scholarly journals Molecular Characterization of Multidrug-Resistant Mycobacterium tuberculosis Isolated in Nepal

2012 ◽  
Vol 56 (6) ◽  
pp. 2831-2836 ◽  
Author(s):  
Ajay Poudel ◽  
Chie Nakajima ◽  
Yukari Fukushima ◽  
Haruka Suzuki ◽  
Basu Dev Pandey ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Promoter Region ◽  
Multidrug Resistant ◽  
Content Type ◽  
Molecular Tests ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
Substitution Mutations ◽  
Drug Resistant Strains

ABSTRACTDespite the fact that Nepal is one of the first countries globally to introduce multidrug-resistant tuberculosis (MDR-TB) case management, the number of MDR-TB cases is continuing to rise in Nepal. Rapid molecular tests applicable in this setting to identify resistant organisms would be an effective tool in reversing this trend. To develop such tools, information about the frequency and distribution of mutations that are associated with phenotypic drug resistance inMycobacterium tuberculosisis required. In the present study, we investigated the prevalence of mutations inrpoBandkatGgenes and theinhApromoter region in 158M. tuberculosisisolates (109 phenotypically MDR and 49 non-MDR isolates collected in Nepal) by DNA sequencing. Mutations affecting the 81-bp rifampin (RIF) resistance-determining region (RRDR) ofrpoBwere identified in 106 of 109 (97.3%) RIF-resistant isolates. Codons 531, 526, and 516 were the most commonly affected, at percentages of 58.7, 15.6, and 15.6%, respectively. Of 113 isoniazid (INH)-resistant isolates, 99 (87.6%) had mutations in thekatGgene, with Ser315Thr being the most prevalent (81.4%) substitution. Mutations in theinhApromoter region were detected in 14 (12.4%) INH-resistant isolates. The results from this study provide an overview of the current situation of RIF and INH resistance inM. tuberculosisin Nepal and can serve as a basis for developing or improving rapid molecular tests to monitor drug-resistant strains in this country.

scholarly journals Mode of Action of Clofazimine and Combination Therapy with Benzothiazinones against Mycobacterium tuberculosis

2015 ◽  
Vol 59 (8) ◽  
pp. 4457-4463 ◽  
Author(s):  
Benoit Lechartier ◽  
Stewart T. Cole
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Bacterial Load ◽  
Multidrug Resistant ◽  
Content Type ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Drug Resistant Strains ◽  
Transfer Chain

ABSTRACTClofazimine (CZM) is an antileprosy drug that was recently repurposed for treatment of multidrug-resistant tuberculosis. InMycobacterium tuberculosis, CZM appears to act as a prodrug, which is reduced by NADH dehydrogenase (NDH-2), to release reactive oxygen species upon reoxidation by O2. CZM presumably competes with menaquinone (MK-4), a key cofactor in the mycobacterial electron transfer chain, for its reduction by NDH-2. We studied the effect of MK-4 supplementation on the activity of CZM againstM. tuberculosisand found direct competition between CZM and MK-4 for the cidal effect of CZM, against nonreplicating and actively growing bacteria, as MK-4 supplementation blocked the drug's activity against nonreplicating bacteria. We demonstrated that CZM, like bedaquiline, is synergisticin vitrowith benzothiazinones such as 2-piperazino-benzothiazinone 169 (PBTZ169), and this synergy also occurs against nonreplicating bacteria. The synergy between CZM and PBTZ169 was lost in an MK-4-rich medium, indicating that MK-4 is the probable link between their activities. The efficacy of the dual combination of CZM and PBTZ169 was testedin vivo, where a great reduction in bacterial load was obtained in a murine model of chronic tuberculosis. Taken together, these data confirm the potential of CZM in association with PBTZ169 as the basis for a new regimen against drug-resistant strains ofM. tuberculosis.

scholarly journals Sequence Analysis of Fluoroquinolone Resistance-Associated GenesgyrAandgyrBin Clinical Mycobacterium tuberculosis Isolates from Patients Suspected of Having Multidrug-Resistant Tuberculosis in New Delhi, India

2016 ◽  
Vol 54 (9) ◽  
pp. 2298-2305 ◽  
Author(s):  
Ritu Singhal ◽  
Paul R. Reynolds ◽  
Jamie L. Marola ◽  
L. Elaine Epperson ◽  
Jyoti Arora ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Indian Subcontinent ◽  
Amino Acid Position ◽  
Multidrug Resistant ◽  
High Rate ◽  
Fluoroquinolone Resistance ◽  
Content Type ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb

