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Sample records for anti-tuberculosis drug resistance

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

    OpenAIRE

    Cobelens, F.G.J.; Joloba, M.L.; 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 meta-analysis of drug-resistant TB in sub-Saharan Africa. It provides a general introduction to anti-tuberculosis drug resistance in the world and associated risk factors. Results from the drug resist...

  2. Anti tuberculosis drug resistance in west of Iran

    Directory of Open Access Journals (Sweden)

    Parviz Mohajeri

    2014-01-01

    Full Text Available Background and Objective: Mycobacterium tuberculosis has developed resistance to antituberculosis drugs and becoming a major and alarming public health problem in worldwide. This study was aimed to determine antituberculosis drug resistance rate and to identify multidrug resistant tuberculosis (MDR-TB in West of Iran. Materials and Methods: Of 130 samples were included between December 2011 and July 2012 in the study from that 112 cases were M. tuberculosis. The proportional method was carried out according to the Clinical and Laboratory Standards Institute on Lowenstein-Jensen against isoniazid, rifampicin, streptomycin, ethambutol, pyrazinamide, para aminosalicylic acid, ethionamide, cycloserine (CYC. The microdilution method was carried out using 7H9 broth with 96 well-plates. Results: From 112 isolates, resistance was observed to isoniazid 18 (16.07%, rifampicin 16 (14.28%, streptomycin 25 (22.32%, ethambutol 15 (13.39%, pyrazinamide 27 (24.10%, para aminosalicylic acid 19 (16.96%, CYC 4 (3.57%, and ethionamide 14 (12.5% cases. 16 isolates were MDR. Conclusion: The high prevalence of MDR-TB in our study is assumed to be due to recent transmission of drug-resistant strains. Overall, the rate of drug resistance in our study was high, which is in line with findings of some high-burden countries. Hence that early case detection, rapid drug susceptibility testing, and effective anti-TB treatment is necessary.

  3. 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.

  4. 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

  5. Sensitivity Pattern of Second Line Anti-Tuberculosis Drugs against Clinical Isolates of Multidrug Resistant Mycobacterium Tuberculosis

    International Nuclear Information System (INIS)

    Objective:To determine the current sensitivity pattern of second line anti-tuberculosis drugs against clinical isolates of Multidrug Resistant Mycobacterium tuberculosis (MDR-TB). Study Design: A cross-sectional study. Place and Duration of Study: Department of Microbiology, Armed Forces Institute of Pathology (AFIP), Rawalpindi, from November 2011 to April 2013. Methodology: Samples received during the study period were processed on BACTEC MGIT 960 system for Mycobacterium tuberculosis (MTB) culture followed by first line drugs susceptibility testing of culture proven MTB isolates. On the basis of resistance to rifampicin and isoniazid, 100 clinical isolates of MDR-TB were further subjected to susceptibility testing against amikacin (AMK), capreomycin (CAP), ofloxacin (OFL) and ethionamide (ETH) as per standard BACTEC MGIT 960 instructions. Results: Out of 100 MDR-TB isolates, 62% were from male patients and 38% from female patients. 97% were sensitive to AMK, 53% to OFL, 87% to CAP; and 87% were sensitive to ETH. Conclusion: The majority of the MDR-TB isolates showed excellent sensitivity against AMK, CAP and ETH. However, sensitivity of MDR-TB isolates against fluoroquinolones like OFL was not encouraging. (author)

  6. GenoType® Mtbdrsl assay for resistance to second-line anti-tuberculosis drugs

    Science.gov (United States)

    Theron, Grant; Peter, Jonny; Richardson, Marty; Warren, Rob; Dheda, Keertan; Steingart, Karen R

    2016-01-01

    Background Genotype® MTBDRsl (MTBDRsl) is a rapid DNA-based test for detecting specific mutations associated with resistance to fluoroquinolones and second-line injectable drugs (SLIDs) in Mycobacterium tuberculosis complex. MTBDRsl version 2.0 (released in 2015) identifies the mutations detected by version 1.0, as well as additional mutations. The test may be performed on a culture isolate or a patient specimen, which eliminates delays associated with culture. Version 1.0 requires a smear-positive specimen, while version 2.0 may use a smear-positive or -negative specimen. We performed this updated review as part of a World Health Organization process to develop updated guidelines for using MTBDRsl. Objectives To assess and compare the diagnostic accuracy of MTBDRsl for: 1. fluoroquinolone resistance, 2. SLID resistance, and 3. extensively drug-resistant tuberculosis, indirectly on a M. tuberculosis isolate grown from culture or directly on a patient specimen. Participants were people with rifampicin-resistant or multidrug-resistant tuberculosis. The role of MTBDRsl would be as the initial test, replacing culture-based drug susceptibility testing (DST), for detecting second-line drug resistance. Search methods We searched the following databases without language restrictions up to 21 September 2015: the Cochrane Infectious Diseases Group Specialized Register; MEDLINE; Embase OVID; Science Citation Index Expanded, Conference Proceedings Citation Index-Science, and BIOSIS Previews (all three from Web of Science); LILACS; and SCOPUS; registers for ongoing trials; and ProQuest Dissertations & Theses A&I. We reviewed references from included studies and contacted specialists in the field. Selection criteria We included cross-sectional and case-control studies that determined MTBDRsl accuracy against a defined reference standard (culture-based DST, genetic sequencing, or both). Data collection and analysis Two review authors independently extracted data and assessed

  7. Trends of anti-tuberculosis drug resistance pattern in new cases and previously treated cases of extrapulmonary tuberculosis cases in referral hospitals in northern India

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    A K Maurya

    2012-01-01

    Full Text Available Background: Drug-resistant tuberculosis is one of major current challenges to global public health. The transmission of resistant strains is increasing as a burden of multidrug-resistant tuberculosis (MDR-TB patients in extra pulmonary tuberculosis (EPTB cases in India. Aim and Objectives: The aim was to study trends of anti-tuberculosis drug resistance pattern in new cases and previously treated cases of EPTB in referral hospitals in northern India. Study Design and Setting: A prospectively observational study and referral medical institutions in northern India. Materials and Methods: All EPTB specimens were processed for Ziehl Neelsen staining, BACTEC culture and BACTEC NAP test for Mycobacterium tuberculosis complex. All M. tuberculosis complex isolates were performed for radiometric-based drug susceptibility pattern against streptomycin, isoniazid, rifampicin and ethambutol using the 1% proportion method. Results: We found that 165/756 (20.5% isolates were identified as M. tuberculosis complex by the NAP test. We observed that 39.9% were resistant to first-line antitubercular drugs. The resistance rate was higher in previously treated patients: H (30.3%, R (16.3%, E (15.7% and S (16.3%. MDR-TB was observed in 13.4%, but, in new cases, this was 11.4% and 19.1% of the previously treated patients (P<0.05. Conclusion: MDR-TB is gradually increased in EPTB cases and predominant resistance to previous treated cases of EPTB. The molecular drug sensitivity test (DST method can be an early decision for chemotherapy in MDR-TB patients. The International Standards of TB Care need to be used by the RNTCP and professional medical associations as a tool to improve TB care in the country.

  8. Rates of Anti-Tuberculosis Drug Resistance in Kampala-Uganda Are Low and Not Associated with HIV Infection

    NARCIS (Netherlands)

    D. Lukoye; F.G.J. Cobelens; N. Ezati; S. Kirimunda; F.E. Adatu; J.K. Lule; F. Nuwaha; M.L. Joloba

    2011-01-01

    Background: Drug resistance among tuberculosis patients in sub-Saharan Africa is increasing, possibly due to association with HIV infection. We studied drug resistance and HIV infection in a representative sample of 533 smear-positive tuberculosis patients diagnosed in Kampala, Uganda. Methods/Princ

  9. Epidemiology of anti-tuberculosis drug resistance patterns and trends in tuberculosis referral hospital in Addis Ababa, Ethiopia

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    Abate Dereje

    2012-08-01

    Full Text Available Abstract Background Drug-resistant TB has emerged as a major challenge facing TB prevention and control efforts. In Ethiopia, the extent/trend of drug resistance TB is not well known. The aim of this study was to determine the pattern and trend of resistance to first line anti-TB drugs among culture positive retreatment cases at St.Peter’s TB Specialized Hospital. Findings A hospital based retrospective study was used to assess the pattern of anti-TB drug resistance among previously treated TB patients referred to St.Peter’s TB Specialized Hospital from January 2004-December 2008 Gregorian calendar(GC for better diagnosis and treatment. Among 376 culture positive for M. tuberculosis one hundred and two (27.1% were susceptible to all of the four first line anti-TB drugs -Isoniazid (INH, Rifampicin (RIF, Ethambutol (ETB & Streptomycin (STM. While 274 (72.9% were resistant to at least one drug. Any resistance to STM (67.3% was found to be the most common and the prevalence of MDR-TB was 174 (46.3%. Trend in resistance rate among re-treatment cases from 2004 to 2008 showed a significant increase for any drug as well as for INH, RIF, and MDR resistance (P Conclusions There has been an increasing trend in drug resistance in recent years, particularly in retreatment cases. Therefore, establishing advanced diagnostic facilities for early detection of MDR-TB and expanding second line treatment center to treat MDR-TB patients and to prevent its transmission is recommended.

  10. Is resistance to anti-tuberculosis drugs associated with type 2 diabetes mellitus? A register review in Beijing, China

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    Fengling Mi

    2014-05-01

    Full Text Available Background: China has a high burden of drug-resistant tuberculosis (TB and diabetes mellitus (DM. Objective: The objectives of this study were to determine the following in patients with culture-confirmed TB: 1 demographic characteristics and disease patterns in relation to the presence or absence of type 2 diabetes and 2 presence or absence of drug resistance to isoniazid (INH, rifampicin (RMP or both in relation to duration of diabetes and control of diabetes. Design: This is a cross-sectional and retrospective study involving record reviews. Results: There were 621 patients with culture-positive TB, of whom 187 (30% had previously known or new type 2 diabetes. In those with diabetes, there was a significantly higher proportion of males, persons aged ≥35 years and patients registered with new TB (p<0.05. Prevalence of multidrug-resistant TB (MDR-TB was 6.2% in new patients (N=422 and 62.3% in previously treated patients (N=199, with no significant differences between those with and without diabetes. In patients with diabetes, there was no association of drug resistance with diabetes duration or disease control [assessed by fasting blood glucose (FBG at 1 week]. Conclusion: A high proportion of patients with TB in a tertiary health facility, Beijing, China, had diabetes, but there was no association between type 2 diabetes and drug-resistant TB. Further prospective studies are needed to confirm these findings.

  11. The epidemic status of drug-resistant tuberculosis and research progress of anti-tuberculosis drugs%耐药结核病流行现状及抗结核药物研究进展

    Institute of Scientific and Technical Information of China (English)

    许寅; 孟现民; 张永信

    2013-01-01

    China is one of the 22 countries with serious tuberculosis epidemic in the whole world and is also one of the 27 countries with the serious multidrug-resistant tuberculosis (MDR-TB). MDR-TB has become the tough problem of public health in many countries. It is an important link to study and develop the new anti-tuberculosis drugs to prevent and control tuberculosis and to improve their efficacy. This article introduces the tuberculosis, especially epidemic status of drug-resistant tuberculosis and research progress of anti-tuberculosis drugs.%  我国是全球22个结核病流行严重的国家之一,同时也是全球27个耐多药结核病流行严重的国家之一。耐多药结核病在许多国家已成为主要公共卫生问题,而研发新型抗结核药物是有效遏制结核病流行和提高结核病防治效果的重要环节之一。本文介绍结核病、尤其是耐多药结核病的流行现状以及抗结核药物研发的最新进展。

  12. 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.

  13. 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.

  14. The search for new sterilizing anti-tuberculosis drugs.

    Science.gov (United States)

    Mitchison, Denis A

    2004-05-01

    To be of use in the control of tuberculosis, any new drug must be capable of shortening the duration of treatment by accelerating sterilizing activity, that is the rate at which Mycobacterium tuberculosis is killed in the lesions. The most difficult to kill are the extra-cellular bacilli in cavities. Persistence during therapy arises because there is a proportion of slowly metabolising bacilli (persisters) in the cavitary bacterial population at the start of treatment. Bacterial growth is slowed by low oxygen tension, quorum sensing and old age, but probably not by cellular immunity, since there are few professional phagocytic cells in cavities. The degree of phenotypic resistance to the bactericidal action of drugs can go through several stages: (i) the non-replicating stages 1 and 2 of micro-aerophilic adaptation, described by Wayne; (ii) a "tolerant" population that survives exposure to high rifampicin concentrations and is capable of growth in liquid medium but not on solid medium; and (iii) a population found in the sterile state of Cornell model mice which cannot grow initially in either liquid or solid medium but will eventually cause re-activation of tuberculosis. In all of these stages the bacilli are phenotypically resistant; there is no selection for genomic drug resistance. Rifampicin and pyrazinamide are the two drugs largely responsible for sterilizing activity during current treatment. Pyrazinamide is unique amongst anti-tuberculosis drugs in having no genomic site of action and having greater bactericidal activity as bacillary metabolism slows down; it is remarkably effective in human disease. The development of a new drug with a similar mode of activity might be very fruitful, especially if there were no need for an acid environment. Current methods advocated for drug development pass through a number of complex stages: choice of a genomic target, development of an in vitro assay, high throughput screening and identification of lead compounds

  15. 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

  16. Drug-induced Hepatotoxicity of Anti-tuberculosis Drugs and Their Serum Levels

    OpenAIRE

    Jeong, Ina; Park, Jong-Sun; Cho, Young-Jae; Yoon, Ho Il; Song, Junghan; Lee, Choon-Taek; Lee, Jae-Ho

    2015-01-01

    The correlation between serum anti-tuberculosis (TB) drug levels and the drug-induced hepatotoxicity (DIH) remains unclear. The purpose of this study was to investigate whether anti-TB DIH is associated with basal serum drug levels. Serum peak levels of isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA), and ethambutol (EMB) were analyzed in blood samples 2 hr after the administration of anti-TB medication. Anti-TB DIH and mild liver function test abnormality were diagnosed on the basis of...

  17. Time-kill kinetics of anti-tuberculosis drugs, and emergence of resistance, in relation to metabolic activity of Mycobacterium tuberculosis.

    NARCIS (Netherlands)

    Steenwinkel, J.E. de; Knegt, G.J. de; Kate, M.T. Ten; Belkum, A. van; Verbrugh, H.A.; Kremer, K.; Soolingen, D. van; Bakker-Woudenberg, I.A.

    2010-01-01

    OBJECTIVES: The pharmacodynamics of tuberculosis (TB) treatment should be further explored, to prevent emergence of resistance, treatment failure and relapse of infection. The diagnostic drug susceptibility tests guiding TB therapy investigate metabolically active Mycobacterium tuberculosis (Mtb) is

  18. Surveillance on first-line anti-tuberculosis drug resistance at Shanghai Port%上海口岸结核分枝杆菌一线抗结核药物耐药情况调查

    Institute of Scientific and Technical Information of China (English)

    王健; 章琪; 方筠; 叶魏; 陆晔; 张晓航; 韩晓辉; 贾哲甫; 鞠志英; 周娴

    2012-01-01

    Objective To investigate the first-line drug-resistant TB rate at Shanghai Port, and provide DST data and other evidence decision-making for directly observed treatment (DOT) as well as TB quarantine at Chinese ports. Methods From Dec. 2009 to Dec. 2011, international travel applicants who were suspected of TB patients by abnormal chest radiological exam atShanghai port were enrolled in this study. Their sputum specimen were smeared and cultured for 3 consecutive days in the early morning for mycobacterium tuberculosis isolation. MGIT 960 method wag used to detect first-line anti-tuberculosis drug resistance (streptomycin, rifampicin, isoniazid, ethambutol, pyrazinamide). Results There were 38 active tuberculosis applicants whose sputum specimen culture were positive for MTB Complex. Of which, 11 isolated strains were resistant to at least one first line anti-tuberculosis drugs. The total drug-resistant TB rale was 29.0% (11/38) which was similar to those of other five provinces in China (31.7%), and was higher than that of Hong Kong(14.4%)and global median(12.2%).There were 9 isolated strains(23.7%) which were only resistant to one anti-tuberculosis drug. Among them, 2 strains(5.3%) were resistant to streptomycin, 2 strains (5.3%) were resistant to isoniazid, five strains (13.2%) were resistant to pyrazinamide. There was 1 MDR (2.6% ) and 1 isolate (2.6% ) resistant to 3 drugs(ethambutol , isoniazid, pyrazinamide). No rifampicin and ethambutol single-resistant strain was found in this study. Conclusion The risk of drug resistance does exist in Shanghai Port currently. The overall resistance rate is above the average in other provinces in the mainland China, but higher than Hongkong and international median. DOT regimen recommended by WHO is suitable for Shanghai Pott. . It is necessary to enhance the surveillance on managing and treating these infectious TB to ensure their health and safety for international travel applicants.%目的 了解上海口岸结核分

  19. New anti-tuberculosis drugs and regimens: 2015 update

    OpenAIRE

    Lia D'Ambrosio; Rosella Centis; Giovanni Sotgiu; Emanuele Pontali; Antonio Spanevello; Giovanni Battista Migliori

    2015-01-01

    Over 480 000 cases of multidrug-resistant (MDR) tuberculosis (TB) occur every year globally, 9% of them being affected by extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis. The treatment of MDR/XDR-TB is unfortunately long, toxic and expensive, and the success rate largely unsatisfactory (

  20. New anti-tuberculosis drugs and regimens: 2015 update

    Directory of Open Access Journals (Sweden)

    Lia D'Ambrosio

    2015-05-01

    Full Text Available Over 480 000 cases of multidrug-resistant (MDR tuberculosis (TB occur every year globally, 9% of them being affected by extensively drug-resistant (XDR strains of Mycobacterium tuberculosis. The treatment of MDR/XDR-TB is unfortunately long, toxic and expensive, and the success rate largely unsatisfactory (<20% among cases with resistance patterns beyond XDR. The aim of this review is to summarise the available evidence-based updated international recommendations to manage MDR/XDR-TB, and to update the reader on the role of newly developed drugs (delamanid, bedaquiline and pretomanid as well as repurposed drugs (linezolid and meropenem clavulanate, among others used to treat these conditions within new regimens. A nonsystematic review based on historical trials results as well as on recent literature and World Health Organization (WHO guidelines has been performed, with special focus on the approach to managing MDR/XDR-TB. The new, innovative global public health interventions, recently approved by WHO and known as the “End TB Strategy”, support the vision of a TB-free world with zero death, disease and suffering due to TB. Adequate, universally accessed treatment is a pre-requisite to reach TB elimination. New shorter, cheap, safe and effective anti-TB regimens are necessary to boost TB elimination.

  1. Anti-tuberculosis drugs related hepatotoxicity; incidence, risk factors, pattern of changes in liver enzymes and outcome

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    H Khalili

    2009-10-01

    Full Text Available "nBackground and the purpose of the study: Tuberculosis is a curable disease if diagnosed and treated properly with anti-tuberculosis drugs. These drugs can cause severe adverse reactions including hepatotoxicity.The goal of this study was to evaluate the rate and the time of incidence, pattern of alterations in liver enzyme, risk factors and outcome of anti-tuberculosis drugs induced hepatotoxicity in Iranian Tuberculosis patients. "nMethod: In a prospective cohort study, 102 patients (68 male, 34 female, mean age 43.21±18 years with tuberculosis diagnosis were followed during anti-tuberculosis drug treatment course. Drug related hepatotoxicity was defined as increase in serum alanine aminotransfrase or aspartate aminotransfrase greater than three or five times of the upper limit of normal, with or without symptoms of hepatitis, respectively. "nResults: anti-tuberculosis induced hepatotoxicity was detected in 32 (31.37% of the patients. Human immunodeficiency virus and hepatitis C virus infections, concomitant use of hepatotoxic drugs, and abnormal baseline serum alanine aminotransfrase and aspartate aminotransfrase level were risk factors for anti-tuberculosis drugs induced hepatotoxicity. "nConclusion: Anti-tuberculosis drugs induced hepatotoxicity is a major problem in Iranian tuberculosis patients and cause treatment interruption in 31.37% of patients.

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

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    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

  3. 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

    information on treatment regimen and the patient's weight. Treatment was successful in 89.4%. Prescriptions of tablets/vials conforming to recommendations were found for respectively 91.2%, 89.9%, 92.3% and 94.6% of the patients for RMP/isoniazid, pyrazinamide, ethambutol and streptomycin. Patients in the 25......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 representative sample of 30 treatment units was randomly selected. All patient treatment cards enrolled in these units were obtained, and data were double-entered and validated before calculating the adequacy of the individual drug prescriptions. RESULTS: Of 3412 tuberculosis treatment cards, 3225 (94.5%) had...

  4. 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

  5. 1034例利福平耐药结核杆菌对其它一线抗结核药物耐药性分布特征%Distribution characteristics of resistance to other first line anti-tuberculosis drugs among 1034 rifampin-resistant mycobacterium tuberculosis strains

    Institute of Scientific and Technical Information of China (English)

    谢贝; 苏雯婕; 刘志辉; 张言斌

    2011-01-01

    目的 了解广州市近17年来,结核分枝杆菌临床分离株利福平耐药情况及对其它一线抗结核药物的敏感性分布特征.方法 回顾性分析广州市胸科医院1992年2月-2008年7月期间门诊结核病人一线抗结核药物敏感性试验结果.结果 10 167例结核分支杆菌分离株中,耐R菌株1034例,耐H菌株2214例,耐S菌株1073例,耐E菌株622例,总体耐药率为25.80%;在1034例R耐药株中,H、R共同耐药者927例,占R耐药株总数的89.65%,却只占2214例H耐药株的41.87%;而R、S共同耐药者502例,R、E共同耐药者237例,分别占耐R株总数的48.55%及22.92%,明显少于R、H共同耐药者.结论 耐RFP菌株绝大部分同时对INH耐药,但反之不然,现有的耐药机制难以解释此种现象,结核杆菌是否存在其它耐药机制有待进一步研究.%Objective To explore rifampicin-resistant status of mycobacterium tuberculosis isolates in Guangzhou during the recent seventeen years, and their distribution characteristics of susceptibility to other first line anti-tuberculosis drugs. Methods The results of first line anti-tuberculosis drug susceptibility testing performed during the period of February 1992 to July 2008 in clinic patients were retrospectively analyzed. Results Of 10 167 mycobacterium tuberculosis isolates, 1034 were rifampin-resistant, 2214 isoniazid-resistant, 1073 streptomycinresistant, and 622 ethambutol-resistant; with a total drug resistance rate of 25.80%. Of 1034 rifampin-resistant isolates, 927 also developed isoniazid resistance, being 89.65% for the total number of rifampin-resistant isolates but only 41.87% for 2214 isoniazid-resistant isolates. Meanwhile, the number of rifampin- and streptomycin -resistant(502 strains)and rifampin- and ethambutol-resistant(237 strains)isolates was significantly smaller than that of rifampin- and isoniazid-resistant isolats. Conclusions Most of rifampin-resistant isolates also develop resistance to isoniazid, but not vice

  6. 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.

  7. 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.

  8. 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

    -control pairs did not indicate a teratogenic effect of these drugs in any group with congenital abnormality. CONCLUSION: Maternal exposure to oral anti-tuberculosis drugs during pregnancy did not show a detectable teratogenic risk to the fetus; however, the number of pregnant women who were treated...... 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......; the corresponding figures for cases were 22,865 and 11 (0.05%). The prevalence odds ratio was 0.6 (95%CI 0.3-1.3). Analysis of isoniazid and other oral antituberculosis drug use during the second and third months of gestation, i.e., in the critical period for most major congenital abnormalities, in case...

  9. Patients with secondary amenorrhea due to tuberculosis endometritis towards the induced anti-tuberculosis drug category 1.

    Science.gov (United States)

    Perdhana, Raditya; Sutrisno, Sutrisno; Sugiri, Yani Jane; Baktiyani, Siti Candra Windu; Wiyasa, Arsana

    2016-01-01

    Tuberculosis (TB) is a disease which can affect various organs, including human's genital organs such as the endometrium. Tuberculosis endometritis can cause clinical symptoms of secondary amenorrhea and infertility. Infertility in genital TB caused by the involvement of the endometrium. The case presentation is 33-year-old woman from dr. Saiful Anwar Public Hospital to consult that she has not menstruated since 5 years ago (28 years old). The diagnosis was done by performing a clinical examination until the diagnosis of secondary amenorrhea due to tuberculosis endometritis is obtained. A treatment by using category I of anti-tuberculosis drugs was done for 6 months, afterward an Anatomical Pathology observation found no signs of the tuberculosis symptoms. Based on that, patient, who was diagnosed to have secondary amenorrhea due to tuberculosis endometritis, has no signs of tuberculosis process after being treated by using category I of anti-tuberculosis drugs for 6 months. PMID:27642459

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

    OpenAIRE

    Padmapriyadarsini C; Chandrabose J; Victor L; Hanna L; Arunkumar N; Swaminathan Soumya

    2006-01-01

    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 R...

  11. Anti-tuberculosis Drugs with Novel Mechanism of Action%具有新型作用机制的抗结核药物

    Institute of Scientific and Technical Information of China (English)

    2013-01-01

    Tuberculosis is one of major health problems worldwide. Approximately 1.8 mil ion people died from Tuberculosis each year which has become a global public health issue. Recently the emergence of drug resistant strains and HIV co-infection has resulted in a high incidence. As a result, there is an urgent need for us to understand the resistance mechanism and discover new anti-tuberculosis drugs. A number of new potential anti-tuberculosis drug candidates with novel modes of action have entered clinical trials in recent years. These agents are most likely to be effective against resistant strains. The paper summarized structure-activity relationships, in vitro and in vivo activity, pharmacokinetics, mechanism of action and combination regimens about several novel anti-tuberculosis drugs.%  结核病(Tuberculosis)是世界范围里的主要疾病之一,近年来,每年约有180万人死于结核病,结核病已经成为全球性的公众健康问题。近年来药物耐受以及伴有 HIV 感染的结核病发病率急剧增加,迫切需要深入了解目前抗结核药物的作用机制及耐药机制,以指导开发对持留菌和耐药菌更加有效的新型药物。近年来,一批具有全新作用机制的抗结核候选药物相继进入了临床研究,并且这些药物对耐药株表现出有效的抑制活性。文章对几类新型抗结核药物的化学结构、作用机制、构效关系、抗结核活性以及临床应用进行了综述。

  12. Facing multi-drug resistant tuberculosis.

    Science.gov (United States)

    Sotgiu, Giovanni; Migliori, Giovanni Battista

    2015-06-01

    Multi-drug resistant tuberculosis (MDR-TB) is caused by Mycobacterium tuberculosis strains resistant to at least two of the most effective anti-tuberculosis drugs (i.e., isoniazid and rifampicin). Therapeutic regimens based on second- and third-line anti-tuberculosis medicines showed poor efficacy, safety, and tolerability profiles. It was estimated that in 2012 the multi-drug resistant tuberculosis incidence ranged from 300,000 to 600,000 cases, mainly diagnosed in the Eastern European and Central Asian countries. The highest proportion of cases is among individuals previously exposed to anti-tuberculosis drugs. Three main conditions can favour the emergence and spread of multi-drug resistant tuberculosis: the poor implementation of the DOTS strategy, the shortage or the poor quality of the anti-tuberculosis drugs, and the poor therapeutic adherence of the patients to the prescribed regimens. Consultation with tuberculosis experts (e.g., consilium) is crucial to tailor the best anti-tuberculosis therapy. New therapeutic options are necessary: bedaquiline and delamanid seem promising drugs; in particular, during the development phase they demonstrated a protective effect against the emergence of further resistances towards the backbone drugs. In the recent past, other antibiotics have been administered off-label: the most relevant efficacy, safety, and tolerability profile was proved in linezolid-, meropenem/clavulanate-, cotrimoxazole-containing regimens. New research and development activities are needed in the diagnostic, therapeutic, preventive fields. PMID:24792579

  13. Impact of glutathione S-transferase M1 and T1 on anti-tuberculosis drug-induced hepatotoxicity in Chinese pediatric patients.

    Directory of Open Access Journals (Sweden)

    Fang Liu

    Full Text Available Anti-tuberculosis drug induced hepatotoxicity (ATDH is a major adverse drug reaction associated for anti-tuberculosis therapy. The glutathione S-transferases (GST plays a crucial role in the detoxification of hepatotoxic metabolites of anti-tuberculosis drugs.An association between GSTM1/GSTT1 null mutations and increased risk of ATDH has been demonstrated in adults. Given the ethnic differences and developmental changes, our study aims to investigate the potential impacts of GSTM1/GSTT1 genotypes on the development of ATDH in Han Chinese children treated with anti-tuberculosis therapy.Children receiving anti-tuberculosis therapy with or without evidence of ATDH were considered as the cases or controls, respectively. The GSTM1 and GSTT1 genotyping were performed using the polymerase chain reaction.One hundred sixty-three children (20 cases and 143 controls with a mean age of 4.7 years (range: 2 months-14.1 years were included. For the GSTM1, 14 (70.0% cases and 96 (67.1% controls had homozygous null mutations. For the GSTT1, 13 (65.0% cases and 97 (67.8% controls had homozygous null mutations. Neither the GSTM1, nor the GSTT1 polymorphism was significantly correlated with the occurrence of ATHD.Our results did not support the GSTM1 and GSTT1 polymorphisms as the predictors of ADTH in Chinese Han children treated with anti-tuberculosis drugs. An age-related association between pharmacogenetics and ATHD need to be confirmed in the further study.

  14. 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.

  15. Recent patents and advances on anti - tuberculosis drug delivery and formulations.

    Science.gov (United States)

    Vora, Chintan; Patadia, Riddhish; Mittal, Karan; Mashru, Rajashree

    2013-08-01

    Tuberculosis has remained, unambiguously, a significant health care problem since long times, particularly in developing countries. The endeavoring battle against multi drug resistant TB, multiple dosing, their prominent side effects and bioavailability hiccups related to fixed dose combinations has undeniably become a Herculean task indicating rigorous research requirement in anti TB drug therapy. In view of the fact that patenting a drug molecule, a drug delivery system or a formulation has been very fruitful for the growth and sustainment of pharmaceutical industry, a meticulous review of recent developments, providing a balanced view on merits/demerits, will facilitate researchers to update themselves, thereby focusing their research in more relevant areas to furnish desired quality traits. This article reviews the present scenario in terms of drug delivery approaches for TB chemotherapy. The review encompasses and summarizes recent patents and advances on variegated facets of dosage forms, together with from conventional solid oral to novel controlled release oral formulations and additionally alternative weapons for anti TB drug delivery. A critical review of multidisciplinary approaches to boost anti TB therapy may facilitate the scientists to resolve existing technological gaps. PMID:23244680

  16. A new method for identifying causal genes of schizophrenia and anti-tuberculosis drug-induced hepatotoxicity.

    Science.gov (United States)

    Huang, Tao; Liu, Cheng-Lin; Li, Lin-Lin; Cai, Mei-Hong; Chen, Wen-Zhong; Xu, Yi-Feng; O'Reilly, Paul F; Cai, Lei; He, Lin

    2016-01-01

    Schizophrenia (SCZ) may cause tuberculosis, the treatments for which can induce anti-tuberculosis drug-induced hepatotoxicity (ATDH) and SCZ-like disorders. To date, the causal genes of both SCZ and ATDH are unknown. To identify them, we proposed a new network-based method by integrating network random walk with restart algorithm, gene set enrichment analysis, and hypergeometric test; using this method, we identified 500 common causal genes. For gene validation, we created a regularly updated online database ATDH-SCZgenes and conducted a systematic meta-analysis of the association of each gene with either disease. Till now, only GSTM1 and GSTT1 have been well studied with respect to both diseases; and a total of 23 high-quality association studies were collected for the current meta-analysis validation. Finally, the GSTM1 present genotype was confirmed to be significantly associated with both ATDH [Odds Ratio (OR): 0.71, 95% confidence interval (CI): 0.56-0.90, P = 0.005] and SCZ (OR: 0.78, 95% CI: 0.66-0.92, P = 0.004) according to the random-effect model. Furthermore, these significant results were supported by "moderate" evidence according to the Venice criteria. Our findings indicate that GSTM1 may be a causal gene of both ATDH and SCZ, although further validation pertaining to other genes, such as CYP2E1 or DRD2, is necessary. PMID:27580934

  17. 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

  18. 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...

  19. Anti-Tuberculosis Drug Induced Hepatotoxicity among TB/HIV Co-Infected Patients at Jimma University Hospital, Ethiopia: Nested Case-Control Study

    OpenAIRE

    Alima Hassen Ali; Tefera Belachew; Alemeshet Yami; Wubeante Yenet Ayen

    2013-01-01

    BACKGROUND: This study was carried out to determine the incidence and predictors of anti-tuberculosis drug induced hepatotoxicity among TB/HIV co-infected patients at Jimma University Hospital, Ethiopia. METHODS/PRINCIPAL FINDINGS: A nested case-control study was conducted by reviewing charts of all TB/HIV co-infected patients who commenced anti-TB treatment from January 2008 to December 2011 at Jimma University Hospital. Patients who had developed hepatotoxicity after at least 5 days of stan...

  20. Role of polymorphic bile salt export pump (BSEP, ABCB11) transporters in anti-tuberculosis drug-induced liver injury in a Chinese cohort

    OpenAIRE

    Ru Chen; Jing Wang; Shaowen Tang; Yuan Zhang; Xiaozhen Lv; Shanshan Wu; Zhirong Yang; Yinyin Xia; Dafang Chen; Siyan Zhan

    2016-01-01

    Evidence indicates that the polymorphisms in bile salt export pump (BSEP, encoded by ABCB11) may play an important role in the development of anti-tuberculosis drug-induced liver injury (ATDILI) and we aim to investigate the association between genetic variants of ABCB11 and the risk of ATDILI in a Chinese cohort. A total of 89 tuberculosis patients with ATDILI and 356 matched ATDILI -free patients constituted cases and controls. Genetic polymorphisms of ABCB11 were determined by TaqMan singl...

  1. Role of polymorphic bile salt export pump (BSEP, ABCB11) transporters in anti-tuberculosis drug-induced liver injury in a Chinese cohort.

