusters and limited geographic spread. Our observations highlight the need for supplementing DOTS

  2. Tuberculosis in Australia: bacteriologically confirmed cases and drug resistance, 2007. A report of the Australian Mycobacterium Reference Laboratory Network.

    Science.gov (United States)

    Lumb, Richard; Bastion, Ivan; Carter, Robyn; Jelfs, Peter; Keehner, Terillee; Sievers, Aina

    2009-09-01

    The Australian Mycobacterium Reference Laboratory Network collects and analyses laboratory data on new cases of disease caused by the Mycobacterium tuberculosis complex. In 2007, a total of 872 cases were identified by bacteriology; an annual reporting rate of 4.1 cases per 100,000 population. Isolates were identified as M. tuberculosis (n=867), M. africanum (n=4) and M. bovis (n=1). Fifteen children aged under 10 years had bacteriologically-confirmed tuberculosis. Results of in vitro drug susceptibility testing were available for 871 of 872 isolates for isoniazid (H), rifampicin (R), ethambutol (E), and pyrazinamide (Z). A total of 98 (11.3%) isolates of M. tuberculosis were resistant to at least one of these anti-tuberculosis agents. Resistance to at least H and R (defined as multi-drug resistance, MDR) was detected in 24 (2.8%) isolates, all from overseas-born patients; 17 were from the respiratory tract (sputum n=16, endotracheal aspirate n=1). Thirteen patients with MDR-TB were from the Papua New Guinea-Torres Strait Islands zone. Of the 98 M. tuberculosis isolates resistant to at least one of the standard drugs, 54 (55.1%) were from new cases, 9 (9.2%) from previously treated cases, and no information was available on the remaining 35 cases. Seven were Australian-born, 90 were overseas- born, and the country of birth of 1 was unknown. Of the 90 overseas-born persons with drug resistant disease, 66 (73.3%) were from 5 countries: India (n=16); Papua New Guinea (n=15); the Philippines (n=12); Vietnam (n=12); and China (n=11). No XDR-TB was detected in 2007.

  3. Comparative Proteomic Analysis of Aminoglycosides Resistant and Susceptible Mycobacterium tuberculosis Clinical Isolates for Exploring Potential Drug Targets.

    Science.gov (United States)

    Sharma, Divakar; Kumar, Bhavnesh; Lata, Manju; Joshi, Beenu; Venkatesan, Krishnamurthy; Shukla, Sangeeta; Bisht, Deepa

    2015-01-01

    Aminoglycosides, amikacin (AK) and kanamycin (KM) are second line anti-tuberculosis drugs used to treat tuberculosis (TB) and resistance to them affects the treatment. Membrane and membrane associated proteins have an anticipated role in biological processes and pathogenesis and are potential targets for the development of new diagnostics/vaccine/therapeutics. In this study we compared membrane and membrane associated proteins of AK and KM resistant and susceptible Mycobacterium tuberculosis isolates by 2DE coupled with MALDI-TOF/TOF-MS and bioinformatic tools. Twelve proteins were found to have increased intensities (PDQuest Advanced Software) in resistant isolates and were identified as ATP synthase subunit alpha (Rv1308), Trigger factor (Rv2462c), Dihydrolipoyl dehydrogenase (Rv0462), Elongation factor Tu (Rv0685), Transcriptional regulator MoxR1(Rv1479), Universal stress protein (Rv2005c), 35kDa hypothetical protein (Rv2744c), Proteasome subunit alpha (Rv2109c), Putative short-chain type dehydrogenase/reductase (Rv0148), Bacterioferritin (Rv1876), Ferritin (Rv3841) and Alpha-crystallin/HspX (Rv2031c). Among these Rv2005c, Rv2744c and Rv0148 are proteins with unknown functions. Docking showed that both drugs bind to the conserved domain (Usp, PspA and SDR domain) of these hypothetical proteins and GPS-PUP predicted potential pupylation sites within them. Increased intensities of these proteins and proteasome subunit alpha might not only be neutralized/modulated the drug molecules but also involved in protein turnover to overcome the AK and KM resistance. Besides that Rv1876, Rv3841 and Rv0685 were found to be associated with iron regulation signifying the role of iron in resistance. Further research is needed to explore how these potential protein targets contribute to resistance of AK and KM.

  4. Duration of anti-tuberculosis therapy and timing of antiretroviral therapy initiation: association with mortality in HIV-related tuberculosis.

    Directory of Open Access Journals (Sweden)

    Claudia P Cortes

    Full Text Available BACKGROUND: Antiretroviral therapy (ART decreases mortality risk in HIV-infected tuberculosis patients, but the effect of the duration of anti-tuberculosis therapy and timing of anti-tuberculosis therapy initiation in relation to ART initiation on mortality, is unclear. METHODS: We conducted a retrospective observational multi-center cohort study among HIV-infected persons concomitantly treated with Rifamycin-based anti-tuberculosis therapy and ART in Latin America. The study population included persons for whom 6 months of anti-tuberculosis therapy is recommended. RESULTS: Of 253 patients who met inclusion criteria, median CD4+ lymphocyte count at ART initiation was 64 cells/mm(3, 171 (68% received >180 days of anti-tuberculosis therapy, 168 (66% initiated anti-tuberculosis therapy before ART, and 43 (17% died. In a multivariate Cox proportional hazards model that adjusted for CD4+ lymphocytes and HIV-1 RNA, tuberculosis diagnosed after ART initiation was associated with an increased risk of death compared to tuberculosis diagnosis before ART initiation (HR 2.40; 95% CI 1.15, 5.02; P = 0.02. In a separate model among patients surviving >6 months after tuberculosis diagnosis, after adjusting for CD4+ lymphocytes, HIV-1 RNA, and timing of ART initiation relative to tuberculosis diagnosis, receipt of >6 months of anti-tuberculosis therapy was associated with a decreased risk of death (HR 0.23; 95% CI 0.08, 0.66; P=0.007. CONCLUSIONS: The increased risk of death among persons diagnosed with tuberculosis after ART initiation highlights the importance of screening for tuberculosis before ART initiation. The decreased risk of death among persons receiving > 6 months of anti-tuberculosis therapy suggests that current anti-tuberculosis treatment duration guidelines should be re-evaluated.

  5. Understanding drug resistance in human intestinal protozoa.

    Science.gov (United States)

    El-Taweel, Hend Aly

    2015-05-01

    Infections with intestinal protozoa continue to be a major health problem in many areas of the world. The widespread use of a limited number of therapeutic agents for their management and control raises concerns about development of drug resistance. Generally, the use of any antimicrobial agent should be accompanied by meticulous monitoring of its efficacy and measures to minimize resistance formation. Evidence for the occurrence of drug resistance in different intestinal protozoa comes from case studies and clinical trials, sometimes with a limited number of patients. Large-scale field-based assessment of drug resistance and drug sensitivity testing of clinical isolates are needed. Furthermore, the association of drug resistance with certain geographic isolates or genotypes deserves consideration. Drug resistance has been triggered in vitro and has been linked to modification of pyruvate:ferredoxin oxidoreductase, nitroreductases, antioxidant defense, or cytoskeletal system. Further mechanistic studies will have important implications in the development of second generation therapeutic agents.

  6. Temperature-mediated heteroduplex analysis for the detection of drug-resistant gene mutations in clinical isolates of Mycobacterium tuberculosis by denaturing HPLC, SURVEYOR nuclease.

    Science.gov (United States)

    Shi, Ruiru; Otomo, Koji; Yamada, Hiroyuki; Tatsumi, Taiga; Sugawara, Isamu

    2006-01-01

    Denaturing high-performance liquid chromatography (DHPLC) is a relatively new technique, which utilizes heteroduplex formation between wild-type and mutated DNA strands to identify point mutations. Heteroduplex molecules are separated from homoduplex molecules by ion-pair, reverse-phase liquid chromatography on a special column matrix with partial heat denaturation of the DNA strands. In order to investigate the application of this method for point mutation detection in drug-resistant genes of Mycobacterium tuberculosis, katG, rpoB, embB, gyrA, pncA and rpsL genes, which are responsible for isoniazid, rifampicin, ethambutol, fluoroquinolone, pyrazinamide and streptomycin resistance, respectively, were detected by temperature-mediated DHPLC in 10 multidrug-resistant and 10 drug-susceptible clinical isolates. The DHPLC data were compared with those from a conventional MIC test. The results show that DHPLC is cost-effective with high capacity and accuracy, and is potentially useful for genotypic screening for mutations associated with anti-tuberculosis drug resistance.

  7. New Drugs and Drug Resistance in Malaria: Molecular Genetic Analysis.

    Science.gov (United States)

    1996-06-26

    heterologous expressions system in yeast for potential drug target enzymes. The yeast expression system should allow rapid screening of new drugs , greatly...medication yet the world faces a crisis-drug resistance is emerging and spreading faster than drugs are being developed and the flow in the pipeline of new ... drugs has all but stopped. This represents a particular threat to the US Military. In a short time there may be parts of the world where no effective

  8. Mechanisms of Anticancer Drugs Resistance: An Overview

    Directory of Open Access Journals (Sweden)

    M. R. Chorawala

    2012-01-01

    Full Text Available The management of cancer involves surgery, radiotherapy and chemotherapy. Development of chemoresistance is a persistent problem during the chemotherapy treatment. Cytotoxic drugs that selectively, but not exclusively, target actively proliferating cells include such diverse groups as DNA-alkylating agents, anti-metabolites, intercalating agents and mitotic inhibitors. Resistance constitutes a lack of response to drug-induced tumour growth inhibition; it may be inherent in a subpopulation of heterogeneous cancer cells or be acquired as a cellular response to drug exposure. Principle mechanisms may include altered membrane transport involving the p-glycoprotein product of the multidrug resistance (MDR gene as well as other associated proteins, altered target enzyme, decreased drug activation, increased drug degradation due to altered expression of drug metabolising enzymes, drug inactivation due to conjugation with increased glutathione, subcellular redistribution, drug interaction, enhanced DNA repair and failure to apoptosis as a result of mutated cell cycle proteins such as p53. Attempts to overcome resistance involves the use of combination drug therapy using different classes of drugs with minimally overlapping toxicities to allow maximal dosages, necessary for bone marrow recovery. Adjuvant therapy with p-glycoprotein inhibitors and in specific instances, the use of growth factor and protein kinase C inhibitors are newer experimental approaches that may also prove effective in delaying onset of resistance. Gene knockout using antisense molecules may be effective way of blocking drug resistance.

  9. 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.

  10. Multidrug resistant to extensively drug resistant tuberculosis: What is next?

    Indian Academy of Sciences (India)

    Amita Jain; Pratima Dixit

    2008-11-01

    Drug resistant tuberculosis is a man made problem. While tuberculosis is hundred percent curable, multidrug resistant tuberculosis (MDR-TB) is difficult to treat. Inadequate and incomplete treatment and poor treatment adherence has led to a newer form of drug resistance known as extensively drug resistant tuberculosis (XDR-TB). XDR-TB is defined as tuberculosis caused by Mycobacterium tuberculosis strain, which is resistant to at least rifampicin and isoniazid among the first line anti tubercular drugs (MDR-TB) in addition to resistance to any fluroquinolones and at least one of three injectable second line anti tubercular drugs i.e. amikacin, kanamycin and/or capreomycin. Mismanagement of tuberculosis paves the way to drug resistant tuberculosis. Emergence of XDR-TB is reported world wide. Reported prevalence rates of XDR-TB of total MDR cases are; 6.6% overall worldwide, 6.5% in industrialized countries, 13.6% in Russia and Eastern Europe, 1.5% in Asia, 0.6% in Africa and Middle East and 15.4% in Republic of Korea. Better management and control of tuberculosis specially drug resistant TB by experienced and qualified doctors, access to standard microbiology laboratory, co-morbitidy of HIV and tuberculosis, new anti-TB drug regimens, better diagnostic tests, international standards for second line drugs (SLD)-susceptibility testing, invention of newer anti-tubercular molecules and vaccines and knowing the real magnitude of XDR-TB are some of the important issues to be addressed for effective prevention and management of XDR-TB.

  11. Mechanisms of drug resistance: daptomycin resistance.

    Science.gov (United States)

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

    2015-09-01

    Daptomycin (DAP) is a cyclic lipopeptide with in vitro activity against a variety of Gram-positive pathogens, including multidrug-resistant organisms. Since its introduction into clinical practice in 2003, DAP has become an important key frontline antibiotic for severe or deep-seated infections caused by Gram-positive organisms. Unfortunately, DAP resistance (DAP-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-R 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 provided 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.

  12. Multidrug-resistant tuberculosis

    Directory of Open Access Journals (Sweden)

    McNerney Ruth

    2008-01-01

    Full Text Available Abstract Background With almost 9 million new cases each year, tuberculosis remains one of the most feared diseases on the planet. Led by the STOP-TB Partnership and WHO, recent efforts to combat the disease have made considerable progress in a number of countries. However, the emergence of mutated strains of Mycobacterium tuberculosis that are resistant to the major anti-tuberculosis drugs poses a deadly threat to control efforts. Multidrug-resistant tuberculosis (MDR-TB has been reported in all regions of the world. More recently, extensively drug resistant-tuberculosis (XDR-TB that is also resistant to second line drugs has emerged in a number of countries. To ensure that adequate resources are allocated to prevent the emergence and spread of drug resistance it is important to understand the scale of the problem. In this article we propose that current methods of describing the epidemiology of drug resistant tuberculosis are not adequate for this purpose and argue for the inclusion of population based statistics in global surveillance data. Discussion Whereas the prevalence of tuberculosis is presented as the proportion of individuals within a defined population having disease, the prevalence of drug resistant tuberculosis is usually presented as the proportion of tuberculosis cases exhibiting resistance to anti-tuberculosis drugs. Global surveillance activities have identified countries in Eastern Europe, the former Soviet Union and regions of China as having a high proportion of MDR-TB cases and international commentary has focused primarily on the urgent need to improve control in these settings. Other regions, such as sub-Saharan Africa have been observed as having a low proportion of drug resistant cases. However, if one considers the incidence of new tuberculosis cases with drug resistant disease in terms of the population then countries of sub-Saharan Africa have amongst the highest rates of transmitted MDR-TB in the world. We propose

  13. 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.

  14. THE QUESTIONS OF ALLERGY AND ANTI-TUBERCULOSIS IMMUNITY IN THE WORKS OF М.М. TSEHNOVITSER

    Directory of Open Access Journals (Sweden)

    Kuchma Y.U

    2014-10-01

    Full Text Available The mechanism of anti-tuberculosis immunity drew the attention of scientists since the established of the infectious nature of tuberculosis. The famous ukrainian microbiologist and immunologist M.M. Tsehnovitser in period from 1921 to 1940 years spent a lot of original experiments for elucidation of the role of allergy in the anti-tuberculosis immunity. M.M. Tsehnovitser believed that a common cause of infectious allergy is tuberculosis granuloma, which even at rest eliminated weakened microbes and their products in general lymphatic and blood stream of the body. In his experiments M.M. Tsehnovitser discovered: 1 When the body comes in contact with M.tuberculosisi formed tuberculosis centre. Infection meets local tissue reaction and in incubation period formed sensitization. In this state the body manifested as a natural susceptibility and resistance to infection. During this period organism going through the initial stage of allergy. 2. Meanwhile, the infectious process goes on and the M.tuberculosisi giving rise. The body reacts to this change in the formula blood - leukocytosis, monocytosis, eosinophilia. Tuberculosis focus represents a formed granuloma. This phase of tuberculosis infection accompanied by severe allergy. 3. Then there are two versions of the process. In the first case happened the generalization of tuberculosis infection. The blood reacts are leukopenia, monocytosis, eosinophilia and lymphocytosis due to toxic processes. In the second case M.tuberculosi multiplied only local in the granuloma and is not generalization of tuberculosis process. In this case, natural immunity is raised. There are allergy and positive anergy in later. 4. It is exclusively unique phenomenon for tuberculous process is the regression of the fire with his sterilization. This type of tuberculous process is in BCG-infection. In the source of infection observed complete resolution of pathological tissue, blood initially reacts slightly, but quickly comes

  15. A database of antimalarial drug resistance

    Directory of Open Access Journals (Sweden)

    Ringwald Pascal

    2006-06-01

    Full Text Available Abstract A large investment is required to develop, license and deploy a new antimalarial drug. Too often, that investment has been rapidly devalued by the selection of parasite populations resistant to the drug action. To understand the mechanisms of selection, detailed information on the patterns of drug use in a variety of environments, and the geographic and temporal patterns of resistance is needed. Currently, there is no publically-accessible central database that contains information on the levels of resistance to antimalaria drugs. This paper outlines the resources that are available and the steps that might be taken to create a dynamic, open access database that would include current and historical data on clinical efficacy, in vitro responses and molecular markers related to drug resistance in Plasmodium falciparum and Plasmodium vivax. The goal is to include historical and current data on resistance to commonly used drugs, like chloroquine and sulfadoxine-pyrimethamine, and on the many combinations that are now being tested in different settings. The database will be accessible to all on the Web. The information in such a database will inform optimal utilization of current drugs and sustain the longest possible therapeutic life of newly introduced drugs and combinations. The database will protect the valuable investment represented by the development and deployment of novel therapies for malaria.

  16. 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.

  17. Plasmodium falciparum drug resistance in Angola

    OpenAIRE

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

    2016-01-01

    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 ...

  18. Drug resistance in Schistosomiasis: a review

    Directory of Open Access Journals (Sweden)

    John I. Bruce

    1987-01-01

    Full Text Available Drug resistance associated with the treatment of human schistosomiasis appears to be an emerging problem requiring more attention from the scientific community than the subject currently receives. Drug-resistant strains of Schistosoma mansoni have been isolated by various investigators as a result of laboratory experimentation or from a combination of field and laboratory studies. Review of this data appears to indicate that the lack of susceptibility observed for some of the isolated strains cannot be ascribed solely to previous administration of antischistosome drugs and thus further studies are required to elucidate this phenomena. Strains of S. mansoni have now been identified from Brazil which are resistant to oxamniquine, hycanthone and niridazole; from Puerto Rico which are resistant to hycanthone and oxamniquine; and from Kenya which are resistant to niridazole and probably oxamniquine. Strains derived by in vitro selection and resistant to oxamniquine and possibly to oltipraz are also available. All of these strains are currently maintained in the laboratory in snails and mice, thus providing for the first time an opportunity for indepth comparative studies. Preliminary data indicates that S. haematobium strains resistant to metrifonate may be occurring in Kenya. This problem could poise great difficulty in the eventual development of antischistosomal agents. Biomphalaria glabrata from Puerto Rico and Brazil were found to be susceptible to drug-resistant S. mansoni from each country.

  19. Malaria Epidemic and Drug Resistance, Djibouti

    OpenAIRE

    Rogier, Christophe; Pradines, Bruno; Bogreau, H.; Koeck, Jean-Louis; Kamil, Mohamed-Ali; Mercereau-Puijalon, Odile

    2005-01-01

    Analysis of Plasmodium falciparum isolates collected before, during, and after a 1999 malaria epidemic in Djibouti shows that, despite a high prevalence of resistance to chloroquine, the epidemic cannot be attributed to a sudden increase in drug resistance of local parasite populations.

  20. Antifungal Drug Resistance - Concerns for Veterinarians

    Directory of Open Access Journals (Sweden)

    Bharat B. Bhanderi

    2009-10-01

    Full Text Available In the 1990s, there were increased incidences of fungal infectious diseases in human population which might be due to increase in immunosuppressive diseases. But the major concern was increase in prevalence of resistance to antifungal drugs which were reported both in the fungal isolates of human beings and that of animal origin. In both animals and human beings, resistance to antimicrobial agents has important implications for morbidity, mortality and health care costs, because resistant strains are responsible for bulk of infection in animals and human beings, and large number of antimicrobial classes offers more diverse range of resistance mechanisms to study and resistance determinants move into standard well-characterized strains that facilitates the detailed study of molecular mechanisms of resistance in microorganisms. Studies on resistance to antifungal agents has been lagging behind that of antibacterial resistance for several reasons, the foremost reason might be fungal agents were not recognized as important animal and human pathogens, until relatively in recent past. But the initial studies of antifungal drug resistance in the early 1980s, have accumulated a wealth of knowledge concerning the clinical, biochemical, and genetic aspects of this phenomenon. Presently, exploration of the molecular aspects for antifungal drug resistance has been undertaken. Recently, the focus was on several points like developing a more detailed understanding of the mechanisms of antimicrobial resistance, improved methods to detect resistance when it occurs, methods to prevent the emergence and spread of resistance and new antimicrobial options for the treatment of infections caused by resistant organisms. [Vet. World 2009; 2(5.000: 204-207

  1. Multiple drug resistance and bacterial infection

    Institute of Scientific and Technical Information of China (English)

    Asad U Khan

    2008-01-01

    Drug resistance is becoming a great problem in developing countries due to excessive use and misuse of antibi-otics.The emergence of new pathogenic strains with resistance developed against most of the antibiotics which may cause,difficult to treat infection.To understand the current scenario in different mode of infection is most important for the clinicians and medical practitioners.This article summarized some common infections and an-tibiotic resistance pattern found among these pathogens.

  2. [Drug resistant epilepsy. Clinical and neurobiological concepts].

    Science.gov (United States)

    Espinosa-Jovel, Camilo A; Sobrino-Mejía, Fidel E

    2015-08-16

    Drug-resistant epilepsy, is a condition defined by the International League Against Epilepsy as persistent seizures despite having used at least two appropriate and adequate antiepileptic drug treatments. Approximately 20-30% of patients with epilepsy are going to be resistant to antiepileptic drugs, with different patterns of clinical presentation, which are related to the biological basis of this disease (de novo resistance, relapsing-remitting and progressive). Drug resistant epilepsy, impacts negatively the quality of life and significantly increases the risk of premature death. From the neurobiological point of view, this medical condition is the result of the interaction of multiple variables related to the underlying disease, drug interactions and proper genetic aspects of each patient. Thanks to advances in pharmacogenetics and molecular biology research, currently some hypotheses may explain the cause of this condition and promote the study of new therapeutic options. Currently, overexpression of membrane transporters such as P-glycoprotein, appears to be one of the most important mechanisms in the development of drug resistant epilepsy. The objective of this review is to deepen the general aspects of this clinical condition, addressing the definition, epidemiology, differential diagnosis and the pathophysiological bases.

  3. Transporter protein and drug resistance of Trypanosoma.

    Science.gov (United States)

    Medina, Noraine P; Mingala, Claro N

    2016-01-01

    Trypanosoma infection is one of the most important infections in livestock and humans. One of the main problems of its therapeutic control and treatment is the resurgence of drug resistance. One of the most studied causes of such resistance is the function of its adenosine transporter gene. A trypanosomal gene TbAT1 from Trypanosoma brucei has been cloned in yeast to demonstrate its function in the transport of adenosine and trypanocidal agents. Drug resistant trypanosomes showed a defective TbAT1 variant; furthermore, deletion of the gene and set point mutations in the transporter gene has been demonstrated from isolates from relapse patients. The molecular understanding of the mechanism of action trypanocidal agents and function of transporter gene can lead to control of drug resistance of Trypanosomes.

  4. New Non-Toxic Semi-Synthetic Derivatives from Natural Diterpenes Displaying Anti-Tuberculosis Activity.

    Science.gov (United States)

    Matos, Priscilla M; Mahoney, Brian; Chan, Yohan; Day, David P; Cabral, Mirela M W; Martins, Carlos H G; Santos, Raquel A; Bastos, Jairo K; Page, Philip C Bulman; Heleno, Vladimir C G

    2015-10-07

    We report herein the synthesis of six diterpene derivatives, three of which are new, generated through known organic chemistry reactions that allowed structural modification of the existing natural products kaurenoic acid (1) and copalic acid (2). The new compounds were fully characterized using high resolution mass spectrometry, infrared spectroscopy, ¹H- and (13)C-NMR experiments. We also report the evaluation of the anti-tuberculosis potential for all compounds, which showed some promising results for Micobacterium tuberculosis inhibition. Moreover, the toxicity for each of the most active compounds was also assessed.

  5. Some Nigerian Anti-Tuberculosis Ethnomedicines: A Preliminary Efficacy Assessment

    Science.gov (United States)

    Ibekwe, Nneka N.; Nvau, John B.; Oladosu, Peters O.; Usman, Auwal M.; Ibrahim, Kolo; Boshoff, Helena I.; Dowd, Cynthia S.; Orisadipe, Abayomi T.; Aiyelaagbe, Olapeju; Adesomoju, Akinbo A.; Barry, Clifton E.; Okogun, Joseph I.

    2014-01-01

    Ethnopharmacological significance Nigerian herbalists possess indigenous ethnomedicinal recipes for the management of tuberculosis and related ailments. Aim of the study To carry out a collaborative preliminary modern scientific evaluation of the efficacy of some Nigerian ethnomedicines used by traditional medicine practitioners (TMPs) in the management of tuberculosis and related ailments Materials and methods Ethnomedicinal recipes (ETMs) were collected from TMPs from locations in various ecological zones of Nigeria under a collaborative understanding. The aqueous methanolic extracts of the ETMs were screened against Mycobacterium bovis, BCG and Mycobacterium tuberculosis (M. tb.) strain H37Rv using the broth microdilution method. Results Extracts of ETMs screened against BCG showed 69% activity against the organism. The activities varied from weak, ≤ 2500μg /mL to highly active, 33μg /mL 64% of the extracts were active against M. tb. The activities of the extracts against M.tb. varied from weak, ≤ 2500μg /mL to highly active, 128μg/mL. There was 77% agreement in results obtained using BCG or M. tb. as test organisms Conclusion The results show clear evidence for the efficacy of the majority of indigenous Nigerian herbal recipes in the ethnomedicinal management of tuberculosis and related ailments. BCG may be effectively used, to a great extent, as the organism for screening for potential anti-M. tb. agents. A set of prioritization criteria for the selection of plants for initial further studies for the purpose of antituberculsis drug discovery research is proposed. PMID:24911338

  6. Prevalence of primary multidrug resistance to anti-tuberculosis drugs in Pakistan%巴基斯坦原发性耐多药结核病流行情况

    Institute of Scientific and Technical Information of China (English)

    A. Javaid; K.Shah; M.Ansari; N.Rizvi; S.U.Khan; S.R.Awan; Z.A.Syed; Z.H. lqbal; Z.Shaheen; N.ur Rehman; 邢超; R. Hasan; A. Zafar; A. Ghafoor; A. J. Pathan; A. Rab; A. Sadiq; C.M.Akram; I.Burki

    2008-01-01

    背景:巴基斯坦是世界第6位结核病高负担国家.据世界卫生组织(WHO)估计,巴基斯坦结核病发病率为181/10万,全国每年新增结核病患者28.6万例.来自于医院的资料表明:巴基斯坦耐多药结核病(MDR-TB)问题已十分严重,急需在社区水平对耐多药结核病的严重程度开展评估.本研究为针对巴基斯坦耐药结核病流行状况开展的横段面研究,所使用的痰标本来自于巴基斯坦全国742例未经治疗的新诊断的肺结核患者.目的:评估巴基斯坦原发性耐药的流行情况结果:在 672 例痰培养阳性患者中,有 76 例(11.3%)出现了对1种或多种抗结核药物耐药.36例(5.4%)患者对链霉素(10μg/ml)耐药;51例(7.6%)患者对异烟肼(1μg/ml)耐药;15例(2.2%)患者对利福平(5μg/ml)耐药;12例(1.8%)患者对乙胺丁醇(10/μg/ml)耐药;22例(3.3%)患者对吡嗪酰胺耐药.有 46 例(6.8%)患者痰标本中分离的结核菌株耐1种抗结核药物,10例(1.5%)同时耐2种抗结核药物,12 例(1.8%)同时耐 3 种抗结核药物,6例(0.9%)同时耐4种抗结核药物,2例(0.3%)同时耐全部5种抗结核-线药.原发性耐多药率为1.8%,(n=12)(异烟肼1μg/ml,利福平5μg/ml).结论:研究结果表明,巴基斯坦原发性耐多药率<2%,需要进一步实施有效的DOTS策略.

  7. 住院肺结核病人耐药状况与疗效分析%Status and treatment effect analysis of the anti-tuberculosis drugresistance and multi-drug resistance TB cases in a tuberculosis hospital

    Institute of Scientific and Technical Information of China (English)

    陈峥; 孙桂芝; 李京红; 马伟路

    2000-01-01

    目的了解结核病医院中住院病人的耐药及多耐药结核病(MDR-TB)流行情况、特点及影响因素.方法用临床流行病学方法进行统计和分析.结果耐药率为30.71%,MDR-TB发病率为11.68%,初始MDR-TB为2.55%,继发MDR-TB为9.13%,MDR-TB死亡率为9.48%.结论耐药及MDR-TB发病率逐年增加,高死亡率.

  8. Antifungal drug resistance to azoles and polyenes.

    Science.gov (United States)

    Masiá Canuto, Mar; Gutiérrez Rodero, Félix

    2002-09-01

    There is an increased awareness of the morbidity and mortality associated with fungal infections caused by resistant fungi in various groups of patients. Epidemiological studies have identified risk factors associated with antifungal drug resistance. Selection pressure due to the continuous exposure to azoles seems to have an essential role in developing resistance to fluconazole in Candida species. Haematological malignancies, especially acute leukaemia with severe and prolonged neutropenia, seem to be the main risk factors for acquiring deep-seated mycosis caused by resistant filamentous fungi, such us Fusarium species, Scedosporium prolificans, and Aspergillus terreus. The still unacceptably high mortality rate associated with some resistant mycosis indicates that alternatives to existing therapeutic options are needed. Potential measures to overcome antifungal resistance ranges from the development of new drugs with better antifungal activity to improving current therapeutic strategies with the present antifungal agents. Among the new antifungal drugs, inhibitors of beta glucan synthesis and second-generation azole and triazole derivatives have characteristics that render them potentially suitable agents against some resistant fungi. Other strategies including the use of high doses of lipid formulations of amphotericin B, combination therapy, and adjunctive immune therapy with cytokines are under investigation. In addition, antifungal control programmes to prevent extensive and inappropriate use of antifungals may be needed.

  9. What is Multidrug and Extensively Drug Resistant TB?

    Science.gov (United States)

    ... and Extensively Drug Resistant TB? Multidrug-resistant tuberculosis ( MDR TB ) is a very dangerous form of tuberculosis. Some ... TB medicine so that you will not develop MDR TB. Extensively drug-resistant TB ( XDR TB ) is an ...

  10. Communicating trends in resistance using a drug resistance index.

    Science.gov (United States)

    Laxminarayan, Ramanan; Klugman, Keith P

    2011-01-01

    Background Antibiotic resistance is a growing problem worldwide, but communicating this challenge to policymakers and non-experts is complicated by the multiplicity of bacterial pathogens and the distinct classes of antibiotics used to treat them. It is difficult, even for experts aware of the pharmacodynamics of antibiotics, to infer the seriousness of resistance without information on how commonly the antibiotic is being used and whether alternative antibiotics are available. Difficulty in aggregating resistance to multiple drugs to assess trends poses a further challenge to quantifying and communicating changes in resistance over time and across locations. Methods We developed a method for aggregating bacterial resistance to multiple antibiotics, creating an index comparable to the composite economic indices that measure consumer prices and stock market values. The resulting drug resistance index (DRI) and various subindices show antibiotic resistance and consumption trends in the USA but can be applied at any geographical level. Findings The DRI based on use patterns in 1999 for Escherichia coli rose from 0.25 (95% CI 0.23 to 0.26) to 0.30 (95% CI 0.29 to 0.32) between 1999 and 2006. However, the adaptive DRI, which includes treatment of baseline resistant strains with alternative agents, climbed from 0.25 to 0.27 (95% CI 0.25 to 0.28) during that period. In contrast, both the static-use and the adaptive DRIs for Acinetobacter spp. rose from 0.41 (95% CI 0.4 to 0.42) to 0.48 (95% CI 0.46 to 0.49) between 1999 and 2006. Interpretation Divergence between the static-use and the adaptive-use DRIs for E coli reflects the ability of physicians to adapt to increasing resistance. However, antibiotic use patterns did not change much in response to growing resistance to Acinetobacter spp. because physicians were unable to adapt; new drugs for Acinetobacter spp. are therefore needed. Composite indices that aggregate resistance to various drugs can be useful for assessing

  11. Recommendations for Optimizing Tuberculosis Treatment: Therapeutic Drug Monitoring, Pharmacogenetics, and Nutritional Status Considerations.

    Science.gov (United States)

    Choi, Rihwa; Jeong, Byeong Ho; Koh, Won Jung; Lee, Soo Youn

    2017-03-01

    Although tuberculosis is largely a curable disease, it remains a major cause of morbidity and mortality worldwide. Although the standard 6-month treatment regimen is highly effective for drug-susceptible tuberculosis, the use of multiple drugs over long periods of time can cause frequent adverse drug reactions. In addition, some patients with drug-susceptible tuberculosis do not respond adequately to treatment and develop treatment failure and drug resistance. Response to tuberculosis treatment could be affected by multiple factors associated with the host-pathogen interaction including genetic factors and the nutritional status of the host. These factors should be considered for effective tuberculosis control. Therefore, therapeutic drug monitoring (TDM), which is individualized drug dosing guided by serum drug concentrations during treatment, and pharmacogenetics-based personalized dosing guidelines of anti-tuberculosis drugs could reduce the incidence of adverse drug reactions and increase the likelihood of successful treatment outcomes. Moreover, assessment and management of comorbid conditions including nutritional status could improve anti-tuberculosis treatment response.

  12. The comparison of the efficacy of different anti -tuberculosis schemes in the treatment of tuberculous meningitis%不同抗结核方案治疗结核性脑膜炎的疗效比较

    Institute of Scientific and Technical Information of China (English)

    王敬; 周杰

    2016-01-01

    目的:探讨改良抗结核方案治疗结核性脑膜炎的疗效与安全性。方法对60例结核性脑膜炎患者采用随机数字表法分为两组,每组30例,传统抗结核组采用异烟肼、利福平、吡嗪酰胺、链霉素等传统抗结核方案治疗,改良抗结核组采用含异烟肼、利福平、吡嗪酰胺、左氧氟沙星的抗结核方案进行12个月的治疗,通过临床表现和辅助检查、脑脊液动态变化、统计学方法等手段评价其疗效与安全性。结果改良抗结核组总有效率明显高于传统抗结核组(86.6%比63.3%,χ2=4.36,P <0.05);改良抗结核组治疗后脑脊液常规及生化指标明显优于传统抗结核组(均 P <0.05);两组不良反应发生率差异无统计学意义(26.6%比16.7%,χ2=0.88,P >0.05)。结论左氧氟沙星联合其他一线抗结核药,并结合激素、脱水、改善脑功能等综合措施治疗结核性脑膜炎是值得推荐的抗结核方案。%Objective To evaluate the clinical efficacy and safety of modified anti -tuberculosis scheme in the treatment of tuberculous meningitis.Methods 60 cases with tuberculous meningitis were randomly divided into two groups.We enrolled 30 patients in each group.The traditional anti -tuberculosis group used traditional anti -tuberculosis scheme with isoniazid,rifampicin,pyrazinamide,streptomycin,and the modified anti -tuberculosis group was given isoniazid,rifampicin,pyrazinamide,levofloxacin,the treatment course of tuberculous meningitis was 12 months.The efficacy and safety through clinical manifestations and laboratory examinations,the dynamic changes of cerebrospinal fluid were evaluated by statistical methods.Results The total effective rate of the modified anti -tuberculosis group was significantly higher than the traditional anti -tuberculosis group(86.6% vs.63.3%,χ2 =4.36,P 0.05).Conclusion Levofloxacin combined with other first -line anti

  13. 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 ag

  14. [Estimation of Probiotic Lactobacilli Drug Resistance].

    Science.gov (United States)

    Bruslik, N L; Akhatova, D R; Toimentseva, A A; Abdulkhakov, S R; Ilyinskaya, O N; Yarullina, D R

    2015-01-01

    An actual problem of analysis of probiotic lactobacilli resistance to antibiotics and other drugs used in the treatment of gastro-intestinal disturbances has been for the first time solved. The levels of resistance of 19 strains of Lactobacillus (14 strains of L. fermentum, 4 strains of L.plantarum and 1 strain of L.rhamnosus) isolated from commercial probiotics and sour milk products to 14 antibiotics of various nature, i.e. β-lactams, aminoglycosides, macrolides, clindamycin, vancomycin, rifampicin, ciprofloxacin, tetracycline and chloramphenicol were determined. All the isolates were practically susceptible to the drugs of the first line antihelicobacterial therapy, i.e. amoxicillin and clarithromycin, that makes inexpedient the parallel use of the probiotics containing the above lactobacilli in the treatment of gastritis and gastric ulcer, despite the lactobacilli antagonism with respect to Helicobacter pylory. Lactobacilli are as well resistant to mesalazin and can be used for correction of dysbiosis in inflammatory affections of the intestine.

  15. [Travellers and multi-drug resistance bacteria].

    Science.gov (United States)

    Takeshita, Nozomi

    2012-02-01

    The number of international travellers has increased. There is enormous diversity in medical backgrounds, purposes of travel, and travelling styles among travellers. Travellers are hospitalized abroad because of exotic and common diseases via medical tourism. This is one way of transporting and importing human bacteria between countries, including multi-drug resistant organisms. In developing countries, the antimicrobial resistance in Shigella sp. and Salmonella sp. have been a problem, because of this trend, the first choice of antibiotics has changed in some countries. Community acquired infections as well as hospital acquired infections with MRSA, multi-drug resistance (MDR) Pseudomonas aeruginosa, and ESBL have been a problem. This review will discuss the risk of MDR bacterial infectious diseases for travellers.

  16. Cancer Exosomes as Mediators of Drug Resistance.

    Science.gov (United States)

    André, Maria do Rosário; Pedro, Ana; Lyden, David

    2016-01-01

    In the last decades, several studies demonstrated that the tumor microenvironment is a critical determinant not only of tumor progression and metastasis, but also of resistance to therapy. Exosomes are small membrane vesicles of endocytic origin, which contain mRNAs, DNA fragments, and proteins, and are released by many different cell types, including cancer cells. Mounting evidence has shown that cancer-derived exosomes contribute to the recruitment and reprogramming of constituents associated with the tumor microenvironment. Understanding how exosomes and the tumor microenvironment impact drug resistance will allow novel and better strategies to overcome drug resistance and treat cancer. Here, we describe a technique for exosome purification from cell culture, and fresh and frozen plasma, and further analysis by electron microscopy, NanoSight microscope, and Western blot.

  17. Fresh Air and Good Food: Children and the Anti-Tuberculosis Campaign in the Netherlands c.1900-1940

    Science.gov (United States)

    Bakker, Nelleke

    2010-01-01

    As elsewhere in the Western world, between 1900 and 1940 the anti-tuberculosis campaign in the Netherlands produced a wide range of initiatives to promote child health. In each of these the social and the medical were linked, as the hygienic "mood" was encouraged by a child-saving ethos that focused upon the poor. In this article the…

  18. Fresh air and good food : Children and the anti-tuberculosis campaign in the Netherlands c.1900-1940

    NARCIS (Netherlands)

    Bakker, Nelleke

    2010-01-01

    As elsewhere in the Western world, between 1900 and 1940 the anti-tuberculosis campaign in the Netherlands produced a wide range of initiatives to promote child health. In each of these the social and the medical were linked, as the hygienic 'mood' was encouraged by a child-saving ethos that focused

  19. Early stationary phase culture supernatant accelerates growth of sputum cultures collected after initiation of anti-tuberculosis treatment.

    Science.gov (United States)

    Kolwijck, E; Friedrich, S O; Karinja, M N; van Ingen, J; Warren, R M; Diacon, A H

    2014-07-01

    We investigated the effect of Mycobacterium tuberculosis culture supernatant added to sputum cultures collected during the first 8 weeks of anti-tuberculosis treatment. With ongoing treatment duration, time to culture positivity decreased significantly in supernatant-enriched cultures, possibly due to stimulation of dormant or slowly metabolizing M. tuberculosis cells.

  20. Frequency of Mycobacterium tuberculosis-specific CD8+ T-cells in the course of anti-tuberculosis treatment

    Directory of Open Access Journals (Sweden)

    Rebecca Axelsson-Robertson

    2015-03-01

    Full Text Available Anti-tuberculosis drug treatment is known to affect the number, phenotype, and effector functionality of antigen-specific T-cells. In order to objectively gauge Mycobacterium tuberculosis (MTB-specific CD8+ T-cells at the single-cell level, we developed soluble major histocompatibility complex (MHC class I multimers/peptide multimers, which allow analysis of antigen-specific T-cells without ex vivo manipulation or functional tests. We constructed 38 MHC class I multimers covering some of the most frequent MHC class I alleles (HLA-A*02:01, A*24:02, A*30:01, A*30:02, A*68:01, B*58:01, and C*07:01 pertinent to a South African or Zambian population, and presenting the following MTB-derived peptides: the early expressed secreted antigens TB10.4 (Rv0288, Ag85B (Rv1886c, and ESAT-6 (Rv3875, as well as intracellular enzymes, i.e., glycosyltransferase 1 (Rv2957, glycosyltransferase 2 (Rv2958c, and cyclopropane fatty acid synthase (Rv0447c. Anti-TB treatment appeared to impact on the frequency of multimer-positive CD8+ T-cells, with a general decrease after 6 months of therapy. Also, a reduction in the total central memory CD8+ T-cell frequencies, as well as the antigen-specific compartment in CD45RA−CCR7+ T-cells was observed. We discuss our findings on the basis of differential dynamics of MTB-specific T-cell frequencies, impact of MTB antigen load on T-cell phenotype, and antigen-specific T-cell responses in tuberculosis.

  1. Qualitative and quantitative results of interferon-γ release assays for monitoring the response to anti-tuberculosis treatment

    Science.gov (United States)

    Park, I-Nae; Shim, Tae Sun

    2017-01-01

    Background/Aims The usefulness of interferon-γ release assays (IGRAs) in monitoring to responses to anti-tuberculosis (TB) treatment is controversial. We compared the results of two IGRAs before and after anti-TB treatment in same patients with active TB. Methods From a retrospective review, we selected patients with active TB who underwent repeated QuantiFERON-TB Gold (QFN-Gold, Cellestis Limited) and T-SPOT.TB (Oxford Immunotec) assays before and after anti-TB treatment with first-line drugs. Both tests were performed prior to the start of anti-TB treatment or within 1 week after the start of anti-TB treatment and after completion of treatment. Results A total of 33 active TB patients were included in the study. On the QFN-Gold test, at baseline, 23 cases (70%) were early secreted antigenic target 6-kDa protein 6 (ESAT-6) or culture filtrate protein 10 (CFP-10) positive. On the T-SPOT. TB test, at baseline, 31 cases (94%) were ESAT-6 or CFP-10 positive. Most of patients remained both test-positive after anti-TB treatment. Although changes in interferon-γ release responses over time were highly variable in both tests, there was a mean decline of 27 and 24 spot-forming counts for ESAT-6 and CFP-10, respectively on the T-SPOT.TB test (p < 0.05 for all). Conclusions Although limited by the small number of patients and a short-term follow-up, there was significant decline in the quantitative result of the T-SPOT. TB test with treatment. However, both commercial IGRAs may not provide evidence regarding the cure of disease in Korea, a country where the prevalence of TB is within the intermediate range. PMID:27951621

  2. Resistance patterns, prevalence, and predictors of fluoroquinolones resistance in multidrug resistant tuberculosis patients

    Directory of Open Access Journals (Sweden)

    Nafees Ahmad

    2016-02-01

    Full Text Available Abstract Background Fluoroquinolones are the backbone of multidrug resistant tuberculosis treatment regimens. Despite the high burden of multidrug resistant tuberculosis in the country, little is known about drug resistance patterns, prevalence, and predictors of fluoroquinolones resistance among multidrug resistant tuberculosis patients from Pakistan. Objective To evaluate drug resistance patterns, prevalence, and predictors of fluoroquinolones resistance in multidrug resistant tuberculosis patients. Methods This was a cross-sectional study conducted at a programmatic management unit of drug resistant tuberculosis, Lady Reading Hospital Peshawar, Pakistan. Two hundred and forty-three newly diagnosed multidrug resistant tuberculosis patients consecutively enrolled for treatment at study site from January 1, 2012 to July 28, 2013 were included in the study. A standardized data collection form was used to collect patients’ socio-demographic, microbiological, and clinical data. SPSS 16 was used for data analysis. Results High degree of drug resistance (median 5 drugs, range 2–8 was observed. High proportion of patients was resistant to all five first-line anti-tuberculosis drugs (62.6%, and more than half were resistant to second line drugs (55.1%. The majority of the patients were ofloxacin resistant (52.7%. Upon multivariate analysis previous tuberculosis treatment at private (OR = 1.953, p = 0.034 and public private mix (OR = 2.824, p = 0.046 sectors were predictors of ofloxacin resistance. Conclusion The high degree of drug resistance observed, particularly to fluoroquinolones, is alarming. We recommend the adoption of more restrictive policies to control non-prescription sale of fluoroquinolones, its rational use by physicians, and training doctors in both private and public–private mix sectors to prevent further increase in fluoroquinolones resistant Mycobacterium tuberculosis strains.

  3. Management of multiple drug-resistant tuberculosis.

    Science.gov (United States)

    Hutchison, D C S; Drobniewski, F A; Milburn, H J

    2003-01-01

    There has been a worldwide increase in multiple drug-resistant tuberculosis (MDR-TB) which has in the past been associated with a poor prognosis. In the U.K., about half of the cases live in the London area and we have set out to obtain further information on their treatment and outcome. We examined the risk factors, drug resistance, drug treatment, sputum conversion, and outcome in patients with MDR-TB at three hospitals in South London and diagnosed during the period June 1995-January 1999. Human Immunodeficiency Virus (HIV)-positive patients were excluded. There were 760 patients resident in Lambeth, Southwark and Lewisham Health Authority (LSLHA) who were notified as tuberculosis (TB) during the time period and who were of negative or unknown HIV status. (The population of LSLHA is approx.750,000.) There was a total of 13 patients with MDR-TB, known or presumed to be HlV negative. Their median age was 28 years (range 15-53); nine (69%) were born outside the U.K. and 11 had pulmonary disease; they had organisms resistant to a median of two first-line drugs (range 2-4) and to a median of four of all drugs tested (range 2-10). They received treatment with a median of six drugs (range 3-9). Eight were followed up for at least 3 years (range 3-6) after the completion of treatment; at their last assessment none had features of active TB and all were sputum negative (smear and culture). Two returned to their countries of origin during treatment; they were sputum negative at that time. Two patients are well and continue on treatment in the U.K. One patient (known HIV negative) died following treatment failure. In conclusion, we obtained disease-free survival in eight cases of MDR-TB, known or presumed to be HIV negative and followed up for 3 years or more. The prognosis for patients treated at specialised centres is good (and better than is generally believed). We describe a new protocol for the detection and management of MDR-TB.

  4. Inhibition of Glutamine Synthetase: A Potential Drug Target in Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Sherry L. Mowbray

    2014-08-01

    Full Text Available Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. Globally, tuberculosis is second only to AIDS in mortality and the disease is responsible for over 1.3 million deaths each year. The impractically long treatment schedules (generally 6–9 months and unpleasant side effects of the current drugs often lead to poor patient compliance, which in turn has resulted in the emergence of multi-, extensively- and totally-drug resistant strains. The development of new classes of anti-tuberculosis drugs and new drug targets is of global importance, since attacking the bacterium using multiple strategies provides the best means to prevent resistance. This review presents an overview of the various strategies and compounds utilized to inhibit glutamine synthetase, a promising target for the development of drugs for TB therapy.

  5. Drug resistance in Indian visceral leishmaniasis.

    Science.gov (United States)

    Sundar, S

    2001-11-01

    Throughout the world, pentavalent antimonial compounds (Sb(v)) have been the mainstay of antileishmanial therapy for more than 50 years. Sb(v) has been highly effective in the treatment of Indian visceral leishmaniasis (VL: kala-azar) at a low dose (10 mg/kg) for short durations (6-10 days). But in the early 1980s reports of its ineffectiveness emerged, and the dose of Sb(v) was eventually raised to 20 mg/kg for 30-40 days. This regimen cures most patients with VL except in India, where the proportion of patients unresponsive to Sb(v) has steadily increased. In hyperendemic districts of north Bihar, 50-65% patients fail treatment with Sb(v). Important reasons are rampant use of subtherapeutic doses, incomplete duration of treatment and substandard drugs. In vitro experiments have established emergence of Sb(v) resistant strains of Leishmania donovani, as isolates from unresponsive patients require 3-5 times more Sb(v) to reach similarly effectiveness against the parasite as in Sb(v) responders. Anthroponotic transmission in India has been an important factor in rapid increase in the Sb(v) refractoriness. Pentamidine was the first drug to be used and cured 99% of these refractory patients, but over time even with double the amount of initial doses, it cures only 69-78% patients now and its use has largely been abandoned in India. Despite several disadvantages, amphotericin B is the only drug available for use in these areas and should be used as first-line drug instead of Sb(v). The new oral antileishmanial drug miltefosine is likely to be the first-line drug in future. Unfortunately, development of newer antileishmanial drugs is rare; two promising drugs, aminosidine and sitamaquine, may be developed for use in the treatment of VL. Lipid associated amphotericin B has an excellent safety and efficacy profile, but remains out of reach for most patients because of its high cost.

  6. 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...

  7. Drug resistance reversal--are we getting closer?

    Science.gov (United States)

    Baird, R D; Kaye, S B

    2003-11-01

    Clinical drug resistance is a major barrier to overcome before chemotherapy can become curative for most patients presenting with metastatic cancer. Rational attempts to tackle clinical drug resistance need to be based on an understanding of the mechanisms involved; these are likely to be complex and multifactorial, and may be due to inadequate drug exposure or alterations in the cancer cell itself. This article reviews a number of strategies used to tackle drug resistance, focussing on work in our institution related to the treatment of ovarian cancer and resistance to platinum and taxane-based chemotherapy. Further progress towards drug resistance reversal will require a three-pronged approach, namely: the development of novel cytotoxics which exploit selectively expressed targets; modulation of resistance to conventional agents and, most importantly, a serious attempt to understand resistance mechanisms in tumour samples taken both pre- and post-chemotherapy.

  8. 异烟肼耐药耻垢分枝杆菌的建立及药物敏感性的测定%Establishment and drug susceptibility test of isoniazid resistant Mycobacterium smegmatis

    Institute of Scientific and Technical Information of China (English)

    贾平平; 赵莉莉; 李晓宇; 张全; 刘振龙; 王鑫; 余利岩; 赵立勋; 岑山

    2011-01-01

    With the emergence of drug resistant tuberculosis, it is very urgent to find novel anti-tuberculosis drugs, especially novel anti-drug-resistant tuberculosis drugs. Because of the slow growth and the need to work in a biosafty environment of Mycobacterium tuberculosis, the development of evaluation of drug effect is severely impeded. In order to solve these issues, non-pathogenic fast-growing Mycobacterium smegmatis is introduced as test organism. The inhA is one of a target of isoniazid (INH) overexpression or mutation of this gene in Mycobacterium tuberculosis conferring resistant to INH. A recombinant plasmid bearing inhA was constructed and electroporated into Mycobacterium smegmatis, using shuttle expression vector pMV261. Transformants were induced to express a protein of inhA, identified by SDS-PAGE. Results show that Mycobacterium smegmatis containing inhA plasmids exhibited 100-fold or greater increased resistance to INH, but it conferred no increased resistance to others first-line anti-tuberculosis drugs. Resazurin microtiter assay plate testing of Mycobacterium smegmatis susceptibility to drugs is a rapid, simple, and inexpensive method and could decrease color background of drugs by detecting fluorescence. It will be benefit for highthroughout screening of drugs of anti-isoniazid-resistant Mycobacteria.%耐药结核病的涌现,使发展新型抗耐药结核药物变得尤为迫切.本研究选择生长快且无致病性的耻垢分枝杆菌为研究对象,探索快速评价药物抗异烟肼耐药结核分枝杆菌的能力.inhA是异烟肼的作用靶点,由于inhA的突变或者过表达可以引起结核分枝杆菌对异烟肼耐药性的产生.通过将inhA克隆入pMV261中,构建过表达inhA的耻垢分枝杆菌.结果显示,过量表达inhA的耻垢分枝杆菌对异烟肼的敏感性下降了100倍以上.建立了利用刃天青为指示剂的抗异烟肼耐药株的快速药效评价方法,可快速对药物的活性进行定性或定量

  9. Proteomic insights into Acinetobacter baumannii drug resistance and pathogenesis.

    Science.gov (United States)

    Long, Quanxin; Huang, Changwu; Liao, Pu; Xie, Jianping

    2013-01-01

    Acinetobacter baumannii is an important opportunist pathogen, due to severe antibiotic resistance and nosocomial infection. The epidemiology and antibiotic resistance of A.baumannii have been extensively reviewed, but the pathogenesis and virulence remain unclear. Proteomics analysis has been applied to study the mechanism of drug resistance, biofilm, micronutrient acquisition, and the extracellular compartment. This review summarizes applications of proteomics in A. baumannii, aiming to summarize novel insights into the mechanism of A. baumannii pathogenesis and drug resistance.

