scholarly journals Characterization of rifampicin-resistant Mycobacterium tuberculosis in Khyber Pakhtunkhwa, Pakistan

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anwar Sheed Khan ◽  
Jody E. Phelan ◽  
Muhammad Tahir Khan ◽  
Sajid Ali ◽  
Muhammad Qasim ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Gene Mutations ◽  
Multidrug Resistant ◽  
Rifampicin Resistance ◽  
Resistance Mutations ◽  
Khyber Pakhtunkhwa ◽  
Tb Control ◽  
Mdr Tb ◽  
Compensatory Mutations

AbstractTuberculosis (TB), caused by Mycobacterium tuberculosis, is endemic in Pakistan. Resistance to both firstline rifampicin and isoniazid drugs (multidrug-resistant TB; MDR-TB) is hampering disease control. Rifampicin resistance is attributed to rpoB gene mutations, but rpoA and rpoC loci may also be involved. To characterise underlying rifampicin resistance mutations in the TB endemic province of Khyber Pakhtunkhwa, we sequenced 51 M. tuberculosis isolates collected between 2016 and 2019; predominantly, MDR-TB (n = 44; 86.3%) and lineage 3 (n = 30, 58.8%) strains. We found that known mutations in rpoB (e.g. S405L), katG (e.g. S315T), or inhA promoter loci explain the MDR-TB. There were 24 unique mutations in rpoA, rpoB, and rpoC genes, including four previously unreported. Five instances of within-host resistance diversity were observed, where two were a mixture of MDR-TB strains containing mutations in rpoB, katG, and the inhA promoter region, as well as compensatory mutations in rpoC. Heteroresistance was observed in two isolates with a single lineage. Such complexity may reflect the high transmission nature of the Khyber Pakhtunkhwa setting. Our study reinforces the need to apply sequencing approaches to capture the full-extent of MDR-TB genetic diversity, to understand transmission, and to inform TB control activities in the highly endemic setting of Pakistan.

scholarly journals Constraints of Drug Resistance in Mycobacterium tuberculosis - Prospects for Pharmacological Reversion of Susceptibility to Antibiotics

2017 ◽  
Vol 8 (1) ◽  
pp. 33-43 ◽  
Author(s):  
Aleksandr I. Ilin ◽  
Murat E. Kulmanov ◽  
Ilya S. Korotetskiy ◽  
Marina V. Lankina ◽  
Gulshara K. Akhmetova ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Genetic Heterogeneity ◽  
Multidrug Resistant ◽  
Resistance Mutations ◽  
General Increase ◽  
Drug Induced ◽  
Mdr Tb ◽  
Resistant Strains

Emergence of multidrug resistant strains ofMycobacterium tuberculosis(MDR-TB) threatens humanity. This problem was complicated by the crisis in development of new anti-tuberculosis antibiotics. Induced reversion of drug resistance seems promising to overcome the problem. Successful clinical trial of a new anti-tuberculosis nanomolecular complex FS-1 has demonstrated prospectively of this approach in combating MDR-TB. Several clinical MDR-TB cultures were isolated from sputum samples prior and in the process of the clinical trial. Every isolate was tested for susceptibility to antibiotics and then they were sequenced for comparative genomics. It was found that the treatment with FS-1 caused an increase in the number of antibiotic susceptible strains among Mtb isolates that was associated with a general increase of genetic heterogeneity of the isolates. Observed impairing of phthiocerol dimycocerosate biosynthesis by disruptive mutations inppsACDsubunits indicated a possible virulence remission for the sake of persistence. It was hypothesized that the FS-1 treatment eradicated the most drug resistant Mtb variants from the population by aggravating the fitness cost of drug resistance mutations. Analysis of distribution of these mutations in the global Mtb population revealed that many of them were incompatible with each other and dependent on allelic states of many other polymorphic loci. The latter discovery may explain the negative correlation between the genetic heterogeneity of the population and the level of drug tolerance. To the best of our knowledge, this work was the first experimental confirmation of the drug induced antibiotic resistance reversion by the induced synergy mechanism that previously was predicted theoretically.

scholarly journals Prevalence and Molecular Characterization of Second-Line Drugs Resistance among Multidrug-ResistantMycobacterium tuberculosisIsolates in Southwest of China