    Science.gov (United States)

    Chen, Ru; Wang, Jing; Tang, Shaowen; Zhang, Yuan; Lv, Xiaozhen; Wu, Shanshan; Yang, Zhirong; Xia, Yinyin; Chen, Dafang; Zhan, Siyan

    2016-01-01

    Evidence indicates that the polymorphisms in bile salt export pump (BSEP, encoded by ABCB11) may play an important role in the development of anti-tuberculosis drug-induced liver injury (ATDILI) and we aim to investigate the association between genetic variants of ABCB11 and the risk of ATDILI in a Chinese cohort. A total of 89 tuberculosis patients with ATDILI and 356 matched ATDILI -free patients constituted cases and controls. Genetic polymorphisms of ABCB11 were determined by TaqMan single-nucleotide polymorphism (SNP) genotyping assay. Odds ratio (OR) with 95% confidence intervals (CIs) was estimated by conditional logistic regression model. There were no significant differences in genotype frequencies of ABCB11 between cases and controls. In the subgroup analysis, polymorphisms of rs2287616 were found to be associated with cholestatic/mixed pattern of liver injury under dominant and addictive model (OR = 3.84, 95% CI:1.16-12.75, P = 0.028 and OR = 2.51, 95% CI:1.12-5.62, P = 0.025, respectively), however the significance disappeared after Bonferroni correction. This study suggested that genetic variants of ABCB11 gene might contribute to anti-tuberculosis drug-induced cholestatic liver injury in Chinese patients. Studies in larger, varied populations are required to confirm these findings. PMID:27293027

  2. Tuberculosis in Sudan: a study of Mycobacterium tuberculosis strain genotype and susceptibility to anti-tuberculosis drugs

    Directory of Open Access Journals (Sweden)

    Sharaf Eldin Ghada S

    2011-08-01

    Full Text Available Abstract Background Sudan is a large country with a diverse population and history of civil conflict. Poverty levels are high with a gross national income per capita of less than two thousand dollars. The country has a high burden of tuberculosis (TB with an estimated 50,000 incident cases during 2009, when the estimated prevalence was 209 cases per 100,000 of the population. Few studies have been undertaken on TB in Sudan and the prevalence of drug resistant disease is not known. Methods In this study Mycobacterium tuberculosis isolates from 235 patients attending three treatment centers in Sudan were screened for susceptibility to isoniazid, rifampicin, ethambutol and streptomycin by the proportion method on Lowenstein Jensen media. 232 isolates were also genotyped by spoligotyping. Demographic details of patients were recorded using a structured questionnaire. Statistical analyses were conducted to examine the associations between drug resistance with risk ratios computed for a set of risk factors (gender, age, case status - new or relapse, geographic origin of the patient, spoligotype, number of people per room, marital status and type of housing. Results Multi drug-resistant tuberculosis (MDR-TB, being resistance to at least rifampicin and isoniazid, was found in 5% (95% CI: 2,8 of new cases and 24% (95% CI: 14,34 of previously treated patients. Drug resistance was associated with previous treatment with risk ratios of 3.51 (95% CI: 2.69-4.60; p Conclusions We conclude that emergence of drug resistant tuberculosis has the potential to be a serious public health problem in Sudan and that strengthened tuberculosis control and improved monitoring of therapy is needed. Further surveillance is required to fully ascertain the extent of the problem.

  3. Availability of second-line drugs and anti-tuberculosis drug susceptibility testing in China: a situational analysis

    NARCIS (Netherlands)

    G.X. He; S. van den Hof; M.W. Borgdorff; M.J. van der Werf; S.M. Cheng; Y.L. Hu; L.X. Zhang; L.X. Wang

    2010-01-01

    OBJECTIVE: To assess the availability of second-line drugs (SLDs) and the use of drug susceptibility testing (DST) results for the treatment of tuberculosis (TB) in China. DESIGN: Cross-sectional survey in 4675 health care facilities, 1960 of which have a dedicated TB clinic, in 12 provinces in Chin

  4. Multiplex Assay of Second-Line Anti-Tuberculosis Drugs in Dried Blood Spots Using Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry.

    Science.gov (United States)

    Lee, Kyunghoon; Jun, Sun Hee; Han, Minje; Song, Sang Hoon; Park, Jong Sun; Lee, Jae Ho; Park, Kyoung Un; Song, Junghan

    2016-09-01

    As dried blood spots (DBSs) have various advantages over conventional venous blood sampling, some assays for detection of one or two anti-tuberculosis (TB) drugs in DBSs have been developed. However, there are no assays currently available for the simultaneous measurement of three or more anti-TB drugs in DBSs. In this study, we developed and evaluated a multiplex method for detecting nine anti-TB drugs including streptomycin, kanamycin, clarithromycin, cycloserine, moxifloxacin, levofloxacin, para-aminosalicylic acid, prothionamide, and linezolid in DBSs by using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Seventy-nine patient samples of DBS were analyzed on the UPLC-MS/MS system. All drug concentrations were determined within 4 min, and assay performance was evaluated. All drugs were clearly separated without ion suppression. Within-run and between-run precisions were 1.7-13.0% and 5.7-17.0%, respectively, at concentrations representing low and high levels for the nine drugs. Lower limits of detection and quantification were 0.06-0.6 and 0.5-5.0 μg/mL, respectively. Linearity was acceptable at five level concentrations for each drug. Correlations between drug concentrations in plasma and DBSs by using Passing-Bablock regression and Pearson's rho (ρ 0.798-0.989) were acceptable. In conclusion, we developed a multiplex assay to measure nine second-line anti-TB drugs in DBSs successfully. This assay provided convenient and rapid drug quantification and could have applications in drug monitoring during treatment. PMID:27374716

  5. Reaserch progress of anti-tuberculosis drugs induced hepatotoxicity%抗结核药致肝损害的研究进展

    Institute of Scientific and Technical Information of China (English)

    周应初; 刘斌

    2011-01-01

    Drug induced hepatotoxicity (DIH), especially the anti-tuberculosis (anti-TB) drugs induced hepatotoxicity(ATDH) , impacts greatly on hunman body, and is one of the most common causes of stoping chemotherapy in tuberculosis patients. The pathogenesis of ATDH is not very clear, but the toxicity and idiosyncratic reaction have been widely studied. Its risk factors are as follows: old age, female, slow acetylation status, malnutrition, human immunodeficiency virus infection, liver diseases, excessive intake of alcohol, combination therapy, and so on. Of ATDH, the early prevention, detection, diagnosis, and treatment will be helpful to successfully complete the tuberculosis chemodierapy. Therefore , it is crucial to understand the pathogenesis and risk factors of ATDH and it is urgent to strengthen the prevention of ATDH.%tuberculosis药物性肝痛(drug induced hepatotoxicity,DIH)以抗结核药诱导的肝毒性(anti-tuberculosis drugs induced hepatotoxicity,ATDH)较常见,其对人体影响最大,是导致结核病人停止化学治疗最常见的原因之一.ATDH的发病机制尚不十分清楚,但目前以毒性反应及特异质反应研究较多,其危险因素包括高龄、女性、慢乙酰化状态、营养不良、人类免疫缺陷病毒(human immunodeficiency virus,HIV)感染、肝疾病、过多撮入酒精,联合用药等.对ATDH的早预防、早发现、早诊断、早治疗是顺利完成结核化疗的保障.因此,了解ATDH的发病机制及危险因素显得至关重要,加强ATDH的防治是一个亟需解决的临床问题.

  6. 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.

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

    Science.gov (United States)

    Couto, Rosa A S; Quinaz, Maria Beatriz

    2016-01-01

    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. PMID:27376291

  8. 抗结核药物致皮疹的临床分析%Clinical Analysis of the Durg Eruptions Caused by Anti-tuberculosis Drugs

    Institute of Scientific and Technical Information of China (English)

    侍羽; 赵丽

    2015-01-01

    目的:探讨抗结核药物所致药物性皮疹的常见类型、常见的致药物以及发生过敏的预后。方法研究2013年1月~2015年4月在我院住院抗结核治疗过程中发生药物性皮疹的85例结核病患者,分析导致药物性皮疹的抗结核药物以及皮疹类型。结果有17人因各种原因未能明确致敏药物,最终明确致敏药物的为68人89例次,依次为:利福平(RFP)28例、盐酸乙胺丁醇(EMB)19例、吡嗪酰胺(PZA)15例、利福喷丁(RFT)9例、异烟肼(INH)7例、对氨基水杨酸异烟肼(DIP)4例、盐酸左氧氟沙星3例、加替沙星3例、丙硫异烟胺1例。有10例利福平过敏者未发生利福喷丁过敏,1例对利福平及利福喷丁均过敏。皮疹类型有荨麻疹型、红斑型、湿疹型、猩红热型、麻疹型、疱疹型、紫癜型等不同表现。结论抗结核药引起的过敏反应表现多种多样;发生皮疹的抗结核药物最多的是利福平,其余依次为盐酸乙胺丁醇、吡嗪酰胺、利福喷丁、异烟肼、对氨基水杨酸异烟肼,利福平与利福喷丁交叉过敏者较少;经停药抗过敏治疗预后良好。%Objective To study the the type of the medicine for al ergy induced by anti-tuberculosis drugs, and categories sequences of the sensitized drugs that induced drug eruptions, clinical features, consequences. Methods 85 patients with tuberculosis treated in the fourth hospital of Lianyungang from January 2013 to April 2015 who occur skin rashes after receiving anti-tuberculosis treatment. To study the the type of the medicine for al ergy, categories sequences of the sensitized drugs, clinical features and consequences. Results 17 patients can not be clearly induced drug hypersensitivity due to various reasons. 68 people in 89 cases ultimately defined by sensitive drugs, fol owed by rifampicin (RFP) in 28 cases, ethambutol hydrochloride (EMB) in 19 cases, pyrazinamide (PZA) in 15 cases, rifapentine (RFT) in 9 cases, 7 cases

  9. 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

  10. Drug Resistance

    Science.gov (United States)

    HIV Treatment Drug Resistance (Last updated 3/1/2016; last reviewed 3/1/2016) Key Points As HIV multiplies in the ... the risk of drug resistance. What is HIV drug resistance? Once a person becomes infected with HIV, ...

  11. Determination of the activity of standard anti-tuberculosis drugs against intramacrophage Mycobacterium tuberculosis, in vitro: MGIT 960 as a viable alternative for BACTEC 460

    Directory of Open Access Journals (Sweden)

    Sarbjit Singh Jhamb

    2014-06-01

    Full Text Available BACTEC 460 has now been phased out, so the search for an alternative is imperative. We have determined the activity of standard anti-tuberculosis drugs against intramacrophage Mycobacterium tuberculosis, in vitro, by using BACTEC 460 and MGIT 960 methods. The minimum inhibitory concentrations of isoniazid, rifampicin, ethambutol and streptomycin against intracellular M. tuberculosis H37Rv were found to be 0.2, 0.8, 8.0, and 5.0 µg/mL, respectively, by both methods. These results show a significant (p < 0.001 concordance between minimum inhibitory concentrations obtained by these two different methods. MGIT 960 system uses a robust florescence quenching-based oxygen sensor, requires no radioisotope, is safe, and relatively easy to operate. Apparently, this is the first report wherein MGIT 960 has been validated for anti-tubercular susceptibility testing against intracellular M. tuberculosis H37Rv. Our preliminary data thus clearly demonstrate that the MGIT 960 method can be considered as a promising alternative to BACTEC 460 method.

  12. 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

  13. Metabolism and pharmacokinetics of the anti-tuberculosis drug ethionamide in a flavin-containing monooxygenase null mouse.

    Science.gov (United States)

    Palmer, Amy L; Leykam, Virginia L; Larkin, Andrew; Krueger, Sharon K; Phillips, Ian R; Shephard, Elizabeth A; Williams, David E

    2012-01-01

    Multiple drug resistance (MDR) in Mycobacterium tuberculosis (mTB), the causative agent for tuberculosis (TB), has led to increased use of second-line drugs, including ethionamide (ETA). ETA is a prodrug bioactivated by mycobacterial and mammalian flavin-containing monooxygenases (FMOs). FMO2 is the major isoform in the lungs of most mammals, including primates. In humans a polymorphism exists in the expression of FMO2. FMO2.2 (truncated, inactive) protein is produced by the common allele, while the ancestral allele, encoding active FMO2.1, has been documented only in individuals of African and Hispanic origin, at an incidence of up to 50% and 7%, respectively. We hypothesized that FMO2 variability in TB-infected individuals would yield differences in concentrations and ratios of ETA prodrug and metabolites. In this study we assessed the impact of the FMO2 genetic polymorphism on the pharmacokinetics of ETA after administration of a single oral dose of ETA (125 mg/kg) to wild type and triple Fmo1/2/4-null mice, measuring levels of prodrug vs. metabolites in plasma collected from 0 to 3.5 h post-gavage. All mice metabolized ETA to ETA S-oxide (ETASO) and 2-ethyl-4-amidopyridine (ETAA). Wild type mice had higher plasma concentrations of metabolites than of parent compound (p = 0.001). In contrast, Fmo1/2/4-null mice had higher plasma concentrations of parent compound than of metabolites (p = 0.0001). Thus, the human FMO2 genotype could impact the therapeutic efficacy and/or toxicity of ETA. PMID:23580869

  14. Anti-tuberculosis drug induced hepatotoxicity among TB/HIV co-infected patients at Jimma University Hospital, Ethiopia: nested case-control study.

    Directory of Open Access Journals (Sweden)

    Alima Hassen Ali

    Full Text Available BACKGROUND: This study was carried out to determine the incidence and predictors of anti-tuberculosis drug induced hepatotoxicity among TB/HIV co-infected patients at Jimma University Hospital, Ethiopia. METHODS/PRINCIPAL FINDINGS: A nested case-control study was conducted by reviewing charts of all TB/HIV co-infected patients who commenced anti-TB treatment from January 2008 to December 2011 at Jimma University Hospital. Patients who had developed hepatotoxicity after at least 5 days of standard doses of anti-TB drug therapy were labeled as "cases" and those without hepatotoxicity were "controls". Each case with anti-TB drug induced hepatotoxicity was compared with 3 controls selected randomly from the cohort. From a cohort of 296 TB/HIV co-infected patients 8 were excluded from the study as the causality between anti-TB drugs and hepatotoxicity was not confirmed, 33 had developed hepatotoxicity. On bivariate logistic regression analysis, body mass index (BMI <18.5 Kg/m(2 [P = 0.01; OR (95%CI: 3.6 (1.4-9.5], disseminated pulmonary TB [P = 0.00; OR (95%CI: 5.6 (2.2-14.6], CD4 count ≤50 [P = 0.016; OR (95%CI: 3.6(1.27-10.23] and WHO stage 4 [P = 0.004, OR (95%CI: 3.8 (1.68-8.77] were significantly associated with anti-TB drug induced hepatotoxicity. Predictor variables with p-value <0.05 by bivariate analysis were analyzed using multivariable logistic regression analysis and identified disseminated pulmonary TB [P = 0.001; AOR (95%CI = 5.6 (2.1-15.0] and BMI <18.5 [P = 0.014; AOR (95%CI= 3.6 (1.3-10.1] as independent predictors of anti-TB drug induced hepatotoxicity. CONCLUSIONS: The incidence of anti-TB drug induced hepatotoxicity was 11.5%. The results suggest that in the presence of disseminated pulmonary TB and/or BMI <18.5 Kg/m(2, TB/HIV co-infected patients should be closely followed for the occurrence of hepatotoxicity during the intensive phase of TB treatment to prevent morbidity and mortality.

  15. GenoType棆MTBDRsl试验检测喹诺酮类抗结核药耐药性准确性的Meta分析%Diagnostic value of GenoType® MTBDRsl assay for the resistance to fluoroquinolones anti-tuberculosis drugs:a Meta-analysis

    Institute of Scientific and Technical Information of China (English)

    崔喆; 胡文飞; 韩璐

    2015-01-01

    Objective To evaluate the diagnostic accuracy of GenoType® M TBDRsl for the resistance to fluoroquinolones anti‐tuberculosis drugs .Methods Systematic and comprehensive literature was searched in PubMed ,Embase ,Web of Science ,CBM , CNKI ,VIP and Wanfang database .The relative studies of GenoType® MTBDRsl to fluoroquinolones anti‐tuberculosis drugs were included .After quality assessment ,Meta‐Disc1 .4 software was used to analyze the data .Results A total of 16 trials ,involving 1 766 participants ,were included .The results of Meta‐analysis showed that the weighted sensitivity ,specificity ,positive likelihood ra‐tio ,negative likelihood ratio ,diagnostic odds ratio ,and the area under summary receiver operation curve were 0 .83 ,0 .96 ,17 .50 , 0 .20 ,108 .46 and 0 .934 9 ,respectively .Conclusion GenoType® M TBDRsl assay for the resistance to fluoroquinolones anti‐tuber‐culosis drugs might be with high sensitivity and specificity ,which could be recommended as efficacy diagnostic tool .%目的:系统评价GenoType® MTBDRsl试验检测喹诺酮类抗结核药耐药性的准确性。方法检索 PubMed、Em‐base、Web of Science、中国生物医学文献数据库、中国知网、维普数据库和万方数据库,采集以GenoType® M TBDRsl试验作为喹诺酮类抗结核药耐药性检测诊断性试验的文献,对纳入研究进行方法学质量评价后,采用 M eta‐Disc1.4软件进行统计学分析。结果最终纳入16篇文献,共1766例患者。Meta分析结果显示,GenoType® MTBDRsl试验检测喹诺酮类抗结核药耐药性的合并敏感度、合并特异度、阳性似然比、阴性似然比、诊断比值比和综合受试者工作特征曲线下面积分别为0.83、0.96、17.50、0.20、108.46和0.9349。结论 GenoType棆 MTBDRsl试验对喹诺酮类抗结核药耐药性的诊断敏感度和特异度较高,可作为喹诺酮类抗结核药耐药性检测的有效方法之一。

  16. 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

    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....

  17. 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

  18. 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

  19. Therapeutic efficacy of drug susceptibility test-guided individualized anti-tuberculosis chemotherapy for spinal tuberculosis%脊柱结核个体化药物治疗的临床效果观察

    Institute of Scientific and Technical Information of China (English)

    吴铮; 张泽华; 许建中

    2010-01-01

    system. The drug susceptibility testing was performed using absolute concentration method, which included 11 first-line and second-line drugs. Four or five anti-tuberculosis drug regimen was chosen according to the results of drug susceptibility testing. All the patients were followed up a month later, and then once 3 months in the following 11 months, and subsequently at intervals of half a year. The clinical status, erythrocyte sedimentation rate ( ESR), roentgenogram, MRI and 3D-CT were concerned to estimate the progress of tuberculosis. Results The culture positive rate was 45. 2% (28/62). The average detection time was 42 d (ranging from 28-58 d). The drug susceptibility testing showed a total drug resistance level of 24. 2% : 12.9% for isoniazid, 4. 8% for rifampicin, 3. 2% for ethambutol, 9.7% for streptomycin, 6. 4% for pasiniazid, 14.5% for levofloxacin, 1.6% for rifapentine. The mean follow-up period was 21 months (ranging from 12-44 months). According to Bridwell criteria, grade Ⅰ bony fusion was obtained in all patients in 8-12 months. Conclusion Guided by drug susceptibility testing, individualized anti-tuberculosis chemotherapy for 12 to 18 months is effective for spinal tuberculosis.

  20. 肺结核患者抗结核药物治疗不良反应%The monitoring of adverse reaction in patients with pulmonary tuberculosis treated by anti-tuberculosis drugs (a report of 247cases)

    Institute of Scientific and Technical Information of China (English)

    曾安津; 董霞

    2012-01-01

    目的 探讨肺结核在抗结核药物治疗过程中发生的不良反应.方法 对247例行抗结核药物治疗的肺结核患者出现不良反应进行分类分析.结果 不良反应主要表现为肝肾功能损害,消化道症状和中枢神经症状等;年龄超过50岁者不良反应发生率明显高于年龄低于50岁者(P<0.05).结论 肺结核患者使用抗结核药治疗应加强督导和随访,定期复查肝肾功能,及时有效处理药物不良反应.%Objective To investigate the adverse reaction of patients with pulmonary tuberculosis during the processes of anti-tu berculosis drug treatment, and provide the evidence for the development of effective prevention and treatment measures. Method The ad verse reactions of 247 patients with pulmonary tuberculosis treated with anti-tuberculosis drug therapy were classified and statistical ana lyzed. Results The main adverse reactions were liver and kidney dysfunction, gastrointestinal symptoms and nervous symptoms. The in cidence of adverse reactions in patients over the age of 50 years was significantly higher than that of patients under the age of 50 years ( P < 0. 05 ). Conclusion The treatment of anti-tuberculosis drug in patients with pulmonary tuberculosis should be strengthened supervision and follow-up, reviewing the function of liver and kidney regularly, adverse and drug reactions should be treated timely and effective, par ticularly patients over the age of 50 years.

  1. 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.

  2. Pharmacokinetics of para-Aminosalicylic Acid in HIV-Uninfected and HIV-Coinfected Tuberculosis Patients Receiving Antiretroviral Therapy, Managed for Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis

    OpenAIRE

    de Kock, Lizanne; Sy, Sherwin K.B.; Rosenkranz, Bernd; Diacon, Andreas H; Prescott, Kim; Hernandez, Kenneth R.; Yu, Mingming; Derendorf, Hartmut; Donald, Peter R.

    2014-01-01

    The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis prompted the reintroduction of para-aminosalicylic acid (PAS) to protect companion anti-tuberculosis drugs from additional acquired resistance. In sub-Saharan Africa, MDR/XDR tuberculosis with HIV coinfection is common, and concurrent treatment of HIV infection and MDR/XDR tuberculosis is required. Out of necessity, patients receive multiple drugs, and PAS therapy is frequent; however, n...

  3. Study on the Effect of Anti Tuberculosis Drug Induced Liver Injury on the Length of Stay in Hospital%抗结核药物性肝损伤对住院天数的影响的研究

    Institute of Scientific and Technical Information of China (English)

    张宏; 覃红娟; 汪敏; 冯治宇

    2016-01-01

    Objective To evaluate the anti-tuberculosis drug-induced liver injury (DILI)impact on the the length of hospital stay.Methods According to the diagnostic criteria of drug-induced liver injury,there were 141 tuberculosis(TB)patients with DILI screened as the observation group,anther 143 TB patients without DILI screened as control group.Cinical data was recorded and studyed on the method of retrospective analysis.Results In the observation group,the median of length of hospital stay was 20.While it was 14 in the control group.The difference on the length of hospital stay between two groups was 6.Conclusion Anti-tuberculosis drug-induced liver injury will extend the length of hospital stay,resulting in a negative impact on anti-TB treatment.The DILI treatment time and the length of hospital stay have a positive corelation.%目的:探讨抗结核药物性肝损伤(drug induced liver injury,DILI)对结核病患者的住院天数影响。方法依照药物性肝损伤的诊断标准,筛选出结核药物性肝损伤病例141例作为观察组,同时筛选143例结核病作为对照组。记录两组的临床资料,从而研究抗结核药物性肝损伤对结核病患者住院天数影响。结果观察组住院天数的中位数是20,对照组住院时间的中位数是14,两者相差6。结论抗结核药物性肝损伤会延长患者的住院天数,从而对抗结核治疗产生负面的影响。

  4. 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.

  5. Drug-induced liver injury caused by anti-tuberculosis drugs%抗结核药所致药物性肝损害

    Institute of Scientific and Technical Information of China (English)

    李锋; 卢水华

    2014-01-01

    Incidence of antituberculosis drug-induced liver injury (DILI) is different according to reports of various areas, and different anti-TB drugs have different chances to cause liver injury. Pyrazinamide and rifampicin are the most common drugs resulted in DILI in our country. The related risk factors of DILI includes gender, age, lifestyle, genetic factors and complications. The main mechanism of anti-TB DILI includes liver toxicity and allergic liver damage. The patients with DILI require closely observation and have enough rest. The anti-TB regiment should stop if necessary, and protective therapy should be given. Most patients with DILI could recover gradually after proper medication. After liver functional improvement, the anti-TB regiment should be chosen carefully according to the patient's case history. Prophylactic treatment for hepatic injury is currently not conclusive. Therefore, the patients’ liver function should be paid attention to during the overall anti-TB process, and the factors that could cause hepatic damage other than anti-TB drugs should be avoided comprehensively.%不同国家、地区报道的抗结核药物性肝损伤(DILI)发生率不同,不同抗结核药物引起DILI的概率也不相同。在我国吡嗪酰胺与利福平是最常见的导致DILI的药物。DILI的相关危险因素包括:性别和年龄、生活方式、遗传因素、并发症等。抗结核药物发生DILI的主要机制包括中毒性肝损害和变态反应性肝损害。发生DILI后需密切观察,可给予停药,充分的休息,积极保肝治疗,大部分患者可逐渐恢复。应当根据患者的具体情况酌情选择抗结核方案。预防性保肝治疗目前正在研究中。抗结核过程中应当关注导致患者的肝功能指标,避免导致肝损伤的其他因素,更全面地保护肝脏。

  6. Association of the CYP2B6 gene with anti-tuberculosis drug-induced hepatotoxicity in a Brazilian Amazon population

    OpenAIRE

    Débora Christina Ricardo Oliveira Fernandes; Ney Pereira Carneiro Santos; Milene Raiol Moraes; Ana Cristina Oliveira Braga; Cleonardo Augusto Silva; Andrea Ribeiro-dos-Santos; Sidney Santos

    2015-01-01

    Objectives: The treatment of tuberculosis (TB) remains a challenge owing to the high incidence of drug-induced hepatotoxicity. The aim of this study was to examine the effect of two gene polymorphisms, one in the CYP2B6 (rs3745274) gene and one in the CYP3A5 (rs776746) gene, on the development of hepatotoxicity in patients treated with anti-TB drugs in a Brazilian Amazon population. Methods: TB patients who were treated with anti-TB drugs were examined for hepatotoxicity, an adverse effect...

  7. Hepatitis C Virus Co-Infection Increases the Risk of Anti-Tuberculosis Drug-Induced Hepatotoxicity among Patients with Pulmonary Tuberculosis

    OpenAIRE

    Nino Lomtadze; Lali Kupreishvili; Archil Salakaia; Sergo Vashakidze; Lali Sharvadze; Kempker, Russell R.; Matthew J Magee; Carlos del Rio; Blumberg, Henry M.

    2013-01-01

    BACKGROUND: The country of Georgia has a high prevalence of tuberculosis (TB) and hepatitis C virus (HCV) infection. PURPOSE: To determine whether HCV co-infection increases the risk of incident drug-induced hepatitis among patients on first-line anti-TB drug therapy. METHODS: Prospective cohort study; HCV serology was obtained on all study subjects at the time of TB diagnosis; hepatic enzyme tests (serum alanine aminotransferase [ALT] activity) were obtained at baseline and monthly during tr...

  8. Hepatitis C virus co-infection increases the risk of anti-tuberculosis drug-induced hepatotoxicity among patients with pulmonary tuberculosis.

    Directory of Open Access Journals (Sweden)

    Nino Lomtadze

    Full Text Available BACKGROUND: The country of Georgia has a high prevalence of tuberculosis (TB and hepatitis C virus (HCV infection. PURPOSE: To determine whether HCV co-infection increases the risk of incident drug-induced hepatitis among patients on first-line anti-TB drug therapy. METHODS: Prospective cohort study; HCV serology was obtained on all study subjects at the time of TB diagnosis; hepatic enzyme tests (serum alanine aminotransferase [ALT] activity were obtained at baseline and monthly during treatment. RESULTS: Among 326 study patients with culture-confirmed TB, 68 (21% were HCV co-infected, 14 (4.3% had chronic hepatitis B virus (HBV infection (hepatitis B virus surface antigen positive [HBsAg+], and 6 (1.8% were HIV co-infected. Overall, 19% of TB patients developed mild to moderate incident hepatotoxicity. In multi-variable analysis, HCV co-infection (adjusted Hazards Ratio [aHR]=3.2, 95% CI=1.6-6.5 was found to be an independent risk factor for incident anti-TB drug-induced hepatotoxicity. Survival analysis showed that HCV co-infected patients developed hepatitis more quickly compared to HCV seronegative patients with TB. CONCLUSION: A high prevalence of HCV co-infection was found among patients with TB in Georgia. Drug-induced hepatotoxicity was significantly associated with HCV co-infection but severe drug-induced hepatotoxicity (WHO grade III or IV was rare.

  9. Multicenter evaluation of the nitrate reductase assay for drug resistance detection of Mycobacterium tuberculosis.

    Science.gov (United States)

    Martin, Anandi; Montoro, Ernesto; Lemus, Dihadenys; Simboli, Norberto; Morcillo, Nora; Velasco, Maritza; Chauca, José; Barrera, Lucía; Ritacco, Viviana; Portaels, Françoise; Palomino, Juan Carlos

    2005-11-01

    The performance of the nitrate reductase assay was evaluated in a multicenter laboratory study to detect resistance of Mycobacterium tuberculosis to the first-line anti-tuberculosis drugs rifampicin, isoniazid, ethambutol and streptomycin using a set of coded isolates. Compared with the gold standard proportion method on Löwenstein-Jensen medium, the assay was highly accurate in detecting resistance to rifampicin, isoniazid and ethambutol with an accuracy of 98%, 96.6% and 97.9%, respectively. For streptomycin, discrepant results were obtained with an overall accuracy of 85.3%. The assay proved easy to be implemented in countries with limited laboratory facilities. PMID:15893391

  10. 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.

  11. TSH-CHECK-1 test: diagnostic accuracy and potential application to initiating treatment for hypothyroidism in patients on anti-tuberculosis drugs.

    Directory of Open Access Journals (Sweden)

    Cara S Kosack

    Full Text Available BACKGROUND: Thyroid-stimulating hormone (TSH promotes expression of thyroid hormones which are essential for metabolism, growth, and development. Second-line drugs to treat tuberculosis (TB can cause hypothyroidism by suppressing thyroid hormone synthesis. Therefore, TSH levels are routinely measured in TB patients receiving second-line drugs, and thyroxin treatment is initiated where indicated. However, standard TSH tests are technically demanding for many low-resource settings where TB is prevalent; a simple and inexpensive test is urgently needed. METHODS: As a proof of concept study TSH was measured in routinely collected sera at the University Medical Center Utrecht, Netherlands, using the TSH-CHECK-1 (VEDALAB, Alençon, France, a lateral-flow rapid immunochromatographic assay with a TSH cut-off value of 10 µIU/mL, the standard threshold for initiating treatment. These results were compared with TSH levels measured by a reference standard (UniCel DXi 800 imunoassay system, Beckman Coulter, USA. Sensitivity, specificity, and likelihood ratios were then calculated. RESULTS: A total of 215 serum samples were evaluated: 107 with TSH values <10 µIU/mL and 108 with values ≥10 µIU/mL. TSH-CHECK-1 test sensitivity was found to be 100.0% (95% CI: 96.6-100.0 and specificity was 76.6% (95% CI: 67.5-84.3. Predictive values (PV were modelled for different levels of prevalence. For a prevalence of 10% and 50%, the positive PV was 32.2% (95% CI: 25.0-39.7% and 81.1% (95% CI: 75.0-85.5%, respectively; the negative PV was 100% (95% CI: 98.9-100% and 100% (95% CI: 91.3-100% respectively. DISCUSSION/CONCLUSIONS: The TSH-CHECK-1 rapid test was practical and simple to perform but difficult to interpret on weak positive results. All sera with TSH≥10 µIU/mL were correctly identified, but the test lacked sufficient specificity. Given its excellent negative PV in this evaluation, the test shows promise for ruling out hypothyroidism. However, so far it

  12. 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. PMID:26260983

  13. Drug resistance profiles of Mycobacterium tuberculosis isolates to first line anti-tuberculous drugs: A five years study

    Directory of Open Access Journals (Sweden)

    Sarala Menon

    2012-01-01

    Full Text Available Background: Drug resistance is a major problem in the treatment of tuberculosis (TB. An estimate of drug resistance is extremely important in the epidemiology and control of TB. However, an assessment of the magnitude of drug resistance in TB is not very well described globally and data remains scantier for India. In view of this, we reviewed our data over last five years. Materials and Methods: Six hundred and seventy-three Mycobacterium tuberculosis isolates were subjected to drug susceptibility against primary anti-tuberculosis drugs by economic variant proportion method. All isolates resistant to isoniazid and rifampicin were taken as multi-drug resistant (MDR. Results: Out of the 673 strains tested, 95 (14.11% showed monoresistance, 365 (54.23% strains were found to be resistant to more than one drug. A total of 118 (17.53% strains were found to be resistant to all the four drugs tested. MDR was seen with 320 (47.54% isolates. This study observed maximum resistance with rifampicin (74.4% followed by streptomycin (70.0%, isoniazid (53.2%, and ethambutol (21.7%. Conclusion: While this information may not reflect true prevalence of drug resistance in the region, this may help in further planning long term surveillance studies to know the trend of drug resistance in this area.

  14. 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

  15. Detection and management of drug-resistant tuberculosis in HIV-infected patients in lower-income countries

    DEFF Research Database (Denmark)

    Ballif, M; Nhandu, V; Wood, R;

    2014-01-01

    SETTING: Drug resistance threatens tuberculosis (TB) control, particularly among human immunodeficiency virus (HIV) infected persons. OBJECTIVE: To describe practices in the prevention and management of drug-resistant TB under antiretroviral therapy (ART) programs in lower-income countries. DESIGN......%) provided directly observed therapy (DOT) during the entire course of treatment, 16 (34%) during the intensive phase only, and 11 (23%) did not follow DOT. Fourteen (30%) ART programs reported no access to second-line anti-tuberculosis regimens; 18 (38%) reported TB drug shortages. CONCLUSIONS: Capacity to...... diagnose and treat drug-resistant TB was limited across ART programs in lower-income countries. DOT was not always implemented and drug supplies were regularly interrupted, which may contribute to the global emergence of drug resistance....

  16. Arrival of Imidazo[2,1-b]thiazole-5-carboxamides: Potent Anti-tuberculosis Agents That Target QcrB.

    Science.gov (United States)

    Moraski, Garrett C; Seeger, Natalie; Miller, Patricia A; Oliver, Allen G; Boshoff, Helena I; Cho, Sanghyun; Mulugeta, Surafel; Anderson, Jeffery R; Franzblau, Scott G; Miller, Marvin J

    2016-06-10

    Increasing interest in the potent anti-tuberculosis activity and the novel target (QcrB) of imidazo[1,2-a]pyridine-3-carboxamides encouraged extended structure-activity relationship studies of additional scaffolds. This study reports on the in vitro profiling of the imidazo[2,1-b]thiazole-5-carboxamides as a new promising class of anti-tuberculosis compounds endowed with nanomolar potency against replicating and drug-resistant Mycobacterium tuberculosis (Mtb) as well as low toxicity to VERO cells. Compounds 6, 16, and 17 had MIC values 100 μM. On-target selectivity of this series was confirmed by cross-resistance of specific QcrB mutants as well as the hypersusceptibility of a mutant with a functional gene deletion of the alternative cytochrome bd oxidase. Additionally, to demonstrate selectivity, three analogues (6, 15, 17) were broadly screened against a diverse set of eight strains of bacteria, including both Gram-positive and Gram-negative as well as six disease-causing non-tuberculosis mycobacteria. Finally, compounds 16 and 17 were found to be active in macrophages infected with Mtb. PMID:27627627

  17. 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

  18. 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.

  19. 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.

  20. 针对不同靶点新型抗结核药物的药效和药动学性质研究%Pharmacokinetics and pharmacodynamics of new anti-tuberculosis drugs for different targets

    Institute of Scientific and Technical Information of China (English)

    周爽; 肖春玲

    2013-01-01

    Tuberculosis,as the most significant infectious disease seriously threatening the human health,has worldwide reappeared in recent years.With the increase of multi-drug resistant strains,the current anti-TB drugs can no longer meet the requirements of clinical therapy.The research and development of new anti-TB drugs has been extremely urgent.This paper summarized the pharmacokinetics and pharmacodynamics of new anti-TB drug candidates for different targets,which are in clinical or preclinical studies.This will provide a reference to the future development ofanti-TB drugs.%结核病作为危害人类健康最重大的传染病,近年来在全球范围内又死灰复燃.随着多药耐药菌株的不断增加,原有的抗结核药物己不能满足临床的治疗要求,新型抗结核药物的研发迫在眉睫.本文选取了最新进入临床研究或临床前研究的抗结核候选药物,按照其不同的作用靶点综述了各个药物的药效学及药动学性质,为今后抗结核药物的研发提供参考和依据.

  1. 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

  2. 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....

  3. 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。

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. Drug resistance in mycobacterium tuberculosis

    OpenAIRE

    Abate, Getahun

    1999-01-01

    Drug-resistant tuberculosis is a global public health problem. This investigation was performed to find ways of improving regimens that could be used for the treatment of drug- and multidrug-resistant TB and also to find a rapid method of diagnosis of drug resistant TB, particularly MDR-TB. Among 107 isolates of M. tuberculosis from re-treatment cases of pulmonary TB in Ethiopia (study 1), 48% were resistant at least to one of the four first-line drugs tested and 12 % were A...