  10. Targeting efflux pumps to overcome antifungal drug resistance.

    Science.gov (United States)

    Holmes, Ann R; Cardno, Tony S; Strouse, J Jacob; Ivnitski-Steele, Irena; Keniya, Mikhail V; Lackovic, Kurt; Monk, Brian C; Sklar, Larry A; Cannon, Richard D

    2016-08-01

    Resistance to antifungal drugs is an increasingly significant clinical problem. The most common antifungal resistance encountered is efflux pump-mediated resistance of Candida species to azole drugs. One approach to overcome this resistance is to inhibit the pumps and chemosensitize resistant strains to azole drugs. Drug discovery targeting fungal efflux pumps could thus result in the development of azole-enhancing combination therapy. Heterologous expression of fungal efflux pumps in Saccharomyces cerevisiae provides a versatile system for screening for pump inhibitors. Fungal efflux pumps transport a range of xenobiotics including fluorescent compounds. This enables the use of fluorescence-based detection, as well as growth inhibition assays, in screens to discover compounds targeting efflux-mediated antifungal drug resistance. A variety of medium- and high-throughput screens have been used to identify a number of chemical entities that inhibit fungal efflux pumps.

  11. Drug resistance in Leishmania: similarities and differences to other organisms.

    Science.gov (United States)

    Papadopoulou, B; Kündig, C; Singh, A; Ouellette, M

    1998-01-01

    The main line of defense available against parasitic protozoa is chemotherapy. Drug resistance has emerged however, as a primary obstacle to the successful treatment and control of parasitic diseases. Leishmania spp., the causative agents of leishmaniasis, have served as a useful model for studying mechanisms of drug resistance in vitro. Antimonials and amphotericin B are the first line drugs to treat Leishmania followed by pentamidine and a number of other drugs. Parasites resistant against all these classes of drugs have been selected under laboratory conditions. A multiplicity of resistance mechanisms has been detected, the most prevalent being gene amplification and transport mutations. With the tools now available, it should be possible to elucidate the mechanisms that govern drug resistance in field isolates and develop more effective chemotherapeutic agents.

  12. Treatment of falciparum malaria in the age of drug resistance

    Directory of Open Access Journals (Sweden)

    Shanks G

    2006-01-01

    Full Text Available The growing problem of drug resistance has greatly complicated the treatment for falciparum malaria. Whereaschloroquine and sulfadoxine/pyrimethamine could once cure most infections, this is no longer true and requiresexamination of alternative regimens. Not all treatment failures are drug resistant and other issues such asexpired antimalarials and patient compliance need to be considered. Continuation of a failing treatment policyafter drug resistance is established suppresses infections rather than curing them, leading to increasedtransmission of malaria, promotion of epidemics and loss of public confidence in malaria control programs.Antifolate drug resistance (i.e. pyrimethamine means that new combinations are urgently needed particularlybecause addition of a single drug to an already failing regimen is rarely effective for very long. Atovaquone/proguanil and mefloquine have been used against multiple drug resistant falciparum malaria with resistance toeach having been documented soon after drug introduction. Drug combinations delay further transmission ofresistant parasites by increasing cure rates and inhibiting formation of gametocytes. Most currentlyrecommended drug combinations for falciparum malaria are variants of artemisinin combination therapy wherea rapidly acting artemisinin compound is combined with a longer half-life drug of a different class. Artemisininsused include dihydroartemisinin, artesunate, artemether and companion drugs include mefloquine, amodiaquine,sulfadoxine/pyrimethamine, lumefantrine, piperaquine, pyronaridine, chlorproguanil/dapsone. The standard ofcare must be to cure malaria by killing the last parasite. Combination antimalarial treatment is vital not only tothe successful treatment of individual patients but also for public health control of malaria.

  13. 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

    Resistance arises quickly during chemotherapeutic selection and is particularly problematic during long-term treatment regimens such as those for tuberculosis, HIV infections, or cancer. Although drug combination therapy reduces the evolution of drug resistance, drug pairs vary in their ability...

  14. 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 mech

  15. DRUG-RESISTANCE, SUPPORTIVE CARE AND DOSE INTENSITY

    NARCIS (Netherlands)

    DEVRIES, EGE; HAMILTON, TC; LIND, M; DAUPLAT, J; NEIJT, JP; OZOLS, RF

    1993-01-01

    Background: Both intrinsic and acquired drug resistance occur in ovarian cancer. Much work on in vivo or in vitro, obtained drug resistance has been done and this knowledge is presently being converted into clinical studies. Materials and methods: The review focuses on the detoxifying system, MDR (m

  16. Synthesis, characterization and pharmacological studies of copper complexes of flavone derivatives as potential anti-tuberculosis agents.

    Science.gov (United States)

    Joseph, J; Nagashri, K; Suman, A

    2016-09-01

    Novel series of different hydroxyflavone derivatives and their copper complexes were synthesized. They were characterized using analytical and spectral techniques. The superoxide dismutase (SOD) mimetic activity of the synthesized complexes demonstrated that copper complex of L(10) has promising SOD-mimetic activity than other ligands & complexes. The in vitro antimicrobial activities of the synthesized compounds were tested against the bacterial species and fungal species. The DNA binding properties of copper complexes were studied using cyclic voltametry and electronic absorption techniques. Anti-tuberculosis activity was also performed. The effective complexes was subjected to antimycobacterial activity using MABA method and summarized. The antimycobacterial activity of copper complexes have been evaluated and discussed.

  17. Epidemiological control of drug resistance and compensatory mutation under resistance testing and second-line therapy.

    Science.gov (United States)

    Saddler, Clare A; Wu, Yue; Valckenborgh, Frank; Tanaka, Mark M

    2013-12-01

    The fitness cost of antibiotic resistance in the absence of treatment raises the possibility that prudent use of drugs may slow or reverse the rise of resistance. Unfortunately, compensatory mutations that lower this cost may lead to entrenched resistance. Here, we develop a mathematical model of resistance evolution and compensatory mutation to determine whether reversion to sensitivity can occur, and how disease control might be facilitated by a second-line therapy. When only a single antibiotic is available, sensitive bacteria reach fixation only under treatment rates so low that hardly any cases are treated. We model a scenario in which drug sensitivity can be accurately tested so that a second-line therapy is administered to resistant cases. Before the rise of resistance to the second drug, disease eradication is possible if resistance testing and second-line treatment are conducted at a high enough rate. However, if double drug resistance arises, the possibility of disease eradication is greatly reduced and compensated resistance prevails in most of the parameter space. The boundary separating eradication from fixation of compensated resistance is strongly influenced by the underlying basic reproductive number of the pathogen and drug efficacy in sensitive cases, but depends less on the resistance cost and compensation. When double resistance is possible, the boundary is affected by the relative strengths of resistance against the two drugs in the double-resistant-compensated strain.

  18. 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 provide insight into the empiric treatment of TBM. METHODS: Mycobacterium tuberculosis was cultured from the cerebrospinal fluid (CSF) of 142 patients and was tested for susceptibility to first-line antituberculosis drugs, streptomycin (SM), isoniazid (INH), rifampicin (RIF) and ethambutol (EMB). RESULTS...

  19. Fitness cost of chromosomal drug resistance-conferring mutations.

    Science.gov (United States)

    Sander, Peter; Springer, Burkhard; Prammananan, Therdsak; Sturmfels, Antje; Kappler, Martin; Pletschette, Michel; Böttger, Erik C

    2002-05-01

    To study the cost of chromosomal drug resistance mutations to bacteria, we investigated the fitness cost of mutations that confer resistance to different classes of antibiotics affecting bacterial protein synthesis (aminocyclitols, 2-deoxystreptamines, macrolides). We used a model system based on an in vitro competition assay with defined Mycobacterium smegmatis laboratory mutants; selected mutations were introduced by genetic techniques to address the possibility that compensatory mutations ameliorate the resistance cost. We found that the chromosomal drug resistance mutations studied often had only a small fitness cost; compensatory mutations were not involved in low-cost or no-cost resistance mutations. When drug resistance mutations found in clinical isolates were considered, selection of those mutations that have little or no fitness cost in the in vitro competition assay seems to occur. These results argue against expectations that link decreased levels of antibiotic consumption with the decline in the level of resistance.

  20. Challenges in the development of drugs for the treatment of tuberculosis

    Directory of Open Access Journals (Sweden)

    Adeeb Shehzad

    2013-02-01

    Full Text Available Tuberculosis infection is a serious human health threat and the early 21st century has seen a remarkable increase in global tuberculosis activity. The pathogen responsible for tuberculosis is Mycobacterium tuberculosis, which adopts diverse strategies in order to survive in a variety of host lesions. These survival mechanisms make the pathogen resistant to currently available drugs, a major contributing factor in the failure to control the spread of tuberculosis. Multiple drugs are available for clinical use and several potential compounds are being screened, synthesized, or evaluated in preclinical or clinical studies. Lasting and effective achievements in the development of anti-tuberculosis drugs will depend largely on the proper understanding of the complex interactions between the pathogen and its human host. Ample evidence exists to explain the characteristics of tuberculosis. In this study, we highlighted the challenges for the development of novel drugs with potent bacteriostatic or bactericidal activity, which reduce the minimum time required to cure tuberculosis infection.

  1. The evolution of drug-resistant malaria: the role of drug elimination half-life.

    OpenAIRE

    Hastings, Ian M.; Watkins, William M; White, Nicholas J

    2002-01-01

    This paper seeks to define and quantify the influence of drug elimination half-life on the evolution of antimalarial drug resistance. There are assumed to be three general classes of susceptibility of the malaria parasite Plasmodium falciparum to a drug: Res0, the original, susceptible wildtype; Res1, a group of intermediate levels of susceptibility that are more tolerant of the drug but still cleared by treatment; and Res2, which is completely resistant to the drug. Res1 and Res2 resistance ...

  2. 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.

  3. Design, synthesis and study of quinoxaline-2- carboxamide 1,4-DI-N-Oxide derivatives as anti-tuberculosis agents

    OpenAIRE

    Moreno-Viguri, E. (Elsa); Monge, A; Perez-Silanes, S. (Silvia)

    2013-01-01

    The experimental work presented in this memory is based on the hypothesis that quinoxalines di-N-oxide, considered to be the core of the structure, which present a carboxamide moiety on position two and aliphatic linker between this group and an aromatic system, can be proposed as potent anti-tuberculosis agents. The main purpose of this project is the synthesis of new quinoxaline di-N-oxide derivatives as anti-tuberculosis agents. The strategy consists of the design and synthesis of several ...

  4. Drug-resistance mechanisms and prevalence of Enterobacter cloacae resistant to multi-antibiotics

    Institute of Scientific and Technical Information of China (English)

    张杰; 顾怡明; 俞云松; 周志慧; 杜小玲

    2004-01-01

    @@The main drug-resistance mechanism of gram-negative bacteria is producing β-lactamases. Two kinds of enzymes cause drug resistance by hydrolyzing oxyimino-cephalosporins and aztreonam: one is chromosomally encoded AmpC β-lactamases, the other is plasmid-mediated extended-spectrum β-lactamases (ESBLs). Enterobacter cloacae can produce both of them, so that these strains are seriously resistance to many antibiotics. In order to study the main drug-resistant mechanism in Enterobacter cloacae, PCR and nucleotide sequencing were performed on 58 multidrug resistant strains.

  5. Exploiting bacterial drug resistance: a single construct for the diagnosis and treatment of drug resistant infections

    Science.gov (United States)

    Sallum, Ulysses W.; Zheng, Xiang; Verma, Sarika; Hasan, Tayyaba

    2009-06-01

    β-lactamase enzyme-activated photosensitizer (β-LEAP). We aim to exploit drug resistance mechanisms to selectively release photosensitizers (PSs) for a specific photodynamic antimicrobial effect and reduced host tissue damage. Consequently, the fluorescence emission intensity of the PSs increases and allows for the detection of enzyme activity. In this work we sought to evaluate β-LEAP for use as a sensitive molecular probe. We have reported the enzyme specific antibacterial action of β-LEAP. Here we report the use of β-LEAP for the rapid functional definition of a β-lactamase.

  6. Current Status of Methods to Assess Cancer Drug Resistance

    Directory of Open Access Journals (Sweden)

    Theodor H. Lippert, Hans-Jörg Ruoff, Manfred Volm

    2011-01-01

    Full Text Available Drug resistance is the main cause of the failure of chemotherapy of malignant tumors, resistance being either preexisting (intrinsic resistance or induced by the drugs (acquired resistance. At present, resistance is usually diagnosed during treatment after a long period of drug administration.In the present paper, methods for a rapid assessment of drug resistance are described. Three main classes of test procedures can be found in the literature, i.e. fresh tumor cell culture tests, cancer biomarker tests and positron emission tomography (PET tests. The methods are based on the evaluation of molecular processes, i.e. metabolic activities of cancer cells. Drug resistance can be diagnosed before treatment in-vitro with fresh tumor cell culture tests, and after a short time of treatment in-vivo with PET tests. Cancer biomarker tests, for which great potential has been predicted, are largely still in the development stage. Individual resistance surveillance with tests delivering rapid results signifies progress in cancer therapy management, by providing the possibility to avoid drug therapies that are ineffective and only harmful.

  7. Defeating pathogen drug resistance: guidance from evolutionary theory.

    Science.gov (United States)

    Pepper, John W

    2008-12-01

    Many of the greatest challenges in medicine and public health involve the evolution of drug resistance by pathogens. Recent advances in the theory of natural selection suggest that there are two broad classes of pathogen traits that can be targeted by drugs or vaccines. The first class, consisting of traits that benefit the individual organisms bearing them, causes a strong evolutionary response and the rapid emergence of drug resistance. The second class, consisting of traits that benefit groups of pathogen organisms including the individual provider, causes a weaker evolutionary response and less drug resistance. Although most previous drug development has targeted the first class, it would be advantageous to focus on the second class as targets for drug and vaccine development. Specific examples and test cases are discussed.

  8. Delamanid: A new armor in combating drug-resistant tuberculosis

    Directory of Open Access Journals (Sweden)

    Alphienes Stanley Xavier

    2014-01-01

    Full Text Available Intense search has been made in the discovery of newer anti-TB drugs to tackle the issues such as drug resistance, HIV co-infection and risk of drug-drug interactions in the management of TB. Delamanid, a newer mycobacterial cell wall synthesis inhibitor, received a conditional approval from European medicines agency (EMA for the treatment of MDR-TB. Preclinical and clinical studies have shown that delamanid has high potency, least risk for drug-drug interactions and better tolerability.

  9. Epigenetic strategies to reverse drug resistance in heterogeneous multiple myeloma.

    Science.gov (United States)

    Issa, Mark E; Takhsha, Farnaz Sedigheh; Chirumamilla, Chandra Sekhar; Perez-Novo, Claudina; Vanden Berghe, Wim; Cuendet, Muriel

    2017-01-01

    Multiple myeloma (MM) is a hematological malignancy, which remains incurable because most patients eventually relapse or become refractory to current treatments. Due to heterogeneity within the cancer cell microenvironment, cancer cell populations employ a dynamic survival strategy to chemotherapeutic treatments, which frequently results in a rapid acquisition of therapy resistance. Besides resistance-conferring genetic alterations within a tumor cell population selected during drug treatment, recent findings also reveal non-mutational mechanisms of drug resistance, involving a small population of "cancer stem cells" (CSCs) which are intrinsically more refractory to the effects of a variety of anticancer drugs. Other studies have implicated epigenetic mechanisms in reversible drug tolerance to protect the population from eradication by potentially lethal exposures, suggesting that acquired drug resistance does not necessarily require a stable heritable genetic alteration. Clonal evolution of MM cells and the bone marrow microenvironment changes contribute to drug resistance. MM-CSCs may not be a static population and survive as phenotypically and functionally different cell types via the transition between stem-like and non-stem-like states in local microenvironments, as observed in other types of cancers. Targeting MM-CSCs is clinically relevant, and different approaches have been suggested to target molecular, metabolic and epigenetic signatures, and the self-renewal signaling characteristic of MM CSC-like cells. Here, we summarize epigenetic strategies to reverse drug resistance in heterogeneous multiple myeloma.

  10. Mechanisms of Resistance to Antibody-Drug Conjugates.

    Science.gov (United States)

    Loganzo, Frank; Sung, Matthew; Gerber, Hans-Peter

    2016-12-01

    Drug resistance limits the effectiveness of cancer therapies. Despite attempts to develop curative anticancer treatments, tumors evolve evasive mechanisms limiting durable responses. Hence, diverse therapies are used to attack cancer, including cytotoxic and targeted agents. Antibody-drug conjugates (ADC) are biotherapeutics designed to deliver potent cytotoxins to cancer cells via tumor-specific antigens. Little is known about the clinical manifestations of drug resistance to this class of therapy; however, recent preclinical studies reveal potential mechanisms of resistance. Because ADCs are a combination of antibody and small molecule cytotoxin, multifactorial modes of resistance are emerging that are inherent to the structure and function of the ADC. Decreased cell-surface antigen reduces antibody binding, whereas elevated drug transporters such as MDR1 and MRP1 reduce effectiveness of the payload. Inherent to the uniqueness of the ADC, other novel resistance mechanisms are emerging, including altered antibody trafficking, ADC processing, and intracellular drug release. Most importantly, the modular nature of the ADC allows components to be switched and replaced, enabling development of second-generation ADCs that overcome acquired resistance. This review is intended to highlight recent progress in our understanding of ADC resistance, including approaches to create preclinical ADC-refractory models and to characterize their emerging mechanisms of resistance. Mol Cancer Ther; 15(12); 2825-34. ©2016 AACR.

  11. Antimicrobial resistance determinant microarray for analysis of multi-drug resistant isolates

    Science.gov (United States)

    Taitt, Chris Rowe; Leski, Tomasz; Stenger, David; Vora, Gary J.; House, Brent; Nicklasson, Matilda; Pimentel, Guillermo; Zurawski, Daniel V.; Kirkup, Benjamin C.; Craft, David; Waterman, Paige E.; Lesho, Emil P.; Bangurae, Umaru; Ansumana, Rashid

    2012-06-01

    The prevalence of multidrug-resistant infections in personnel wounded in Iraq and Afghanistan has made it challenging for physicians to choose effective therapeutics in a timely fashion. To address the challenge of identifying the potential for drug resistance, we have developed the Antimicrobial Resistance Determinant Microarray (ARDM) to provide DNAbased analysis for over 250 resistance genes covering 12 classes of antibiotics. Over 70 drug-resistant bacteria from different geographic regions have been analyzed on ARDM, with significant differences in patterns of resistance identified: genes for resistance to sulfonamides, trimethoprim, chloramphenicol, rifampin, and macrolide-lincosamidesulfonamide drugs were more frequently identified in isolates from sources in Iraq/Afghanistan. Of particular concern was the presence of genes responsible for resistance to many of the last-resort antibiotics used to treat war traumaassociated infections.

  12. The evolution of drug-resistant malaria

    OpenAIRE

    Plowe, Christopher V.

    2008-01-01

    Molecular epidemiological investigations have uncovered the patterns of emergence and global spread of Plasmodium falciparum resistance to chloroquine and sulfadoxine-pyrimethamine. Malaria parasites highly resistant to chloroquine and pyrimethamine spread from Asian origins to Africa, at great cost to human health and life. If artemisinin-resistant falciparum malaria follows the same pattern, renewed efforts to eliminate and eradicate malaria will be gravely threatened. This paper, adapted f...

  13. 75 FR 33317 - Antibacterial Resistance and Diagnostic Device and Drug Development Research for Bacterial...

    Science.gov (United States)

    2010-06-11

    ... Development Research for Bacterial Diseases; Public Workshop AGENCY: Food and Drug Administration, HHS. ACTION.... The workshop will address antibacterial drug resistance, mechanisms of resistance, epidemiology of... Drug Evaluation and Research, Food and Drug Administration, Office of Antimicrobial Products, 10903...

  14. Structure-based drug design to overcome drug resistance: challenges and opportunities.

    Science.gov (United States)

    Ferreira, Rafaela S; Andricopulo, Adriano D

    2014-01-01

    Drug resistance is a common concern for the development of novel antiviral, antimicrobial and anticancer therapies. To overcome this problem, several strategies have been developed, many of which involving the theme of this review, the use of structure-based drug design (SBDD) approaches. These include the successful design of new compounds that target resistant mutant proteins, as well as the development of drugs that target multiple proteins involved in specific biochemical pathways. Finally, drug resistance can also be considered in the early stages of drug discovery, through the use of strategies to delay the development of resistance. The purpose of this brief review is to underline the usefulness of SBDD approaches based on case studies, highlighting present challenges and opportunities in drug design.

  15. Emerging Infections Program as Surveillance for Antimicrobial Drug Resistance.

    Science.gov (United States)

    Fridkin, Scott K; Cleveland, Angela A; See, Isaac; Lynfield, Ruth

    2015-09-01

    Across the United States, antimicrobial drug-resistant infections affect a diverse population, and effective interventions require concerted efforts across various public health and clinical programs. Since its onset in 1994, the Centers for Disease Control and Prevention Emerging Infections Program has provided robust and timely data on antimicrobial drug-resistant infections that have been used to inform public health action across a spectrum of partners with regard to many highly visible antimicrobial drug-resistance threats. These data span several activities within the Program, including respiratory bacterial infections, health care-associated infections, and some aspects of foodborne diseases. These data have contributed to estimates of national burden, identified populations at risk, and determined microbiological causes of infection and their outcomes, all of which have been used to inform national policy and guidelines to prevent antimicrobial drug-resistant infections.

  16. Drug resistance in cancer: molecular evolution and compensatory proliferation.

    Science.gov (United States)

    Friedman, Ran

    2016-03-15

    Targeted therapies have revolutionized cancer treatment. Unfortunately, their success is limited due to the development of drug resistance within the tumor, which is an evolutionary process. Understanding how drug resistance evolves is a prerequisite to a better success of targeted therapies. Resistance is usually explained as a response to evolutionary pressure imposed by treatment. Thus, evolutionary understanding can and should be used in the design and treatment of cancer. In this article, drug-resistance to targeted therapies is reviewed from an evolutionary standpoint. The concept of apoptosis-induced compensatory proliferation (AICP) is developed. It is shown that AICP helps to explain some of the phenomena that are observed experimentally in cancers. Finally, potential drug targets are suggested in light of AICP.

  17. Drug resistance in African trypanosomiasis: the melarsoprol and pentamidine story.

    Science.gov (United States)

    Baker, Nicola; de Koning, Harry P; Mäser, Pascal; Horn, David

    2013-03-01

    Melarsoprol and pentamidine represent the two main classes of drugs, the arsenicals and diamidines, historically used to treat the diseases caused by African trypanosomes: sleeping sickness in humans and Nagana in livestock. Cross-resistance to these drugs was first observed over 60 years ago and remains the only example of cross-resistance among sleeping sickness therapies. A Trypanosoma brucei adenosine transporter is well known for its role in the uptake of both drugs. More recently, aquaglyceroporin 2 (AQP2) loss of function was linked to melarsoprol-pentamidine cross-resistance. AQP2, a channel that appears to facilitate drug accumulation, may also be linked to clinical cases of resistance. Here, we review these findings and consider some new questions as well as future prospects for tackling the devastating diseases caused by these parasites.

  18. [Cluster of multidrug-resistant tuberculosis cases in a school of the district of Ica, Peru].

    Science.gov (United States)

    Torres, Julio; Sardón, Victoria; Soto, Mirtha G; Anicama, Rolado; Arroyo-Hernández, Hugo; Munayco, César V

    2011-01-01

    We describe the evolution and features of a cluster of Multidrug-resistant tuberculosis (MDR TB) cases that occurred in 2001, in a school located in a sub-urban area of the district of Ica, Peru. We identified 15 students related before becoming infected with tuberculosis. The mean age of the cluster was 15 years. A total of 12 students were MDR-TB cases and 7 were drug-resistant to 5 first-line drugs (RHEZS). Five out of the 15 cases received at least 3 different anti-tuberculosis treatment schemes. The average treatment duration was 37 months (minimum 21 and maximum 59 months). A total of 13 cases recovered and 2 died. This study describes a cluster of MDR -TB cases in an educational facility, which due to the epidemiological link and time presentation, is probably an outbreak of MDR TB with a satisfactory outcome after prolonged treatment.

  19. Highly active ozonides selected against drug resistant malaria

    Directory of Open Access Journals (Sweden)

    Lis Lobo

    2016-01-01

    Full Text Available Ever increasing multi-drug resistance by Plasmodium falciparum is creating new challenges in malaria chemotherapy. In the absence of licensed vaccines, treatment and prevention of malaria is heavily dependent on drugs. Potency, range of activity, safety, low cost and ease of administration are crucial issues in the design and formulation of antimalarials. We have tested three synthetic ozonides NAC89, LC50 and LCD67 in vitro and in vivo against multidrug resistant Plasmodium. In vitro, LC50 was at least 10 times more efficient inhibiting P. falciparum multidrug resistant Dd2 strain than chloroquine and mefloquine and as efficient as artemisinin (ART, artesunate and dihydroartemisinin. All three ozonides showed high efficacy in clearing parasitaemia in mice, caused by multi-drug resistant Plasmodium chabaudi strains, by subcutaneous administration, demonstrating high efficacy in vivo against ART and artesunate resistant parasites.

  20. Highly active ozonides selected against drug resistant malaria

    Science.gov (United States)

    Lobo, Lis; de Sousa, Bruno; Cabral, Lília; Cristiano, Maria LS; Nogueira, Fátima

    2016-01-01

    Ever increasing multi-drug resistance by Plasmodium falciparum is creating new challenges in malaria chemotherapy. In the absence of licensed vaccines, treatment and prevention of malaria is heavily dependent on drugs. Potency, range of activity, safety, low cost and ease of administration are crucial issues in the design and formulation of antimalarials. We have tested three synthetic ozonides NAC89, LC50 and LCD67 in vitro and in vivo against multidrug resistant Plasmodium. In vitro, LC50 was at least 10 times more efficient inhibiting P. falciparum multidrug resistant Dd2 strain than chloroquine and mefloquine and as efficient as artemisinin (ART), artesunate and dihydroartemisinin. All three ozonides showed high efficacy in clearing parasitaemia in mice, caused by multi-drug resistant Plasmodium chabaudi strains, by subcutaneous administration, demonstrating high efficacy in vivo against ART and artesunate resistant parasites. PMID:27276364

  1. Drug resistance in the sexually transmitted protozoan Trichomonas vaginalis

    Institute of Scientific and Technical Information of China (English)

    REBECCA L DUNNE; LINDA A DUNN; PETER UPCROFT; PETER J O'DONOGHUE; JACQUELINE A UPCROFT

    2003-01-01

    Trichomoniasis is the most common, sexually transmitted infection. It is caused by the flagellated protozoan parasite Trichomonas vaginalis. Symptoms include vaginitis and infections have been associated with preterm delivery, low birth weight and increased infant mortality, as well as predisposing to HIV/AIDS and cervical cancer. Trichomoniasis has the highest prevalence and incidence of any sexually transmitted infection. The 5-nitroimidazole drugs, of which metronidazole is the most prescribed, are the only approved,effective drugs to treat trichomoniasis. Resistance against metronidazole is frequently reported and crossresistance among the family of 5-nitroimidazole drugs is common, leaving no alternative for treatment, with some cases remaining unresolved. The mechanism of metronidazole resistance in T. vaginalis from treatment failures is not well understood, unlike resistance which is developed in the laboratory under increasing metronidazole pressure. In the latter situation, hydrogenosomal function which is involved in activation of the prodrug, metronidazole, is down-regulated. Reversion to sensitivity is incomplete after removal of drug pressure in the highly resistant parasites while clinically resistant strains, so far analysed, maintain their resistance levels in the absence of drug pressure. Although anaerobic resistance has been regarded as a laboratory induced phenomenon, it clearly has been demonstrated in clinical isolates. Pursuit of both approaches will allow dissection of the underlying mechanisms. Many alternative drugs and treatments have been tested in vivo in cases of refractory trichomoniasis, as well as in vitro with some successes including the broad spectrum anti-parasitic drug nitazoxanide. Drug resistance incidence in T. vaginalis appears to be on the increase and improved surveillance of treatment failures is urged.

  2. Drug-resistant tuberculosis: time for visionary political leadership

    OpenAIRE

    Abubakar, I; Zignol, M; Falzon, D; Raviglione, M.; Ditiu, L; Masham, S; Adetifa, I; Ford, N.; Cox, H.; Lawn, SD; Marais, BJ; McHugh, TD; Mwaba, P.; Bates, M; M. Lipman

    2013-01-01

    Two decades ago, WHO declared tuberculosis a global emergency, and invested in the highly cost-effective directly observed treatment short-course programme to control the epidemic. At that time, most strains of Mycobacterium tuberculosis were susceptible to first-line tuberculosis drugs, and drug resistance was not a major issue. However, in 2013, tuberculosis remains a major public health concern worldwide, with prevalence of multidrug-resistant (MDR) tuberculosis rising. WHO estimates rough...

  3. Identifying clinically relevant drug resistance genes in drug-induced resistant cancer cell lines and post-chemotherapy tissues.

    Science.gov (United States)

    Tong, Mengsha; Zheng, Weicheng; Lu, Xingrong; Ao, Lu; Li, Xiangyu; Guan, Qingzhou; Cai, Hao; Li, Mengyao; Yan, Haidan; Guo, You; Chi, Pan; Guo, Zheng

    2015-12-01

    Until recently, few molecular signatures of drug resistance identified in drug-induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5-fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens.

  4. The challenges of multi-drug-resistance in hepatology.

    Science.gov (United States)

    Fernández, Javier; Bert, Frédéric; Nicolas-Chanoine, Marie-Hélène

    2016-11-01

    Antimicrobial resistance has become a major global public health security problem that needs coordinated approaches at regional, national and international levels. Antibiotic overuse and the failure of control measures to prevent the spread of resistant bacteria in the healthcare environment have led to an alarming increase in the number of infections caused by resistant bacteria, organisms that resist many (multi-drug and extensively drug-resistant strains), if not all (pan-drug-resistant bacteria) currently available antibiotics. While Gram-positive cocci resistance (methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci) shows a heterogeneous geographical distribution, extended-spectrum β-lactamase-producing Enterobacteriaceae and carbapenem-resistant Enterobacteriaceae have become pandemic worldwide and endemic in some parts of the world, respectively. Moreover, currently available therapeutic options for resistant bacteria are very limited, with very few new agents in development. Antimicrobial resistance is especially relevant in decompensated cirrhosis. Firstly, cirrhotic patients are highly susceptible to develop infections caused by resistant bacteria as risk factors of multiresistance concentrate in this population (mainly repeated hospitalizations and antibiotic exposure). Secondly, inappropriate empirical antibiotic schedules easily translate into increased morbidity (acute kidney injury, acute-on-chronic liver failure, septic shock) and hospital mortality in advanced cirrhosis. Therefore, hepatologists must face nowadays a complex clinical scenario that requires new empirical antibiotic strategies that may further spread resistance. Global, regional and local preventive measures should therefore be implemented to combat antimicrobial resistance in cirrhosis including the restriction of antibiotic prophylaxis to high-risk populations, investigation on non-antibiotic prophylaxis, stewardship programs on adequate antibiotic

  5. Identification of New Drug Targets in Multi-Drug Resistant Bacterial Infections

    Science.gov (United States)

    2012-10-01

    COVERED 26 September 2011 25 September 2012 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Identification of New Drug Targets in Multi-Drug Resistant...will be necessary for the fragment based screening and subsequent design of new drug lead compounds. To accompany and validate the structural studies

  6. Drug efflux pump deficiency and drug target resistance masking in growing bacteria

    Science.gov (United States)

    Fange, David; Nilsson, Karin; Tenson, Tanel; Ehrenberg, Måns

    2009-01-01

    Recent experiments have shown that drug efflux pump deficiency not only increases the susceptibility of pathogens to antibiotics, but also seems to “mask” the effects of mutations, that decrease the affinities of drugs to their intracellular targets, on the growth rates of drug-exposed bacteria. That is, in the presence of drugs, the growth rates of drug-exposed WT and target mutated strains are the same in a drug efflux pump deficient background, but the mutants grow faster than WT in a drug efflux pump proficient background. Here, we explain the mechanism of target resistance masking and show that it occurs in response to drug efflux pump inhibition among pathogens with high-affinity drug binding targets, low cell-membrane drug-permeability and insignificant intracellular drug degradation. We demonstrate that target resistance masking is fundamentally linked to growth-bistability, i.e., the existence of 2 different steady state growth rates for one and the same drug concentration in the growth medium. We speculate that target resistance masking provides a hitherto unknown mechanism for slowing down the evolution of target resistance among pathogens. PMID:19416855

  7. Drug Resistance in Patients with Pulmonary Tuberculosis at Different Ages in Huizhou City%惠州市不同年龄段肺结核患者耐药情况分析

    Institute of Scientific and Technical Information of China (English)

    许爱东; 李静; 徐志强; 黄国楼

    2014-01-01

    Objective To analysis the drug resistance in patients with pulmonary tuberculosis at different ages in Huizhou city,to provide references for diagnosis and treatment of drug resistant tuberculosis. Methods From 2010 to 2013,1 484 pulmonary tuberculosis patients were randomly chosen in the Tuberculosis Institute of Huizhou,and then divided into 18-35 years old group of 356 cases,36-59 years old group of 612 cases,≥60 years old group of 516 cases. The drug resistant rate of first-line anti-tuberculosis drugs and multi-drugs resistant rate of 3 groups were retrospectively analyzed. Results INH and SM resistant rates of 18-35 years old group were higher than those of 36-59 years old group,INH,RFP,SM,EMB resistant rates and total drug resistant rate were higher than those of ≥60 years old group(P﹤0. 05);the RFP resistant rate in 36-59 years old group was higher than that of ≥60 years old group ( P﹤0. 05 ) . The multi-drugs resistant rate of 18 -35 year old group was higher than that of 36-59 years old group,3 drugs resistant rate,4 drugs resistant rate and multi-drugs resistant rate were higher than those of≥60 years old group(P﹤0. 05). Conclusion There is a big difference of drug resistance in patients with pulmonary tuberculosis at different ages in Huizhou city,while young patients are easy to get acquired drug resistance,for which is necessary to take individual measures to prevent and control.%目的:分析惠州市不同年龄段肺结核患者耐药情况,为耐药肺结核的诊断与治疗提供参考依据。方法抽取2010-2013年惠州市结核病防治研究所结核科收治的肺结核患者1484例,按照年龄分为18~35岁组356例,36~59岁组612例,≥60岁组516例。回顾性分析3组患者一线抗结核药物耐药情况及耐多药情况。结果18~35岁组患者异烟肼( INH)和链霉素( SM)耐药率均高于36~59岁组,INH、利福平( RFP)、SM、乙胺丁醇( EMB)耐药

  8. Bacteremic pneumonia caused by extensively drug-resistant Streptococcus pneumoniae.

    Science.gov (United States)

    Kang, Cheol-In; Baek, Jin Yang; Jeon, Kyeongman; Kim, So Hyun; Chung, Doo Ryeon; Peck, Kyong Ran; Lee, Nam Yong; Song, Jae-Hoon

    2012-12-01

    The emergence of antimicrobial resistance threatens the successful treatment of pneumococcal infections. Here we report a case of bacteremic pneumonia caused by an extremely drug-resistant strain of Streptococcus pneumoniae, nonsusceptible to at least one agent in all classes but vancomycin and linezolid, posing an important new public health threat in our region.

  9. 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

  10. World Antimalarial Resistance Network I: Clinical efficacy of antimalarial drugs

    Directory of Open Access Journals (Sweden)

    Olliaro Piero

    2007-09-01

    Full Text Available Abstract The proliferation of antimalarial drug trials in the last ten years provides the opportunity to launch a concerted global surveillance effort to monitor antimalarial drug efficacy. The diversity of clinical study designs and analytical methods undermines the current ability to achieve this. The proposed World Antimalarial Resistance Network (WARN aims to establish a comprehensive clinical database from which standardised estimates of antimalarial efficacy can be derived and monitored over time from diverse geographical and endemic regions. The emphasis of this initiative is on five key variables which define the therapeutic response. Ensuring that these data are collected at the individual patient level in a consistent format will facilitate better data management and analytical practices, and ensure that clinical data can be readily collated and made amenable for pooled analyses. Such an approach, if widely adopted will permit accurate and timely recognition of trends in drug efficacy. This will guide not only appropriate interventions to deal with established multidrug resistant strains of malaria, but also facilitate prompt action when new strains of drug resistant plasmodia first emerge. A comprehensive global database incorporating the key determinants of the clinical response with in vitro, molecular and pharmacokinetic parameters will bring together relevant data on host, drug and parasite factors that are fundamental contributors to treatment efficacy. This resource will help guide rational drug policies that optimize antimalarial drug use, in the hope that the emergence and spread of resistance to new drugs can be, if not prevented, at least delayed.

  11. Sphingolipids in neuroblastoma : Their role in drug resistance mechanisms

    NARCIS (Netherlands)

    Sietsma, H; Dijkhuis, AJ; Kamps, W; Kok, JW

    2002-01-01

    Disseminated neuroblastoma usually calls for chemotherapy as the primary approach for treatment. Treatment failure is often attributable to drug resistance. This involves a variety of cellular mechanisms, including increased drug efflux through expression of ATP-binding cassette transporters (e.g.,

  12. DISTRIBUTION OF PHAGE TYPES AND TRANSFERABLE DRUG RESISTANCE IN SHIGELLAE

    Directory of Open Access Journals (Sweden)

    K.Badalian

    1981-08-01

    Full Text Available A total of 610 strains of Shigellae isolated from cases of diarrhea in Iran during 1962-73 were studied with respect to their phage type, as well as antibiotic resistance and transferable drug resistance along with serotyping. It was shown that there was some relation between serotypes and phage types but no association could be found between phage types and resistance pattern.

  13. Study on Drug Resistance and Relative Mechanisms of Chlamydia Trachomatis

    Institute of Scientific and Technical Information of China (English)

    侯淑萍; 刘全忠

    2004-01-01

    Abstract: Chlamydia Trachomatis (C.T.) is one of the most common pathogens of human sexually transmitted diseases. Treatment of C.T. infection primarily depends on Tetracyclines, Macrolides and Quinolones, but with the wide use of antibiotics an increasing number of drug-resistant Chlamydia trachomatis cases have been reported. This review summarizes the resistant conditions and the possible resistance mechanisms of C.T..

  14. Acquisition of drug resistance and dependence by prions.

    Science.gov (United States)

    Oelschlegel, Anja M; Weissmann, Charles

    2013-02-01

    We have reported that properties of prion strains may change when propagated in different environments. For example, when swainsonine-sensitive 22L prions were propagated in PK1 cells in the presence of swainsonine, drug-resistant variants emerged. We proposed that prions constitute quasi- populations comprising a range of variants with different properties, from which the fittest are selected in a particular environment. Prion populations developed heterogeneity even after biological cloning, indicating that during propagation mutation-like processes occur at the conformational level. Because brain-derived 22L prions are naturally swainsonine resistant, it was not too surprising that prions which had become swa sensitive after propagation in cells could revert to drug resistance. Because RML prions, both after propagation in brain or in PK1 cells, are swainsonine sensitive, we investigated whether it was nonetheless possible to select swainsonine-resistant variants by propagation in the presence of the drug. Interestingly, this was not possible with the standard line of PK1 cells, but in certain PK1 sublines not only swainsonine-resistant, but even swainsonine-dependent populations (i.e. that propagated more rapidly in the presence of the drug) could be isolated. Once established, they could be passaged indefinitely in PK1 cells, even in the absence of the drug, without losing swainsonine dependence. The misfolded prion protein (PrP(Sc)) associated with a swainsonine-dependent variant was less rapidly cleared in PK1 cells than that associated with its drug-sensitive counterpart, indicating that likely structural differences of the misfolded PrP underlie the properties of the prions. In summary, propagation of prions in the presence of an inhibitory drug may not only cause the selection of drug-resistant prions but even of stable variants that propagate more efficiently in the presence of the drug. These adaptations are most likely due to conformational changes of

  15. INDUCTION OF DRUG RESISTANCE IN PLASMODIUM FALCIPARUM: AN INTERMITTENT DRUG EXPOSURE METHOD

    Directory of Open Access Journals (Sweden)

    M.Nateghpour

    1998-03-01

    Full Text Available The production of experimentally induced drug resistance in the laboratory provides valuable opportunities for investigators to study the nature and genetics of drug resistance mechanisms to a given agent, patterns of cross resistance and the mode of action of drugs. At the beginning the continuous drug exposure was chosen as a standard procedure to produce drug— resistant strains of P. falciparum,.but later on some other methods were also applied. An intermittent drug exposure method as a novel procedure has been introduced in this study. Intermittent exposure of chloroquine resistant Kl and chloroquine sensitive T9.96 strains of P. falciparum to halofantrine culminated in a relatively rapid reduction in sensitivity to the drug. The response of halofantrifle - resistnat K1HF and T9.96 strains and parent parasites to halofantrifle, inefloquine, quinine and chloroquine was determined. The results indicated that the effectiveness of halofantrine to K1HF and T9.96HF strains decreased 9 and 3 folds respectively, compared to the parent parasites. Cross -resistance occurred among halofantrine. mefloquine and quinine. Halofantrine resistance was associated with enhanced chloroquine sensitivity in the strain derived from chloroquine - resistant K1 strain, hut not in the strain derived from chloroquine - sensitive T9.96 parasites.

  16. Rational drug design approach for overcoming drug resistance: application to pyrimethamine resistance in malaria.

    Science.gov (United States)

    McKie, J H; Douglas, K T; Chan, C; Roser, S A; Yates, R; Read, M; Hyde, J E; Dascombe, M J; Yuthavong, Y; Sirawaraporn, W

    1998-04-23

    Pyrimethamine acts by selectively inhibiting malarial dihydrofolate reductase-thymidylate synthase (DHFR-TS). Resistance in the most important human parasite, Plasmodium falciparum, initially results from an S108N mutation in the DHFR domain, with additional mutation (most commonly C59R or N51I or both) imparting much greater resistance. From a homology model of the 3-D structure of DHFR-TS, rational drug design techniques have been used to design and subsequently synthesize inhibitors able to overcome malarial pyrimethamine resistance. Compared to pyrimethamine (Ki 1.5 nM) with purified recombinant DHFR fromP. falciparum, the Ki value of the m-methoxy analogue of pyrimethamine was 1.07 nM, but against the DHFR bearing the double mutation (C59R + S108N), the Ki values for pyrimethamine and the m-methoxy analogue were 71.7 and 14.0 nM, respectively. The m-chloro analogue of pyrimethamine was a stronger inhibitor of both wild-type DHFR (with Ki 0.30 nM) and the doubly mutant (C59R +S108N) purified enzyme (with Ki 2.40 nM). Growth of parasite cultures of P. falciparum in vitro was also strongly inhibited by these compounds with 50% inhibition of growth occurring at 3.7 microM for the m-methoxy and 0.6 microM for the m-chloro compounds with the K1 parasite line bearing the double mutation (S108N + C59R), compared to 10.2 microM for pyrimethamine. These inhibitors were also found in preliminary studies to retain antimalarial activity in vivo in P. berghei-infected mice.

  17. 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.

  18. Detection and confirmation of alkaloids in leaves of Justicia adhatoda and bioinformatics approach to elicit its anti-tuberculosis activity.

    Science.gov (United States)

    Jha, Deepak Kumar; Panda, Likun; Lavanya, P; Ramaiah, Sudha; Anbarasu, Anand

    2012-11-01

    The extraction and determination of alkaloids was performed and confirmed by phytochemical analysis. Six different quinazoline alkaloids (vasicoline, vasicolinone, vasicinone, vasicine, adhatodine and anisotine) were found in the leaf of Justicia adhatoda (J. adhatoda). The presence of the peaks obtained through HPLC indicated the diverse nature of alkaloid present in the leaf. The enzyme β-ketoacyl-acyl-carrier protein synthase III that catalyses the initial step of fatty acid biosynthesis (FabH) via a type II fatty acid synthase has unique structural features and universal occurrence in Mycobacterium tuberculosis (M. tuberculosis). Thus, it was considered as a target for designing of anti-tuberculosis compounds. Docking simulations were conducted on the above alkaloids derived from J. adhatoda. The combination of docking/scoring provided interesting insights into the binding of different inhibitors and their activity. These results will be useful for designing inhibitors for M. tuberculosis and also will be a good starting point for natural plant-based pharmaceutical chemistry.

  19. Hsp90 governs dispersion and drug resistance of fungal biofilms.

    Directory of Open Access Journals (Sweden)

    Nicole Robbins

    2011-09-01

    Full Text Available Fungal biofilms are a major cause of human mortality and are recalcitrant to most treatments due to intrinsic drug resistance. These complex communities of multiple cell types form on indwelling medical devices and their eradication often requires surgical removal of infected devices. Here we implicate the molecular chaperone Hsp90 as a key regulator of biofilm dispersion and drug resistance. We previously established that in the leading human fungal pathogen, Candida albicans, Hsp90 enables the emergence and maintenance of drug resistance in planktonic conditions by stabilizing the protein phosphatase calcineurin and MAPK Mkc1. Hsp90 also regulates temperature-dependent C. albicans morphogenesis through repression of cAMP-PKA signalling. Here we demonstrate that genetic depletion of Hsp90 reduced C. albicans biofilm growth and maturation in vitro and impaired dispersal of biofilm cells. Further, compromising Hsp90 function in vitro abrogated resistance of C. albicans biofilms to the most widely deployed class of antifungal drugs, the azoles. Depletion of Hsp90 led to reduction of calcineurin and Mkc1 in planktonic but not biofilm conditions, suggesting that Hsp90 regulates drug resistance through different mechanisms in these distinct cellular states. Reduction of Hsp90 levels led to a marked decrease in matrix glucan levels, providing a compelling mechanism through which Hsp90 might regulate biofilm azole resistance. Impairment of Hsp90 function genetically or pharmacologically transformed fluconazole from ineffectual to highly effective in eradicating biofilms in a rat venous catheter infection model. Finally, inhibition of Hsp90 reduced resistance of biofilms of the most lethal mould, Aspergillus fumigatus, to the newest class of antifungals to reach the clinic, the echinocandins. Thus, we establish a novel mechanism regulating biofilm drug resistance and dispersion and that targeting Hsp90 provides a much-needed strategy for improving

  20. 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

  1. Alcohol and drug use disorders, HIV status and drug resistance in a sample of Russian TB patients

    Science.gov (United States)

    Fleming, M. F.; Krupitsky, E.; Tsoy, M.; Zvartau, E.; Brazhenko, N.; Jakubowiak, W.; E. McCaul, M.

    2006-01-01

    SUMMARY SETTING: Alcohol use, tuberculosis (TB) drug resistance and human immunodeficiency virus (HIV) risk behavior are of increasing concern in Russian TB patients. DESIGN: A prevalence study of alcohol use and HIV risk behavior was conducted in a sample of 200 adult men and women admitted to TB hospitals in St Petersburg and Ivanovo, Russia. RESULTS: Of the subjects, 72% were men. The mean age was 41. Active TB was diagnosed using a combination of chest X-ray, sputum smears and sputum cultures. Sixty-two per cent met DSM-IV criteria for current alcohol abuse or dependence. Drug use was uncommon, with only two patients reporting recent intravenous heroin use. There was one case of HIV infection. The mean total risk assessment battery score was 3.4. Depression was present in 60% of the sample, with 17% severely depressed. Alcohol abuse/dependence was associated with an eight-fold increase in drug resistance (OR 8.58; 95% CI 2.09-35.32). Patients with relapsing or chronic TB were more likely to meet the criteria for alcohol abuse/dependence (OR 2.56; 95% CI 1.0-6.54). CONCLUSION: Alcohol use disorders are common in patients being treated for active TB, and are associated with significant morbidity. Additional surveys are needed to examine the relationship between alcohol use disorders and anti-tuberculosis drug resistance. CONTEXTE: Chezles patients tuberculeux russes, l’utilisation d’alcool, la résistance aux médicaments antituberculeux et un comportement à risque pour le virus de l’immunodéficience humaine (VIH) sont des sujets croissants d’inquiétude. SCHÉMA: Une étude: de prévalence de l’utilisation d’alcool et du comportement à risque pour le VIH a été menée sur un échantillon de 200 hommes et femmes adultes, admis dans des hôpitaux pour la tuberculose (TB) de Saint-Pétersbourg et d’Ivanovo en Russie. RÉSULTATS: Il y avait 72% d’hommes dans l’échantillon. L’âge moyen est de 41 ans. On a diagnostiqué la TB active par l

  2. Discovery of potent anti-tuberculosis agents targeting leucyl-tRNA synthetase.

    Science.gov (United States)

    Gudzera, Olga I; Golub, Andriy G; Bdzhola, Volodymyr G; Volynets, Galyna P; Lukashov, Sergiy S; Kovalenko, Oksana P; Kriklivyi, Ivan A; Yaremchuk, Anna D; Starosyla, Sergiy A; Yarmoluk, Sergiy M; Tukalo, Michail A

    2016-03-01

    Tuberculosis is a serious infectious disease caused by human pathogen bacteria Mycobacterium tuberculosis. Bacterial drug resistance is a very significant medical problem nowadays and development of novel antibiotics with different mechanisms of action is an important goal of modern medical science. Leucyl-tRNA synthetase (LeuRS) has been recently clinically validated as antimicrobial target. Here we report the discovery of small-molecule inhibitors of M. tuberculosis LeuRS. Using receptor-based virtual screening we have identified six inhibitors of M. tuberculosis LeuRS from two different chemical classes. The most active compound 4-{[4-(4-Bromo-phenyl)-thiazol-2-yl]hydrazonomethyl}-2-methoxy-6-nitro-phenol (1) inhibits LeuRS with IC50 of 6μM. A series of derivatives has been synthesized and evaluated in vitro toward M. tuberculosis LeuRS. It was revealed that the most active compound 2,6-Dibromo-4-{[4-(4-nitro-phenyl)-thiazol-2-yl]-hydrazonomethyl}-phenol inhibits LeuRS with IC50 of 2.27μM. All active compounds were tested for antimicrobial effect against M. tuberculosis H37Rv. The compound 1 seems to have the best cell permeability and inhibits growth of pathogenic bacteria with IC50=10.01μM and IC90=13.53μM.

  3. HIV resistance testing and detected drug resistance in Europe

    DEFF Research Database (Denmark)

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

    2015-01-01

    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 

  4. The action of Pseudomonas aeruginosa biofilms in intrinsic drug resistance

    Institute of Scientific and Technical Information of China (English)

    XIE Yi; JIA Wen-xiang; ZENG Wei; YANG Wei-qing; CHENG Xi; LI Xue-ru; WANG Lan-lan; KANG Mei; ZHANG Zai-rong

    2005-01-01

    Background There is a growing interest in studying the relationship between intrinsic resistance and biofilms resistance to drugs. However, the relationship still remains unclear in the macroscopic bacterial growth. Our study is to illuminate the change of bacterial drug resistance of gyrA mutant and active efflux pump during the development of Pseudomonas aeruginosa (P. aeruginosa) biofilms. Methods The strains of type Ⅱ topoisomerase gene mutant (gyrA mutant) and multidrug resistance (MDR) efflux pump were clinical isolates and detected by polymerase chain reaction (PCR). The process of bacterial biofilms development was observed by scanning electron microscope. Triparental mating experiments were performed to transfer report gene of green fluorescent protein (GFP) into P. aeruginosa biofilms strains and followed by analysis of bacterial survival rate between intrinsic resistance and biofilms resistance.Results The fluorescent strains with pGFPuv could develop mature biofilms on Teflon surface. Before a period of 72 hours, the survival rate of biofilms bacteria and intrinsic resistance strains in ciprofloxacin solution was significantly different (P0.05). The carbonyl cyanide m-chlorophenylhydrazone and azithromycin could significantly reduce the drug resistance of biofilm strains and efflux pump strains.Conclusions In the development of P. aeruginosa biofilms, the strains of gyrA mutation and MDR efflux could be conferred with new level of drug resistance. When co-cultured mutated strains with biofilm strains, biofilms may play a major role in bacterial resistance. But after 72 hours incubation (a mature biofilms had been developed), there was no clearly difference between the number of mutant strains and biofilm strains.

  5. Drug efflux proteins in multidrug resistant bacteria

    NARCIS (Netherlands)

    vanVeen, HW; Konings, WN

    1997-01-01

    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

  6. Oncolytic Virotherapy Targeting Lung Cancer Drug Resistance

    Science.gov (United States)

    2013-08-01

    peptides that bind to and inactivate small molecules such as cisplatin; (3) upregulate DNA repair enzymes that reverse therapy-induced DNA lesions; and...but multidrug-resistant tumor cells still possess clonal potential and after a short period of remission expand further and acquire metastatic

  7. 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.

  8. Drugs resistance and penicillinase activity in skin isolated Staphylococcus aureus

    Directory of Open Access Journals (Sweden)

    Bhat K

    1990-01-01

    Full Text Available A study was carried out to evaluate the drug resistance pattern and penicillinase production in skin isolated Staphylococcus aurpus. The disk diffusion method showed prevalence of: multidrug resistance among S. aureus, strains, isolated from locafised skin abscesses. method for detection of penicilfinase could detect this enzyme m 98.60/o of the isolates all fo which were resistant to penicillin and ampicillin. C16xacillin resistance as detected by the agar dilution method was found in 1.4% of the isolates. On the whole cloxacillin and gentamy′cin were found to be the most effective ′antistaphylococcal antibotics.