Fluoroquinolones (FQs) are broad-spectrum antibiotics recommended for the treatment of multidrug-resistant tuberculosis (MDR-TB) patients. FQ resistance, caused by mutations in thegyrAandgyrBgenes ofMycobacterium tuberculosis, is increasingly reported worldwide; however, information on mutations occurring in strains from the Indian subcontinent is scarce. Hence, in this study, we aimed to characterize mutations in thegyrAandgyrBgenes of acid-fast bacillus (AFB) smear-positive sediments or ofM. tuberculosisisolates from AFB smear-negative samples from patients in India suspected of having MDR-TB. A total of 152 samples from patients suspected of having MDR-TB were included in the study. One hundred forty-six strains detected in these samples were characterized by sequencing of thegyrAandgyrBgenes. The extracted DNA was subjected to successive amplifications using a nested PCR protocol, followed by sequencing. A total of 27 mutations were observed in thegyrAgenes of 25 strains, while no mutations were observed in thegyrBgenes. The most common mutations occurred at amino acid position 94 (13/27 [48.1%]); of these, the D94G mutation was the most prevalent. ThegyrAmutations were significantly associated with patients with rifampin (RIF)-resistant TB. Heterozygosity was seen in 4/27 (14.8%) mutations, suggesting the occurrence of mixed populations with different antimicrobial susceptibilities. A high rate of FQ-resistant mutations (17.1%) was obtained among the isolates of TB patients suspected of having MDR-TB. These observations emphasize the need for accurate and rapid molecular tests for the detection of FQ-resistant mutations at the time of MDR-TB diagnosis.

scholarly journals Mycobacterium tuberculosis Mutations Associated with Reduced Susceptibility to Linezolid

2016 ◽  
Vol 60 (4) ◽  
pp. 2542-2544 ◽  
Author(s):  
Shuo Zhang ◽  
Jiazhen Chen ◽  
Peng Cui ◽  
Wanliang Shi ◽  
Xiaohong Shi ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Rapid Detection ◽  
Multidrug Resistant ◽  
Mechanisms Of Resistance ◽  
Content Type ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb

ABSTRACTLinezolid (LZD) has become increasingly important for the treatment of multidrug-resistant tuberculosis (MDR-TB), but its mechanisms of resistance are not well characterized. We isolated 32 mutants ofMycobacterium tuberculosiswith reduced susceptibility to LZD, which was accounted for byrrlandrplCmutations in almost equal proportions, causing lower and higher MICs, respectively. Our findings provide useful information for the rapid detection of LZD resistance for improved treatment of MDR-TB.

Fidaxomicin has high in vitro activity against Mycobacterium tuberculosis

2021 ◽  
Author(s):  
Qing Sun ◽  
Shuqi Wang ◽  
Xinlei Liao ◽  
Guanglu Jiang ◽  
Hairong Huang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Type Species ◽  
Multidrug Resistant ◽  
Alamar Blue ◽  
In Vitro Activity ◽  
Content Type ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb

This study aimed to evaluate whether the antibiotic fidaxomicin has in vitro activity against Mycobacterium tuberculosis (Mtb). 38 fully drug-sensitive Mtb strains and 34 multidrug-resistant tuberculosis (MDR-TB) strains were tested using the microplate alamar blue assay (MABA) method to determine the minimum inhibitory concentrations (MICs) for fidaxomicin and rifampicin. Fidaxomicin has high in vitro activity against Mtb and is a potential drug to treat Mtb, and MDR-TB infections in particular.

scholarly journals Sulfamethoxazole Susceptibility of Mycobacterium tuberculosis Isolates from HIV-Infected Ugandan Adults with Tuberculosis Taking Trimethoprim-Sulfamethoxazole Prophylaxis

2015 ◽  
Vol 59 (9) ◽  
pp. 5844-5846 ◽  
Author(s):  
Sam Ogwang ◽  
Caryn E. Good ◽  
Brenda Okware ◽  
Mary Nsereko ◽  
Michael R. Jacobs ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Multidrug Resistant ◽  
Sub Saharan Africa ◽  
Content Type ◽  
Pulmonary Tb ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Sub Saharan