  11. 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

  12. NAT2*6A,a haplotype of the N-acetyltransferase 2 gene, is an important biomarker for risk of anti-tuberculosis drug-induced hepatotoxicity in Japanese patients with tuberculosis

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To investigate an association between N-acetyltransferase 2 (NAT2)-haplotypes/diplotypes and adverse effects in apanese pulmonary tuberculosis patients.METHODS: We studied 100 patients with pulmonary TB treated with anti-TB drugs including INH. The frequencies and distributions of single nucleotide polymorphisms, haplotypes, and diplotypes of NAT2 were determined by the PCR-restriction fragment length polymorphism method, and the results were compared between TB patients with and without adverse effect,using multivariate logistic regression analysis.RESULTS: Statistical analysis revealed that the frequency of a variant haplotype, NAT2*6A, was significantly increased in TB patients with hepatotoxicity,compared with those without hepatotoxicity [P = 0.001,odds ratio (OR) = 3.535]. By contrast, the frequency of a wild-type (major) haplotype,"NAT2*4″, was significantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P < 0.001, OR = 0.265).There was no association between NAT2-haplotypes and skin rash or eosinophilia.CONCLUSION: The present study shows that NAT2 is one of the determinants of anti-TB drug-induced hepatotoxicity. Moreover, the haplotypes, NAT2*4 and NAT2*6A, are useful new biomarkers for predicting antiTB drug-induced hepatotoxicity.

  13. Drugs reverting multidrug resistance (chemosensitizers)

    Energy Technology Data Exchange (ETDEWEB)

    Gualtieri, F. [Florence Univ. (Italy). Dip. di Scienze Farmaceutiche

    1996-12-01

    Drug resistance is a phenomenon that frequently impairs proper treatment of cancer. Multidrug resistance (MDR) is a particular case of acquired drug resistance, resulting from overexpression of a protein (P-170) that functions as a pump, clearing cells from the chemotherapic. The P-170 protein functions can be inhibited by a variety of lipophilic drugs containing a hydrophilic nitrogen, protonated at physiological pH. A considerable effort is underway to identify new drugs able to reverse MDR. Few of these molecules are already undergoing clinical trials.

  14. 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.

  15. Mycobacterial Interspersed Repetitive Unit Locus –A New Way to Predict the Drug-Resistant Tuberculosis

    Directory of Open Access Journals (Sweden)

    feng Yu Wen

    2015-02-01

    Full Text Available The MIRU-VNTR (Mycobacterial Interspersed Repetitive Unit-Variable Number of Tandem Repeat typing has been a widely-used molecular method for Mycobacterium tuberculosis genotyping. It is unknown whether MIRU-VNTR is associated with drug resistance of Mycobacterium tuberculosis. The purpose of this study was to explore the ability of twenty-four MIRU loci to predict the drug resistance of Isoniazid (INH, Rifampicin (RFP, Streptomycin (SM, Ethambutol (EMB and Pyrazinamide (PZA. We collected the drug resistance and twenty-four MIRU loci information of 109 strains of Mycobacterium tuberculosis from an open database. The results of multivariate logistic regression showed that the variable number of tandem repeat polymorphism of MTUB04 was related to INH resistance (odds ratio (OR = 2.82, p=0.00, RFP resistance (OR =1.91, P=0.02, SM resistance (OR=1.98, P=0.01 and EMB resistance (OR = 1.95, P=0.03. MIRU40 was associated with INH resistance (OR = 2.22, P=0.00. MTUB21 was connected with INH resistance (OR=1.63, P=0.02 and SM resistance (OR=1.69, P=0.01. MIRU26 was correlated with SM resistance (OR=1.52, P=0.04. MIRU39 was associated with EMB resistance (OR=4.07, P=0.02. The areas under receiver operating characteristic curve of INH, RFP, SM, EMB and PZA resistance prediction models were 0.84, 0.70, 0.85 and 0.74 respectively. Our results showed that MIRU loci were related to anti-tuberculosis drug and could predict the drug resistance of tuberculosis.

  16. Drug resistance profile of human Mycobacterium avium complex strains from India

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    Venugopal D

    2007-01-01

    Full Text Available Purpose: To determine minimum inhibitory concentration (MIC of various anti-tuberculosis drugs for Mycobacterium avium complex (MAC strains isolated from clinical samples. Methods: Forty-nine human isolates of MAC were tested for susceptibility to nine chemotherapeutic agents. All isolates were from Indian patients suffering from chronic pulmonary mycobacteriosis. Drug susceptibility was performed both by agar dilution and MIC method. MIC values were analysed, both visually and by enzyme-linked immunosorbent assay reader. Results: More than 40% of the MAC isolates were sensitive to ciprofloxacine (48.98%, amikacin (46.94% and roxithromycin (42.86% by the MIC method. In contrast, the isolates showed high degree of resistance to the first line antituberculosis drugs: only 28.6% were sensitive to rifampicine, 22.85% to isoniazid and ethambutol each and 36.7% were sensitive to streptomycin. In addition, 22.85% of the strains were sensitive to clofazimine and 34.7% to kanamycin. Conclusions: Results of the study confirm the suitability of the rapid broth micro dilution (MIC method as a simple yet reliable method to assay for the drug susceptibility of nontuberculosis mycobacterium.

  17. 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

  18. Antimicrobial (Drug) Resistance: Gonorrhea

    Science.gov (United States)

    ... Marketing Share this: Main Content Area Multidrug-Resistant Neisseria gonorrhoeae (Gonorrhea) During the past 50 years, the use ... Gonorrhea is a sexually transmitted disease caused by Neisseria gonorrhoeae , a bacterium that can infect areas of the ...

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

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    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

  20. Prevalence of resistance to second-line tuberculosis drug among multidrug-resistant tuberculosis patients in Viet Nam, 2011

    Science.gov (United States)

    Tran, Huong Thi Giang; Bui, Quyen Thi Tu

    2016-01-01

    Introduction Extensively drug-resistant tuberculosis (XDR-TB) represents an emerging public health problem worldwide. According to the World Health Organization, an estimated 9.7% of multidrug-resistant TB (MDR-TB) cases are defined as XDR-TB globally. The objective of this study was to determine the prevalence of drug resistance to second-line TB drugs among MDR-TB cases detected in the Fourth National Anti-Tuberculosis Drug Resistance Survey in Viet Nam. Methods Eighty clusters of TB cases were selected using a probability-proportion-to-size approach. To identify MDR-TB cases, drug susceptibility testing (DST) was performed for the four major first-line TB drugs. DST of second-line drugs (ofloxacin, amikacin, kanamycin, capreomycin) was performed on isolates from MDR-TB cases to identify pre-XDR and XDR cases. Results A total of 1629 smear-positive TB cases were eligible for culture and DST. Of those, DST results for first-line drugs were available for 1312 cases, and 91 (6.9%) had MDR-TB. Second-line DST results were available for 84 of these cases. Of those, 15 cases (17.9%) had ofloxacin resistance and 6.0% were resistant to kanamycin and capreomycin. Five MDR-TB cases (6.0%) met the criteria of XDR-TB. Conclusion This survey provides the first estimates of the proportion of XDR-TB among MDR-TB cases in Viet Nam and provides important information for local policies regarding second-line DST. Local policies and programmes that are geared towards TB prevention, early diagnosis and treatment with effective regimens are of high importance. PMID:27508089

  1. Antiviral Drug Resistance: Mechanisms and Clinical Implications

    OpenAIRE

    Strasfeld, Lynne; Chou, Sunwen

    2010-01-01

    Antiviral drug resistance is an increasing concern in immunocompromised patient populations, where ongoing viral replication and prolonged drug exposure lead to the selection of resistant strains. Rapid diagnosis of resistance can be made by associating characteristic viral mutations with resistance to various drugs as determined by phenotypic assays. Management of drug resistance includes optimization of host factors and drug delivery, selection of alternative therapies based on knowledge of...

  2. Extensively drug-resistant tuberculosis.

    Science.gov (United States)

    Jassal, Mandeep; Bishai, William R

    2009-01-01

    Extensively drug-resistant (XDR) tuberculosis is defined as disease caused by Mycobacterium tuberculosis with resistance to at least isoniazid and rifampicin, any fluoroquinolone, and at least one of three injectable second-line drugs (amikacin, capreomycin, or kanamycin). The definition has applicable clinical value and has allowed for more uniform surveillance in varied international settings. Recent surveillance data have indicated that the prevalence of tuberculosis drug resistance has risen to the highest rate ever recorded. The gold standard for drug-susceptibility testing has been the agar proportion method; however, this technique requires several weeks for results to be determined. More sensitive and specific diagnostic tests are still unavailable in resource-limited settings. Clinical manifestations, although variable in different settings and among different strains, have in general shown that XDR tuberculosis is associated with greater morbidity and mortality than non-XDR tuberculosis. The treatment of XDR tuberculosis should include agents to which the organism is susceptible, and should continue for a minimum of 18-24 months. However, treatment continues to be limited in tuberculosis-endemic countries largely because of weaknesses in national tuberculosis health-care models. The ultimate strategy to control drug-resistant tuberculosis is one that implements a comprehensive approach incorporating innovation from the political, social, economic, and scientific realms. PMID:18990610

  3. Bedaquiline – The first ATP synthase inhibitor against multi drug resistant tuberculosis

    OpenAIRE

    Lakshmanan, Mageshwaran; Xavier, Alphienes Stanley

    2013-01-01

    Increasing incidence of MDR-TB, long duration of treatment and co-infection with HIV are the significant problems in achieving the eradication of tuberculosis. Bedaquiline is an anti-tuberculosis drug with unique mechanism of action. It selectively inhibits the mycobacterial energy metabolism i.e. ATP synthesis and found to be effective against all states of Mycobacterium tuberculosis like active, dormant, replicating, non-replicating, intracellular and extracellular. Preclinical studies have...

  4. 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.

    2016-01-01

    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 mc27000 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.

  5. 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.

  6. Antimicrobial peptides as novel anti-tuberculosis therapeutics.

    Science.gov (United States)

    Silva, João P; Appelberg, Rui; Gama, Francisco Miguel

    2016-01-01

    Tuberculosis (TB), a disease caused by the human pathogen Mycobacterium tuberculosis, has recently joined HIV/AIDS as the world's deadliest infectious disease, affecting around 9.6 million people worldwide in 2014. Of those, about 1.2 million died from the disease. Resistance acquisition to existing antibiotics, with the subsequent emergence of Multi-Drug Resistant mycobacteria strains, together with an increasing economic burden, has urged the development of new anti-TB drugs. In this scope, antimicrobial peptides (AMPs), which are small, cationic and amphipathic peptides that make part of the innate immune system, now arise as promising candidates for TB treatment. In this review, we analyze the potential of AMPs for this application. We address the mechanisms of action, advantages and disadvantages over conventional antibiotics and how problems associated with its use may be overcome to boost their therapeutic potential. Additionally, we address the challenges of translational development from benchside to bedside, evaluate the current development pipeline and analyze the expected global impact from a socio-economic standpoint. The quest for more efficient and more compliant anti-TB drugs, associated with the great therapeutic potential of emerging AMPs and the rising peptide market, provide an optimal environment for the emergence of AMPs as promising therapies. Still, their pharmacological properties need to be enhanced and manufacturing-associated issues need to be addressed. PMID:27235189

  7. 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.

  8. Drug Susceptibility Pattern of M.Tuberculosis Isolated from Patients Attending a Private Hospital

    Directory of Open Access Journals (Sweden)

    D. Sureshkumar

    2011-01-01

    Full Text Available Problem statement: Drug resistance in Tuberculosis (TB is an emerging problem that adversely affects patient outcome and public health in the developing world. Although much of tuberculosis care is provided by the private sector in India, the magnitude of drug resistance in TB in the private sector is not well described. The present study was carried out to determine the resistance pattern of tuberculosis in patients attending a large tertiary care hospital in South India. Approach: Anti-tuberculosis resistance patterns of all Mycobacterium tuberculosis (M.tb isolates in a tertiary care referral hospital from January 2010 to December 2010 were studied retrospectively. Isolates were grown in MB/BacT automated liquid culture system. Sensitivities to various anti-tuberculosis drugs were done by the proportion method on Lowenstein-Jensen (L-J media. Results: During the study period, sensitivity reports for 50 Mycobacterium isolates were available.14 (28% of the isolates were multi-drug resistant isolates (resistant to both isoniazid and rifampicin. Isolated resistance to isoniazid, rifampicin, ethambutol, pyrazinamide and streptomycin were 42, 32, 28, 48.28 and 44% respectively. Moxifloxacin was tested against only 12 tuberculosis isolates and was uniformly sensitive against all isolates tested. Conclusion: Nearly one third of M.tb isolates in a private sector tertiary care hospital were multi-drug resistant. Isolated resistance to ethambutol was the lowest among the first line anti-tuberculosis drugs and resistance to moxifloxacin was not seen in this study. Even allowing for referral bias, our results suggest that tertiary care hospitals which see complicated tuberculosis patients should routinely ask for susceptibility tests whenever M.tb is cultured.

  9. Risk factors and drug-resistance patterns among pulmonary tuberculosis patients in northern Karnataka region, India

    Directory of Open Access Journals (Sweden)

    Gajanan S Gaude

    2014-01-01

    Full Text Available Background: India is one of the high tuberculosis (TB-burden countries in the world. Resistance to anti-tuberculosis (anti-TB drugs has already become an important and alarming threat in most of the regions worldwide. India ranks second in the world in harbouring multi-drug resistant cases (MDRTB. Prevalence of MDR-TB mirrors the functional state and efficacy of TB control programmes and realistic attitude of the community towards implementation of such programmes. The most important risk factor in the development of MDRTB is improper implementation in the guidelines in the management of TB, and high rate of defaults on the part of the patients. The study was carried out to evaluate the drug resistance pattern to first line anti-TB drugs in Northern Karnataka region, India. Materials and Methods: A prospective study was conducted at J. N. Medical College and its associated Hospitals, Belgaum. Between January 2011 and December 2012, 150 sputum samples of suspected pulmonary TB patients based on the history were examined for the AFB culture by Lowenstein-Jensen (LJ culture technique. A total of two early morning samples were collected for the smear [Ziehl-Neelsen (ZN staining] and culture methods. It was observed that ZN staining for AFB was positive in 113 patients (75%, while AFB culture by LJ medium yielded growth in 66 cases (44%. Thus, a total of 66 AFB culture-positive samples by LJ medium were subjected for AFB drug-sensitivity testing (DST. DST was done for Isoniazid (INH, Rifampicin (RIF, Pyrazinamide (PZA, Ethambutol (EMB and Streptomycin (SM after isolation by using the resistance proportion method. Results: A total of 66 AFB culture-positive specimens, 20 (30.3% cases were sensitive to all the five drugs while 46 (69.7% cases showed resistance to one or more drugs. Among these, the resistance to rifampicin was highest (80.4%, while resistance to isoniazid, pyrazinamide, ethambutol and streptomycin were observed to be 60%, 58.7%, 52

  10. 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.

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

    Directory of Open Access Journals (Sweden)

    Divakar Sharma

    Full Text Available 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.

  12. 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. PMID:26436944

  13. 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.

  14. Comparative proteomic analysis of sequential isolates of Mycobacterium tuberculosis from a patient with pulmonary tuberculosis turning from drug sensitive to multidrug resistant

    Directory of Open Access Journals (Sweden)

    Amit Singh

    2015-01-01

    Full Text Available Background & objectives: Tuberculosis is a major health problem in India, and the emergence of multidrug resistant (MDR and extensively drug resistant (XDR strains of Mycobacterium tuberculosis (Mtb has further complicated the situation. Though several studies characterizing drug sensitive and drug resistant strains are available in literature, almost all studies are done on unrelated strains. Therefore, the objective of this study was to compare the proteomic data of four sequential isolates of Mtb from a single patient who developed MDR-TB during the course of anti-tuberculosis therapy (ATT. Methods: In this study, using two-dimensional (2D gel electrophoresis and MALDI-TOF mass spectrometry, we compared and analyzed the cell lysate proteins of Mtb sequential clinical isolates from a patient undergoing anti-TB treatment. The mRNA expression levels of selected identified proteins were determined by quantitative real-time polymerase chain reaction (qRT-PCR. Results: The genotypes of all four isolates remained homologous, indicating no re-infection. The initial isolate (before treatment was sensitive to all first-line drugs, but the consecutive isolates were found to be resistant to isoniazid (INH and rifampicin (RIF and developed mutations in the katG, inhA and rpoB. the intensities of 27 protein spots were found to be consistently overexpressed in INH and RIF resistant isolates. The most prominent and overexpressed proteins found during the development of drug resistance were GarA (Rv1827, wag31 (Rv2145c, Rv1437 and Rv2970c. Interpretation & conclusions: This preliminary proteomic study provides an insight about the proteins that are upregulated during drug resistance development. These upregulated proteins, identified here, could prove useful as immunodiagnostic and possibly drug resistant markers in future. However, more studies are required to confirm these findings.

  15. 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.

  16. Duration of Anti-Tuberculosis Therapy and Timing of Antiretroviral Therapy Initiation: Association with Mortality in HIV-Related Tuberculosis

    Science.gov (United States)

    Cortes, Claudia P.; Wehbe, Firas H.; McGowan, Catherine C.; Shepherd, Bryan E.; Duda, Stephany N.; Jenkins, Cathy A.; Gonzalez, Elsa; Carriquiry, Gabriela; Schechter, Mauro; Padgett, Denis; Cesar, Carina; Madero, Juan Sierra; Pape, Jean W.; Masys, Daniel R.; Sterling, Timothy R.

    2013-01-01

    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/mm3, 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. PMID:24066096

  17. Drug-resistant tuberculosis in Sindh

    International Nuclear Information System (INIS)

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

  18. Drug-Resistant Tuberculosis: Challenges and Progress.

    Science.gov (United States)

    Kurz, Sebastian G; Furin, Jennifer J; Bark, Charles M

    2016-06-01

    Antimicrobial resistance is a natural evolutionary process, which in the case of Mycobacterium tuberculosis is based on spontaneous chromosomal mutations, meaning that well-designed combination drug regimens provided under supervised therapy will prevent the emergence of drug-resistant strains. Unfortunately, limited resources, poverty, and neglect have led to the emergence of drug-resistant tuberculosis throughout the world. The international community has responded with financial and scientific support, leading to new rapid diagnostics, new drugs and regimens in advanced clinical development, and an increasingly sophisticated understanding of resistance mechanisms and their application to all aspects of TB control and treatment. PMID:27208770

  19. Overcoming drug resistance by regulating nuclear receptors

    OpenAIRE

    Chen, Taosheng

    2010-01-01

    Drug resistance involves multiple mechanisms. Multidrug resistance (MDR) is the leading cause of treatment failure in cancer therapy. Elevated levels of MDR proteins [members of the ATP-binding cassette (ABC) transporter family] increase cellular efflux and decrease the effectiveness of chemotherapeutic agents. As a salvage approach to overcome drug resistance, inhibitors of MDR proteins have been developed, but have had limited success mainly due to undesired toxicities. Nuclear receptors (N...

  20. Mycobacterium tuberculosis complex drug resistance pattern and identification of species causing tuberculosis in the West and Centre regions of Cameroon

    Directory of Open Access Journals (Sweden)

    Tedom Jean-Claude

    2011-04-01

    Full Text Available Abstract Background Data on the levels of resistance of Mycobacterium tuberculosis complex (MTBC strains to first line anti-tuberculosis drugs in Cameroon, and on the species of MTBC circulating in the country are obsolete. The picture about 10 years after the last studies, and 6 years after the re-organisation of the National Tuberculosis (TB Control Programme (NTBCP is not known. Methods The study was conducted from February to July 2009 in the West and Centre regions of Cameroon. A total of 756 suspected patients were studied. MTBC species were detected by the standard Ziehl-Neelsen staining method. Bacterial susceptibility to the first line drugs [isoniazid (INH, rifampicin (RIF, ethambutol (EMB and streptomycin (SM] were performed on cultures using the indirect proportion method. MTBC species were identified by standard biochemical and culture methods. Results Of the 756 suspected patients, 154 (20.37% were positive by smear microscopy. Of these, 20.77% were HIV patients. The growth of Mycobacterium was observed with the sputa from 149 (96.75% subjects. All the isolates were identified as either M. tuberculosis or M. africanum. Among these, 16 (10.73% were resistant to at least one drug (13.3% for the West region and 8.1% for the Centre. The initial resistance rates were 7.35% for the Centre region and 11.29% for the West region, while the acquired resistance rates were 16.66% (1/6 for the Centre region and 23.07% (3/13 for the West. Within the two regions, the highest total resistance to one drug was obtained with INH and SM (2.68% each. Multidrug-resistance (MDR was observed only in the West region at a rate of 6.67%. No resistance was recorded for EMB. Conclusions M. tuberculosis and M. africanum remain the MTBC species causing pulmonary TB in the West and Centre regions of Cameroon. Following the re-organisation of the NTBCP, resistance to all first line anti-TB drugs has declined significantly (p p

  1. 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.

  2. 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.

  3. 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

  4. 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.

  5. Antifungal drugs and resistance: Current concepts

    Directory of Open Access Journals (Sweden)

    Pramod Kumar Nigam

    2015-04-01

    Full Text Available Recently, clinical failure and relapses have been observed in patients treated with antifungals. Drug resistance has become an important problem leading to significant negative social, psychological, and occupational health effects and quality of life. Early recognition and treatment is essential to reduce morbidity and possibility of transmission. The increased use, inappropriate prescribing and over the counter sale of antifungal agents has also added in the development of resistance to these drugs. The main biochemical and molecular mechanisms that contribute to antifungal resistance include reduced uptake of the drug, an active transport out of the cell or modified drug metabolic degradation of the cell, changes in the interaction of the drug to the target site or other enzymes involved in the process by point mutations, overexpression of the target molecule, overproduction or mutation of the target enzyme, amplification and gene conversion (recombination, and increased cellular efflux and occurrence of biofilm. Although, there is considerable knowledge concerning the biochemical, genetic and clinical aspects of resistance to antifungal agents, expansion of our understanding of the mechanisms by which antifungal resistance emerges and spreads, quicker methods for the determination of resistance, targetting efflux pumps, especially ATP binding cassette (ABC transporters and heat shock protein 90, new drug delivery systems, optimizing therapy according to pharmacokinetic and pharmacodynamic characteristics, new classes of antifungal drugs that are active against azole-resistant isolates, and use of combinations of antifungal drugs or use of adjunctive immunostimulatory therapy and other modalities of treatment will clearly be important for future treatment strategies and in preventing development of resistance.

  6. Antimalarial drug resistance and combination chemotherapy.

    OpenAIRE

    White, N.

    1999-01-01

    Antimarial drug resistance develops when spontaneously occurring parasite mutants with reduced susceptibility are selected, and are then transmitted. Drugs for which a single point mutation confers a marked reduction in susceptibility are particularly vulnerable. Low clearance and a shallow concentration-effect relationship increase the chance of selection. Use of combinations of antimalarials that do not share the same resistance mechanisms will reduce the chance of selection because the cha...

  7. 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 ...

  8. 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.

  9. 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.

  10. Drug Resistance Proteins and Refractory Epilepsy

    OpenAIRE

    J Gordon Millichap

    2002-01-01

    Expression of multi-drug resistance gene-1 P-glycoprotein (MDR1) and multidrug resistance-associated protein 1 (MRP1) in refractory epilepsy was studied at the Epilepsy Research Group, Institutes of Neurology and Child Health, University College, London, and Radcliffe Infirmary, Oxford, UK.

  11. 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.

  12. 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

  13. 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.

  14. [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.

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

    Directory of Open Access Journals (Sweden)

    Veitch Zachary

    2008-11-01

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

  16. Coinfection and the evolution of drug resistance.

    Science.gov (United States)

    Hansen, J; Day, T

    2014-12-01

    Recent experimental work in the rodent malaria model has shown that when two or more strains share a host, there is competitive release of drug-resistant strains upon treatment. In other words, the propagule output of a particular strain is repressed when competing with other strains and increases upon the removal of this competition. This within-host effect is predicted to have an important impact on the evolution and growth of resistant strains. However, how this effect translates to epidemiological parameters at the between-host level, the level at which disease and resistance spread, has yet to be determined. Here we present a general, between-host epidemiological model that explicitly takes into account the effect of coinfection and competitive release. Although our model does show that when there is coinfection competitive release may contribute to the emergence of resistance, it also highlights an additional between-host effect. It is the combination of these two effects, the between-host effect and the within-host effect, that determines the overall influence of coinfection on the emergence of resistance. Therefore, even when competitive release of drug-resistant strains occurs, within an infected individual, it is not necessarily true that coinfection will result in the increased emergence of resistance. These results have important implications for the control of the emergence and spread of drug resistance. PMID:25417787

  17. Antimicrobial Drugs in Fighting against Antimicrobial Resistance.

    Science.gov (United States)

    Cheng, Guyue; Dai, Menghong; Ahmed, Saeed; Hao, Haihong; Wang, Xu; Yuan, Zonghui

    2016-01-01

    The outbreak of antimicrobial resistance, together with the lack of newly developed antimicrobial drugs, represents an alarming signal for both human and animal healthcare worldwide. Selection of rational dosage regimens for traditional antimicrobial drugs based on pharmacokinetic/pharmacodynamic principles as well as development of novel antimicrobials targeting new bacterial targets or resistance mechanisms are key approaches in tackling AMR. In addition to the cellular level resistance (i.e., mutation and horizontal gene transfer of resistance determinants), the community level resistance (i.e., bilofilms and persisters) is also an issue causing antimicrobial therapy difficulties. Therefore, anti-resistance and antibiofilm strategies have currently become research hotspot to combat antimicrobial resistance. Although metallic nanoparticles can both kill bacteria and inhibit biofilm formation, the toxicity is still a big challenge for their clinical applications. In conclusion, rational use of the existing antimicrobials and combinational use of new strategies fighting against antimicrobial resistance are powerful warranties to preserve potent antimicrobial drugs for both humans and animals. PMID:27092125

  18. Antimicrobial Drugs in Fighting against Antimicrobial Resistance

    Directory of Open Access Journals (Sweden)

    Guyue eCheng

    2016-04-01

    Full Text Available The outbreak of antimicrobial resistance, together with the lack of newly developed antimicrobial drugs, represents an alarming signal for both human and animal healthcare worldwide. Selection of rational dosage regimens for traditional antimicrobial drugs based on pharmacokinetic/pharmacodynamic principles as well as development of novel antimicrobials targeting new bacterial targets or resistance mechanisms are key approaches in tackling AMR. In addition to the cellular level resistance (i.e., mutation and horizontal gene transfer of resistance determinants, the community level resistance (i.e., bilofilms and persisters is also an issue causing antimicrobial therapy difficulties. Therefore, anti-resistance and antibiofilm strategies have currently become research hotspot to combat antimicrobial resistance. Although metallic nanoparticles can both kill bacteria and inhibit biofilm formation, the toxicity is still a big challenge for their clinical applications. In conclusion, rational use of the existing antimicrobials and combinational use of new strategies fighting against antimicrobial resistance are powerful warranties to preserve potent antimicrobial drugs for both humans and animals.

  19. Epithelial-mesenchymal Transition and Tumor Drug Resistance

    Directory of Open Access Journals (Sweden)

    Linlin ZHANG

    2013-01-01

    Full Text Available Resistance to antineoplastic drugs is a common problem in cancer treatments. Epithelial-mesenchymal transition (EMT, which plays an important role in the process of drug resistance, may provide opportunity to solve this problem. This article reviews the characteristics of EMT, relationship between EMT and drug resistance, mechanism of EMT in tumor drug resistance in details.

  20. Epithelial-mesenchymal Transition and Tumor Drug Resistance

    OpenAIRE

    Zhang, Linlin; Wu, Zhihao; Zhou, Qinghua

    2013-01-01

    Resistance to antineoplastic drugs is a common problem in cancer treatments. Epithelial-mesenchymal transition (EMT), which plays an important role in the process of drug resistance, may provide opportunity to solve this problem. This article reviews the characteristics of EMT, relationship between EMT and drug resistance, mechanism of EMT in tumor drug resistance in details.

  1. Drug resistance genomics of the antimalarial drug artemisinin.

    Science.gov (United States)

    Winzeler, Elizabeth A; Manary, Micah J

    2014-01-01

    Across the globe, over 200 million annual malaria infections result in up to 660,000 deaths, 77% of which occur in children under the age of five years. Although prevention is important, malaria deaths are typically prevented by using antimalarial drugs that eliminate symptoms and clear parasites from the blood. Artemisinins are one of the few remaining compound classes that can be used to cure multidrug-resistant Plasmodium falciparum infections. Unfortunately, clinical trials from Southeast Asia are showing that artemisinin-based treatments are beginning to lose their effectiveness, adding renewed urgency to the search for the genetic determinants of parasite resistance to this important drug class. We review the genetic and genomic approaches that have led to an improved understanding of artemisinin resistance, including the identification of resistance-conferring mutations in the P. falciparum kelch13 gene. PMID:25470531

  2. 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.

  3. Genomic diversity among drug sensitive and multidrug resistant isolates of Mycobacterium tuberculosis with identical DNA fingerprints.

    Directory of Open Access Journals (Sweden)

    Stefan Niemann

    and exogenous reinfection might be impossible using standard genotyping tools if the overall diversity of circulating clones is limited. These findings have important implications for clinical trials of new anti-tuberculosis drugs.

  4. 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.

  5. Antifungal drugs and resistance: Current concepts

    OpenAIRE

    Pramod Kumar Nigam

    2015-01-01

    Recently, clinical failure and relapses have been observed in patients treated with antifungals. Drug resistance has become an important problem leading to significant negative social, psychological, and occupational health effects and quality of life. Early recognition and treatment is essential to reduce morbidity and possibility of transmission. The increased use, inappropriate prescribing and over the counter sale of antifungal agents has also added in the development of resistance to the...

  6. Challenges of drug-resistant malaria

    OpenAIRE

    Sinha Shweta; Medhi Bikash; Sehgal Rakesh

    2014-01-01

    Over the past six decades, the drug resistance of Plasmodium falciparum has become an issue of utmost concern. Despite the remarkable progress that has been made in recent years in reducing the mortality rate to about 30% with the scaling-up of vector control, introduction of artemisinin-based combination therapies and other malaria control strategies, the confirmation of artemisinin resistance on the Cambodia–Thailand border threatened all the previous success. This review addresses the glob...

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

    Directory of Open Access Journals (Sweden)

    Rajmohan Rajamuthiah

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

  8. [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.

  9. [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. PMID:22413540

  10. 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.

  11. Challenges of drug-resistant malaria.

    Science.gov (United States)

    Sinha, Shweta; Medhi, Bikash; Sehgal, Rakesh

    2014-01-01

    Over the past six decades, the drug resistance of Plasmodium falciparum has become an issue of utmost concern. Despite the remarkable progress that has been made in recent years in reducing the mortality rate to about 30% with the scaling-up of vector control, introduction of artemisinin-based combination therapies and other malaria control strategies, the confirmation of artemisinin resistance on the Cambodia-Thailand border threatened all the previous success. This review addresses the global scenario of antimalarial resistance and factors associated with it, with the main emphasis on futuristic approaches like nanotechnology and stem cell therapy that may impede resistant malaria, along with novel medications which are preparing to enter the global antimalarial market. These novel studies are likely to escalate over the coming years and will hopefully help to reduce the burden of malaria. PMID:25402734

  12. Drug resistance genomics of the antimalarial drug artemisinin

    OpenAIRE

    Elizabeth A Winzeler; Manary, Micah J

    2014-01-01

    Across the globe, over 200 million annual malaria infections result in up to 660,000 deaths, 77% of which occur in children under the age of five years. Although prevention is important, malaria deaths are typically prevented by using antimalarial drugs that eliminate symptoms and clear parasites from the blood. Artemisinins are one of the few remaining compound classes that can be used to cure multidrug-resistant Plasmodium falciparum infections. Unfortunately, clinical trials from Southeast...

  13. 浙江省耐多药结核病例中二线耐药状况分析%Analysis on second-line drug resistance situation of multiple drug resistant tuberculosis in Zhejiang, China

    Institute of Scientific and Technical Information of China (English)

    陈松华; 王晓萌; 柳正卫; 何海波; 陈彬; 黄玉

    2011-01-01

    目的 通过对肺结核病耐药状况和耐药趋势的调查研究,掌握浙江省目前主要二线抗结核药的耐药状况,为耐药结核病疫情控制提供科学依据.方法 在全省随机抽取30个县区作为样本县,将选例期间发现的1077例涂阳病例纳入耐药监测;按规定要求进行分离培养、分枝杆菌菌种初步鉴定,用H37RV标准菌株常规质控监测,先使用比例法筛选耐药病例,对人组二线抗结核药耐药监测病例的菌株再使用绝对浓度法检测.结果 在耐多药(MDR)病例中各种二线抗结核药物的耐药率卡那霉素(K)9.62%,卷曲霉素(CPM)11.54%,丁胺卡那霉素(AK)7.69%,环丝氨酸(CS)5.77%,氧氟沙星(OFLX)28.85%,对氨基水杨酸(PAS)32.69%.MDR病例中广泛耐药结核病(XDR )耐药率3.85%.结论 调查结果显示浙江省的二线抗结核药物耐药状况比较严重,耐药结核病的控制面临挑战,有必要在今后的工作中进一步提高现代结核病控制策略(DOTS)执行质量,加强实验室对MDR,XDR的检测能力,完善耐药结核病诊疗管理综合体系建设.%Objective To investigate mycobacteriutn tuberculosis drug resistance to second-line drugs in Zhejiang and provide a scientific basis for the prevention and control of drug-resistant TB epidemic. Methods We randomly selected 30 counties for the study. Samples from the selected counties were entered into the group of surveillance if the specimens were smear-positive. The procedures of mycobacteri-um isolation, culture and primary species identification were performed under the guidelines of the Laboratory Procedure of Diagnostic Bacteriology in Tuberculosis. Results The surveillance group had 1 077 smear-positive tuberculosis specimens. Among multiple drug resistant (MDR) cases, the rates of anti-tuberculosis drug resistance to second-line drugs were 9.62%, 11.54%, 7.69%, 5.77%, 28.85% and 32.69% respectively for kanamycin (K), capreomycin (CPM), amikacin (AK), cycloserine (CS

  14. 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.