  9. 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.

  10. Rewired Metabolism in Drug-resistant Leukemia Cells

    Science.gov (United States)

    Stäubert, Claudia; Bhuiyan, Hasanuzzaman; Lindahl, Anna; Broom, Oliver Jay; Zhu, Yafeng; Islam, Saiful; Linnarsson, Sten; Lehtiö, Janne; Nordström, Anders

    2015-01-01

    Cancer cells that escape induction therapy are a major cause of relapse. Understanding metabolic alterations associated with drug resistance opens up unexplored opportunities for the development of new therapeutic strategies. Here, we applied a broad spectrum of technologies including RNA sequencing, global untargeted metabolomics, and stable isotope labeling mass spectrometry to identify metabolic changes in P-glycoprotein overexpressing T-cell acute lymphoblastic leukemia (ALL) cells, which escaped a therapeutically relevant daunorubicin treatment. We show that compared with sensitive ALL cells, resistant leukemia cells possess a fundamentally rewired central metabolism characterized by reduced dependence on glutamine despite a lack of expression of glutamate-ammonia ligase (GLUL), a higher demand for glucose and an altered rate of fatty acid β-oxidation, accompanied by a decreased pantothenic acid uptake capacity. We experimentally validate our findings by selectively targeting components of this metabolic switch, using approved drugs and starvation approaches followed by cell viability analyses in both the ALL cells and in an acute myeloid leukemia (AML) sensitive/resistant cell line pair. We demonstrate how comparative metabolomics and RNA expression profiling of drug-sensitive and -resistant cells expose targetable metabolic changes and potential resistance markers. Our results show that drug resistance is associated with significant metabolic costs in cancer cells, which could be exploited using new therapeutic strategies. PMID:25697355

  11. 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.

  12. Extensively Drug-Resistant Tuberculosis: Principles of Resistance, Diagnosis, and Management.

    Science.gov (United States)

    Wilson, John W; Tsukayama, Dean T

    2016-04-01

    Extensively drug-resistant (XDR) tuberculosis (TB) is an unfortunate by-product of mankind's medical and pharmaceutical ingenuity during the past 60 years. Although new drug developments have enabled TB to be more readily curable, inappropriate TB management has led to the emergence of drug-resistant disease. Extensively drug-resistant TB describes Mycobacterium tuberculosis that is collectively resistant to isoniazid, rifampin, a fluoroquinolone, and an injectable agent. It proliferates when established case management and infection control procedures are not followed. Optimized treatment outcomes necessitate time-sensitive diagnoses, along with expanded combinations and prolonged durations of antimicrobial drug therapy. The challenges to public health institutions are immense and most noteworthy in underresourced communities and in patients coinfected with human immunodeficiency virus. A comprehensive and multidisciplinary case management approach is required to optimize outcomes. We review the principles of TB drug resistance and the risk factors, diagnosis, and managerial approaches for extensively drug-resistant TB. Treatment outcomes, cost, and unresolved medical issues are also discussed.

  13. 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.

  14. Molecular and biochemical mechanisms of drug resistance in fungi.

    Science.gov (United States)

    Yamaguchi, H

    1999-01-01

    This paper reviews the current status of our understanding of resistance mechanisms of three major classes of antifungal drugs for systemic use, amphotericin B (AMPH), flucytosine (5-FC) and several azole antifungals, in particular fluconazole (FLCZ), at the molecular and cellular levels. Although the number of reports of AMPH- or 5-FC-resistant fungal species and strains is limited, several mechanisms of resistance have been described. AMPH-resistant Candida have a marked decrease in ergosterol content compared with AMPH-susceptible control isolates. A lesion in the UMP-pyrophosphorylase is the most frequent determinant of 5-FC resistance in C. albicans. Recently resistance of C. albicans to azoles has become an increasing problem. Extensive biochemical studies have highlighted a significant diversity in mechanisms conferring resistance to FLCZ and other azoles, which include alterations in sterol biosynthesis, target site, uptake and efflux. Among them, the most important mechanism clinically is reduced access of the drug to the intracellular P450 14 DM target, probably because of the action of a multidrug resistance efflux pump, and overproduction of that target. However, other possible resistance mechanisms for azoles remain to be identified.

  15. Sunitinib treatment enhances metastasis of innately drug resistant breast tumors

    Science.gov (United States)

    Wragg, Joseph W; Heath, Victoria L; Bicknell, Roy

    2017-01-01

    Anti-angiogenic therapies have failed to confer survival benefits in patients with metastatic breast cancer (mBC). However, to date there has not been an inquiry into roles for acquired versus innate drug resistance in this setting. In this study, we report roles for these distinct phenotypes in determining therapeutic response in a murine model of mBC resistance to the anti-angiogenic tyrosine kinase inhibitor sunitinib. Using tumor measurement and vascular patterning approaches, we differentiated tumors displaying innate versus acquired resistance. Bioluminescent imaging of tumor metastases to the liver, lungs and spleen revealed that sunitinib administration enhances metastasis, but only in tumors displaying innate resistance to therapy. Transcriptomic analysis of tumors displaying acquired versus innate resistance allowed the identification of specific biomarkers, many of which have a role in angiogenesis. In particular, aquaporin-1 upregulation occurred in acquired resistance, mTOR in innate resistance, and pleiotrophin in both settings, suggesting their utility as candidate diagnostics to predict drug response or to design tactics to circumvent resistance. Our results unravel specific features of antiangiogenic resistance, with potential therapeutic implications. PMID:28011623

  16. Antiviral Drug- and Multidrug Resistance in Cytomegalovirus Infected SCT Patients

    Directory of Open Access Journals (Sweden)

    Katharina Göhring

    2015-01-01

    Full Text Available In pediatric and adult patients after stem cell transplantation (SCT disseminated infections caused by human cytomegalovirus (HCMV can cause life threatening diseases. For treatment, the three antivirals ganciclovir (GCV, foscarnet (PFA and cidofovir (CDV are approved and most frequently used. Resistance to all of these antiviral drugs may induce a severe problem in this patient cohort. Responsible for resistance phenomena are mutations in the HCMV phosphotransferase-gene (UL97 and the polymerase-gene (UL54. Most frequently mutations in the UL97-gene are associated with resistance to GCV. Resistance against all three drugs is associated to mutations in the UL54-gene. Monitoring of drug resistance by genotyping is mostly done by PCR-based Sanger sequencing. For phenotyping with cell culture the isolation of HCMV is a prerequisite. The development of multidrug resistance with mutation in both genes is rare, but it is often associated with a fatal outcome. The manifestation of multidrug resistance is mostly associated with combined UL97/UL54-mutations. Normally, mutations in the UL97 gene occur initially followed by UL54 mutation after therapy switch. The appearance of UL54-mutation alone without any detection of UL97-mutation is rare. Interestingly, in a number of patients the UL97 mutation could be detected in specific compartments exclusively and not in blood.

  17. Histone modification as a drug resistance driver in brain tumors

    Institute of Scientific and Technical Information of China (English)

    Guifa Xi; Barbara Mania-Farnell; Ting Lei; Tadanori Tomita

    2016-01-01

    Patients with brain tumors, specificaly, malignant forms such as glioblastoma, meduloblas-toma and ependymoma, exhibit dismal survival rates despite advances in treatment strategies. Chemotherapeutics, the primary adjuvant treatment for human brain tumors folowing surgery, commonly lack eficacy due to either intrinsic or acquired drug resistance. New treatments tar-geting epigenetic factors are being explored. Post-translational histone modification provides a critical regulatory platform for processes such as chromosome condensation and segregation, apoptosis, gene transcription, and DNA replication and repair. This work reviews how aberrant histone modifications and alterations in histone-modifying enzymes can drive the acquisition of drug resistance in brain tumors. Elucidating these mechanisms should lead to new treatments for overcoming drug resistance.

  18. New strategies against drug resistance to herpes simplex virus

    Institute of Scientific and Technical Information of China (English)

    Yu-Chen Jiang; Hui Feng; Yu-Chun Lin; Xiu-Rong Guo

    2016-01-01

    Herpes simplex virus (HSV), a member of the Herpesviridae family, is a significant human pathogen that results in mucocutaneous lesions in the oral cavity or genital infections. Acyclovir (ACV) and related nucleoside analogues can successfully treat HSV infections, but the emergence of drug resistance to ACV has created a barrier for the treatment of HSV infections, especially in immunocompromised patients. There is an urgent need to explore new and effective tactics to circumvent drug resistance to HSV. This review summarises the current strategies in the development of new targets (the DNA helicase/primase (H/P) complex), new types of molecules (nature products) and new antiviral mechanisms (lethal mutagenesis of Janus-type nucleosides) to fight the drug resistance of HSV.

  19. HIV Drug-resistant Strains as Epidemiologic Sentinels

    Science.gov (United States)

    Grant, Robert M.; Porco, Travis C.; Getz, Wayne M.

    2006-01-01

    Observed declines in drug resistance to nucleoside reverse transcriptase inhibitors among persons recently infected with HIV-1 in monitored subpopulations can be interpreted as a positive sign and lead public health officials to decrease efforts towards HIV prevention. By means of a mathematical model, we identified 3 processes that can account for the observed decline: increase in high-risk behavior, decrease in proportion of acutely infected persons whose conditions are treated, and change in treatment efficacy. These processes, singly or in combination, can lead to increases or decreases in disease and drug-resistance prevalence in the general population. We discuss the most appropriate public health response under each scenario and emphasize how further data collection and analyses are required to more reliably evaluate the observed time trends and the relative importance of forces shaping the epidemic. Our study highlights how drug resistance markers can be used as epidemiologic sentinels to devise public health solutions. PMID:16494741

  20. New strategies against drug resistance to herpes simplex virus

    Science.gov (United States)

    Jiang, Yu-Chen; Feng, Hui; Lin, Yu-Chun; Guo, Xiu-Rong

    2016-01-01

    Herpes simplex virus (HSV), a member of the Herpesviridae family, is a significant human pathogen that results in mucocutaneous lesions in the oral cavity or genital infections. Acyclovir (ACV) and related nucleoside analogues can successfully treat HSV infections, but the emergence of drug resistance to ACV has created a barrier for the treatment of HSV infections, especially in immunocompromised patients. There is an urgent need to explore new and effective tactics to circumvent drug resistance to HSV. This review summarises the current strategies in the development of new targets (the DNA helicase/primase (H/P) complex), new types of molecules (nature products) and new antiviral mechanisms (lethal mutagenesis of Janus-type nucleosides) to fight the drug resistance of HSV. PMID:27025259

  1. Drugs that target pathogen public goods are robust against evolved drug resistance.

    Science.gov (United States)

    Pepper, John W

    2012-11-01

    Pathogen drug resistance is a central problem in medicine and public health. It arises through somatic evolution, by mutation and selection among pathogen cells within a host. Here, we examine the hypothesis that evolution of drug resistance could be reduced by developing drugs that target the secreted metabolites produced by pathogen cells instead of directly targeting the cells themselves. Using an agent-based computational model of an evolving population of pathogen cells, we test this hypothesis and find support for it. We also use our model to explain this effect within the framework of standard evolutionary theory. We find that in our model, the drugs most robust against evolved drug resistance are those that target the most widely shared external products, or 'public goods', of pathogen cells. We also show that these drugs exert a weak selective pressure for resistance because they create only a weak correlation between drug resistance and cell fitness. The same principles apply to design of vaccines that are robust against vaccine escape. Because our theoretical results have crucial practical implications, they should be tested by empirical experiments.

  2. Antimicrobial drug resistance ofStaphylococcus aureus in dairy products

    Institute of Scientific and Technical Information of China (English)

    Sasidharan S; Prema B; Yoga Latha L

    2011-01-01

    Objective:To evaluate the prevalence of multidrug resistantStaphylococcus aureus(S. aureus) in dairy products.Methods:Isolation and identification ofS. aureus were performed in3 dairy-based food products. The isolates were tested for their susceptibility to5 different common antimicrobial drugs.Results:Of50 samples examined,5 (10%) were contaminated with S. aureus. Subsequently, the5 isolates were subjected to antimicrobial resistance pattern using five antibiotic discs (methicillin, vancomycin, kanamycin, chloramphenicol and tetracycline). Sample 29 showed resistance to methicillin and vancomycin. Sample18 showed intermediate response to tetracycline. The other samples were susceptible to all the antibiotics tested.Conclusions:The results provide preliminary data on sources of food contamination which may act as vehicles for the transmission of antimicrobial-resistantStaphylococcus.Therefore, it enables us to develop preventive strategies to avoid the emergence of new strains of resistantS. aureus.

  3. Multidrug resistance in oncology and beyond : from imaging of drug efflux pumps to cellular drug targets

    NARCIS (Netherlands)

    Nagengast, Wouter B; Oude Munnink, Thijs H; Dijkers, Eli; Hospers, Geesiena; Brouwers, Adrienne H; Schröder, Carolien P; Lub-de Hooge, Marjolijn; de Vries, Elisabeth G E

    2010-01-01

    Resistance of tumor cells to several structurally unrelated classes of natural products, including anthracyclines, taxanes, and epipodophyllotoxines, is often referred as multidrug resistance (MDR). This is associated with ATP-binding cassette transporters, which function as drug efflux pumps such a

  4. A new antihypertensive drug ameliorates insulin resistance

    Institute of Scientific and Technical Information of China (English)

    Yan-xia LIU

    2012-01-01

    Insulin resistance (IR)is defined as decreased sensitivity and/or responsiveness to insulin that promote glucose disposal.A growing body of clinical and epidemiologic evidence indicates that essential hypertension and IR often coexist[1].Approximately 50 percent of patients with hypertension can be considered to have IR and hyperinsulinemia[1].This inextricable linkage between hypertension and IR has been identified to increase the prevalence of cardiovascular disease (CVD)and new onset of type Ⅱ diabetes that is the major cause of morbidity and mortality in this clinical syndrome[2].However,the driving force linking IR and hypertension remains to be fully elucidated.

  5. 32例耐药结核性脑膜炎的疗效及预后分析%Analysis of the Curative Effect and Prognosis of 32 Cases of Drug Resistant Tuberculosis Meningitis

    Institute of Scientific and Technical Information of China (English)

    邓倩; 赖晓晖

    2016-01-01

    目的 分析耐药结核性脑膜炎(TBM)的疗效及预后.方法 对2010年1月-2015年12月住院的32例成人耐药TBM患者病历资料进行回顾性分析并电话随访了解患者的预后情况,采用改良Rankin量表(mRS)对预后进行评分.结果 32例耐药TBM患者中好转31例(96.9%),治疗无效死亡1例(3.1%).治疗后1例出现激素相关性青光眼及骨质疏松,1例出现药物性库欣综合征.27例(84.4%)患者mRS评分≤2分.结论 耐药TBM早期诊断困难,经积极抗结核并辅助治疗,疗效满意.%Objective To analyze the curative effect and prognosis of drug resistant tuberculosis meningitis (TBM).Methods Retrospective analysis was carried out on the clinical data of thirty-two cases of drug resistant tuberculous meningitis patients hospitalized from January 2010 to December 2015.And the prognosis of the patients was evaluated by meliorated Rankin Scale (mRS).Results Thirty-one cases (96.9%) were improved in 32 patients with drug resistant TBM,and 1 case (3.1%) was ineffective.After treatment,one patient had hormone-related glaucoma and osteoporosis,and one patient had drug Cushing syndrome.Twenty-seven patients (84.4%) had an mRS score equal to or less than 2 points.Conclusion Drug resistant TBM is difficult to diagnose in the early stage,and the curative effect is satisfying with active anti-tuberculosis treatment.

  6. Environment-Mediated Drug Resistance in Neuroblastoma

    Science.gov (United States)

    2013-10-01

    cells, including not only monocytes but also regulatory T cells ( Treg ) and non-myeloid stromal cells. Task 2. Role of S1P on STAT3 activation and drug...presence of reciprocal activation of STAT3 between tumor cells and bonemarrow stromal cells including not only monocytes but also regulatory T cells ( Treg ...CD45/GD2 nonmyeloid, nontumor cells, CD45/GD2þ tumor cells, CD45þ/CD14þ monocytes, and CD45þ/CD3þ/ CD4þ/CD25þ/FoxP3þ regulatory T cells ( Treg

  7. 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.

  8. "DRUG RESISTANCE PATTERN IN ISOLATED BACTERIA FROM BLOOD CULTURES"

    OpenAIRE

    A Sobhani; H. Shodjai S. Javanbakht

    2004-01-01

    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 pos...

  9. Determinants of Genetic Diversity of Spontaneous Drug Resistance in Bacteria.

    Science.gov (United States)

    Couce, Alejandro; Rodríguez-Rojas, Alexandro; Blázquez, Jesús

    2016-07-01

    Any pathogen population sufficiently large is expected to harbor spontaneous drug-resistant mutants, often responsible for disease relapse after antibiotic therapy. It is seldom appreciated, however, that while larger populations harbor more mutants, the abundance distribution of these mutants is expected to be markedly uneven. This is because a larger population size allows early mutants to expand for longer, exacerbating their predominance in the final mutant subpopulation. Here, we investigate the extent to which this reduction in evenness can constrain the genetic diversity of spontaneous drug resistance in bacteria. Combining theory and experiments, we show that even small variations in growth rate between resistant mutants and the wild type result in orders-of-magnitude differences in genetic diversity. Indeed, only a slight fitness advantage for the mutant is enough to keep diversity low and independent of population size. These results have important clinical implications. Genetic diversity at antibiotic resistance loci can determine a population's capacity to cope with future challenges (i.e., second-line therapy). We thus revealed an unanticipated way in which the fitness effects of antibiotic resistance can affect the evolvability of pathogens surviving a drug-induced bottleneck. This insight will assist in the fight against multidrug-resistant microbes, as well as contribute to theories aimed at predicting cancer evolution.

  10. pncA Gene Mutations Associated with Pyrazinamide Resistance in Drug-Resistant Tuberculosis, South Africa and Georgia.

    Science.gov (United States)

    Allana, Salim; Shashkina, Elena; Mathema, Barun; Bablishvili, Nino; Tukvadze, Nestani; Shah, N Sarita; Kempker, Russell R; Blumberg, Henry M; Moodley, Pravi; Mlisana, Koleka; Brust, James C M; Gandhi, Neel R

    2017-03-01

    Although pyrazinamide is commonly used for tuberculosis treatment, drug-susceptibility testing is not routinely available. We found polymorphisms in the pncA gene for 70% of multidrug-resistant and 96% of extensively drug-resistant Mycobacterium tuberculosis isolates from South Africa and Georgia. Assessment of pyrazinamide susceptibility may be prudent before using it in regimens for drug-resistant tuberculosis.

  11. Hepatitis C Virus and Antiviral Drug Resistance

    Science.gov (United States)

    Kim, Seungtaek; Han, Kwang-Hyub; Ahn, Sang Hoon

    2016-01-01

    Since its discovery in 1989, hepatitis C virus (HCV) has been intensively investigated to understand its biology and develop effective antiviral therapies. The efforts of the previous 25 years have resulted in a better understanding of the virus, and this was facilitated by the development of in vitro cell culture systems for HCV replication. Antiviral treatments and sustained virological responses have also improved from the early interferon monotherapy to the current all-oral regimens using direct-acting antivirals. However, antiviral resistance has become a critical issue in the treatment of chronic hepatitis C, similar to other chronic viral infections, and retreatment options following treatment failure have become important questions. Despite the clinical challenges in the management of chronic hepatitis C, substantial progress has been made in understanding HCV, which may facilitate the investigation of other closely related flaviviruses and lead to the development of antiviral agents against these human pathogens. PMID:27784846

  12. [Multidrug-resistant tuberculosis: current epidemiology, therapeutic regimens, new drugs].

    Science.gov (United States)

    Gómez-Ayerbe, C; Vivancos, M J; Moreno, S

    2016-09-01

    Multidrug and extensively resistant tuberculosis are especially severe forms of the disease for which no efficacious therapy exists in many cases. All the countries in the world have registered cases, although most of them are diagnosed in resource-limited countries from Asia, Africa and South America. For adequate treatment, first- and second-line antituberculosis drugs have to be judiciously used, but the development of new drugs with full activity, good tolerability and little toxicity is urgently needed. There are some drugs in development, some of which are already available through expanded-access programs.

  13. Biophysical principles predict fitness landscapes of drug resistance.

    Science.gov (United States)

    Rodrigues, João V; Bershtein, Shimon; Li, Anna; Lozovsky, Elena R; Hartl, Daniel L; Shakhnovich, Eugene I

    2016-03-15

    Fitness landscapes of drug resistance constitute powerful tools to elucidate mutational pathways of antibiotic escape. Here, we developed a predictive biophysics-based fitness landscape of trimethoprim (TMP) resistance for Escherichia coli dihydrofolate reductase (DHFR). We investigated the activity, binding, folding stability, and intracellular abundance for a complete set of combinatorial DHFR mutants made out of three key resistance mutations and extended this analysis to DHFR originated from Chlamydia muridarum and Listeria grayi We found that the acquisition of TMP resistance via decreased drug affinity is limited by a trade-off in catalytic efficiency. Protein stability is concurrently affected by the resistant mutants, which precludes a precise description of fitness from a single molecular trait. Application of the kinetic flux theory provided an accurate model to predict resistance phenotypes (IC50) quantitatively from a unique combination of the in vitro protein molecular properties. Further, we found that a controlled modulation of the GroEL/ES chaperonins and Lon protease levels affects the intracellular steady-state concentration of DHFR in a mutation-specific manner, whereas IC50 is changed proportionally, as indeed predicted by the model. This unveils a molecular rationale for the pleiotropic role of the protein quality control machinery on the evolution of antibiotic resistance, which, as we illustrate here, may drastically confound the evolutionary outcome. These results provide a comprehensive quantitative genotype-phenotype map for the essential enzyme that serves as an important target of antibiotic and anticancer therapies.

  14. Recent developments in genomics, bioinformatics and drug discovery to combat emerging drug-resistant tuberculosis.

    Science.gov (United States)

    Swaminathan, Soumya; Sundaramurthi, Jagadish Chandrabose; Palaniappan, Alangudi Natarajan; Narayanan, Sujatha

    2016-12-01

    Emergence of drug-resistant tuberculosis (DR-TB) is a big challenge in TB control. The delay in diagnosis of DR-TB leads to its increased transmission, and therefore prevalence. Recent developments in genomics have enabled whole genome sequencing (WGS) of Mycobacterium tuberculosis (M. tuberculosis) from 3-day-old liquid culture and directly from uncultured sputa, while new bioinformatics tools facilitate to determine DR mutations rapidly from the resulting sequences. The present drug discovery and development pipeline is filled with candidate drugs which have shown efficacy against DR-TB. Furthermore, some of the FDA-approved drugs are being evaluated for repurposing, and this approach appears promising as several drugs are reported to enhance efficacy of the standard TB drugs, reduce drug tolerance, or modulate the host immune response to control the growth of intracellular M. tuberculosis. Recent developments in genomics and bioinformatics along with new drug discovery collectively have the potential to result in synergistic impact leading to the development of a rapid protocol to determine the drug resistance profile of the infecting strain so as to provide personalized medicine. Hence, in this review, we discuss recent developments in WGS, bioinformatics and drug discovery to perceive how they would transform the management of tuberculosis in a timely manner.

  15. "Applied" Aspects of the Drug Resistance Strategies Project

    Science.gov (United States)

    Hecht, Michael L.; Miller-Day, Michelle A.

    2010-01-01

    This paper discusses the applied aspects of our Drug Resistance Strategies Project. We argue that a new definitional distinction is needed to expand the notion of "applied" from the traditional notion of utilizing theory, which we call "applied.1," in order to consider theory-grounded, theory testing and theory developing applied research. We…

  16. P-Glycoprotein and Drug Resistance in Systemic Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    Andrea Picchianti-Diamanti

    2014-03-01

    Full Text Available Autoimmune diseases such as systemic lupus erythematosus (SLE, rheumatoid arthritis (RA and psoriatic arthritis (PsA are chronic inflammatory disorders of unknown etiology characterized by a wide range of abnormalities of the immune system that may compromise the function of several organs, such as kidney, heart, joints, brain and skin. Corticosteroids (CCS, synthetic and biologic immunosuppressive agents have demonstrated the capacity to improve the course of autoimmune diseases. However, a significant number of patients do not respond or develop resistance to these therapies over time. P-glycoprotein (P-gp is a transmembrane protein that pumps several drugs out of the cell, including CCS and immunosuppressants; thus, its over-expression or hyper-function has been proposed as a possible mechanism of drug resistance in patients with autoimmune disorders. Recently, different authors have demonstrated that P-gp inhibitors, such as cyclosporine A (CsA and its analogue Tacrolimus, are able to reduce P-gp expression and or function in SLE, RA and PsA patients. These observations suggest that P-gp antagonists could be adopted to revert drug resistance and improve disease outcome. The complex inter-relationship among drug resistance, P-gp expression and autoimmunity still remains elusive.

  17. Leukemia stem cells in drug resistance and metastasis

    Institute of Scientific and Technical Information of China (English)

    DENG Chao-hua; ZHANG Qiu-ping

    2010-01-01

    Objective To review the central role of leukemia stem cells (LSCs) in drug resistance and metastasis, aiming to provide key insights into leukemogenic pathology and developing novel therapeutic strategies against the relapse of leukemia.Data sources The data used in this review were obtained mainly from the studies reported in PubMed using the key terms "tumor-initiating cells", "leukemia stem cells", "drug resistance" and "metastasis".Study selection Relevant articles on studies of leukemia stem cells were selected.Results Increasing numbers of studies have suggested the importance of cancer stem cells (CSCs) in the initiation and maintenance of cancer, especially in leukemia. This review has summarized the origin, characteristics, isolation and identification of LSCs. It highlights the crucial role of LSCs in drug resistance and metastasis of leukemia by illustrating possible mechanisms and aims to provide novel therapeutic strategies for LSCs-targeted treatment.Conclusion LSCs play a crucial role in drug resistance and metastasis of leukemia and new promising LSCs-targeted therapies warrant investigation in both experimental models and clinical practice.

  18. 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…

  19. Drug-resistant tuberculosis: time for visionary political leadership.

    Science.gov (United States)

    Abubakar, Ibrahim; Zignol, Matteo; Falzon, Dennis; Raviglione, Mario; Ditiu, Lucica; Masham, Susan; Adetifa, Ifedayo; Ford, Nathan; Cox, Helen; Lawn, Stephen D; Marais, Ben J; McHugh, Timothy D; Mwaba, Peter; Bates, Matthew; Lipman, Marc; Zijenah, Lynn; Logan, Simon; McNerney, Ruth; Zumla, Adam; Sarda, Krishna; Nahid, Payam; Hoelscher, Michael; Pletschette, Michel; Memish, Ziad A; Kim, Peter; Hafner, Richard; Cole, Stewart; Migliori, Giovanni Battista; Maeurer, Markus; Schito, Marco; Zumla, Alimuddin

    2013-06-01

    Two decades ago, WHO declared tuberculosis a global emergency, and invested in the highly cost-effective directly observed treatment short-course programme to control the epidemic. At that time, most strains of Mycobacterium tuberculosis were susceptible to first-line tuberculosis drugs, and drug resistance was not a major issue. However, in 2013, tuberculosis remains a major public health concern worldwide, with prevalence of multidrug-resistant (MDR) tuberculosis rising. WHO estimates roughly 630 000 cases of MDR tuberculosis worldwide, with great variation in the frequency of MDR tuberculosis between countries. In the past 8 years, extensively drug-resistant (XDR) tuberculosis has emerged, and has been reported in 84 countries, heralding the possibility of virtually untreatable tuberculosis. Increased population movement, the continuing HIV pandemic, and the rise in MDR tuberculosis pose formidable challenges to the global control of tuberculosis. We provide an overview of the global burden of drug-resistant disease; discuss the social, health service, management, and control issues that fuel and sustain the epidemic; and suggest specific recommendations for important next steps. Visionary political leadership is needed to curb the rise of MDR and XDR tuberculosis worldwide, through sustained funding and the implementation of global and regional action plans.

  20. Flu Resistance to Antiviral Drug in North Carolina

    Centers for Disease Control (CDC) Podcasts

    2011-12-19

    Dr. Katrina Sleeman, Associate Service Fellow at CDC, discusses resistance to an antiviral flu drug in North Carolina.  Created: 12/19/2011 by National Center for Emerging and Zoonotic Infectious Diseases (NCEZID).   Date Released: 12/19/2011.

  1. Structure-based design,synthesis of novel inhibitors of Mycobacterium tuberculosis FabH as potential anti-tuberculosis agents

    Institute of Scientific and Technical Information of China (English)

    Xue Hui Zhang; Hong Yu; Wu Zhong; Li Li Wang; Song Li

    2009-01-01

    Mycobacterium tuberculosis FabH,an essential enzyme in mycolic acids biosynthetic pathway,is an attractive target for novel anti-tuberculosis agents.Structure-based design,synthesis of novel inhibitors of mrFabH was reported in this paper.A novel scaffold structure was designed,and 12 candidate compounds that displayed favorable binding with the active site were identified and synthesized.

  2. 1,4-Di-N-oxide quinoxaline-2-carboxamide: Cyclic voltammetry and relationship between electrochemical behavior, structure and anti-tuberculosis activity

    OpenAIRE

    Moreno-Viguri, E. (Elsa); Perez-Silanes, S. (Silvia); Gouravaram, S. (S.); Macharam, A. (Abinav); Ancizu, S. (Saioa); Torres, E; Aldana, I.; Monge, A; Crawford, P.W. (Philip W.)

    2011-01-01

    To gain insight into the mechanism of action, the redox properties of 37 quinoxaline-2-carboxamide 1,4-di-N-oxides with varying degrees of anti-tuberculosis activity were studied in dimethylformamide (DMF) using cyclic voltammetry and first derivative cyclic voltammetry. For all compounds studied, electrochemical reduction in DMF is consistent with the reduction of the N-oxide functionality to form a radical anion. The influence of molecular structure on reduction potential is addressed and i...

  3. 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.

  4. Modeling mass drug treatment and resistant filaria disease transmission

    Science.gov (United States)

    Fuady, A. M.; Nuraini, N.; Soewono, E.; Tasman, H.; Supriatna, A. K.

    2014-03-01

    It has been indicated that a long term application of combined mass drug treatment may contribute to the development of drug resistance in lymphatic filariasis. This phenomenon is not well understood due to the complexity of filaria life cycle. In this paper we formulate a mathematical model for the spread of mass drug resistant in a filaria endemic region. The model is represented in a 13-dimensional Host-Vector system. The basic reproductive ratio of the system which is obtained from the next generation matrix, and analysis of stability of both the disease free equilibrium and the coexistence equilibria are shown. Numerical simulation for long term dynamics for possible field conditions is also shown.

  5. 抗结核药物联合蜂蜡巴豆治疗耐药肺结核的疗效观察%The Observation of Clinical Effect of Anti-tuberculosis Drugs Combined with Beeswax Croton in Treatment of Drug-resistant Tuberculosis

    Institute of Scientific and Technical Information of China (English)

    卢俊敏; 赵中夫

    2009-01-01

    目的:抗结核药物联合蜂蜡巴豆治疗耐药肺结核的临床疗效观察.方法:97例耐药患者入选,随机分配为A、B两组,A组47例,化疗联合蜂蜡巴豆;B组50例,单纯化疗.两组疗程均为18个月.结果:痰菌阴转率:治疗3个月末,A组60.87%,B组30.43%(P<0.05), 疗程结束时A组为84.8%,B组65.2%(P<0.05).A组病灶有效变化率为91.30%,B组为73.91%(P <0.0 5).虽然两组的病情好转情况无显著差异(P>0.05), 但A组不良反应发生率显著低于B 组(P<0.01).结论: 抗结核药物联合蜂蜡巴豆治疗耐药肺结核患者,对耐药结核有良好的治疗效果 ,并可减少化疗药物引起的毒副反应.

  6. Clinically relevant transmitted drug resistance to first line antiretroviral drugs and implications for recommendations.

    Directory of Open Access Journals (Sweden)

    Susana Monge

    Full Text Available BACKGROUND: The aim was to analyse trends in clinically relevant resistance to first-line antiretroviral drugs in Spain, applying the Stanford algorithm, and to compare these results with reported Transmitted Drug Resistance (TDR defined by the 2009 update of the WHO SDRM list. METHODS: We analysed 2781 sequences from ARV naive patients of the CoRIS cohort (Spain between 2007-2011. Using the Stanford algorithm "Low-level resistance", "Intermediate resistance" and "High-level resistance" categories were considered as "Resistant". RESULTS: 70% of the TDR found using the WHO list were relevant for first-line treatment according to the Stanford algorithm. A total of 188 patients showed clinically relevant resistance to first-line ARVs [6.8% (95%Confidence Interval: 5.8-7.7], and 221 harbored TDR using the WHO list [7.9% (6.9-9.0]. Differences were due to a lower prevalence in clinically relevant resistance for NRTIs [2.3% (1.8-2.9 vs. 3.6% (2.9-4.3 by the WHO list] and PIs [0.8% (0.4-1.1 vs. 1.7% (1.2-2.2], while it was higher for NNRTIs [4.6% (3.8-5.3 vs. 3.7% (3.0-4.7]. While TDR remained stable throughout the study period, clinically relevant resistance to first line drugs showed a significant trend to a decline (p = 0.02. CONCLUSIONS: Prevalence of clinically relevant resistance to first line ARVs in Spain is decreasing, and lower than the one expected looking at TDR using the WHO list. Resistance to first-line PIs falls below 1%, so the recommendation of screening for TDR in the protease gene should be questioned in our setting. Cost-effectiveness studies need to be carried out to inform evidence-based recommendations.

  7. Balancing drug resistance and growth rates via compensatory mutations in the Plasmodium falciparum chloroquine resistance transporter.

    Science.gov (United States)

    Petersen, Ines; Gabryszewski, Stanislaw J; Johnston, Geoffrey L; Dhingra, Satish K; Ecker, Andrea; Lewis, Rebecca E; de Almeida, Mariana Justino; Straimer, Judith; Henrich, Philipp P; Palatulan, Eugene; Johnson, David J; Coburn-Flynn, Olivia; Sanchez, Cecilia; Lehane, Adele M; Lanzer, Michael; Fidock, David A

    2015-07-01

    The widespread use of chloroquine to treat Plasmodium falciparum infections has resulted in the selection and dissemination of variant haplotypes of the primary resistance determinant PfCRT. These haplotypes have encountered drug pressure and within-host competition with wild-type drug-sensitive parasites. To examine these selective forces in vitro, we genetically engineered P. falciparum to express geographically diverse PfCRT haplotypes. Variant alleles from the Philippines (PH1 and PH2, which differ solely by the C72S mutation) both conferred a moderate gain of chloroquine resistance and a reduction in growth rates in vitro. Of the two, PH2 showed higher IC50 values, contrasting with reduced growth. Furthermore, a highly mutated pfcrt allele from Cambodia (Cam734) conferred moderate chloroquine resistance and enhanced growth rates, when tested against wild-type pfcrt in co-culture competition assays. These three alleles mediated cross-resistance to amodiaquine, an antimalarial drug widely used in Africa. Each allele, along with the globally prevalent Dd2 and 7G8 alleles, rendered parasites more susceptible to lumefantrine, the partner drug used in the leading first-line artemisinin-based combination therapy. These data reveal ongoing region-specific evolution of PfCRT that impacts drug susceptibility and relative fitness in settings of mixed infections, and raise important considerations about optimal agents to treat chloroquine-resistant malaria.

  8. The population genetics of drug resistance evolution in natural populations of viral, bacterial and eukaryotic pathogens.

    Science.gov (United States)

    Wilson, Benjamin A; Garud, Nandita R; Feder, Alison F; Assaf, Zoe J; Pennings, Pleuni S

    2016-01-01

    Drug resistance is a costly consequence of pathogen evolution and a major concern in public health. In this review, we show how population genetics can be used to study the evolution of drug resistance and also how drug resistance evolution is informative as an evolutionary model system. We highlight five examples from diverse organisms with particular focus on: (i) identifying drug resistance loci in the malaria parasite Plasmodium falciparum using the genomic signatures of selective sweeps, (ii) determining the role of epistasis in drug resistance evolution in influenza, (iii) quantifying the role of standing genetic variation in the evolution of drug resistance in HIV, (iv) using drug resistance mutations to study clonal interference dynamics in tuberculosis and (v) analysing the population structure of the core and accessory genome of Staphylococcus aureus to understand the spread of methicillin resistance. Throughout this review, we discuss the uses of sequence data and population genetic theory in studying the evolution of drug resistance.

  9. Systematic review of the performance of rapid rifampicin resistance testing for drug-resistant tuberculosis.

    Directory of Open Access Journals (Sweden)

    Matthew Arentz

    Full Text Available INTRODUCTION: Rapid tests for rifampicin resistance may be useful for identifying isolates at high risk of drug resistance, including multidrug-resistant TB (MDR-TB. However, choice of diagnostic test and prevalence of rifampicin resistance may both impact a diagnostic strategy for identifying drug resistant-TB. We performed a systematic review to evaluate the performance of WHO-endorsed rapid tests for rifampicin resistance detection. METHODS: We searched MEDLINE, Embase and the Cochrane Library through January 1, 2012. For each rapid test, we determined pooled sensitivity and specificity estimates using a hierarchical random effects model. Predictive values of the tests were determined at different prevalence rates of rifampicin resistance and MDR-TB. RESULTS: We identified 60 publications involving six different tests (INNO-LiPA Rif. TB assay, Genotype MTBDR assay, Genotype MTBDRplus assay, Colorimetric Redox Indicator (CRI assay, Nitrate Reductase Assay (NRA and MODS tests: for all tests, negative predictive values were high when rifampicin resistance prevalence was ≤ 30%. However, positive predictive values were considerably reduced for the INNO-LiPA Rif. TB assay, the MTBDRplus assay and MODS when rifampicin resistance prevalence was < 5%. LIMITATIONS: In many studies, it was unclear whether patient selection or index test performance could have introduced bias. In addition, we were unable to evaluate critical concentration thresholds for the colorimetric tests. DISCUSSION: Rapid tests for rifampicin resistance alone cannot accurately predict rifampicin resistance or MDR-TB in areas with a low prevalence of rifampicin resistance. However, in areas with a high prevalence of rifampicin resistance and MDR-TB, these tests may be a valuable component of an MDR-TB management strategy.

  10. Smart doxorubicin nanoparticles with high drug payload for enhanced chemotherapy against drug resistance and cancer diagnosis

    Science.gov (United States)

    Yu, Caitong; Zhou, Mengjiao; Zhang, Xiujuan; Wei, Weijia; Chen, Xianfeng; Zhang, Xiaohong

    2015-03-01

    Considering the obvious advantages in efficacy and price, doxorubicin (DOX) has been widely used for a range of cancers, which is usually encapsulated in various nanocarriers for drug delivery. Although effective, in most nanocarrier-based delivery systems, the drug loading capacity of DOX is rather low; this can lead to undesired systemic toxicity and excretion concern. Herein, we report for the first time the usage of pure doxorubicin nanoparticles (DOX NPs) without addition of any carriers for enhanced chemotherapy against drug-resistance. The drug payload reaches as high as 90.47%, which largely surpassed those in previous reports. These PEG stabilized DOX NPs exhibit good biocompatibility and stability, long blood circulation time, fast release in an acidic environment and high accumulation in tumors. Compared with free DOX, DOX NPs display a dramatically enhanced anticancer therapeutic efficacy in the inhibition of cell and tumor growth. Moreover, they can also be readily incorporated with other anticancer drugs for synergistic chemotherapy to overcome the drug resistance of cancers. The fluorescence properties of DOX also endow these NPs with imaging capabilities, thus making it a multifunctional system for diagnosis and treatment. This work demonstrates great potential of DOX NPs for cancer diagnosis, therapy and overcoming drug tolerance.Considering the obvious advantages in efficacy and price, doxorubicin (DOX) has been widely used for a range of cancers, which is usually encapsulated in various nanocarriers for drug delivery. Although effective, in most nanocarrier-based delivery systems, the drug loading capacity of DOX is rather low; this can lead to undesired systemic toxicity and excretion concern. Herein, we report for the first time the usage of pure doxorubicin nanoparticles (DOX NPs) without addition of any carriers for enhanced chemotherapy against drug-resistance. The drug payload reaches as high as 90.47%, which largely surpassed those in

  11. Effect of anti-tuberculosis therapy on liver function of pulmonary tuberculosis patients infected with hepatitis B virus

    Institute of Scientific and Technical Information of China (English)

    Lei Pan; Zhan-Sheng Jia; Lin Chen; En-Qing Fu; Guang-Yu Li

    2005-01-01

    AIM: To observe the effect of anti-tuberculosis therapy on liver function of pulmonary tuberculosis patients with hepatitis B virus (HBV) infection, and to compare the differences of liver function by two treatments of antituberculosis.METHODS: Forty-seven TB patients with HBV infection and 170 TB patients without HBV infection were divided into HPBE(S) and HLAMKO treatment groups. Liver function tests before and after the treatments were performed once in 2 wk or monthly, and their clinical manifestations were recorded.RESULTS: The rate of hepatotoxicity occurred in 26 (59%)TB patients with HBV during anti-TB treatment, higher than that in 40 (24%) TB patients without HBV. Hepatotoxicity occurred in 66 out of 217 patients, and the incidence of liver dysfunction was 46.1% in HPBE(S) group, significantly higher than that in HLAMKO group (12.7%) (P<0.01).CONCLUSION: TB patients with HBV should choose HLAMKO treatment because of fewer hepatotoxicity.

  12. Antimalarial drug resistance in Bangladesh, 1996-2012.

    Science.gov (United States)

    Haque, Ubydul; Glass, Gregory E; Haque, Waziul; Islam, Nazrul; Roy, Shyamal; Karim, Jahirul; Noedl, Harald

    2013-12-01

    Malaria remains an important health problem in Bangladesh, with approximately 14 million people at risk. Antimalarial drug resistance is a major obstacle to the control of malaria in endemic countries. In 2012, Bangladesh reported an estimated 29 522 malaria episodes, of which 94% were reported as being caused by Plasmodium falciparum. In this study, we reviewed and summarized antimalarial drug resistance data from Bangladesh published until June 2013. We searched published sources for data referring to any type of P. falciparum drug resistance (in vivo, in vitro, or molecular) and found 169 articles published in peer-reviewed journals. Of these, 143 articles were excluded because they did not meet our inclusion criteria. After detailed review of the remaining 26 articles, 14 were selected for evaluation. Published studies indicate that P. falciparum shows varying levels of resistance to chloroquine, mefloquine and sulfadoxine-pyrimethamine. Combination therapy of chloroquine and primaquine has proven ineffective and combinations of sulfadoxine-pyrimethamine with either quinine or chloroquine have also shown poor efficacy. Recent studies indicate that artemisinin derivatives, such as artesunate, remain highly efficacious in treating P. falciparum malaria. Available data suggest that artemisinins, quinine, doxycyline, mefloquine-artesunate and azithromycin-artesunate combination therapy remain efficacious in the treatment of P. falciparum malaria in Bangladesh.

  13. 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.

  14. Experience with pulmonary resection for extensively drug-resistant tuberculosis.

    Science.gov (United States)

    Shiraishi, Yuji; Katsuragi, Naoya; Kita, Hidefumi; Toishi, Masayuki; Onda, Takahito

    2008-12-01

    Extensively drug-resistant tuberculosis is becoming a global threat. It is a relatively new phenomenon, and its optimal management remains undetermined. We report our experience in using pulmonary resection for treating patients with this disease. Records were reviewed of 54 consecutive patients undergoing a pulmonary resection for multidrug-resistant tuberculosis at Fukujuji Hospital between 2000 and 2006. These patients were identified using the definition approved by the World Health Organization Global Task Force on extensively drug-resistant tuberculosis in October 2006. Five (9%) patients (3 men and 2 women) aged 31-60 years met the definition. None of the patients was HIV-positive. Although the best available multidrug regimens were initiated, no patient could achieve sputum conversion. Adjuvant resectional surgery was considered because the patients had localized disease. Procedures performed included pneumonectomy (2) and upper lobectomy (3). There was no operative mortality or morbidity. All patients attained sputum-negative status after the operation, and they were maintained on multidrug regimens for 12-25 months postoperatively. All patients remained free from disease at the time of follow-up. Pulmonary resection under cover of state-of-the-art chemotherapy is safe and effective for patients with localized extensively drug-resistant tuberculosis.

  15. Magnitude of drug resistant shigellosis: A report from Bangalore

    Directory of Open Access Journals (Sweden)

    Srinivasa H

    2009-01-01

    Full Text Available Shigella is an important cause of acute invasive diarrhea in children and others. Antimicrobial susceptibility of Shigella spp. isolated from diarrhoeal/ dysenteric patients in Bangalore was studied in our hospital from January 2002 to December 2007. One hundred and thirty-four isolates were identified as Shigella species. S. flexneri, S. sonnei , S. boydii and S. dysenteriae were accounted respectively for 64.9%, 21.6%, 8.2% and 3.7% of the total number of Shigella isolated. Of these 56 (41.8% were from children (0 to 14 years and 78 (58.2% were from adults and elderly patients. Over 70% of Shigella isolates were resistant to two or more drugs including Ampicillin and Co-trimoxazole. During 2002 to 2007, resistance to Ampicillin had increased from 46.7% to 68%. For Co-trimoxazole, though the resistance had gradually decreased from 100% to 72%, but still the resistance is high. Chloramphenicol resistance showed sudden decline from 73.3% to 25% from 2002 to 2003, but gradually has reached 48%. Nalidixic acid resistance was more than 70%. All isolates were sensitive to Ciprofloxacin during the period 2002 to 2004, but over the years the resistance pattern gradually increased up to 48%. Ceftriaxone had shown no resistance. The results of the study revealed the endemicity of Shigellosis with S. flexneri as the predominant serogroup. Children were at a higher risk of severe shigellosis. The results also suggest that Ampicillin, Co-trimoxazole, Chloramphenicol, Nalidixic acid and Ciprofloxacin should not be used empirically as the first line drugs in the treatment of Shigellosis. Periodic analysis and reporting of antibiotic susceptibility is an important measure to guide antibiotic treatment.

  16. Insights into the mechanism of drug resistance. X-ray structure analysis of multi-drug resistant HIV-1 protease ritonavir complex

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Zhigang [Wayne State Univ., Detroit, MI (United States); Harbor Hospital Baltimore, MD (United States); Yedidi, Ravikiran S. [Wayne State Univ., Detroit, MI (United States); National Inst. of Health (NIH), Bethesda, MD (United States); Wang, Yong [Wayne State Univ., Detroit, MI (United States); Dewdney, Tamaria G. [Wayne State Univ., Detroit, MI (United States); Reiter, Samuel J. [Wayne State Univ., Detroit, MI (United States); Brunzelle, Joseph S. [Northwestern Univ., Chicago, IL (United States); Kovari, Iulia A. [Wayne State Univ., Detroit, MI (United States); Kovari, Ladislau C. [Wayne State Univ., Detroit, MI (United States)

    2013-01-08

    Ritonavir (RTV) is a first generation HIV-1 protease inhibitor with rapidly emerging drug resistance. Mutations at residues 46, 54, 82 and 84 render the HIV-1 protease drug resistant against RTV. We report the crystal structure of multi-drug resistant (MDR) 769 HIV-1 protease (carrying resistant mutations at residues 10, 36, 46, 54, 62, 63, 71, 82, 84 and 90) complexed with RTV and the in vitro enzymatic IC50 of RTV against MDR HIV-1 protease. The structural and functional studies demonstrate significant drug resistance of MDR HIV-1 protease against RTV, arising from reduced hydrogen bonds and Van der Waals interactions between RTV and MDR HIV-1 protease.

  17. Drug induced superinfection in HIV and the evolution of drug resistance.

    Science.gov (United States)

    Leontiev, Vladimir V; Maury, Wendy J; Hadany, Lilach

    2008-01-01

    The rapid evolution of HIV drug resistance is a major cause of AIDS treatment failure. Superinfection, the infection of an already infected cell by additional virions, can be a major factor contributing to the evolution of drug resistance. However, the pattern and consequences of superinfection in HIV populations are far from fully understood. In this paper we study the implications of the fact that superinfection is regulated by HIV. We propose that superinfection is negatively associated with the success of the virus, so that more successful viruses are less likely to allow superinfection. We use computational models to investigate the effect that regulated superinfection would have on the evolution of drug resistance in HIV population. We find that regulated, fitness-associated superinfection can provide a distinct advantage to the virus in adapting to anti-HIV drugs in comparison with unregulated superinfection. Based on the results of the computational models and on current biological evidence, we suggest that the mechanism of fitness-associated regulation of coinfection in HIV is plausible, and that its investigation can lead to new ways to fight viral drug resistance.

  18. Fighting drug-resistant Plasmodium falciparum: the challenge of artemisinin resistance.

    Science.gov (United States)

    Wongsrichanalai, C; Sibley, C H

    2013-10-01

    Following a decade-long scale up of malaria control through vector control interventions, the introduction of rapid diagnostic tests and highly efficacious Artemisinin-based Combination Therapy (ACT) along with other measures, global malaria incidence declined significantly. The recent development of artemisinin resistance on the Cambodia-Thailand border, however, is of great concern. This review encompasses the background of artemisinin resistance in Plasmodium falciparum, its situation, especially in the Greater Mekong Sub-region (GMS), and the responses taken to overcome this resistance. The difficulties in defining resistance are presented, particularly the necessity of measuring the clinical response to artemisinins using the slow parasite-clearance phenotype. Efforts to understand the molecular basis of artemisinin resistance and the search for molecular markers are reviewed. The markers, once identified, can be applied as an efficient tool for resistance surveillance. Despite the limitation of current surveillance methods, it is important to continue vigilance for artemisinin resistance. The therapeutic efficacy "in vivo study" network for monitoring antimalarial resistance in the GMS has been strengthened. GMS countries are working together in response to artemisinin resistance and aim to eliminate all P. falciparum parasites. These efforts are crucial since a resurgence of malaria due to drug and/or insecticide resistance, program cuts, lack of political support and donor fatigue could set back malaria control success in the sub-region and threaten malaria control and elimination if resistance spreads to other regions.

  19. [MOLECULAR MECHANISMS OF DRUG RESISTANCE NEISSERIA GONORRHOEAE HISTORY AND PROSPECTS].

    Science.gov (United States)

    Bodoev, I N; Il'ina, E N

    2015-01-01

    Neisseria gonorrhoeae (gonococcus) is a strict human pathogen, which causes gonorrhea--an infectious disease, whose origin dates back to more than two thousand years. Due to the unique plasticity of the genetic material, these bacteria have acquired the capacity to adapt to the host immune system, cause repeated infections, as well as withstand antimicrobials. Since the introduction of antibiotics in 1930s, gonococcus has displayed its propensity to develop resistance to all clinically useful antibiotics. It is important to note that the known resistance determinants of N. gonorrhoeae were acquired through horizontal gene transfer, recombination and spontaneous mutagenesis, and may be located both in the chromosome and on the plasmid. After introduction of a new antimicrobial drug, gonococcus becomes resistant within two decades and replaces sensitive bacterial population. Currently Ceftriaxone is the last remaining antibiotic for first-line treatment of gonorrhea. However, the first gonococcus displaying high-level resistance to Ceftriaxone was isolated in Japan a few years ago. Therefore, in the near future, gonorrhea may become untreatable. In the present review, we discuss the chronology of the anti-gonorrhea drugs (antibiotics) replacement, the evolution of resistance mechanisms emergence and future perspectives of N. gonorrhoeae treatment.

  20. Flu channel drug resistance: a tale of two sites.

    Science.gov (United States)

    Pielak, Rafal M; Chou, James J

    2010-03-01

    The M2 proteins of influenza A and B virus, AM2 and BM2, respectively, are transmembrane proteins that oligomerize in the viral membrane to form proton-selective channels. Proton conductance of the M2 proteins is required for viral replication; it is believed to equilibrate pH across the viral membrane during cell entry and across the trans-Golgi membrane of infected cells during viral maturation. In addition to the role of M2 in proton conductance, recent mutagenesis and structural studies suggest that the cytoplasmic domains of the M2 proteins also play a role in recruiting the matrix proteins to the cell surface during virus budding. As viral ion channels of minimalist architecture, the membrane-embedded channel domain of M2 has been a model system for investigating the mechanism of proton conduction. Moreover, as a proven drug target for the treatment of influenza A infection, M2 has been the subject of intense research for developing new anti-flu therapeutics. AM2 is the target of two anti-influenza A drugs, amantadine and rimantadine, both belonging to the adamantane class of compounds. However, resistance of influenza A to adamantane is now widespread due to mutations in the channel domain of AM2. This review summarizes the structure and function of both AM2 and BM2 channels, the mechanism of drug inhibition and drug resistance of AM2, as well as the development of new M2 inhibitors as potential anti-flu drugs.

  1. 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.