ABSTRACTAdditional drugs are needed for the treatment of multidrug-resistant tuberculosis (TB). Sulfamethoxazole has been shown to havein vitroactivity againstMycobacterium tuberculosis; however, there is concern about resistance given the widespread use of trimethoprim-sulfamethoxazole prophylaxis among HIV-infected patients in sub-Saharan Africa. Thirty-eight of 40Mycobacterium tuberculosisisolates (95%) from pretreatment sputum samples from Ugandan adults with pulmonary TB, including HIV-infected patients taking trimethoprim-sulfamethoxazole prophylaxis, were susceptible with MICs of ≤38.4 μg/ml.

scholarly journals Multidrug-Resistant Tuberculosis in Alberta and British Columbia, 1989 to 1998

1999 ◽  
Vol 6 (2) ◽  
pp. 155-160 ◽  
Author(s):  
Ahmed Hersi ◽  
Kevin Elwood ◽  
Robert Cowie ◽  
Dennis Kunimoto ◽  
Richard Long
Keyword(s):  
British Columbia ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Foreign Born ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Culture Positive

OBJECTIVE: To describe the extent of the problem of multidrug-resistant tuberculosis (MDR-TB) in Alberta and British Columbia from 1989 to 1998.DESIGN: A retrospective, population-based descriptive study of all notified MDR-TB cases in the context of all notified TB cases, all notified culture-positive TB cases and all notified drug-resistant TB cases.SETTING: Provinces of Alberta and British Columbia, and their TB registries.PATIENTS: All people with TB reported to the TB registries of Alberta and British Columbia between January 1, 1989 and June 30, 1998.MAIN OUTCOME MEASURES: Drug susceptibility testing was performed in all cases of culture-positive TB. Demographic, clinical and laboratory data on all cases of MDR-TB were recorded.RESULTS: Of 4606 notified cases of TB, 3553 (77.1%) were culture positive. Of these, 365 (10.3%) were drug resistant; of the drug-resistant cases, 24 (6.6%) were MDR. Most MDR-TB patients were foreign-born; of the four Canadian-born patients, two were infected while travelling abroad. Although foreign-born patients were significantly more likely to harbour drug-resistant strains, 14.3% versus 4.8%, respectively (P<0.001), among those who were harbouring a drug-resistant strain, the proportion of Canadian-born versus foreign-born patients with an MDR strain was the same (6.7% versus 6.6%, respectively). From 1994 to 1998 versus 1989 to 1993, the proportion of all drug-resistant strains that were MDR was greater (9.0% versus 4.3%, respectively), but the difference was not statistically significant. Isolates from 16 of the 24 MDR-TB cases had been archived. Each of these was fingerprinted and found to be unique. Most MDR-TB cases (88%) were respiratory. Of those tested for human immunodeficiency virus (n=17), only one was seropositive. MDR-TB was ‘acquired’ in 67% and ‘primary’ in 33% of cases. Eight (33%) of the MDR-TB cases received curative courses of treatment, six (25%) are still being treated, and the remainder have either died (five, 21%), transferred out (four, 17%) or become ‘chronic’ (one, 4%). No secondary case of MDR-TB has been identified in Alberta and British Columbia.CONCLUSIONS: Most MDR-TB in Alberta and British Columbia is imported. The proportion of all drug-resistant cases that are MDR appears to be increasing, but not because of disease acquired from recent contact with MDR-TB in Canada.

scholarly journals Novel Regimens Identified in Mice for Treatment of Latent Tuberculosis Infection in Contacts of Patients with Multidrug-Resistant Tuberculosis

2014 ◽  
Vol 58 (4) ◽  
pp. 2316-2321 ◽  
Author(s):  
Jean-Philippe Lanoix ◽  
Fabrice Betoudji ◽  
Eric Nuermberger
Keyword(s):  
Clinical Trials ◽  
Latent Tuberculosis ◽  
Multidrug Resistant ◽  
Content Type ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
New Chemical Entities ◽  
Mdr Tb ◽  
Latent Tb Infection ◽  
Effective Drugs