  15. Multi Drug Resistant (MDR and Extensively Resistant (XDR Tuberculosis

    Directory of Open Access Journals (Sweden)

    Salih Cesur

    2013-08-01

    Full Text Available Multi drug resistant tuberculosis (MDR-TB is defined as tuberculosis that is resistant to at least isoniazid and rifampicin, the two most powerful first-line anti-TB drugs. Extensively drug resistant tuberculosis (XDR-TB is defined as tuberculosis that is resistant to resistant to isoniazid and rifampin and to any fluoroquinolone and at least one of three injectable second-line drugs (namely, amikacin, kanamicin, or capreomycin. MDR-TB and XDR- TB are great dangers that threaten the public health. XDR-TB has been reported from many countries including the United States. In Turkey, among newly diagnosed cases, it was reported that the number of MDR-TB patients was 101 (3.1%, MDR-TB rate in the retreatment cases was 17.7% (90 patients, and MDR-TB rate in all cases was 5.1 (191 patients in 2005. The percentages were calculated through the number of patients who were tested in terms of susceptibility for both isoniazide and rifampin. In 2009, it was reported that the number of MDR-TB patients was 99 (2.7% among newly diagnosed cases, it was 123 (20.5 % in the retreatment cases and the total number of MDR-TB cases was 222 (5.1%. The first patient with XDR-TB was identified in 2010 in Turkey. Diagnosis of XDR TB takes several weeks by using conventional culture-based methods, although (however some molecular test can detect it rapidly. Treatment of XDR-TB patients is difficult and usually requiring at least 18-24 months of four to six second-line anti-TB drugs. The success rate with the treatment is about 30-50%, and mortality rate is higher in HIV-infected patients. Prevention of contact to XDR-TB patients is more complicated by the lack of a proven effective preventive treatment for XDR latent tuberculosis infection. Rapid diagnostic tests and new anti-TB drugs are needed to control the spread of this worldwide public health problem. [Dis Mol Med 2013; 1(4.000: 72-76

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

    Science.gov (United States)

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

    2011-10-01

    Among the aetiological agents of treatable sexually transmitted diseases (STDs), Neissseria gonorrhoeae is considered to be most important because of emerging antibiotic resistant strains that compromise the effectiveness of treatment of the disease - gonorrhoea. In most of the developing countries, treatment of gonorrhoea relies mainly on syndromic management rather than the aetiological based therapy. Gonococcal infections are usually treated with single-dose therapy with an agent found to cure > 95 per cent of cases. Unfortunately during the last few decades, N. gonorrhoeae has developed resistance not only to less expensive antimicrobials such as sulphonamides, penicillin and tetracyclines but also to fluoroquinolones. The resistance trend of N. gonorrhoeae towards these antimicrobials can be categorised into pre-quinolone, quinolone and post-quinolone era. Among the antimicrobials available so far, only the third-generation cephalosporins could be safely recommended as first-line therapy for gonorrhoea globally. However, resistance to oral third-generation cephalosporins has also started emerging in some countries. Therefore, it has become imperative to initiate sustained national and international efforts to reduce infection and misuse of antibiotics so as to prevent further emergence and spread of antimicrobial resistance. It is necessary not only to monitor drug resistance and optimise treatment regimens, but also to gain insight into how gonococcus develops drug resistance. Knowledge of mechanism of resistance would help us to devise methods to prevent the occurrence of drug resistance against existing and new drugs. Such studies could also help in finding out new drug targets in N. gonorrhoeae and also a possibility of identification of new drugs for treating gonorrhoea. PMID:22089602

  17. 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 ...

  18. Antibacterial Cleaning Products and Drug Resistance

    OpenAIRE

    Aiello, Allison E.; Marshall, Bonnie; Levy, Stuart B.; Della-Latta, Phyllis; Lin, Susan X.; Larson, Elaine

    2005-01-01

    We examined whether household use of antibacterial cleaning and hygiene products is an emerging risk factor for carriage of antimicrobial drug–resistant bacteria on hands of household members. Households (N = 224) were randomized to use of antibacterial or nonantibacterial cleaning and hygiene products for 1 year. Logistic regression was used to assess the influence of antibacterial product use in homes. Antibacterial product use did not lead to a significant increase in antimicrobial drug re...

  19. The challenge of developing robust drugs to overcome resistance

    OpenAIRE

    Anderson, Amy C; Schiffer, Celia; Pollastri, Michael; Peet, Norton P.

    2011-01-01

    Drug resistance is problematic in microbial disease, viral disease and cancer. Understanding at the outset that resistance will impact the effectiveness of any new drug that is developed for these disease categories is imperative. In this Feature, we detail approaches that have been taken with selected drug targets to reduce the susceptibility of new drugs to resistance mechanisms. We will also define the concepts of robust drugs and resilient targets, and discuss how the design of robust dru...

  20. HIV antiviral drug resistance: patient comprehension.

    Science.gov (United States)

    Racey, C Sarai; Zhang, Wendy; Brandson, Eirikka K; Fernandes, Kimberly A; Tzemis, Despina; Harrigan, P Richard; Montaner, Julio S G; Barrios, Rolando; Toy, Junine; Hogg, Robert S

    2010-07-01

    A patient's understanding and use of healthcare information can affect their decisions regarding treatment. Better patient understanding about HIV resistance may improve adherence to therapy, decrease population viral load and extend the use of first-line HIV therapies. We examined knowledge of developing HIV resistance and explored treatment outcomes in a cohort of HIV+ persons on highly active antiretroviral therapy (HAART). The longitudinal investigations into supportive and ancillary health services (LISA) cohort is a prospective study of HIV+ persons on HAART. A comprehensive interviewer-administrated survey collected socio-demographic variables. Drug resistance knowledge was determined using a three-part definition. Clinical markers were collected through linkage with the Drug Treatment Program (DTP) at the British Columbia Centre for Excellence in HIV/AIDS. Categorical variables were compared using Fisher's Exact Test and continuous variables using the Wilcoxon rank-sum test. Proportional odds logistic regression was performed for the adjusted multivariable analysis. Of 457 LISA participants, less than 4% completely defined HIV resistance and 20% reported that they had not discussed resistance with their physician. Overall, 61% of the cohort is >or=95% adherent based on prescription refills. Owing to small numbers pooling was preformed for analyses. The model showed that being younger (OR=0.97, 95% CI: 0.95-0.99), having greater than high school education (OR=1.64, 95% CI: 1.07-2.51), discussing medication with physicians (OR=3.67, 95% CI: 1.76-7.64), having high provider trust (OR=1.02, 95% CI: 1.01-1.03), and receiving one-to-one counseling by a pharmacist (OR=2.14, 95% CI: 1.41-3.24) are predictive of a complete or partial definition of HIV resistance. The probability of completely defining HIV resistance increased from 15.8 to 63.9% if respondents had discussed HIV medication with both a physician and a pharmacist. Although the understanding of HIV

  1. 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.

  2. Drug Resistant Tuberculosis — Is There Hope?

    OpenAIRE

    Manish Kumar Goel; Pardeep Khanna

    2010-01-01

    Tuberculosis remains a worldwide public healthproblem. India has the highest burden of tuberculosis inthe world and accounts for nearly 2/5th of global burdenand 2/3rd of burden in SEAR countries. The XDR- TB wasfirst described in March 2006 and has also beenreported in India. The emergence of XDR – TB isassociated with a very low probability cure and a highcase fatality as evidenced by various researchers.Extensively drug-resistant tuberculosis is rapidly fatal ifnot treated. Some studies re...

  3. Aberrant splicing and drug resistance in AML.

    Science.gov (United States)

    de Necochea-Campion, Rosalia; Shouse, Geoffrey P; Zhou, Qi; Mirshahidi, Saied; Chen, Chien-Shing

    2016-01-01

    The advent of next-generation sequencing technologies has unveiled a new window into the heterogeneity of acute myeloid leukemia (AML). In particular, recurrent mutations in spliceosome machinery and genome-wide aberrant splicing events have been recognized as a prominent component of this disease. This review will focus on how these factors influence drug resistance through altered splicing of tumor suppressor and oncogenes and dysregulation of the apoptotic signaling network. A better understanding of these factors in disease progression is necessary to design appropriate therapeutic strategies recognizing specific alternatively spliced or mutated oncogenic targets. PMID:27613060

  4. 交联可调式抗结核药物缓释型纳米人工骨体内成骨的观察%Osteogenetic capacity of cross-linked adjustable anti-tuberculosis drug sustained-release artificial composite

    Institute of Scientific and Technical Information of China (English)

    席焱海; 薛敏涛; 叶晓健; 徐宁; 瞿金涛; 刘希麟; 何海龙

    2013-01-01

    目的 观察新型复合材料交联可调式抗结核药物缓释型纳米人工骨复合体(TPB/SA-RFP/PLA)的成骨效能.方法 建立兔股骨骨缺损模型,将TPB/SA-RFP/PLA复合体作为实验组(A组),缺损区填入TPB/SA/PLA材料作为对照组(B组),缺损区不做处理作为空白对照组(C组).分别在术后4、8、12周进行取材,对大体标本进行X线扫描、固定后组织染色和免疫组化定性分析,进而确定交联抗结核药的人工骨复合体的体内成骨性能.结果 大体及组织学观察和X线显示TPB/SA-RFP/PLA复合体同对照组相比较有着良好的成骨效能.同TPB/SA/PLA组比较成骨效能无明显差别.lane-sandhu组织学评分:A组(7.5±0.5)分、B组(7.2±0.3)分、C组(2.5±0.4)分.lane-sandhuX线评分术后12周:A组(8.3±0.3)分、B组(8.6±0.2)分、C组(2.2±0.4)分.TPB/SA-RFP/PLA材料组与空白对照组差异有统计学意义(P<0.05),与TPB/SA/PLA材料组间差异无统计学意义(P>0.05).免疫组化结果显示两组材料组ALP染色呈强阳性,对照组呈弱阳性.结论 复合材料TPB/SA-RFP/PLA具有很好的骨传导性和骨再生能力,复合利福平抗结核药物后不影响复合材料的体内成骨能力.%Objective To explore the osteogenetic capacity of cross-linked adjustable antituberculosis drug sustained-release artificial composite (TPB/SA-RFP/PLA).Methods The model of femur bone defect was established in rabbits.TPB/SA-RFP/PLA complex was implanted into defect parts in the experimental group while TPB/SA/PLA in the blank control group.At Weeks 4,8 and 12,gross specimens received radiographic,histological and immunohistochemical examinations to determine the osteogenetic performance of TPB/SA-RFP/PLA.Results As compared with the control group,TPB/SA-RFP/PLA complex had excellent osteogenic capacities while the TPB/SA/PLA group had no obvious osteogenic difference.Lane-sandhu histological and radiographic ratings demonstrated significant difference between

  5. The medical and surgical treatment of drug-resistant tuberculosis

    OpenAIRE

    Calligaro, Gregory L.; Moodley, Loven; Symons, Greg; Dheda, Keertan

    2014-01-01

    Multi drug-resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB) are burgeoning global problems with high mortality which threaten to destabilise TB control programs in several parts of the world. Of alarming concern is the emergence, in large numbers, of patients with resistance beyond XDR-TB (totally drug-resistant TB; TDR-TB or extremely drug resistant TB; XXDR-TB). Given the burgeoning global phenomenon of MDR-TB, XDR-TB and TDR-TB, and increasing international migrat...

  6. Evaluation of Idaho's DARE "Drug Abuse Resistance Education Projects."

    Science.gov (United States)

    Silva, Roberta K.

    The goal of DARE (Drug Abuse Resistance Education) is not to completely eliminate the drug and alcohol problems of society. It is a proactive prevention program designed to equip youth (focusing on elementary school) with skills for resisting peer pressure to experiment with drugs, and to manage anger without resorting to violence or the use of…

  7. Evaluation of Idaho's DARE "Drug Abuse Resistance Education" Projects.

    Science.gov (United States)

    Silva, Roberta K.

    The DARE (Drug Abuse Resistance Education) program teaches students decision-making skills, shows them how to resist peer pressure to experiment with drugs and alcohol, and provides positive alternatives to drug use. This report looks at one state's DARE programs. Included are an overview of the implementation process, a program appraisal with…

  8. Bedaquiline: A novel antitubercular drug for multidrug-resistant tuberculosis

    Directory of Open Access Journals (Sweden)

    H Nagabushan

    2014-01-01

    Full Text Available Multidrug-resistant and extensively drug-resistant tuberculosis (TB are emerging global health threats. Bedaquiline is a new antituberculous drug belonging to the diarylquinoline class that efficiently inhibits the adenosine triphosphate synthase enzyme of Mycobacterium tuberculosis. It is a bactericidal and long-acting drug. It inhibits both dormant as well as replicating bacterial sub-populations and thus shortens the duration of TB treatment. This drug has been approved by the Food and Drug Administration in December 2012 for the management of multidrug resistant-TB. The drug marks the introduction of a new addition to the TB armamentarium after four decades.

  9. Predicted levels of HIV drug resistance

    DEFF Research Database (Denmark)

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

    2014-01-01

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

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

    International Nuclear Information System (INIS)

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

  11. Molecular epidemiology study of Mycobacterium tuberculosis and its susceptibility to anti-tuberculosis drugs in Indonesia

    OpenAIRE

    Lisdawati, Vivi; Puspandari, Nelly; Rif’ati, Lutfah; Soekarno, Triyani; M, Melatiwati; K, Syamsidar; Ratnasari, Lies; Izzatun, Nur; Parwati, Ida

    2015-01-01

    Background Genotyping of Mycobacterium tuberculosis helps to understand the molecular epidemiology of tuberculosis and to address evolutionary questions about the disease spread. Certain genotypes also have implications for the spread of infection and treatment. Indonesia is a very diverse country with a population with multiple ethnicities and cultures and a history of many trade and tourism routes. This study describes the first attempt to map the molecular epidemiology of TB in the Indones...

  12. 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

  13. Stop the Spread of Superbugs: Help Fight Drug Resistant Bacteria

    Science.gov (United States)

    ... the Spread of Superbugs Help Fight Drug-Resistant Bacteria For nearly a century, bacteria-fighting drugs known as antibiotics have helped to control and destroy many of the harmful bacteria that can make us sick. But in recent ...

  14. Nanomedicine therapeutic approaches to overcome cancer drug resistance.

    Science.gov (United States)

    Markman, Janet L; Rekechenetskiy, Arthur; Holler, Eggehard; Ljubimova, Julia Y

    2013-11-01

    Nanomedicine is an emerging form of therapy that focuses on alternative drug delivery and improvement of the treatment efficacy while reducing detrimental side effects to normal tissues. Cancer drug resistance is a complicated process that involves multiple mechanisms. Here we discuss the major forms of drug resistance and the new possibilities that nanomedicines offer to overcome these treatment obstacles. Novel nanomedicines that have a high ability for flexible, fast drug design and production based on tumor genetic profiles can be created making drug selection for personal patient treatment much more intensive and effective. This review aims to demonstrate the advantage of the young medical science field, nanomedicine, for overcoming cancer drug resistance. With the advanced design and alternative mechanisms of drug delivery known for different nanodrugs including liposomes, polymer conjugates, micelles, dendrimers, carbon-based, and metallic nanoparticles, overcoming various forms of multi-drug resistance looks promising and opens new horizons for cancer treatment. PMID:24120656

  15. Klebsiella pneumoniae Antimicrobial Drug Resistance, United States, 1998–2010

    OpenAIRE

    Sanchez, Guillermo V.; Master, Ronald N; Clark, Richard B.; Fyyaz, Madiha; Duvvuri, Padmaraj; Ekta, Gupta; Bordon, Jose

    2013-01-01

    We studied antimicrobial-resistant Klebsiella pneumoniae for 1998–2010 by using data from The Surveillance Network. Susceptibility results (n = 3,132,354) demonstrated significant increases in resistance to all antimicrobial drugs studied, except tetracycline. Cross-resistance among carbapenem-resistant K. pneumoniae was lower for tetracycline and amikacin.

  16. New Developments in Antiepileptic Drug Resistance: An Integrative View

    OpenAIRE

    Schmidt, Dieter; Löscher, Wolfgang

    2009-01-01

    Current theories on drug resistance in epilepsy include the drug transporter hypothesis, the drug target hypothesis, and a novel approach called the inherent severity model of epilepsy, which posits that the severity of the disease determines its relative response to medication. Valuable as each of these hypotheses is, none is currently a stand-alone theory that is able to convincingly explain drug resistance in human epilepsy. As a consequence, it may be of interest to update and integrate t...

  17. Bedaquiline: A novel antitubercular drug for multidrug-resistant tuberculosis

    OpenAIRE

    Nagabushan, H.; H. S. Roopadevi

    2014-01-01

    Multidrug-resistant and extensively drug-resistant tuberculosis (TB) are emerging global health threats. Bedaquiline is a new antituberculous drug belonging to the diarylquinoline class that efficiently inhibits the adenosine triphosphate synthase enzyme of Mycobacterium tuberculosis. It is a bactericidal and long-acting drug. It inhibits both dormant as well as replicating bacterial sub-populations and thus shortens the duration of TB treatment. This drug has been approved by the Food and Dr...

  18. 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. PMID:27463566

  19. Public health implications of antiretroviral therapy and HIV drug resistance.

    Science.gov (United States)

    Wainberg, M A; Friedland, G

    1998-06-24

    Widespread use of antiretroviral agents and increasing occurrence of human immunodeficiency virus (HIV) strains resistant to these drugs have given rise to a number of important issues. Some of these concerns are distinct from the obvious question of the relationship between drug resistance and treatment failure and have potentially widespread public health implications. The relevant issues include but are not limited to the following: (1) frequency with which drug-resistant virus may be transmitted via sexual, intravenous, or mother-to-child routes; (2) ability of drug-resistant variants to be transmitted, a question that relates, in part, to the relative fitness of such strains; (3) effectiveness of antiviral therapy in diminishing viral burden in both blood and genital secretions, and whether this may be compromised in persons harboring resistant virus; and (4) importance of patient adherence to antiviral therapy and its relationship to sustained reduction in viral load to minimize the appearance in and transmission of drug-resistant virus from both blood and genital secretions. Thus, prevention of both development of HIV drug resistance as well as transmission of drug-resistant variants is a central issue of public health importance. Unless this topic is appropriately addressed, the likelihood is that drug-resistant variants of HIV, if able to successfully replicate, will sustain the epidemic and limit the effectiveness of antiviral therapy. PMID:9643862

  20. Explaining risk factors for drug-resistant tuberculosis in England and Wales: contribution of primary and secondary drug resistance

    OpenAIRE

    Conaty, S. J.; Hayward, A. C.; Story, A; Glynn, J.R.; Drobniewski, F A; Watson, J.M.

    2004-01-01

    Drug-resistant tuberculosis can be transmitted (primary) or develop during the course of treatment (secondary). We investigated risk factors for each type of resistance. We compared all patients in England and Wales with isoniazid- and multidrug-resistant tuberculosis in two time-periods (1993-1994 and 1998-2000) with patients with fully sensitive tuberculosis, examining separately patients without and with previous tuberculosis (a proxy for primary and secondary drug-resistant tuberculosis)....

  1. 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.

  2. Adaptation and evolution of drug-resistant Mycobacterium tuberculosis

    NARCIS (Netherlands)

    I.L. Bergval

    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

  3. 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.

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

    Directory of Open Access Journals (Sweden)

    Guillaume Chevereau

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

  5. Overcome Cancer Cell Drug Resistance Using Natural Products

    Directory of Open Access Journals (Sweden)

    Pu Wang

    2015-01-01

    Full Text Available Chemotherapy is one of the major treatment methods for cancer. However, failure in chemotherapy is not uncommon, mainly due to dose-limiting toxicity associated with drug resistance. Management of drug resistance is important towards successful chemotherapy. There are many reports in the Chinese literature that natural products can overcome cancer cell drug resistance, which deserve sharing with scientific and industrial communities. We summarized the reports into four categories: (1 in vitro studies using cell line models; (2 serum pharmacology; (3 in vivo studies using animal models; and (4 clinical studies. Fourteen single compounds were reported to have antidrug resistance activity for the first time. In vitro, compounds were able to overcome drug resistance at nontoxic or subtoxic concentrations, in a dose-dependent manner, by inhibiting drug transporters, cell detoxification capacity, or cell apoptosis sensitivity. Studies in vivo showed that single compounds, herbal extract, and formulas had potent antidrug resistance activities. Importantly, many single compounds, herbal extracts, and formulas have been used clinically to treat various diseases including cancer. The review provides comprehensive data on use of natural compounds to overcome cancer cell drug resistance in China, which may facilitate the therapeutic development of natural products for clinical management of cancer drug resistance.

  6. Mycobacterium tuberculosis resistance to antituberculosis drugs in Mozambique

    Directory of Open Access Journals (Sweden)

    Germano Manuel Pires

    2014-04-01

    Full Text Available OBJECTIVE: To determine the drug resistance profile of Mycobacterium tuberculosis in Mozambique. METHODS: We analyzed secondary data from the National Tuberculosis Referral Laboratory, in the city of Maputo, Mozambique, and from the Beira Regional Tuberculosis Referral Laboratory, in the city of Beira, Mozambique. The data were based on culture-positive samples submitted to first-line drug susceptibility testing (DST between January and December of 2011. We attempted to determine whether the frequency of DST positivity was associated with patient type or provenance. RESULTS: During the study period, 641 strains were isolated in culture and submitted to DST. We found that 374 (58.3% were resistant to at least one antituberculosis drug and 280 (43.7% were resistant to multiple antituberculosis drugs. Of the 280 multidrug-resistant tuberculosis cases, 184 (65.7% were in previously treated patients, most of whom were from southern Mozambique. Two (0.71% of the cases of multidrug-resistant tuberculosis were confirmed to be cases of extensively drug-resistant tuberculosis. Multidrug-resistant tuberculosis was most common in males, particularly those in the 21-40 year age bracket. CONCLUSIONS: M. tuberculosis resistance to antituberculosis drugs is high in Mozambique, especially in previously treated patients. The frequency of M. tuberculosis strains that were resistant to isoniazid, rifampin, and streptomycin in combination was found to be high, particularly in samples from previously treated patients.

  7. Bedaquiline: A novel drug to combat multiple drug-resistant tuberculosis

    OpenAIRE

    Divya Goel

    2014-01-01

    Tuberculosis (TB) is among the most common infectious diseases and continues as a major global health problem. The scenario is worsened by the emergence and spread of multiple drug-resistant tuberculosis (MDR-TB) and extensive drug-resistant tuberculosis (XDR-TB). Cure rates are high for drug sensitive strains of Myobacterium tuberculosis if treatment protocols are adhered to, but treatment of MDR-TB and extensive drug drug-resistant strains is virtually impossible. The treatment of MDR-TB an...

  8. 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.

  9. Totally drug-resistant tuberculosis and adjunct therapies.

    Science.gov (United States)

    Parida, S K; Axelsson-Robertson, R; Rao, M V; Singh, N; Master, I; Lutckii, A; Keshavjee, S; Andersson, J; Zumla, A; Maeurer, M

    2015-04-01

    The first cases of totally drug-resistant (TDR) tuberculosis (TB) were reported in Italy 10 years ago; more recently, cases have also been reported in Iran, India and South Africa. Although there is no consensus on terminology, it is most commonly described as 'resistance to all first- and second-line drugs used to treat TB'. Mycobacterium tuberculosis (M.tb) acquires drug resistance mutations in a sequential fashion under suboptimal drug pressure due to monotherapy, inadequate dosing, treatment interruptions and drug interactions. The treatment of TDR-TB includes antibiotics with disputed or minimal effectiveness against M.tb, and the fatality rate is high. Comorbidities such as diabetes and infection with human immunodeficiency virus further impact on TB treatment options and survival rates. Several new drug candidates with novel modes of action are under late-stage clinical evaluation (e.g., delamanid, bedaquiline, SQ109 and sutezolid). 'Repurposed' antibiotics have also recently been included in the treatment of extensively drug resistant TB. However, because of mutations in M.tb, drugs will not provide a cure for TB in the long term. Adjunct TB therapies, including therapeutic vaccines, vitamin supplementation and/or repurposing of drugs targeting biologically and clinically relevant molecular pathways, may achieve better clinical outcomes in combination with standard chemotherapy. Here, we review broader perspectives of drug resistance in TB and potential adjunct treatment options. PMID:24809736

  10. Antimicrobial (Drug) Resistance: Methicillin-Resistant Staphylococcus aureus (MRSA)

    Science.gov (United States)

    ... Marketing Share this: Main Content Area Methicillin-Resistant Staphylococcus aureus (MRSA) During the past four decades, methicillin-resistant Staphylococcus aureus , or MRSA, has evolved from a controllable ...

  11. 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.

  12. Fitness of Leishmania donovani parasites resistant to drug combinations.

    Directory of Open Access Journals (Sweden)

    Raquel García-Hernández

    2015-04-01

    Full Text Available Drug resistance represents one of the main problems for the use of chemotherapy to treat leishmaniasis. Additionally, it could provide some advantages to Leishmania parasites, such as a higher capacity to survive in stress conditions. In this work, in mixed populations of Leishmania donovani parasites, we have analyzed whether experimentally resistant lines to one or two combined anti-leishmanial drugs better support the stress conditions than a susceptible line expressing luciferase (Luc line. In the absence of stress, none of the Leishmania lines showed growth advantage relative to the other when mixed at a 1:1 parasite ratio. However, when promastigotes from resistant lines and the Luc line were mixed and exposed to different stresses, we observed that the resistant lines are more tolerant of different stress conditions: nutrient starvation and heat shock-pH stress. Further to this, we observed that intracellular amastigotes from resistant lines present a higher capacity to survive inside the macrophages than those of the control line. These results suggest that resistant parasites acquire an overall fitness increase and that resistance to drug combinations presents significant differences in their fitness capacity versus single-drug resistant parasites, particularly in intracellular amastigotes. These results contribute to the assessment of the possible impact of drug resistance on leishmaniasis control programs.

  13. 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 ...

  14. 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.

  15. 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.

  16. Bedaquiline for the treatment of drug-resistant tuberculosis.

    Science.gov (United States)

    Bélard, Sabine; Heuvelings, Charlotte C; Janssen, Saskia; Grobusch, Martin P

    2015-05-01

    Bedaquiline is a much-needed novel drug which is highly effective against drug-resistant tuberculosis. While its clinical development has been laudably fast-tracked and the drug is now available for inclusion into treatment regimens when no suitable alternatives exist, clinical experience with bedaquiline is still limited. Phase III trial data and Phase IV studies are needed particularly to study different patient populations and to optimize treatment regimens. Drug resistance to bedaquiline needs to be monitored carefully, and full access to bedaquiline treatment where it is appropriate and needed must be promoted. PMID:25797824

  17. Drug-resistant epilepsy associated with cortical dysplasias

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    I. E. Poverennova

    2013-12-01

    Full Text Available Epilepsy associated with malformations of the cerebral cortex is reported in the literature to account for up to 25% of the total cases of symptomatic epilepsies. It is characterized by the most severe course and often induces drug-resistance in seizures. A group of patients with resistant seizures is singled out among the total number of patients with symptomatic epilepsy caused by cerebral cortical dysgenesis. The most important risk factors for resistance are identified in dysplasias. The prognostically unfavorable clinical features of epilepsy are described. A diagnostic algorithm is proposed to identify risk groups and to prevent drug-resistant forms of epilepsy.

  18. Bedaquiline: A novel drug to combat multiple drug-resistant tuberculosis

    Directory of Open Access Journals (Sweden)

    Divya Goel

    2014-01-01

    Full Text Available Tuberculosis (TB is among the most common infectious diseases and continues as a major global health problem. The scenario is worsened by the emergence and spread of multiple drug-resistant tuberculosis (MDR-TB and extensive drug-resistant tuberculosis (XDR-TB. Cure rates are high for drug sensitive strains of Myobacterium tuberculosis if treatment protocols are adhered to, but treatment of MDR-TB and extensive drug drug-resistant strains is virtually impossible. The treatment of MDR-TB and XDR-TB relies on the drugs, which are less potent, more toxic and more costly and have to be administered for the longer duration. No new drug had come in to market for last 40 years, but the emergence of MDR-TB and XDR-TB has spurred interest in the development of novel drugs. For the effective treatment outcome, there is a dire need of new drugs with a different mechanism of action that can tackle both drug sensitive as well as drug-resistant strains. Bedaquiline is one such new drug with unique mechanism of action. Food and Drug Administration has approved bedaquiline for MDR-TB in December 2012. This article reviews the available evidence of efficacy and safety of bedaquiline.

  19. 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...

  20. Antibiotics in Animal Feed Contribute to Drug-Resistant Germs

    Science.gov (United States)

    ... medlineplus/news/fullstory_158316.html Antibiotics in Animal Feed Contribute to Drug-Resistant Germs: Study Individual farm ... HealthDay News) -- Use of antibiotics in farm animal feed is helping drive the worldwide increase in antibiotic- ...

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

    Directory of Open Access Journals (Sweden)

    Silvie Huijben

    2013-09-01

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

  2. Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis.

    NARCIS (Netherlands)

    Gandhi, N.R.; Nunn, P.; Dheda, K.; Schaaf, H.S.; Zignol, M.; Soolingen, D. van; Jensen, P.; Bayona, J.

    2010-01-01

    Although progress has been made to reduce global incidence of drug-susceptible tuberculosis, the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis during the past decade threatens to undermine these advances. However, countries are responding far too slowly. Of

  3. 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

  4. Targeting imperfect vaccines against drug-resistance determinants: a strategy for countering the rise of drug resistance.

    Directory of Open Access Journals (Sweden)

    Regina Joice

    Full Text Available The growing prevalence of antimicrobial resistance in major pathogens is outpacing discovery of new antimicrobial classes. Vaccines mitigate the effect of antimicrobial resistance by reducing the need for treatment, but vaccines for many drug-resistant pathogens remain undiscovered or have limited efficacy, in part because some vaccines selectively favor pathogen strains that escape vaccine-induced immunity. A strain with even a modest advantage in vaccinated hosts can have high fitness in a population with high vaccine coverage, which can offset a strong selection pressure such as antimicrobial use that occurs in a small fraction of hosts. We propose a strategy to target vaccines against drug-resistant pathogens, by using resistance-conferring proteins as antigens in multicomponent vaccines. Resistance determinants may be weakly immunogenic, offering only modest specific protection against resistant strains. Therefore, we assess here how varying the specific efficacy of the vaccine against resistant strains would affect the proportion of drug-resistant vs. -sensitive strains population-wide for three pathogens--Streptococcus pneumoniae, Staphylococcus aureus, and influenza virus--in which drug resistance is a problem. Notably, if such vaccines confer even slightly higher protection (additional efficacy between 1% and 8% against resistant variants than sensitive ones, they may be an effective tool in controlling the rise of resistant strains, given current levels of use for many antimicrobial agents. We show that the population-wide impact of such vaccines depends on the additional effect on resistant strains and on the overall effect (against all strains. Resistance-conferring accessory gene products or resistant alleles of essential genes could be valuable as components of vaccines even if their specific protective effect is weak.

  5. 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.

  6. Fitness of Leishmania donovani parasites resistant to drug combinations.

    OpenAIRE

    Raquel García-Hernández; Verónica Gómez-Pérez; Santiago Castanys; Francisco Gamarro

    2015-01-01

    Drug resistance represents one of the main problems for the use of chemotherapy to treat leishmaniasis. Additionally, it could provide some advantages to Leishmania parasites, such as a higher capacity to survive in stress conditions. In this work, in mixed populations of Leishmania donovani parasites, we have analyzed whether experimentally resistant lines to one or two combined anti-leishmanial drugs better support the stress conditions than a susceptible line expressing luciferase (Luc lin...

  7. Tiagabine add-on for drug-resistant partial epilepsy

    OpenAIRE

    Pereira, J; Marson, A G; Hutton, J L

    2012-01-01

    Cochrane Database Syst Rev. 2002;(3):CD001908. Tiagabine add-on for drug-resistant partial epilepsy. Pereira J, Marson AG, Hutton JL. Servico de Neurologia, Hospital de Santo Antonio, Largo Prof. Abel Salazar, 4099-001 Porto, Portugal. Abstract BACKGROUND: Epilepsy is a common neurological condition, affecting almost 0.5 to 1 per cent of the population. Nearly 30 per cent of people with epilepsy are resistant to currently available drugs. Tiagabine...

  8. Nanodrug Formed by Coassembly of Dual Anticancer Drugs to Inhibit Cancer Cell Drug Resistance.

    Science.gov (United States)

    Zhao, Yuanyuan; Chen, Fei; Pan, Yuanming; Li, Zhipeng; Xue, Xiangdong; Okeke, Chukwunweike Ikechukwu; Wang, Yifeng; Li, Chan; Peng, Ling; Wang, Paul C; Ma, Xiaowei; Liang, Xing-Jie

    2015-09-01

    Carrier-free pure nanodrugs (PNDs) that are composed entirely of pharmaceutically active molecules are regarded as promising candidates to be the next generation of drug formulations and are mainly formulated from supramolecular self-assembly of drug molecules. It benefits from the efficient use of drug compounds with poor aqueous solubility and takes advantage of nanoscale drug delivery systems. Here, a type of all-in-one nanoparticle consisting of multiple drugs with enhanced synergistic antiproliferation efficiency against drug-resistant cancer cells has been created. To nanoparticulate the anticancer drugs, 10-hydroxycamptothecin (HCPT) and doxorubicin (DOX) were chosen as a typical model. The resulting HD nanoparticles (HD NPs) were formulated by a "green" and convenient self-assembling method, and the water-solubility of 10-hydroxycamptothecin (HCPT) was improved 50-fold after nanosizing by coassembly with DOX. The formation process was studied by observing the morphological changes at various reaction times and molar ratios of DOX to HCPT. Molecular dynamics (MD) simulations showed that DOX molecules tend to assemble around HCPT molecules through intermolecular forces. With the advantage of nanosizing, HD NPs could improve the intracellular drug retention of DOX to as much as 2-fold in drug-resistant cancer cells (MCF-7R). As a dual-drug-loaded nanoformulation, HD NPs effectively enhanced drug cytotoxicity to drug-resistant cancer cells. The combination of HCPT and DOX exhibited a synergistic effect as the nanosized HD NPs improved drug retention in drug-resistant cancer cells against P-gp efflux in MCF-7R cells. Furthermore, colony forming assays were applied to evaluate long-term inhibition of cancer cell proliferation, and these assays confirmed the greatly improved cytotoxicity of HD NPs in drug-resistant cells compared to free drugs. PMID:26270258

  9. 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.

  10. Sublineages of Mycobacterium tuberculosis Beijing genotype strains and unfavorable outcomes of anti-tuberculosis treatment.

    Science.gov (United States)

    Hang, Nguyen T L; Maeda, Shinji; Keicho, Naoto; Thuong, Pham H; Endo, Hiroyoshi

    2015-05-01

    The influence of Mycobacterium tuberculosis (MTB) lineages/sublineages on unfavorable tuberculosis (TB) treatment outcomes is poorly understood. We investigated the effects of Beijing genotype sublineages and other factors contributing to treatment outcome. Patients newly diagnosed with sputum smear-positive and culture-positive TB in Hanoi, Vietnam, participated in the study. After receiving anti-TB treatment, they were intensively followed up for the next 16 months. MTB isolates collected before treatment were subjected to drug susceptibility testing, and further analyzed to determine MTB (sub) lineages and their clonal similarities. Of 430 patients, 17 had treatment failure and 30 had TB recurrence. Rifampicin resistance was associated with treatment failure {adjusted odds ratio = 6.64 [95% confidence interval (CI), 1.48-29.73]}. The modern Beijing genotype was significantly associated with recurrent TB within 16 months [adjusted hazard ratio = 3.29 (95% CI, 1.17-9.27)], particularly after adjustment for the relevant antibiotic resistance. Human immunodeficiency virus coinfection and severity on chest radiographs were not significantly associated with unfavorable outcomes. Our findings provide further understanding of the influence of MTB strains on unfavorable treatment outcomes. Multiple risk factors should be considered for the optimal management of TB. PMID:25732626

  11. Phenotypic drug profiling in droplet microfluidics for better targeting of drug-resistant tumors

    Science.gov (United States)

    Sarkar, S.; Cohen, N.; Sabhachandani, P.; Konry, T.