  2. Physiological Stress-Induced Drug Resistance and its Reversal

    Science.gov (United States)

    2004-07-01

    resistance but does shift the dose response curve . • Demonstrate that p53 status does not alter sensitization to drug by NFkB inhibitors such as PGA1...Figure 13). The presence of p53 (ON) shifts the dose response curve to the right but the response remains the same. PGA1 pretreatment, sensitizes...shift the dose response curve . • Demonstrate that p53 status does not alter sensitization to drug by NFkB inhibitors such as PGA1. • Demonstrated that

  3. Erythromycin resistance by L4/L22 mutations and resistance masking by drug efflux pump deficiency

    Science.gov (United States)

    Lovmar, Martin; Nilsson, Karin; Lukk, Eliisa; Vimberg, Vladimir; Tenson, Tanel; Ehrenberg, Måns

    2009-01-01

    We characterized the effects of classical erythromycin resistance mutations in ribosomal proteins L4 and L22 of the large ribosomal subunit on the kinetics of erythromycin binding. Our data are consistent with a mechanism in which the macrolide erythromycin enters and exits the ribosome through the nascent peptide exit tunnel, and suggest that these mutations both impair passive transport through the tunnel and distort the erythromycin-binding site. The growth-inhibitory action of erythromycin was characterized for bacterial populations with wild-type and L22-mutated ribosomes in drug efflux pump deficient and proficient backgrounds. The L22 mutation conferred reduced erythromycin susceptibility in the drug efflux pump proficient, but not deficient, background. This ‘masking' of drug resistance by pump deficiency was reproduced by modelling with input data from our biochemical experiments. We discuss the general principles behind the phenomenon of drug resistance ‘masking', and highlight its potential importance for slowing down the evolution of drug resistance among pathogens. PMID:19197244

  4. Treatments and Effects of Congenital Tuberculosis by Early Venous Anti-tuberculosis%早期静脉抗结核治疗先天性结核病的方法与效果

    Institute of Scientific and Technical Information of China (English)

    庄晓玲; 杨尧

    2015-01-01

    Objective To explore the clinical characteristics of congenital tuberculosis and the value of early venous an-ti-tuberculosis treatment,as well as to deepen the understanding of the disease and improve the treatment efficiency. Methods By giving the 9 patients in our hospital,who were suffering from congenital tuberculosis early venous anti-tuberculosis treatment. Re-sults In these 9 cases,5 were cured,and the follow-up survey suggested that they were of good growth and development. Unfortu-nately,there were 3 patients who gave up treatment and died not long. Another 1 patient did not receive regular treatment and died 20 days later because of tuberculosis meningitis. Conclusion Congenital tuberculosis lacks of specific clinical manifestations,it should be combined with the chest imaging and the etiology examination results of various kinds of body fluids to reach a clear diag-nosis. Early venous anti-tuberculosis treatment can effectively treat this disease,as well as reducing the side effects of taking an-ti-tuberculosis drugs.%目的 探讨先天性结核的临床特点及早期静脉抗结核治疗的价值,加深对本病的认识. 方法 对我院收治的9例先天性结核的患儿给予早期静脉抗结核治疗. 结果 9例患儿中治愈5例,随访生长发育良好. 3例未坚持治疗,不久死亡.1例未正规治疗,20d合并结核性脑膜炎死亡. 结论 先天性结核缺乏特异性临床表现,需结合胸部影像学,各种体液的病原学检查明确诊断. 早期静脉抗结核治疗可有效治疗该病,同时减少口服抗结核药的副反应.

  5. Analysis of Etiology and Drug Resistance of Biliary Infections

    Institute of Scientific and Technical Information of China (English)

    王欣; 李秋; 邹声泉; 孙自庸; 朱峰

    2004-01-01

    The bile was collected from fro patients with biliary infections, with the bacterium isolated to study the sensitivity of each kind of the bacterium to several antibiotics in common use. Except G- bacterium, we also found some kinds of G+ bacterium in infection bile. G- bacterium were not sensitive to Clindamycin, G+ bacterium were sensitive to Ciprofloxacin. Escherichia coli,Xanthomonas maltophilia, Enterobacter cloacae, Pseudomonas aeruginosa were sensitive to Ampicillin. G+ bacterium were not sensitive to Azactam. Enterococcus faecalis, Enterococcus faecium,Enterobacter cloacae were not sensitive to Ceftazidime. Enterococcus faecalis, Staphylococcus coagulase negative, Staphylococcus epidermidis, Pseudomonas aeruginosa were not sensitive to Ceftriaxone Sodium. We didn't found any bacterium resistance Imipenem. The possibility of the existence of G+ bacterium as well as drug resistance should be considered n patients with biliary infections.The value of susceptibility test should be respected to avoid drug abuse of antibiotics.

  6. Clinical Prediction Rule of Drug Resistant Epilepsy in Children

    OpenAIRE

    2015-01-01

    Background and Purpose: Clinical prediction rules (CPR) are clinical decision-making tools containing variables such as history, physical examination, diagnostic tests by developing scoring model from potential risk factors. This study is to establish clinical prediction scoring of drug-resistant epilepsy (DRE) in children using clinical manifestationa and only basic electroencephalography (EEG). Methods: Retrospective cohort study was conducted. A total of 308 children with diagnosed epileps...

  7. Exploiting Knowledge on Leishmania Drug Resistance to Support the Quest for New Drugs.

    Science.gov (United States)

    Hefnawy, Aya; Berg, Maya; Dujardin, Jean-Claude; De Muylder, Géraldine

    2017-03-01

    New drugs are needed to control leishmaniasis and efforts are currently on-going to counter the neglect of this disease. We discuss here the utility and the impact of associating drug resistance (DR) studies to drug discovery pipelines. We use as paradigm currently used drugs, antimonials and miltefosine, and complement our reflection by interviewing three experts in the field. We suggest DR studies to be involved at two different stages of drug development: (i) the efficiency of novel compounds should be confirmed on sets of strains including recent clinical isolates with DR; (ii) experimental DR should be generated to promising compounds at an early stage of their development, to further optimize them and monitor clinical trials.

  8. Effect of mutation and genetic background on drug resistance in Mycobacterium tuberculosis.

    Science.gov (United States)

    Fenner, Lukas; Egger, Matthias; Bodmer, Thomas; Altpeter, Ekkehardt; Zwahlen, Marcel; Jaton, Katia; Pfyffer, Gaby E; Borrell, Sonia; Dubuis, Olivier; Bruderer, Thomas; Siegrist, Hans H; Furrer, Hansjakob; Calmy, Alexandra; Fehr, Jan; Stalder, Jesica Mazza; Ninet, Béatrice; Böttger, Erik C; Gagneux, Sebastien

    2012-06-01

    Bacterial factors may contribute to the global emergence and spread of drug-resistant tuberculosis (TB). Only a few studies have reported on the interactions between different bacterial factors. We studied drug-resistant Mycobacterium tuberculosis isolates from a nationwide study conducted from 2000 to 2008 in Switzerland. We determined quantitative drug resistance levels of first-line drugs by using Bactec MGIT-960 and drug resistance genotypes by sequencing the hot-spot regions of the relevant genes. We determined recent transmission by molecular methods and collected clinical data. Overall, we analyzed 158 isolates that were resistant to isoniazid, rifampin, or ethambutol, 48 (30.4%) of which were multidrug resistant. Among 154 isoniazid-resistant strains, katG mutations were associated with high-level and inhA promoter mutations with low-level drug resistance. Only katG(S315T) (65.6% of all isoniazid-resistant strains) and inhA promoter -15C/T (22.7%) were found in molecular clusters. M. tuberculosis lineage 2 (includes Beijing genotype) was associated with any drug resistance (adjusted odds ratio [OR], 3.0; 95% confidence interval [CI], 1.7 to 5.6; P mutations (OR, 6.4; 95% CI, 2.0 to 20.7; P = 0.002). We found that the genetic strain background influences the level of isoniazid resistance conveyed by particular mutations (interaction tests of drug resistance mutations across all lineages; P tuberculosis drug resistance mutations were associated with various levels of drug resistance and transmission, and M. tuberculosis lineages were associated with particular drug resistance-conferring mutations and phenotypic drug resistance. Our study also supports a role for epistatic interactions between different drug resistance mutations and strain genetic backgrounds in M. tuberculosis drug resistance.

  9. A Quantitative Model to Estimate Drug Resistance in Pathogens

    Directory of Open Access Journals (Sweden)

    Frazier N. Baker

    2016-12-01

    Full Text Available Pneumocystis pneumonia (PCP is an opportunistic infection that occurs in humans and other mammals with debilitated immune systems. These infections are caused by fungi in the genus Pneumocystis, which are not susceptible to standard antifungal agents. Despite decades of research and drug development, the primary treatment and prophylaxis for PCP remains a combination of trimethoprim (TMP and sulfamethoxazole (SMX that targets two enzymes in folic acid biosynthesis, dihydrofolate reductase (DHFR and dihydropteroate synthase (DHPS, respectively. There is growing evidence of emerging resistance by Pneumocystis jirovecii (the species that infects humans to TMP-SMX associated with mutations in the targeted enzymes. In the present study, we report the development of an accurate quantitative model to predict changes in the binding affinity of inhibitors (Ki, IC50 to the mutated proteins. The model is based on evolutionary information and amino acid covariance analysis. Predicted changes in binding affinity upon mutations highly correlate with the experimentally measured data. While trained on Pneumocystis jirovecii DHFR/TMP data, the model shows similar or better performance when evaluated on the resistance data for a different inhibitor of PjDFHR, another drug/target pair (PjDHPS/SMX and another organism (Staphylococcus aureus DHFR/TMP. Therefore, we anticipate that the developed prediction model will be useful in the evaluation of possible resistance of the newly sequenced variants of the pathogen and can be extended to other drug targets and organisms.

  10. Molecular Genetics of Drug-resistance in Epilepsies

    Directory of Open Access Journals (Sweden)

    Kurupath Radhakrishnan

    2015-06-01

    Full Text Available Nearly one-third of newly diagnosed patients with epilepsy remain unresponsive to antiepileptic drugs (AEDs, etiopathogenesis of which is poorly understood. The genes encoding the proteins that regulate the pharmacokinetics such as P-glycoprotein [ABCBI], major vault protein [MVP gene] and drug metabolizing enzymes [ABCB1, ABCG2, MVP, CYP2C9, CYP2C19, CYP3A4, CYP3A5, EPHX1, UGT1A1, UGT2B7], and pharmacodynamics such as sodium channels [SCN1A, SCN2A] and GABA receptors [GABRA1, GABRA6, GABRB2, GABRG2] of AEDs are under intense investigation to unravel the mysteries of AED-resistance. However, till today, a consistent and reliable result that could help the clinician either to predict drug resistance or to overcome it has not been forthcoming. The discrepant results may be related to variations in the definition of drug-resistance, heterogeneous patient populations, ethnic variations in the frequency distribution of single nucleotide polymorphisms (SNPs and the selection of SNPs. Understanding of these limitations of existing studies, hopefully, will help in designing better studies. Nearly one-third of newly diagnosed patients with epilepsy remain unresponsive toantiepileptic drugs (AEDs, etiopathogenesis of which is poorly understood. The genesencoding the proteins that regulate the pharmacokinetics such as P-glycoprotein[ABCBI], major vault protein [MVP gene] and drug metabolizing enzymes [ABCB1,ABCG2, MVP, CYP2C9, CYP2C19, CYP3A4, CYP3A5, EPHX1, UGT1A1, UGT2B7],and pharmacodynamics such as sodium channels [SCN1A, SCN2A] and GABAreceptors [GABRA1, GABRA6, GABRB2, GABRG2] of AEDs are under intenseinvestigation to unravel the mysteries of AED-resistance. However, till today, aconsistent and reliable result that could help the clinician either to predict drugresistanceor to overcome it has not been forthcoming. The discrepant results may berelated to variations in the definition of drug-resistance, heterogeneous patientpopulations, ethnic

  11. Assessing transmissibility of HIV-1 drug resistance mutations from treated and from drug-naive individuals

    Science.gov (United States)

    Winand, Raf; Theys, Kristof; Eusébio, Mónica; Aerts, Jan; Camacho, Ricardo J.; Gomes, Perpetua; Suchard, Marc A.; Vandamme, Anne-Mieke; Abecasis, Ana B.

    2015-01-01

    Objectives: Surveillance drug resistance mutations (SDRMs) in drug-naive patients are typically used to survey HIV-1-transmitted drug resistance (TDR). We test here how SDRMs in patients failing treatment, the original source of TDR, contribute to assessing TDR, transmissibility and transmission source of SDRMs. Design: This is a retrospective observational study analyzing a Portuguese cohort of HIV-1-infected patients. Methods: The prevalence of SDRMs to protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) in drug-naive and treatment-failing patients was measured for 3554 HIV-1 subtype B patients. Transmission ratio (prevalence in drug-naive/prevalence in treatment-failing patients), average viral load and robust linear regression with outlier detection (prevalence in drug-naive versus in treatment-failing patients) were analyzed and used to interpret transmissibility. Results: Prevalence of SDRMs in drug-naive and treatment-failing patients were linearly correlated, but some SDRMs were classified as outliers – above (PRO: D30N, N88D/S, L90 M, RT: G190A/S/E) or below (RT: M184I/V) expectations. The normalized regression slope was 0.073 for protease inhibitors, 0.084 for NRTIs and 0.116 for NNRTIs. Differences between SDRMs transmission ratios were not associated with differences in viral loads. Conclusion: The significant linear correlation between prevalence of SDRMs in drug-naive and in treatment-failing patients indicates that the prevalence in treatment-failing patients can be useful to predict levels of TDR. The slope is a cohort-dependent estimate of rate of TDR per drug class and outlier detection reveals comparative persistence of SDRMs. Outlier SDRMs with higher transmissibility are more persistent and more likely to have been acquired from drug-naive patients. Those with lower transmissibility have faster reversion dynamics after transmission and are associated with

  12. 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.

  13. 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-dam...

  14. The new concepts on overcoming drug resistance in lung cancer

    Directory of Open Access Journals (Sweden)

    Zhang W

    2014-06-01

    Full Text Available Weisan Zhang,1 Ping Lei,1 Xifeng Dong,2 Cuiping Xu31Department of Geriatrics, 2Department of Hematology-Oncology, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 3Qianfoshan Hospital, Shandong University, Jinan, People’s Republic of ChinaAbstract: Lung cancer is one of the most deadly diseases worldwide. The current first-line therapies include chemotherapy using epidermal growth factor receptor tyrosine kinase inhibitors and radiotherapies. With the current progress in identifying new molecular targets, acquired drug resistance stands as an obstacle for good prognosis. About half the patients receiving epidermal growth factor receptor-tyrosine kinase inhibitor treatments develop resistance. Although extensive studies have been applied to elucidate the underlying mechanisms, evidence is far from enough to establish a well-defined picture to correct resistance. In the review, we will discuss four different currently developed strategies that have the potential to overcome drug resistance in lung cancer therapies and facilitate prolonged anticancer effects of the first-line therapies.Keywords: ALK receptors cancer stem cell, chemotherapy, EGFR-TKI, target therapy, pharmacology, molecular biology, biotherapy

  15. 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.

  16. Ethanol-resistant polymeric film coatings for controlled drug delivery.

    Science.gov (United States)

    Rosiaux, Y; Muschert, S; Chokshi, R; Leclercq, B; Siepmann, F; Siepmann, J

    2013-07-10

    The sensitivity of controlled release dosage forms to the presence of ethanol in the gastro intestinal tract is critical, if the incorporated drug is potent and exhibits severe side effects. This is for instance the case for most opioid drugs. The co-ingestion of alcoholic beverages can lead to dose dumping and potentially fatal consequences. For these reasons the marketing of hydromorphone HCl extended release capsules (Palladone) was suspended. The aim of this study was to develop a novel type of controlled release film coatings, which are ethanol-resistant: even the presence of high ethanol concentrations in the surrounding bulk fluid (e.g., up to 40%) should not affect the resulting drug release kinetics. Interestingly, blends of ethylcellulose and medium or high viscosity guar gums provide such ethanol resistance. Theophylline release from pellets coated with the aqueous ethylcellulose dispersion Aquacoat® ECD 30 containing 10 or 15% medium and high viscosity guar gum was virtually unaffected by the addition of 40% ethanol to the release medium. Furthermore, drug release was shown to be long term stable from this type of dosage forms under ambient and stress conditions (without packaging material), upon appropriate curing.

  17. Exosomes in development, metastasis and drug resistance of breast cancer.

    Science.gov (United States)

    Yu, Dan-dan; Wu, Ying; Shen, Hong-yu; Lv, Meng-meng; Chen, Wei-xian; Zhang, Xiao-hui; Zhong, Shan-liang; Tang, Jin-hai; Zhao, Jian-hua

    2015-08-01

    Transport through the cell membrane can be divided into active, passive and vesicular types (exosomes). Exosomes are nano-sized vesicles released by a variety of cells. Emerging evidence shows that exosomes play a critical role in cancers. Exosomes mediate communication between stroma and cancer cells through the transfer of nucleic acid and proteins. It is demonstrated that the contents and the quantity of exosomes will change after occurrence of cancers. Over the last decade, growing attention has been paid to the role of exosomes in the development of breast cancer, the most life-threatening cancer in women. Breast cancer could induce salivary glands to secret specific exosomes, which could be used as biomarkers in the diagnosis of early breast cancer. Exosome-delivered nucleic acid and proteins partly facilitate the tumorigenesis, metastasis and resistance of breast cancer. Exosomes could also transmit anti-cancer drugs outside breast cancer cells, therefore leading to drug resistance. However, exosomes are effective tools for transportation of anti-cancer drugs with lower immunogenicity and toxicity. This is a promising way to establish a drug delivery system.

  18. Seasonal distribution of anti-malarial drug resistance alleles on the island of Sumba, Indonesia

    NARCIS (Netherlands)

    Asih, P.B.; Rogers, W.O.; Susanti, A.I.; Rahmat, A.; Rozi, I.E.; Kusumaningtyas, M.A.; Dewi, R.M.; Coutrier, F.N.; Sutamihardja, A.; Ven, A.J.A.M. van der; Sauerwein, R.W.; Syafruddin, D.

    2009-01-01

    BACKGROUND: Drug resistant malaria poses an increasing public health problem in Indonesia, especially eastern Indonesia, where malaria is highly endemic. Widespread chloroquine (CQ) resistance and increasing sulphadoxine-pyrimethamine (SP) resistance prompted Indonesia to adopt artemisinin-based com

  19. Impact of fungal drug transporters on fungicide sensitivity, multidrug resistance and virulence

    NARCIS (Netherlands)

    Waard, de M.A.; Andrade, A.C.; Hayashi, K.; Schoonbeek, H.; Stergiopoulos, I.; Zwiers, L.H.

    2006-01-01

    Drug transporters are membrane proteins that provide protection for organisms against natural toxic products and fungicides. In plant pathogens, drug transporters function in baseline sensitivity to fungicides, multidrug resistance (MDR) and virulence on host plants. This paper describes drug transp

  20. Drug delivery by a self-assembled DNA tetrahedron for overcoming drug resistance in breast cancer cells.

    Science.gov (United States)

    Kim, Kyoung-Ran; Kim, Da-Rae; Lee, Taemin; Yhee, Ji Young; Kim, Byeong-Su; Kwon, Ick Chan; Ahn, Dae-Ro

    2013-03-11

    A DNA tetrahedron is employed for efficient delivery of doxorubicin into drug-resistant breast cancer cells. The drug delivered with the DNA nanoconstruct is considerably cytotoxic, whereas free doxorubicin is virtually non-cytotoxic for the drug-resistant cells. Thus, the DNA tetrahedron, made of the inherently natural and biocompatible material, can be a good candidate for the drug carrier to overcome MDR in cancer cells.

  1. Cross-resistance patterns and antigen expression in Vinca alkaloid- and other multiple drug-resistant human leukemic cell lines.

    Science.gov (United States)

    Beck, W T; Danks, M K; Cirtain, M C; van Heiningen, J N

    1986-01-01

    The studies presented in this report demonstrate that Vinca alkaloid-resistant human leukemic lymphoblasts display patterns of cross-resistance to other drugs that differ from those of cell lines selected for primary resistance to anthracyclines or epipodophyllotoxins. These various drug-resistant cell lines also showed differential expression of an antigen recognized by an antibody that distinguishes VLB-resistant from VLB-sensitive cells. Furthermore, comparable levels of resistance or cross-resistance to one drug are not predictive of cross-resistance to other drugs. Our data suggest, then, that the MDR phenotype is complex and may be the result of many and different biochemical lesions. Thus, in order to predict MDR, it may be necessary to document more than one of these changes with specific reagents.

  2. Transmission of extensively drug-resistant and multidrug resistant Mycobacterium tuberculosis in families identified by genotyping

    Institute of Scientific and Technical Information of China (English)

    YAN Li-ping; QIN Lian-hua; ZHANG Qing; SUN Hua; HAN Min; XIAO He-ping

    2013-01-01

    Background Diagnosis and appropriate treatment of multidrug-resistant tuberculosis (MDR-TB) remain major challenges.We sought to elucidate that persons who share a household with drug resistance tuberculosis patients are at high risk for primary drug resistance tuberculosis and how to prevent these outbreaks.Methods We used 12-locus mycobacterial interspersed repetitive unit and 7-locus variable-number tandem repeat to identify household transmission of extensively drug resistant and multiple drug resistant Mycobacterium tuberculosis in three families admitted in Shanghai Pulmonary Hospital affiliated with Tongji University.Drug susceptibility tests were done by the modified proportion method in the MGIT 960 system in the same time.Clinical data were also obtained from the subjects' medical records.Results All of the six strains were defined as Beijing genotype by the deletion-targeted multiplex PCR (DTM-PCR) identification on the genomic deletion RD105.Strains from family-1 had the same minisatellite interspersed repetitive unit (MIRU) pattem (232225172531) and the same MIRU pattern (3677235).Strains from family-2 had the same MIRU pattern (2212261553323) and the same MIRU pattern (3685134).Strains from family-3 did not have the same MIRU pattern and they differed at only one locus (223326173533,223325173533),and did not have the same VNTR pattern with two locus differed (3667233,3677234).Conclusions Household transmission exists in the three families.A clear chain of tuberculosis transmission within family exists.Tuberculosis susceptibility should be considered when there is more than one tuberculosis patients in a family.Household tuberculosis transmission could be prevented with adequate treatment of source patients.

  3. The epidemiology and spread of drug resistant human influenza viruses.

    Science.gov (United States)

    Hurt, Aeron C

    2014-10-01

    Significant changes in the circulation of antiviral-resistant influenza viruses have occurred over the last decade. The emergence and continued circulation of adamantane-resistant A(H3N2) and A(H1N1)pdm09 viruses mean that the adamantanes are no longer recommended for use. Resistance to the newer class of drugs, the neuraminidase inhibitors, is typically associated with poorer viral replication and transmission. But 'permissive' mutations, that compensated for impairment of viral function in A(H1N1) viruses during 2007/2008, enabled them to acquire the H275Y NA resistance mutation without fitness loss, resulting in their rapid global spread. Permissive mutations now appear to be present in A(H1N1)pdm09 viruses thereby increasing the risk that oseltamivir-resistant A(H1N1)pdm09 viruses may also spread globally, a concerning scenario given that oseltamivir is the most widely used influenza antiviral.

  4. "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.

  5. Management of multidrug-resistant tuberculosis and patients in retreatment.

    Science.gov (United States)

    Caminero, J A

    2005-05-01

    Retreatment of tuberculosis involves the management of entities as diverse as relapse, failure, treatment after default, and poor patient adherence to the previous treatment. The emergence of conditions for selection of resistance (failure and partial abandonment) is a matter of great concern. The development of a retreatment regimen for tuberculosis requires consideration of certain basic premises. The importance of a comprehensive and directed history of drugs taken in the past, and the limited reliability of susceptibility tests to many of these drugs, should be kept in mind. Taking this into account, and possessing a thorough knowledge of all anti-tuberculosis medications, it is possible to cure almost all patients with an appropriate retreatment regimen including a minimum of three or four drugs not previously used. Nonetheless, the treatment of these patients is so complex that it should only be carried out by experienced staff. Concern about treating tuberculosis patients with drug resistance varies greatly depending on the available resources. High-income countries should provide individual treatment regimens adapted to each patient; however, in other settings, restricted resources could justify the implementation of standardised therapeutic guidelines with second-line drugs in order to facilitate management and reduce costs.

  6. Definition of drug-resistant epilepsy: is it evidence based?

    Science.gov (United States)

    Wiebe, Samuel

    2013-05-01

    Clinical case definitions are the cornerstone of clinical communication and of clinical and epidemiologic research. The ramifications of establishing a case definition are extensive, including potentially large changes in epidemiologic estimates of frequency, and decisions for clinical management. Yet, defining a condition entails numerous challenges such as defining the scope and purpose, incorporating the strongest evidence base with clinical expertise, accounting for patients' values, and considering impact on care. The clinical case definition of drug-resistant epilepsy, in addition, must address what constitutes an adequate intervention for an individual drug, what are the outcomes of relevance, what period of observation is sufficient to determine success or failure, how many medications should be tried, whether seizure frequency should play a role, and what is the role of side effects and tolerability. On the other hand, the principles of evidence-based medicine (EBM) aim at providing a systematic approach to incorporating the best available evidence into the process of clinical decision for individual patients. The case definition of drug-resistant epilepsy proposed by the the International League Against Epilepsy (ILAE) in 2009 is evaluated in terms of the principles of EBM as well as the stated goals of the authors of the definition.

  7. Reversal of Vinca alkaloid resistance but not multiple drug resistance in human leukemic cells by verapamil.

    Science.gov (United States)

    Beck, W T; Cirtain, M C; Look, A T; Ashmun, R A

    1986-02-01

    We examined the ability of verapamil, a Ca2+ channel blocker, to overcome Vinca alkaloid and multiple drug resistance in our CEM/VLB100 and CEM/DOX human leukemic lymphoblasts. Compared with the parent CCRF-CEM cells, CEM/VLB100 cells are approximately equal to 200- to 800-fold resistant to vinblastine and express cross-resistance to vincristine, doxorubicin, and other "natural product" drugs, as determined by comparing 50% inhibitory concentrations in a 48-h growth inhibition assay. Verapamil (10 microM) decreased the 50% inhibitory concentrations for Vinca alkaloids in CEM/VLB100 cells by approximately equal to 75- to 85-fold but caused only slight (approximately equal to 2- to 5-fold) decreases in 50% inhibitory concentrations for anthracyclines, epipodophyllotoxins, and other tubulin-binding drugs (colchicine and podophyllotoxin). Qualitatively similar results were obtained with doxorubicin-resistant cells, termed CEM/DOX; verapamil caused a 19-fold increase in doxorubicin toxicity but 67- and 3500-fold increases in the toxicities of vinblastine and vincristine, respectively. These results indicate that the effect of verapamil is relatively greater for Vinca alkaloids, with less pronounced effects for the other natural product drugs against which these cells express multiple drug resistance. In flow cytometric studies, individually nontoxic or minimally toxic concentrations of vinblastine plus verapamil caused measurable accumulation in the G2 + M phase as early as 4 h after the drug combination was added to cultures of CEM/VLB100 cells; this finding correlated with a comparable increase in the number of cells in mitosis and measurable decreases in the total number of cells. Since similar effects on cell cycle distribution, percentage of cells in mitosis, and cell number were seen when CEM/VLB100 cells were treated with toxic concentrations of vinblastine alone, we conclude that the primary toxicity of the vinblastine-verapamil combination stems from the

  8. Drug sensitivity and drug resistance profiles of human intrahepatic cholangiocarcinoma cell lines

    Institute of Scientific and Technical Information of China (English)

    Nisana Tepsiri; Liengchai Chaturat; Banchob Sripa; Wises Namwat; Sopit Wongkham; Vajarabhongsa Bhudhisawasdi; Wichittra Tassaneeyakul

    2005-01-01

    AIM: To study the effect of a number of chemotherapeutic drugs on five human intrahepatic cholangiocarcinoma (CCA) cell lines. The expressions of genes that have been proposed to influence the resistance of chemotherapeutic drugs including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), glutathione-S-transferase P1 (GSTP1), multidrug resistance protein (MDR1) and multidrug resistance-associated proteins (MRPs) were also determined.METHODS: Five human CCA cell lines (KKU-100, KKU M055, KKU-M156, KKU-M214 and KKU-OCA17) weretreated with various chemotherapeutic drugs and growth inhibition was determined by 3-(4,5-dimethylthiazol-2-yl)5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Semi-quantitative levels of gene expression were determined by a reverse transcriptase polymerase chain reaction (RT-PCR). Results of IC50 values and the ratios of gene expression were analyzed by linear regression to predict their relationship. RESULTS: Among five CCA cell lines, KKU-M055 was the most sensitive cell line towards all chemotherapeutic drugs investigated, particularly taxane derivatives with IC50 values of 0.02-3 nmol/L, whereas KKU-100 was apparently the least sensitive cell line. When compared to other chemotherapeutic agents, doxorubicin and pirarubicin showed the lowest IC50 values (<5 μmol/L) in all five CCA cell lines. Results from RT-PCR showed that TS, MRP1, MRP3 and GSTP1 were highly expressed in these five CCA cell lines while DPD and MRP2 were only moderately expressed. It should be noted that MDR1 expression was detected only in KKU-OCA17 cell lines. A strong correlation was only found between the level of MRP3 expression and the IC50 values of etoposide, doxorubicin and pirarubicin (r = 0.86-0.98, ,P<0.05). CONCLUSION: Sensitivity to chemotherapeutic agents is not associated with the histological type of CCA. Choosing of the appropriate chemotherapeutic regimen for the treatment of CCA requires knowledge of drug

  9. 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.

  10. The Structure of the Anti-tuberculosis Antibiotics Viomycin and Capreomycin Bound to the 70S Ribosome

    Energy Technology Data Exchange (ETDEWEB)

    Stanley, R.; Blaha, G; Grodzicki, R; Strickler, M; Steitz, T

    2010-01-01

    Viomycin and capreomycin belong to the tuberactinomycin family of antibiotics, which are among the most effective antibiotics against multidrug-resistant tuberculosis. Here we present two crystal structures of the 70S ribosome in complex with three tRNAs and bound to either viomycin or capreomycin at 3.3- and 3.5-{angstrom} resolution, respectively. Both antibiotics bind to the same site on the ribosome, which lies at the interface between helix 44 of the small ribosomal subunit and helix 69 of the large ribosomal subunit. The structures of these complexes suggest that the tuberactinomycins inhibit translocation by stabilizing the tRNA in the A site in the pretranslocation state. In addition, these structures show that the tuberactinomycins bind adjacent to the binding sites for the paromomycin and hygromycin B antibiotics, which may enable the development of new derivatives of tuberactinomycins that are effective against drug-resistant strains.

  11. The structures of the anti-tuberculosis antibiotics viomycin and capreomycin bound to the 70S ribosome

    Energy Technology Data Exchange (ETDEWEB)

    Stanley, Robin E.; Blaha, Gregor; Grodzicki, Robert L.; Strickler, Michael D.; Steitz, Thomas A. (Yale)

    2010-05-03

    Viomycin and capreomycin belong to the tuberactinomycin family of antibiotics, which are among the most effective antibiotics against multidrug-resistant tuberculosis. Here we present two crystal structures of the 70S ribosome in complex with three tRNAs and bound to either viomycin or capreomycin at 3.3- and 3.5-{angstrom} resolution, respectively. Both antibiotics bind to the same site on the ribosome, which lies at the interface between helix 44 of the small ribosomal subunit and helix 69 of the large ribosomal subunit. The structures of these complexes suggest that the tuberactinomycins inhibit translocation by stabilizing the tRNA in the A site in the pretranslocation state. In addition, these structures show that the tuberactinomycins bind adjacent to the binding sites for the paromomycin and hygromycin B antibiotics, which may enable the development of new derivatives of tuberactinomycins that are effective against drug-resistant strains.

  12. 湖南长沙市结核分枝杆菌耐药情况分析%Drug resistance analysis on Mycobacterium tuberculosis in patients with pulmonary tuberculosis in Changsha area

    Institute of Scientific and Technical Information of China (English)

    潘建华; 罗丹; 石国民; 彭雪峰; 向延根

    2016-01-01

    Objective To investigate the current situation of Mycobacterium tuberculosis drug resistance in Changsha area. Methods A total of 6198 Mycobacterium tuberculosis strains were identified in Changsha Central Hospital from 2011 to 2015 and the sensitivity of Mycobacterium tuberculosis strains to 7 kinds of anti-tuberculosis drugs was performed. Results The top 5 of the drug resistance rates of 6198 strains of Mycobacterium tuberculosis complex group were INH(14. 18% ),RFP(13. 57% ),SM(12. 31% ),EMB(3. 87)and OFLX(2. 60). The o-verall rate of resistance to anti-TB drugs was 20. 56% . MDR rate was 9. 31%. PDR rate was 4. 52% and XDR rate was 0. 45% . The detection rate of drug resistant tuberculosis of male was higher than female in all age groups except the female under 20 years old in 2012. The resistance in retreated patients was higher than in initial patients. Con-clusion The prevalence of drug resistance of Mycobacterium tuberculosis in our hospital is lower than that of the fifth national tuberculosis epidemiological survey,but MDR rate is higher than the national level. Therefore,its drug re-sistance situation is still grim.%目的:了解长沙地区结核分枝杆菌耐药情况。方法分析本院2012年1月-2015年10月分离的6198株结核分枝杆菌对7种抗结核药物的耐药情况。结果6198株结核分枝杆菌复合群菌株耐药率顺位前5位依次为 INH(14.18%)、RFP(13.57%)、SM(12.31%)、EMB(3.87)、OFLX(2.60);总耐药率为20.56%,耐多药占9.31%,多耐药占4.52%,广泛耐药占0.45%;除2012年20岁以下年龄组女性耐药结核菌的检出率略高于男性外,其余年份各年龄组男性均高于女性;复治患者的耐药率(24.76%)高于初治患者(19.49%),两者差异有统计学意义(χ2=176.21,P <0.001);结论本院结核分枝杆菌耐药率总体低于全国第五次结核病流行病学调查结果,但耐多药率高于全国水平,耐药状况仍然严峻。

  13. Chrysin and its emerging role in cancer drug resistance.

    Science.gov (United States)

    Kasala, Eshvendar Reddy; Bodduluru, Lakshmi Narendra; Barua, Chandana C; Gogoi, Ranadeep

    2015-07-05

    This letter illustrates the significant chemosensitizing effects of chrysin to resistance cancer cells and refers to the article on "Combination of chrysin and cisplatin promotes the apoptosis of Hep G2 cells by up-regulating p53" by Li et al., published in your journal recently. Recent studies have demonstrated that chrysin is able to sensitize or kill cancer cells which are resistant to chemotherapeutic drugs such as cisplatin, doxorubicin and adriamycin. Owing to its potential anti-cancer effects and devoid of toxicity to non-transformed cells, further research is required to completely explore its chemosensitizing effects in other cancers and also assess and evaluate its safety, before going for possible human application.

  14. Factors Associated with Fatality during the Intensive Phase of Anti-Tuberculosis Treatment

    Science.gov (United States)

    Casals, M.; Caminero, J. A.; García-García, J. M.; Jiménez-Fuentes, M. A.; Medina, J. F.; Millet, J. P.; Ruiz-Manzano, J.; Caylá, J.

    2016-01-01

    Objective To determine the case-fatality rate (CFR) at the end of the intensive phase of tuberculosis (TB) treatment, and factors associated with fatality. Methods TB patients diagnosed between 2006 and 2013 were followed-up during treatment. We computed the CFR at the end of the intensive phase of TB treatment, and the incidence of death per 100 person-days (pd) of follow-up. We performed survival analysis using the Kaplan-Meier method and Cox regression, and calculate hazard ratios (HR) and 95% confidence intervals (CI). Results A total of 5,182 patients were included, of whom 180 (3.5%) died; 87 of these deaths (48.3%) occurred during the intensive phase of treatment, with a CFR of 1.7%. The incidence of death was 0.028/100 pd. The following factors were associated with death during the intensive phase: being >50 years (HR = 36.9;CI:4.8–283.4); being retired (HR = 2.4;CI:1.1–5.1); having visited the emergency department (HR = 3.1;CI:1.2–7.7); HIV infection (HR = 3.4;CI:1.6–7.2); initial standard treatment with 3 drugs (HR = 2.0;CI:1.2–3.3) or non-standard treatments (HR = 2.68;CI:1.36–5.25); comprehension difficulties (HR = 2.8;CI:1.3–6.1); and smear-positive sputum (HR = 2.3-CI:1.0–4.8). Conclusion There is a non-negligible CFR during the intensive phase of TB, whose reduction should be prioritised. The CFR could be a useful indicator for evaluating TB programs. PMID:27487189

  15. Identification and Characterization of Novel Drug Resistance Loci in Plasmodium falciparum

    OpenAIRE

    Van Tyne, Daria Natalie

    2012-01-01

    Malaria has plagued mankind for millennia. Antimalarial drug use over the last century has generated highly drug-resistant parasites, which amplify the burden of this disease and pose a serious obstacle to control efforts. This dissertation is motivated by the simple fact that malaria parasites have become resistant to nearly every antimalarial drug that has ever been used, yet the precise genetic mechanisms of parasite drug resistance remain largely unknown. Our work pairs genomics-age techn...

  16. Treatment options for carbapenem-resistant and extensively drug-resistant Acinetobacter baumannii infections.

    Science.gov (United States)

    Viehman, J Alexander; Nguyen, M Hong; Doi, Yohei

    2014-08-01

    Acinetobacter baumannii is a leading cause of healthcare-associated infections worldwide. Because of 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.

  17. Antibiotic Restriction Might Facilitate the Emergence of Multi-drug Resistance.

    Science.gov (United States)

    Obolski, Uri; Stein, Gideon Y; Hadany, Lilach

    2015-06-01

    High antibiotic resistance frequencies have become a major public health issue. The decrease in new antibiotics' production, combined with increasing frequencies of multi-drug resistant (MDR) bacteria, cause substantial limitations in treatment options for some bacterial infections. To diminish overall resistance, and especially the occurrence of bacteria that are resistant to all antibiotics, certain drugs are deliberately scarcely used--mainly when other options are exhausted. We use a mathematical model to explore the efficiency of such antibiotic restrictions. We assume two commonly used drugs and one restricted drug. The model is examined for the mixing strategy of antibiotic prescription, in which one of the drugs is randomly assigned to each incoming patient. Data obtained from Rabin medical center, Israel, is used to estimate realistic single and double antibiotic resistance frequencies in incoming patients. We find that broad usage of the hitherto restricted drug can reduce the number of incorrectly treated patients, and reduce the spread of bacteria resistant to both common antibiotics. Such double resistant infections are often eventually treated with the restricted drug, and therefore are prone to become resistant to all three antibiotics. Thus, counterintuitively, a broader usage of a formerly restricted drug can sometimes lead to a decrease in the emergence of bacteria resistant to all drugs. We recommend re-examining restriction of specific drugs, when multiple resistance to the relevant alternative drugs already exists.

  18. 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...

  19. Anti-tuberculosis drug resistance among new and previously treated pulmonary tuberculosis patients in Cotonou, Benin%贝宁-科托努地区初治和复治肺结核患者抗结核药物耐药研究

    Institute of Scientific and Technical Information of China (English)

    D. Affolabi; O.A.B.G.Adjagba; B. Tanimomo-Kledjo; M. Gninafon; S.Y. Anagonou; F. Portaels; 徐彩红

    2008-01-01

    目的:评估贝宁最大的结核病中心科托努地区目前抗结核药物的耐药形势.方法:共计分析从肺结核患者分离出的 470 株结核分枝杆菌复合群:其中 244 株来自新病人,226 株来自复治病人.使用比例法对分离菌株进行一线药物的敏感性试验.结果:原发耐多药情况与患者的来源有关:若分析所有的患者,则新病人中耐多药相对较高(1.6%);若仅考虑贝宁常住人口,该比例则较低(0.5%),并与 1994 年国家的耐药监测结果比较.复治患者的耐多药率(11.1%),也与贝宁1994年的耐药监测结果持平.没有发现合并感染人类免疫缺陷病毒与抗结核药物的耐药性相关.结论:本研究表明在流行病学调查中正确的区分患者的重要性,研究人口不同,结果就可能不相同.

  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

    revealed that resistance to drug combinations was mediated largely by mutations in the same genes as single-drug-evolved lineages highlighting the importance of the component drugs in determining the rate of resistance evolution. Results of this work suggest that the mechanisms of resistance to constituent......As drug-resistant pathogens continue to emerge, combination therapy will increasingly be relied upon to treat infections and to help combat further development of multidrug resistance. At present a dichotomy exists between clinical practice, which favors therapeutically synergistic combinations......, and the scientific model emerging from in vitro experimental work, which maintains that this interaction provides greater selective pressure toward resistance development than other interaction types. We sought to extend the current paradigm, based on work below or near minimum inhibitory concentration levels...

  1. Managing drug-resistant epilepsy: challenges and solutions

    Directory of Open Access Journals (Sweden)

    Dalic L

    2016-10-01

    Full Text Available Linda Dalic,1 Mark J Cook2,3 1Department of Neurology, Austin Health, 2St Vincent’s Hospital, Centre for Clinical Neurosciences and Neurological Research, 3Department of Medicine, The University of Melbourne, Melbourne, Australia Abstract: Despite the development of new antiepileptic drugs (AEDs, ~20%–30% of people with epilepsy remain refractory to treatment and are said to have drug-resistant epilepsy (DRE. This multifaceted condition comprises intractable seizures, neurobiochemical changes, cognitive decline, and psychosocial dysfunction. An ongoing challenge to both researchers and clinicians alike, DRE management is complicated by the heterogeneity among this patient group. The underlying mechanism of DRE is not completely understood. Many hypotheses exist, and relate to both the intrinsic characteristics of the particular epilepsy (associated syndrome/lesion, initial response to AED, and the number and type of seizures prior to diagnosis and other pharmacological mechanisms of resistance. The four current hypotheses behind pharmacological resistance are the “transporter”, “target”, “network”, and “intrinsic severity” hypotheses, and these are reviewed in this paper. Of equal challenge is managing patients with DRE, and this requires a multidisciplinary approach, involving physicians, surgeons, psychiatrists, neuropsychologists, pharmacists, dietitians, and specialist nurses. Attention to comorbid psychiatric and other diseases is paramount, given the higher prevalence in this cohort and associated poorer health outcomes. Treatment options need to consider the economic burden to the patient and the likelihood of AED compliance and tolerability. Most importantly, higher mortality rates, due to comorbidities, suicide, and sudden death, emphasize the importance of seizure control in reducing this risk. Overall, resective surgery offers the best rates of seizure control. It is not an option for all patients, and there is

  2. 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

  3. Use of collateral sensitivity networks to design drug cycling protocols that avoid resistance development

    DEFF Research Database (Denmark)

    Imamovic, Lejla; Sommer, Morten

    2013-01-01

    New drug deployment strategies are imperative to address the problem of drug resistance, which is limiting the management of infectious diseases and cancers. We evolved resistance in Escherichia coli toward 23 drugs used clinically for treating bacterial infections and mapped the resulting...

  4. Extensively drug-resistant Streptococcus pneumoniae, South Korea, 2011-2012.

    Science.gov (United States)

    Cho, Sun Young; Baek, Jin Yang; Kang, Cheol-In; Kim, So Hyun; Ha, Young Eun; Chung, Doo Ryeon; Lee, Nam Yong; Peck, Kyong Ran; Song, Jae-Hoon

    2014-05-01

    To better understand extensively drug resistant Streptococcus pneumoniae, we assessed clinical and microbiological characteristics of 5 extensively drug-resistant pneumococcal isolates. We concluded that long-term care facility residents who had undergone tracheostomy might be reservoirs of these pneumococci; 13- and 23-valent pneumococcal vaccines should be considered for high-risk persons; and antimicrobial drugs should be used judiciously.

  5. [Progress in researches on molecular markers of Plasmodium falciparum drug resistance].

    Science.gov (United States)

    Zhang, Mei-hua; Lu, Feng; Cao, Jun; Gao, Qi

    2015-06-01

    Effective chemotherapy is the mainstay of malaria control. However, it is undergoing the serious threat by resis- tance of falciparum malaria to antimalarial drugs. In recent years, with the development of molecular biology technology, molec- ular markers have been widely used to monitor antimalarial drug resistance. This paper reviews the researches on the common molecular markers related to Plasmodiumfalciparum drug resistance.

  6. Amplification of a Gene Related to Mammalian mdr Genes in Drug-Resistant Plasmodium falciparum

    Science.gov (United States)

    Wilson, Craig M.; Serrano, Adelfa E.; Wasley, Annemarie; Bogenschutz, Michael P.; Shankar, Anuraj H.; Wirth, Dyann F.

    1989-06-01

    The malaria parasite Plasmodium falciparum contains at least two genes related to the mammalian multiple drug resistance genes, and at least one of the P. falciparum genes is expressed at a higher level and is present in higher copy number in a strain that is resistant to multiple drugs than in a strain that is sensitive to the drugs.

  7. Managing drug-resistant epilepsy: challenges and solutions

    Science.gov (United States)

    Dalic, Linda; Cook, Mark J

    2016-01-01

    Despite the development of new antiepileptic drugs (AEDs), ~20%–30% of people with epilepsy remain refractory to treatment and are said to have drug-resistant epilepsy (DRE). This multifaceted condition comprises intractable seizures, neurobiochemical changes, cognitive decline, and psychosocial dysfunction. An ongoing challenge to both researchers and clinicians alike, DRE management is complicated by the heterogeneity among this patient group. The underlying mechanism of DRE is not completely understood. Many hypotheses exist, and relate to both the intrinsic characteristics of the particular epilepsy (associated syndrome/lesion, initial response to AED, and the number and type of seizures prior to diagnosis) and other pharmacological mechanisms of resistance. The four current hypotheses behind pharmacological resistance are the “transporter”, “target”, “network”, and “intrinsic severity” hypotheses, and these are reviewed in this paper. Of equal challenge is managing patients with DRE, and this requires a multidisciplinary approach, involving physicians, surgeons, psychiatrists, neuropsychologists, pharmacists, dietitians, and specialist nurses. Attention to comorbid psychiatric and other diseases is paramount, given the higher prevalence in this cohort and associated poorer health outcomes. Treatment options need to consider the economic burden to the patient and the likelihood of AED compliance and tolerability. Most importantly, higher mortality rates, due to comorbidities, suicide, and sudden death, emphasize the importance of seizure control in reducing this risk. Overall, resective surgery offers the best rates of seizure control. It is not an option for all patients, and there is often a significant delay in referring to epilepsy surgery centers. Optimization of AEDs, identification and treatment of comorbidities, patient education to promote adherence to treatment, and avoidance of triggers should be periodically performed until further

  8. 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.

  9. Second-line drug resistance in multidrug-resistant tuberculosis cases of various origins in the Netherlands.

    NARCIS (Netherlands)

    Ingen, J. van; Boeree, M.J.; Wright, A.; Laan, T.; Dekhuijzen, P.N.R.; Soolingen, D van

    2008-01-01

    SETTING: The Netherlands. OBJECTIVE: To investigate the frequency of resistance to second-line drugs among multidrug-resistant tuberculosis (MDR-TB) cases and its correlation with patients' geographic origin. DESIGN: Retrospective laboratory database study of multidrug-resistant Mycobacterium tuberc

  10. High Levels of Transmitted HIV Drug Resistance in a Study in Papua New Guinea

    Science.gov (United States)

    Lavu, Evelyn; Kave, Ellan; Mosoro, Euodia; Markby, Jessica; Aleksic, Eman; Gare, Janet; Elsum, Imogen A.; Nano, Gideon; Kaima, Petronia; Dala, Nick; Gurung, Anup; Bertagnolio, Silvia; Crowe, Suzanne M.; Myatt, Mark

    2017-01-01

    Introduction Papua New Guinea is a Pacific Island nation of 7.3 million people with an estimated HIV prevalence of 0.8%. ART initiation and monitoring are guided by clinical staging and CD4 cell counts, when available. Little is known about levels of transmitted HIV drug resistance in recently infected individuals in Papua New Guinea. Methods Surveillance of transmitted HIV drug resistance in a total of 123 individuals recently infected with HIV and aged less than 30 years was implemented in Port Moresby (n = 62) and Mount Hagen (n = 61) during the period May 2013-April 2014. HIV drug resistance testing was performed using dried blood spots. Transmitted HIV drug resistance was defined by the presence of one or more drug resistance mutations as defined by the World Health Organization surveillance drug resistance mutations list. Results The prevalence of non-nucleoside reverse transcriptase inhibitor transmitted HIV drug resistance was 16.1% (95% CI 8.8%-27.4%) and 8.2% (95% CI 3.2%-18.2%) in Port Moresby and Mount Hagen, respectively. The prevalence of nucleoside reverse transcriptase inhibitor transmitted HIV drug resistance was 3.2% (95% CI 0.2%-11.7%) and 3.3% (95% CI 0.2%-11.8%) in Port Moresby and Mount Hagen, respectively. No protease inhibitor transmitted HIV drug resistance was observed. Conclusions The level of non-nucleoside reverse transcriptase inhibitor drug resistance in antiretroviral drug naïve individuals recently infected with HIV in Port Moresby is amongst the highest reported globally. This alarming level of transmitted HIV drug resistance in a young sexually active population threatens to limit the on-going effective use of NNRTIs as a component of first-line ART in Papua New Guinea. To support the choice of nationally recommended first-line antiretroviral therapy, representative surveillance of HIV drug resistance among antiretroviral therapy initiators in Papua New Guinea should be urgently implemented. PMID:28146591

  11. The problem of resistant Trichomonas vaginalis to antiprotozoal drugs

    Directory of Open Access Journals (Sweden)

    A. L. Poznyak

    2011-01-01

    Full Text Available This review presents recent data on the energy metabolism of Trichomonas vaginalis and ways the activation of metronidazole. The sensitivity of microorganisms to the 5-nitroimidazole by the presence of their enzyme systems, generating and transporting electrons, which can then transfer them to the nitro group of the drug. In T.vaginalis these are pyruvate ferredoxin-oxydoreductase, thioredoxin reductase and flavin reductase. The development of resistance T.vaginalis to metronidazole preparations of this multistep process, based on the gradual reduction (up to a loss activity hydrogenosomal enzymes and / or violation of the flavindependent metabolic pathways.

  12. Natural solution to antibiotic resistance: bacteriophages 'The Living Drugs'.

    Science.gov (United States)

    Jassim, Sabah A A; Limoges, Richard G

    2014-08-01

    Antibiotics have been a panacea in animal husbandry as well as in human therapy for decades. The huge amount of antibiotics used to induce the growth and protect the health of farm animals has lead to the evolution of bacteria that are resistant to the drug's effects. Today, many researchers are working with bacteriophages (phages) as an alternative to antibiotics in the control of pathogens for human therapy as well as prevention, biocontrol, and therapy in animal agriculture. Phage therapy and biocontrol have yet to fulfill their promise or potential, largely due to several key obstacles to their performance. Several suggestions are shared in order to point a direction for overcoming common obstacles in applied phage technology. The key to successful use of phages in modern scientific, farm, food processing and clinical applications is to understand the common obstacles as well as best practices and to develop answers that work in harmony with nature.

  13. 3-Halo Chloroquine Derivatives Overcome Plasmodium falciparum Chloroquine Resistance Transporter-Mediated Drug Resistance in P. falciparum.

    Science.gov (United States)

    Edaye, Sonia; Tazoo, Dagobert; Bohle, D Scott; Georges, Elias

    2015-12-01

    Polymorphism in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) was shown to cause chloroquine resistance. In this report, we examined the antimalarial potential of novel 3-halo chloroquine derivatives (3-chloro, 3-bromo, and 3-iodo) against chloroquine-susceptible and -resistant P. falciparum. All three derivatives inhibited the proliferation of P. falciparum; with 3-iodo chloroquine being most effective. Moreover, 3-iodo chloroquine was highly effective at potentiating and reversing chloroquine toxicity of drug-susceptible and -resistant P. falciparum.

  14. 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.

  15. 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.