ABSTRACTPreventing the development of tuberculosis (TB) in contacts of patients with multidrug-resistant TB (MDR-TB) by the treatment of latent TB infection (LTBI) is highly desirable. However, few safe, well tolerated, and effective drugs are available to treat MDR-LTBI and the published guidance is limited. Fortunately, six new chemical entities from four classes developed to treat TB have entered clinical trials in the past decade. We tested three of these drugs alone and in combination in an experimental paucibacillary LTBI chemotherapy model using BALB/c and C3HeB/FeJ mice immunized with a recombinant strain ofMycobacterium bovisbacillus Calmette-Guérin (rBCG30) and then challenged with a low-dose aerosol ofM. tuberculosisH37Rv. The regimens tested contained bedaquiline (TMC), PA-824 (Pa), sutezolid (PNU), and/or one of two fluoroquinolones. Control mice received rifampin (RIF) or isoniazid (INH). In BALB/c mice, TMC-containing regimens and the Pa-PNU combination were the most active test regimens and were at least as effective as RIF. Pa, PNU, and levofloxacin had activity comparable to that of INH. Virtually identical results were observed in C3HeB/FeJ mice. This study confirms the potent activity of TMC observed previously in BALB/c mice and highlights Pa alone or in combination with either PNU or a fluoroquinolone as a regimen worthy of evaluation in future clinical trials of MDR-LTBI. Given their closer pathological representation of human TB lesions, C3HeB/FeJ mice may become a preferred model for the experimental chemotherapy of LTBI. Future studies should evaluate additional clinically relevant LTBI regimens in this strain including relapse as an endpoint.

Tuberculosis Multidrug-resistant Tuberculosis – From Epidemiology to Treatment Design

2015 ◽  
Vol 01 (01) ◽  
pp. 20
Author(s):  
Jean-Pierre Zellweger ◽  
Keyword(s):  
Multidrug Resistant ◽  
Rapid Identification ◽  
Drug Management ◽  
Duration Of Treatment ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Selection Of

Multidrug-resistant tuberculosis (MDR-TB) and extensively resistant tuberculosis (XDR-TB) are present in most regions of the world and represent a serious threat to the control of tuberculosis. They usually result from errors somewhere along the chain of management of the disease that favoured the selection of resistant mutants, progressively replacing drug-sensitive strains and transmitted to further patients. The currently recommended strategies for the control of this serious situation is the rapid identification of drug-resistant strains, careful drug management of patients with second-line drugs and prevention of the transmission of mycobacteria to contacts. Optimal selection and number of drugs and duration of treatment are not clearly defined. Prevention of the creation of additional cases of MDR-TB is crucial.

scholarly journals Draft Genome Sequences of Two Drug-Resistant Mycobacterium tuberculosis Isolates from Myanmar

2016 ◽  
Vol 4 (5) ◽  
Author(s):  
Htin Lin Aung ◽  
Thanda Tun ◽  
Elizabeth Permina ◽  
Wint Wint Nyunt ◽  
Si Thu Aung ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Draft Genome ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Genome Sequences ◽  
Health Concerns ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Extensively Drug Resistant ◽  
Mdr Tb

Multidrug-resistant tuberculosis (MDR-TB) and lately, extensively drug-resistant TB (XDR-TB) are increasing global health concerns. Here, we present the genome sequences of two MDR-TB isolates from Myanmar, one of 27 countries with a high MDR-TB burden, and describe a number of mutations consistent with these being XDR-TB isolates.

scholarly journals Some Synonymous and Nonsynonymous gyrA Mutations in Mycobacterium tuberculosis Lead to Systematic False-Positive Fluoroquinolone Resistance Results with the Hain GenoType MTBDRsl Assays

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Adebisi Ajileye ◽  
Nataly Alvarez ◽  
Matthias Merker ◽  
Timothy M. Walker ◽  
Suriya Akter ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Specific Resistance ◽  
Multidrug Resistant ◽  
Fluoroquinolone Resistance ◽  
Wild Type ◽  
Resistance Mutations ◽  
Content Type ◽  
Synonymous Mutations ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis

ABSTRACT In this study, using the Hain GenoType MTBDRsl assays (versions 1 and 2), we found that some nonsynonymous and synonymous mutations in gyrA in Mycobacterium tuberculosis result in systematic false-resistance results to fluoroquinolones by preventing the binding of wild-type probes. Moreover, such mutations can prevent the binding of mutant probes designed for the identification of specific resistance mutations. Although these mutations are likely rare globally, they occur in approximately 7% of multidrug-resistant tuberculosis strains in some settings.

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