    2015-01-01

    Acquired drug resistance is a key factor in the failure of chemotherapy. Due to intratumoral heterogeneity, cancer cells depict variations in intracellular drug uptake and efflux at the single cell level, which may not be detectable in bulk assays. In this study we present a droplet microfluidics-based approach to assess the dynamics of drug uptake, efflux and cytotoxicity in drug-sensitive and drug-resistant breast cancer cells. An integrated droplet generation and docking microarray was utilized to encapsulate single cells as well as homotypic cell aggregates. Drug-sensitive cells showed greater death in the presence or absence of Doxorubicin (Dox) compared to the drug-resistant cells. We observed heterogeneous Dox uptake in individual drug-sensitive cells while the drug-resistant cells showed uniformly low uptake and retention. Dox-resistant cells were classified into distinct subsets based on their efflux properties. Cells that showed longer retention of extracellular reagents also demonstrated maximal death. We further observed homotypic fusion of both cell types in droplets, which resulted in increased cell survival in the presence of high doses of Dox. Our results establish the applicability of this microfluidic platform for quantitative drug screening in single cells and multicellular interactions. PMID:26456240

  12. 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.,

  13. Mechanisms of acquired resistance to androgen receptor targeting drugs in castration resistant prostate cancer

    OpenAIRE

    Chism, David D.; De Silva, Dinuka; Whang, Young E.

    2014-01-01

    After initial response to androgen receptor targeting drugs abiraterone or enzalutamide, most patients develop progressive disease and therefore, castration resistant prostate cancer (CRPC) remains a terminal disease. Multiple mechanisms underlying acquired resistance have been postulated. Intratumoral androgen synthesis may resume after abiraterone treatment. A point mutation in the ligand binding domain of androgen receptor may confer resistance to enzalutamide. Emergence of androgen recept...

  14. (Post-)genomic approaches to tackle drug resistance in Leishmania

    OpenAIRE

    Berg, Maya; Mannaert, An; Vanaerschot, Manu; Van Der Auwera, Gert; Dujardin, Jean-Claude

    2013-01-01

    Abstract: Leishmaniasis, like other neglected diseases is characterized by a small arsenal of drugs for its control. To safeguard the efficacy of current drugs and guide the development of new ones it is thus of utmost importance to acquire a deep understanding of the phenomenon of drug resistance and its link with treatment outcome. We discuss here how (post-) genomic approaches may contribute to this purpose. We highlight the need for a clear definition of the phenotypes under consideration...

  15. 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..

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

    Directory of Open Access Journals (Sweden)

    Gerald F Davies

    2009-03-01

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

  17. Extensively Drug-Resistant Tuberculosis (XDR TB)

    Science.gov (United States)

    ... American Community Summit Background Slideset Children Correctional Facilities Homelessness International Travelers Pregnancy Health Disparities Laboratory Information Model Performance Evaluation Program (MPEP) Drug Susceptibility Testing The Uses of Nucleic Acid Amplification ...

  18. 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.

  19. Update on antifungal drug resistance mechanisms of Aspergillus fumigatus.

    Science.gov (United States)

    Chamilos, G; Kontoyiannis, D P

    2005-12-01

    Although the arsenal of agents with anti-Aspergillus activity has expanded over the last decade, mortality due to invasive aspergillosis (IA) remains unacceptably high. Aspergillus fumigatus still accounts for the majority of cases of IA; however less susceptible to antifungals non-fumigatus aspergilli began to emerge. Antifungal drug resistance of Aspergillus might partially account for treatment failures. Recent advances in our understanding of mechanisms of antifungal drug action in Aspergillus, along with the standardization of in vitro susceptibility testing methods, has brought resistance testing to the forefront of clinical mycology. In addition, molecular biology has started to shed light on the mechanisms of resistance of A. fumigatus to azoles and the echinocandins, while genome-based assays show promise for high-throughput screening for genotypic antifungal resistance. Several problems remain, however, in the study of this complex area. Large multicenter clinical studies--point prevalence or longitudinal--to capture the incidence and prevalence of antifungal resistance in A. fumigatus isolates are lacking. Correlation of in vitro susceptibility with clinical outcome and susceptibility breakpoints has not been established. In addition, the issue of cross-resistance between the newer triazoles is of concern. Furthermore, in vitro resistance testing for polyenes and echinocandins is difficult, and their mechanisms of resistance are largely unknown. This review examines challenges in the diagnosis, epidemiology, and mechanisms of antifungal drug resistance in A. fumigatus. PMID:16488654

  20. Drug resistance pattern among afb smear positive retreatment completed cases

    International Nuclear Information System (INIS)

    Worldwide, multidrug resistance (MDR TB) is a serious issue. It has increased over the last decade. Re-treatment completed sputum smear positive cases have much higher incidence of MDR- TB as compared to primary MDR - TB. Objective: To estimate the incidence of drug resistance pattern among AFB smear positive re-treatment completed cases. Study Design: Evidence based prospective study. Study Setting: Institute of Chest Medicine, Mayo Hospital Lahore, Tertiary care hospital affiliated with King Edward Medical University, Lahore, Pakistan. Methodology: A total 50 (Male 22, Female 28) pulmonary TB patients who had completed Re- treatment regimen in the past and are still sputum smear positive for acid fast Bacilli were included in the study. Three consecutive sputum specimens were collected at Aga Khan University collection center at Lahore. The specimen were sent to Aga Khan University Lab Karachi for AFB smear, culture and drug sensitivity both for essential and reserve drugs. Reports for AFB smear were received within a week, while culture and drug sensitivity' reports after 6 weeks. Reports data was analyzed for essential and reserve anti tuberculous drug sensitivity for mycobacterium tuberculosis. Results: Data Analysis revealed MDR TB in 31(62%) patients which include 11 males and 23 females. Individual drug resistance to essential drugs was INH - 62%, Rifampicin - 68%, Ethambutol - 24%, PZA - 25% and Streptomycin - 21 %. Poly drug resistance was determined in' 38% cases. Individual drug resistance to reserve drugs - kanamycin, Amikacin, ofloxacin, Ethionamide and PAS was 4%, 4%, 36%, 10% and 2% respectively. Conclusion: There is a very high proportion of MDR TB in sputum smear AFB positive retreatment cases. Suggestion: Comprehensive measures including DO- TS PLUS are needed to control MDR TB in Pakistan. (author)

  1. Modeling and predicting drug resistance rate and strength.

    Science.gov (United States)

    Fullybright, R; Dwivedi, A; Mallawaarachchi, I; Sinsin, B

    2016-08-01

    Drug resistance has been worsening in human infectious diseases medicine over the past several decades. Our ability to successfully control resistance depends to a large extent on our understanding of the features characterizing the process. Part of that understanding includes the rate at which new resistance has been emerging in pathogens. Along that line, resistance data covering 90 infectious diseases, 118 pathogens, and 337 molecules, from 1921 through 2007, are modeled using various statistical tools to generate regression models for the rate of new resistance emergence and for cumulative resistance build-up in pathogens. Thereafter, the strength of the association between the number of molecules put on the market and the number of resulting cases of resistance is statistically tested. Predictive models are presented for the rate at which new resistance has been emerging in infectious diseases medicine, along with predictive models for the rate of cumulative resistance build-up in the aggregate of 118 pathogens as well as in ten individual pathogens. The models are expressed as a function of time and/or as a function of the number of molecules put on the market by the pharmaceutical industry. It is found that molecules significantly induce resistance in pathogens and that new or cumulative drug resistance across infectious diseases medicine has been arising at exponential rates. PMID:27209288

  2. Supramolecular Antibiotic Switches: A Potential Strategy for Combating Drug Resistance.

    Science.gov (United States)

    Bai, Haotian; Lv, Fengting; Liu, Libing; Wang, Shu

    2016-08-01

    Bacterial infectious disease is a serious public health concern throughout the world. Pathogen drug resistance, arising from both rational use and abuse/misuse of germicides, complicates the situation. Aside from developing novel antibiotics and antimicrobial agents, molecular approaches have become another significant method to overcome the problem of pathogen drug resistance. Established supramolecular systems, the antibiotic properties of which can be switched "on" and "off" through host-guest interactions, show great potential in combating issues regarding antibiotic resistance in the long term, as indicated by several recent studies. In this Concept, recently developed strategies for antibacterial regulation are summarized and further directions for research into antibiotic switches are proposed. PMID:27312106

  3. Nanoparticles: Alternatives Against Drug-Resistant Pathogenic Microbes.

    Science.gov (United States)

    Rudramurthy, Gudepalya Renukaiah; Swamy, Mallappa Kumara; Sinniah, Uma Rani; Ghasemzadeh, Ali

    2016-01-01

    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. PMID:27355939

  4. 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.

  5. Long non-coding RNAs in cancer drug resistance development.

    Science.gov (United States)

    Majidinia, Maryam; Yousefi, Bahman

    2016-09-01

    The presence or emergence of chemoresistance in tumor cells is a major burden in cancer therapy. While drug resistance is a multifactorial phenomenon arising from altered membrane transport of drugs, altered drug metabolism, altered DNA repair, reduced apoptosis rate and alterations of drug metabolism, it can also be linked to genetic and epigenetic factors. Long non-coding RNAs (lncRNAs) have important regulatory roles in many aspects of genome function including gene transcription, splicing, and epigenetics as well as biological processes involved in cell cycle, cell differentiation, development, and pluripotency. As such, it may not be surprising that some lncRNAs have been recently linked to carcinogenesis and drug resistance/sensitivity. Research is accelerating to decipher the exact molecular mechanism of lncRNA-regulated drug resistance and its therapeutic implications. In this article, we will review the structure, biogenesis, and mode of action of lncRNAs. Then, the involvement of lncRNAs in drug resistance will be discussed in detail. PMID:27427176

  6. 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

  7. 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

  8. 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

  9. Dynamics of immune response and drug resistance in malaria infection

    Directory of Open Access Journals (Sweden)

    Gurarie David

    2006-10-01

    Full Text Available Abstract Background Malaria parasites that concurrently infect a host compete on the basis of their intrinsic growth rates and by stimulating cross-reactive immune responses that inhibit each others' growth. If the phenotypes also show different drug sensitivities ('sensitive' vs. 'resistant' strains, drug treatment can change their joint dynamics and the long-term outcome of the infection: most obviously, persistent drug pressure can permit the more resistant, but otherwise competitively-inferior, strains to dominate. Methods Here a mathematical model is developed to analyse how these and more subtle effects of antimalarial drug use are modulated by immune response, repeated re-inoculation of parasites, drug pharmacokinetic parameters, dose and treatment frequency. Results The model quantifies possible effects of single and multiple (periodic treatment on the outcome of parasite competition. In the absence of further inoculation, the dosage and/or treatment frequency required for complete clearance can be estimated. With persistent superinfection, time-average parasite densities can be derived in terms of the basic immune-regulating parameters, the drug efficacy and treatment regimen. Conclusion The functional relations in the model are applicable to a wide range of conditions and transmission environments, allowing predictions to be made on both the individual and the community levels, and, in particular, transitions from drug-sensitive to drug-resistant parasite dominance to be projected on both levels.

  10. 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 

  11. 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.

  12. Efflux Pump-mediated Drug Resistance in Burkholderia

    Directory of Open Access Journals (Sweden)

    Nicole L Podnecky

    2015-04-01

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

  13. 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

  14. 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.

  15. TWO OPTIMAL CONTROL PROBLEMS IN CANCER CHEMOTHERAPY WITH DRUG RESISTANCE

    Directory of Open Access Journals (Sweden)

    Werner Krabs

    2012-01-01

    Full Text Available We investigate two well-known basic optimal control problems forchemotherapeutic cancer treatment modified by introducing a timedependent “resistance factor”. This factor should be responsible for the effect of the drug resistance of tumor cells on the dynamical growth for the tumor. Both optimal control problems have common pointwise but different integral constraints on the control. We show that in both models the usually practised bang-bang control is optimal if the resistance is sufficiently strong. Further, we discuss different optimal strategies in both models for general resistance.

  16. Drug Repurposing Identifies Inhibitors of Oseltamivir-Resistant Influenza Viruses.

    Science.gov (United States)

    Bao, Ju; Marathe, Bindumadhav; Govorkova, Elena A; Zheng, Jie J

    2016-03-01

    The neuraminidase (NA) inhibitor, oseltamivir, is a widely used anti-influenza drug. However, oseltamivir-resistant H1N1 influenza viruses carrying the H275Y NA mutation spontaneously emerged as a result of natural genetic drift and drug treatment. Because H275Y and other potential mutations may generate a future pandemic influenza strain that is oseltamivir-resistant, alternative therapy options are needed. Herein, we show that a structure-based computational method can be used to identify existing drugs that inhibit resistant viruses, thereby providing a first line of pharmaceutical defense against this possible scenario. We identified two drugs, nalidixic acid and dorzolamide, that potently inhibit the NA activity of oseltamivir-resistant H1N1 viruses with the H275Y NA mutation at very low concentrations, but have no effect on wild-type H1N1 NA even at a much higher concentration, suggesting that the oseltamivir-resistance mutation itself caused susceptibility to these drugs. PMID:26833677

  17. 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.

  18. 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.

  19. 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.

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

    Directory of Open Access Journals (Sweden)

    Dondorp Arjen M

    2008-11-01

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

  1. 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.

  2. Drug resistance mechanisms of fungal biofilms

    OpenAIRE

    Seneviratne, CJ; Samaranayake, LP

    2011-01-01

    Fungi are ubiquitous in nature and exist in soil, water, plants, and in animals and humans. Similar to bacteria, fungi also form confluent biofilms either singly (mono-species) or with other microbial species (mixed-species). Fungal biofilms are known to be highly resistant to the adverse environmental conditions including antimicrobials and biocide compared to its planktonic (free-floating) counterparts. Although bacterial biofilms have been studied in detail, relatively little is known of f...

  3. 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.

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

    Directory of Open Access Journals (Sweden)

    Andrew S Bell

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

  5. 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.

  6. 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

  7. 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

  8. 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.

  9. 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

  10. 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

    to do so. Thus, predictive models are needed to rationally design resistance-limiting therapeutic regimens. Using adaptive evolution, we studied the resistance response of the common pathogen Escherichia coli to 5 different single antibiotics and all 10 different antibiotic drug pairs. By analyzing...

  11. Drug Resistance and Cancer Stem Cells

    OpenAIRE

    Fonseca, João Pedro Couto

    2012-01-01

    O cancro do pulmão é a principal causa de morte por cancro a nível mundial. Apesar do crescente conhecimento sobre os mecanismos subjacentes ao processo tumorigénico não se tem observado alteração significativa na sobrevivência dos pacientes. É, por isso, urgente encontrar novas estratégias terapêuticas que visem superar a resistência, tanto intrínseca como extrínseca, observada com a quimioterapia corrente. Os tumores são caracterizados pela sua heterogeneidade celular, devido à coexistên...

  12. 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.

  13. Determinants of poor adherence to anti-tuberculosis treatment in Mumbai, India

    Directory of Open Access Journals (Sweden)

    Suparna Bagchi

    2010-01-01

    Conclusions: An approach, targeting easier access to drugs, an ensured drug supply, effective solutions for travel-related concerns and modification of smoking and alcohol related behaviors are essential for treatment adherence.

  14. (Post-) Genomic approaches to tackle drug resistance in Leishmania.

    Science.gov (United States)

    Berg, Maya; Mannaert, An; Vanaerschot, Manu; Van Der Auwera, Gert; Dujardin, Jean-Claude

    2013-10-01

    Leishmaniasis, like other neglected diseases is characterized by a small arsenal of drugs for its control. To safeguard the efficacy of current drugs and guide the development of new ones it is thus of utmost importance to acquire a deep understanding of the phenomenon of drug resistance and its link with treatment outcome. We discuss here how (post-)genomic approaches may contribute to this purpose. We highlight the need for a clear definition of the phenotypes under consideration: innate and acquired resistance versus treatment failure. We provide a recent update of our knowledge on the Leishmania genome structure and dynamics, and compare the contribution of targeted and untargeted methods for the understanding of drug resistance and show their limits. We also present the main assays allowing the experimental validation of the genes putatively involved in drug resistance. The importance of analysing information downstream of the genome is stressed and further illustrated by recent metabolomics findings. Finally, the attention is called onto the challenges for implementing the acquired knowledge to the benefit of the patients and the population at risk. PMID:23480865

  15. Multi drug resistance to cancer chemotherapy: Genes involved and blockers

    International Nuclear Information System (INIS)

    During the last three decades, important and considerable research efforts had been performed to investigate the mechanism through which cancer cells overcome the cytotoxic effects of a variety of chemotherapeutic drugs. Most of the previously published work has been focused on the resistance of tumor cells to those anticancer drugs of natural source. Multidrug resistance (MDR) is a cellular cross-resistance to a broad spectrum of natural products used in cancer chemotherapy and is believed to be the major cause of the therapeutic failures of the drugs belonging to different naturally obtained or semisynthetic groups including vinca alkaloids, taxans, epipodophyllotoxins and certain antibiotics. This phenomenon results from overexpression of four MDR genes and their corresponding proteins that act as membrane-bound ATP consuming pumps. These proteins mediate the efflux of many structurally and functionally unrelated anticancer drugs of natural source. MDR may be intrinsic or acquired following exposure to chemotherapy. The existence of intrinsically resistant tumor cell clone before and following chemotherapeutic treatment has been associated with a worse final outcome because of increased incidence of distant metasis. In view of irreplaceability of natural product anticancer drugs as effective chemotherapeutic agents, and in view of MDR as a major obstacle to successful chemotherapy, this review is aimed to highlight the genes involved in MDR, classical MDR blockers and gene therapy approaches to overcome MDR. (author)

  16. Live-cell luciferase assay of drug resistant cells

    OpenAIRE

    sprotocols

    2015-01-01

    To date, multiplexing cell-based assay is essential for high-throughput screening of molecular targets. Measuring multiple parameters of a single sample increases consistency and decrease time and cost of assay. Functional assay of living cell is useful as a first step of multiplexing assay, because live-cell assay allows following second assay using cell lysate or stained cell. However, live-cell assay of drug resistant cells that are highly activated of drug efflux mechanisms is sometimes u...

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

    OpenAIRE

    Singh, Yashik; Mars, Maurice

    2012-01-01

    Introduction The science of information systems, management, and interpretation plays an important part in the continuity of care of patients. This is becoming more evident in the treatment of human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS), the leading cause of death in sub-Saharan Africa. The high replication rates, selective pressure, and initial infection by resistant strains of HIV infer that drug resistance will inevitably become an important health car...

  18. Antibiotic residues and drug resistance in human intestinal flora.

    OpenAIRE

    Corpet, D. E.

    1987-01-01

    The effect of residual levels of ampicillin on the drug resistance of fecal flora was studied in human volunteers given 1.5 mg of ampicillin orally per day for 21 days. This treatment failed to have any significant reproducible effect on the number of resistant Escherichia coli in their feces. The effect of continuous administration of small doses of ampicillin, chlortetracycline, or streptomycin in the drinking water was studied in gnotobiotic mice inoculated with a human fecal flora. In thi...

  19. Extensively drug-resistant tuberculosis: epidemiology and management

    Directory of Open Access Journals (Sweden)

    Matteelli A

    2014-04-01

    Full Text Available Alberto Matteelli,1 Alberto Roggi,1 Anna CC Carvalho21Institute of Infectious and Tropical Diseases, WHO Collaborating Centre for TB/HIV Co-Infection, University of Brescia, Brescia, Italy; 2Laboratory of Innovations in Therapies, Education and Bioproducts (LITEB, Oswaldo Cruz Institute (IOC, Oswaldo Cruz Foundation (Fiocruz, Rio de Janeiro, BrazilAbstract: The advent of antibiotics for the treatment of tuberculosis (TB represented a major breakthrough in the fight against the disease. However, since its first use, antibiotic therapy has been associated with the emergence of resistance to drugs. The incorrect use of anti-TB drugs, either due to prescription errors, low patient compliance, or poor quality of drugs, led to the widespread emergence of Mycobacterium tuberculosis strains with an expanding spectrum of resistance. The spread of multidrug-resistant (MDR strains (ie, strains resistant to both isoniazid and rifampicin has represented a major threat to TB control since the 1990s. In 2006, the first cases of MDR strains with further resistance to fluoroquinolone and injectable drugs were described and named extensively drug-resistant TB (XDR-TB. The emergence of XDR-TB strains is a result of mismanagement of MDR cases, and treatment relies on drugs that are less potent and more toxic than those used to treat drug-susceptible or MDR strains. Furthermore, treatment success is lower and mortality higher than achieved in MDR-TB cases, and the number of drugs necessary in the intensive phase of treatment may be higher than the four drugs recommended for MDR-TB. Linezolid may represent a valuable drug to treat cases of XDR-TB. Delamanid, bedaquiline, and PA-824 are new anti-TB agents in the development pipeline that have the potential to enhance the cure rate of XDR-TB. The best measures to prevent new cases of XDR-TB are the correct management of MDR-TB patients, early detection, and proper treatment of existing patients with XDR

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

    Science.gov (United States)

    Lee, Jinsoo; Son, Kwanghyun; Hwang, Gwiseo; Kim, Moonju

    2016-01-01

    Objective. Herbal medicine has been widely used to treat drug resistant epilepsy. Shihogyejitang (SGT) has been commonly used to treat epilepsy. We investigated the effect and safety of SGT in children with drug resistant epilepsy. Design. We reviewed medical records of 54 patients with epilepsy, who failed to respond to at least two antiepileptic drugs and have been treated with SGT between April 2006 and June 2014 at the Department of Pediatric Neurology, I-Tomato Hospital, Korea. Effect was measured by the response rate, seizure-free rate, and retention rate at six months. We also checked adverse events, change in antiepileptic drugs use, and the variables related to the outcome. Results. Intent-to-treat analysis showed that, after six months, 44.4% showed a >50% seizure reduction, 24.1% including seizure-free, respectively, and 53.7% remained on SGT. Two adverse events were reported, mild skin rash and fever. Focal seizure type presented significantly more positive responses when compared with other seizure types at six months (p = 0.0284, Fisher's exact test). Conclusion. SGT is an effective treatment with excellent tolerability for drug resistant epilepsy patients. Our data provide evidence that SGT may be used as alternative treatment option when antiepileptic drug does not work in epilepsy children. PMID:27047568

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

    Directory of Open Access Journals (Sweden)

    Jinsoo Lee

    2016-01-01

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

  2. 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.

  3. Evidence for epistatic interactions in antiepileptic drug resistance.

    Science.gov (United States)

    Kim, Myeong-Kyu; Moore, Jason H; Kim, Jong-Ki; Cho, Ki-Hyun; Cho, Yong-Won; Kim, Yo-Sik; Lee, Min-Cheol; Kim, Young-Ok; Shin, Min-Ho

    2011-01-01

    To investigate the epistatic interactions involved in antiepileptic drug (AED) resistance, 26 coding single-nucleotide polymorphisms (SNPs) were selected from 16 candidate genes. A total of 200 patients with drug-resistant localization-related epilepsy and 200 patients with drug-responsive localization-related epilepsy were genotyped individually for the SNPs. Rather than using the traditional parametric statistical method, a new statistical method, multifactor dimensionality reduction (MDR), was used to determine whether gene-gene interactions increase the risk of AED resistance. The MDR method indicated that a combination of four SNPs (rs12658835 and rs35166395 from GABRA1, rs2228622 from EAAT3 and rs2304725 from GAT3) was the best model for predicting susceptibility to AED resistance with a statistically significant testing accuracy of 0.625 (P < 0.001) and cross-validation consistency of 10/10. This best model had an odds ratio of 3.68 with a significant 95% confidence interval of 2.32-5.85 (P < 0.0001). Our results may provide meaningful information on the mechanism underlying AED resistance and, to the best of our knowledge, this is the first report of evidence for gene-gene interactions underlying AED resistance. PMID:21124337

  4. Multidrug-resistant tuberculosis in Lithuania - Still a long way ahead.

    Science.gov (United States)

    Musteikienė, Greta; Miliauskas, Skaidrius; Sakalauskas, Raimundas; Vitkauskienė, Astra; Žemaitis, Marius

    2016-01-01

    Despite the recent advances in the diagnosis of tuberculosis, treatment of the disease, for the most part, remains the same as it was half a century ago. In recent years only two new anti-tuberculosis drugs have been approved by the European Medicines Agency and Food and Drug Administration. Though the prevalence of this disease is slowly decreasing all over Europe, new challenges appear. One of them is multidrug-resistant tuberculosis (MDR-TB). This problem is especially prominent in Lithuania, which is one of the 27 high MDR-TB burden countries in the world and falls behind neighboring countries in terms of the prevalence of the disease. The objective of this paper was to review the situation of tuberculosis and MDR-TB in Lithuania, and current available methods of treatment, control and diagnosis of this disease. PMID:27170479

  5. 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

  6. Additional drug resistance of multidrug-resistant tuberculosis in patients in 9 countries.

    Science.gov (United States)

    Kurbatova, Ekaterina V; Dalton, Tracy; Ershova, Julia; Tupasi, Thelma; Caoili, Janice Campos; Van Der Walt, Martie; Kvasnovsky, Charlotte; Yagui, Martin; Bayona, Jaime; Contreras, Carmen; Leimane, Vaira; Via, Laura E; Kim, HeeJin; Akksilp, Somsak; Kazennyy, Boris Y; Volchenkov, Grigory V; Jou, Ruwen; Kliiman, Kai; Demikhova, Olga V; Cegielski, J Peter

    2015-06-01

    Data from a large multicenter observational study of patients with multidrug-resistant tuberculosis (MDR TB) were analyzed to simulate the possible use of 2 new approaches to treatment of MDR TB: a short (9-month) regimen and a bedaquiline-containing regimen. Of 1,254 patients, 952 (75.9%) had no resistance to fluoroquinolones and second-line injectable drugs and thus would qualify as candidates for the 9-month regimen; 302 (24.1%) patients with resistance to a fluoroquinolone or second-line injectable drug would qualify as candidates for a bedaquiline-containing regimen in accordance with published guidelines. Among candidates for the 9-month regimen, standardized drug-susceptibility tests demonstrated susceptibility to a median of 5 (interquartile range 5-6) drugs. Among candidates for bedaquiline, drug-susceptibility tests demonstrated susceptibility to a median of 3 (interquartile range 2-4) drugs; 26% retained susceptibility to <2 drugs. These data may assist national TB programs in planning to implement new drugs and drug regimens. PMID:25988299

  7. 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.

  8. 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. PMID:26929328

  9. "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…

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. Drug Resistance Characteristics and Macrolide-Resistant Mechanisms of Streptococcus pneumoniae in Wenzhou City, China.

    Science.gov (United States)

    Hu, Dakang; Sun, Zheng; Luo, Xinhua; Liu, Shuangchun; Yu, Lianhua; Qu, Ying; Yang, Jinhong; Yu, Jian; Li, Xiangyang; Zhang, Jin

    2016-01-01

    BACKGROUND Streptococcus pneumoniae (SP) is a Gram-positive, alpha-hemolytic, facultative anaerobic member of the genus Streptococcus. The erythromycin-resistant methylase (erm) gene and macrolide efflux (mef) gene are the 2 main genes that can mediate SP. Transposon (Tn) also plays an important role in the collection and metastasis of the gene. In the present study we investigated the drug resistance characteristics and the macrolide-resistant mechanisms of SP in Wenzhou City, China. MATERIAL AND METHODS Sixty-eight strains of SP were isolated from sputum samples of hospitalized children in the Second Affiliated Hospital of Wenzhou Medical University. These strains were analyzed using antimicrobial susceptibility tests to determine their drug resistance to 10 kinds of antibacterials. Macrolide-resistant phenotypes were identified using K-B method. PCR method was used to analyze the erm B gene, mef A gene, and int Tn gene. RESULTS Drug resistance rates of 68 strains of SP were 98.5%, 100.0%, 63.2%, 52.9%, 94.1%, 89.7%, 0.0%, 0.0%, 16.2%, and 14.7% for clindamycin, erythromycin, penicillin G, cefotaxime, tetracycline, sulfamethoxazole/trimethoprim, levofloxacin, vancomycin, chloramphenicol, and amoxicillin, respectively. Total detection rates of the erm B gene, mef A gene, and int Tn gene were 98.5%, 91.2%, and 100.0%, respectively. CONCLUSIONS SP shows significant multi-drug resistance in Wenzhou City, whereas there is no clinical value of macrolides antibiotics for SP. cMLSB mediated by erm B gene is the most predominant phenotype among macrolide-resistant SP. The int Tn gene may play an important role in horizontal transfer and clonal dissemination of SP drug resistance genes in Wenzhou City. PMID:27483416

  15. 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.

  16. 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...

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. A study on application of BacT/ALERT 3D liquid culture technology on tuberculosis drug resistance detection%BacT/ALERT 3D 技术在结核杆菌耐药检测中的应用研究

    Institute of Scientific and Technical Information of China (English)

    黄文忠; 王平平; 吴红照; 周燕珍; 胡真宝

    2014-01-01

    目的:比较 BacT/ALERT 3D 法与传统罗氏(L -J)比例法在耐药结核分枝杆菌检测中的差异,评价BacT/ALERT 3D 快速培养系统在结核分枝杆菌耐药检测中的应用价值。方法对219份固体培养结核杆菌阳性的培养物采用 BacT/ALERT 3D 液体培养技术和 L -J 比例法同时进行药敏试验,并进行比对分析。结果BacT/ALERT 3D 法平均检出时间(8.02±3.85)d,比 L -J 比例法检出时间平均缩短约20 d;BacT/ALERT 3D 法检出耐药菌60株,L -J 比例法检出耐药菌79株,差异无统计学意义(P >0.05);以 L -J 比例法结果为判定标准, BacT/ALERT 3D 法对 INH、RFP、EMB 和 SM 4种抗结核药耐药检测结果符合率分别为95.43%、92.69%、95.43%和92.24%。结论与 L -J 比例法比较,BacT/ALERT 3D 药敏检测方法对结核杆菌的耐药检出结果有较高的一致性,BacT/ALERT 3D 法检出时间明显短于 L -J 比例法。%Objective To evaluate the BacT/ALERT 3D liquid culture technology on the detection of drug resistance of Mycobacterium tuberculosis(MTB)and to compare the difference between this technology and Lowenstein -Jensen (L -J) proportion method.Methods BacT/ALERT 3D liquid culture technology and L -J proportion technology were applied to detect the drug resistance of tuberculosis from the positive cultures of 219 solid culture samples.Results The average detection time of BacT/ALERT 3D method was 8.02 ±3.85 d,which was about 20 days shorter than that of L -J proportion method.60 drug resistance strains were found using BacT/ALERT 3D technology,While 79 drug resistance strains were found using L -J proportion technology.There showed no significant difference (P >0.05).The compliance rate of BacT/ALERT 3D method and L -J proportion method on the anti -tuberculosis drugs INH,RFP,EMB and SMwas 95.43%,92.69%,95.43% and 92.24% respectively.Conclusion BacT/ALERT 3D liquid culture technology could detect drug resistant TB

  2. Drug resistance of bacteria——present situation and treatment

    Directory of Open Access Journals (Sweden)

    Min ZHAO

    2011-02-01

    Full Text Available Antimicrobial resistance of bacteria is a serious problem worldwide.It has become the difficulty of anti-infection that multidrug-resistance(MDR and drug wide-resistance(DWR gram-negative bacteria are increasing year and year.Alarm has been knolled again on the emerging of Gram-negative pathogens producing the NDM-1 worldwide in 2010.NDM-1 is a new metallo-carbapenemase which is highly resistant to all antibiotics,and has been mostly found among Escherichia coli and Klebsiella pneumoniae.Infections of MDR and DWR Enterobacteriaceae can be effectively treated with tigecycline,polymyxin and fosfomycin on clinic trail.Prevention is very important for reducing the occurring and spreading of MDR and DWR bacteria.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. Genome-wide screening of loci associated with drug resistance to 5-fluorouracil-based drugs.

    Science.gov (United States)

    Ooyama, Akio; Okayama, Yoshihiro; Takechi, Teiji; Sugimoto, Yoshikazu; Oka, Toshinori; Fukushima, Masakazu

    2007-04-01

    Resistance to chemotherapeutic agents represents the chief cause of mortality in cancer patients with advanced disease. Chromosomal aberration and altered gene expression are the main genetic mechanisms of tumor chemoresistance. In this study, we have established an algorithm to calculate DNA copy number using the Affymetrix 10K array, and performed a genome-wide correlation analysis between DNA copy number and antitumor activity against 5-fluorouracil (5-FU)-based drugs (S-1, tegafur + uracil [UFT], 5'-DFUR and capecitabine) to screen for loci influencing drug resistance using 27 human cancer xenografts. A correlation analysis confirmed that the single nucleotide polymorphism (SNP) showing significant associations with drug sensitivity were concentrated in some cytogenetic regions (18p, 17p13.2, 17p12, 11q14.1, 11q11 and 11p11.12), and we identified some genes that have been indicated their relations to drug sensitivity. Among these regions, 18p11.32 at the location of the thymidylate synthase gene (TYMS) was strongly associated with resistance to 5-FU-based drugs. A change in copy number of the TYMS gene was reflected in the TYMS expression level, and showed a significant negative correlation with sensitivity against 5-FU-based drugs. These results suggest that amplification of the TYMS gene is associated with innate resistance, supporting the possibility that TYMS copy number might be a predictive marker of drug sensitivity to fluoropyrimidines. Further study is necessary to clarify the functional roles of other genes coded in significant cytogenetic regions. These promising data suggest that a comprehensive DNA copy number analysis might aid in the quest for optimal markers of drug response. PMID:17425594

  8. Antiviral drug resistance in Cuban children infected with HIV-1

    Directory of Open Access Journals (Sweden)

    L Pérez

    2012-11-01

    Full Text Available Between 1986 and 2011, 100 children have been diagnosed with HIV-1 in Cuba. 38 have acquired HIV-1 by vertical transmission, 6 by blood transfusion and 56 by sexual contacts (teenager. Currently, AZT/D4T + 3TC + NVP/KALETRA are available for the treatment of pediatric patients. The aim of the study was to monitor the subtype distribution and emergence of drug resistance in pediatric HIV-1 infections. Plasma from 46 HIV-1-infected children were collected from November 2005 to November 2011, subsequently extracted, amplified and sequenced. Phylogenetic analysis was performed using Mega 4 (Neighbour joining, Kimura 2. The CPR tool v6.0 (WHO list 2009 was used to interpret transmitted drug resistance (TDR. In addition, acquired drug resistance was interpreted according to HIVdb v6.1.1. Experiments were successful for 28 samples from 20 patients (5 patients with multiple samples. At the moment of analysis, 17 children were receiving ART. The median age at diagnosis was 1.9 years, whereas the median age at sampling was 4.5 years. Ten children were male (50%, 16 (80% were infected by vertical transmission, 1 by blood transfusion (5% and 3 by sexual route (15%. The subtypes were CRF18_cpx (25%, CRF19_cpx (25%, B (20%, CRF20_BG (10%, G (10%, CRF24_BG (5% and C (5%. 82.3% of the children who were receiving ART at sampling (14/17 displayed at least one drug resistance mutation. The most common NRTI and NNRT mutations were: M184V (55.5%, T215FY (16.6% and K70R (16.6%; and K103NS (61.1% and G190A (22.0%. In contrast, only one PI mutation, L90M (5.5%, was observed. 5.8% of these children displayed single NRTI class resistance, 17.4% single NNRTI class resistance, 59% double NRTI + NNRTI class resistance and 5.8% triple NRTI + NNRTI + PI class resistance. According to HIVdb, NRTI, NNRTI and PI resistance was present in respectively 42.8%, 58.7% and 8.08% of the treated children. High-level NVP and EFV resistance was observed in 76.5% and 58

  9. Sensitive, resistant and multi-drug resistant Acinetobacter baumanii at Saudi Arabia hospital eastern region.

    Science.gov (United States)

    Ahmed, Mughis Uddin; Farooq, Reshma; Al-Hawashim, Nadia; Ahmed, Motasim; Yiannakou, Nearchos; Sayeed, Fatima; Sayed, Ali Rifat; Lutfullah, Sualiha

    2015-05-01

    Since the Physicians start use of antibiotics long ago with un-notice drug resistance. However actual problem was recognized about 85 years ago. Antibiotic resistant and Multi-drug resistant bacterial strains are at rise throughout the world. It is physicians and researchers to take scientific research based appropriate action to overcome this ever-spreading problem. This study is designed to find out sensitive (S), resistant (R) and multi-drug resistant (MDR) Acinetobacter baumanii strain along with other isolates in the resident patients of Eastern Region of Saudi Arabia. Pseudomonas aeruginosa is excluded from other gram-negative organisms isolated from different sites as it will be dealt separately. This study is based in was retrospective observations designed to collect data of different stains of Acinetobacter baumanii with reference to their Sensitivity (S), Resistance (R), Multi-Drug Resistance (MDR) along with other Gram negative isolated from different sites (from 1st January 2004 to 31st December 2011) at King Abdulaziz Hospital located Eastern Region of Kingdom of Saudi Arabia (KSA). All necessary techniques were used to culture and perform sensitivity of these isolates. There were 4532 isolates out of which 3018 (67%) were from patients. Out of Acinetobacter baumanii infected were 906 (20%) while other 3626 (80%) isolates were miscellaneous. Numbers of patients or cases were 480 (53%) out of 906 isolates and numbers of patients or cases in other organisms were 2538 (70%) out of 3626 isolates. Acinetobacter baumanii infected patients 221 (46%) were male and 259 (54%) were female and the male and female ratio of 1:1.2. In other organisms this male female ratio was almost same. There was steady rise in number of patients and the hence the isolates from 2004 to 2011. Majority of the bacterial strains were isolated as single organism but some were isolated as double or triple or quadruple or more organisms from different sites. Sensitive, Resistant and

  10. Elaboration of a global strategy for containing microbial drug resistance.

    Science.gov (United States)

    Zabicki, W

    2001-01-01

    The World Health Organization is engaged in developing the Global Strategy for Containment of Antimicrobial Resistance. The preliminary document WHO/CDC/CSR/DRS/2000.I Draft has already been distributed, and remarks have been solicited. The World Health Assembly Resolution of 1998 urged Member States to encourage the appropriate and cost-effective use of antimicrobials. Member States were requested to implement effective systems of microbial resistance surveillance and to monitor volumes and patterns of antimicrobial drug use. The phenomenon of antimicrobial resistance is rising rapidly and causing growing international concern. Many countries have undertaken their own national plans to address the problem. The overall aim of the strategy being developed is to find the most effective forms and to prevent the spread of antimicrobial resistance and resistant microbes. The strategy covers the following topics: patients and general community, prescribers, hospitals, veterinarians, manufacturers and drug dispensers, and international aspects. The strategy is being developed on the basis of expert opinions, published reports, reviews of specific topics specially commissioned by various international and national bodies, and a large body of literature with a list of publications containing over 100 items. PMID:17986973

  11. [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.