  16. Reversal of multidrug resistance in drug-resistant human gastric cancer cell line SGC7901/VCR by antiprogestin drug mifepristone

    Institute of Scientific and Technical Information of China (English)

    Da-Qiang Li; Zhi-Biao Wang; Jin Bai; Jie Zhao; Yuan Wang; Kai Hu; Yong-Hong Du

    2004-01-01

    AIM: To explore the reversal effect of mifepristone on multidrug resistance (MDR) in drug-resistant human gastric cancer cell line SGC7901/VCR and its mechanisms.METHODS: Expression of multidrug resistance-associated protein(MRP) was detected using reverse transcriptionpolymerase chain reaction(RT-PCR). Flow cytometry was used to assay the expression of P-glycoprotein(P-gp), Bcl-2,Bax, and the mean fluorescent intensity of intracellular rhodamine 123 in the cells. Meanwhile, the protein levels of Bcl-2 and Bax were also detected by Western blotting analysis. The sensitivity of cells to the anticancer agent,vincrimycin(VCR), and the intracellular [3H]VCR accumulation were determined by tetrazolium blue (MTT) assay and a liquid scintillation counter, respectively.RESULTS: Expression of MRP and P-gp in SGC7901/VCR cells was 6.04-and 8.37-fold higher as compared with its parental SGC7901 cells, respectively. After treatment with 1, 5, 10, and 20 μmol/L mifepristone, SGC7901/VCR cells showed a 1.34-, 2.29-, 3.11-, and 3.71-fold increase in the accumulation of intracellular VCR, a known substrate of MRP,and a 1.03-, 2.04-, 3.08-, and 3.68-fold increase in the retention of rhodamine 123, an indicator of P-gp function, respectively.MTT assay revealed that the resistance of SGC7901/VCR cells to VCR was 11.96-fold higher than that of its parental cells. The chemosensitivity of SGC7901/VCR cells to VCR was enhanced by 1.02-, 7.19-, 12.84-, and 21.17-fold after treatment with mifepristone at above-mentioned dose. After 96 h of incubation with mifepristone 10 μmol/L, a concentration close to plasma concentrations achievable in human, the expression of Bcl-2 protein was decreased to (9.21±0.65)%from (25.32±1.44)%, whereas the expression of Bax protein was increased to (19.69±1.13)% from (1.24±0.78)%(P<0.01). Additionally, the effects of mifepristone on the expression of Bcl-2 and Bax proteins in SGC7901/VCR cells were further demonstrated by Western blotting analysis

  17. In-depth molecular characterization of Mycobacterium tuberculosis from New Delhi--predominance of drug resistant isolates of the 'modern' (TbD1 type.

    Directory of Open Access Journals (Sweden)

    Ruth Stavrum

    Full Text Available BACKGROUND: India has the highest estimated burden of tuberculosis in the world, accounting for 21% of all tuberculosis cases world-wide. However, due to lack of systematic analysis using multiple markers the available information on the genomic diversity of Mycobacterium tuberculosis in India is limited. METHODOLOGY/PRINCIPAL FINDINGS: Thus, 65 M. tuberculosis isolates from New Delhi, India were analyzed by spoligotyping, MIRU-VNTR, large deletion PCR typing and single nucleotide polymorphism analysis (SNP. The Central Asian (CAS 1 _DELHI sub-lineage was the most prevalent sub-lineage comprising 46.2% (n = 30 of all isolates, with shared-type (ST 26 being the most dominant genotype comprising 24.6% (n = 16 of all isolates. Other sub-lineages observed were: East-African Indian (EAI-5 (9.2%, n = 6, EAI6_BGD1 (6.2%, n = 4, EAI3_IND, CAS and T1 with 6.2% each (n = 4 each, Beijing (4.6%, n = 3, CAS2 (3.1%, n = 2, and X1 and X2 with 1 isolate each. Genotyping results from five isolates (7.7% did not match any existing spoligopatterns, and one isolate, ST124, belonged to an undefined lineage. Twenty-six percent of the isolates belonged to the TbD1+ PGG1 genogroup. SNP analysis of the pncA gene revealed a CAS-lineage specific silent mutation, S65S, which was observed for all CAS-lineage isolates (except two ST26 isolates and in 1 orphan. Mutations in the pncA gene, conferring resistance to pyrazinamide, were observed in 15.4% of all isolates. Collectively, mutations in the rpoB gene, the katG gene and in both rpoB and katG genes, conferring resistance to rifampicin and isoniazid, respectively, were more frequent in CAS1_DELHI isolates compared to non-CAS_DELHI isolates (OR: 3.1, CI95% [1.11, 8.70], P = 0.045. The increased frequency of drug-resistance could not be linked to the patients' history of previous anti-tuberculosis treatment (OR: 1.156, CI95% [0.40, 3.36], P = 0.79. Fifty-six percent of all new tuberculosis patients had mutations in either

  18. Detection of Low Frequency Multi-Drug Resistance and Novel Putative Maribavir Resistance in Immunocompromised Pediatric Patients with Cytomegalovirus

    Science.gov (United States)

    Houldcroft, Charlotte J.; Bryant, Josephine M.; Depledge, Daniel P.; Margetts, Ben K.; Simmonds, Jacob; Nicolaou, Stephanos; Tutill, Helena J.; Williams, Rachel; Worth, Austen J. J.; Marks, Stephen D.; Veys, Paul; Whittaker, Elizabeth; Breuer, Judith

    2016-01-01

    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 pediatric patients receiving single or combination anti-HCMV treatment, serially sampled over 1–27 weeks. Changes in consensus sequence and resistance mutations were analyzed 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 11 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. PMID:27667983

  19. 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.

  20. Drug resistance of Mycobacterium tuberculosis strains in southern Brazil

    Directory of Open Access Journals (Sweden)

    Laynara Katize Grutzmacher

    2012-02-01

    Full Text Available INTRODUCTION: The aim of this work was to evaluate the prevalence of Mycobacterium tuberculosis (MT strains with mutations that could result in resistance to the main drugs used in treatment in a region with one of the highest numbers of tuberculosis (TB cases in southern Brazil. METHODS: Deoxyribonucleic acid (DNA from 120 sputum samples from different patients suspicious of pulmonary tuberculosis who attended the Municipal Public Laboratory for Mycobacterium sp. diagnosis was directly amplified and analyzed by PCR-SSCP. The DNA was amplified in known hotspot mutation regions of the genes rpoB, ahpC, embB, katG, inhA, and pncA. RESULTS: The percentage of samples positive by culture was 9.2% (11/120; 5% (6/120 were positive by bacilloscopy and MT-PCR, and DNA fragments of the aforementioned resistance genes could be amplified from seven (7 of the eleven (11 samples with positive results, either by culture or PCR/bacilloscopy. All presented a SSCP pattern similar to a native, nonresistant genotype, with the ATCC strain 25177 as control, except for one sample (0.01%, which presented a SSCP profile demonstrating mutation at the embB gene. CONCLUSIONS: These results are consistent with the empirical observations by physicians treating TB patients in our region of a low occurrence of cases that are refractory to conventional treatment schemes, in contrast to other parts of the country. Continued surveillance, especially molecular, is essential to detect and monitor the outbreak of MT-resistant strains.

  1. 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.

  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. Overcoming of multidrug resistance by introducing the apoptosis gene, bcl-Xs, into MRP-overexpressing drug resistant cells.

    Science.gov (United States)

    Ohi, Y; Kim, R; Toge, T

    2000-05-01

    Multidrug resistance associated protein (MRP) is one of drug transport membranes that confer multidrug resistance in cancer cells. Multidrug resistance has been known to be associated with resistance to apoptosis. In this study, using MRP overexpressing multidrug resistant nasopharyngeal cancer cells, we examined the expression of apoptosis related genes including p53, p21WAF1, bax and bcl-Xs between drug sensitive KB and its resistant KB/7D cells. We also examined whether the introduction of apoptosis related gene could increase the sensitivity to anticancer drugs in association with apoptotic cell death. The relative resistances to anticancer drugs in KB/7D cells evaluated by IC50 values were 3.6, 61.3, 10.4 and 10.5 to adriamycin (ADM), etoposide (VP-16), vincristine (VCR) and vindesine (VDS), respectively. The resistance to anticancer drugs in KB/7D cells was associated with the attenuation of internucleosomal DNA ladder formation in apoptosis. Of important, the mRNA expression of bcl-Xs gene in KB/7D cells was decreased in one-fourth as compared to that of KB cells among the apoptosis genes. The mRNA expression of bcl-Xs gene in a bcl-Xs transfected clone (KB/7Dbcl-Xs) was increased about 2-fold compared to that of KB/7Dneo cells, while the mRNA expression of MRP gene was not significantly different in KB/7bcl-Xs and KB/7Dneo cells. The sensitivities to anticancer drugs including ADM, VCR and VDS except VP-16 were increased in KB/7Dbcl-Xs cells, in turn, the relative resistance in KB/7Dbcl-Xs cells was decreased to 1.4, 4.0, and 3.0 in ADM, VCR and VDS, respectively, as compared to those of KB/7Dneo cells. Of interest, the studies on the accumulation of [3H]VCR showed that the decrease of [3H]VCR accumulation in KB/7Dbcl-Xs was not significantly different from that of KB/7Dneo cells. Collectively, these results indicated that the mechanism(s) of drug resistance in KB/7D cells could be explained at least by two factors: a) reduced drug accumulation mediated by

  4. A reaction-diffusion system modeling the spread of resistance to an antimalarial drug.

    Science.gov (United States)

    Bacaer, Nicolas; Sokhna, Cheikh

    2005-04-01

    A mathematical model representing the difusion of resistance to an antimalarial drug is developed. Resistance can spread only when the basic reproduction number of the resistant parasites is bigger than the basic reproduction number of the sensitive parasites (which depends on the fraction of infected people treated with the antimalarial drug). Based on a linearization study and on numerical simulations, an expression for the speed at which resistance spreads is conjectured. It depends on the ratio of the two basic reproduction numbers, on a coefficient representing the difusion of mosquitoes, on the death rate of mosquitoes infected by resistant parasites, and on the recovery rate of nonimmune humans infected by resistant parasites.

  5. Prevalence of Pre-Extensively Drug-Resistant Tuberculosis (Pre XDR-TB) and Extensively Drug-Resistant Tuberculosis (XDR-TB) among Pulmonary Multidrug Resistant Tuberculosis (MDR-TB) at a Tertiary Care Center in Mumbai

    OpenAIRE

    Unnati D. Desai; Joshi, Jyotsna M

    2016-01-01

    Background: India is a high burden country for Tuberculosis (TB). As per the World Health Organization (WHO) statistics, 24000 cases of Multi Drug Resistant (MDR) TB were diagnosed in India in 2014. MDR-TB patients consist of a heterogeneous cohort and management has its challenges. Aims and objectives: We studied the prevalence of PreExtensively Drug Resistant TB (Pre XDR-TB) and Extensively Drug Resistant TB (XDR-TB) among patients of pulmonary MDR-TB not previous...

  6. Toward genetic transformation of mitochondria in mammalian cells using a recoded drug-resistant selection marker

    Institute of Scientific and Technical Information of China (English)

    Young Geol Yoon; Michael Duane Koob

    2011-01-01

    Due to technical difficulties, the genetic transformation of mitochondria in mammalian cells is still a challenge. In this report, we described our attempts to transform mammalian mitochondria with an engineered mitochondrial genome based on selection using a drug resistance gene. Because the standard drug-resistant neomycin phosphotransferase confers resistance to high concentrations of G418 when targeted to the mitochondria, we generated a recoded neomycin resistance gene that uses the mammalian mitochondrial genetic code to direct the synthesis of this protein in the mitochondria, but not in the nucleus (mitochondrial version). We also generated a universal version of the recoded neomycin resistance gene that allows synthesis of the drug-resistant proteins both in the mitochondria and nucleus. When we transfected these recoded neomycin resistance genes that were incorporated into the mouse mitochondrial genome clones into mouse tissue culture cells by electroporation, no DNA constructs were delivered into the mitochondria. We found that the universal version of the recoded neomycin resistance gene was expressed in the nucleus and thus conferred drug resistance to G418 selection, while the synthetic mitochondrial version of the gene produced no background drug-resistant cells from nuclear transformation. These recoded synthetic drug-resistant genes could be a useful tool for selecting mitochondrial genetic transformants as a precise technology for mitochondrial transformation is developed.

  7. New drugs to treat multidrug-resistant tuberculosis: the case for bedaquiline.

    Science.gov (United States)

    Leibert, Eric; Danckers, Mauricio; Rom, William N

    2014-01-01

    Mycobacterium tuberculosis develops spontaneous resistance mutants to virtually every drug in use. Courses of therapy select for these mutants and drug-resistant organisms emerge. The development of drug-resistant organisms has reached the point that drug resistance now threatens to undermine global success against tuberculosis (TB). New drugs are needed. The last new class of drugs specifically developed for treatment of TB was the rifamycins over 40 years ago. New funding sources and the development of product development partnerships have energized the TB drug development effort. There are now more TB drugs in development than at any time in the past. The first of these drugs to be developed and marketed was bedaquiline. Bedaquiline has an entirely novel mechanism of action and so should be active against otherwise highly resistant organisms. It acts on the transmembrane component of adenosine triphosphate synthase and acts by preventing electron transport. This raises the exciting possibility that bedaquiline may be active against less metabolically active organisms. Drug-drug interactions between rifamycins and the cytochrome P450-3A system will limit bedaquiline's utility and create complexity in treatment regimens. In clinical trials, treatment with bedaquiline added to a background multidrug-resistant TB regimen was associated with earlier culture conversion and higher cure rates, but there were unexplained excess deaths in the bedaquiline arms of these trials. Food and Drug Administration approved bedaquiline for the treatment of multidrug-resistant TB when an effective treatment regimen cannot otherwise be provided. They required a black box warning about excess deaths and require that a phase III trial be completed. A planned Phase III trial is being reorganized. While bedaquiline is an exciting drug and marks a dramatic moment in the history of TB treatment, its ultimate place in the anti-TB drug armamentarium is unclear pending the Phase III trial and

  8. HIV-1 drug resistance among antiretroviral treatment-naïve Ethiopian patients

    Directory of Open Access Journals (Sweden)

    A Mulu

    2012-11-01

    Full Text Available Background: In many African countries, access to antiretroviral treatment (ART has been significantly scaled up over the last five years. Nevertheless, data on drug resistance mutation are scarce. The objective of the current study was to determine the predominant subtypes of HIV-1 as well as to identify baseline mutations with potential drug resistance among ART-naïve patients from Ethiopia. Methods: Genotypic drug resistance on the entire protease and partial reverse transcriptase (codons 1–335 regions of the pol gene was determined by an in-house protocol in 160 ART-naïve patients. Genotypic drug resistance was defined as the presence of one or more resistance-related mutations, as specified by the consensus of the Stanford University HIV drug resistance database (HIVDB available at http://hivdb.stanford.edu/ and the 2011 International AIDS Society (IAS mutation list (http://www.iasusa.org/resistance-mutations/. Results: A predominance of HIV-1 subtype C (98.7% was observed. According to the IAS mutation list, antiretroviral drug resistance mutations were detected in 20 patients (13%. However, the level of drug resistance is 5.2% (8/155 when the most conservative method, HIVDB algorithms were applied. In both algorithms, none had major PI mutation and mutation-conferring resistance to NRTI and NNRTI were not overlapping. Conclusions: There is strong evidence for clade homogeneity in Ethiopia and low influx of other subtypes to the country. The level of transmitted drug resistance exceeds that of WHO estimates and indicates that many HIV-infected individuals on ART are practicing risk-related behaviours. The results also show that HIV drug resistance testing should be installed in resource limited settings.

  9. 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....

  10. 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...

  11. 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...

  12. Transmission Intensity and Drug Resistance in Malaria Population Dynamics : Implications for Climate Change

    NARCIS (Netherlands)

    Artzy-Randrup, Yael; Alonso, David; Pascual, Mercedes

    2010-01-01

    Although the spread of drug resistance and the influence of climate change on malaria are most often considered separately, these factors have the potential to interact through altered levels of transmission intensity. The influence of transmission intensity on the evolution of drug resistance has b

  13. Prevalence and Risk Factors of Primary Drug-Resistant Tuberculosis in China

    Institute of Scientific and Technical Information of China (English)

    WANG Sheng Fen; ZHOU Yang; PANG Yu; ZHENG Hui Wen; ZHAO Yan Lin

    2016-01-01

    ObjectiveTo investigatetheprevalence of primary drug-resistant tuberculosis (TB) and associated risk factors in China.We also explored factors contributing tothe transmission of multidrug-resistant tuberculosis (MDR-TB). MethodsA total of 2794 representative,Mycobacterium tuberculosis isolates from treatment-naive patients were subjected to drug susceptibility testing, and risk factors for drug-resistant TBwere analyzed. We also analyzed MDR-TB strain sublineages, drug-resistance-conferring mutations, and risk factors associated with clustered primary MDR strains. ResultsAmong 2794Mycobacterium tuberculosis isolates from treatment-naive patients, the prevalence of any resistance to first-line drugs was 33.2%andthe prevalence of MDR-TB was 5.7%. We did not find any risk factors significantly associated with resistance to first-line drugs.The93 primary MDR-TB isolates were classified into six sublineages, of which, 75 (80.6%) isolates were the RD105-deleted Beijing lineage.The largest sublineage included 65 (69.9%) isolates with concurrent deletions of RD105, RD207, and RD181.Twenty-nine (31.2%) primary MDR strains grouped in clusters;MDR isolates in clusters were more likely to have S531LrpoBmutation. ConclusionThis study indicates that primary drug-resistantTBand MDR-TBstrains are prevalent in China,and multiplemeasures should be taken toaddress drug-resistant TB.

  14. 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 c

  15. 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 consistentl

  16. Hospital costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition

    Directory of Open Access Journals (Sweden)

    Morales Eva

    2012-05-01

    Full Text Available Abstract Background We aimed to assess the hospital economic costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition. Methods A retrospective study of all hospital admissions between January 1, 2005, and December 31, 2006 was carried out in a 420-bed, urban, tertiary-care teaching hospital in Barcelona (Spain. All patients with a first positive clinical culture for P. aeruginosa more than 48 h after admission were included. Patient and hospitalization characteristics were collected from hospital and microbiology laboratory computerized records. According to antibiotic susceptibility, isolates were classified as non-resistant, resistant and multi-drug resistant. Cost estimation was based on a full-costing cost accounting system and on the criteria of clinical Activity-Based Costing methods. Multivariate analyses were performed using generalized linear models of log-transformed costs. Results Cost estimations were available for 402 nosocomial incident P. aeruginosa positive cultures. Their distribution by antibiotic susceptibility pattern was 37.1% non-resistant, 29.6% resistant and 33.3% multi-drug resistant. The total mean economic cost per admission of patients with multi-drug resistant P. aeruginosa strains was higher than that for non-resistant strains (15,265 vs. 4,933 Euros. In multivariate analysis, resistant and multi-drug resistant strains were independently predictive of an increased hospital total cost in compared with non-resistant strains (the incremental increase in total hospital cost was more than 1.37-fold and 1.77-fold that for non-resistant strains, respectively. Conclusions P. aeruginosa multi-drug resistance independently predicted higher hospital costs with a more than 70% increase per admission compared with non-resistant strains. Prevention of the nosocomial emergence and spread of antimicrobial resistant microorganisms is essential to limit the strong economic impact.

  17. Extraction and identification of exosomes from drug-resistant breast cancer cells and their potential role in cell-to-cell drug-resistance transfer

    Institute of Scientific and Technical Information of China (English)

    许金金

    2014-01-01

    Objective To explore whether docetaxel-resistant cells(MCF-7/Doc)and doxorubicin-resistant cells(MCF-7/ADM)can secrete Exosomes and their potential role in cell-cell drug-resistance transfer.Methods Exosomes were extracted from the cell culture supernatants of MCF-7/Doc and MCF-7/ADM cells by fractionation ultracentrifugation,and were identified by transmission

  18. Drug-resistant tuberculosis control in China: progress and challenges

    Institute of Scientific and Technical Information of China (English)

    Qian Long; Yan Qu; Henry Lucas

    2016-01-01

    Background:China has the second highest caseload of multidrug-resistant tuberculosis (MDR-TB) in the world.In 2009,the Chinese government agreed to draw up a plan for MDR-TB prevention and control in the context of a comprehensive health system reform launched in the same year.Discussion:China is facing high prevalence rates of drug-resistant TB and MDR-TB.MDR-TB disproportionally affects the poor rural population and the highest rates are in less developed regions largely due to interrupted and/or inappropriate TB treatment.Most households with an affected member suffer a heavy financial burden because of a combination of treatment and other related costs.The influential Global Fund programme for MDR-TB control in China provides technical and financial support for MDR-TB diagnosis and treatment.However,this programme has a fixed timeline and cannot provide a long term solution.In 2009,the Bill and Melinda Gates Foundation,in cooperation with the National Health and Family Planning Commission of China,started to develop innovative approaches to TB/MDR-TB management and case-based payment mechanisms for treatment,alongside increased health insurance benefits for patients,in order to contain medical costs and reduce financial barriers to treatment.Although these efforts appear to be in the right direction,they may not be sufficient unless (a) domestic sources are mobilized to raise funding for TB/MDR-TB prevention and control and (b) appropriate incentives are given to both health facilities and their care providers.Summary:Along with the on-going Chinese health system reform,sustained government financing and social health protection schemes will be critical to ensure universal access to appropriate TB treatment in order to reduce risk of developing MDR-TB and systematic MDR-TB treatment and management.

  19. 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 BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: 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.

  20. Phylogeny and drug resistance of HIV PR gene among HIV patients receiving RT inhibitors in Iran

    Institute of Scientific and Technical Information of China (English)

    Kazem Baesi; Majedeh Moradbeigi; Mehrdad Ravanshad; Ashrafolnesa Baghban

    2016-01-01

    Objective: To survey the level and patterns of reverse transcriptase-based drug resistance and subtype distribution among antiretroviral-treated HIV-infected patients receiving only reverse transcriptase inhibitors in Iran. Methods: A total of 25 samples of antiretroviral therapy experienced patients with no history of using protease inhibitors were collected. After RNA extraction, reverse transcriptase-nested PCR was performed. The final products were sequenced and then analysed for drug-resistant mutations and subtypes. Results: No drug resistant mutations were observed among the 25 subjects. The results showed the following subtypes among patients:CRF 35_AD (88%), CRF 28_BF (8%), and CRF 29_BF (4%). Conclusions: A significant increase in drug resistance has been noted in recently-infected patients worldwide. Subtype distributions are needed to perform properly-designed surveillance studies to continuously monitor rates and patterns of transmitted drug resistance and subtypes to help guide therapeutic approaches and limit transmission of these variants.

  1. Functional analysis of a wheat pleiotropic drug resistance gene involved in Fusarium head blight resistance

    Institute of Scientific and Technical Information of China (English)

    WANG Gui-ping; KONG Ling-rang; HOU Wen-qian; ZHANG Lei; WU Hong-yan; ZHAO Lan-fei; DU Xu-ye; MA Xin; LI An-fei; WANG Hong-wei

    2016-01-01

    The pleiotropic drug resistance (PDR) sub-family of adenosine triphosphate (ATP)-binding cassette (ABC) transporter had been reported to participate in diverse biological processes of plant. In this study, we cloned three novelPDR genes in Fusarium head blight (FHB) resistant wheat cultivar Ning 7840, which were located on wheat chromosomes 6A, 6B and 6D. In phylogeny, these genes were members of cluster I together with AePDR7 andBdPDR7. Subcelular localization analysis showed thatTaPDR7 was expressed on the plasmalemma. The quantitative real time PCR (RT-PCR) analysis showed that this gene and its probable orthologues in chromosomes 6B and 6D were both up-regulated sharply at 48 h after infected byFusarium graminearum and trichothecene deoxynivalenol (DON) in spike. When knocking down the transcripts of alTaPDR7 members by barely stripe mosaic virus-induced gene silencing (BSMV-VIGS) system, it could promote the F. graminearum hyphae growth and made larger pathogen inoculation points in Ning 7840, which suggested that TaPDR7 might play an important role in response toF. graminearum. Although salicylic acid (SA), methyl jasmonate (MeJA) and abscisic acid (ABA) had been reported to possibly regulate wheat FHB resistance, here, we found that the three members ofTaPDR7 were negatively regulated by these three hormones but positively regulated by indoleacetic acid (IAA).

  2. Management of patients with multidrug-resistant/extensively drug-resistant tuberculosis in Europe : a TBNET consensus statement

    NARCIS (Netherlands)

    Lange, Christoph; Abubakar, Ibrahim; Alffenaar, Jan-Willem C.; Bothamley, Graham; Caminero, Jose A.; Carvalho, Anna Cristina C.; Chang, Kwok-Chiu; Codecasa, Luigi; Correia, Ana; Crudu, Valeriu; Davies, Peter; Dedicoat, Martin; Drobniewski, Francis; Duarte, Raquel; Ehlers, Cordula; Erkens, Connie; Goletti, Delia; Guenther, Gunar; Ibraim, Elmira; Kampmann, Beate; Kuksa, Liga; de lange, Wiel; van Leth, Frank; van Lunzen, Jan; Matteelli, Alberto; Menzies, Dick; Monedero, Ignacio; Richter, Elvira; Ruesch-Gerdes, Sabine; Sandgren, Andreas; Scardigli, Anna; Skrahina, Alena; Tortoli, Enrico; Volchenkov, Grigory; Wagner, Dirk; van der Werf, Marieke J.; Williams, Bhanu; Yew, Wing-Wai; Zellweger, Jean-Pierre; Cirillo, Daniela Maria

    2014-01-01

    The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) substantially challenges TB control, especially in the European Region of the World Health Organization, where the highest prevalence of MDR/XDR cases is reported. The current management of patients wit

  3. Molecular diagnosis and treatment of drug-resistant hepatitis B virus.

    Science.gov (United States)

    Kim, Jeong Han; Park, Yong Kwang; Park, Eun-Sook; Kim, Kyun-Hwan

    2014-05-21

    Oral antiviral agents have been developed in the last two decades for the treatment of chronic hepatitis B (CHB). However, antiviral resistance remains an important challenge for long-term CHB therapy. All of the clinically available oral antiviral agents are nucleoside or nucleotide analogues that target the activity of viral reverse transcriptase (RT), and all are reported to have resistant mutations. Since the hepatitis B virus (HBV) RT, like other viral polymerases, lacks proofreading activity, the emergence of drug-resistance occurs readily under selective pressure from the administration of antiviral agents. The molecular diagnosis of drug-resistant HBV is based on sequence variations, and current diagnostic methods include sequencing, restriction fragment polymorphism analysis, and hybridization. Here, we will discuss the currently available molecular diagnosis tools, in vitro phenotypic assays for validation of drug-resistant HBV, and treatment options for drug-resistant HBV.

  4. Prevalence and risk factors associated with drug resistant TB in South West, Nigeria

    Institute of Scientific and Technical Information of China (English)

    Olusoji Daniel; Eltayeb Osman

    2011-01-01

    Objective:To determine the prevalence and risk factors associated with drug resistant tuberculosis(TB) in South West Nigeria.Methods: A retrospective study conducted among pulmonary tuberculosis (PTB) patients from Oyo and Osun States in South West Nigeria who had their culture and drug susceptibility test performed at the institute of tropical medicine Antwerp, Belgium between2007 and2009. Data on the patient’s characteristics were retrieved from the TB treatment card. Univariate analysis was performed to assess the risk factors for drug resistant tuberculosis. The Level of significance was atP<0.05.Results:Among the88 patients who had drug-susceptibility test result, there were50 males and38 females. Of the88patients,55 (62.5%) had strains resistant to at least one or more anti-drugs. The proportion ofTBcases with resistance to a single drug was12.7%. The multi-drug resistantTB (MDR-TB) rate was76.4%. The only significant factor for the development of drug resistance andMDR was the history of previous anti TB treatment (P<0.01). Other factors such as age[OR 0.86 (0.35-2.13);P=0.72] and gender[OR 1.24 (0.49-3.14);P=0.62] were not significantly associated with drug resistanceTB.Conclusions: The study highlighted a high prevalence ofMDR-TBamong the study population. History of previous TB treatment was associated withMDR-TB. There is an urgent need to conduct a nationalTB drug resistance survey to determine the actual burden and risk factors associated with drug resistance TB in the country.

  5. 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.

  6. Multimodal neuroimaging in presurgical evaluation of drug-resistant epilepsy

    Directory of Open Access Journals (Sweden)

    Jing Zhang

    2014-01-01

    Full Text Available 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.

  7. Drug Resistance Strategies and Substance Use among Adolescents in Monterrey, Mexico

    OpenAIRE

    Kulis, Stephen; Marsiglia, Flavio Francisco; Castillo, Jason; Becerra, David; Nieri, Tanya

    2008-01-01

    This study examined drug resistance strategies and substance use among adolescents from Monterrey, Mexico. The focus was strategies that U.S. adolescents use most often to resist using substances, including refuse (saying no), explain (declining with an explanation), avoid (staying away from situations where drugs are offered), and leave (exiting situations where drugs are offered). Using self-administered questionnaire data from a convenience sample of 327 Mexican students enrolled at two se...

  8. Evaluation of efflux pump gene expression among drug susceptible and drug resistant strains of Mycobacterium tuberculosis from Iran.

    Science.gov (United States)

    Kardan Yamchi, Jalil; Haeili, Mehri; Gizaw Feyisa, Seifu; Kazemian, Hossein; Hashemi Shahraki, Abdolrazagh; Zahednamazi, Fatemeh; Imani Fooladi, Abbas Ali; Feizabadi, Mohammad Mehdi

    2015-12-01

    Absence of mutations within the genes encoding drug targets in some phenotypically drug resistant strains of Mycobacterium tuberculosis suggests possible involvement of alternative mechanisms such as over-expression of efflux pumps. We investigated the expression level of Rv1410c, Rv2459, Rv1218c and Rv1273c efflux pumps gene by real-time quantitative reverse transcription PCR (qRT-PCR) in 31 clinical isolates of M. tuberculosis. Susceptibility to first-line drugs was performed using the proportion method. Twenty one isolates were characterized with drug resistance (DR), and among them 12 showed a significantly elevated level of expression (>4 fold) for at least one of the studied genes encoding for efflux pumps. Point mutations in the katG (codons 315 or 335) and rpoB (codons 456 and 441) genes were found in 42.85% and 66.6% of drug resistant isolates, respectively. Only one isolate showed mutation at position -15 of the inhA promoter region. Among the 7 isolates (33.33%) which had no mutation in the studied regions of drug target genes, 5 isolates showed over-expression for efflux pumps. Our results demonstrated that over-expression of efflux pumps can contribute to drug resistance in M. tuberculosis.

  9. 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... OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological Reagents § 866.3950 In vitro human immunodeficiency virus (HIV) drug resistance genotype assay....

  10. Use of Lot Quality Assurance Sampling to Ascertain Levels of Drug Resistant Tuberculosis in Western Kenya.

    Directory of Open Access Journals (Sweden)

    Julia Jezmir

    Full Text Available To classify the prevalence of multi-drug resistant tuberculosis (MDR-TB in two different geographic settings in western Kenya using the Lot Quality Assurance Sampling (LQAS methodology.The prevalence of drug resistance was classified among treatment-naïve smear positive TB patients in two settings, one rural and one urban. These regions were classified as having high or low prevalence of MDR-TB according to a static, two-way LQAS sampling plan selected to classify high resistance regions at greater than 5% resistance and low resistance regions at less than 1% resistance.This study classified both the urban and rural settings as having low levels of TB drug resistance. Out of the 105 patients screened in each setting, two patients were diagnosed with MDR-TB in the urban setting and one patient was diagnosed with MDR-TB in the rural setting. An additional 27 patients were diagnosed with a variety of mono- and poly- resistant strains.Further drug resistance surveillance using LQAS may help identify the levels and geographical distribution of drug resistance in Kenya and may have applications in other countries in the African Region facing similar resource constraints.

  11. Label-free recognition of drug resistance via impedimetric screening of breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Bilge Eker

    Full Text Available We present a novel study on label-free recognition and distinction of drug resistant breast cancer cells (MCF-7 DOX from their parental cells (MCF-7 WT via impedimetric measurements. Drug resistant cells exhibited significant differences in their dielectric properties compared to wild-type cells, exerting much higher extracellular resistance (Rextra . Immunostaining revealed that MCF-7 DOX cells gained a much denser F-actin network upon acquiring drug resistance indicating that remodeling of actin cytoskeleton is probably the reason behind higher Rextra , providing stronger cell architecture. Moreover, having exposed both cell types to doxorubicin, we were able to distinguish these two phenotypes based on their substantially different drug response. Interestingly, impedimetric measurements identified a concentration-dependent and reversible increase in cell stiffness in the presence of low non-lethal drug doses. Combined with a profound frequency analysis, these findings enabled distinguishing distinct cellular responses during drug exposure within four concentration ranges without using any labeling. Overall, this study highlights the possibility to differentiate drug resistant phenotypes from their parental cells and to assess their drug response by using microelectrodes, offering direct, real-time and noninvasive measurements of cell dependent parameters under drug exposure, hence providing a promising step for personalized medicine applications such as evaluation of the disease progress and optimization of the drug treatment of a patient during chemotherapy.

  12. Different frequencies of drug resistance mutations among HIV-1 subtypes circulating in China: a comprehensive study.

    Directory of Open Access Journals (Sweden)

    Hongshuai Sui

    Full Text Available The rapid spreading of HIV drug resistance is threatening the overall success of free HAART in China. Much work has been done on drug-resistant mutations, however, most of which were based on subtype B. Due to different genetic background, subtypes difference would have an effect on the development of drug-resistant mutations, which has already been proved by more and more studies. In China, the main epidemic subtypes are CRF07_BC, CRF08_BC, Thai B and CRF01_AE. The depiction of drug resistance mutations in those subtypes will be helpful for the selection of regimens for Chinese. In this study, the distributions difference of amino acids at sites related to HIV drug resistance were compared among subtype B, CRF01_AE, CRF07_BC and CRF08_BC strains prevalent in China. The amino acid composition of sequences belonging to different subtypes, which were obtained from untreated and treated individuals separately, were also compared. The amino acids proportions of 19 sites in RT among subtype B, CRF01_AE and CRF08_BC have significant difference in drug resistance groups (chi-square test, p<0.05. Genetic barriers analysis revealed that sites 69, 138, 181, 215 and 238 were significantly different among subtypes (Kruskal Wallis test, p<0.05. All subtypes shared three highest prevalent drug resistance sites 103, 181 and 184 in common. Many drug resistant sites in protease show surprising high proportions in almost all subtypes in drug-naïve patients. This is the first comprehensive study in China on different development of drug resistance among different subtypes. The detailed data will lay a foundation for HIV treatment regimens design and improve HIV therapy in China.

  13. Molecular approaches for detection of the multi-drug resistant tuberculosis (MDR-TB in Bangladesh.

    Directory of Open Access Journals (Sweden)

    Tafsina Haque Aurin

    Full Text Available The principal obstacles in the treatment of tuberculosis (TB are delayed and inaccurate diagnosis which often leads to the onset of the drug resistant TB cases. To avail the appropriate treatment of the patients and to hinder the transmission of drug-resistant TB, accurate and rapid detection of resistant isolates is critical. Present study was designed to demonstrate the efficacy of molecular techniques inclusive of line probe assay (LPA and GeneXpert MTB/RIF methods for the detection of multi-drug resistant (MDR TB. Sputum samples from 300 different categories of treated and new TB cases were tested for the detection of possible mutation in the resistance specific genes (rpoB, inhA and katG through Genotype MTBDRplus assay or LPA and GeneXpert MTB/RIF tests. Culture based conventional drug susceptibility test (DST was also carried out to measure the efficacy of the molecular methods employed. Among 300 samples, 191 (63.7% and 193 (64.3% cases were found to be resistant against rifampicin in LPA and GeneXpert methods, respectively; while 189 (63% cases of rifampicin resistance were detected by conventional DST methods. On the other hand, 196 (65.3% and 191 (63.7% isolates showed isoniazid resistance as detected by LPA and conventional drug susceptibility test (DST, respectively. Among the drug resistant isolates (collectively 198 in LPA and 193 in conventional DST, 189 (95.6% and 187 (96.9% were considered to be MDR as examined by LPA and conventional DST, respectively. Category-II and -IV patients encountered higher frequency of drug resistance compared to those from category-I and new cases. Considering the higher sensitivity, specificity and accuracy along with the required time to results significantly shorter, our study supports the adoption of LPA and GeneXpert assay as efficient tools in detecting drug resistant TB in Bangladesh.

  14. Molecular characterization of drug-resistant and drug-sensitive Aspergillus isolates causing infectious keratitis

    Directory of Open Access Journals (Sweden)

    Niranjan Nayak

    2011-01-01

    Full Text Available Purpose: To study the susceptibilities of Aspergillus species against amphotericin B in infectious keratitis and to find out if drug resistance had any association with the molecular characteristics of the fungi. Materials and Methods: One hundred and sixty Aspergillus isolates from the corneal scrapings of patients with keratitis were tested for susceptibilities to amphotericin B by broth microdilution method. These included Aspergillus flavus (64 isolates, A. fumigatus (43 and A. niger (53. Fungal DNA was extracted by glass bead vertexing technique. Polymerase chain reaction (PCR assay was standardized and used to amplify the 28S rRNA gene. Single-stranded conformational polymorphism (SSCP of the PCR product was performed by the standard protocol. Results: Of the 160 isolates, 84 (52.5% showed low minimum inhibitory concentration (MIC values (≤ 1.56 μg/ml and were designated as amphotercin B-sensitive. Similarly, 76 (47.5% had high MICs (≥ 3.12 μg/ml and were categorized as amphotericin B-resistant. MIC 50 and MIC 90 values ranged between 3.12-6.25 μg/ml and 3.12-12.5 μg/ml respectively. A. flavus and A. niger showed higher MIC 50 and MIC 90 values than A. fumigatus. The SSCP pattern exhibited three extra bands (150 bp, 200 bp and 250 bp each in addition to the 260 bp amplicon. Strains (lanes 1 and 7 lacking the 150 bp band showed low MIC values (≤ 1.56 μg/ml. Conclusion: A. niger and A. flavus isolates had higher MICs compared to A. fumigatus, suggesting a high index of suspicion for amphotericin B resistance. PCR-SSCP was a good molecular tool to characterize Aspergillus phenotypes in fungal keratitis.

  15. Transmission of HIV Drug Resistance and the Predicted Effect on Current First-line Regimens in Europe

    NARCIS (Netherlands)

    L.M. Hofstra (L. Marije); N. Sauvageot (Nicolas); J. Albert (Jan); I. Alexiev (Ivailo); F. Garcia (Federico); D. Struck (Daniel); D.A.M.C. van de Vijver (David); B. Asjö (Birgitta); D. Beshkov (Danail); S. Coughlan (Suzie); D. Descamps (Diane); A. Griskevicius (Algis); O. Hamouda (Osamah); A. Horban (Andrzej); M.E.E. van Kasteren (Marjo); T. Kolupajeva (Tatjana); L.G. Kostrikis (Leondios); K. Liitsola (Kirsi); M. Linka (Marek); O. Mor (Orna); C. Nielsen (Claus); D. Otelea (Dan); D. Paraskevis (Dimitrios); R. Paredes (Roger); M. Poljak (Mario); E. Puchhammer-Stockl E. (E.); A. Sonnerborg (Anders); D. Stanekova (Danica); M. Stanojevic (Maja); K. Van Laethem (Kristel); M. Zazzi (Maurizio); S. Zidovec Lepej (Snjezana); C.A.B. Boucher (Charles A. B.); J.-C. Schmit (Jean-Claude); A.M.J. Wensing (Annemarie); E. Puchhammer-Stöckl (Elisabeth); M. Sarcletti (M.); B. Schmied (B.); M. Geit (M.); G. Balluch (G.); A.-M. Vandamme; J. Vercauteren (Jurgen); I. Derdelinckx; A. Sasse; M. Bogaert; H. Ceunen (H.); A. de Roo (Annie); S. De Wit; F. Echahidi (F.); K. Fransen; J.-C. Goffard (J.); P. Goubau; E. Goudeseune (E.); J.-C. Yombi (J.); P. Lacor; C. Liesnard (C.); M. Moutschen; L.A. Pierard; R. Rens (R.); J. Schrooten; D. Vaira; L.P.R. Vandekerckhove; A. van den Heuvel (A.); B. van der Gucht (B.); M. Van Ranst; E. Van Wijngaerden; B. Vandercam; M. Vekemans; C. Verhofstede; N. Clumeck (N.); K. van Laethem (Kristel); D. Beshkov; I. Alexiev; S.Z. Lepej (Snjezana); J. Begovac; L.G. Kostrikis (Leondios); I. Demetriades (I.); I. Kousiappa (Ioanna); V.L. Demetriou (Victoria); J. Hezka (Johana); M. Linka; M. Maly; L. MacHala; C. Nielsen; L.B. Jørgensen; J. Gerstoft (J.); L. Mathiesen (L.); C. Pedersen (Court); H. Nielsen; A. Laursen (A.); B. Kvinesdal (B.); K. Liitsola (Kirsi); M. Ristola (M.); J. Suni; J. Sutinen (J.); D. Descamps; L. Assoumou; G. Castor; M. Grude; P. Flandre; A. Storto; O. Hamouda (Osamah); C. K̈ucherer (C.); T. Berg; P. Braun; G. Poggensee; M. Daumer (Martin); J. Eberle; H. Heiken; R. Kaiser; H. Knechten (H.); K. Korn; H. Müller; S. Neifer; B. Schmidt; H. Walter; B. Gunsenheimer-Bartmeyer (B.); T. Harrer (T.); D. Paraskevis (Dimitrios); A. Hatzakis (Angelos); A. Zavitsanou (A.); A. Vassilakis; M. Lazanas; L. Chini; A. Lioni; V. Sakka (V.); S. Kourkounti (S.); V. Paparizos (V.); A. Antoniadou (A.); A. Papadopoulos; G. Poulakou; I. Katsarolis; K. Protopapas; G. Chryssos (G.); S. Drimis (S.); P. Gargalianos; G. Xylomenos; G. Lourida; M. Psichogiou (M.); G.L. Daikos (G.); N.V. Sipsas; A. Kontos (Angelos); M.N. Gamaletsou; G. Koratzanis (G.); H. Sambatakou; H. Mariolis; A. Skoutelis; V. Papastamopoulos; O. Georgiou; P. Panagopoulos (P.); E. Maltezos; S. Coughlan (Suzie); C. de Gascun (Cillian); C. Byrne; M. Duffy; P. Bergin; D. Reidy; G. Farrell; J. Lambert; E. O'Connor; A. Rochford; J. Low; P. Coakely (P.); S. O'Dea; W. Hall; O. Mor; I. Levi (I.); D. Chemtob (D.); Z. Grossman (Zehava); M. Zazzi; A. de Luca (Andrea); C. Balotta (Claudia); C. Riva (Chiara); C. Mussini (C.); I. Caramma (I.); A. Capetti (A.); M. Colombo (Massimo); C. Rossi; F. Prati (Francesco); F. Tramuto; F. Vitale (F.); M. Ciccozzi; G. Angarano (Guiseppe); G. Rezza (G.); T. Kolupajeva; O. Vasins; A. Griskevicius (Algis); V. Lipnickiene; J.C. Schmit; D. Struck (Daniel); N. Sauvageot; R. Hemmer (R.); V. Arendt (V.); C. Michaux; T. Staub (T.); C. Sequin-Devaux; A.M.J. Wensing (Annemarie); C.A. Boucher (Charles); D.A.M.C. van de Vijver (David); A. Van Kessel; P.H.M. Van Bentum; K. Brinkman; B.J. Connell; M.E. van der Ende (Marchina); I.M. Hoepelman (Ilja Mohandas); M.E.E. van Kasteren (Marjo); M. Kuipers; N. Langebeek (Nienke); C. Richter; R.M.W.J. Santegoets (R. M W J); L. Schrijnders-Gudde (L.); R. Schuurman (Rob); B.J.M. van de Ven (B. J M); B. Åsjö (Birgitta); A.-M.B. Kran (A.-M. Bakken); V. Ormaasen (Vidar); P. Aavitsland (P.); A. Horban (Andrzej); J. Stanczak (J.); G.P. Stanczak (G.); E. Firlag-Burkacka (E.); A. Wiercinska-Drapalo; E. Jablonowska (E.); E. Maolepsza; M. Leszczyszyn-Pynka (M.); W. Szata (W.); R.J. Camacho (Ricardo Jorge); A. de Palma (Andre); F. Borges (F.); T. Paixão; V. Duque (V.); F. Araújo; D. Otelea; C. Paraschiv (Corina); A.M. Tudor; R. Cernat; C. Chiriac; F. Dumitrescu; L.J. Prisecariu; M. Stanojevic (Maja); D.J. Jevtovic (D.); D. Salemovic (D.); D. Stanekova; M. Habekova (M.); Z. Chabadová; T. Drobkova; P. Bukovinova; A. Shunnar; P. Truska; M. Poljak (Mario); M.M. Lunar (Maja M.); D. Babic; J. Tomazic (J.); S. Vidmar (Suzanna); T. Vovko; P. Karner (P.); F. Garcia; R. Paredes (Roger); S. Monge; S. Moreno; J. Del Amo; V. Asensi; J.L. Sirvent; C. de Mendoza (Carmen); R. Delgado; F. Gutiérrez; J. Berenguer; S. Garcia-Bujalance; N. Stella; I. De Los Santos; J.R. Blanco; D. Dalmau; M. Rivero; F. Segura; M.J.P. Elías (M. J. Pcrossed); M. Alvarez; N. Chueca; C. Rodríguez-Martín; C. Vidal; J.C. Palomares; I. Viciana; P. Viciana; J. Cordoba; A. Aguilera; P. Domingo; M.J. Galindo; C. Miralles; M.A. Del Pozo; E. Ribera; C. Iribarren (Carlos); L. Ruiz; J. De La Torre; F. Vidal; B. Clotet (Bonaventura); J. Albert; A. Heidarian; K. Aperia-Peipke (K.); M. Axelsson; M. Mild; A. Karlsson; A. Sonnerborg (Anders); A. Thalme; L. Navénr; G. Bratt (G.); A. Karlsson; A. Blaxhult; M. Gisslénn; B. Svennerholm; I.-M. Bergbrant (I.); P. Bj̈orkman (P.); C. Säll; A. Mellgren; A. Lindholm; N. Kuylenstierna; R. Montelius; F. Azimi; B. Johansson; M. Carlsson; E. Johansson; B. Ljungberg; H. Ekvall; A. Strand; S. Mäkitalo; S. Öberg; P. Holmblad; M. Höfer; H. Holmberg; P. Josefson; U. Ryding

    2016-01-01

    textabstractBackground. Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, the

  16. European recommendations for the clinical use of HIV drug resistance testing: 2011 update

    DEFF Research Database (Denmark)

    Vandamme, Anne-Mieke; Camacho, Ricardo J; Ceccherini-Silberstein, Francesca;

    2011-01-01

    ) consider testing earliest detectable plasma RNA when a successful nonnucleoside reverse transcriptase inhibitor-containing therapy was inappropriately interrupted; (v) genotype source patient when postexposure prophylaxis is considered; for HIV-2, (vi) consider resistance testing where treatment change......The European HIV Drug Resistance Guidelines Panel, established to make recommendations to clinicians and virologists, felt that sufficient new information has become available to warrant an update of its recommendations, explained in both pocket guidelines and this full paper. The Panel makes...... the following recommendations concerning the indications for resistance testing: for HIV-1 (i) test earliest sample for protease and reverse transcriptase drug resistance in drug-naive patients with acute or chronic infection; (ii) test protease and reverse transcriptase drug resistance at virologic failure...

  17. Resistance to antimalarial drugs: An endless world war against Plasmodium that we risk losing.

    Science.gov (United States)

    Severini, Carlo; Menegon, Michela

    2015-06-01

    The objective of this review was to describe the 'state of the art' of Plasmodium falciparum resistance to the main antimalarial drugs. A brief note on Plasmodium vivax is also included. Resistance of P. falciparum to the various antimalarials has a long history of hits and misses. During the last 60 years, the pace at which this parasite has developed resistance to antimalarial drugs has exceeded the pace at which new drugs have been developed. In the last decade, the introduction of artemisinin-based combination therapies (ACTs) as a first-line drug treatment for non-complicated P. falciparum malaria had led to extraordinary results in disease control, especially in sub-Saharan Africa. However, the emergence and spread of resistance to artemisinin in Southeast Asia jeopardise these results. In conclusion, the possible spread of artemisinin resistance in Africa should be considered as an epochal disaster.

  18. STUDIES ON ANTIBACTERIAL EFFECT OF APAMARGA (ACHYRANTHES ASPERA ON MULTI-DRUG RESISTANT CLINICAL ISOLATES

    Directory of Open Access Journals (Sweden)

    Patil Usha

    2013-04-01

    Full Text Available Recent reports on emergence of multidrug resistant bacteria are cause of concern in medical world. Several ayurvedic drugs have been proved to contain the antimicrobial activity. Literature on effect of ayurvedic drugs on multidrug resistant bacterial pathogens is limited. Present study reports the antimicrobial effect of Achyranthes aspera (Apamarga crude extracts on the clinical isolates of multidrug resistant bacteria. The drug was evaluated by using phytochemical tests. Crude extracts of aqueous, methanol, ethanol and chloroform was prepared. Antibacterial activity against clinically isolated multidrug resistant bacteria belonging to groups of bacillus, citrobacter, E.coli, klebsiella, proteus and salmonella was tested. The drug showed highest efficacy against Bacillus organism while least effectiveness on Proteus spp bacteria. Results of the study conclude that the medicinal plant A. aspera might be useful against multidrug resistance in pathogens of clinical importance.

  19. European recommendations for the clinical use of HIV drug resistance testing: 2011 update

    DEFF Research Database (Denmark)

    Vandamme, Anne-Mieke; Camacho, Ricardo J; Ceccherini-Silberstein, Francesca;

    2011-01-01

    The European HIV Drug Resistance Guidelines Panel, established to make recommendations to clinicians and virologists, felt that sufficient new information has become available to warrant an update of its recommendations, explained in both pocket guidelines and this full paper. The Panel makes...... the following recommendations concerning the indications for resistance testing: for HIV-1 (i) test earliest sample for protease and reverse transcriptase drug resistance in drug-naive patients with acute or chronic infection; (ii) test protease and reverse transcriptase drug resistance at virologic failure......) consider testing earliest detectable plasma RNA when a successful nonnucleoside reverse transcriptase inhibitor-containing therapy was inappropriately interrupted; (v) genotype source patient when postexposure prophylaxis is considered; for HIV-2, (vi) consider resistance testing where treatment change...

  20. The emergence of drug resistant HIV variants and novel anti-retroviral therapy

    Institute of Scientific and Technical Information of China (English)

    Koosha Paydary; Parisa Khaghani; Sahra Emamzadeh-Fard; SeyedAhmad SeyedAlinaghi; Kazem Baesi

    2013-01-01

    After its identification in 1980s, HIV has infected more than 30 million people worldwide. In the era of highly active anti-retroviral therapy, anti-retroviral drug resistance results from insufficient anti-retroviral pressure, which may lead to treatment failure. Preliminary studies support the idea that anti-retroviral drug resistance has evolved largely as a result of low-adherence of patients to therapy and extensive use of anti-retroviral drugs in the developed world;however, a highly heterogeneous horde of viral quasi-species are currently circulating in developing nations. Thus, the prioritizing of strategies adopted in such two worlds should be quite different considering the varying anti-retroviral drug resistance prevalence. In this article, we explore differences in anti-retroviral drug resistance patterns between developed and developing countries, as they represent two distinct ecological niches of HIV from an evolutionary standpoint.

  1. Adaptive Landscape by Environment Interactions Dictate Evolutionary Dynamics in Models of Drug Resistance.

    Directory of Open Access Journals (Sweden)

    C Brandon Ogbunugafor

    2016-01-01

    Full Text Available The adaptive landscape analogy has found practical use in recent years, as many have explored how their understanding can inform therapeutic strategies that subvert the evolution of drug resistance. A major barrier to applications of these concepts is a lack of detail concerning how the environment affects adaptive landscape topography, and consequently, the outcome of drug treatment. Here we combine empirical data, evolutionary theory, and computer simulations towards dissecting adaptive landscape by environment interactions for the evolution of drug resistance in two dimensions-drug concentration and drug type. We do so by studying the resistance mediated by Plasmodium falciparum dihydrofolate reductase (DHFR to two related inhibitors-pyrimethamine and cycloguanil-across a breadth of drug concentrations. We first examine whether the adaptive landscapes for the two drugs are consistent with common definitions of cross-resistance. We then reconstruct all accessible pathways across the landscape, observing how their structure changes with drug environment. We offer a mechanism for non-linearity in the topography of accessible pathways by calculating of the interaction between mutation effects and drug environment, which reveals rampant patterns of epistasis. We then simulate evolution in several different drug environments to observe how these individual mutation effects (and patterns of epistasis influence paths taken at evolutionary "forks in the road" that dictate adaptive dynamics in silico. In doing so, we reveal how classic metrics like the IC50 and minimal inhibitory concentration (MIC are dubious proxies for understanding how evolution will occur across drug environments. We also consider how the findings reveal ambiguities in the cross-resistance concept, as subtle differences in adaptive landscape topography between otherwise equivalent drugs can drive drastically different evolutionary outcomes. Summarizing, we discuss the results with

  2. Adaptive Landscape by Environment Interactions Dictate Evolutionary Dynamics in Models of Drug Resistance.

    Science.gov (United States)

    Ogbunugafor, C Brandon; Wylie, C Scott; Diakite, Ibrahim; Weinreich, Daniel M; Hartl, Daniel L

    2016-01-01

    The adaptive landscape analogy has found practical use in recent years, as many have explored how their understanding can inform therapeutic strategies that subvert the evolution of drug resistance. A major barrier to applications of these concepts is a lack of detail concerning how the environment affects adaptive landscape topography, and consequently, the outcome of drug treatment. Here we combine empirical data, evolutionary theory, and computer simulations towards dissecting adaptive landscape by environment interactions for the evolution of drug resistance in two dimensions-drug concentration and drug type. We do so by studying the resistance mediated by Plasmodium falciparum dihydrofolate reductase (DHFR) to two related inhibitors-pyrimethamine and cycloguanil-across a breadth of drug concentrations. We first examine whether the adaptive landscapes for the two drugs are consistent with common definitions of cross-resistance. We then reconstruct all accessible pathways across the landscape, observing how their structure changes with drug environment. We offer a mechanism for non-linearity in the topography of accessible pathways by calculating of the interaction between mutation effects and drug environment, which reveals rampant patterns of epistasis. We then simulate evolution in several different drug environments to observe how these individual mutation effects (and patterns of epistasis) influence paths taken at evolutionary "forks in the road" that dictate adaptive dynamics in silico. In doing so, we reveal how classic metrics like the IC50 and minimal inhibitory concentration (MIC) are dubious proxies for understanding how evolution will occur across drug environments. We also consider how the findings reveal ambiguities in the cross-resistance concept, as subtle differences in adaptive landscape topography between otherwise equivalent drugs can drive drastically different evolutionary outcomes. Summarizing, we discuss the results with regards to their

  3. Adaptive Landscape by Environment Interactions Dictate Evolutionary Dynamics in Models of Drug Resistance

    Science.gov (United States)

    Ogbunugafor, C. Brandon; Wylie, C. Scott; Diakite, Ibrahim; Weinreich, Daniel M.; Hartl, Daniel L.