  12. 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.

  13. The management of drug resistant seizures in tuberous sclerosis

    Directory of Open Access Journals (Sweden)

    Romina MOAVERO

    2009-12-01

    Full Text Available Tuberous Sclerosis Complex (TSC is a multisystem autosomal dominant genetic disorder resulting from mutations in one of two genes, TSC1 and TSC2. Pathologically TSC is characterized by abnormal cellular differentiation and proliferation, as well as abnormal neuronal migration. The majority of patients with TSC have epilepsy, although the mechanisms underlying epileptogenesis remain unknown. Seizures onset is frequently during the first year of life, and in a sizable proportion of individuals tend to be refractory to antiepileptic drug treatment. This article reviews the progress in understanding drug resistant seizures in TSC, from molecular pathogenesis to the pathophysiological mechanisms of epileptogenesis, and the rationale for appropriate medical and surgical treatment.

  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 resistant...... P388 leukemia cell line, P388/ADR. The time course of accumulation of these drugs, and the effect of energy starvation and the presence of chloroquine on the level of their steady-state accumulation were quite disparate. Vinblastine inhibited the accumulation of verapamil whereas it enhanced...

  15. 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.

  16. 钛表面聚多巴胺、聚乙二醇、聚乳酸-聚羟基乙酸、异烟肼抗结核控释涂层的构建及生物学性能%Fabrication of the anti-tuberculosis controlled drug delivery system with Ti-PDA-PEG-PLGA-INH and investigation of the biological characteristics

    Institute of Scientific and Technical Information of China (English)

    马云龙; 马远征; 李力韬; 李丹; 彭明丽; 赵冠人; 李大伟; 罗展鹏; 顾苏熙; 杨飞

    2016-01-01

    Objective To fabricate an anti⁃tuberculosis controlled drug release coating with Ti⁃PDA⁃PEG⁃PLGA⁃INH and to investigate its surface characteristics, in vivo and in vitro drug release behavior, and tissue biocompatibility. Methods 4⁃arm⁃polyethylene glycol (PEG) was synthesized first. Then cover the surface of titanium (Ti) with a layer of poly dopamine (PDA) by Michael addition reaction. Use porous starch and 4⁃arm⁃PEG as a carrier, load with isoniazid (INH), then attach to the surface of titanium by casting or sol⁃gel dip coating methods, and then cover with a layer of poly lactic⁃co⁃glycolic acid (PLGA) by the same method, to fabricate the Ti⁃PDA⁃PEG⁃PLGA⁃INH composite coating finally. The functional group of 4⁃arm⁃PEG was charac⁃terized by proton nuclear resonance spectroscopy (HNMR). The surface characteristics of Ti⁃PDA⁃PEG⁃PLGA⁃INH were evaluated by scanning electron microscope (SEM), while drug release behaviors were detected by high performance liquid chromatography (HPLC) and the cumulative release rate was calculated, and carry out the antibacterial performance in vitro. The animal model of femoral condyle bone defect was established in 25 New Zealand white rabbits. Titanium rods covered with PDA⁃PEG⁃PLGA⁃INH coating were implanted into defect area. INH concentrations were detected by HPLC in venous blood, muscle and bone tissue at each time point postoperatively. Another 12 rabbits were randomly divided into experimental group and control group, the experi⁃mental group was implanted with titanium tablets and titanium rods coated with PDA⁃PEG⁃PLGA⁃INH in the paraspinous muscle and left femoral condyles respectively, while the control group was implanted with a blank sheet of titanium tablets and titanium rods in the same place. Hematoxylin and Eosin Staining were used to observe the biocompatibility of the composite system in vivo at 28 and 56 days postoperatively. Results Ti

  17. 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.

  18. A rare adverse reaction to ethambutol: drug-induced haemolytic anaemia.

    Science.gov (United States)

    Nicolini, A; Perazzo, A; Gatto, P; Piroddi, I M G; Barlascini, C; Karamichali, S; Strada, P

    2016-05-01

    Anti-tuberculosis drugs seldom cause serious haematological side effects. However, among these drugs, isoniazid and rifampicin, especially when administered intermittently, may very rarely be linked to acute autoimmune haemolytic anaemia. Ethambutol (EMB) can cause dose-related retrobulbar neuritis. In this paper, we present the first reported case of acute fatal autoimmune haemolytic anaemia due to EMB. PMID:27084828

  19. Mathematical models of tumor heterogeneity and drug resistance

    Science.gov (United States)

    Greene, James

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

  20. Multi-drug resistant Acinetobacter ventilator-associated pneumonia

    OpenAIRE

    Shete, Vishal B.; Dnyaneshwari P Ghadage; Vrishali A Muley; Bhore, Arvind V.

    2010-01-01

    Background: Ventilator-associated pneumonia (VAP) due to a multi-drug resistant (MDR) Acinetobacter is one of the most dreadful complications, which occurs in the critical care setting. Aims and objectives: To find out the incidence of Acinetobacter infection in VAP cases, to determine various risk factors responsible for acquisition of Acinetobacter infection and to determine the antimicrobial susceptibility pattern of Acinetobacter. Materials and Methods: A total of 60 endotracheal aspirate...

  1. Risk factors for anti-MRSA drug resistance.

    Science.gov (United States)

    Abe, Yasuhisa; Shigemura, Katsumi; Yoshida, Hiroyuki; Fujisawa, Masato; Arakawa, Soichi

    2012-11-01

    Meticillin-resistant Staphylococcus aureus (MRSA)-related infections have recently been spreading and are difficult to control, partly because affected patients are frequently in a poor condition. This study retrospectively investigated recent MRSA-related infections focusing on the relationship between clinical risk factors and anti-MRSA drug resistance. The patients with MRSA-related infections in Kobe University Hospital (Kobe, Japan) in 2009 were enrolled in the study. The relationships between various clinical risk factors as well as MRSA bacterial DNA concentration with minimum inhibitory concentrations (MICs) of anti-MRSA drugs were examined. In total, 44 patients were enrolled in the study and MRSA was isolated from blood (23 patients), urine (12 patients) and nasal secretions (9 patients). There was only one resistant strain to linezolid (LZD) among the anti-MRSA drugs tested, and this strain was considered staphylococcal cassette chromosome mec (SCCmec) type IIa from phage open-reading frame typing analyses. Statistical analyses showed that MRSA bacterial DNA concentration, cancer and use of a respirator, respectively, had a significant relationship with the MICs of LZD (P=0.0058) and arbekacin (ABK) (P=0.0003), of quinupristin/dalfopristin (Q/D) (P=0.0500) and ABK (P=0.0133), and of Q/D (P=0.0198) and vancomycin (P=0.0036). In conclusion, bacterial DNA concentration, cancer and use of a respirator were found to be significant risk factors for lower susceptibilities to anti-MRSA drugs; one strain was resistant to LZD. We suggest that further investigation and surveillance for MRSA-related infection are necessary for preventing the spread of MRSA-related infections. PMID:22999766

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

    OpenAIRE

    Leibert E; Danckers M; Rom WN

    2014-01-01

    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 undermi...

  3. 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

  4. 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

  5. Additional Drug Resistance of Multidrug-Resistant Tuberculosis in Patients in 9 Countries

    OpenAIRE

    Kurbatova, Ekaterina V.; Dalton, Tracy; Ershova, Julia; Tupasi, Thelma; Caoili, Janice Campos; van der Walt, Martie; Kvasnovsky, Charlotte; Yagui, Martin; Bayona, Jaime; Contreras, Carmen; Leimane, Vaira; Via, Laura E.; Kim, HeeJin; Akksilp, Somsak; Kazennyy, Boris Y.

    2015-01-01

    Data from a large multicenter observational study of patients with multidrug-resistant tuberculosis (MDR TB) were analyzed to simulate the possible use of 2 new approaches to treatment of MDR TB: a short (9-month) regimen and a bedaquiline-containing regimen. Of 1,254 patients, 952 (75.9%) had no resistance to fluoroquinolones and second-line injectable drugs and thus would qualify as candidates for the 9-month regimen; 302 (24.1%) patients with resistance to a fluoroquinolone or second-line ...

  6. 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.

  7. Surfactant-based drug delivery systems for treating drug-resistant lung cancer.

    Science.gov (United States)

    Kaur, Prabhjot; Garg, Tarun; Rath, Goutam; Murthy, R S R; Goyal, Amit K

    2016-01-01

    Among all cancers, lung cancer is the major cause of deaths. Lung cancer can be categorized into two classes for prognostic and treatment purposes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Both categories of cancer are resistant to certain drugs. Various mechanisms behind drug resistance are over-expression of superficial membrane proteins [glycoprotein (P-gp)], lung resistance-associated proteins, aberration of the intracellular enzyme system, enhancement of the cell repair system and deregulation of cell apoptosis. Structure-performance relationships and chemical compatibility are consequently major fundamentals in surfactant-based formulations, with the intention that a great deal investigation is committed to this region. With the purpose to understand the potential of P-gp in transportation of anti-tumor drugs to cancer cells with much effectiveness and specificity, several surfactant-based delivery systems have been developed which may include microspheres, nanosized drug carriers (nanoparticles, nanoemulsions, stealth liposomes, nanogels, polymer-drug conjugates), novel powders, hydrogels and mixed micellar systems intended for systemic and/or localized delivery. PMID:25013959

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

    Directory of Open Access Journals (Sweden)

    Soo-Yon Rhee

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

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

    Science.gov (United States)

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

    2015-01-01

    The increasing prevalence of acquired and transmitted HIV-1 drug resistance is an obstacle to successful antiretroviral therapy (ART) in the low- and middle-income countries (LMICs) hardest hit by the HIV-1 pandemic. Genotypic drug resistance testing could facilitate the choice of initial ART in areas with rising transmitted drug resistance (TDR) and enable care-providers to determine which individuals with virological failure (VF) on a first- or second-line ART regimen require a change in treatment. An inexpensive near point-of-care (POC) genotypic resistance test would be useful in settings where the resources, capacity, and infrastructure to perform standard genotypic drug resistance testing are limited. Such a test would be particularly useful in conjunction with the POC HIV-1 viral load tests that are currently being introduced in LMICs. A POC genotypic resistance test is likely to involve the use of allele-specific point mutation assays for detecting drug-resistance mutations (DRMs). This study proposes that two major nucleoside reverse transcriptase inhibitor (NRTI)-associated DRMs (M184V and K65R) and four major NNRTI-associated DRMs (K103N, Y181C, G190A, and V106M) would be the most useful for POC genotypic resistance testing in LMIC settings. One or more of these six DRMs was present in 61.2% of analyzed virus sequences from ART-naïve individuals with intermediate or high-level TDR and 98.8% of analyzed virus sequences from individuals on a first-line NRTI/NNRTI-containing regimen with intermediate or high-level acquired drug resistance. The detection of one or more of these DRMs in an ART-naïve individual or in a individual with VF on a first-line NRTI/NNRTI-containing regimen may be considered an indication for a protease inhibitor (PI)-containing regimen or closer virological monitoring based on cost-effectiveness or country policy. PMID:26717411

  10. 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.

  11. Bypass of Tumor Drug Resistance by Antivascular Therapy

    Directory of Open Access Journals (Sweden)

    Dina Preise

    2003-11-01

    Full Text Available Multidrug resistance (MDR presents a major obstacle for the successful chemotherapy of cancer. Its emergence during chemotherapy is attributed to a selective process, which gives a growth advantage to MDR cells within the genetically unstable neoplastic cell population. The pleiotropic nature of clinical MDR poses a great difficulty for the development of treatment strategies that aim at blocking MDR at the tumor cell level. Targeting treatment to the nonmalignant vascular network—the lifeline of the tumor—is a promising alternative for the treatment of drug-resistant tumors. The present study demonstrates that MDR in cancer can be successfully circumvented by photodynamic therapy (PDT using an antivascular treatment protocol. We show that, although P-glycoprotein-expressing human HT29/MDR colon carcinoma cells in culture are resistant to PDT with Pd-bacteriopheophorbide (TOOKAD, the same treatment induces tumor necrosis with equal efficacy (88% vs 82% in HT29/MDR-derived xenografts and their wild type counterparts, respectively. These results are ascribed to the rapid antivascular effects of the treatment, supporting the hypothesis that MDR tumors can be successfully eradicated by indirect approaches that bypass their inherent drug resistance. We suggest that with progress in ongoing clinical trials, TOOKAD-PDT may offer a novel option for local treatment of MDR tumors.

  12. 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

  13. 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.

  14. 社会家庭支持对耐多药肺结核患者治疗依从性的影响%Analysis of multi drug resistant tuberculosis treatment compliance and effect of family social support

    Institute of Scientific and Technical Information of China (English)

    石静; 李燕; 田瑞英

    2014-01-01

    目的:分析社会家庭支持对耐多药肺结核患者治疗依从性的影响。方法:将2011年1月~2012年8月在我院治疗80例耐多药肺结核患者,随机等分为观察组和对照组,对照组常规给予医务人员支持,观察组在对照组基础上进行社会家庭支持干预,抗结核治疗1年后对两组患者治疗依从性效果比较。结果:观察组通过社会家庭支持后,患者对治疗依从性效果明显高于对照组,差异有统计学意义(P<0.05)。结论:社会家庭支持有利于耐多药患者的心理康复和行为改善,提高患者治疗的依从性和疗效,而且能有效地控制耐多药肺结核病的传播与流行。%Objective:To analyze the treatment compliance effect of family and social support for patients with multi drug resistant pulmonary tuberculosis. Methods:80 patients in our hospital treatment of MDR-TB patients,were randomly divided into obserbvation group and control group. Support intervention in the observation group were family social,the control group only routine support intervention. Anti tuberculosis treatment compared to one year after treat-ment compliance of two groups of patients. Results:The observation group through the family social support,patients on treatment compliance of fruit was sig-nificantly higher than the control group,there was statistically significant differences between the two groups (P<0. 05). Conclusion:Family and social sup-port for multi drug resistant patients psychological rehabilitation and improvement of behavior,To improve the compliance and therapeutic effect of the treat-ment of patients with,Popular and can effectively control the multi drug resistant pulmonary tuberculosis.

  15. 21 CFR 866.3950 - In vitro human immunodeficiency virus (HIV) drug resistance genotype assay.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false In vitro human immunodeficiency virus (HIV) drug... Serological Reagents § 866.3950 In vitro human immunodeficiency virus (HIV) drug resistance genotype assay. (a) Identification. The in vitro HIV drug resistance genotype assay is a device that consists of nucleic acid...

  16. 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

  17. Conjugation to polymeric chains of influenza drugs targeting M2 ion channels partially restores inhibition of drug-resistant mutants

    OpenAIRE

    Larson, Alyssa M.; Chen, Jianzhu; Klibanov, Alexander M.

    2013-01-01

    By attaching multiple copies of the influenza M2 ion channel inhibitors amantadine (1) and rimantadine (2) to polymeric chains, we endeavored to recover their potency in inhibiting drug-resistant influenza viruses. Depending on loading densities, as well as the nature of the drug, the polymer, and the spacer arm, polymer-conjugated drugs were up to 30-fold more potent inhibitors of drug-resistant strains than their monomeric parents. In particular, a 20% loading density and a short linker gro...

  18. 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.

  19. Repurposing Clinical Molecule Ebselen to Combat Drug Resistant Pathogens.

    Directory of Open Access Journals (Sweden)

    Shankar Thangamani

    Full Text Available Without a doubt, our current antimicrobials are losing the battle in the fight against newly-emerged multidrug-resistant pathogens. There is a pressing, unmet need for novel antimicrobials and novel approaches to develop them; however, it is becoming increasingly difficult and costly to develop new antimicrobials. One strategy to reduce the time and cost associated with antimicrobial innovation is drug repurposing, which is to find new applications outside the scope of the original medical indication of the drug. Ebselen, an organoselenium clinical molecule, possesses potent antimicrobial activity against clinical multidrug-resistant Gram-positive pathogens, including Staphylococcus, Streptococcus, and Enterococcus, but not against Gram-negative pathogens. Moreover, the activity of ebselen against Gram-positive pathogens exceeded those activities determined for vancomycin and linezolid, drugs of choice for treatment of Enterococcus and Staphylococcus infections. The minimum inhibitory concentrations of ebselen at which 90% of clinical isolates of Enterococcus and Staphylococcus were inhibited (MIC90 were found to be 0.5 and 0.25 mg/L, respectively. Ebselen showed significant clearance of intracellular methicillin-resistant S. aureus (MRSA in comparison to vancomycin and linezolid. We demonstrated that ebselen inhibits the bacterial translation process without affecting mitochondrial biogenesis. Additionally, ebselen was found to exhibit excellent activity in vivo in a Caenorhabditis elegans MRSA-infected whole animal model. Finally, ebselen showed synergistic activities with conventional antimicrobials against MRSA. Taken together, our results demonstrate that ebselen, with its potent antimicrobial activity and safety profiles, can be potentially used to treat multidrug resistant Gram-positive bacterial infections alone or in combination with other antibiotics and should be further clinically evaluated.

  20. 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.

  1. "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.

  2. Comparative genomics of drug resistance in Trypanosoma brucei rhodesiense.

    Science.gov (United States)

    Graf, Fabrice E; Ludin, Philipp; Arquint, Christian; Schmidt, Remo S; Schaub, Nadia; Kunz Renggli, Christina; Munday, Jane C; Krezdorn, Jessica; Baker, Nicola; Horn, David; Balmer, Oliver; Caccone, Adalgisa; de Koning, Harry P; Mäser, Pascal

    2016-09-01

    Trypanosoma brucei rhodesiense is one of the causative agents of human sleeping sickness, a fatal disease that is transmitted by tsetse flies and restricted to Sub-Saharan Africa. Here we investigate two independent lines of T. b. rhodesiense that have been selected with the drugs melarsoprol and pentamidine over the course of 2 years, until they exhibited stable cross-resistance to an unprecedented degree. We apply comparative genomics and transcriptomics to identify the underlying mutations. Only few mutations have become fixed during selection. Three genes were affected by mutations in both lines: the aminopurine transporter AT1, the aquaporin AQP2, and the RNA-binding protein UBP1. The melarsoprol-selected line carried a large deletion including the adenosine transporter gene AT1, whereas the pentamidine-selected line carried a heterozygous point mutation in AT1, G430R, which rendered the transporter non-functional. Both resistant lines had lost AQP2, and both lines carried the same point mutation, R131L, in the RNA-binding motif of UBP1. The finding that concomitant deletion of the known resistance genes AT1 and AQP2 in T. b. brucei failed to phenocopy the high levels of resistance of the T. b. rhodesiense mutants indicated a possible role of UBP1 in melarsoprol-pentamidine cross-resistance. However, homozygous in situ expression of UBP1-Leu(131) in T. b. brucei did not affect the sensitivity to melarsoprol or pentamidine. PMID:26973180

  3. Multiple myeloma and persistence of drug resistance in the age of novel drugs (Review).

    Science.gov (United States)

    Krishnan, Sabna Rajeev; Jaiswal, Ritu; Brown, Ross D; Luk, Frederick; Bebawy, Mary

    2016-07-01

    Multiple myeloma (MM) is a mature B cell neoplasm that results in multi-organ failure. The median age of onset, diverse clinical manifestations, heterogeneous survival rate, clonal evolution, intrinsic and acquired drug resistance have impact on the therapeutic management of the disease. Specifically, the emergence of multidrug resistance (MDR) during the course of treatment contributes significantly to treatment failure. The introduction of the immunomodulatory agents and proteasome inhibitors has seen an increase in overall patient survival, however, for the majority of patients, relapse remains inevitable with evidence that these agents, like the conventional chemotherapeutics are also subject to the development of MDR. Clinical management of patients with MM is currently compromised by lack of a suitable procedure to monitor the development of clinical drug resistance in individual patients. The current MM prognostic measures fail to pick the clonotypic tumor cells overexpressing drug efflux pumps, and invasive biopsy is insufficient in detecting sporadic tumors in the skeletal system. This review summarizes the challenges associated with treating the complex disease spectrum of myeloma, with an emphasis on the role of deleterious multidrug resistant clones orchestrating relapse. PMID:27175906

  4. 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.

  5. Pharmacogenomic association study on the role of drug metabolizing, drug transporters and drug target gene polymorphisms in drug-resistant epilepsy in a north Indian population

    OpenAIRE

    Ritu Kumari; Ram Lakhan; Garg, R. K.; Kalita, J; Misra, U K; Balraj Mittal

    2011-01-01

    Background: In epilepsy, in spite of the best possible medications and treatment protocols, approximately one-third of the patients do not respond adequately to anti-epileptic drugs. Such interindividual variations in drug response are believed to result from genetic variations in candidate genes belonging to multiple pathways. Materials and Methods: In the present pharmacogenetic analysis, a total of 402 epilepsy patients were enrolled. Of them, 128 were diagnosed as multiple drug-resist...

  6. 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

  7. 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.

  8. Combined drug medium with isoniazid and rifampicin for identification of multi-drug resistant Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Nalini S

    2010-01-01

    Full Text Available A low-cost method of detecting multi-drug resistant Mycobacterium tuberculosis (MDR-TB with the possibility of quick adoption in a resource limited setting is urgently required. We conducted a study combining isoniazid and rifampicin in a single LJ medium, to detect MDR-TB strains. Combined and individual drug media showed 100% concordance for the detection of MDR-TB and susceptible strains by proportion method. Considering the results, combined isoniazid and rifampicin containing medium could be considered for use in settings where the sole detection of MDR-TB strains is justified.

  9. Positron emission tomography in patients with drug-resistant epilepsy

    International Nuclear Information System (INIS)

    Positron emission tomography with 18Fluor-deoxyglucose (18FDG PET) was introduced as method of evaluation of the cerebral metabolism in the early 80s. 18FDG PET/computed tomography (PET/CT) has rapidly become a method of epileptogenic zone localization because of the hypometaboilsm of this zone during the interictal period. This paper represents the first Bulgarian series of patients with drug- resistant epilepsy who were evaluated with 18FDG PET as part of the presurgical work-up. Our study has included 21 patients with drug-resistant epilepsy who were evaluated with 18FDG PET/CT from January 2010 to May 2013. All patients were evaluated with dedicated MRI epilepsy protocol. PET/CT study was fused with 3D MRI study using FSL or GE software. Video EEG monitoring was performed in all 21 patients and seizures were recorded in 18 patients. Hypometabolic zones were found in 15 patients. The hypometabolism was focal in 5 patients, multilobar in 9 patients and hemispheric in 1 patient. The MRI was normal in 8 patients. Hypometabolic zones were found in 3 of these 8 patients with cryptogenic epilepsy. Epilepsy surgery was performed in 6 cases. All operated patients were with hypometabolic zones. Significant seizure reduction after surgery was observed in 5 of 6 operated patients. 18FDG PET/CT is a valuable method for epileptogenic zone localization in patients with drug-resistant epilepsy. The introduction of this method in the bulgarian epilepsy surgery program increases the chances for successful resective surgery. (authors)

  10. Predicting drug resistance of the HIV-1 protease using molecular interaction energy components

    OpenAIRE

    Hou, Tingjun; Zhang, Wei; Wang, Jian; Wang, Wei

    2009-01-01

    Drug resistance significantly impairs the efficacy of AIDS therapy. Therefore, precise prediction of resistant viral mutants is particularly useful for developing effective drugs and designing therapeutic regimen. In this study, we applied a structure-based computational approach to predict mutants of the HIV-1 protease resistant to the seven FDA approved drugs. We analyzed the energetic pattern of the protease-drug interaction by calculating the molecular interaction energy components (MIECs...

  11. Studies of overcoming acquired resistance : molecular mechanisms and development of novel drugs

    OpenAIRE

    Wang, Xin

    2014-01-01

    Chemotherapeutic agents have become widely applied for treatment of various types of malignancies. Drug resistance unfortunately remains as a major obstacle for the effectiveness of chemotherapy. Cancer drug resistance includes two broad categories: intrinsic and acquired. In this thesis I have examined the problem of acquired drug resistance and have aimed to develop novel approaches to overcome acquired resistance. Clofarabine is a second-generation nucleoside analogue which has been ...

  12. Outcome after hemispherectomy in patients with drug-resistant epilepsy

    Directory of Open Access Journals (Sweden)

    Wei-wei WANG

    2015-11-01

    Full Text Available Hemispherectomy, as well as hemispherotomy, is an effective treatment for children and adolescents with drug-resistant epilepsy. The procedure is considered in children and adolescents with hemispheric damage due to congenital (e.g. malformation of cortical development, acquired (e.g. perinatal cerebral infarction or progressive diseases (e.g. Rasmussen encephalitis. As the main objective of this procedure, seizure control can be achieved in up to 80% of selected cases. Besides, the cognitive and motor function as well as the quality of life has shown good outcome. DOI: 10.3969/j.issn.1672-6731.2015.11.016

  13. Plasmonic Nanobubbles Rapidly Detect and Destroy Drug-Resistant Tumors

    Directory of Open Access Journals (Sweden)

    Ekaterina Y. Lukianova-Hleb, Xiaoyang Ren, Debra Townley, Xiangwei Wu, Michael E. Kupferman, Dmitri O. Lapotko

    2012-01-01

    Full Text Available The resistance of residual cancer cells after oncological resection to adjuvant chemoradiotherapies results in both high recurrence rates and high non-specific tissue toxicity, thus preventing the successful treatment of such cancers as head and neck squamous cell carcinoma (HNSCC. The patients' survival rate and quality of life therefore depend upon the efficacy, selectivity and low non-specific toxicity of the adjuvant treatment. We report a novel, theranostic in vivo technology that unites both the acoustic diagnostics and guided intracellular delivery of anti-tumor drug (liposome-encapsulated doxorubicin, Doxil in one rapid process, namely a pulsed laser-activated plasmonic nanobubble (PNB. HNSCC-bearing mice were treated with gold nanoparticle conjugates, Doxil, and single near-infrared laser pulses of low energy. Tumor-specific clusters of gold nanoparticles (solid gold spheres converted the optical pulses into localized PNBs. The acoustic signals of the PNB detected the tumor with high specificity and sensitivity. The mechanical impact of the PNB, co-localized with Doxil liposomes, selectively ejected the drug into the cytoplasm of cancer cells. Cancer cell-specific generation of PNBs and their intracellular co-localization with Doxil improved the in vivo therapeutic efficacy from 5-7% for administration of only Doxil or PNBs alone to 90% thus demonstrating the synergistic therapeutic effect of the PNB-based intracellular drug release. This mechanism also reduced the non-specific toxicity of Doxil below a detectable level and the treatment time to less than one minute. Thus PNBs combine highly sensitive diagnosis, overcome drug resistance and minimize non-specific toxicity in a single rapid theranostic procedure for intra-operative treatment.

  14. 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.

  15. 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.

  16. Low-level quinolone-resistance in multi-drug resistant typhoid

    International Nuclear Information System (INIS)

    To find out the frequency of low-level quinolone-resistance in Multi-Drug Resistant (MDR) typhoid using nalidixic acid screening disc. Blood was obtained from suspected cases of typhoid fever and cultured in to BacT/ALERT. The positive blood cultures bottles were subcultured. The isolates were identified by colony morphology and biochemical tests using API-20E galleries. Susceptibility testing of isolates was done by modified Kirby-Bauer disc diffusion method on Muellar Hinton Agar. For the isolates, which were resistant to nalidixic acid by disc diffusion method, Minimal Inhibitory Concentrations (MICs) of ciprofloxacin and nalidixic acid were determined by using the E-test strips. Disc diffusion susceptibility tests and MICs were interpreted according to the guidelines provided by National Committee for Control Laboratory Standard (NCCLS). A total of 21(65.5%) out of 32 isolates of Salmonellae were nalidixic acid-resistant by disk diffusion method. All the nalidixic acid-resistant isolates by disc diffusion method were confirmed by MICs for both ciprofloxacin and nalidixic acid. All the nalidixic acid-resistant isolates had a ciprofloxacin MIC of 0.25-1 microg/ml (reduced susceptibility) and nalidixic acid MICs > 32 microg (resistant). Out of all Salmonella isolates, 24 (75%) were found to be MDR, and all were S. typbi. Low-level quinolone-resistance in typhoid was high in this small series. Screening for nalidixic acid resistance with a 30 microg nalidixic acid disk is a reliable and cost-effective method to detect low-level fluoroquinolone resistance, especially in the developing countries. (author)

  17. Extensively and Pre-Extensively Drug Resistant Tuberculosis in Clinical Isolates of Multi-Drug Resistant Tuberculosis Using Classical Second Line Drugs (Levofloxacin and Amikacin)

    International Nuclear Information System (INIS)

    Objective:To find out the frequency of Extensively Drug Resistant (XDR) and pre-XDR tuberculosis in clinical isolates of Multi-Drug Resistant (MDR) Tuberculosis (TB) by determining the susceptibilities against Levofloxacin and Amikacin (classical second line antituberculosis drugs). Study Design: A descriptive cross-sectional study. Place and Duration of Study: Microbiology Department, Armed Forces Institute of Pathology (AFIP), Rawalpindi, from September 2011 to August 2013. Methodology: Amikacin (AK) and Levofloxacin (LEVO) were obtained in chemically pure form from Sigma (Taufkirchen, Germany). The breakpoint concentration used for AK was 1.0 micro g/ml and for LEVO 2.0 micro g/ml. Mycobacterial Growth Indicator Tube (MGIT) 960 system was used to carry out drug susceptibility testing as per recommended protocol. Results: A total of 3 MDR-TB isolates (3 percentage) turned out to be XDR-TB based upon simultaneous resistance to injectable second line antituberculosis drug AK and one of the fluoro-quinolones (LEVO). A total of 24 MDR-TB isolates (24 percentage) were found to be pre-XDR based upon resistance to LEVO alone. Treatment status record of patients with XDR and pre-XDRTB isolates revealed that majority of patients had received fluoroquinolones (FQs) during the course of treatment. Conclusion: XDR-TB has started to emerge in MDR-TB isolates in our set up. The worrying sign is the high frequency of pre-XDR tuberculosis. Urgent steps need to be taken to stem the tide of pre-XDR-TB in our population. It is thus recommended to develop facilities to carry out drug susceptibility testing to monitor the status of pre-XDR and XDR-TB in our population. (author)

  18. 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

  19. A genomic and evolutionary approach reveals non-genetic drug resistance in malaria

    OpenAIRE

    Herman, Jonathan D.; Rice, Daniel P.; Ribacke, Ulf; Silterra, Jacob; Deik, Amy A.; Moss, Eli L; Broadbent, Kate M; Neafsey, Daniel E; Desai, Michael M; Clish, Clary B.; Mazitschek, Ralph; Wirth, Dyann F.

    2014-01-01

    Background Drug resistance remains a major public health challenge for malaria treatment and eradication. Individual loci associated with drug resistance to many antimalarials have been identified, but their epistasis with other resistance mechanisms has not yet been elucidated. Results We previously described two mutations in the cytoplasmic prolyl-tRNA synthetase (cPRS) gene that confer resistance to halofuginone. We describe here the evolutionary trajectory of halofuginone resistance of tw...

  20. Adaptive and Mutational Resistance: Role of Porins and Efflux Pumps in Drug Resistance

    OpenAIRE

    Fernández, Lucía; Robert E W Hancock

    2012-01-01

    Summary: The substantial use of antibiotics in the clinic, combined with a dearth of new antibiotic classes, has led to a gradual increase in the resistance of bacterial pathogens to these compounds. Among the various mechanisms by which bacteria endure the action of antibiotics, those affecting influx and efflux are of particular importance, as they limit the interaction of the drug with its intracellular targets and, consequently, its deleterious effects on the cell. This review evaluates t...

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

    Directory of Open Access Journals (Sweden)

    Mario Arturo Alonso-Vanegas

    2012-01-01

    Full Text Available Cerebral cavernous malformations (CM are dynamic lesions characterized by continuous size changes and repeated bleeding. When involving cortical tissue, CM pose a significant risk for the development of drug-resistant epilepsy, which is thought to be result of an altered neuronal network caused by the lesion itself and its blood degradation products. Preoperative evaluation should comprise a complete seizure history, neurological examination, epilepsy-oriented MRI, EEG, video-EEG, completed with SPECT, PET, functional MRI and/or invasive monitoring as needed. Radiosurgery shows variable rates of seizure freedom and a high incidence of complications, thus microsurgical resection remains the optimal treatment for CM coursing with drug-resistant epilepsy.Two thirds of patients reach Engel I class at three-year follow-up, regardless of lobar location. Those with secondarily generalized seizures, a higher seizure frequency, and generalized abnormalities on preoperative or postoperative EEG, show poorer outcomes, while factors such as gender, duration of epilepsy, lesion size, age, bleeding at the time of surgery, do not correlate consistently with seizure outcome. Electrocorticography and a meticulous removal of all cortical hemosiderin –beyond pure lesionectomy– reduce the risk of symptomatic recurrences.

  2. Yeast cells with impaired drug resistance accumulate glycerol and glucose.

    Science.gov (United States)

    Dikicioglu, Duygu; Oc, Sebnem; Rash, Bharat M; Dunn, Warwick B; Pir, Pınar; Kell, Douglas B; Kirdar, Betul; Oliver, Stephen G

    2014-01-01

    Multiple drug resistance (MDR) in yeast is effected by two major superfamilies of membrane transporters: the major facilitator superfamily (MFS) and the ATP-binding cassette (ABC) superfamily. In the present work, we investigated the cellular responses to disruptions in both MFS (by deleting the transporter gene, QDR3) and ABC (by deleting the gene for the Pdr3 transcription factor) transporter systems by growing diploid homozygous deletion yeast strains in glucose- or ammonium-limited continuous cultures. The transcriptome and the metabolome profiles of these strains, as well as the flux distributions in the optimal solution space, reveal novel insights into the underlying mechanisms of action of QDR3 and PDR3. Our results show how cells rearrange their metabolism to cope with the problems that arise from the loss of these drug-resistance genes, which likely evolved to combat chemical attack from bacterial or fungal competitors. This is achieved through the accumulation of intracellular glucose, glycerol, and inorganic phosphate, as well as by repurposing genes that are known to function in other parts of metabolism in order to minimise the effects of toxic compounds. PMID:24157722

  3. Multidrug-resistant and extensively drug-resistant tuberculosis: a review of current concepts and future challenges.

    Science.gov (United States)

    Günther, Gunar

    2014-06-01

    Multidrug-resistant and extensively drug-resistant tuberculosis are recent global health issues, which makes tuberculosis - after the success of short course treatment during the second half of the last century - a major health challenge. Globalisation, health inequalities, competing economic interests and political instability contribute substantially to the spread of drug-resistant strains, which are associated with high rates of morbidity and mortality. Issues such as increasing transmission of drug-resistant strains, poor diagnostic coverage and a lengthy, toxic treatment need to be overcome by innovative approaches to tuberculosis control, prevention, diagnostics and treatment. This review addresses recent developments and future concepts.

  4. [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.

  5. 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.

  6. 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

  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. 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.

  9. Novel TetR family transcriptional factor regulates expression of multiple transport-related genes and affects rifampicin resistance in Mycobacterium smegmatis.

    Science.gov (United States)

    Liu, Huicong; Yang, Min; He, Zheng-Guo

    2016-01-01

    Transport-related genes significantly affect bacterial antibiotic resistance. However, the effects of these genes and their regulation of bacterial drug resistance in several mycobacterial species, including the fast-growing Mycobacterium smegmatis, the pathogen M. tuberculosis and M. avium have not been clearly characterized. We identified Ms4022 (MSMEG_4022) as a novel TetR family regulator that activates the expression of seven transport-related genes and affects drug resistance in M. smegmatis. Overexpression of Ms4022 inhibited M. smegmatis growth and enhanced mycobacterial resistance to the anti-tuberculosis drug rifampicin (RIF). By contrast, the Ms4022-deleted mycobacterial strain has shown sensitive to RIF. Ms4022 recognized three 19 bp non-palindromic motifs containing a 9 bp conserved region at their 5' end and it directly regulated seven transport-related genes, which affects mycobacterial resistance to RIF. Overexpression of three of seven transport-related genes (Ms1448, Ms1613, and Ms5278) inhibited the growth of M. smegmatis. This study improves our understanding of the function of mycobacterial transport-related genes and their regulation of bacterial drug resistance. PMID:27271013

  10. Analysis of Antimicrobial Resistance Genes in Multiple Drug Resistant (MDR) Salmonella enterica Isolated from Animals and Humans

    Science.gov (United States)

    Background: Multiple Drug Resistant (MDR) foodborne bacteria are a concern in animal and human health. Identification of resistance genes in foodborne pathogens is necessary to determine similarities of resistance mechanisms in animal, food and human clinical isolates. This information will help us ...

  11. 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

  12. Global Introduction of New Multidrug-Resistant Tuberculosis Drugs-Balancing Regulation with Urgent Patient Needs.

    Science.gov (United States)

    Sullivan, Timothy; Ben Amor, Yanis

    2016-03-01

    New treatments for multidrug-resistant tuberculosis (MDR TB) are urgently needed. Two new drugs, bedaquiline and delamanid, have recently been released, and several new drugs and treatment regimens are in the pipeline. Misuse of TB drugs is a principal cause of drug resistance. As new drugs and regimens reach the market, the need to make them available to patients must be balanced with regulation of their use so that resistance to the new drugs can be prevented. To foster the rational use of new drugs, we propose 1) expanding/strengthening the capacity for drug susceptibility testing, beginning with countries with a high TB burden; 2) regulating prescribing practices by banning over-the-counter sale of TB drugs and enacting an accreditation system whereby providers must be certified to prescribe new drugs; and 3) decentralizing MDR TB care in rural communities by employing trained community health workers, using promising mobile technologies, and enlisting the aid of civil society organizations. PMID:26889711

  13. Prevalence and determinants of resistance to use drugs among adolescents who had an opportunity to use drugs *

    OpenAIRE

    Lopez-Quintero, Catalina; Neumark, Yehuda

    2015-01-01

    Background As drugs remain ubiquitous and their use increasingly viewed as socially normative, vulnerable population groups such as adolescents face continued and growing risk. A better understanding of the factors that discourage individuals from initiating drug use, particularly in enabling scenarios, is therefore needed. This study aims to identify individual, interpersonal and school-contextual factors associated with resistance to using drugs in the presence of a drug use opportunity amo...

  14. 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.

  15. Drug resistance in sea lice: a threat to salmonid aquaculture.

    Science.gov (United States)

    Aaen, Stian Mørch; Helgesen, Kari Olli; Bakke, Marit Jørgensen; Kaur, Kiranpreet; Horsberg, Tor Einar

    2015-02-01

    Sea lice are copepod ectoparasites with vast reproductive potential and affect a wide variety of fish species. The number of parasites causing morbidity is proportional to fish size. Natural low host density restricts massive parasite dispersal. However, expanded salmon farming has shifted the conditions in favor of the parasite. Salmon farms are often situated near wild salmonid migrating routes, with smolts being particularly vulnerable to sea lice infestation. In order to protect both farmed and wild salmonids passing or residing in the proximity of the farms, several measures are taken. Medicinal treatment of farmed fish has been the most predictable and efficacious, leading to extensive use of the available compounds. This has resulted in drug-resistant parasites occurring on farmed and possibly wild salmonids. PMID:25639521

  16. 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.

  17. Consensus drug resistance mutations for epidemiological surveillance: basic principles and potential controversies.

    Science.gov (United States)

    Shafer, Robert W; Rhee, Soo-Yon; Bennett, Diane E

    2008-01-01

    Programmes that monitor local, national and regional levels of transmitted HIV-1 drug resistance inform treatment guidelines and provide feedback on the success of HIV-1 treatment and prevention programmes. The World Health Organization (WHO) has established a global programme for genotypic surveillance of HIV-1 drug resistance and has recommended the adoption of a consensus definition of genotypic drug resistance. Such a definition is necessary to accurately compare transmitted drug resistance rates across geographical regions and time periods. HIV-1 diversity and the large number of mutations associated with antiretroviral drug resistance complicate the development of a consensus definition for genotypic drug resistance. This paper reviews the data that must be considered to determine which of the many HIV-1 drug resistance mutations are likely to be both sensitive and specific indicators of transmitted drug resistance. The process used to create a previously published list of drug resistance mutations for HIV-1 surveillance is reviewed and alternative approaches to this process are discussed. PMID:18575192

  18. 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.

  19. Harnessing evolutionary fitness in Plasmodium falciparum for drug discovery and suppressing resistance

    OpenAIRE

    Lukens, Amanda Kathleen; Ross, L. S.; Heidebrecht, Richard W; Javier Gamo, F.; Lafuente-Monasterio, M. J.; Booker, M. L.; Hartl, Daniel L.; Wiegand, R C; Wirth, Dyann F

    2013-01-01

    Drug resistance emerges in an ecological context where fitness costs restrict the diversity of escape pathways. These pathways are targets for drug discovery, and here we demonstrate that we can identify small-molecule inhibitors that differentially target resistant parasites. Combining wild-type and mutant-type inhibitors may prevent the emergence of competitively viable resistance. We tested this hypothesis with a clinically derived chloroquine-resistant (CQr) malaria parasite and with para...

  20. Autophagy and Transporter-Based Multi-Drug Resistance

    Directory of Open Access Journals (Sweden)

    Zhe-Sheng Chen

    2012-08-01

    Full Text Available All the therapeutic strategies for treating cancers aim at killing the cancer cells via apoptosis (programmed cell death type I. Defective apoptosis endow tumor cells with survival. The cell can respond to such defects with autophagy. Autophagy is a cellular process by which cytoplasmic material is either degraded to maintain homeostasis or recycled for energy and nutrients in starvation. A plethora of evidence has shown that the role of autophagy in tumors is complex. A lot of effort is needed to underline the functional status of autophagy in tumor progression and treatment, and elucidate how to tweak autophagy to treat cancer. Furthermore, during the treatment of cancer, the limitation for the cure rate and survival is the phenomenon of multi drug resistance (MDR. The development of MDR is an intricate process that could be regulated by drug transporters, enzymes, anti-apoptotic genes or DNA repair mechanisms. Reports have shown that autophagy has a dual role in MDR. Furthermore, it has been reported that activation of a death pathway may overcome MDR, thus pointing the importance of other death pathways to regulate tumor cell progression and growth. Therefore, in this review we will discuss the role of autophagy in MDR tumors and a possible link amongst these phenomena.

  1. Multi-drug resistant Acinetobacter ventilator-associated pneumonia

    Directory of Open Access Journals (Sweden)

    Shete Vishal

    2010-01-01

    Full Text Available Background: Ventilator-associated pneumonia (VAP due to a multi-drug resistant (MDR Acinetobacter is one of the most dreadful complications, which occurs in the critical care setting. Aims and objectives: To find out the incidence of Acinetobacter infection in VAP cases, to determine various risk factors responsible for acquisition of Acinetobacter infection and to determine the antimicrobial susceptibility pattern of Acinetobacter. Materials and Methods: A total of 60 endotracheal aspirate specimens from intubated patients diagnosed clinically and microscopically as VAP were studied bacteriologically. All clinical details and prior exposure to antibiotics were recorded. Results: An incidence of 11.6% of Acinetobacter VAP cases was recorded. Various underlying conditions like head injury, cerebral hemorrhage and chronic obstructive pulmonary disease (COPD were found to be associated with Acinetobacter VAP. Acinetobacter strains exhibited MDR pattern. Conclusion: Strict infection control measures, judicious prescribing of antibiotics, antibiotic resistance surveillance programs and antibiotic cycling should be adopted to control infections due to these bacteria in patients admitted to intensive care units.

  2. 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

  3. Monitoring results on Mycobacterium tuberculosis drug resistance from 2010 to 2013 in Kaihua County of Zhejiang Province%浙江省开化县2010-2013年结核分枝杆菌耐药监测结果

    Institute of Scientific and Technical Information of China (English)

    方红艳

    2015-01-01

    目的:分析浙江省开化县219例痰涂片阳性(涂阳)肺结核病例结核分枝杆菌的耐药情况,为制订结核病控制对策提供科学依据。方法对2010年1月至2013年12月在开化县人民医院结核门诊诊治的涂阳肺结核病例的痰标本进行结核分枝杆菌培养,菌型鉴定为结核分枝杆菌的菌株采用比例法进行6种抗结核药物异烟肼、利福平、乙胺丁醇、链霉素、左氧氟沙星、卡那霉素耐药性监测。结果219例培养阳性病例中,总耐药率为21.46%,耐多药率3.20%,初始耐药率为19.69%,初始耐多药率为0.52%,获得性耐药率34.62%,获得性耐多药率23.08%。结论开化县2010至2013年结核分枝杆菌总耐药率、耐多药率、初始耐药率、初始耐多药率、获得性耐药率均低于全国第五次结核病流行病学调查结果,而获得性耐多药率则高于全国第五次结核病流行病学调查结果。%Objective To analyze the multidrug resistant situation with Mycobacterium tuberculosis in Kaihua county in order to provide technical basis for formulating measures on tuberculosis control. Methods Mycobacterium tuberculosis were cultivated, which were collected from smear positive tuberculosis patients'sputum in People's Hospital of Kaihua County from January 2010 to December 2013. Proportion method for Mycobacterium tuberculosis drug sensitivity test was conducted to 6 anti-tuberculosis drugs (isoniazide, rifampin, ethambutol, streptomycin, levofloxacin, kanamycin). Results In 219 Mycobacterium tuberculosis culture positive patients, the rate of total drug resistance was 21.46% and the rate of total multidrug resistance 3 .20%;the rate of initial drug resistance was 19 .69%, and the rate of initial multidrug resistance 0.52%;the rate of acquired drug resistance was 34.62%, and the rate of acquired multidrug resistance 23.08%. Conclusion The rate of total drug resistance, total multidrug

  4. Pay close attention to prevalence and treatment of multi-drug-resistant tuberculosis

    Directory of Open Access Journals (Sweden)

    Hong-bing CHEN

    2011-03-01

    Full Text Available Multi-drug-resistant tuberculosis(MDR-TB and extensive-drug-resistant tuberculosis(XDR-TB has become more prevalent worldwide.It is a disease which is difficult and expensive to treatment,with poor prognosis and high mortality.The spread of HIV accelerated the progression of malignancy of infection of tuberculosis.The evolution of MDR-and XDR-Mycobacterium tuberculosis had been a complicated and dynamic process related to the drug-resistant genes and phenotypes.The new diagnostic and therapeutic methods,research on vaccines,and the research and application of new drugs would be conducive to inhibit the prevalence of MDR-TB and XDR-TB.Prevention of initial drug-resistance infection should be emphasized in the prevention of drug-resistant TB.

  5. 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.

  6. 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.

  7. 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

  8. 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.

  9. 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

    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, to reflect drug concentrations more likely to be encountered during treatment. We performed a series of adaptive evolution experiments using Staphylococcus aureus. Interestingly, no relationship between drug interaction type and resistance evolution was found as resistance increased...

  10. Predicting drug resistance of the HIV-1 protease using molecular interaction energy components.

    Science.gov (United States)

    Hou, Tingjun; Zhang, Wei; Wang, Jian; Wang, Wei

    2009-03-01

    Drug resistance significantly impairs the efficacy of AIDS therapy. Therefore, precise prediction of resistant viral mutants is particularly useful for developing effective drugs and designing therapeutic regimen. In this study, we applied a structure-based computational approach to predict mutants of the HIV-1 protease resistant to the seven FDA approved drugs. We analyzed the energetic pattern of the protease-drug interaction by calculating the molecular interaction energy components (MIECs) between the drug and the protease residues. Support vector machines (SVMs) were trained on MIECs to classify protease mutants into resistant and nonresistant categories. The high prediction accuracies for the test sets of cross-validations suggested that the MIECs successfully characterized the interaction interface between drugs and the HIV-1 protease. We conducted a proof-of-concept study on a newly approved drug, darunavir (TMC114), on which no drug resistance data were available in the public domain. Compared with amprenavir, our analysis suggested that darunavir might be more potent to combat drug resistance. To quantitatively estimate binding affinities of drugs and study the contributions of protease residues to causing resistance, linear regression models were trained on MIECs using partial least squares (PLS). The MIEC-PLS models also achieved satisfactory prediction accuracy. Analysis of the fitting coefficients of MIECs in the regression model revealed the important resistance mutations and shed light into understanding the mechanisms of these mutations to cause resistance. Our study demonstrated the advantages of characterizing the protease-drug interaction using MIECs. We believe that MIEC-SVM and MIEC-PLS can help design new agents or combination of therapeutic regimens to counter HIV-1 protease resistant strains. PMID:18704937

  11. 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....

  12. 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...... alone or in combinations were the most common traits transferred....

  13. An Invitation to Project DARE: Drug Abuse Resistance Education. Program Brief.

    Science.gov (United States)

    Marx, Eva; DeJong, William

    Project DARE (Drug Abuse Resistance Education) is a substance use prevention education program designed to equip elementary school children with skills for resisting peer pressure to experiment with tobacco, drugs, and alcohol. This unique program, which was developed in 1983 as a cooperative effort by the Los Angeles Police Department and the Los…

  14. 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...

  15. 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.

  16. 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

  17. 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.

  18. The Association between Mycobacterium Tuberculosis Genotype and Drug Resistance in Peru.

    Directory of Open Access Journals (Sweden)

    Louis Grandjean

    Full Text Available The comparison of Mycobacterium tuberculosis bacterial genotypes with phenotypic, demographic, geospatial and clinical data improves our understanding of how strain lineage influences the development of drug-resistance and the spread of tuberculosis.To investigate the association of Mycobacterium tuberculosis bacterial genotype with drug-resistance. Drug susceptibility testing together with genotyping using both 15-loci MIRU-typing and spoligotyping, was performed on 2,139 culture positive isolates, each from a different patient in Lima, Peru. Demographic, geospatial and socio-economic data were collected using questionnaires, global positioning equipment and the latest national census.The Latin American Mediterranean (LAM clade (OR 2.4, p<0.001 was significantly associated with drug-resistance and alone accounted for more than half of all drug resistance in the region. Previously treated patients, prisoners and genetically clustered cases were also significantly associated with drug-resistance (OR's 2.5, 2.4 and 1.8, p<0.001, p<0.05, p<0.001 respectively.Tuberculosis disease caused by the LAM clade was more likely to be drug resistant independent of important clinical, genetic and socio-economic confounding factors. Explanations for this include; the preferential co-evolution of LAM strains in a Latin American population, a LAM strain bacterial genetic background that favors drug-resistance or the "founder effect" from pre-existing LAM strains disproportionately exposed to drugs.

  19. Epigenetic mechanisms of cell adhesion-mediated drug resistance in multiple myeloma.

    Science.gov (United States)

    Furukawa, Yusuke; Kikuchi, Jiro

    2016-09-01

    Multiple myeloma cells acquire the resistance to anti-cancer drugs through physical and functional interactions with the bone marrow microenvironment via two overlapping mechanisms. First, bone marrow stromal cells (BMSCs) produce soluble factors, such as interleukin-6 and insulin-like growth factor-1, to activate signal transduction pathways leading to drug resistance (soluble factor-mediated drug resistance). Second, BMSCs up-regulate the expression of cell cycle inhibitors, anti-apoptotic members of the Bcl-2 family and ABC drug transporters in myeloma cells upon direct adhesion [cell adhesion-mediated drug resistance (CAM-DR)]. Elucidation of the mechanisms underlying drug resistance may greatly contribute to the advancement of cancer therapies. Recent investigations, including ours, have revealed the involvement of epigenetic alterations in drug resistance especially CAM-DR. For example, we found that class I histone deacetylases (HDACs) determine the sensitivity of proteasome inhibitors and the histone methyltransferase EZH2 regulates the transcription of anti-apoptotic genes during the acquisition of CAM-DR by myeloma cells. In addition, another histone methyltransferase MMSET was shown to confer drug resistance to myeloma cells by facilitating DNA repair. These findings provide a rationale for the inclusion of epigenetic drugs, such as HDAC inhibitors and histone methylation modifiers, in combination chemotherapy for MM patients to increase the therapeutic index. PMID:27411688

  20. 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.

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

    Science.gov (United States)

    2012-01-01

    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. PMID:22621745

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. Prevalence of drug-resistant tuberculosis in mainland China: systematic review and meta-analysis.

    Directory of Open Access Journals (Sweden)

    Yu Yang

    Full Text Available BACKGROUND: The spread of drug-resistant tuberculosis (TB is one of the major public health problems in the world. Surveillance of anti-TB drug resistance is important for monitoring TB control strategies. However, the status of drug-resistant TB in China has been reported inconsistently. METHODS: We systematically reviewed published studies on drug-resistant TB in China until March 31, 2011, and quantitatively summarized prevalence and patterns of anti-TB drug resistance among new cases and previously treated cases, respectively. RESULTS: Ninety-five eligible articles, published during 1993-2011, were included in this review. The meta-analyses showed that the prevalence of drug-resistant TB in new cases was 27.9% (95% CI, 25.6%-30.2% (n/N = 27,360/104,356 and in previously treated cases was 60.3% (95% CI, 56.2%-64.2% (n/N = 30,350/45,858. Furthermore, in these two study populations, the prevalence of multiple drug resistance was found to be 5.3% (95% CI, 4.4%-6.4% (n/N = 8810/101,718 and 27.4% (95% CI, 24.1%-30.9% (n/N = 10,486/44,530 respectively. However, the results were found to be frequently heterogeneous (p for Q tests <0.001. The most common resistance was observed for isoniazid among both study populations. Different patterns of drug resistance were observed in the subgroup analysis with respect to geographic areas, drug susceptibility testing methods and subject enrollment time. CONCLUSIONS: Results of meta-analyses indicated a severe status of drug-resistant TB in China, which attaches an importance to strength TB prevention and control.

  7. 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.

  8. 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.

  9. A Randomised Trial Comparing Genotypic and Virtual Phenotypic Interpretation of HIV Drug Resistance: The CREST Study

    OpenAIRE

    Hales, Gillian; Birch, Chris; Crowe, Suzanne; Workman, Cassy; Hoy, Jennifer F.; Law, Matthew G; Kelleher, Anthony D.; Lincoln, Douglas; Emery, Sean

    2006-01-01

    Editorial Commentary Background: Antiretroviral drugs are used to treat patients with HIV infection, with good evidence that they improve prognosis. However, mutations develop in the HIV genome that allow it to evade successful treatment—known as drug resistance—and such mutations are known against every class of antiretroviral drug. Resistance can cause treatment failure and limit the treatment options available. Different types of tests are often used to detect resistance and to work out wh...

  10. Studies of resistance factors against chloroethylnitrosourea drugs in malignant tumor cells

    OpenAIRE

    Egyházi, Suzanne

    1996-01-01

    Drug resistance is a major clinical problem in the chemotherapy of tumor diseases and the identification of factors that make tumor cells resistant to drug treatment is therefore of crucial importance. We have investigated a possible involvement of O6-methylguanine-DNA methyltransferase (MGMT), glutathione transferase (GST) and glutathione (GSH) in the resistance to 1,3- bis(2-chloroethyl)- 1 -nitrosourea (BCNU) in two human lung cancer cell lines. The non-small cell lung ca...

  11. 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.

  12. Selective modulation of P-glycoprotein-mediated drug resistance

    OpenAIRE

    Bebawy, M; Morris, M B; Roufogalis, B. D.

    2001-01-01

    Multidrug resistance associated with the overexpression of the multidrug transporter P-glycoprotein is a serious impediment to successful cancer treatment. We found that verapamil reversed resistance of CEM/VLB 100 cells to vinblastine and fluorescein-colchicine, but not to colchicine. Chlorpromazine reversed resistance to vinblastine but not to fluorescein-colchicine, and it increased resistance to colchicine. Initial influx rates of fluorescein-colchicine were similar in resistant and paren...

  13. Overcoming ABC transporter-mediated multidrug resistance: Molecular mechanisms and novel therapeutic drug strategies.

    Science.gov (United States)

    Li, Wen; Zhang, Han; Assaraf, Yehuda G; Zhao, Kun; Xu, Xiaojun; Xie, Jinbing; Yang, Dong-Hua; Chen, Zhe-Sheng

    2016-07-01

    Multidrug resistance is a key determinant of cancer chemotherapy failure. One of the major causes of multidrug resistance is the enhanced efflux of drugs by membrane ABC transporters. Targeting ABC transporters projects a promising approach to eliminating or suppressing drug resistance in cancer treatment. To reveal the functional mechanisms of ABC transporters in drug resistance, extensive studies have been conducted from identifying drug binding sites to elucidating structural dynamics. In this review article, we examined the recent crystal structures of ABC proteins to depict the functionally important structural elements, such as domains, conserved motifs, and critical amino acids that are involved in ATP-binding and drug efflux. We inspected the drug-binding sites on ABC proteins and the molecular mechanisms of various substrate interactions with the drug binding pocket. While our continuous battle against drug resistance is far from over, new approaches and technologies have emerged to push forward our frontier. Most recent developments in anti-MDR strategies include P-gp inhibitors, RNA-interference, nano-medicines, and delivering combination strategies. With the advent of the 'Omics' era - genomics, epigenomics, transcriptomics, proteomics, and metabolomics - these disciplines play an important role in fighting the battle against chemoresistance by further unraveling the molecular mechanisms of drug resistance and shed light on medical therapies that specifically target MDR. PMID:27449595

  14. 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.

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

    Science.gov (United States)

    Cohen, Ted; Zignol, Matteo; Nyakan, Edwin; Hedt-Gauthier, Bethany L.; Gardner, Adrian; Kamle, Lydia; Injera, Wilfred; Carter, E. Jane

    2016-01-01

    Objective 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. Design 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. Results 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. Conclusion 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. PMID:27167381

  16. 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.

  17. 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.

  18. 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.

  19. 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.B. 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; 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

    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

  20. Whole-Genome Sequencing Analysis of Serially Isolated Multi-Drug and Extensively Drug Resistant Mycobacterium tuberculosis from Thai Patients.

    Science.gov (United States)

    Faksri, Kiatichai; Tan, Jun Hao; Disratthakit, Areeya; Xia, Eryu; Prammananan, Therdsak; Suriyaphol, Prapat; Khor, Chiea Chuen; Teo, Yik-Ying; Ong, Rick Twee-Hee; Chaiprasert, Angkana

    2016-01-01

    Multi-drug and extensively drug-resistant tuberculosis (MDR and XDR-TB) are problems that threaten public health worldwide. Only some genetic markers associated with drug-resistant TB are known. Whole-genome sequencing (WGS) is a promising tool for distinguishing between re-infection and persistent infection in isolates taken at different times from a single patient, but has not yet been applied in MDR and XDR-TB. We aim to detect genetic markers associated with drug resistance and distinguish between reinfection and persistent infection from MDR and XDR-TB patients based on WGS analysis. Samples of Mycobacterium tuberculosis (n = 7), serially isolated from 2 MDR cases and 1 XDR-TB case, were retrieved from Siriraj Hospital, Bangkok. The WGS analysis used an Illumina Miseq sequencer. In cases of persistent infection, MDR-TB isolates differed at an average of 2 SNPs across the span of 2-9 months whereas in the case of reinfection, isolates differed at 61 SNPs across 2 years. Known genetic markers associated with resistance were detected from strains susceptible to streptomycin (2/7 isolates), p-aminosalicylic acid (3/7 isolates) and fluoroquinolone drugs. Among fluoroquinolone drugs, ofloxacin had the highest phenotype-genotype concordance (6/7 isolates), whereas gatifloxcain had the lowest (3/7 isolates). A putative candidate SNP in Rv2477c associated with kanamycin and amikacin resistance was suggested for further validation. WGS provided comprehensive results regarding molecular epidemiology, distinguishing between persistent infection and reinfection in M/XDR-TB and potentially can be used for detection of novel mutations associated with drug resistance. PMID:27518818

  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. 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.

  5. Trends of drug resistant Mycobacterium Tuberculosis in a tertiary tuberculosis center in Iran

    International Nuclear Information System (INIS)

    To determine the drug resistance pattern to first line antituberculosis drugs in National Research Institute of Tuberculosis and Lung Disease and to compare resistant rates with the previous studies. An anterograde cross-sectional study was performed. The study includes all adults with documented pulmonary tuberculosis (TB) that were hospitalized in National Research Institute of Tuberculosis and Lung Disease, Tehran from June 2003 to September 2004. Demographic characteristic, TB categories, and drug susceptibility tests were recorded. Two previous studies regarding susceptibility in Iran were selected as historical controls. One hundred and ninety-six new cases and 68 previously treated patients were enrolled in the study. The strains of 61% of new patients and 21% of previously treated patients were fully sensitive to all drugs. The most common resistance was streptomycin (27%) followed by isoniazid (23%) in new cases. Multiple drug resistant strains were noted in 2.6% (95% CI 0.8% to 5.8%) of new cases versus 56% (95% CI 43% to 68%) in previously treated group. The frequency of primary drug resistance to isoniazid was 98%-15% or streptomycin 9.8%-15% or streptomycin 9.8%-13% in the previous studies (p<0.00001). While these rates may not reflect the true prevalence of drug resistance on national scale, it does partially demonstrate some defects in the existing tuberculosis control program. The significant increase of isoniazid and streptomycin resistance in the last few years would present a serious challenge to effective management of TB. (author)

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

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    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

  7. Treatment of complicated intra-abdominal infections in the era of multi-drug resistant Bacteria

    Directory of Open Access Journals (Sweden)

    Herzog T

    2010-11-01

    Full Text Available Abstract The management of severe intra-abdominal infections remains a major challenge facing surgeons and intensive care physicians, because of its association with high morbidity and mortality. Surgical management and intensive care medicine have constantly improved, but in the recent years a rapidly continuing emergence of resistant pathogens led to treatment failure secondary to infections with multi-drug resistant bacteria. In secondary peritonitis the rate of resistant germs at the initial operation is already 30%. The lack of effective antibiotics against these pathogens resulted in the development of new broad-spectrum compounds and antibiotics directed against resistant germs. But so far no "super-drug" with efficacy against all resistant bacteria exists. Even more, soon after their approval, reports on resistance against these novel drugs have been reported, or the drugs were withdrawn from the market due to severe side effects. Since pharmaceutical companies reduced their investigations on antibiotic research, only few new antimicrobial derivates are available. In abdominal surgery you may be in fear that in the future more and more patients with tertiary peritonitis secondary to multi-drug resistant species are seen with an increase of mortality after secondary peritonitis. This article reviews the current treatment modalities for complicated intra-abdominal infections with special reference to the antibiotic treatment of complicated intra-abdominal infections with multi-drug resistant species.

  8. [Erythropoietin and drug resistance in breast and ovarian cancers].

    Science.gov (United States)

    Szenajch, Jolanta M; Synowiec, Agnieszka E

    2016-01-01

    Recombinant human erythropoietin (rhEPO) is used in breast and ovarian cancer patients to alleviate cancer- and chemotherapy-related anemia. Some clinical trials have reported that rhEPO may adversely impact survival and increase the risk of thrombovascular events in patients with breast cancer but not with ovarian cancer. The latter may potentially benefit the most from rhEPO treatment due to the nephrotoxic and myelosuppresive effects of standard platinum-based chemotherapy used in ovarian cancer disease. However, over the last decade the preclinical data have revealed that EPO is not only the principal growth factor and the hormone which regulates erythropoiesis, but also a cytokine with a pleiotropic activity which also can affect cancer cells. EPO can stimulate survival, ability to form metastases and drug resistance not only in continuous breast- and ovarian cancer cell lines but also in breast cancer stem-like cells. EPO receptor (EPOR) can also be constitutively active in both these cancers and, in breast cancer cells, may act in an interaction with estrogen receptor (ER) and epidermal growth factor receptor-2 (HER-2). EPOR, by an EPO-independent mechanism, promotes proliferation of breast cancer cells in cooperation with estrogen receptor, resulting in decreased effectiveness of tamoxifen treatment. In another interaction, as a result of the molecular antagonism between EPOR and HER2, rhEPO protects breast cancer cells against trastuzumab. Both clinical and preclinical evidence strongly suggest the urgent need to reevaluate the traditional use of rhEPO in the oncology setting. PMID:27321103

  9. 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

  10. Patterns of Drug Resistance Among Tuberculosis Patients in West and Northwestern Iran

    Science.gov (United States)

    Sahebi, Leyla; Ansarin, Khalil; Mohajeri, Parviz; Khalili, Majid; Monfaredan, Amir; Farajnia, Safar; Zadeh, Simin Khayyat

    2016-01-01

    Background: Tuberculosis (TB) is the leading cause of morbidity and mortality among chronic infectious diseases. Objective: The goal of this cross-sectional study (2011-2013;2013) was to examine the patterns of TB drug resistance among HIV-negative pulmonary TB patients in regions near the Iranian border. Method: To this end, MTB isolates were harvested from 300 HIV-negative, pulmonary smear-positive TB patients from the northwest and west Iranian border provinces. Isolates were subjected to first and second-line drug susceptibility testing by the 1% proportion method. Demographic and clinical data were provided using a questionnaire and information from patient records. Results were analyzed using SPSS-18. Results: The mean age of the patients was 52.03 years and 54.3% were male. The prevalence of resistance to any TB drug was 13.6% (38 cases). Eleven percent of the new treatment TB group (28 patients) and 40.7% of the retreatment TB group (11 patients) were resistant to all TB drugs. Twelve (4.3%) patients had multidrug-resistant tuberculosis (MDR-TB) (2.38% in the new TB treatment group and 23.1% in the retreatment group). One patient had extensively drug-resistant tuberculosis (XDR-TB). There was a statistically significant relationship between TB drug resistance and smoking (p=0.02) and a history of migration from village to city (p=0.04), also between TB drug resistance and recurrence of TB in patients that had previously received treatment (p<0.001). Conclusion: Knowledge of drug resistance patterns for new and previously treated cases is critical for effective control of MDR-TB in different regions of the country. The burden of MDR-TB in retreatment cases was high. Previous TB treatment was one of the most important mokers and those who had a history of rural to urban migration were at high risk for the occurrence of TB drug resistance.

  11. 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.

  12. Multi-drug resistance in Salmonella enterica: efflux mechanisms and their relationships with the development of chromosomal resistance gene clusters.

    Science.gov (United States)

    Quinn, Teresa; O'Mahony, Rebecca; Baird, Alan W; Drudy, Denise; Whyte, Paul; Fanning, Séamus

    2006-07-01

    Bacterial drug resistance represents one of the most crucial problems in present day antibacterial chemotherapy. Of particular concern to public health is the continuing worldwide epidemic spread of Salmonella enterica serovar Typhimurium phage type DT104 harbouring a genomic island called Salmonella genomic island I (SGI-1). This island contains an antibiotic gene cluster conferring resistance to ampicillin, chloramphenicol, florfenicol, streptomycin, sulfonamides and tetracyclines. These resistance genes are assembled in a mosaic pattern, indicative of several independent recombinational events. The mobility of SGI-1 coupled with the ability of various antibiotic resistance genes to be integrated and lost from the chromosomal resistance locus allows for the transfer of stable antibiotic resistance to most of the commonly used antibiotics and adaptation to new antibiotic challenges. This, coupled with the incidence of increasing fluoroquinolone resistance in these strains increases the risk of therapeutic failure in cases of life-threatening salmonellosis. Fluoroquinolone resistance has largely been attributed to mutations occurring in the genes coding for intracellular targets of these drugs. However, efflux by the AcrAB-TolC multi-drug efflux pump has recently been shown to directly contribute to fluoroquinolone resistance. Furthermore, the resistance to chloramphenicol-florfenicol and tetracyclines in DT104 isolates, is due to interaction between specific transporters for these antibiotics encoded by genes mapping to the SGI-1 and the AcrAB-TolC tripartite efflux pump. The potential for the use of efflux pump inhibitors to restore therapeutic efficacy to fluoroquinolones and other antibiotics offers an exciting developmental area for drug discovery. PMID:16842216

  13. 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. PMID:27310477

  14. Association between Mycobacterium tuberculosis Complex Phylogenetic Lineage and Acquired Drug Resistance

    OpenAIRE

    Courtney M Yuen; Kurbatova, Ekaterina V.; Click, Eleanor S.; J Sean Cavanaugh; J Peter Cegielski

    2013-01-01

    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 a...