    2016-01-01

    The adaptive landscape analogy has found practical use in recent years, as many have explored how their understanding can inform therapeutic strategies that subvert the evolution of drug resistance. A major barrier to applications of these concepts is a lack of detail concerning how the environment affects adaptive landscape topography, and consequently, the outcome of drug treatment. Here we combine empirical data, evolutionary theory, and computer simulations towards dissecting adaptive landscape by environment interactions for the evolution of drug resistance in two dimensions—drug concentration and drug type. We do so by studying the resistance mediated by Plasmodium falciparum dihydrofolate reductase (DHFR) to two related inhibitors—pyrimethamine and cycloguanil—across a breadth of drug concentrations. We first examine whether the adaptive landscapes for the two drugs are consistent with common definitions of cross-resistance. We then reconstruct all accessible pathways across the landscape, observing how their structure changes with drug environment. We offer a mechanism for non-linearity in the topography of accessible pathways by calculating of the interaction between mutation effects and drug environment, which reveals rampant patterns of epistasis. We then simulate evolution in several different drug environments to observe how these individual mutation effects (and patterns of epistasis) influence paths taken at evolutionary “forks in the road” that dictate adaptive dynamics in silico. In doing so, we reveal how classic metrics like the IC50 and minimal inhibitory concentration (MIC) are dubious proxies for understanding how evolution will occur across drug environments. We also consider how the findings reveal ambiguities in the cross-resistance concept, as subtle differences in adaptive landscape topography between otherwise equivalent drugs can drive drastically different evolutionary outcomes. Summarizing, we discuss the results with

  4. Prevalenoe of Drug - Resistant Staphylococci in Teheran University Hospital Wards

    Directory of Open Access Journals (Sweden)

    F. Shafa

    1960-01-01

    Full Text Available 1 Fifty coagulase posittve strains of staphylococc~~ ~folated fr.o~ .the nose"nand wrist of Hospital nurses have been examined for sensltfvlty to pemcilhn, tetracyclines,"nchloramphenicol, dihydrostreptomycin, erythrorriycm, neomycin, kana.n:ycin,"nbacitracin, polymyxin-B and the triple sulfa. The percentages of fully sensittve strains at the present are as followe:                                       Erythromycin                                       100%"nNeomycin                                             78%"nKanamycin                                            78%"nChloramphenicol                                     68%"nDihydrostreptomycin                               52%"nPenicillin                                                18%"nTetracyclines                                         16%"nPolymyxin-B                                            1%"nTriple sulfa                                              0%"n2 The following topics have been discussed:"na The origin anr" mechanism of drug resistance"nb Cross-resistr.nee"nc The hospital epidemiology of Staphylococcus"nd The clinical implications of Staphylococcus drug-resistance

  5. Proteomics for Drug Resistance on the Food Chain? Multidrug-Resistant Escherichia coli Proteomes from Slaughtered Pigs.

    Science.gov (United States)

    Ramos, Sónia; Silva, Nuno; Hébraud, Michel; Santos, Hugo M; Nunes-Miranda, Júlio Dinis; Pinto, Luís; Pereira, José E; Capelo, José-Luis; Poeta, Patrícia; Igrejas, Gilberto

    2016-06-01

    Understanding global drug resistance demands an integrated vision, focusing on both human and veterinary medicine. Omics technologies offer new vistas to decipher mechanisms of drug resistance in the food chain. For example, Escherichia coli resistance to major antibiotics is increasing whereas multidrug resistance (MDR) strains are now commonly found in humans and animals. Little is known about the structural and metabolic changes in the cell that trigger resistance to antimicrobial agents. Proteomics is an emerging field that is used to advance our knowledge in global health and drug resistance in the food chain. In the present proteomic analysis, we offer an overview of the global protein expression of different MDR E. coli strains from fecal samples of pigs slaughtered for human consumption. A full proteomic survey of the drug-resistant strains SU60, SU62, SU76, and SU23, under normal growth conditions, was made by two-dimensional electrophoresis, identifying proteins by MALDI-TOF/MS. The proteomes of these four E. coli strains with different genetic profiles were compared in detail. Identical transport, stress response, or metabolic proteins were discovered in the four strains. Several of the identified proteins are essential in bacterial pathogenesis (GAPDH, LuxS, FKBPs), development of bacterial resistance (Omp's, TolC, GroEL, ClpB, or SOD), and potential antibacterial targets (FBPA, FabB, ACC's, or Fab1). Effective therapies against resistant bacteria are crucial and, to accomplish this, a comprehensive understanding of putative resistance mechanisms is essential. Moving forward, we suggest that multi-omics research will further improve our knowledge about bacterial growth and virulence on the food chain, especially under antibiotic stress.

  6. Differential Persistence of Transmitted HIV-1 Drug Resistance Mutation Classes

    Science.gov (United States)

    Jain, Vivek; Sucupira, Maria C.; Bacchetti, Peter; Hartogensis, Wendy; Diaz, Ricardo S.; Kallas, Esper G.; Janini, Luiz M.; Liegler, Teri; Pilcher, Christopher D.; Grant, Robert M.; Cortes, Rodrigo; Deeks, Steven G.

    2011-01-01

    Background. Transmitted human immunodeficiency virus type 1 (HIV-1) drug resistance (TDR) mutations can become replaced over time by emerging wild-type viral variants with improved fitness. The impact of class-specific mutations on this rate of mutation replacement is uncertain. Methods. We studied participants with acute and/or early HIV infection and TDR in 2 cohorts (San Francisco, California, and São Paulo, Brazil). We followed baseline mutations longitudinally and compared replacement rates between mutation classes with use of a parametric proportional hazards model. Results. Among 75 individuals with 195 TDR mutations, M184V/I became undetectable markedly faster than did nonnucleoside reverse-transcriptase inhibitor (NNRTI) mutations (hazard ratio, 77.5; 95% confidence interval [CI], 14.7–408.2; P < .0001), while protease inhibitor and NNRTI replacement rates were similar. Higher plasma HIV-1 RNA level predicted faster mutation replacement, but this was not statistically significant (hazard ratio, 1.71 log10 copies/mL; 95% CI, .90–3.25 log10 copies/mL; P = .11). We found substantial person-to-person variability in mutation replacement rates not accounted for by viral load or mutation class (P < .0001). Conclusions. The rapid replacement of M184V/I mutations is consistent with known fitness costs. The long-term persistence of NNRTI and protease inhibitor mutations suggests a risk for person-to-person propagation. Host and/or viral factors not accounted for by viral load or mutation class are likely influencing mutation replacement and warrant further study. PMID:21451005

  7. Insulin-like growth factor 2 silencing restores taxol sensitivity in drug resistant ovarian cancer.

    Science.gov (United States)

    Brouwer-Visser, Jurriaan; Lee, Jiyeon; McCullagh, KellyAnne; Cossio, Maria J; Wang, Yanhua; Huang, Gloria S

    2014-01-01

    Drug resistance is an obstacle to the effective treatment of ovarian cancer. We and others have shown that the insulin-like growth factor (IGF) signaling pathway is a novel potential target to overcome drug resistance. The purpose of this study was to validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and to determine the efficacy of targeting IGF2 in vivo. An analysis of The Cancer Genome Atlas (TCGA) data in the serous ovarian cancer cohort showed that high IGF2 mRNA expression is significantly associated with shortened interval to disease progression and death, clinical indicators of drug resistance. In a genetically diverse panel of ovarian cancer cell lines, the IGF2 mRNA levels measured in cell lines resistant to various microtubule-stabilizing agents including Taxol were found to be significantly elevated compared to the drug sensitive cell lines. The effect of IGF2 knockdown on Taxol resistance was investigated in vitro and in vivo. Transient IGF2 knockdown significantly sensitized drug resistant cells to Taxol treatment. A Taxol-resistant ovarian cancer xenograft model, developed from HEY-T30 cells, exhibited extreme drug resistance, wherein the maximal tolerated dose of Taxol did not delay tumor growth in mice. Blocking the IGF1R (a transmembrane receptor that transmits signals from IGF1 and IGF2) using a monoclonal antibody did not alter the response to Taxol. However, stable IGF2 knockdown using short-hairpin RNA in HEY-T30 effectively restored Taxol sensitivity. These findings validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and show that directly targeting IGF2 may be a preferable strategy compared with targeting IGF1R alone.

  8. Diverse and abundant multi-drug resistant E. coli in Matang mangrove estuaries, Malaysia.

    Science.gov (United States)

    Ghaderpour, Aziz; Ho, Wing Sze; Chew, Li-Lee; Bong, Chui Wei; Chong, Ving Ching; Thong, Kwai-Lin; Chai, Lay Ching

    2015-01-01

    E.coli, an important vector distributing antimicrobial resistance in the environment, was found to be multi-drug resistant, abundant, and genetically diverse in the Matang mangrove estuaries, Malaysia. One-third (34%) of the estuarine E. coli was multi-drug resistant. The highest antibiotic resistance prevalence was observed for aminoglycosides (83%) and beta-lactams (37%). Phylogenetic groups A and B1, being the most predominant E. coli, demonstrated the highest antibiotic resistant level and prevalence of integrons (integron I, 21%; integron II, 3%). Detection of phylogenetic group B23 downstream of fishing villages indicates human fecal contamination as a source of E. coli pollution. Enteroaggregative E. coli (1%) were also detected immediately downstream of the fishing village. The results indicated multi-drug resistance among E. coli circulating in Matang estuaries, which could be reflective of anthropogenic activities and aggravated by bacterial and antibiotic discharges from village lack of a sewerage system, aquaculture farms and upstream animal husbandry.

  9. Overcoming drug efflux-based multidrug resistance in cancer with nanotechnology

    Institute of Scientific and Technical Information of China (English)

    Xue Xue; Xing-Jie Liang

    2012-01-01

    Multidrug resistance (MDR),which significantly decreases the efficacy of anticancer drugs and causes tumor recurrence,has been a major challenge in clinical cancer treatment with chemotherapeutic drugs for decades.Several mechanisms of overcoming drug resistance have been postulated.Well known Pglycoprotein (P-gp) and other drug efflux transporters are considered to be critical in pumping anticancer drugs out of cells and causing chemotherapy failure.Innovative theranostic (therapeutic and diagnostic)strategies with nanoparticles are rapidly evolving and are anticipated to offer opportunities to overcome these limits.In this review,we discuss the mechanisms of drug efflux-mediated resistance and the application of multiple nanoparticle-based platforms to overcome chemoresistance and improve therapeutic outcome.

  10. Human therapeutic and agricultural uses of antibacterial drugs and resistance of the enteric flora of humans.

    Science.gov (United States)

    Siegel, D; Huber, W G; Drysdale, S

    1975-11-01

    Fecal samples were collected from five groups of people differing in the manner of their exposure to antibacterial drugs. The groups included: (i) people working on farms who were continuously in contact with the predominantly resistant florae of farm animals receiving rations containing antibacterial drugs, (ii) people residing on the same farms with no direct exposure to the farm animals, (iii) people treated with antibacterial drugs, (iv) untreated people residing with treated individuals, and (v) untreated people with no exposure to farm animals or treated individuals. The samples were examined by quantitative plating for proportions of antibiotic-resistant, gram-negative enteric organisms. Individual isolates were also examined for their susceptibility to 11 different antibacterial drugs. The results indicate that enteric florae unexposed directly to the selective effects of antibacterial drugs may be affected by contact with predominantly resistant florae directly exposed to antibacterial drugs.

  11. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance.

    Science.gov (United States)

    Magiorakos, A-P; Srinivasan, A; Carey, R B; Carmeli, Y; Falagas, M E; Giske, C G; Harbarth, S; Hindler, J F; Kahlmeter, G; Olsson-Liljequist, B; Paterson, D L; Rice, L B; Stelling, J; Struelens, M J; Vatopoulos, A; Weber, J T; Monnet, D L

    2012-03-01

    Many different definitions for multidrug-resistant (MDR), extensively drug-resistant (XDR) and pandrug-resistant (PDR) bacteria are being used in the medical literature to characterize the different patterns of resistance found in healthcare-associated, antimicrobial-resistant bacteria. A group of international experts came together through a joint initiative by the European Centre for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC), to create a standardized international terminology with which to describe acquired resistance profiles in Staphylococcus aureus, Enterococcus spp., Enterobacteriaceae (other than Salmonella and Shigella), Pseudomonas aeruginosa and Acinetobacter spp., all bacteria often responsible for healthcare-associated infections and prone to multidrug resistance. Epidemiologically significant antimicrobial categories were constructed for each bacterium. Lists of antimicrobial categories proposed for antimicrobial susceptibility testing were created using documents and breakpoints from the Clinical Laboratory Standards Institute (CLSI), the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the United States Food and Drug Administration (FDA). MDR was defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories, XDR was defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories) and PDR was defined as non-susceptibility to all agents in all antimicrobial categories. To ensure correct application of these definitions, bacterial isolates should be tested against all or nearly all of the antimicrobial agents within the antimicrobial categories and selective reporting and suppression of results should be avoided.

  12. The draft genome of Mycobacterium aurum, a potential model organism for investigating drugs against Mycobacterium tuberculosis and Mycobacterium leprae

    KAUST Repository

    Phelan, Jody

    2015-06-04

    Mycobacterium aurum (M. aurum) is an environmental mycobacteria that has previously been used in studies of anti-mycobacterial drugs due to its fast growth rate and low pathogenicity. The M. aurum genome has been sequenced and assembled into 46 contigs, with a total length of 6.02 Mb containing 5684 annotated protein-coding genes. A phylogenetic analysis using whole genome alignments positioned M. aurum close to Mycobacterium vaccae and Mycobacterium vanbaalenii, within a clade related to fast-growing mycobacteria. Large-scale genomic rearrangements were identified by comparing the M. aurum genome to those of Mycobacterium tuberculosis and Mycobacterium leprae. M. aurum orthologous genes implicated in resistance to anti-tuberculosis drugs in M. tuberculosis were observed. The sequence identity at the DNA level varied from 68.6% for pncA (pyrazinamide drug-related) to 96.2% for rrs (streptomycin, capreomycin). We observed two homologous genes encoding the catalase-peroxidase enzyme (katG) that is associated with resistance to isoniazid. Similarly, two embB homologues were identified in the M. aurum genome. In addition to describing for the first time the genome of M. aurum, this work provides a resource to aid the use of M. aurum in studies to develop improved drugs for the pathogenic mycobacteria M. tuberculosis and M. leprae.

  13. Efficacy of moxifloxacin & econazole against multidrug resistant (MDR Mycobacterium tuberculosis in murine model

    Directory of Open Access Journals (Sweden)

    U D Gupta

    2015-01-01

    Full Text Available Background & objectives: Studies have shown the bactericidal potential of econazole and clotrimazole against Mycobacterium tuberculosis under in vitro and ex vivo conditions along with their synergism with conventional antituberculosis drugs. These molecules were also found to be effective against different multidrug resistant (MDR M. tuberculosis isolates in vitro. Hence the present study was designed to evaluate the in vivo antimycobacterial potential of moxifloxacin and econazole alone and in combination against multidrug resistant tuberculosis (MDR-TB in a mice model. Methods: Mice were infected with 2.5×10 [7] bacilli of MDR strain of M. tuberculosis by aerosol route of infection. After four weeks of infection, chemotherapy was started orally by moxifloxacin 8.0 mg/kg body wt and econazole 3.3 mg/kg alone and in combination, as well as with four first line anti-tuberculosis drugs as a positive control. The animals were sacrificed and the lungs and spleen were excised under aspetic conditions. The tissues were homogenized with sterile normal saline, an aliquot of the homogenate was plated on Middlebrook 7H11 agar supplemented with oleate albumin dextrose catalase (OADC and incubated at 37°C for four weeks. The number of visible and individual colonies were counted. Results: The first line anti-tuberculosis drugs (RIF+INH+EMB+PZA after eight weeks of therapy had no impact as the bacillary load in lungs and spleens remained unchanged. However, econazole, moxifloxacin alone as well as in combination significantly reduced the bacillary load in lungs as well as in spleens of MDR-TB bacilli infected mice. Interpretation & conclusions: Co-administration of the two drugs (econazole and moxifloxacin to MDR-TB strain JAL-7782 infected mice exhibited additive effect, the efficacy of the drugs in combination being higher as compared with ECZ or MOX alone. These results were substantiated by histopathological studies. This study suggests the utility of

  14. The culturable soil antibiotic resistome: a community of multi-drug resistant bacteria.

    Directory of Open Access Journals (Sweden)

    Fiona Walsh

    Full Text Available 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 than 80% were resistant to 16-23 antibiotics, comprising almost all classes of antibiotic. The mobile resistance genes investigated, (ESBL, bla NDM-1, and plasmid mediated quinolone resistance (PMQR resistance genes were not responsible for the respective resistance phenotypes nor were they present in the extracted soil DNA. Efflux was demonstrated to play an important role in MDR and many resistance phenotypes. Clinically relevant Burkholderia species are intrinsically resistant to ciprofloxacin but the soil Burkholderia species were not intrinsically resistant to ciprofloxacin. Using a phenotypic enzyme assay we identified the antibiotic specific inactivation of trimethoprim in 21 bacteria from different soils. The results of this study identified the importance of the efflux mechanism in the soil resistome and variations between the intrinsic resistance profiles of clinical and soil bacteria of the same family.

  15. The skill and style to model the evolution of resistance to pesticides and drugs.

    Science.gov (United States)

    2010-07-01

    Resistance to pesticides and drugs led to the development of theoretical models aimed at identifying the main factors of resistance evolution and predicting the efficiency of resistance management strategies. We investigated the various ways in which the evolution of resistance has been modelled over the last three decades, by reviewing 187 articles published on models of the evolution of resistance to all major classes of pesticides and drugs. We found that (i) the technical properties of the model were most strongly influenced by the class of pesticide or drug and the target organism, (ii) the resistance management strategies studied were quite similar for the different classes of pesticides or drugs, except that the refuge strategy was mostly used in models of the evolution of resistance to insecticidal proteins, (iii) economic criteria were rarely used to evaluate the evolution of resistance and (iv) the influence of mutation, migration and drift on the speed of resistance development has been poorly investigated. We propose guidelines for the future development of theoretical models of the evolution of resistance. For instance, we stress the potential need to give more emphasis to the three evolutionary forces migration, mutation and genetic drift rather than simply selection.

  16. Update on HIV-1 acquired and transmitted drug resistance in Africa.

    Science.gov (United States)

    Ssemwanga, Deogratius; Lihana, Raphael W; Ugoji, Chinenye; Abimiku, Alash'le; Nkengasong, John; Dakum, Patrick; Ndembi, Nicaise

    2015-01-01

    The last ten years have witnessed a significant scale-up and access to antiretroviral therapy in Africa, which has improved patient quality of life and survival. One major challenge associated with increased access to antiretroviral therapy is the development of antiretroviral resistance due to inconsistent drug supply and/or poor patient adherence. We review the current state of both acquired and transmitted drug resistance in Africa over the past ten years (2001-2011) to identify drug resistance associated with the different drug regimens used on the continent and to help guide affordable strategies for drug resistance surveillance. A total of 161 references (153 articles, six reports and two conference abstracts) were reviewed. Antiretroviral resistance data was available for 40 of 53 African countries. A total of 5,541 adult patients from 99 studies in Africa were included in this analysis. The pooled prevalence of drug resistance mutations in Africa was 10.6%, and Central Africa had the highest prevalence of 54.9%. The highest prevalence of nucleoside reverse transcriptase inhibitor mutations was in the west (55.3%) and central (54.8%) areas; nonnucleoside reverse transcriptase inhibitor mutations were highest in East Africa (57.0%) and protease inhibitors mutations highest in Southern Africa (16.3%). The major nucleoside reverse transcriptase inhibitor mutation in all four African regions was M184V. Major nonnucleoside reverse transcriptase inhibitor as well as protease inhibitor mutations varied by region. The prevalence of drug resistance has remained low in several African countries although the emergence of drug resistance mutations varied across countries. Continued surveillance of antiretroviral therapy resistance remains crucial in gauging the effectiveness of country antiretroviral therapy programs and strategizing on effective and affordable strategies for successful treatment.

  17. Relationship between Methylation Status of Multi-drug Resistance Protein(MRP) and Multi-drug Resistance in Lung Cancer Cell Lines

    Institute of Scientific and Technical Information of China (English)

    LIU Rui-jun; ZHONG Hong

    2007-01-01

    Objective: To study the relationship between the methylation status of multi-drug resistance protein (MRP) gene and the expression of its mRNA and protein in lung cancer cell lines. Methods: Human embryo lung cell line WI-38, lung adenocarcinoma cell line SPCA-1 and its drug-resistant cells induced by different concentrations of doxorubicin were treated with restriction endonuclease Eco47Ⅲ. The methylation status of MRP was examined by PCR, and the expressions of its mRNA and protein were evaluated by in situ hybridization and immunohistochemistry. Results: MRP gene promoter region of WI-38 cells was in hypermethylation status, but the promoter region of MRP in SPCA-1 cells and their resistant derivatives induced by different concentrations of doxorubicin were in hypomethylation status. There were significant differences in the expression of MRP mRNA among WI-38 cell line, SPCA-1 cells and their drug-resistant derivatives induced by different concentration of doxorubicin. Consistently, MRP immunostaining presented similar significant differences. Conclusion: The promoter region of MRP in SPCA-1 lung adenocarcinoma cells was in hypomethylation status. The hypomethylation status of 5' regulatory region of MRP promoter is an important structural basis that can increase the activity of transcription and results in the development of drug resistance in lung cancer.

  18. Potential impact of intermittent preventive treatment (IPT on spread of drug-resistant malaria.

    Directory of Open Access Journals (Sweden)

    Wendy Prudhomme O'Meara

    2006-05-01

    Full Text Available BACKGROUND: Treatment of asymptomatic individuals, regardless of their malaria infection status, with regularly spaced therapeutic doses of antimalarial drugs has been proposed as a method for reducing malaria morbidity and mortality. This strategy, called intermittent preventive treatment (IPT, is currently employed for pregnant women and is being studied for infants (IPTi as well. As with any drug-based intervention strategy, it is important to understand how implementation may affect the spread of drug-resistant parasites. This is a difficult issue to address experimentally because of the limited size and duration of IPTi trials as well as the intractability of distinguishing the spread of resistance due to conventional treatment of malaria episodes versus that due to IPTi when the same drug is used in both contexts. METHODS AND FINDINGS: Using a mathematical model, we evaluated the possible impact of treating individuals with antimalarial drugs at regular intervals regardless of their infection status. We translated individual treatment strategies and drug pharmacokinetics into parasite population dynamic effects and show that immunity, treatment rate, drug decay kinetics, and presumptive treatment rate are important factors in the spread of drug-resistant parasites. Our model predicts that partially resistant parasites are more likely to spread in low-transmission areas, but fully resistant parasites are more likely to spread under conditions of high transmission, which is consistent with some epidemiological observations. We were also able to distinguish between spread of resistance due to treatment of symptomatic infections and that due to IPTi. We showed that IPTi could accelerate the spread of resistant parasites, but this effect was only likely to be significant in areas of low or unstable transmission. CONCLUSIONS: The results presented here demonstrate the importance of considering both the half-life of a drug and the existing level

  19. Selective reversal of drug resistance in drug-resistant lung adenocarcinoma cells by tumor-specific expression of MDR1 ribozyme gene mediated by retrovirus

    Institute of Scientific and Technical Information of China (English)

    高振强; 高志萍; 刘喜富; 张涛

    1997-01-01

    According to the fact that CEA gene expressed only in lung adenocarcinoma and not in normal lung cells, a retroviral vector (pCEAMR) was constructed which carried the CEA promoter coupled to MDR1 ribozyme gene. pCEAMR was introduced into drug-resistant lung adenocarcinoma cells GAOK with CEA expression and HeLaK without CEA expression; the expression of pCEAMR and drug resistance in the infected cells were analyzed in vitro and in vivo ; pCEAMR expressed only in CEA-producing GAOK cells and not in non-CEA-producing HeLa cells. The drug resistance to doxorubicin (DOX) decreased 91.5% in the infected GAOK cells and did not change in the infected HeLa cells. In nude mice, DOX could obviously inhibit the growth of the infected GAOK tumors, and had no effect on the growth of the infected HeLa cells. These results indicated that MDR1 ribozyme gene regulated by CEA promoter expressed only in human adenocarcinoma cells and reversed their drug resistance selectively. This gene-drug therapy might serve as an effe

  20. Longitudinal Detection and Persistence of Minority Drug-Resistant Populations and Their Effect on Salvage Therapy.

    Directory of Open Access Journals (Sweden)

    Masako Nishizawa

    Full Text Available Drug-resistant HIV are more prevalent and persist longer than previously demonstrated by bulk sequencing due to the ability to detect low-frequency variants. To clarify a clinical benefit to monitoring minority-level drug resistance populations as a guide to select active drugs for salvage therapy, we retrospectively analyzed the dynamics of low-frequency drug-resistant population in antiretroviral (ARV-exposed drug resistant individuals.Six HIV-infected individuals treated with ARV for more than five years were analyzed. These individuals had difficulty in controlling viremia, and treatment regimens were switched multiple times guided by standard drug resistance testing using bulk sequencing. To detect minority variant populations with drug resistance, we used a highly sensitive allele-specific PCR (AS-PCR with detection thresholds of 0.3-2%. According to ARV used in these individuals, we focused on the following seven reverse transcriptase inhibitor-resistant mutations: M41L, K65R, K70R, K103N, Y181C, M184V, and T215F/Y. Results of AS-PCR were compared with bulk sequencing data for concordance and presence of additional mutations. To clarify the genetic relationship between low-frequency and high-frequency populations, AS-PCR amplicon sequences were compared with bulk sequences in phylogenetic analysis.The use of AS-PCR enabled detection of the drug-resistant mutations, M41L, K103N, Y181C, M184V and T215Y, present as low-frequency populations in five of the six individuals. These drug resistant variants persisted for several years without ARV pressure. Phylogenetic analysis indicated that pre-existing K103N and T215I variants had close genetic relationships with high-frequency K103N and T215I observed during treatment.Our results demonstrate the long-term persistence of drug-resistant viruses in the absence of drug pressure. The rapid virologic failures with pre-existing mutant viruses detectable by AS-PCR highlight the clinical importance of

  1. Identifying co-targets to fight drug resistance based on a random walk model

    Directory of Open Access Journals (Sweden)

    Chen Liang-Chun

    2012-01-01

    Full Text Available Abstract Background Drug resistance has now posed more severe and emergent threats to human health and infectious disease treatment. However, wet-lab approaches alone to counter drug resistance have so far still achieved limited success due to less knowledge about the underlying mechanisms of drug resistance. Our approach apply a heuristic search algorithm in order to extract active network under drug treatment and use a random walk model to identify potential co-targets for effective antibacterial drugs. Results We use interactome network of Mycobacterium tuberculosis and gene expression data which are treated with two kinds of antibiotic, Isoniazid and Ethionamide as our test data. Our analysis shows that the active drug-treated networks are associated with the trigger of fatty acid metabolism and synthesis and nicotinamide adenine dinucleotide (NADH-related processes and those results are consistent with the recent experimental findings. Efflux pumps processes appear to be the major mechanisms of resistance but SOS response is significantly up-regulation under Isoniazid treatment. We also successfully identify the potential co-targets with literature confirmed evidences which are related to the glycine-rich membrane, adenosine triphosphate energy and cell wall processes. Conclusions With gene expression and interactome data supported, our study points out possible pathways leading to the emergence of drug resistance under drug treatment. We develop a computational workflow for giving new insights to bacterial drug resistance which can be gained by a systematic and global analysis of the bacterial regulation network. Our study also discovers the potential co-targets with good properties in biological and graph theory aspects to overcome the problem of drug resistance.

  2. Mechanism of cancer drug resistance and the involvement of noncoding RNAs.

    Science.gov (United States)

    Xia, Hongping; Hui, Kam M

    2014-01-01

    Drug resistance is one of the major reasons for the failure of cancer therapies. Although our understanding of resistance to targeted cancer drugs remains incomplete, new and more creative approaches are being exploited to intercept this phenomenon. Considerable advances have been made in our understanding that cancer drug resistance can be caused by alterations of drug efflux, increases in drug metabolism, mutations of drug targets, alterations in DNA repair and cell cycle, changes in cell apoptosis and autophagy, induction of epithelial-mesenchymal transition (EMT) and the generation of cancer stem cells (CSCs). Furthermore, intracellular signalling pathways have been shown to play key physiological roles and the abnormal activation of signalling pathways may be correlated with drug resistance. Recently, noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have emerged as important regulators of gene expression and alternative splicing, which provides cells with yet another mode to greatly increase regulatory complexity and fine-tune their transcriptome and can rapidly adjust their proteome in response to stimuli. Consequently, a wide variety of biological functions have been shown to depend on the coordinated interactions between noncoding RNAs and cellular signalling networks to achieve a concerted desired physiological outcome, whereas mutations and dysregulation of ncRNAs have been linked to diverse human diseases, including cancer drug resistance. In this review, we will discuss recent findings on the multiple molecular roles of regulatory ncRNAs on the signalling pathways involved in cancer drug resistance and the therapeutic potential of reverse drug resistance.

  3. Whole animal automated platform for drug discovery against multi-drug resistant Staphylococcus aureus.

    Directory of Open Access Journals (Sweden)

    Rajmohan Rajamuthiah

    Full Text Available Staphylococcus aureus, the leading cause of hospital-acquired infections in the United States, is also pathogenic to the model nematode Caenorhabditis elegans. The C. elegans-S. aureus infection model was previously carried out on solid agar plates where the bacteriovorous C. elegans feeds on a lawn of S. aureus. However, agar-based assays are not amenable to large scale screens for antibacterial compounds. We have developed a high throughput liquid screening assay that uses robotic instrumentation to dispense a precise amount of methicillin resistant S. aureus (MRSA and worms in 384-well assay plates, followed by automated microscopy and image analysis. In validation of the liquid assay, an MRSA cell wall defective mutant, MW2ΔtarO, which is attenuated for killing in the agar-based assay, was found to be less virulent in the liquid assay. This robust assay with a Z'-factor consistently greater than 0.5 was utilized to screen the Biomol 4 compound library consisting of 640 small molecules with well characterized bioactivities. As proof of principle, 27 of the 30 clinically used antibiotics present in the library conferred increased C. elegans survival and were identified as hits in the screen. Surprisingly, the antihelminthic drug closantel was also identified as a hit in the screen. In further studies, we confirmed the anti-staphylococcal activity of closantel against vancomycin-resistant S. aureus isolates and other Gram-positive bacteria. The liquid C. elegans-S. aureus assay described here allows screening for anti-staphylococcal compounds that are not toxic to the host.

  4. Re-sensitizing drug-resistant bacteria to antibiotics by designing Antisense Therapeutics

    Science.gov (United States)

    Courtney, Colleen; Chatterjee, Anushree

    2014-03-01

    ``Super-bugs'' or ``multi-drug resistant organisms'' are a serious international health problem, with devastating consequences to patient health care. The Center for Disease Control has identified antibiotic resistance as one of the world's most pressing public health problems as a significant fraction of bacterial infections contracted are drug resistant. Typically, antibiotic resistance is encoded by ``resistance-genes'' which express proteins that carryout the resistance causing functions inside the bacterium. We present a RNA based therapeutic strategy for designing antimicrobials capable of re-sensitizing resistant bacteria to antibiotics by targeting labile regions of messenger RNAs encoding for resistance-causing proteins. We perform in silico RNA secondary structure modeling to identify labile target regions in an mRNA of interest. A synthetic biology approach is then used to administer antisense nucleic acids to our model system of ampicillin resistant Escherichia coli. Our results show a prolonged lag phase and decrease in viability of drug-resistant E. colitreated with antisense molecules. The antisense strategy can be applied to alter expression of other genes in antibiotic resistance pathways or other pathways of interest.

  5. Evaluation of the resistance of a geopolymer-based drug delivery system to tampering.

    Science.gov (United States)

    Cai, Bing; Engqvist, Håkan; Bredenberg, Susanne

    2014-04-25

    Tamper-resistance is an important property of controlled-release formulations of opioid drugs. Tamper-resistant formulations aim to increase the degree of effort required to override the controlled release of the drug molecules from extended-release formulations for the purpose of non-medical use. In this study, the resistance of a geopolymer-based formulation to tampering was evaluated by comparing it with a commercial controlled-release tablet using several methods commonly used by drug abusers. Because of its high compressive strength and resistance to heat, much more effort and time was required to extract the drug from the geopolymer-based formulation. Moreover, in the drug-release test, the geopolymer-based formulation maintained its controlled-release characteristics after milling, while the drug was released immediately from the milled commercial tablets, potentially resulting in dose dumping. Although the tampering methods used in this study does not cover all methods that abuser could access, the results obtained by the described methods showed that the geopolymer matrix increased the degree of effort required to override the controlled release of the drug, suggesting that the formulation has improved resistance to some common drug-abuse tampering methods. The geopolymer matrix has the potential to make the opioid product less accessible and attractive to non-medical users.

  6. Malaria drug resistance: the impact of human movement and spatial heterogeneity.

    Science.gov (United States)

    Agusto, F B

    2014-07-01

    Human habitat connectivity, movement rates, and spatial heterogeneity have tremendous impact on malaria transmission. In this paper, a deterministic system of differential equations for malaria transmission incorporating human movements and the development of drug resistance malaria in an [Formula: see text] patch system is presented. The disease-free equilibrium of the model is globally asymptotically stable when the associated reproduction number is less than unity. For a two patch case, the boundary equilibria (drug sensitive-only and drug resistance-only boundary equilibria) when there is no movement between the patches are shown to be locally asymptotically stable when they exist; the co-existence equilibrium is locally asymptotically stable whenever the reproduction number for the drug sensitive malaria is greater than the reproduction number for the resistance malaria. Furthermore, numerical simulations of the connected two patch model (when there is movement between the patches) suggest that co-existence or competitive exclusion of the two strains can occur when the respective reproduction numbers of the two strains exceed unity. With slow movement (or low migration) between the patches, the drug sensitive strain dominates the drug resistance strain. However, with fast movement (or high migration) between the patches, the drug resistance strain dominates the drug sensitive strain.

  7. Antitubercular Activity of Disulfiram, an Antialcoholism Drug, against Multidrug- and Extensively Drug-Resistant Mycobacterium tuberculosis Isolates

    Science.gov (United States)

    Horita, Yasuhiro; Yagi, Tetsuya; Ogawa, Kenji; Fujiwara, Nagatoshi; Inagaki, Emi; Kremer, Laurent; Sato, Yasuo; Kuroishi, Ryuji; Lee, YooSa; Makino, Toshiaki; Mizukami, Hajime; Hasegawa, Tomohiro; Yamamoto, Ryuji; Onozaki, Kikuo

    2012-01-01

    The antimycobacterial activities of disulfiram (DSF) and diethyldithiocarbamate (DDC) against multidrug- and extensively drug-resistant tuberculosis (MDR/XDR-TB) clinical isolates were evaluated in vitro. Both DSF and DDC exhibited potent antitubercular activities against 42 clinical isolates of M. tuberculosis, including MDR/XDR-TB strains. Moreover, DSF showed remarkable bactericidal activity ex vivo and in vivo. Therefore, DSF might be a drug repurposed for the treatment of MDR/XDR-TB. PMID:22615274

  8. Distribution of putative virulence genes and antimicrobial drug resistance in Vibrio harveyi

    Digital Repository Service at National Institute of Oceanography (India)

    Parvathi, A.; Mendez, D.; Anto, C.

    environments for understanding the distribution of putative virulence genes and antimicrobial drug resistance. The putative genes targeted for PCR detection included four reversible toxin (Rtx)/hemolysin genes, a gene encoding homologue of Vibrio cholerae...

  9. Translational research in ovarian carcinoma : cell biological aspects of drug resistance and tumor aggressiveness

    NARCIS (Netherlands)

    Zee, Ate Gerard Jan van der

    1994-01-01

    In this thesis diverse cell biological features that in cultured (ovarian) tumor cells have been linked to drug resistance and/or tumor aggressiveness are studied in tumor specimens of epithelial ovarian carcinomas.

  10. Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis

    Science.gov (United States)

    Unciti-Broceta, Juan D.; Arias, José L.; Maceira, José; Soriano, Miguel; Ortiz-González, Matilde; Hernández-Quero, José; Muñóz-Torres, Manuel; de Koning, Harry P.; Magez, Stefan; Garcia-Salcedo, José A.

    2015-01-01

    African trypanosomiasis is a deadly neglected disease caused by the extracellular parasite Trypanosoma brucei. Current therapies are characterized by high drug toxicity and increasing drug resistance mainly associated with loss-of-function mutations in the transporters involved in drug import. The introduction of new antiparasitic drugs into therapeutic use is a slow and expensive process. In contrast, specific targeting of existing drugs could represent a more rapid and cost-effective approach for neglected disease treatment, impacting through reduced systemic toxicity and circumventing resistance acquired through impaired compound uptake. We have generated nanoparticles of chitosan loaded with the trypanocidal drug pentamidine and coated by a single domain nanobody that specifically targets the surface of African trypanosomes. Once loaded into this nanocarrier, pentamidine enters trypanosomes through endocytosis instead of via classical cell surface transporters. The curative dose of pentamidine-loaded nanobody-chitosan nanoparticles was 100-fold lower than pentamidine alone in a murine model of acute African trypanosomiasis. Crucially, this new formulation displayed undiminished in vitro and in vivo activity against a trypanosome cell line resistant to pentamidine as a result of mutations in the surface transporter aquaglyceroporin 2. We conclude that this new drug delivery system increases drug efficacy and has the ability to overcome resistance to some anti-protozoal drugs. PMID:26110623

  11. Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis.

    Science.gov (United States)

    Unciti-Broceta, Juan D; Arias, José L; Maceira, José; Soriano, Miguel; Ortiz-González, Matilde; Hernández-Quero, José; Muñóz-Torres, Manuel; de Koning, Harry P; Magez, Stefan; Garcia-Salcedo, José A

    2015-06-01

    African trypanosomiasis is a deadly neglected disease caused by the extracellular parasite Trypanosoma brucei. Current therapies are characterized by high drug toxicity and increasing drug resistance mainly associated with loss-of-function mutations in the transporters involved in drug import. The introduction of new antiparasitic drugs into therapeutic use is a slow and expensive process. In contrast, specific targeting of existing drugs could represent a more rapid and cost-effective approach for neglected disease treatment, impacting through reduced systemic toxicity and circumventing resistance acquired through impaired compound uptake. We have generated nanoparticles of chitosan loaded with the trypanocidal drug pentamidine and coated by a single domain nanobody that specifically targets the surface of African trypanosomes. Once loaded into this nanocarrier, pentamidine enters trypanosomes through endocytosis instead of via classical cell surface transporters. The curative dose of pentamidine-loaded nanobody-chitosan nanoparticles was 100-fold lower than pentamidine alone in a murine model of acute African trypanosomiasis. Crucially, this new formulation displayed undiminished in vitro and in vivo activity against a trypanosome cell line resistant to pentamidine as a result of mutations in the surface transporter aquaglyceroporin 2. We conclude that this new drug delivery system increases drug efficacy and has the ability to overcome resistance to some anti-protozoal drugs.

  12. Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis.

    Directory of Open Access Journals (Sweden)

    Juan D Unciti-Broceta

    2015-06-01

    Full Text Available African trypanosomiasis is a deadly neglected disease caused by the extracellular parasite Trypanosoma brucei. Current therapies are characterized by high drug toxicity and increasing drug resistance mainly associated with loss-of-function mutations in the transporters involved in drug import. The introduction of new antiparasitic drugs into therapeutic use is a slow and expensive process. In contrast, specific targeting of existing drugs could represent a more rapid and cost-effective approach for neglected disease treatment, impacting through reduced systemic toxicity and circumventing resistance acquired through impaired compound uptake. We have generated nanoparticles of chitosan loaded with the trypanocidal drug pentamidine and coated by a single domain nanobody that specifically targets the surface of African trypanosomes. Once loaded into this nanocarrier, pentamidine enters trypanosomes through endocytosis instead of via classical cell surface transporters. The curative dose of pentamidine-loaded nanobody-chitosan nanoparticles was 100-fold lower than pentamidine alone in a murine model of acute African trypanosomiasis. Crucially, this new formulation displayed undiminished in vitro and in vivo activity against a trypanosome cell line resistant to pentamidine as a result of mutations in the surface transporter aquaglyceroporin 2. We conclude that this new drug delivery system increases drug efficacy and has the ability to overcome resistance to some anti-protozoal drugs.

  13. Prevalence of Drug Resistance Mycobacterium Tuberculosis among Patients Seen in Coast Provincial General Hospital, Mombasa, Kenya

    Science.gov (United States)

    Ombura, Ida Pam; Onyango, Noel; Odera, Susan; Mutua, Florence; Nyagol, Joshua

    2016-01-01

    Background Although prevention and control of spread of multi-drug resistant tuberculosis strains is a global challenge, there is paucity of data on the prevalence of DR-TB in patients diagnosed with TB in referral hospitals in Kenya. The present study assessed patients’ characteristics and prevalence of drug resistant TB in sputa smear positive TB patients presenting to Coast Provincial General Hospital (CPGH) in Mombasa, Kenya. Methods Drug resistance was evaluated in 258 randomly selected sputa smear TB positive cases between the periods of November 2011 to February 2012 at the CPGH-Mombasa. Basic demographic data was obtained using administered questionnaires, and clinical history extracted from the files. For laboratory analyses, 2mls of sputum was obtained, decontaminated and subjected to mycobacteria DNA analyses. Detection of first line drug resistance genes was done using MDRTDR plus kit. This was followed with random selection of 83 cases for second line drug resistance genes testing using Genotype MDRTBsl probe assay kit (HAINS Lifesciences, GmbH, Germany), in which ethambutol mutation probes were included. The data was then analyzed using SPSS statistical package version 19.0. Results Male to female ratio was 1:2. Age range was 9 to 75 years, with median of 30 years. New treatment cases constituted 253(98%), among which seven turned out to be PTB negative, and further grouped as 4 (1.6%) PTB negative and 3(1.1%) NTM. 237(91.7%) new cases were fully susceptible to INH and RIF. The remaining, 8 (3.1%) and 1(0.4%) had mono- resistance to INH and RIF, respectively. All the retreatment cases were fully susceptible to the first line drugs. HIV positivity was found in 48 (18.6%) cases, of which 46(17.8%) were co-infected with TB. Of these, 44 (17.1%) showed full susceptibility to TB drugs, while 2 (0.8%) were INH resistant. For the second line drugs, one case each showed mono resistance to both and FQ. Also, one case each showed drug cross poly resistance to

  14. Prevalence and evolution of drug resistance HIV-1 variants in Henan, China

    Institute of Scientific and Technical Information of China (English)

    Jing; Yun; LI; Han; Ping; LI; Lin; LI; Hong; LI; Zhe; WANG; Kun; YANG; Zuo; Yi; BAO; Dao; Min; ZHUANG; Si; Yang; LIU; Yong; Jian; LIU; Hui; XING; Yi; Ming; SHAO

    2005-01-01

    To understand the prevalence and evolution of drug resistant HIV strains in Henan China after the implementation of free antiretroviral therapy for AIDS patients. 45 drug naive AIDS patients, 118 AIDS patients who received three months antiretroviral therapy and 124 AIDS patients who received six months antiretroviral treatment were recruited in the southern part of Henan province. Information on general condition, antiretroviral medicines, adherence and clinical syndromes were collected by face to face interview. Meanwhile, 14ml EDTA anticoagulant blood was drawn. CD4/CD8 T cell count, viral load and genotypic drug resistance were tested. The rates of clinical improvement were 55.1% and 50.8% respectively three months and six months after antiretroviral therapy. The mean CD4 cell count after antiretroviral therapy was significantly higher than in drug naive patients. The prevalence rate of drug resistant HIV strains were 13.9%, 45.4% and 62.7% in drug naive patients, three month treatment patients and six month treatment patients, respectively.The number of resistance mutation codons and the frequency of mutations increased significantly with continued antiretroviral therapy. The mutation sites were primarily at the 103, 106 and 215 codons in the three-month treatment group and they increased to 15 codon mutations in the six-month treatment group. From this result, the evolution of drug resistant strains was inferred to begin with the high level NNRTI resistant strain, and then develop low level resistant strains to NRTIs. The HIV strains with high level resistance to NVP and low level resistance to AZT and DDI were highly prevalent because of the AZT+DDI+NVP combination therapy. These HIV strains were also cross resistant to DLV, EFV, DDC and D4T. Poor adherence to therapy was believed to be the main reason for the emergence and prevalence of drug resistant HIV strains. The prevalence of drug resistant HIV strains was increased with the continuation of

  15. 270例结核分支杆菌药敏试验结果分析%Analysis of 270 cases of mycobacterium tuberculosis drug susceptility test results

    Institute of Scientific and Technical Information of China (English)

    贾琳; 张红; 魏成翠

    2013-01-01

    Objective Through the 270 cases of mycobacterium tuberculosis drug susceptility test results of the analysis ,to explore the incidence of anti-tuberculosis drug resistance and characteristic ,provide the basis for drug-resistant tuberculosis treatment and prevention. Methords 270 cases of mycobacterium tuberculosis by absolute concentration method for 12kinds of drug sensitive test. Results 270 cases of mycobacterium tuberculosis were detected 142 cases of drug-resistant(52.6%) ,among them multidrug resistance(MDR-TB) 83 cases(30.7%). Conclusions mycobacterium tuberculosis drug-resistant situation is more serious ,should further strengthen clinical treatment and standard medication ,control tuberculosis drug-resistant increase.%  目的通过对270例结核分支杆菌药敏试验结果的分析,探讨抗结核药物耐药性的发生率和特点,为耐药结核病预防和治疗提供依据。方法采用绝对浓度法对270例结核分支杆菌进行12种药物的敏感试验。结果270例结核分支杆菌共检出耐药菌142例(52.6%),其中耐多药结核(MDR-TB)83例(30.7%)。结论结核分支杆菌耐药状况比较严重,应进一步加强结核病的临床治疗和规范用药,控制耐药菌增加。

  16. Drug resistance and adherence to human intestines of enteroaggregative Escherichia coli.

    Science.gov (United States)

    Yamamoto, T; Echeverria, P; Yokota, T

    1992-04-01

    Clinical isolates of enteroaggregative Escherichia coli (EAggEC) were tested for their in vitro susceptibilities to 27 antimicrobial agents. Marked drug resistance was observed with sulfamethoxazole, ampicillin, and chloramphenicol in contrast to such antimicrobial agents as cefixime, sparfloxacin, and ciprofloxacin. One of the EAggEC strains carried a plasmid that conferred on its host resistance to ampicillin, tetracycline, sulfamethoxazole, streptomycin, and spectinomycin and an ability to adhere to child ileal villi or HeLa cells in the characteristic aggregative pattern. This plasmid also mediated D-mannose-resistant hemagglutinin production and bacterial clump formation (autoagglutination). The data demonstrate appearance of marked drug resistance and an intestine-adherence and drug-resistance plasmid in the newest category of diarrheagenic E. coli.

  17. Interrater reliability of the international consensus definition of drug-resistant epilepsy: a pilot study.

    Science.gov (United States)

    Hao, Xiao-ting; Wong, Irina S M; Kwan, Patrick

    2011-10-01

    We evaluated the interrater reliability of the consensus definition of drug-resistant epilepsy proposed by the International League Against Epilepsy. According to the definition framework, outcome of each antiepileptic drug (AED) trial was categorized as "seizure freedom" or "treatment failure." This level 1 assessment was used to determine the level 2 classification, which defined drug-resistant epilepsy as the failure of adequate trials of two or more AED schedules to achieve sustained seizure freedom. Two raters classified treatment outcomes of 150 patients independently. The patients had received a total of 428 trials of AEDs. Categorization of level 1 outcome to individual AED trials by the raters was consistent in 413 (96.5%). For the level 2 classification of drug-resistant or drug-responsive epilepsy, there was absolute agreement between the raters in 141 patients (94%), with a κ index of 0.91 (Pdefinition appeared to have a high degree of interrater reliability in this setting.

  18. Comparison of the Mechanisms of Drug Resistance among HIV, Hepatitis B, and Hepatitis C

    Directory of Open Access Journals (Sweden)

    Robert W. Shafer

    2010-12-01

    Full Text Available Human immunodeficiency virus (HIV, hepatitis B virus (HBV, and hepatitis C virus (HCV are the most prevalent deadly chronic viral diseases. HIV is treated by small molecule inhibitors. HBV is treated by immunomodulation and small molecule inhibitors. HCV is currently treated primarily by immunomodulation but many small molecules are in clinical development. Although HIV is a retrovirus, HBV is a double-stranded DNA virus, and HCV is a single-stranded RNA virus, antiviral drug resistance complicates the development of drugs and the successful treatment of each of these viruses. Although their replication cycles, therapeutic targets, and evolutionary mechanisms are different, the fundamental approaches to identifying and characterizing HIV, HBV, and HCV drug resistance are similar. This review describes the evolution of HIV, HBV, and HCV within individuals and populations and the genetic mechanisms associated with drug resistance to each of the antiviral drug classes used for their treatment.

  19. Tris DBA palladium overcomes hypoxia-mediated drug resistance in multiple myeloma.

    Science.gov (United States)

    de la Puente, Pilar; Azab, Feda; Muz, Barbara; Luderer, Micah; Arbiser, Jack; Azab, Abdel Kareem

    2016-07-01

    Despite recent progress in novel and targeted therapies, multiple myeloma (MM) remains a therapeutically challenging incurable disease. The regulation of important cellular processes and its link to cancer presented Src as an attractive target for MM. We suggest a novel strategy to improve the treatment of MM and overcome the drug resistance for the current therapeutic agents by specific inhibition of Src in MM cells by Tris (Dibenzylideneacetone) dipalladium (Tris DBA). Tris DBA reduces proliferation, induces G1 arrest and apoptosis in MM cells. Tris DBA showed additive effect with proteasome inhibitors reducing proliferation, cell cycle signaling, and increasing apoptosis more than each drug alone. Tris DBA overcame hypoxia-induced effects such as enhanced chemotaxis or drug resistance to proteasome inhibitors by inhibition of HIF1α expression. Moreover, we found that Tris DBA is an effective anti-myeloma agent alone or in combination with other targeted drugs and that it reverses hypoxia-induced drug resistance in myeloma.

  20. Genome Analysis of the First Extensively Drug-Resistant (XDR) Mycobacterium tuberculosis in Malaysia Provides Insights into the Genetic Basis of Its Biology and Drug Resistance.

    Science.gov (United States)

    Kuan, Chee Sian; Chan, Chai Ling; Yew, Su Mei; Toh, Yue Fen; Khoo, Jia-Shiun; Chong, Jennifer; Lee, Kok Wei; Tan, Yung-Chie; Yee, Wai-Yan; Ngeow, Yun Fong; Ng, Kee Peng

    2015-01-01

    The outbreak of extensively drug-resistant tuberculosis (XDR-TB) has become an increasing problem in many TB-burdened countries. The underlying drug resistance mechanisms, including the genetic variation favored by selective pressure in the resistant population, are partially understood. Recently, the first case of XDR-TB was reported in Malaysia. However, the detailed genotype family and mechanisms of the formation of multiple drugs resistance are unknown. We sequenced the whole genome of the UM 1072388579 strain with a 2-kb insert-size library and combined with that from previously sequenced 500-bp-insert paired-end reads to produce an improved sequence with maximal sequencing coverage across the genome. In silico spoligotyping and phylogenetic analyses demonstrated that UM 1072388579 strain belongs to an ancestral-like, non-Beijing clade of East Asia lineage. This is supported by the presence of a number of lineage-specific markers, including fadD28, embA, nuoD and pks7. Polymorphism analysis showed that the drug-susceptibility profile is correlated with the pattern of resistance mutations. Mutations in drug-efflux pumps and the cell wall biogenesis pathway such as mmpL, pks and fadD genes may play an important role in survival and adaptation of this strain to its surrounding environment. In this work, fifty-seven putative promoter SNPs were identified. Among them, we identified a novel SNP located at -4 T allele of TetR/acrR promoter as an informative marker to recognize strains of East Asian lineage. Our work indicates that the UM 1072388579 harbors both classical and uncommon SNPs that allow it to escape from inhibition by many antibiotics. This study provides a strong foundation to dissect the biology and underlying resistance mechanisms of the first reported XDR M. tuberculosis in Malaysia.