  15. Rapid Diagnosis of Extensively Drug-Resistant Tuberculosis by Use of a Reverse Line Blot Hybridization Assay▿†

    OpenAIRE

    Ajbani, Kanchan; Shetty,Anjali; Mehta, Ajita; Rodrigues, Camilla

    2011-01-01

    Drug resistance in tuberculosis (TB) is a matter of grave concern for TB control programs, as there is currently no cure for some extensively drug-resistant (XDR) strains. There is concern that this resistance could transmit, stressing the need for additional control measures, rapid diagnostic methods, and newer drugs for treatment. We developed an in-house assay that can rapidly detect resistance to drugs involved in the definition of XDR-TB directly from smear-positive specimens. Two hundre...

  16. 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.

  17. 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.

  18. 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.

  19. Detection of Multi-drug Resistant Acinetobacter Lwoffii Isolated from Soil of Mink Farm.

    Science.gov (United States)

    Sun, Na; Wen, Yong Jun; Zhang, Shu Qin; Zhu, Hong Wei; Guo, Li; Wang, Feng Xue; Chen, Qiang; Ma, Hong Xia; Cheng, Shi Peng

    2016-07-01

    There were 4 Acinetobacter lwoffii obtained from soil samples. The antimicrobial susceptibility of the strains to 16 antimicrobial agents was investigated using K-B method. Three isolates showed the multi-drug resistance. The presence of resistance genes and integrons was determined using PCR. The aadA1, aac(3')-IIc, aph(3')-VII, aac(6')-Ib, sul2, cat2, floR, and tet(K) genes were detected, respectively. Three class 1 integrons were obtained. The arr-3-aacA4 and blaPSE-1 gene cassette, which cause resistance to aminoglycoside and beta-lactamase antibiotics. Our results reported the detection of multi-drug resistant and carried resistant genes Acinetobacter lwoffii from soil. The findings suggested that we should pay close attention to the prevalence of multi-drug resistant bacterial species of environment. PMID:27554122

  20. 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.

  1. 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.

  2. Is Incident Drug-Resistance of Childhood-Onset Epilepsy Reversible? A Long-Term Follow-Up Study

    Science.gov (United States)

    Sillanpaa, Matti; Schmidt, Dieter

    2012-01-01

    Given the grave morbidity and mortality of drug-resistant epilepsy, it is of great clinical interest to determine how often prior proven drug-resistant epilepsy is reversible without surgery and whether remission can be predicted by clinical features in children with incident drug-resistant epilepsy. We determined the likelihood of 1-, 2- and…

  3. ALTERED MRP IS ASSOCIATED WITH MULTIDRUG-RESISTANCE AND REDUCED DRUG ACCUMULATION IN HUMAN SW-1573 CELLS

    NARCIS (Netherlands)

    EIJDEMS, EWHM; ZAMAN, GJR; DEHAAS, M; VERSANTVOORT, CHM; FLENS, MJ; SCHEPER, RJ; KAMST, E; BORST, P; BAAS, F

    1995-01-01

    We have analysed the contribution of several parameters, e.g. drug accumulation, MDR1 P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and topoisomerase (topo) II, to drug resistance in a large set of drug-resistant variants of the human non-small-cell lung cancer cell line SW-15

  4. 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

  5. Modeling the effects of drug resistant influenza virus in a pandemic

    Directory of Open Access Journals (Sweden)

    Koch Daniel

    2008-10-01

    Full Text Available Abstract Neuraminidase inhibitors (NI play a major role in plans to mitigate future influenza pandemics. Modeling studies suggested that a pandemic may be contained at the source by early treatment and prophylaxis with antiviral drugs. Here, we examine the influence of NI resistant influenza strains on an influenza pandemic. We extend the freely available deterministic simulation program InfluSim to incorporate importations of resistant infections and the emergence of de novo resistance. The epidemic with the fully drug sensitive strain leads to a cumulative number of 19,500 outpatients and 258 hospitalizations, respectively, per 100,000 inhabitants. Development of de novo resistance alone increases the total number of outpatients by about 6% and hospitalizations by about 21%. If a resistant infection is introduced into the population after three weeks, the outcome dramatically deteriorates. Wide-spread use of NI treatment makes it highly likely that the resistant strain will spread if its fitness is high. This situation is further aggravated if a resistant virus is imported into a country in the early phase of an outbreak. As NI-resistant influenza infections with high fitness and pathogenicity have just been observed, the emergence of drug resistance in treated populations and the transmission of drug resistant strains is an important public health concern for seasonal and pandemic influenza.

  6. 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.

  7. Frequent polymorphism at drug resistance sites in HIV-1 protease and reverse transcriptase

    Science.gov (United States)

    Kearney, Mary; Palmer, Sarah; Maldarelli, Frank; Shao, Wei; Polis, Michael A.; Mican, JoAnn; Rock-Kress, Diane; Margolick, Joseph B.; Coffin, John M.; Mellors, John W.

    2009-01-01

    Background Failure of antiretroviral therapy may result from the selection of pre-existing, drug-resistant HIV-1 variants, but the frequency and type of such variants have not been defined. Objective We used single genome sequencing (SGS) to characterize the frequency of polymorphism at drug resistance sites in protease (PR) and reverse transcriptase (RT) in plasma samples from antiretroviral naive individuals. Methods A total of 2229 pro-pol sequences in 79 plasma samples from 30 patients were analyzed by SGS. A mean of 28 single genome sequences was obtained from each sample. The frequency of mutations at all PR and RT sites was compared to those associated with drug resistance. Results We detected polymorphism at one or more drug resistance sites in 27 of 30 (90%) patients. Polymorphism at positions 179 and 215 of RT was most common, both occurring in 23% of patients. Most (68%) of other drug resistance sites were polymorphic with an average of 3.2% of genomes per sample containing at least one variant from wild type. Seven drug resistance sites were polymorphic in more than 1% of genomes: PR position 33; RT positions 69, 98, 118, 179, 210, and 215. Although frequencies of synonymous polymorphism were similar at resistance and nonresistance sites, nonsynonymous polymorphism were significantly less common at drug resistance sites, implying stronger purifying selection at these positions. Conclusions HIV-1 variants that are polymorphic at drug resistance sites pre-exist frequently as minor species in antiretroviral naive individuals. Standard genotype techniques have grossly underestimated their frequency. PMID:18301062

  8. Membrane permeabilization of colistin toward pan-drug resistant Gram-negative isolates

    Directory of Open Access Journals (Sweden)

    Yasmine Fathy Mohamed

    2016-06-01

    Full Text Available Abstract Pan-drug resistant Gram-negative bacteria, being resistant to most available antibiotics, represent a huge threat to the medical community. Colistin is considered the last therapeutic option for patients in hospital settings. Thus, we were concerned in this study to demonstrate the membrane permeabilizing activity of colistin focusing on investigating its efficiency toward those pan-drug resistant isolates which represent a critical situation. We determined the killing dynamics of colistin against pan-drug resistant isolates. The permeability alteration was confirmed by different techniques as: leakage, electron microscopy and construction of an artificial membrane model; liposomes. Moreover, selectivity of colistin against microbial cells was also elucidated. Colistin was proved to be rapid bactericidal against pan-drug resistant isolates. It interacts with the outer bacterial membrane leading to deformation of its outline, pore formation, leakage of internal contents, cell lysis and finally death. Furthermore, variations in membrane composition of eukaryotic and microbial cells provide a key for colistin selectivity toward bacterial cells. Colistin selectively alters membrane permeability of pan-drug resistant isolates which leads to cell lysis. Colistin was proved to be an efficient last line treatment for pan-drug resistant infections which are hard to treat.

  9. 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

  10. 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.

  11. 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

  12. 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.

  13. 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.

  14. 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.

  15. Retroviral transfer of a murine cDNA for multidrug resistance confers pleiotropic drug resistance to cells without prior drug selection.

    OpenAIRE

    Guild, B C; Mulligan, R C; Gros, P.; Housman, D.E.

    1988-01-01

    We have constructed a retrovirus expression vector that carries the murine mdr cDNA transcribed under the control of the human H4 histone promoter to examine the feasibility of efficiently transferring a multidrug resistance phenotype to cells without requiring drug selection. This approach will facilitate the transfer of mdr cDNA to hematopoietic progenitor cells for the study of multidrug resistance in vivo. The retrovirus vector pHmdr has been used for transmission and expression of the md...

  16. 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.

  17. Repurposing—a ray of hope in tackling extensively drug resistance in tuberculosis

    Directory of Open Access Journals (Sweden)

    Arundhati Maitra

    2015-03-01

    Full Text Available Tuberculosis (TB remains a serious concern more than two decades on from when the World Health Organization declared it a global health emergency. The alarming rise of antibiotic resistance in Mycobacterium tuberculosis, the etiological agent of TB, has made it exceedingly difficult to control the disease with the existing portfolio of anti-TB chemotherapy. The development of effective drugs with novel mechanism(s of action is thus of paramount importance to tackle drug resistance. The development of novel chemical entities requires more than 10 years of research, requiring high-risk investment to become commercially available. Repurposing pre-existing drugs offers a solution to circumvent this mammoth investment in time and funds. In this context, several drugs with known safety and toxicity profiles have been evaluated against the TB pathogen and found to be efficacious against its different physiological states. As the endogenous targets of these drugs in the TB bacillus are most likely to be novel, there is minimal chance of cross-resistance with front-line anti-TB drugs. Also, reports that some of these drugs may potentially have multiple targets means that the possibility of the development of resistance against them is minimal. Thus repurposing existing molecules offers immense promise to tackle extensively drug-resistant TB infections.

  18. New developments in the treatment of drug-resistant tuberculosis: clinical utility of bedaquiline and delamanid

    Directory of Open Access Journals (Sweden)

    Brigden G

    2015-10-01

    Full Text Available Grania Brigden,1 Cathy Hewison,2 Francis Varaine21Access Campaign, Médecins Sans Frontières, Geneva, Switzerland; 2Medical Department, Médecins Sans Frontières, Paris, France Abstract: The current treatment for drug-resistant tuberculosis (TB is long, complex, and associated with severe and life-threatening side effects and poor outcomes. For the first time in nearly 50 years, there have been two new drugs registered for use in multidrug-resistant TB (MDR-TB. Bedaquiline, a diarylquinoline, and delamanid, a nitromidoxazole, have received conditional stringent regulatory approval and have World Health Organization interim policy guidance for their use. As countries improve and scale up their diagnostic services, increasing number of patients with MDR-TB and extensively drug-resistant TB are identified. These two new drugs offer a real opportunity to improve the outcomes of these patients. This article reviews the evidence for these two new drugs and discusses the clinical questions raised as they are used outside clinical trial settings. It also reviews the importance of the accompanying drugs used with these new drugs. It is important that barriers hindering the use of these two new drugs are addressed and that the existing clinical experience in using these drugs is shared, such that their routine-use programmatic conditions is scaled up, ensuring maximum benefit for patients and countries battling the MDR-TB crisis. Keywords: MDR-TB, XDR-TB, tuberculosis drugs, group 5 drugs

  19. 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.

  20. 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

  1. [New Drugs for the Treatment of Multidrug-resistant Tuberculosis (MDR-TB)].

    Science.gov (United States)

    Schaberg, T; Otto-Knapp, R; Bauer, T

    2015-05-01

    This article summarizes the state of development of new drugs for the treatment of multidrug-resistant tuberculosis. We focused on delamanid, bedaquiline, pretomanid, SQ 109 and sutezolid. PMID:25970122

  2. U.S. Cases of Drug-Resistant Gonorrhea Rise Fourfold in One Year

    Science.gov (United States)

    ... Cases of Drug-Resistant Gonorrhea Rise Fourfold in One Year CDC statistics for 2013-2014 show troubling ... treat it," Mermin said. "We are running just one step ahead in order to preserve the remaining ...

  3. 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.

  4. 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

  5. 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

  6. 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.

  7. Molecular Characterization of Resistance-Nodulation-Division Transporters from Solvent- and Drug-Resistant Bacteria in Petroleum-Contaminated Soil

    OpenAIRE

    Meguro, Norika; Kodama, Yumiko; Gallegos, Maria-Trinidad; Watanabe, Kazuya

    2005-01-01

    PCR assays for analyzing resistance-nodulation-division transporters from solvent- and drug-resistant bacteria in soil were developed. Sequence analysis of amplicons showed that the PCR successfully retrieved transporter gene fragments from soil. Most of the genes retrieved from petroleum-contaminated soils formed a cluster (cluster PCS) that was distantly related to known transporter genes. Competitive PCR showed that the abundance of PCS genes is increased in petroleum-contaminated soil.

  8. Understanding the Genetic Mechanisms of Cancer Drug Resistance Using Genomic Approaches.

    Science.gov (United States)

    Hu, Xueda; Zhang, Zemin

    2016-02-01

    A major obstacle in precision cancer medicine is the inevitable resistance to targeted therapies. Tremendous effort and progress has been made over the past few years to understand the biochemical and genetic mechanisms underlying drug resistance, with the goal to eventually overcome such daunting challenges. Diverse mechanisms, such as secondary mutations, oncogene bypass, and epigenetic alterations, can all lead to drug resistance, and the number of known involved genes is growing rapidly, thus providing many possibilities to overcome resistance. The finding of these mechanisms and genes invariably requires the application of genomic and functional genomic approaches to tumors or cancer models. In this review, we briefly highlight the major drug-resistance mechanisms known today, and then focus primarily on the technological approaches leading to the advancement of this field.

  9. Understanding the Genetic Mechanisms of Cancer Drug Resistance Using Genomic Approaches.

    Science.gov (United States)

    Hu, Xueda; Zhang, Zemin

    2016-02-01

    A major obstacle in precision cancer medicine is the inevitable resistance to targeted therapies. Tremendous effort and progress has been made over the past few years to understand the biochemical and genetic mechanisms underlying drug resistance, with the goal to eventually overcome such daunting challenges. Diverse mechanisms, such as secondary mutations, oncogene bypass, and epigenetic alterations, can all lead to drug resistance, and the number of known involved genes is growing rapidly, thus providing many possibilities to overcome resistance. The finding of these mechanisms and genes invariably requires the application of genomic and functional genomic approaches to tumors or cancer models. In this review, we briefly highlight the major drug-resistance mechanisms known today, and then focus primarily on the technological approaches leading to the advancement of this field. PMID:26689126

  10. 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......-damaging agents cisplatin, etoposide, and fotemustine. Subarray analyses confirmed 57 candidate genes recovered from a genome-wide scan for differential expression. By specifically addressing cancer genes we retrieved another set of 209 candidates. Exemplary Northern blot studies indicated qualitative concordance...... converged in their expression patterns. A total of 110 genes was transiently or permanently deregulated in at least two resistant sublines. Fourteen genes displayed differential expression in all three of the sublines. We hypothesize that the variations in fotemustine and cisplatin resistance are based...

  11. 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。

  12. Repurposing — a ray of hope in tackling extensively drug resistance in tuberculosis

    OpenAIRE

    Arundhati Maitra; Sadé Bates; Trupti Kolvekar; Devarajan, Padma V.; Guzman, Juan D.; Sanjib Bhakta

    2015-01-01

    Tuberculosis (TB) remains a serious concern more than two decades on from when the World Health Organization declared it a global health emergency. The alarming rise of antibiotic resistance in Mycobacterium tuberculosis, the etiological agent of TB, has made it exceedingly difficult to control the disease with the existing portfolio of anti-TB chemotherapy. The development of effective drugs with novel mechanism(s) of action is thus of paramount importance to tackle drug resistance. The deve...

  13. 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.

  14. Epigenetic modulation of the drug resistance genes MGMT, ABCB1 and ABCG2 in glioblastoma multiforme

    OpenAIRE

    Oberstadt, Moritz C.; Bien-Möller, Sandra; Weitmann, Kerstin; Herzog, Susann; Hentschel, Katharina; Rimmbach, Christian; Vogelgesang, Silke; Balz, Ellen; Fink, Matthias; Michael, Heike; Zeden, Jan-Philip; Bruckmüller, Henrike; Werk, Anneke N.; Cascorbi, Ingolf; Hoffmann, Wolfgang

    2013-01-01

    Background Resistance of the highly aggressive glioblastoma multiforme (GBM) to drug therapy is a major clinical problem resulting in a poor patient’s prognosis. Beside promoter methylation of the O 6 -methylguanine-DNA-methyltransferase (MGMT) gene the efflux transporters ABCB1 and ABCG2 have been suggested as pivotal factors contributing to drug resistance, but the methylation of ABCB1 and ABCG2 has not been assessed before in GBM. Methods Therefore, we evaluated the proportion and pr...

  15. New developments in the treatment of drug-resistant tuberculosis: clinical utility of bedaquiline and delamanid

    OpenAIRE

    Brigden, Grania

    2015-01-01

    Grania Brigden,1 Cathy Hewison,2 Francis Varaine21Access Campaign, Médecins Sans Frontières, Geneva, Switzerland; 2Medical Department, Médecins Sans Frontières, Paris, France Abstract: The current treatment for drug-resistant tuberculosis (TB) is long, complex, and associated with severe and life-threatening side effects and poor outcomes. For the first time in nearly 50 years, there have been two new drugs registered for use in multidrug-resistant...

  16. Drug resistance of organisms isolated from feces of laboratory mice and rats.

    Science.gov (United States)

    Maejima, K; Urano, T; Tamura, H; Terakado, N

    1980-01-01

    A total of 248 strains of EScherichia coli, 132 of Staphylococcus epidermidis, 137 of Streptococcus faecalis and 89 of STr. faecium were collected from feces of 40 mice and 36 rats of 8 colonies in 1978, and drug resistance were examined by an agar dieution method using 23 antibiotics. The results indicated a positive relation between use of antibiotics and appearance of multiple drug resistant organisms. PMID:6772455

  17. 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.

  18. Streptococcus suis, an Emerging Drug-Resistant Animal and Human Pathogen

    OpenAIRE

    Palmieri, Claudio; Varaldo, Pietro E.; Facinelli, Bruna

    2011-01-01

    Streptococcus suis, a major porcine pathogen, has been receiving growing attention not only for its role in severe and increasingly reported infections in humans, but also for its involvement in drug resistance. Recent studies and the analysis of sequenced genomes have been providing important insights into the S. suis resistome, and have resulted in the identification of resistance determinants for tetracyclines, macrolides, aminoglycosides, chloramphenicol, antifolate drugs, streptothricin,...

  19. 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

  20. The Communicative Process of Drug Resistance among High School Students.

    Science.gov (United States)

    Alberts, J. K.; And Others

    1992-01-01

    Analyzed 69 narrative accounts of successful and unsuccessful attempts by high school students to say no to drug offers. Found peer pressure applied in approximately 70 percent of offers. Much of pressure was applied after refusal of initial offer. Simple offers were more likely with alcohol; drug offers were more likely to be persuasive and to…

  1. [Rifampicin-resistant Mycobacterium bovis BCG strain isolated from an infant with NEMO mutation].

    Science.gov (United States)

    Çavuşoğlu, Cengiz; Edeer Karaca, Neslihan; Azarsız, Elif; Ulusoy, Ezgi; Kütükçüler, Necil

    2015-04-01

    It is well known that disseminated Mycobacterium bovis BCG infection is developed after BCG vaccination in infants with congenital cellular immune deficiencies such as mutations in genes along the interleukin (IL)-12/interferon (IFN)-γ pathway and mutations in nuclear factor-kB essential modulator (NEMO). In this report, a rifampicin-resistant M.bovis BCG strain isolated from an infant with NEMO defect was presented. An 8-month-old male infant with NEMO defect admitted to the pediatric outpatient clinic of our hospital with fever, generalized lymphadenopathy and hepatosplenomegaly. Microscopic examination of the smears prepared from lymph node and liver biopsy specimens revealed abundant amount (3+) of acid-fast bacilli (AFB). Rifampicin-susceptible Mycobacterium tuberculosis complex (MTC) was detected by real-time PCR (GeneXpert MTB/RIF; Cepheid, USA) in the samples. The growth of mycobacteria was determined on the 20th day of culture performed in MGIT960 system (Becton Dickinson, USA). The isolate was identified as M.bovis BCG by GenoType MTBC kit (Hain Lifescience, Germany) and defined as M.bovis BCG [SIT 482 (BOV_1)] by spoligotyping. In the primary anti-tuberculosis drug susceptibility test performed by MGIT960 system, the isolate was found susceptible to rifampicin (RIF), isoniazid (INH), streptomycin (STM) and ethambutol (EMB). Then anti-tuberculosis treatment was started to the patient. However, the patient at the age of 2 years, re-admitted to the hospital with the complaint of hepatosplenomegaly. Smear of spontaneously draining abscess material obtained from subcutaneous nodules revealed intensive AFB positivity (3+) once again. In the present instance RIF-resistant MTC was detected with GeneXpert system in the specimen. The growth of mycobacteria was determined on the 13th day of culture and isolate was identified as M.bovis BCG. The present isolate was found susceptible to INH, STM and EMB but resistant to RIF. A mutation in the rpoB gene (codon 531, S

  2. 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

  3. 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.

  4. Multi-Drug Resistant Bacteria Isolated from Fish and Fish Handlers in Maiduguri, Nigeria

    Directory of Open Access Journals (Sweden)

    Hafsat Ali Grema

    2015-07-01

    Full Text Available Multi-drug resistant bacteria were isolated from fresh fish and fish handlers using conventional methods of bacterial isolation such as colonial morphology, gram staining and biochemical tests. The bacteria isolated include Staphylococcus aureus, Streptococcus sp, E. coli, Klebsiella sp, Proteus sp. and Brucella sp. bacterial isolates were subjected to antibiotic susceptibility testing using disc diffusion technique against ten antimicrobial agents. S. aureus isolates showed resistance to gentamycin, tetracycline, oxacillin, ciprofloxacin and cefoxitin while Streptococcus sp were resistant to tetracycline, chloramphenicol and clindamycin. All the bacterial isolates were resistant to tetracycline while susceptible to cefoxitin, cephazolin, erythromycin and clindamycin. The multi drug resistance pattern of Staphylococcus aureus isolates showed resistance to three and more antimicrobial agents while none was resistant to 10 antimicrobial agents. All other isolates were resistant to four and more different antimicrobial agents while no isolates was resistant to one and ten antimicrobial agents. Therefore the continuous monitoring and surveillance of multi-drug resistant bacteria in fish and fish handlers will not only reduce the risk of disease to the fishes but public health hazard to fish handlers and consumers in general.

  5. The global tuberculosis situation and the inexorable rise of drug-resistant disease.

    Science.gov (United States)

    Marais, Ben J

    2016-07-01

    The highly cost-effective DOTS strategy helped to bring the global tuberculosis (TB) epidemic under control in many parts of the world; however, the emergence and spread of drug-resistant strains pose a major threat to these gains. Molecular epidemiology studies, together with recent genomic evidence, provide proof that some drug-resistant strains are highly transmissible with documented epidemic spread. The potential for epidemic replacement of drug-susceptible with drug-resistant strains provides strong motivation for renewed emphasis on TB drug and vaccine development. It also reflects the need for enhanced infection control measures in health care and congregate settings, especially in TB endemic areas. The exploration of preventive therapy options for close contacts of patients with infectious drug-resistant TB also warrants further exploration, in an attempt to break the transmission cycle. Increased population mobility and large scale cross-border migration imply that the inexorable rise of drug-resistant TB is not geographically confined; it is a global concern that poses a very real threat to TB endemic and non-endemic settings. Failure to find new solutions will compromise traditional TB control efforts and derail momentum toward future TB elimination. PMID:26855302

  6. 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.

  7. 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...... discuss the possibility that the development of MDR involves sequential and localized upregulation of ion channels involved in proliferation and migration and a concomitant global and persistent downregulation of ion channels involved in apoptosis. © 2014 The Author(s) Published by the Royal Society....

  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. 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

  10. 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.

  11. 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

  12. 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

  13. Drug-resistance phenomena in major psychoses: their discrimination and causal mechanisms.

    Science.gov (United States)

    Altamura, A C

    1990-01-01

    Drug-resistance phenomena are commonly encountered in psychiatric practice and are of particular concern in the treatment of major psychoses. Of paramount importance is the need to discriminate between drug-resistance problems due to pharmacodynamic factors (i.e., receptor sensitivity) or pharmacokinetic factors (inadequate plasma concentration of the drugs at receptor sites). To exclude the former, plasma level measurements of antidepressant and neuroleptic compounds are desirable. Actually, lack of or poor compliance is a peculiarity (often underestimated) when treating psychotic patients, and the use of the drug plasma level/dose ratio (L/D) approach is useful, particularly with outpatients. Another source of drug resistance stems from the inter-individual metabolic variability, as with haloperidol or anticholinergic drugs, which are used to counteract neuroleptic-induced extrapyramidal side effects. In general, plasma-level measurement is advisable whenever no or poor response is obtained during standard treatments with neuroleptic, antidepressant, or anticholinergic drugs. Finally, this author suggests a four-level discrimination process to determine drug resistance in major psychoses, which includes clinical, pharmacological, pharmacokinetic, and pharmacodynamic factors. PMID:1974169

  14. 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...

  15. Nosocomial Infections and Drug Susceptibility Patterns in Methicillin Sensitive and Methicillin Resistant Staphylococcus aureus

    OpenAIRE

    Sharma, Nitish Kumar; Garg, Raina; Baliga, Shrikala; Bhat K., Gopalkrishna

    2013-01-01

    Aim: Staphylococcus aureus is one of the leading causes of nosocomial infections and is known for its ability to develop resistance to antibiotics. The drug susceptibility pattern of Methicillin Sensitive S. aureus (MSSA) and Methicillin Resistant S. aureus (MRSA) may vary.

  16. Impact of diabetes mellitus on tuberculosis drug resistance in new cases of tuberculosis.

    Science.gov (United States)

    Baghaei, Parvaneh; Tabarsi, Payam; Javanmard, Pedram; Farnia, Parissa; Marjani, Majid; Moniri, Afshin; Masjedi, Mohammad Reza; Velayati, Ali Akbar

    2016-03-01

    The objectives of this study were to determine the impact of diabetes mellitus (DM) on antituberculosis drug resistance in new cases of tuberculosis (TB). A case-control study was conducted on all newly diagnosed pulmonary TB adult patients with DM as cases and without DM as controls who were hospitalised from May 2013 to October 2013 in Iran. A molecular resistance test for rapid detection of resistance to isoniazid and rifampicin was done. Multivariate analysis was performed to determine the impact of DM on any anti-TB drug resistance. In total, 62 TB cases with DM and 64 TB cases without DM were included. TB cases with DM were more likely to be older (59 years vs. 43 years; P=0.001). Two TB-DM patients had multidrug-resistant TB (MDR-TB) (3.2%) compared with no cases of MDR-TB in the control group, and more TB-DM cases had isolates that were resistant to at least one drug (12.9% vs. 10.9%). DM [odds ratio (OR)=4.82, 95% confidence interval (CI) 1-23.57], age resistance in the multivariate analysis. In conclusion, new TB patients with DM are at increased risk of anti-TB drug resistance. More studies are needed to confirm these results. PMID:27436384

  17. 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.

  18. 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...

  19. 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...

  20. Retroviral transfer of a murine cDNA for multidrug resistance confers pleiotropic drug resistance to cells without prior drug selection

    International Nuclear Information System (INIS)

    The authors have constructed a retrovirus expression vector that carries the murine mdr cDNA transcribed under the control of the human H4 histone promoter to examine the feasibility of efficiently transferring a multidrug resistance phenotype to cells without requiring drug selection. This approach will facilitate the transfer of mdr cDNA to hematopoietic progenitor cells for the study of multidrug resistance in vivo. The retrovirus vector pHmdr has been used for transmission and expression of the mdr cDNA in initially drug-sensitive NIH 3T3 fibroblasts. Selection of pHmdr infectants in the cytotoxic agents colchicine or doxorubicin gave rise to highly multidrug-resistant colonies containing a single gene copy of the vector. Moreover, in the analysis of 12 cloned unselected NIH 3T3 cell infectants, a multidrug resistance phenotype was conferred by as few as two copies of the pHmdr vector. Overexpression of the mdr cDNA in drug-selected and unselected pHmdr infectants was directly related to cell survival in three cytotoxic agents tested. These results hold significant implications for the study of multidrug resistance in vivo

  1. 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.

  2. MULTI DRUG RESISTANCE IN METHICILLIN RESISTANT STAPHYLOCOCCUS AUREUS (MRSA ISOLATES FROM A UNIVER SITY HOSPITAL OF WESTERN INDIA

    Directory of Open Access Journals (Sweden)

    Ravi

    2013-03-01

    Full Text Available ABSTRACT: BACKGROUND: Methicillin Resistant Staphylococcus aureus (MRSA has emerged as one of the most important nosocomial pathogen. Its remarkable ability to develop resistance to a variety of antibiotics makes it a major threat to public health. OBJECTIVES: - To detect the prevalence and in vitro antimicrobial susceptibility pattern of the MRSA isolates. MATERIALS & METHODS: - 202 Staphylococcus aureus strains isolated from c linical samples like blood, pus, sputum & body fluids were screened for Methicillin r esistance by standard disk diffusion method and then confirmed with Oxacillin Screening agar. Antibiotic susceptibility of both the MRSA and Methicillin sensitive Staphylococcus aureu s (MSSA for other antibiotics was subsequently carried out by standard disc diffusion method. RESULTS: Methicillin resistance was detected in 114 strains of Staphylococcus aureus giving a prevalence rate of 56.44%. More than 80% of the MRSA isolates were resistant to ant ibiotics such as Penicillins, Cephalosporins, Aminoglycosides, Macrolides and Quinolones. All str ains were uniformly sensitive to Vancomycin & Linezolid. Coexisting resistance to mo st of the antibiotics was significantly higher in the MRSA isolates as compared to the MSSA (Methic illin sensitive Staphylococcus aureus isolates (p < 0.001. INTERPRETATION & CONCLUSIONS: Multi drug resistance among the MRSA isolates poses a major hurdle in treating syste mic infections. Monitoring antibiotic sensitivity pattern, implementing aggressive surveill ance measures & good infection control practices would be helpful in reducing the prevalence of MRSA and its multi drug resistance

  3. 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.

  4. Minimal inhibitory concentrations of first-line drugs of multidrug -resistant tuberculosis isolates

    Directory of Open Access Journals (Sweden)

    Nicolas Schönfeld

    2012-01-01

    Full Text Available Context: The treatment of multidrug-resistant (MDR and extensively drug-resistant (XDR tuberculosis (TB is consistently difficult. Besides resistances, drug availability can be problematic and costs for therapy are high. Aims: Our aim was to evaluate alternatives in treatment of MDR and XDR TB other than using second-line drugs. Materials and Methods: We analyzed retrospectively the minimal inhibitory concentrations (MICs of first-line drugs for 44 multidrug-resistant Mycobacterium tuberculosis isolates determined in our institute over a period of 20 years (1990 - 2010, n = 44. Drug susceptibility testing (DST was performed using the proportion method on Lowenstein-Jensen Medium or Middlebrook 7H10 agar. MICs were defined as the lowest drug concentration after two-fold serially diluted concentration of the drugs that inhibits growth of more than 99.0% of a bacterial proportion of the tested M. tuberculosis within 14 to 21 days of incubation at 37΀C. Statistical Analysis Used: Summation. Results: The MICs of isoniazid and ethambutol were equal or slightly above the critical concentration in most of the strains (92% and 84%, respectively, defined as "low-level resistance". Rifampicin and streptomycin exhibited very high MICs in most of the strains (100% and 77%, respectively, indicating a "high-level resistance". Conclusion: Our results indicate that isoniazid and ethambutol could still play a role in treating MDR and XDR TB patients if low-level resistance is detected. Quantitative DST seems to be promising for the recognition of residual drug activity, but has to be confirmed by clinical studies.

  5. Environment-mediated drug resistance in Bcr/Abl-positive acute lymphoblastic leukemia

    OpenAIRE

    Feldhahn, Niklas; Arutyunyan, Anna; Stoddart, Sonia; ZHANG Bin; Schmidhuber, Sabine; Yi, Sun-ju; Kim, Yong-Mi; Groffen, John; Heisterkamp, Nora

    2012-01-01

    Although cure rates for acute lymphoblastic leukemia (ALL) have increased, development of resistance to drugs and patient relapse are common. The environment in which the leukemia cells are present during the drug treatment is known to provide significant survival benefit. Here, we have modeled this process by culturing murine Bcr/Abl-positive acute lymphoblastic leukemia cells in the presence of stroma while treating them with a moderate dose of two unrelated drugs, the farnesyltransferase i...

  6. ABC Transporters and their Role in Nucleoside and Nucleotide Drug Resistance

    OpenAIRE

    Fukuda, Yu; Schuetz, John D.

    2012-01-01

    ATP-binding cassette (ABC) transporters confer drug resistance against a wide range of chemotherapeutic agents, including nucleoside and nucleotide based drugs. While nucleoside based drugs have been used for many years in the treatment of solid and hematological malignancies as well as viral and autoimmune diseases, the potential contribution of ABC transporters has only recently been recognized. This neglect is likely because activation of nucleoside derivatives require an initial carrier-m...

  7. Reducing the price of treatment for multidrug-resistant tuberculosis through the Global Drug Facility

    OpenAIRE

    Lunte, Kaspars; Cordier-Lassalle, Thierry; Keravec, Joel

    2015-01-01

    Abstract Problem Many countries have limited experience of securing the best prices for drugs and have little negotiating power. This is particularly true for the complex, lengthy and expensive regimens used to treat multidrug-resistant tuberculosis. Approach The Stop TB Partnership’s Global Drug Facility is dedicated to improving worldwide access to antituberculosis medicines and diagnostic techniques that meet international quality standards. Local setting The Global Drug Facility is able t...

  8. Surveillance of antimalarial drug resistance in China in the 1980s–1990s

    OpenAIRE

    Liu, De-Quan

    2014-01-01

    Since the successful preparation of the microplates and the medium for field application, the resistance degree and its geographical distribution of chloroquine-resistant Plasmodium falciparum, the fluctuation of the resistance degree of P. falciparum to chloroquine, and the sensitivity of the parasite to commonly used antimalarial drugs were investigated between 1980 and 2003 by the in vitro microtest and the in vivo four-week test recommended by the World Health Organization (WHO). The resu...

  9. MULTI DRUG RESISTANT ACINETOBACTER BAUMANNII: A SYSTEMATIC REVIEW FOR MICROBIAL AND CLINICAL STUDY

    Directory of Open Access Journals (Sweden)

    Buddha Bahadur Basnet

    2013-04-01

    Full Text Available 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 effective treatment options are briefly highlighted.

  10. Overcoming EMT-associated resistance to anti-cancer drugs via Src/FAK pathway inhibition

    OpenAIRE

    Wilson, Catherine; Nicholes, Katrina; Bustos, Daisy; Lin, Eva; Song, Qinghua; Stephan, Jean-Philippe; Kirkpatrick, Donald S.; Settleman, Jeff

    2014-01-01

    Epithelial to mesenchymal transition (EMT) is a key process in embryonic development and has been associated with cancer metastasis and drug resistance. For example, in EGFR mutated non-small cell lung cancers (NSCLC), EMT has been associated with acquired resistance to the EGFR inhibitor erlotinib. Moreover, “EGFR-addicted” cancer cell lines induced to undergo EMT become erlotinib-resistant in vitro. To identify potential therapeutic vulnerabilities specifically within these mesenchymal, erl...

  11. 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