  1. Genome Analysis of the First Extensively Drug-Resistant (XDR Mycobacterium tuberculosis in Malaysia Provides Insights into the Genetic Basis of Its Biology and Drug Resistance.

    Directory of Open Access Journals (Sweden)

    Chee Sian Kuan

    Full Text Available The outbreak of extensively drug-resistant tuberculosis (XDR-TB has become an increasing problem in many TB-burdened countries. The underlying drug resistance mechanisms, including the genetic variation favored by selective pressure in the resistant population, are partially understood. Recently, the first case of XDR-TB was reported in Malaysia. However, the detailed genotype family and mechanisms of the formation of multiple drugs resistance are unknown. We sequenced the whole genome of the UM 1072388579 strain with a 2-kb insert-size library and combined with that from previously sequenced 500-bp-insert paired-end reads to produce an improved sequence with maximal sequencing coverage across the genome. In silico spoligotyping and phylogenetic analyses demonstrated that UM 1072388579 strain belongs to an ancestral-like, non-Beijing clade of East Asia lineage. This is supported by the presence of a number of lineage-specific markers, including fadD28, embA, nuoD and pks7. Polymorphism analysis showed that the drug-susceptibility profile is correlated with the pattern of resistance mutations. Mutations in drug-efflux pumps and the cell wall biogenesis pathway such as mmpL, pks and fadD genes may play an important role in survival and adaptation of this strain to its surrounding environment. In this work, fifty-seven putative promoter SNPs were identified. Among them, we identified a novel SNP located at -4 T allele of TetR/acrR promoter as an informative marker to recognize strains of East Asian lineage. Our work indicates that the UM 1072388579 harbors both classical and uncommon SNPs that allow it to escape from inhibition by many antibiotics. This study provides a strong foundation to dissect the biology and underlying resistance mechanisms of the first reported XDR M. tuberculosis in Malaysia.

  2. Personalized prediction of EGFR mutation-induced drug resistance in lung cancer

    OpenAIRE

    Wang, Debby D.; Weiqiang Zhou; Hong Yan; Maria Wong; Victor Lee

    2013-01-01

    EGFR mutation-induced drug resistance has significantly impaired the potency of small molecule tyrosine kinase inhibitors in lung cancer treatment. Computational approaches can provide powerful and efficient techniques in the investigation of drug resistance. In our work, the EGFR mutation feature is characterized by the energy components of binding free energy (concerning the mutant-inhibitor complex), and we combine it with specific personal features for 168 clinical subjects to construct a...

  3. ABCB1 gene polymorphisms is not associated with drug-resistant epilepsy in Romanian children

    Directory of Open Access Journals (Sweden)

    Butila Anamaria Todoran

    2015-12-01

    Full Text Available Background: P-glycoprotein (P-gp, a drug efflux transporter, encoded by the gene MDR1 ABCB1 multidrug resistant, reduces the penetration through the brain by the AEDs. Overexpression of Pgp in blood-brain barrier in epileptic patients play an important rol in pharmacoresistance. The aim of this study was to evaluate a possible association between C1236T and G2677T ABCB1 gene polymorphisms and drug-resistant epilepsy in Romanian children.

  4. Gene Expression Noise Facilitates Adaptation and Drug Resistance Independently of Mutation

    CERN Document Server

    Charlebois, Daniel A; Kaern, Mads

    2011-01-01

    We show that the effect of stress on the reproductive fitness of noisy cell populations can be modelled as first-passage time problem, and demonstrate that even relatively short-lived fluctuations in gene expression can ensure long-term survival of a drug-resistant population. We examine how this effect contributes to the development of drug-resistant cancer cells, and demonstrate that permanent immunity can arise independently of mutations.

  5. Nanoparticle-mediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance in vitro.

    Science.gov (United States)

    Khdair, Ayman; Handa, Hitesh; Mao, Guangzhao; Panyam, Jayanth

    2009-02-01

    Drug resistance limits the success of many anticancer drugs. Reduced accumulation of the drug at its intracellular site of action because of overexpression of efflux transporters such as P-glycoprotein (P-gp) is a major mechanism of drug resistance. In this study, we investigated whether photodynamic therapy (PDT) using methylene blue, also a P-gp inhibitor, can be used to enhance doxorubicin-induced cytotoxicity in drug-resistant tumor cells. Aerosol OT (AOT)-alginate nanoparticles were used as a carrier for the simultaneous cellular delivery of doxorubicin and methylene blue. Methylene blue was photoactivated using light of 665 nm wavelength. Induction of apoptosis and necrosis following treatment with combination chemotherapy and PDT was investigated in drug-resistant NCI/ADR-RES cells using flow cytometry and fluorescence microscopy. Effect of encapsulation in nanoparticles on the intracellular accumulation of doxorubicin and methylene blue was investigated qualitatively using fluorescence microscopy and was quantitated using HPLC. Encapsulation in AOT-alginate nanoparticles significantly enhanced the cytotoxicity of combination therapy in resistant tumor cells. Nanoparticle-mediated combination therapy resulted in a significant induction of both apoptosis and necrosis. Improvement in cytotoxicity could be correlated with enhanced intracellular and nuclear delivery of the two drugs. Further, nanoparticle-mediated combination therapy resulted in significantly elevated reactive oxygen species (ROS) production compared to single drug treatment. In conclusion, nanoparticle-mediated combination chemotherapy and PDT using doxorubicin and methylene blue was able to overcome resistance mechanisms and resulted in improved cytotoxicity in drug-resistant tumor cells.

  6. New drugs to treat multidrug-resistant tuberculosis: the case for bedaquiline

    Directory of Open Access Journals (Sweden)

    Leibert E

    2014-07-01

    Full Text Available Eric Leibert, Mauricio Danckers, William N Rom Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, New York University School of Medicine, New York, NY, USA Abstract: Mycobacterium tuberculosis develops spontaneous resistance mutants to virtually every drug in use. Courses of therapy select for these mutants and drug-resistant organisms emerge. The development of drug-resistant organisms has reached the point that drug resistance now threatens to undermine global success against tuberculosis (TB. New drugs are needed. The last new class of drugs specifically developed for treatment of TB was the rifamycins over 40 years ago. New funding sources and the development of product development partnerships have energized the TB drug development effort. There are now more TB drugs in development than at any time in the past. The first of these drugs to be developed and marketed was bedaquiline. Bedaquiline has an entirely novel mechanism of action and so should be active against otherwise highly resistant organisms. It acts on the transmembrane component of adenosine triphosphate synthase and acts by preventing electron transport. This raises the exciting possibility that bedaquiline may be active against less metabolically active organisms. Drug–drug interactions between rifamycins and the cytochrome P450-3A system will limit bedaquiline's utility and create complexity in treatment regimens. In clinical trials, treatment with bedaquiline added to a background multidrug-resistant TB regimen was associated with earlier culture conversion and higher cure rates, but there were unexplained excess deaths in the bedaquiline arms of these trials. Food and Drug Administration approved bedaquiline for the treatment of multidrug-resistant TB when an effective treatment regimen cannot otherwise be provided. They required a black box warning about excess deaths and require that a phase III trial be completed. A planned Phase

  7. Drug resistance of Mycobacterium tuberculosis isolates from tuberculosis lymphadenitis patients in Ethiopia

    Directory of Open Access Journals (Sweden)

    Fantahun Biadglegne

    2014-01-01

    Full Text Available Background & objectives: The emergence of drug resistance tuberculosis (TB is a significant challenge for TB control and prevention programmes, and the major problem is multidrug resistant tuberculosis (MDR-TB. The present study was carried out to determine the frequency of drug resistant Mycobacterium tuberculosis isolates among newly and retreated TB lymphadenitis patients and risk factors for acquiring this infection. Methods: Two hundred twenty five M. tuberculosis isolates from TB lymphadenitis patients who were diagnosed as new and retreated tuberculosis cases between April 2012 and May 2012 were included in this study. Isolates were tested for susceptibility to isoniazed (INH, rifampicin (RMP, streptomycin (SM, ethambutol (EMB and pyrazinamide (PZA using the BacT/AlerT 3D system protocol. Results: Among 225 isolates, 15 (6.7% were resistant to at least one first line anti-TB drug. Three (1.3% were MDR-TB. Resistance to INH, RMP, SM, and EMB was found in 8 (3.6%, 4 (1.8%, 10 (4.4%, and 4 (1.8% isolates, respectively. Of the 212 new TB lymphadenitis cases three (1.4% were MDR-TB. A rifampicin resistant M. tuberculosis isolate was diagnosed from smear and culture negative newly treated cases. All isolates were susceptible to PZA. Matted cervical lymph nodes were the prominent sites involved. Newly treated TB lymphadenitis patients had a greater risk for presenting resistance to anti-TB drugs ( p =0.046. Interpretation & conclusions: Our study showed that TB lymphadenitis patients harboured drug resistant TB and MDR-TB, although at a low rate. Resistance was not associated with age, sex, patients′ education and contact history. Further research is required to determine transmission dynamics of drug resistant strains.

  8. Leprosy Drug Resistance Surveillance in Colombia: The Experience of a Sentinel Country

    Science.gov (United States)

    Beltrán-Alzate, Camilo; López Díaz, Fernando; Romero-Montoya, Marcela; Sakamuri, Rama; Li, Wei; Kimura, Miyako; Brennan, Patrick

    2016-01-01

    An active search for Mycobacterium leprae drug resistance was carried out, 243 multibacillary patients from endemic regions of Colombia were included from 2004 to 2013 in a surveillance program. This program was a World Health Organization initiative for drug resistance surveillance in leprosy, where Colombia is a sentinel country. M. leprae DNA from slit skin smear and/or skin biopsy samples was amplified and sequenced to identify mutations in the drug resistance determining region (DRDR) in rpoB, folP1, gyrA, and gyrB, the genes responsible for rifampicin, dapsone and ofloxacin drug-resistance, respectively. Three isolates exhibited mutations in the DRDR rpoB gene (Asp441Tyr, Ser456Leu, Ser458Met), two in the DRDR folP1 gene (Thr53Ala, Pro55Leu), and one isolate exhibited mutations in both DRDR rpoB (Ser456Met) and DRDR folP1 (Pro55Leu), suggesting multidrug resistance. One isolate had a double mutation in folP1 (Thr53Ala and Thr88Pro). Also, we detected mutations outside of DRDR that required in vivo evaluation of their association or not with drug resistance: rpoB Arg505Trp, folP1 Asp91His, Arg94Trp, and Thr88Pro, and gyrA Ala107Leu. Seventy percent of M. leprae mutations were related to drug resistance and were isolated from relapsed patients; the likelihood of relapse was significantly associated with the presence of confirmed resistance mutations (OR range 20.1–88.7, p < 0.05). Five of these relapsed patients received dapsone monotherapy as a primary treatment. In summary, the current study calls attention to M. leprae resistance in Colombia, especially the significant association between confirmed resistance mutations and relapse in leprosy patients. A high frequency of DRDR mutations for rifampicin was seen in a region where dapsone monotherapy was used extensively. PMID:27706165

  9. Mechanisms of Evolution in High-Consequence Drug Resistance Plasmids

    Directory of Open Access Journals (Sweden)

    Susu He

    2016-12-01

    Full Text Available The dissemination of resistance among bacteria has been facilitated by the fact that resistance genes are usually located on a diverse and evolving set of transmissible plasmids. However, the mechanisms generating diversity and enabling adaptation within highly successful resistance plasmids have remained obscure, despite their profound clinical significance. To understand these mechanisms, we have performed a detailed analysis of the mobilome (the entire mobile genetic element content of a set of previously sequenced carbapenemase-producing Enterobacteriaceae (CPE from the National Institutes of Health Clinical Center. This analysis revealed that plasmid reorganizations occurring in the natural context of colonization of human hosts were overwhelmingly driven by genetic rearrangements carried out by replicative transposons working in concert with the process of homologous recombination. A more complete understanding of the molecular mechanisms and evolutionary forces driving rearrangements in resistance plasmids may lead to fundamentally new strategies to address the problem of antibiotic resistance.

  10. A Mathematical Model for HIV Drug-Resistance

    Science.gov (United States)

    Faedo, Ivan; Raimundo, Silvia Martorano; Venturino, Ezio

    2010-09-01

    In this paper we present a mathematical model of the transmission of HIV infection here the individuals receive antiretroviral drugs but may not respond to treatment. In such case the latter can be changed to a different therapy, and individuals may or may not respond also to this second set of drugs.

  11. Clinical and epidemiological profiles of individuals with drug-resistant tuberculosis

    Directory of Open Access Journals (Sweden)

    Heloisa da Silveira Paro Pedro

    2015-04-01

    Full Text Available Drug-resistant tuberculosis (TB is a growing global threat. Approximately 450,000 people developed multidrug-resistant TB worldwide in 2012 and an estimated 170,000 people died from the disease. This paper describes the sociodemographic, clinical-epidemiological and bacteriological aspects of TB and correlates these features with the distribution of anti-TB drug resistance. Mycobacterium tuberculosis (MT cultures and drug susceptibility testing were performed according to the BACTEC MGIT 960 method. The results demonstrated that MT strains from individuals who received treatment for TB and people who were infected with human immunodeficiency virus were more resistant to TB drugs compared to other individuals (p < 0.05. Approximately half of the individuals received supervised treatment, but most drug-resistant cases were positive for pulmonary TB and exhibited positive acid-fast bacilli smears, which are complicating factors for TB control programs. Primary healthcare is the ideal level for early disease detection, but tertiary healthcare is the most common entry point for patients into the system. These factors require special attention from healthcare managers and professionals to effectively control and monitor the spread of TB drug-resistant cases.

  12. Clinical and epidemiological profiles of individuals with drug-resistant tuberculosis

    Science.gov (United States)

    Pedro, Heloisa da Silveira Paro; Nardi, Susilene Maria Tonelli; Pereira, Maria Izabel Ferreira; Oliveira, Rosângela Siqueira; Suffys, Philip Noel; Gomes, Harrison Magdinier; Finardi, Amanda Juliane; de Moraes, Eloise Brasil; Baptista, Ida Maria Foschiani Dias; Machado, Ricardo Luiz Dantas; Castiglioni, Lilian

    2015-01-01

    Drug-resistant tuberculosis (TB) is a growing global threat. Approximately 450,000 people developed multidrug-resistant TB worldwide in 2012 and an estimated 170,000 people died from the disease. This paper describes the sociodemographic, clinical-epidemiological and bacteriological aspects of TB and correlates these features with the distribution of anti-TB drug resistance. Mycobacterium tuberculosis (MT) cultures and drug susceptibility testing were performed according to the BACTEC MGIT 960 method. The results demonstrated that MT strains from individuals who received treatment for TB and people who were infected with human immunodeficiency virus were more resistant to TB drugs compared to other individuals (p < 0.05). Approximately half of the individuals received supervised treatment, but most drug-resistant cases were positive for pulmonary TB and exhibited positive acid-fast bacilli smears, which are complicating factors for TB control programs. Primary healthcare is the ideal level for early disease detection, but tertiary healthcare is the most common entry point for patients into the system. These factors require special attention from healthcare managers and professionals to effectively control and monitor the spread of TB drug-resistant cases. PMID:25946248

  13. Quantitative predictions of binding free energy changes in drug-resistant influenza neuraminidase.

    Directory of Open Access Journals (Sweden)

    Daniel R Ripoll

    Full Text Available Quantitatively predicting changes in drug sensitivity associated with residue mutations is a major challenge in structural biology. By expanding the limits of free energy calculations, we successfully identified mutations in influenza neuraminidase (NA that confer drug resistance to two antiviral drugs, zanamivir and oseltamivir. We augmented molecular dynamics (MD with Hamiltonian Replica Exchange and calculated binding free energy changes for H274Y, N294S, and Y252H mutants. Based on experimental data, our calculations achieved high accuracy and precision compared with results from established computational methods. Analysis of 15 micros of aggregated MD trajectories provided insights into the molecular mechanisms underlying drug resistance that are at odds with current interpretations of the crystallographic data. Contrary to the notion that resistance is caused by mutant-induced changes in hydrophobicity of the binding pocket, our simulations showed that drug resistance mutations in NA led to subtle rearrangements in the protein structure and its dynamics that together alter the active-site electrostatic environment and modulate inhibitor binding. Importantly, different mutations confer resistance through different conformational changes, suggesting that a generalized mechanism for NA drug resistance is unlikely.

  14. Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma

    Science.gov (United States)

    Müller, Judith; Krijgsman, Oscar; Tsoi, Jennifer; Robert, Lidia; Hugo, Willy; Song, Chunying; Kong, Xiangju; Possik, Patricia A.; Cornelissen-Steijger, Paulien D.M.; Foppen, Marnix H. Geukes; Kemper, Kristel; Goding, Colin R.; McDermott, Ultan; Blank, Christian; Haanen, John; Graeber, Thomas G.; Ribas, Antoni; Lo, Roger S.; Peeper, Daniel S.

    2015-01-01

    Increased expression of the Microphthalmia-associated transcription factor (MITF) contributes to melanoma progression and resistance to BRAF pathway inhibition. Here we show that the lack of MITF is associated with more severe resistance to a range of inhibitors, while its presence is required for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. The dichotomous behaviour of MITF in drug response is corroborated in vemurafenib-resistant biopsies, including MITF-high and -low clones in a relapsed patient. Furthermore, drug cocktails containing AXL inhibitor enhance melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas. PMID:25502142

  15. A better resolution for integrating methods for monitoring Plasmodium falciparum resistance to antimalarial drugs.

    Science.gov (United States)

    Abdul-Ghani, Rashad; Al-Maktari, Mohamed T; Al-Shibani, Latifa A; Allam, Amal F

    2014-09-01

    Effective chemotherapy is the mainstay of malaria control. However, resistance of falciparum malaria to antimalarial drugs compromised the efforts to eliminate the disease and led to the resurgence of malaria epidemics. Three main approaches are used to monitor antimalarial drug efficacy and drug resistance; namely, in vivo trials, in vitro/ex vivo assays and molecular markers of drug resistance. Each approach has its implications of use as well as its advantages and drawbacks. Therefore, there is a need to use an integrated approach that would give the utmost effect to detect resistance as early as its emergence and to track it once spread. Such integration becomes increasingly needed in the era of artemisinin-based combination therapy as a forward action to deter resistance. The existence of regional and global networks for the standardization of methodology, provision of high quality reagents for the assessment of antimalarial drug resistance and dissemination of open-access data would help in approaching an integrated resistance surveillance system on a global scale.

  16. Antimicrobial drug resistance of Salmonella isolates from meat and humans, Denmark

    DEFF Research Database (Denmark)

    Skov, Marianne; Andersen, Jens Strodl; Aabo, Søren

    2007-01-01

    We compared 8,144 Salmonella isolates collected from meat imported to or produced in Denmark, as well as from Danish patients. Isolates from imported meat showed a higher rate of antimicrobial drug resistance, including multidrug resistance, than did isolates from domestic meat. Isolates from hum...... humans showed resistance rates lower than those found in imported meat but higher than in domestic meat. These findings indicate that programs for controlling resistant Salmonella spp. are a global issue.......We compared 8,144 Salmonella isolates collected from meat imported to or produced in Denmark, as well as from Danish patients. Isolates from imported meat showed a higher rate of antimicrobial drug resistance, including multidrug resistance, than did isolates from domestic meat. Isolates from...

  17. Antimicrobial drug resistance of Salmonella isolates from meat and humans, Denmark

    DEFF Research Database (Denmark)

    Skov, Marianne Nielsine; Andersen, Jens Strodl; Aabo, Søren

    2007-01-01

    We compared 8,144 Salmonella isolates collected from meat imported to or produced in Denmark, as well as from Danish patients. Isolates from imported meat showed a higher rate of antimicrobial drug resistance, including multidrug resistance, than did isolates from domestic meat. Isolates from hum...... humans showed resistance rates lower than those found in imported meat but higher than in domestic meat. These findings indicate that programs for controlling resistant Salmonella spp. are a global issue......We compared 8,144 Salmonella isolates collected from meat imported to or produced in Denmark, as well as from Danish patients. Isolates from imported meat showed a higher rate of antimicrobial drug resistance, including multidrug resistance, than did isolates from domestic meat. Isolates from...

  18. Protease Inhibitors Drug Resistance Mutations in Turkish Patients with Chronic Hepatitis C

    Directory of Open Access Journals (Sweden)

    Elif Sargin Altunok

    2016-09-01

    Conclusion: We are of the opinion that drug resistance analyses can be beneficial and necessary in revealing which variants are responsible for pre-treatment natural resistance and which mutations are responsible for the viral breakthrough that may develop during the treatment.

  19. Estimating prevalence of accumulated HIV-1 drug resistance in a cohort of patients on antiretroviral therapy

    DEFF Research Database (Denmark)

    Bannister, Wendy P; Cozzi-Lepri, Alessandro; Kjær, Jesper;

    2011-01-01

    Estimating the prevalence of accumulated HIV drug resistance in patients receiving antiretroviral therapy (ART) is difficult due to lack of resistance testing at all occasions of virological failure and in patients with undetectable viral load. A method to estimate this for 6498 EuroSIDA patients...

  20. Enzastaurin inhibits tumours sensitive and resistant to anti-EGFR drugs

    Science.gov (United States)

    Gelardi, T; Caputo, R; Damiano, V; Daniele, G; Pepe, S; Ciardiello, F; Lahn, M; Bianco, R; Tortora, G

    2008-01-01

    We investigated the antitumour effect and ability to overcome the resistance to anti-EGFR drugs of enzastaurin, an inhibitor of VEGFR-dependent PKCβ signalling. Enzastaurin was evaluated alone and in combination with the EGFR inhibitor gefitinib, on growth and signalling protein expression in human cancer cells sensitive and resistant to anti-EGFR drugs, both in vitro and in nude mice. We demonstrated the marked inhibitory activity of enzastaurin against GEO colon and PC3 prostate cancer cells and their gefitinib-resistant counterparts GEO-GR and PC3-GR, accompanied by inhibition of pAkt and its effector pp70S6K, pGSK3β and VEGF expression and secretion. Moreover, enzastaurin showed a cooperative effect with gefitinib in parental and in gefitinib-resistant cells. Remarkably, these results were confirmed in vivo, where enzastaurin showed antitumour activity and cooperativity with gefitinib in mice grafted with GEO and GEO-GR tumours, incrementing their median survival and inhibiting the aforesaid protein expression and secretion in tumour specimens. In conclusion, enzastaurin by interfering with signalling proteins implicated in EGFR drug resistance markedly cooperates with gefitinib in sensitive and gefitinib-resistant tumours, thus overcoming and reverting such resistance and providing a rational basis for its development in patients resistant to anti-EGFR drugs. PMID:18665191

  1. Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia

    DEFF Research Database (Denmark)

    Göllner, Stefanie; Oellerich, Thomas; Agrawal-Singh, Shuchi

    2017-01-01

    In acute myeloid leukemia (AML), therapy resistance frequently occurs, leading to high mortality among patients. However, the mechanisms that render leukemic cells drug resistant remain largely undefined. Here, we identified loss of the histone methyltransferase EZH2 and subsequent reduction of h...

  2. [From the discovery of antibiotics to emerging highly drug-resistant bacteria].

    Science.gov (United States)

    Meunier, Olivier

    2015-01-01

    The discovery of antibiotics has enabled serious infections to be treated. However, bacteria resistant to several families of antibiotics and the emergence of new highly drug-resistant bacteria constitute a public health issue in France and across the world. Actions to prevent their transmission are being put in place.

  3. Genomic insights into intrinsic and acquired drug resistance mechanisms in Achromobacter xylosoxidans.

    Science.gov (United States)

    Hu, Yongfei; Zhu, Yuying; Ma, Yanan; Liu, Fei; Lu, Na; Yang, Xi; Luan, Chunguang; Yi, Yong; Zhu, Baoli

    2015-02-01

    Achromobacter xylosoxidans is an opportunistic pathogen known to be resistant to a wide range of antibiotics; however, the knowledge about the drug resistance mechanisms is limited. We used a high-throughput sequencing approach to sequence the genomes of the A. xylosoxidans type strain ATCC 27061 and a clinical isolate, A. xylosoxidans X02736, and then we used different bioinformatics tools to analyze the drug resistance genes in these bacteria. We obtained the complete genome sequence for A. xylosoxidans ATCC 27061 and the draft sequence for X02736. We predicted a total of 50 drug resistance-associated genes in the type strain, including 5 genes for β-lactamases and 17 genes for efflux pump systems; these genes are also conserved among other A. xylosoxidans genomes. In the clinical isolate, except for the conserved resistance genes, we also identified several acquired resistance genes carried by a new transposon embedded in a novel integrative and conjugative element. Our study provides new insights into the intrinsic and acquired drug resistance mechanisms in A. xylosoxidans, which will be helpful for better understanding the physiology of A. xylosoxidans and the evolution of antibiotic resistance in this bacterium.

  4. Parallel selection of chemotherapy-resistant cell lines to illuminate mechanisms of drug resistance in human tumors

    DEFF Research Database (Denmark)

    Krzystanek, Marcin; Eklund, Aron Charles; Birkbak, Nicolai Juul

    2011-01-01

    Treatment of cancer often involves the use of chemotherapeutic agents that preferentially target tumor cells. The idea behind personalized medicine is to characterize differences between individual cancer cases that will and to direct the therapy to those most likely to respond. This will require....... Our findings are validated on already existing gene expression profiles of patient cohorts treated with the drugs in question, and the most promising ones will be chosen for functional validation by RNAi knock down. Successful validation will improve understanding of drug resistance mechanisms......, suggest future drug targets, and enable more efficacious treatment of cancer patients....

  5. Resistance to anticoccidial drugs : Alternative strategies to control coccidiosis in broilers

    NARCIS (Netherlands)

    Peek, H.W.

    2010-01-01

    Manuscripts documenting the occurrence of resistance against all commonly used anticoccidial drugs abroad, together with the high incidence of clinical coccidiosis in the field (60-90% of flocks) in the Netherlands, were the reasons to start investigations on the occurrence of anticoccidial drug res

  6. Antimicrobial Drug Resistance of Vibrio cholerae, Democratic Republic of the Congo.

    Science.gov (United States)

    Miwanda, Berthe; Moore, Sandra; Muyembe, Jean-Jacques; Nguefack-Tsague, Georges; Kabangwa, Ickel Kakongo; Ndjakani, Daniel Yassa; Mutreja, Ankur; Thomson, Nicholas; Thefenne, Helene; Garnotel, Eric; Tshapenda, Gaston; Kakongo, Denis Kandolo; Kalambayi, Guy; Piarroux, Renaud

    2015-05-01

    We analyzed 1,093 Vibrio cholerae isolates from the Democratic Republic of the Congo during 1997-2012 and found increasing antimicrobial drug resistance over time. Our study also demonstrated that the 2011-2012 epidemic was caused by an El Tor variant clonal complex with a single antimicrobial drug susceptibility profile.

  7. Prophylactic activity of mefloquine hydrochloride (WR 142 490) in drug-resistant malaria*

    Science.gov (United States)

    Rieckmann, K. H.; Trenholme, G. M.; Williams, R. L.; Carson, P. E.; Frischer, H.; Desjardins, R. E.

    1974-01-01

    In preliminary studies with mefloquine (WR 142 490) a single dose exerted prolonged suppressive activity against a drug-resistant strain of Plasmodium falciparum. Development of patent parasitaemia was prevented when nonimmune persons were exposed to infected mosquitos 2 weeks after medication, and it was delayed when exposure occurred 3 weeks after drug administration. PMID:4619059

  8. Fluoroquinolones, the cornerstone of treatment of drug-resistant tuberculosis: a pharmacokinetic and pharmacodynamic approach.

    NARCIS (Netherlands)

    Pranger, A.D.; Alffenaar, J.W.C.; Aarnoutse, R.E.

    2011-01-01

    Fluoroquinolones (FQs) are important drugs to treat drug-resistant tuberculosis. In this review we integrated pharmacokinetic properties (PK) and microbiological susceptibility against M. tuberculosis and eventually evaluated the pharmcodynamic (PD) properties, as well as the influence of co-adminis

  9. Imperfect drug penetration leads to spatial monotherapy and rapid evolution of multidrug resistance

    NARCIS (Netherlands)

    Moreno-Gamez, Stefany; Hill, Alison L.; Rosenbloom, Daniel I. S.; Petrov, Dmitri A.; Nowak, Martin A.; Pennings, Pleuni S.

    2015-01-01

    Infections with rapidly evolving pathogens are often treated using combinations of drugs with different mechanisms of action. One of the major goal of combination therapy is to reduce the risk of drug resistance emerging during a patient's treatment. Although this strategy generally has significant

  10. Fluoroquinolones, the Cornerstone of Treatment of Drug-Resistant Tuberculosis : A Pharmacokinetic and Pharmacodynamic Approach

    NARCIS (Netherlands)

    Pranger, A. D.; Alffenaar, J. W. C.; Aarnoutse, R. E.

    2011-01-01

    Fluoroquinolones (FQs) are important drugs to treat drug-resistant tuberculosis. In this review we integrated pharmacokinetic properties (PK) and microbiological susceptibility against M. tuberculosis and eventually evaluated the pharmcodynamic (PD) properties, as well as the influence of co-adminis

  11. Beauvericin counteracted multi-drug resistant Candida albicans by blocking ABC transporters

    DEFF Research Database (Denmark)

    Tong, Yaojun; Liu, Mei; Zhang, Yu

    2016-01-01

    screening and whole-cell based mechanism study, identified a natural product, beauvericin (BEA) as a drug efflux pump modulator, which can reverse the multi-drug resistant phenotype of Candida albicans by specifically blocking the ATP-binding cassette (ABC) transporters; meantime, BEA alone has fungicidal...

  12. A Short-Term Evaluation of Project DARE (Drug Abuse Resistance Education): Preliminary Indications of Effectiveness.

    Science.gov (United States)

    DeJong, William

    1987-01-01

    Assessed impact of Project DARE (Drug Abuse Resistance Education) on knowledge, attitudes, and self-reported behavior of seventh graders who received DARE curriculum in sixth grade. Compared to controls, DARE students reported significantly lower use of alcohol, cigarettes, and other drugs. Findings were especially strong for boys. (Author/NB)

  13. Signaling to P-glycoprotein-A new therapeutic target to treat drug-resistant epilepsy?

    NARCIS (Netherlands)

    Hartz, A.M.; Notenboom, S.; Bauer, B.

    2009-01-01

    Epilepsy affects more than 60 million people worldwide. While most patients can be treated with antiepileptic drugs, up to 40% of patients respond poorly to pharmacotherapy. This drug resistance is not well understood and presents a major clinical problem. In this short review we provide background

  14. Sequence and gene expression of chloroquine resistance transporter (pfcrt in the association of in vitro drugs resistance of Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Bray Patrick G

    2011-02-01

    Full Text Available Abstract Background Plasmodium falciparum chloroquine resistance (CQR transporter protein (PfCRT is known to be the important key of CQR. Recent studies have definitively demonstrated a link between mutations in the gene pfcrt and resistance to chloroquine in P. falciparum. Although these mutations are predictive of chloroquine resistance, they are not quantitatively predictive of the degree of resistance. Methods In this study, a total of 95 recently adapted P. falciparum isolates from Thailand were included in the analysis. Parasites were characterized for their drug susceptibility phenotypes and genotypes with respect to pfcrt. From the original 95 isolates, 20 were selected for complete pfcrt sequence analysis. Results Almost all of the parasites characterized carried the previously reported mutations K76T, A220S, Q271E, N326S, I356T and R371I. On complete sequencing, isolates were identified with novel mutations at K76A and E198K. There was a suggestion that parasites carrying E198K were less resistant than those that did not. In addition, pfcrt and pfmdr1 gene expression were investigated by real-time PCR. No relationship between the expression level of either of these genes and response to drug was observed. Conclusion Data from the present study suggest that other genes must contribute to the degree of resistance once the resistance phenotype is established through mutations in pfcrt.

  15. Rapid detection of drug resistance and mutational patterns of extensively drug-resistant strains by a novel GenoType® MTBDRsl assay

    Directory of Open Access Journals (Sweden)

    A K Singh

    2013-01-01

    Full Text Available Background: The emergence of extensively drug-resistant tuberculosis (XDR-TB is a major concern in the India. The burden of XDR-TB is increasing due to inadequate monitoring, lack of proper diagnosis, and treatment. The GenoType ® Mycobacterium tuberculosis drug resistance second line (MTBDRsl assay is a novel line probe assay used for the rapid detection of mutational patterns conferring resistance to XDR-TB. Aim: The aim of this study was to study the rapid detection of drug resistance and mutational patterns of the XDR-TB by a novel GenoType ® MTBDRsl assay. Materials and Methods: We evaluated 98 multidrug-resistant (MDR M. tuberculosis isolates for second line drugs susceptibility testing by 1% proportion method (BacT/ALERT 3D system and GenoType ® MTBDRsl assay for rapid detection of conferring drug resistance to XDR-TB. Results: A total of seven (17.4% were identified as XDR-TB by using standard phenotypic method. The concordance between phenotypic and GenoType ® MTBDRsl assay was 91.7-100% for different antibiotics. The sensitivity and specificity of the MTBDRsl assay were 100% and 100% for aminoglycosides; 100% and 100% for fluoroquinolones; 91.7% and 100% for ethambutol. The most frequent mutations and patterns were gyrA MUT1 (A90V in seven (41.2% and gyrA + WT1-3 + MUT1 in four (23.5%; rrs MUT1 (A1401G in 11 (64.7%, and rrs WT1-2 + MUT1 in eight (47.1%; and embB MUT1B (M306V in 11 (64.7% strains. Conclusions: These data suggest that the GenoType ® MTBDRsl assay is rapid, novel test for detection of resistance to second line anti-tubercular drugs. This assay provides additional information about the frequency and mutational patterns responsible for XDR-TB resistance.

  16. Glutamate-gated chloride channels of Haemonchus contortus restore drug sensitivity to ivermectin resistant Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Susan K Glendinning

    Full Text Available Anthelmintic resistance is a major problem in livestock farming, especially of small ruminants, but our understanding of it has been limited by the difficulty in carrying out functional genetic studies on parasitic nematodes. An important nematode infecting sheep and goats is Haemonchus contortus; in many parts of the world this species is resistant to almost all the currently available drugs, including ivermectin. It is extremely polymorphic and to date it has proved impossible to relate any sequence polymorphisms to its ivermectin resistance status. Expression of candidate drug-resistance genes in Caenorhabditis elegans could provide a convenient means to study the effects of polymorphisms found in resistant parasites, but may be complicated by differences between the gene families of target and model organisms. We tested this using the glutamate-gated chloride channel (GluCl gene family, which forms the ivermectin drug target and are candidate resistance genes. We expressed GluCl subunits from C. elegans and H. contortus in a highly resistant triple mutant C. elegans strain (DA1316 under the control of the avr-14 promoter; expression of GFP behind this promoter recapitulated the pattern previously reported for avr-14. Expression of ivermectin-sensitive subunits from both species restored drug sensitivity to transgenic worms, though some quantitative differences were noted between lines. Expression of an ivermectin-insensitive subunit, Hco-GLC-2, had no effect on drug sensitivity. Expression of a previously uncharacterised parasite-specific subunit, Hco-GLC-6, caused the transgenic worms to become ivermectin sensitive, suggesting that this subunit also encodes a GluCl that responds to the drug. These results demonstrate that both orthologous and paralogous subunits from C. elegans and H. contortus are able to rescue the ivermectin sensitivity of mutant C. elegans, though some quantitative differences were observed between transgenic lines in

  17. Glutamate-gated chloride channels of Haemonchus contortus restore drug sensitivity to ivermectin resistant Caenorhabditis elegans.

    Science.gov (United States)

    Glendinning, Susan K; Buckingham, Steven D; Sattelle, David B; Wonnacott, Susan; Wolstenholme, Adrian J

    2011-01-01

    Anthelmintic resistance is a major problem in livestock farming, especially of small ruminants, but our understanding of it has been limited by the difficulty in carrying out functional genetic studies on parasitic nematodes. An important nematode infecting sheep and goats is Haemonchus contortus; in many parts of the world this species is resistant to almost all the currently available drugs, including ivermectin. It is extremely polymorphic and to date it has proved impossible to relate any sequence polymorphisms to its ivermectin resistance status. Expression of candidate drug-resistance genes in Caenorhabditis elegans could provide a convenient means to study the effects of polymorphisms found in resistant parasites, but may be complicated by differences between the gene families of target and model organisms. We tested this using the glutamate-gated chloride channel (GluCl) gene family, which forms the ivermectin drug target and are candidate resistance genes. We expressed GluCl subunits from C. elegans and H. contortus in a highly resistant triple mutant C. elegans strain (DA1316) under the control of the avr-14 promoter; expression of GFP behind this promoter recapitulated the pattern previously reported for avr-14. Expression of ivermectin-sensitive subunits from both species restored drug sensitivity to transgenic worms, though some quantitative differences were noted between lines. Expression of an ivermectin-insensitive subunit, Hco-GLC-2, had no effect on drug sensitivity. Expression of a previously uncharacterised parasite-specific subunit, Hco-GLC-6, caused the transgenic worms to become ivermectin sensitive, suggesting that this subunit also encodes a GluCl that responds to the drug. These results demonstrate that both orthologous and paralogous subunits from C. elegans and H. contortus are able to rescue the ivermectin sensitivity of mutant C. elegans, though some quantitative differences were observed between transgenic lines in some assays. C

  18. MULTI DRUG RESISTANT ACINETOBACTER BAUMANNII: A SYSTEMATIC REVIEW FOR MICROBIAL AND CLINICAL STUDY

    OpenAIRE

    Buddha Bahadur Basnet; Til Bahadur Basnet; Bishnu Joshi; Rajan Kumar Dahal; Rajani Malla

    2013-01-01

    Infections due to Mutli Drug Resistant A. baumannii (MDRAB) is now recognized as a major public health problem worldwide. The nosocomial infection due to MDRAB has leaded to increased in morbidity and mortality which has added noticeably to significant challenge to modern antibiotic therapy system. This is due to rapid phenomenon of A. baumannii to acquire antibiotic resistance. Thus, in this review the overview of current knowledge on epidemiology, infections, mechanism of resistance and eff...

  19. EMERGENCE OF MULTI DRUG RESISTANT STRAINS OF E. COLI ISOLATED FROM URINARY TRACT INFECTION IN NAMAKKAL

    OpenAIRE

    2012-01-01

    In this study we evaluated the multi drug resistant strains of Escherichia coli isolated from urinary tract infection in different age groups in Namakkal. Totally 153 isolates of E.coli were obtained from 700 urine samples. Present study indicates that there is a high prevalence of multidrug resistant E. coli in female 24.34% followed by male 18.14%. After confirmation, isolates were performed to resistance patterns of different antibiotics were determined by standard disk diffusion method. T...

  20. High prevalence of drug-resistance mutations in Plasmodium falciparum and Plasmodium vivax in southern Ethiopia

    OpenAIRE

    Schunk, Mirjam; Kumma, Wondimagegn P.; Barreto Miranda, Isabel; Maha E. Osman; Roewer, Susanne; Alano, Abraham; Loescher, Thomas; Bienzle, Ulrich; Mockenhaupt, Frank P

    2006-01-01

    Background: In Ethiopia, malaria is caused by both Plasmodium falciparum and Plasmodium vivax. Drug resistance of P. falciparum to sulfadoxine-pyrimethamine (SP) and chloroquine (CQ) is frequent and intense in some areas. Methods: In 100 patients with uncomplicated malaria from Dilla, southern Ethiopia, P. falciparum dhfr and dhps mutations as well as P. vivax dhfr polymorphisms associated with resistance to SP and P. falciparum pfcrt and pfmdr1 mutations conferring CQ resistance were assesse...

  1. MRP- and BCL-2-mediated drug resistance in human SCLC: effects of apoptotic sphingolipids in vitro.

    Science.gov (United States)

    Khodadadian, M; Leroux, M E; Auzenne, E; Ghosh, S C; Farquhar, D; Evans, R; Spohn, W; Zou, Y; Klostergaard, J

    2009-10-01

    Multidrug-resistance-associated protein (MRP) and BCL-2 contribute to drug resistance expressed in SCLC. To establish whether MRP-mediated drug resistance affects sphingolipid (SL)-induced apoptosis in SCLC, we first examined the human SCLC cell line, UMCC-1, and its MRP over-expressing, drug-resistant subline, UMCC-1/VP. Despite significantly decreased sensitivity to doxorubicin (Dox) and to the etoposide, VP-16, the drug-selected line was essentially equally as sensitive to treatment with exogenous ceramide (Cer), sphingosine (Sp) or dimethyl-sphingosine (DMSP) as the parental line. Next, we observed that high BCL-2-expressing human H69 SCLC cells, that were approximately 160-fold more sensitive to Dox than their combined BCL-2 and MRP-over-expressing (H69AR) counterparts, were only approximately 5-fold more resistant to DMSP. Time-lapse fluorescence microscopy of either UMCC cell line treated with DMSP-Coumarin revealed comparable extents and kinetics of SL uptake, further ruling out MRP-mediated effects on drug uptake. DMSP potentiated the cytotoxic activity of VP-16 and Taxol, but not Dox, in drug-resistant UMCC-1/VP cells. However, this sensitization did not appear to involve DMSP-mediated effects on the function of MRP in drug export; nor did DMSP strongly shift the balance of pro-apoptotic Sps and anti-apoptotic Sp-1-Ps in these cells. We conclude that SL-induced apoptosis markedly overcomes or bypasses MRP-mediated drug resistance relevant to SCLC and may suggest a novel therapeutic approach to chemotherapy for these tumors.

  2. Drug-resistant tuberculosis among HIV-infected patients starting antiretroviral therapy in Durban, South Africa.

    Directory of Open Access Journals (Sweden)

    Jeffrey K Hom

    Full Text Available OBJECTIVE: To estimate the prevalence of drug-resistant tuberculosis (TB and describe the resistance patterns in patients commencing antiretroviral therapy (ART in an HIV clinic in Durban, South Africa. DESIGN: Cross-sectional cohort study. METHODS: Consecutive HIV-infected adults (≥ 18y/o initiating HIV care were enrolled from May 2007-May 2008, regardless of signs or symptoms of active TB. Prior TB history and current TB treatment status were self-reported. Subjects expectorated sputum for culture (MGIT liquid and 7H11 solid medium. Positive cultures were tested for susceptibility to first- and second-line anti-tuberculous drugs. The prevalence of drug-resistant TB, stratified by prior TB history and current TB treatment status, was assessed. RESULTS: 1,035 subjects had complete culture results. Median CD4 count was 92/µl (IQR 42-150/µl. 267 subjects (26% reported a prior history of TB and 210 (20% were receiving TB treatment at enrollment; 191 (18% subjects had positive sputum cultures, among whom the estimated prevalence of resistance to any antituberculous drug was 7.4% (95% CI 4.0-12.4. Among those with prior TB, the prevalence of resistance was 15.4% (95% CI 5.9-30.5 compared to 5.2% (95% CI 2.1-8.9 among those with no prior TB. 5.1% (95% CI 2.4-9.5 had rifampin or rifampin plus INH resistance. CONCLUSIONS: The prevalence of TB resistance to at least one drug was 7.4% among adults with positive TB cultures initiating ART in Durban, South Africa, with 5.1% having rifampin or rifampin plus INH resistance. Improved tools for diagnosing TB and drug resistance are urgently needed in areas of high HIV/TB prevalence.

  3. [Benefits of spironolactone as the optimal treatment for drug resistant hypertension. Pathway-2 trial review].

    Science.gov (United States)

    Prado, J C; Ruilope, L M; Segura, J

    Pathway-2 is the first randomised, double-blind and crossover trial that compares spironolactone as a fourth drug with alfa-blocker, beta-blocker and placebo. This study shows that spironolactone is the drug with more possibilities of success for the management of patients with difficult-to-treat hypertension in patients with a combination of three drugs and poor control. The results validate the widespread treatment with mineralocorticoid receptor antagonists in resistant hypertension.

  4. Recent highlights in anti-protozoan drug development and resistance research

    OpenAIRE

    Buckner, Frederick S.; Waters, Norman C; Avery, Vicky M.

    2012-01-01

    This article summarizes the highlights of research presented in January, 2012, at the Keystone Symposium on “Drug Discovery for Protozoan Parasites” held in Santa Fe, New Mexico. This symposium which convenes approximately every 2 years provides a forum for leading investigators around the world to present data covering basic sciences to clinical trials relating to anti-protozoan drug development and drug resistance. Many talks focused on malaria, but other protozoan diseases receiving attent...

  5. Antiretroviral drug resistance in HIV-1 therapy-naive patients in Cuba.

    Science.gov (United States)

    Pérez, Lissette; Kourí, Vivian; Alemán, Yoan; Abrahantes, Yeisel; Correa, Consuelo; Aragonés, Carlos; Martínez, Orlando; Pérez, Jorge; Fonseca, Carlos; Campos, Jorge; Álvarez, Delmis; Schrooten, Yoeri; Dekeersmaeker, Nathalie; Imbrechts, Stijn; Beheydt, Gertjan; Vinken, Lore; Soto, Yudira; Álvarez, Alina; Vandamme, Anne-Mieke; Van Laethem, Kristel

    2013-06-01

    In Cuba, antiretroviral therapy rollout started in 2001 and antiretroviral therapy coverage has reached almost 40% since then. The objectives of this study were therefore to analyze subtype distribution, and level and patterns of drug resistance in therapy-naive HIV-1 patients. Four hundred and one plasma samples were collected from HIV-1 therapy-naive patients in 2003 and in 2007-2011. HIV-1 drug resistance genotyping was performed in the pol gene and drug resistance was interpreted according to the WHO surveillance drug-resistance mutations list, version 2009. Potential impact on first-line therapy response was estimated using genotypic drug resistance interpretation systems HIVdb version 6.2.0 and Rega version 8.0.2. Phylogenetic analysis was performed using Neighbor-Joining. The majority of patients were male (84.5%), men who have sex with men (78.1%) and from Havana City (73.6%). Subtype B was the most prevalent subtype (39.3%), followed by CRF20-23-24_BG (19.5%), CRF19_cpx (18.0%) and CRF18_cpx (10.3%). Overall, 29 patients (7.2%) had evidence of drug resistance, with 4.0% (CI 1.6%-4.8%) in 2003 versus 12.5% (CI 7.2%-14.5%) in 2007-2011. A significant increase in drug resistance was observed in recently HIV-1 diagnosed patients, i.e. 14.8% (CI 8.0%-17.0%) in 2007-2011 versus 3.8% (CI 0.9%-4.7%) in 2003 (OR 3.9, CI 1.5-17.0, p=0.02). The majority of drug resistance was restricted to a single drug class (75.8%), with 55.2% patients displaying nucleoside reverse transcriptase inhibitor (NRTI), 10.3% non-NRTI (NNRTI) and 10.3% protease inhibitor (PI) resistance mutations. Respectively, 20.7% and 3.4% patients carried viruses containing drug resistance mutations against NRTI+NNRTI and NRTI+NNRTI+PI. The first cases of resistance towards other drug classes than NRTI were only detected from 2008 onwards. The most frequent resistance mutations were T215Y/rev (44.8%), M41L (31.0%), M184V (17.2%) and K103N (13.8%). The median genotypic susceptibility score for the

  6. First findings on the seroepidemiology of human paragonimosis at the anti-tuberculosis centre of Divo, Republic of Ivory Coast (West Africa

    Directory of Open Access Journals (Sweden)

    Aka N.A.

    2008-06-01

    Full Text Available An epidemiological study was carried out in 2004-2005 at the anti-tuberculosis centre of Divo (Ivory Coast to collect sera from patients who consulted for tuberculosis suspicion and to estimate the seroprevalence of human paragonimosis in the context of a systematic screening. No Paragonimus egg was found in the stools and/or sputa of the 167 persons investigated. In contrast, 41 sera were ascertained with antibodies against Paragonimus africanus using ELISA testing. As the optical density (OD values related to seropositive findings were found under 0.6 (the minimal OD to detect an active paragonimosis, the above antibody titres might originate from patients in chronic or in convalescent stages, or might result of cross reactions with trematodes. Concomitantly, dissection of local crabs (Callinectes marginatus demonstrated the presence of Paragonimus metacercariae in six out of 34 examined. The parasite burdens in crabs ranged from two to 35 cysts with a mean diameter of 302 μm. In Ivory Coast, the locality of Divo must be considered an at-risk zone in reason of the presence of anti-Paragonimus antibodies in several human sera and the presence of infected crabs at the local market.

  7. Differentiation and the multiple drug resistance phenotype in human leukemic cells.

    Science.gov (United States)

    Beck, W T; Cirtain, M C; Ashmun, R A; Mirro, J

    1986-09-01

    A common feature of mammalian cell lines selected for multiple drug resistance is the overexpression of a high-molecular-weight surface membrane glycoprotein(s). While its amount has been shown to be related to the degree of resistance of such cells, its function in this phenomenon remains obscure. Because there are some biochemical and functional similarities between drug-resistant cells and differentiated cells, we asked if resistance-associated glycoproteins were also associated with cellular differentiation. Using three monoclonal antibodies against antigens known to be associated with differentiation and three monoclonal antibodies that distinguish our multiple drug-resistant human leukemic CEM/VLB100 cells from their drug-sensitive counterparts, we found that the resistant cells were neither altered in their apparent state of differentiation nor were they altered in their ability to respond to a differentiation stimulus with the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate. We did find, however, that one antibody that recognizes the resistance-associated glycoprotein, Mr 180,000 glycoprotein (gp180), was only minimally altered in amount bound after treatment with the phorbol ester, but two other resistance-associated glycoproteins, Mr 155,000 glycoprotein (gp155) and, to a lesser extent, Mr 130,000 glycoprotein (gp130), were reduced in expression after this treatment. We suggest that the function of the previously described "marker" glycoprotein associated with multiple drug resistance remains unknown, but that the expression of two other resistance-associated glycoproteins also appears to be related to cellular differentiation or maturation in these cells.

  8. Hyperparasitaemia and low dosing are an important source of anti-malarial drug resistance

    Directory of Open Access Journals (Sweden)

    Lee Sue J

    2009-11-01

    Full Text Available Abstract Background Preventing the emergence of anti-malarial drug resistance is critical for the success of current malaria elimination efforts. Prevention strategies have focused predominantly on qualitative factors, such as choice of drugs, use of combinations and deployment of multiple first-line treatments. The importance of anti-malarial treatment dosing has been underappreciated. Treatment recommendations are often for the lowest doses that produce "satisfactory" results. Methods The probability of de-novo resistant malaria parasites surviving and transmitting depends on the relationship between their degree of resistance and the blood concentration profiles of the anti-malarial drug to which they are exposed. The conditions required for the in-vivo selection of de-novo emergent resistant malaria parasites were examined and relative probabilities assessed. Results Recrudescence is essential for the transmission of de-novo resistance. For rapidly eliminated anti-malarials high-grade resistance can arise from a single drug exposure, but low-grade resistance can arise only from repeated inadequate treatments. Resistance to artemisinins is, therefore, unlikely to emerge with single drug exposures. Hyperparasitaemic patients are an important source of de-novo anti-malarial drug resistance. Their parasite populations are larger, their control of the infection insufficient, and their rates of recrudescence following anti-malarial treatment are high. As use of substandard drugs, poor adherence, unusual pharmacokinetics, and inadequate immune responses are host characteristics, likely to pertain to each recurrence of infection, a small subgroup of patients provides the particular circumstances conducive to de-novo resistance selection and transmission. Conclusion Current dosing recommendations provide a resistance selection opportunity in those patients with low drug levels and high parasite burdens (often children or pregnant women. Patients with

  9. Stability Analysis of an HIV/AIDS Dynamics Model with Drug Resistance

    Directory of Open Access Journals (Sweden)

    Qianqian Li

    2012-01-01

    Full Text Available A mathematical model of HIV/AIDS transmission incorporating treatment and drug resistance was built in this study. We firstly calculated the threshold value of the basic reproductive number (R0 by the next generation matrix and then analyzed stability of two equilibriums by constructing Lyapunov function. When R0<1, the system was globally asymptotically stable and converged to the disease-free equilibrium. Otherwise, the system had a unique endemic equilibrium which was also globally asymptotically stable. While an antiretroviral drug tried to reduce the infection rate and prolong the patients’ survival, drug resistance was neutralizing the effects of treatment in fact.

  10. Differential expression of putative drug resistance genes in Mycobacterium tuberculosis clinical isolates.

    Science.gov (United States)

    González-Escalante, Laura; Peñuelas-Urquides, Katia; Said-Fernández, Salvador; Silva-Ramírez, Beatriz; Bermúdez de León, Mario

    2015-12-01

    Understanding drug resistance in Mycobacterium tuberculosis requires an integrated analysis of strain lineages, mutations and gene expression. Previously, we reported the differential expression of esxG, esxH, infA, groES, rpmI, rpsA and lipF genes in a sensitive M. tuberculosis strain and in a multidrug-resistant clinical isolate. Here, we have evaluated the expression of these genes in 24 clinical isolates that belong to different lineages and have different drug resistance profiles. In vitro, growth kinetics analysis showed no difference in the growth of the clinical isolates, and thus drug resistance occurred without a fitness cost. However, a quantitative reverse transcription PCR analysis of gene expression revealed high variability among the clinical isolates, including those with similar drug resistance profiles. Due to the complexity of gene regulation pathways and the wide diversity of M. tuberculosis lineages, the use of gene expression as a molecular signature for drug resistance is not straightforward. Therefore, we recommend that the expression of M. tuberculosis genes be performed individually, and baseline expression levels should be verified among several different clinical isolates, before any further applications of these findings.

  11. HIV-1 drug resistance among untreated patients in India: Current status

    Directory of Open Access Journals (Sweden)

    Pachamuthu Balakrishnan

    2006-01-01

    Full Text Available HAART has dramatically improved survival and quality of life among people living with HIV and AIDS globally. However, drug resistant mutations of HIV are a great challenge to the benefits of HAART. Antiviral resistance can be mediated either by changes in the molecular target of therapy (the primary mechanism observed in HIV-1 or in other viral proteins that indirectly interfere with a drug′s activity. Drug resistant mutations easily evolve in the presence of sub-optimal adherence. With the introduction of generic HAART, there has been a steep increase in the number of patients put on HAART in India. It should also be noted that since most patients pay for medications out of their own pockets, interruptions in therapy due to monetary constraints are not uncommon. There is little information on HIV drug resistance in resource constrained settings like India where the predominant circulating HIV-1 sub-type is C. The transmissibility of drug-resistant forms of the virus is also a major concern especially when formulating treatment guidelines. This article reviews published data available on the patterns of HIV-1 drug resistance among treatment naοve in India.

  12. Pathogen distribution and drug resistance of nephrology patients with urinary tract infections

    Directory of Open Access Journals (Sweden)

    Yunqian Wang

    2016-05-01

    Full Text Available Objective: Pathogen distribution characteristics of nephrology patients with urinary tract infections are studied, and drug resistance of nephrology and urinary tract infection disease are analyzed, so as to provide sufficient evidence for treatment of patients. Methods: Conduct randomized control study of 3500 cases of nephrology patients with urinary tract infections treated in different hospitals from December 2013 to December 2015, isolate pathogens in patients’ urine samples, perform identification and drug sensitive test and then conduct detailed analysis of drug resistance of pathogens. Results: Through isolation of pathogens, it can be found that all pathogens include Escherichia coli, Gram-positive cocci, gram-negative bacteria, fungi, Acinetobacter baumannii, Enterococcus faecalis, and urinary Enterococcus. Among them, proportion of E. coli is the largest. Patients have relatively high drug resistance to ceftriaxone, gentamicin, ciprofloxacin and cotrimoxazole. Conclusion: For nephrology patients with urinary tract infection, the main pathogen is E. coli, which has had some drug resistance. Drug resistance detection of pathogen should be strengthened in clinics, so as to provide strong guidance for clinical treatment and promote effective treatment of patients.

  13. New approaches to overcome transport related drug resistance in trypanosomatid parasites

    Directory of Open Access Journals (Sweden)

    Jose A Garcia-Salcedo

    2016-09-01

    Full Text Available Leishmania and Trypanosoma are members of the Trypanosomatidae family that cause severe human infections such as leishmaniasis, Chagas disease, and sleeping sickness affecting millions of people worldwide. Despite efforts to eradicate them, migrations are expanding these infections to developing countries. There are no vaccines available and current treatments depend only on chemotherapy. Drug resistance is a major obstacle for the treatment of these diseases given that existing drugs are old and limited, with some having severe side effects. Most resistance mechanisms developed by these parasites are related with a decreased uptake or increased efflux of the drug due to mutations or altered expression of membrane transporters. Different new approaches have been elaborated that can overcome these mechanisms of resistance including the use of inhibitors of efflux pumps and drug carriers for both active and passive targeting. Here we review new formulations that have been successfully applied to circumvent resistance related to drug transporters, opening alternative ways to solve drug resistance in protozoan parasitic diseases.

  14. New Approaches to Overcome Transport Related Drug Resistance in Trypanosomatid Parasites

    Science.gov (United States)

    Garcia-Salcedo, Jose A.; Unciti-Broceta, Juan D.; Valverde-Pozo, Javier; Soriano, Miguel

    2016-01-01

    Leishmania and Trypanosoma are members of the Trypanosomatidae family that cause severe human infections such as leishmaniasis, Chagas disease, and sleeping sickness affecting millions of people worldwide. Despite efforts to eradicate them, migrations are expanding these infections to developing countries. There are no vaccines available and current treatments depend only on chemotherapy. Drug resistance is a major obstacle for the treatment of these diseases given that existing drugs are old and limited, with some having severe side effects. Most resistance mechanisms developed by these parasites are related with a decreased uptake or increased efflux of the drug due to mutations or altered expression of membrane transporters. Different new approaches have been elaborated that can overcome these mechanisms of resistance including the use of inhibitors of efflux pumps and drug carriers for both active and passive targeting. Here we review new formulations that have been successfully applied to circumvent resistance related to drug transporters, opening alternative ways to solve drug resistance in protozoan parasitic diseases. PMID:27733833

  15. Acinetobacter baumannii: biology and drug resistance - role of carbapenemases.

    Science.gov (United States)

    Nowak, Pawel; Paluchowska, Paulina

    2016-01-01

    Acinetobacter baumannii is a Gram-negative, glucose-non-fermenting, oxidase-negative coccobacillus, most commonly associated with the hospital settings. The ability to survive in adverse environmental conditions as well as high level of natural and acquired antimicrobial resistance make A. baumannii one of the most important nosocomial pathogens. While carbapenems have long been considered as antimicrobials of last-resort, the rates of clinical A. baumannii strains resistant to these antibiotics are increasing worldwide. Carbapenem resistance among A. baumannii is conferred by coexisting mechanisms including: decrease in permeability of the outer membrane, efflux pumps, production of beta-lactamases, and modification of penicillin-binding proteins. The most prevalent mechanism of carbapenem resistance among A. baumannii is associated with carbapenem-hydro-lysing enzymes that belong to Ambler class D and B beta-lactamases. In addition, there have also been reports of resistance mediated by selected Ambler class A carbapenemases among A. baumannii strains. Resistance determinants in A. baumannii are located on chromosome and plasmids, while acquisition of new mechanisms can be mediated by insertion sequences, integrons, transposons, and plasmids. Clinical relevance of carbapen-em resistance among strains isolated from infected patients, carriers and hospital environment underlines the need for carbapenemase screening. Currently available methods vary in principle, accuracy and efficiency. The techniques that deserve particular attention belong to both easily accessible unsophisticated methods as well as advanced techniques based on mass spectrometry or molecular biology. While carbapenemases limit the therapeutic options in A. baumannii infections, studies concerning novel beta-lactamase inhibitors offer a new insight into effective therapy.

  16. In vitro Development of Chemotherapy and Targeted Therapy Drug-Resistant Cancer Cell Lines: A Practical Guide with Case Studies.

    Science.gov (United States)

    McDermott, Martina; Eustace, Alex J; Busschots, Steven; Breen, Laura; Crown, John; Clynes, Martin; O'Donovan, Norma; Stordal, Britta

    2014-01-01

    The development of a drug-resistant cell line can take from 3 to 18 months. However, little is published on the methodology of this development process. This article will discuss key decisions to be made prior to starting resistant cell line development; the choice of parent cell line, dose of selecting agent, treatment interval, and optimizing the dose of drug for the parent cell line. Clinically relevant drug-resistant cell lines are developed by mimicking the conditions cancer patients experience during chemotherapy and cell lines display between two- and eight-fold resistance compared to their parental cell line. Doses of drug administered are low, and a pulsed treatment strategy is often used where the cells recover in drug-free media. High-level laboratory models are developed with the aim of understanding potential mechanisms of resistance to chemotherapy agents. Doses of drug are higher and escalated over time. It is common to have difficulty developing stable clinically relevant drug-resistant cell lines. A comparative selection strategy of multiple cell lines or multiple chemotherapeutic agents mitigates this risk and gives insight into which agents or type of cell line develops resistance easily. Successful selection strategies from our research are presented. Pulsed-selection produced platinum or taxane-resistant large cell lung cancer (H1299 and H460) and temozolomide-resistant melanoma (Malme-3M and HT144) cell lines. Continuous selection produced a lapatinib-resistant breast cancer cell line (HCC1954). Techniques for maintaining drug-resistant cell lines are outlined including; maintaining cells with chemotherapy, pulse treating with chemotherapy, or returning to master drug-resistant stocks. The heterogeneity of drug-resistant models produced from the same parent cell line with the same chemotherapy agent is explored with reference to P-glycoprotein. Heterogeneity in drug-resistant cell lines reflects the heterogeneity that can occur in clinical

  17. In vitro development of chemotherapy and targeted therapy drug-resistant cancer cell lines: A practical guide with case studies

    Directory of Open Access Journals (Sweden)

    Martina eMcDermott

    2014-03-01

    Full Text Available The development of a drug-resistant cell line can take from 3-18 months. However, little is published on the methodology of this development process. This article will discuss key decisions to be made prior to starting resistant cell line development; the choice of parent cell line, dose of selecting agent, treatment interval and optimising the dose of drug for the parent cell line. Clinically-relevant drug-resistant cell lines are developed by mimicking the conditions cancer patients experience during chemotherapy and cell lines display between 2-8 fold resistance compared to their parental cell line. Doses of drug administered are low, and a pulsed treatment strategy is often used where the cells recover in drug-free media. High-level laboratory models are developed with the aim of understanding potential mechanisms of resistance to chemotherapy agents. Doses of drug are higher and escalated over time. It is common to have difficulty developing stable clinically-relevant drug-resistant cell lines. A comparative selection strategy of multiple cell lines or multiple chemotherapeutic agents mitigates this risk and gives insight into which agents or type of cell line develops resistance easily. Successful selection strategies from our research are presented. Pulsed-selection produced platinum or taxane-resistant large cell lung cancer (H1299, H460 and temozolomide-resistant melanoma (Malme-3M and HT144 cell lines. Continuous selection produced lapatinib-resistant breast cancer cell line (HCC1954. Techniques for maintaining drug-resistant cell lines are outlined including; maintaining cells with chemotherapy, pulse treating with chemotherapy or returning to master drug-resistant stocks. The heterogeneity of drug-resistant models produced from the same parent cell line with the same chemotherapy agent is explored with reference to P-glycoprotein. Heterogeneity in drug-resistant cell lines reflects the heterogeneity that can occur in clinical drug

  18. Targeting oncoprotein stability overcomes drug resistance caused by FLT3 kinase domain mutations.

    Directory of Open Access Journals (Sweden)

    Chuanjiang Yu

    Full Text Available FLT3 is the most frequently mutated kinase in acute myeloid leukemia (AML. Internal tandem duplications (ITDs in the juxta-membrane region constitute the majority of activating FLT3 mutations. Several FLT3 kinase inhibitors were developed and tested in the clinic with significant success. However, recent studies have reported the development of secondary drug resistance in patients treated with FLT3 inhibitors. Since FLT3-ITD is an HSP90 client kinase, we here explored if targeting the stability of drug-resistant FLT3 mutant protein could be a potential therapeutic option. We observed that HSP90 inhibitor treatment resulted in the degradation of inhibitor-resistant FLT3-ITD mutants and selectively induced toxicity in cells expressing FLT3-ITD mutants. Thus, HSP90 inhibitors provide a potential therapeutic choice to overcome secondary drug resistance following TKI treatment in FLT3-ITD positive AML.

  19. Scabies: molecular perspectives and therapeutic implications in the face of emerging drug resistance.

    Science.gov (United States)

    Mounsey, Kate E; Holt, Deborah C; McCarthy, James; Currie, Bart J; Walton, Shelley F

    2008-02-01

    Limited effective treatments, coupled with recent observations of emerging drug resistance to oral ivermectin and 5% permethrin, raise concerns regarding the future control of scabies, especially in severe cases and in endemic areas where repeated community treatment programs are in place. There is consequently an urgent need to define molecular mechanisms of drug resistance in scabies mites and to develop and assess alternative therapeutic options, such as tea tree oil, in the event of increasing treatment failure. Molecular studies on scabies mites have, until recently, been restricted; however, recent advances are providing new insights into scabies mite biology and genetic mechanisms underlying drug resistance. These may assist in overcoming many of the current difficulties in monitoring treatment efficacy and allow the development of more sensitive tools for monitoring emerging resistance.

  20. Monitoring and Analysis on Multi Drug Resistance of Escherichia coli from Captive Population Amur Tiger

    Institute of Scientific and Technical Information of China (English)

    Xue; Yuan; Li; Fengyong; Sun; Jing; Cai; Longhui; Wu; Qingming; Zhou; Ming; Huang; Xianguang; Hua; Yuping

    2014-01-01

    In order to investigate the multi drug resistance to Escherichia coli from captive population Amur tiger,E. coli strains were isolated from the fecal samples of tiger in Heilongjiang Amur Tiger Park in Harbin. The sensitivity of E. coli isolates to 14 antibiotics was determined by scrip diffusion method. The results indicated that all the isolates varied in drug resistance to different antibiotics; the isolates gave high resistance to ampicillin,with a drug fast rate of 100%; over80% of the isolates were resistant to tetracycline and Paediatric Compound Sulfamethoxazole Tablets(SMZ- TMP),and over 70% of the isolates were sensitive to aztreonam,amoxicillin /potassium clavulanate. Most of the isolates had high sensitive to aztreonam and amoxicillin / clavulanate acid.

  1. Assessment of clinical risk factors for drug-resistant epilepsy in children and teenagers

    Directory of Open Access Journals (Sweden)

    Marta Kasprzyk

    2014-09-01

    Full Text Available Introduction: Epilepsy is one of the most common neurological illnesses occurring in children. In approximately 20–30% of cases it is drug-resistant. Aim of the research: To assess the already-known risk factors, analyse the rarely described ones, and find new causes of epilepsy drug resistance in children, taking into account the level of impact of each factor. Material and methods : The study comprised 152 of all 383 children hospitalised in 2012 at the Neurology Department of the Polish Mother’s Memorial Hospital in Lodz due to epilepsy. Based on medical documentation, neurological examination, and our own questionnaire, we divided patients into two groups: drug-resistant epilepsy or drug-sensitive epilepsy. We compared the type, level of influence, and prevalence of different factors. For statistical analysis, the 2 test was used. Statistical significance was set at p < 0.05. Results: Drug-resistant epilepsy was found in 64 patients (42.1%, and drug-sensitive epilepsy was found in 88 patients (57.9%. Factors that were most probable to cause drug resistance included: high prevalence of seizures (Cramer’s V = 0.66, type of epileptic syndrome (V = 0.62, psychomotor developmental delay (V = 0.62, and occurrence of status epilepticus (V = 0.6. Factors such as infections of CNS in early childhood, repeated severe infections of airways in childhood, and mother’s infectious diseases with high fever during pregnancy were rare or non occurring (Cramer’s V = 0.41, 0.32, and 0.31, respectively. Conclusions : The study confirmed the previously known causes of drug resistance and indicated the significance of underestimated inflammatory and infectious factors involving pyrexia, in children and also in mothers during pregnancy.

  2. In vivo selection of resistant E. coli after ingestion of milk with added drug residues.

    Directory of Open Access Journals (Sweden)

    Richard Van Vleck Pereira

    Full Text Available Antimicrobial resistance represents a major global threat to modern medicine. In vitro studies have shown that very low concentrations of drugs, as frequently identified in the environment, and in foods and water for human and animal consumption, can select for resistant bacteria. However, limited information is currently available on the in vivo impact of ingested drug residues. The objective of our study was to evaluate the effect of feeding preweaned calves milk containing antimicrobial drug residues (below the minimum inhibitory concentration, similar to concentrations detected in milk commonly fed to dairy calves, on selection of resistant fecal E. coli in calves from birth to weaning. At birth, thirty calves were randomly assigned to a controlled feeding trial where: 15 calves were fed raw milk with no drug residues (NR, and 15 calves were fed raw milk with drug residues (DR by adding ceftiofur, penicillin, ampicillin, and oxytetracycline at final concentrations in the milk of 0.1, 0.005, 0.01, and 0.3 µg/ml, respectively. Fecal samples were rectally collected from each calf once a week starting at birth prior to the first feeding in the trial (pre-treatment until 6 weeks of age. A significantly greater proportion of E. coli resistant to ampicillin, cefoxitin, ceftiofur, streptomycin and tetracycline was observed in DR calves when compared to NR calves. Additionally, isolates from DR calves had a significant decrease in susceptibility to ceftriaxone and ceftiofur when compared to isolates from NR calves. A greater proportion of E. coli isolates from calves in the DR group were resistant to 3 or more antimicrobial drugs when compared to calves in the ND group. These findings highlight the role that low concentrations of antimicrobial drugs have on the evolution and selection of resistance to multiple antimicrobial drugs in vivo.

  3. Co-occurrence of antibiotic drugs, resistant bacteria and resistance genes in runoff from cattle feedlots

    Science.gov (United States)

    Agricultural uses of antibiotics raises concerns about the development of antibiotic resistance in food animals, and the potential to transmit resistance to human clinical settings via fecal contamination of surface and ground water. Although there is broad agreement that agricultural resistance can...

  4. 两性霉素B联合抗结核药物治疗结核性脑膜炎合并隐球菌性脑膜炎的疗效观察%Efficacy Observation of Amphoterincin B Combined with Anti-tuberculosis Agents for Tuberculous Meningifts Complicating with Cryptococcal Neoformans Meningitis

    Institute of Scientific and Technical Information of China (English)

    银春莲; 黄欣欣

    2011-01-01

    combined with anti-tuberculosis agents for tuberculous meningitis complicating with cryptococcal neoformans meningitis could effectively lower the protein of cerebrospinal fluid. Adverse drug reaction was small and low.

  5. Host candidate gene polymorphisms and clearance of drug-resistant Plasmodium falciparum parasites

    Directory of Open Access Journals (Sweden)

    Rockett Kirk

    2011-08-01

    Full Text Available Abstract Background Resistance to anti-malarial drugs is a widespread problem for control programmes for this devastating disease. Molecular tests are available for many anti-malarial drugs and are useful tools for the surveillance of drug resistance. However, the correlation of treatment outcome and molecular tests with particular parasite markers is not perfect, due in part to individuals who are able to clear genotypically drug-resistant parasites. This study aimed to identify molecular markers in the human genome that correlate with the clearance of malaria parasites after drug treatment, despite the drug resistance profile of the protozoan as predicted by molecular approaches. Methods 3721 samples from five African countries, which were known to contain genotypically drug resistant parasites, were analysed. These parasites were collected from patients who subsequently failed to clear their infection following drug treatment, as expected, but also from patients who successfully cleared their infections with drug-resistant parasites. 67 human polymorphisms (SNPs on 17 chromosomes were analysed using Sequenom's mass spectrometry iPLEX gold platform, to identify regions of the human genome, which contribute to enhanced clearance of drug resistant parasites. Results An analysis of all data from the five countries revealed significant associations between the phenotype of ability to clear drug-resistant Plasmodium falciparum infection and human immune response loci common to all populations. Overall, three SNPs showed a significant association with clearance of drug-resistant parasites with odds ratios of 0.76 for SNP rs2706384 (95% CI 0.71-0.92, P = 0.005, 0.66 for SNP rs1805015 (95% CI 0.45-0.97, P = 0.03, and 0.67 for SNP rs1128127 (95% CI 0.45-0.99, P = 0.05, after adjustment for possible confounding factors. The first two SNPs (rs2706384 and rs1805015 are within loci involved in pro-inflammatory (interferon-gamma and anti-inflammatory (IL-4

  6. Molecular detection of fluoroquinolone-resistance in multi-drug resistant tuberculosis in Cambodia suggests low association with XDR phenotypes

    Directory of Open Access Journals (Sweden)

    Murray Alan

    2011-09-01

    Full Text Available Abstract Background Drug susceptibility testing (DST remains an important concern for implementing treatment of MDR tuberculosis patients. Implementation of molecular tests for drug resistance identification would facilitate DST particularly in developing countries where culturing is difficult to perform. We have characterized multidrug resistant strains in Cambodia using MDTDRsl tests, drug target sequencing and phenotypic tests. Methods A total of 65 non-MDR and 101 MDR TB isolates collected between May 2007 and June 2009 were tested for resistance to fluoroquinolones and aminoglycosides/cyclic peptides using the GenoType® MTBDRsl assay and gene sequencing. Rifampicin resistance (RMP-R was tested using gene sequencing and genotyping was assessed by spoligotyping. Results A total of 95 of the 101 MDR strains were confirmed to be RMP-R by rpoB gene sequencing. Fourteen of the 101 MDR isolates (14% carried a gyrA mutation associated with fluoroquinolone-resistance (FQ-R (detected by the MTBDRsl assay and sequencing compared with only 1 (1.5% of the 65 non-MDR strains. Only 1 (1% of the MDR isolates was found to be XDR TB. The MDR group contained a higher proportion of Beijing or Beijing like strains (58% than the non MDR group (28%. This percentage is higher in MDR FQ-R strains (71%. Conclusions The new GenoType® MTBDRsl assay combined with molecular tests to detect RMP-R and isoniazid resistance (INH-R represents a valuable tool for the detection of XDR TB. In Cambodia there is a low rate of XDR amongst MDR TB including MDR FQ-R TB. This suggests a low association between FQ-R and XDR TB. Strain spoligotyping confirms Beijing strains to be more prone to accumulate antibiotic resistance.

  7. Assessment of three Resistance-Nodulation-Cell Division drug efflux transporters of Burkholderia cenocepacia in intrinsic antibiotic resistance

    Directory of Open Access Journals (Sweden)

    Venturi Vittorio

    2009-09-01

    Full Text Available Abstract Background Burkholderia cenocepacia are opportunistic Gram-negative bacteria that can cause chronic pulmonary infections in patients with cystic fibrosis. These bacteria demonstrate a high-level of intrinsic antibiotic resistance to most clinically useful antibiotics complicating treatment. We previously identified 14 genes encoding putative Resistance-Nodulation-Cell Division (RND efflux pumps in the genome of B. cenocepacia J2315, but the contribution of these pumps to the intrinsic drug resistance of this bacterium remains unclear. Results To investigate the contribution of efflux pumps to intrinsic drug resistance of B. cenocepacia J2315, we deleted 3 operons encoding the putative RND transporters RND-1, RND-3, and RND-4 containing the genes BCAS0591-BCAS0593, BCAL1674-BCAL1676, and BCAL2822-BCAL2820. Each deletion included the genes encoding the RND transporter itself and those encoding predicted periplasmic proteins and outer membrane pores. In addition, the deletion of rnd-3 also included BCAL1672, encoding a putative TetR regulator. The B. cenocepacia rnd-3 and rnd-4 mutants demonstrated increased sensitivity to inhibitory compounds, suggesting an involvement of these proteins in drug resistance. Moreover, the rnd-3 and rnd-4 mutants demonstrated reduced accumulation of N-acyl homoserine lactones in the growth medium. In contrast, deletion of the rnd-1 operon had no detectable phenotypes under the conditions assayed. Conclusion Two of the three inactivated RND efflux pumps in B. cenocepacia J2315 contribute to the high level of intrinsic resistance of this strain to some antibiotics and other inhibitory compounds. Furthermore, these efflux systems also mediate accumulation in the growth medium of quorum sensing molecules that have been shown to contribute to infection. A systematic study of RND efflux systems in B. cenocepacia is required to provide a full picture of intrinsic antibiotic resistance in this opportunistic

  8. A differential drug screen for compounds that select against antibiotic resistance.

    Directory of Open Access Journals (Sweden)

    Remy Chait

    Full Text Available Antibiotics increase the frequency of resistant bacteria by providing them a competitive advantage over sensitive strains. Here, we develop a versatile assay for differential chemical inhibition of competing microbial strains, and use it to identify compounds that preferentially inhibit tetracycline-resistant relative to sensitive bacteria, thus "inverting" selection for resistance. Our assay distinguishes compounds selecting directly against specific resistance mechanisms and compounds whose selection against resistance is based on their physiological interaction with tetracycline and is more general with respect to resistance mechanism. A pilot screen indicates that both types of selection-inverting compounds are secreted by soil microbes, suggesting that nature has evolved a repertoire of chemicals that counteracts antibiotic resistance. Finally, we show that our assay can more generally permit simple, direct screening for drugs based on their differential activity against different strains or targets.

  9. Multidrug and extensively drug-resistant tuberculosis management: Evidences and controversies

    Directory of Open Access Journals (Sweden)

    R Prasad

    2012-01-01

    Full Text Available Multi-drug and extensively drug resistant tuberculosis (M/XDR-TB has been an area of growing concern among clinicians, epidemiologists, and public health workers worldwide. Lack of controlled trials in M/XDR-TB patients hinders the optimal management of such patients, and guidelines that have been developed based largely on expert opinion are controversial. Lack of new effective drugs, improper regimens prescribed by poorly trained doctors and unreliable drug susceptibility testing add to the magnitude of the problem. M/XDR-TB is mostly a man made problem and its emergence can be checked by prompt diagnosis and effective use of first-line drugs in every new patient. DOTS-Plus proposed by World Health Organization (WHO has highlighted the comprehensive management strategy to control multi-drug resistant tuberculosis (MDR-TB. Laboratory services must be strengthened for adequate and timely diagnosis of M/extensively drug resistant tuberculosis (XDR-TB and programmatic management of M/XDR-TB must be scaled up as per target set by global plan to stop TB 2011-2015. In MDR-TB patients with localized disease, surgery, as an adjunct to chemotherapy, can improve outcomes and should be considered when there is poor response to appropriate chemotherapy. Proper use of second-line drugs must be ensured to cure existing MDR-TB, to reduce its transmission and to prevent emergence of XDR-TB.

  10. Parallel screening of wild-type and drug-resistant targets for anti-resistance neuraminidase inhibitors.

    Directory of Open Access Journals (Sweden)

    Kai-Cheng Hsu

    Full Text Available Infection with influenza virus is a major public health problem, causing serious illness and death each year. Emergence of drug-resistant influenza virus strains limits the effectiveness of drug treatment. Importantly, a dual H275Y/I223R mutation detected in the pandemic influenza A 2009 virus strain results in multidrug resistance to current neuraminidase (NA drugs. Therefore, discovery of new agents for treating multiple drug-resistant (MDR influenza virus infections is important. Here, we propose a parallel screening strategy that simultaneously screens wild-type (WT and MDR NAs, and identifies inhibitors matching the subsite characteristics of both NA-binding sites. These may maintain their potency when drug-resistant mutations arise. Initially, we analyzed the subsite of the dual H275Y/I223R NA mutant. Analysis of the site-moiety maps of NA protein structures show that the mutant subsite has a relatively small volume and is highly polar compared with the WT subsite. Moreover, the mutant subsite has a high preference for forming hydrogen-bonding interactions with polar moieties. These changes may drive multidrug resistance. Using this strategy, we identified a new inhibitor, Remazol Brilliant Blue R (RB19, an anthraquinone dye, which inhibited WT NA and MDR NA with IC(50 values of 3.4 and 4.5 µM, respectively. RB19 comprises a rigid core scaffold and a flexible chain with a large polar moiety. The former interacts with highly conserved residues, decreasing the probability of resistance. The latter forms van der Waals contacts with the WT subsite and yields hydrogen bonds with the mutant subsite by switching the orientation of its flexible side chain. Both scaffolds of RB19 are good starting points for lead optimization. The results reveal a parallel screening strategy for identifying resistance mechanisms and discovering anti-resistance neuraminidase inhibitors. We believe that this strategy may be applied to other diseases with high

  11. Pharmacokinetics of Isoniazid, Pyrazinamide, and Ethambutol in Newly Diagnosed Pulmonary TB Patients in Tanzania

    DEFF Research Database (Denmark)

    Denti, Paolo; Kidola, Jeremiah; Chigutsa, Emmanuel;

    2015-01-01

    Exposure to lower-than-therapeutic levels of anti-tuberculosis drugs is likely to cause selection of resistant strains of Mycobacterium tuberculosis and treatment failure. The first-line anti-tuberculosis (TB) regimen consists of rifampicin, isoniazid, pyrazinamide, and ethambutol, and correct ma...

  12. The calculated genetic barrier for antiretroviral drug resistance substitutions is largely similar for different HIV-1 subtypes

    NARCIS (Netherlands)

    Vijver, D.A. van de; Wensing, A.M.J.; Angarano, G.; Asjo, B.; Balotta, C.; Camacho, R.; Chaix, M.; Costagliola, D.; De Luca, A.; Derdelinckx, I.; Grossman, Z.; Hamouda, O.; Hatzakis, A.; Hemmer, R.; Hoepelman, A.I.M.; Horban, A.; Korn, K.; Kücherer, C.; Leitner, T.; Loveday, C.; MacRae, E.; Maljkovic, I.; Mendoza, C. de; Meyer, L.; Nielsen, C.; Op de Coul, E.L.M.; Omaasen, V.; Paraskevis, D.; Perrin, L.; Puchhammer-Stöckl, E.; Salminen, M.; Schmit, J.; Scheider, F.; Schuurman, R.; Soriano, V.; Stanczak, G.; Stanojevic, M.; Vandamme, A.; Laethem, K. van; Violin, M.; Wilde, K.; Yerly, S.; Zazzi, M.; Boucher, C.A.B.

    2006-01-01

    The genetic barrier, defined as the number of mutations required to overcome drug-selective pressure, is an important factor for the development of HIV drug resistance. Because of high variability between subtypes, particular HIV-1 subtypes could have different genetic barriers for drug resistance s

  13. Quadruple-first line drug resistance in Mycobacterium tuberculosis in Vietnam: What can we learn from genes?

    Science.gov (United States)

    Nguyen, Huy Quang; Nguyen, Nhung Viet; Contamin, Lucie; Tran, Thanh Hoa Thi; Vu, Thuong Thi; Nguyen, Hung Van; Nguyen, Ngoc Lan Thi; Nguyen, Son Thai; Dang, Anh Duc; Bañuls, Anne-Laure; Nguyen, Van Anh Thi

    2017-02-21

    In Vietnam, a country with high tuberculosis (137/100.000 population) and multidrug-resistant (MDR)-TB burdens (7.8/100.000 population), little is known about the molecular signatures of drug resistance in general and more particularly of second line drug (SLD) resistance. This study is specifically focused on Mycobacterium tuberculosis isolates resistant to four first-line drugs (FLDs) that make TB much more difficult to treat. The aim is to determine the proportion of SLD resistance in these quadruple drug resistant isolates and the genetic determinants linked to drug resistance to better understand the genetic processes leading to quadruple and extremely drug resistance (XDR). 91 quadruple (rifampicin, isoniazid, ethambutol and streptomycin) FLD resistant and 55 susceptible isolates were included. Spoligotyping and 24-locus MIRU-VNTR techniques were performed and 9 genes and promoters linked to FLD and SLD resistance were sequenced. SLD susceptibility testing was carried out on a subsample of isolates. High proportion of quadruple-FLD resistant isolates was resistant to fluoroquinolones (27%) and second-line injectable drugs (30.2%) by drug susceptibility testing. The sequencing revealed high mutation diversity with prevailing mutations at positions katG315, inhA-15, rpoB531, embB306, rrs1401, rpsL43 and gyrA94. The sensitivity and specificity were high for most drug resistances (>86%), but the sensitivity was lower for injectable drug resistances (<69%). The mutation patterns revealed 23.1% of pre-XDR and 7.7% of XDR isolates, mostly belonging to Beijing family. The genotypic diversity and the variety of mutations reflect the existence of various evolutionary paths leading to FLD and SLD resistance. Nevertheless, particular mutation patterns linked to high-level resistance and low fitness costs seem to be favored.

  14. 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 resista...

  15. Resistance mechanisms and drug susceptibility testing of nontuberculous mycobacteria.

    NARCIS (Netherlands)

    Ingen, J. van; Boeree, M.J.; Soolingen, D. van; Mouton, J.W.

    2012-01-01

    Nontuberculous mycobacteria (NTM) are increasingly recognized as causative agents of opportunistic infections in humans. For most NTM infections the therapy of choice is drug treatment, but treatment regimens differ by species, in particular between slow (e.g. Mycobacterium avium complex, Mycobacter

  16. Sensitivity of a ribavirin resistant mutant of hepatitis C virus to other antiviral drugs.

    Directory of Open Access Journals (Sweden)

    Kathleen B Mihalik

    Full Text Available BACKGROUND: While ribavirin mono-therapy regimens have minimal effect on patients with chronic hepatitis C virus (HCV infections, they can be efficacious when combined with interferon. Clinical studies show that interferon-free combination therapies containing ribavirin are also efficacious, suggesting that an interferon-free therapy could be adopted in the near future. However, generation of drug resistant mutants and cross resistance to other drugs could impair the efficacy of the treatment. Therefore, understanding the mechanism of HCV resistance to ribavirin and cross resistance to other antiviral drugs could be of major importance. METHODS: We tested the ability of a J6/JFH1 derived HCV ribavirin resistant mutant to grow in tissue cultured Huh7D cells in the presence of the mutagen 5-Fluorouracil and the nucleoside analog 2'-C-Methylcytidine. Virus replication was assessed by detecting HCV antigens by immunofluorescence and by titrating virus present in the supernatants. Recovered viruses were amplified by RT-PCR and sequenced. RESULTS: The sensitivity of HCV-RR relative to parental J6/JFH1 to the tested drugs varied. HCV-RR was more resistant than J6/JFH1 to 5-Fluorouracil but was not more resistant than J6/JFH1 to 2'-C-Methylcytidine. Growth of HCV-RR in 5-Fluorouracil allowed the selection of an HCV-RR derived mutant resistant to 5-Fluorouracil (HCV-5FU. HCV-5FU grows to moderate levels in the presence of high concentrations of 5-Fluorouracil and to parental levels in the absence of the drug. Sequence of its genome shows that HCV-5FU accumulated multiple synonymous and non-synonymous mutations. CONCLUSIONS: These results indicate that determinants of resistance to ribavirin could also confer resistance to other anti-HCV drugs, shedding light toward understanding the mechanism of action of ribavirin and highlighting the importance of combination drug selection for HCV treatment. The results also show that it is possible to select a 5

  17. Combined Use of Delamanid and Bedaquiline to Treat Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis: A Systematic Review

    Science.gov (United States)

    Migliori, Giovanni Battista; Pontali, Emanuele; Sotgiu, Giovanni; Centis, Rosella; D’Ambrosio, Lia; Tiberi, Simon; Tadolini, Marina; Esposito, Susanna

    2017-01-01

    The new drugs delamanid and bedaquiline are increasingly being used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB). The World Health Organization, based on lack of evidence, recommends their use under specific conditions and not in combination. No systematic review has yet evaluated the efficacy, safety, and tolerability of delamanid and bedaquiline used in combination. A search of peer-reviewed, scientific evidence was carried out, aimed at evaluating the efficacy/effectiveness, safety, and tolerability of delamanid and bedaquiline-containing regimens in individuals with pulmonary/extrapulmonary disease, which were bacteriologically confirmed as M/XDR-TB. We used PubMed to identify any relevant manuscripts in English up to the 23 December 2016, excluding editorials and reviews. Three out of 75 manuscripts retrieved satisfied the inclusion criteria, whilst 72 were excluded for dealing with only one drug (three studies), being recommendations (one study) or identifying need for their use (one study), focusing on drug resistance aspects (six studies) or being generic reviews/other studies (61 papers). The studies retrieved reported two XDR-TB cases observed for six months and achieving consistent sputum smear and culture conversion. Case 2 experienced a short break of bedaquiline, which was re-started after introducing verapamil. After a transient and symptom-free increase of the QT interval from week 5 to 17, it then decreased below the 500 ms threshold. PMID:28178199

  18. Targeted therapeutic nanotubes influence the viscoelasticity of cancer cells to overcome drug resistance.

    Science.gov (United States)

    Bhirde, Ashwinkumar A; Chikkaveeraiah, Bhaskara V; Srivatsan, Avinash; Niu, Gang; Jin, Albert J; Kapoor, Ankur; Wang, Zhe; Patel, Sachin; Patel, Vyomesh; Gorbach, Alexander M; Leapman, Richard D; Gutkind, J Silvio; Hight Walker, Angela R; Chen, Xiaoyuan

    2014-05-27

    Resistance to chemotherapy is the primary cause of treatment failure in over 90% of cancer patients in the clinic. Research in nanotechnology-based therapeutic alternatives has helped provide innovative and promising strategies to overcome multidrug resistance (MDR). By targeting CD44-overexpressing MDR cancer cells, we have developed in a single-step a self-assembled, self-targetable, therapeutic semiconducting single-walled carbon nanotube (sSWCNT) drug delivery system that can deliver chemotherapeutic agents to both drug-sensitive OVCAR8 and resistant OVCAR8/ADR cancer cells. The novel nanoformula with a cholanic acid-derivatized hyaluronic acid (CAHA) biopolymer wrapped around a sSWCNT and loaded with doxorubicin (DOX), CAHA-sSWCNT-DOX, is much more effective in killing drug-resistant cancer cells compared to the free DOX and phospholipid PEG (PL-PEG)-modified sSWCNT formula, PEG-sSWCNT-DOX. The CAHA-sSWCNT-DOX affects the viscoelastic property more than free DOX and PL-PEG-sSWCNT-DOX, which in turn allows more drug molecules to be internalized. Intravenous injection of CAHA-sSWCNT-DOX (12 mg/kg DOX equivalent) followed by 808 nm laser irradiation (1 W/cm(2), 90 s) led to complete tumor eradication in a subcutaneous OVCAR8/ADR drug-resistant xenograft model, while free DOX alone failed to delay tumor growth. Our newly developed CAHA-sSWCNT-DOX nanoformula, which delivers therapeutics and acts as a sensitizer to influence drug uptake and induce apoptosis with minimal resistance factor, provides a novel effective means of counteracting the phenomenon of multidrug resistance.

  19. Toxoplasma gondii: susceptibility and development of resistance to anticoccidial drugs in vitro.

    Science.gov (United States)

    Ricketts, A P; Pfefferkorn, E R

    1993-01-01

    Anticoccidial drugs were evaluated for activity and for the development of resistance in a model of Toxoplasma gondii growing in human fibroblast cultures. Of 13 anticoccidial drugs tested, 9 had selective antitoxoplasma activity (50% inhibitory concentration, in micrograms per milliliter): decoquinate (0.005), arprinocid-N-oxide (0.015), robenidine (0.03), the aryl triazine CP-25,415 (0.2), toltrazuril (0.4), clopidol (1), dinitolmide (Zoalene; Dow) (10), and the carboxylic acid ionophores monensin (0.001) and salinomycin (0.04). Glycarbylamide, amprolium, nicarbazin, and the 6-(p-bromophenoxy)-7-chloro analog of halofuginone (Stenorol; Roussel-UCLAF) (CP-63,567) were toxic for the fibroblasts. Since Eimeria tenella has a similar drug susceptibility profile, anticoccidial durgs can be viewed as a potential source of new antitoxoplasma therapies. The development of resistance has limited the usefulness of most of these drugs as anticoccidial agents; in coccidia, resistance to all except the ionophores occurs readily in vivo. We explored the development of resistance in T. gondii by attempting to select mutants in vitro from parasites mutagenized with ethylnitrosourea. Mutants that had 20- to 50-fold-reduced susceptibility to decoquinate, arprinocid-N-oxide, and CP-25,415 were obtained. Ionophore-resistant T. gondii mutants were also selected in vitro; however, there was only a twofold difference in susceptibility between these mutants and the wild type. For three drugs (clopidol, robenidine, and toltrazuril), we were unable to select resistant mutants. For experimental anticoccidial drugs, there is currently no in vitro method for assessing the risk of development of resistance in Eimeria species. Our results suggest that T. gondii may offer a useful surrogate for this assessment. PMID:8285619

  20. Clinical study of distribution and drug resistance of pathogens in patients with severe acute pancreatitis

    Institute of Scientific and Technical Information of China (English)

    SU Mao-sheng; LIN Mao-hu; ZHAO Qing-hua; LIU Zhi-wei; HE Lei; JIA Ning

    2012-01-01

    Background Previous researches about necrotic pancreatic tissue infections are numerous,but the study on systemic infection related to the severe acute pancreatitis (SAP) treatment period is limited.This study aimed to investigate the distribution and drug resistance of pathogenic bacteria in patients who had hepatobiliary surgery for SAP during the past three years.Methods A retrospective study was conducted on the distribution,category and drug resistance of pathogenic bacteria in patients who had hepatobiliary surgery for SAP from 2008 to 2011.Results A total of 594 pathogenic bacteria samples were isolated.Among them 418 isolates (70.4%) were Gram bacteria negative,142 isolates (23.9%) were Gram bacteria positive,and 34 isolates (5.7%) were found fungi.The most common Gram negative bacteria were Escherichia coli (19.8%),and the dominant Gram positive pathogenic bacteria were Enterococcus faecium.The distribution of SAP-related infectious pathogens was mainly in peritoneal drainage fluid,sputum,bile,and wound secretions.Almost all the Gram negative pathogenic bacteria were sensitive to carbapenum.Extended-spectrum β-lactamases (ESBLs) producing strains were more resistant to penicillins and cephalosprins than the ESBLs non-producing strains.Staphylococcus was sensitive to vancomycin and linezolid.The drug resistance of meticillin-resistant staphylococcus (MRS) to commonly used antibiotics was higher than meticillin-sensitive streptococcus (MSS).Enterococcus sp.exhibited lower drug-resistance rates to vancomycin and linezolid.Conclusions Gram negative bacteria were the dominant SAP-related infection after hepatobiliary surgery.A high number of fungal infections were reported.Drug resistant rates were high.Rational use of antibiotics according to the site of infection,bacterial species and drug sensitivity,correctly executing the course of treatment and enhancing hand washing will contribute to therapy and prevention of SAP-related infection and decrease

  1. Evolution of primary HIV drug resistance in a subtype C dominated epidemic in Mozambique.

    Directory of Open Access Journals (Sweden)

    Dulce Celina Adolfo Bila

    Full Text Available OBJECTIVE: In Mozambique, highly active antiretroviral treatment (HAART was introduced in 2004 followed by decentralization and expansion, resulting in a more than 20-fold increase in coverage by 2009. Implementation of HIV drug resistance threshold surveys (HIVDR-TS is crucial in order to monitor the emergence of transmitted viral resistance, and to produce evidence-based recommendations to support antiretroviral (ARV policy in Mozambique. METHODS: World Health Organization (WHO methodology was used to evaluate transmitted drug resistance (TDR in newly diagnosed HIV-1 infected pregnant women attending ante-natal clinics in Maputo and Beira to non-nucleoside reverse transcriptase inhibitors (NNRTI, nucleoside reverse transcriptase inhibitors (NRTI and protease inhibitors (PI. Subtypes were assigned using REGA HIV-1 subtyping tool and phylogenetic trees constructed using MEGA version 5. RESULTS: Although mutations associated with resistance to all three drug were detected in these surveys, transmitted resistance was analyzed and classified as <5% in Maputo in both surveys for all three drug classes. Transmitted resistance to NNRTI in Beira in 2009 was classified between 5-15%, an increase from 2007 when no NNRTI mutations were found. All sequences clustered with subtype C. CONCLUSIONS: Our results show that the epidemic is dominated by subtype C, where the first-line option based on two NRTI and one NNRTI is still effective for treatment of HIV infection, but intermediate levels of TDR found in Beira reinforce the need for constant evaluation with continuing treatment expansion in Mozambique.

  2. Emergence of Pan-drug resistance amongst gram negative bacteria! The First case series from India

    Directory of Open Access Journals (Sweden)

    Abdul Ghafur

    2014-09-01

    Full Text Available Objective: Increasing prevalence of carbapenem resistant Gram negative bacteria is a serious clinical and public health challenge. Bacteria resistant to all available antibiotics (Pan Drug Resistance herald the onset of post antibiotics era. We hereby report clinical profile of 13 patients with pan drug resistant gram negative isolates. Methods:Retrospective analysis of 13 patients with pan drug resistant gram negative isolates over the last 18 months was done by medical records review. Identification of the isolates and susceptibility testing was done using VITEK auto analyzer in concordance with the corresponding CLSI guidelines. Results:Out of four patients with bacteremic isolates, three patients received colistin based combination therapy. Though two of these patients had microbiologic clearance, all the three died. Out of the 9 patients with non bacteremic isolates, 4 had infection and 5 had colonization. Three (out of four were treated with combination therapy including colistin and one patient received colistin monotherapy. All four patients had microbiological clearance. Three patients had clinical cure and were discharged. One patient later developed bacteremia and died. Conclusion:Infections, particularly blood stream with pan drug resistant organisms has a higher mortality. Urgent studies to reevaluate existing therapeutic options and research into new antibiotic molecules are the need of the hour. J Microbiol Infect Dis 2014; 4(3: 86-91

  3. Total Protein Profile and Drug Resistance in Candida albicans Isolated from Clinical Samples

    Directory of Open Access Journals (Sweden)

    Kamal Uddin Zaidi

    2016-01-01

    Full Text Available This study was done to assess the antifungal susceptibility of clinical isolates of Candida albicans and to evaluate its total protein profile based on morphological difference on drug resistance. Hundred and twenty clinical isolates of C. albicans from various clinical specimens were tested for susceptibility against four antifungal agents, namely, fluconazole, itraconazole, amphotericin B, and ketoconazole. A significant increase of drug resistance in clinical isolates of C. albicans was observed. The study showed 50% fluconazole and itraconazole resistance at 32 μg mL−1 with a MIC50 and MIC90 values at 34 and 47 and 36 and 49 μg mL−1, respectively. All isolates were sensitive to amphotericin B and ketoconazole. The SDS-PAGE protein profile showed a prevalent band of ~52.5 kDa, indicating overexpression of gene in 72% strains with fluconazole resistance. Since the opportunistic infections of Candida spp. are increasing along with drug resistance, the total protein profile will help in understanding the evolutionary changes in drug resistance and also to characterize them.

  4. Candida antifungal drug resistance in sub-Saharan African populations: A systematic review

    Science.gov (United States)

    Africa, Charlene Wilma Joyce; Abrantes, Pedro Miguel dos Santos

    2017-01-01

    Background: Candida infections are responsible for increased morbidity and mortality rates in at-risk patients, especially in developing countries where there is limited access to antifungal drugs and a high burden of HIV co-infection.  Objectives: This study aimed to identify antifungal drug resistance patterns within the subcontinent of Africa.  Methods: A literature search was conducted on published studies that employed antifungal susceptibility testing on clinical Candida isolates from sub-Saharan African countries using Pubmed and Google Scholar.  Results: A total of 21 studies from 8 countries constituted this review. Only studies conducted in sub-Saharan Africa and employing antifungal drug susceptibility testing were included. Regional differences in Candida species prevalence and resistance patterns were identified.  Discussion: The outcomes of this review highlight the need for a revision of antifungal therapy guidelines in regions most affected by Candida drug resistance.  Better controls in antimicrobial drug distribution and the implementation of regional antimicrobial susceptibility surveillance programmes are required in order to reduce the high Candida drug resistance levels seen to be emerging in sub-Saharan Africa. PMID:28154753

  5. Association between Mycobacterium tuberculosis complex phylogenetic lineage and acquired drug resistance.

    Directory of Open Access Journals (Sweden)

    Courtney M Yuen

    Full Text Available BACKGROUND: Development of resistance to antituberculosis drugs during treatment (i.e., acquired resistance can lead to emergence of resistant strains and consequent poor clinical outcomes. However, it is unknown whether Mycobacterium tuberculosis complex species and lineage affects the likelihood of acquired resistance. METHODS: We analyzed data from the U.S. National Tuberculosis Surveillance System and National Tuberculosis Genotyping Service for tuberculosis cases during 2004-2011 with assigned species and lineage and both initial and final drug susceptibility test results. We determined univariate associations between species and lineage of Mycobacterium tuberculosis complex bacteria and acquired resistance to isoniazid, rifamycins, fluoroquinolones, and second-line injectables. We used Poisson regression with backward elimination to generate multivariable models for acquired resistance to isoniazid and rifamycins. RESULTS: M. bovis was independently associated with acquired resistance to isoniazid (adjusted prevalence ratio = 8.46, 95% CI 2.96-24.14 adjusting for HIV status, and with acquired resistance to rifamycins (adjusted prevalence ratio = 4.53, 95% CI 1.29-15.90 adjusting for homelessness, HIV status, initial resistance to isoniazid, site of disease, and administration of therapy. East Asian lineage was associated with acquired resistance to fluoroquinolones (prevalence ratio = 6.10, 95% CI 1.56-23.83. CONCLUSIONS: We found an association between mycobacterial species and lineage and acquired drug resistance using U.S. surveillance data. Prospective clinical studies are needed to determine the clinical significance of these findings, including whether rapid genotyping of isolates at the outset of treatment may benefit patient management.

  6. Expression of cyclooxygenase-2 mRNA in drug-sensitive cell and drug-resistant strains of ovarian cancer cell lines

    Institute of Scientific and Technical Information of China (English)

    Xiaoyan Li; Zehua Wang

    2006-01-01

    Objective: To investigate the expression of cyclooxygenase-2 (COX-2) mRNA in drug-sensitive cell and drugresistant clones of ovarian cancer cell lines. Methods: RT-PCR and immunocytochemistry were used to investigate the expression of cyclooxygenase-2 in 3 clones drug-sensitive and 5 clones drug-resistant ovarian cancer cell. Results: Strong COX-2 mRNA expressions were detected in 3 clones of drug-sensitive cell and weak expressions were detected in 5 clones of drug-resistant cell. The protein expression of COX-2 in drug-sensitive cell was strongly positive reaction in immunocytochemistry stain and there was a weak positive reaction in 5clones of drug-resistant cell. Conclusion: The expression of COX-2 mRNA in drug-sensitive cell strains is much higher than that in drugresistant strains of ovarian cancer cell lines, providing a basis of the chemoprevention for ovarian cancer.

  7. Whole Genome Sequencing Based Characterization of Extensively Drug-Resistant Mycobacterium tuberculosis Isolates from Pakistan

    KAUST Repository

    Ali, Asho

    2015-02-26

    Improved molecular diagnostic methods for detection drug resistance in Mycobacterium tuberculosis (MTB) strains are required. Resistance to first- and second- line anti-tuberculous drugs has been associated with single nucleotide polymorphisms (SNPs) in particular genes. However, these SNPs can vary between MTB lineages therefore local data is required to describe different strain populations. We used whole genome sequencing (WGS) to characterize 37 extensively drug-resistant (XDR) MTB isolates from Pakistan and investigated 40 genes associated with drug resistance. Rifampicin resistance was attributable to SNPs in the rpoB hot-spot region. Isoniazid resistance was most commonly associated with the katG codon 315 (92%) mutation followed by inhA S94A (8%) however, one strain did not have SNPs in katG, inhA or oxyR-ahpC. All strains were pyrazimamide resistant but only 43% had pncA SNPs. Ethambutol resistant strains predominantly had embB codon 306 (62%) mutations, but additional SNPs at embB codons 406, 378 and 328 were also present. Fluoroquinolone resistance was associated with gyrA 91-94 codons in 81% of strains; four strains had only gyr B mutations, while others did not have SNPs in either gyrA or gyrB. Streptomycin resistant strains had mutations in ribosomal RNA genes; rpsL codon 43 (42%); rrs 500 region (16%), and gidB (34%) while six strains did not have mutations in any of these genes. Amikacin/kanamycin/capreomycin resistance was associated with SNPs in rrs at nt1401 (78%) and nt1484 (3%), except in seven (19%) strains. We estimate that if only the common hot-spot region targets of current commercial assays were used, the concordance between phenotypic and genotypic testing for these XDR strains would vary between rifampicin (100%), isoniazid (92%), flouroquinolones (81%), aminoglycoside (78%) and ethambutol (62%); while pncA sequencing would provide genotypic resistance in less than half the isolates. This work highlights the importance of expanded

  8. Drug Mechanisms to Help in Managing Resistant Hypertension in Obesity

    OpenAIRE

    Jansen, Pieter; Danser, Jan; Spiering, Wilko; Meiracker, Anton

    2010-01-01

    textabstractObesity is a major risk factor for the development of hypertension. Because the prevalence of obesity is increasing worldwide, the prevalence of obesity hypertension is also increasing. Importantly, hypertension in obesity is commonly complicated by dyslipidemia and type 2 diabetes mellitus and hence imposes a high cardiovascular disease risk. Furthermore, obesity is strongly associated with resistant hypertension. Activation of the sympathetic nervous system and the renin-angiote...

  9. Low nasal carriage of drug-resistant bacteria among medical students in Vienna

    Science.gov (United States)

    Gualdoni, Guido A.; Lingscheid, Tilman; Tobudic, Selma; Burgmann, Heinz

    2012-01-01

    Backgr