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Y. Hu ◽  
L. Xu ◽  
Y. L. He ◽  
Y. Pang ◽  
N. Lu ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Multidrug Resistant ◽  
Rapid Screening ◽  
Second Line ◽  
Tb Treatment ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Improper Use ◽  
Mdr Tb

This study aimed to investigate the prevalence of multidrug-resistant tuberculosis (MDR-TB) isolates resistant to the second-line antituberculosis drugs (SLDs) and its association with resistant-related gene mutations inMycobacterium tuberculosis(M.tb) isolates from Southwest of China. There were 81 isolates resistant to at least one of the SLDs among 156 MDR-TB isolates (81/156, 51.9%). The rates of general resistance to each of the drugs were as follows: OFX (66/156, 42.3%), KAN (26/156, 16.7%), CAP (13/156, 8.3%), PTO (11/156, 7.1%), PAS (22/156, 14.1%), and AMK (20/156, 12.8%). Therefore, the most predominant pattern was resistant to OFX compared with other SLDs (P<0.001). The results of sequencing showed that 80.2% OFX-resistant MDR-TB isolates containedgyrAmutation and 88.5% KAN-resistant isolates hadrrsmutations with the most frequent mutation being A1401G. These results suggest that improper use of SLDs especially OFX is a real threat to effective MDR-TB treatment not only in China but also in the whole world. Furthermore the tuberculosis control agencies should carry out SLDs susceptibility testing and rapid screening in a broader population of TB patients immediately and the SLDs should be strictly regulated by the administration in order to maintain their efficacy to treat MDR-TB.

scholarly journals Genotypic Analysis of Genes Associated with Independent Resistance and Cross-Resistance to Isoniazid and Ethionamide in Mycobacterium tuberculosis Clinical Isolates

2015 ◽  
Vol 59 (12) ◽  
pp. 7805-7810 ◽  
Author(s):  
Johana Rueda ◽  
Teresa Realpe ◽  
Gloria Isabel Mejia ◽  
Elsa Zapata ◽  
Juan Carlos Rozo ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Resistance Mutations ◽  
Content Type ◽  
Genotypic Analysis ◽  
Mdr Tb ◽  
Proportion Method ◽  
Emergence Of Resistance ◽  
Phenotypic Susceptibility

ABSTRACTEthionamide (ETH) is an antibiotic used for the treatment of multidrug-resistant (MDR) tuberculosis (TB) (MDR-TB), and its use may be limited with the emergence of resistance in theMycobacterium tuberculosispopulation. ETH resistance inM. tuberculosisis phenomenon independent or cross related when accompanied with isoniazid (INH) resistance. In most cases, resistance to INH and ETH is explained by mutations in theinhApromoter and in the following genes:katG,ethA,ethR,mshA,ndh, andinhA. We sequenced the above genes in 64M. tuberculosisisolates (n= 57 ETH-resistant MDR-TB isolates;n= 3 ETH-susceptible MDR-TB isolates; andn= 4 fully susceptible isolates). Each isolate was tested for susceptibility to first- and second-line drugs using the agar proportion method. Mutations were observed in ETH-resistant MDR-TB isolates at the following rates: 100% inkatG, 72% inethA, 45.6% inmshA, 8.7% inndh, and 33.3% ininhAor its promoter. Of the three ETH-susceptible MDR-TB isolates, all showed mutations inkatG; one had a mutation inethA, and another, inmshAandinhA. Finally, of the four fully susceptible isolates, two showed no detectable mutation in the studied genes, and two had mutations inmshAgene unrelated to the resistance. Mutations not previously reported were found in theethA,mshA,katG, andndhgenes. The concordance between the phenotypic susceptibility testing to INH and ETH and the sequencing was 1 and 0.45, respectively. Among isolates exhibiting INH resistance, the high frequency of independent resistance and cross-resistance with ETH in theM. tuberculosisisolates suggests the need to confirm the susceptibility to ETH before considering it in the treatment of patients with MDR-TB.

scholarly journals Epidemiology of Rifampicin Resistant Tuberculosis and Common Mutations in rpoB Gene of Mycobacterium tuberculosis: A Retrospective Study from Six Districts of Punjab (India) Using Xpert MTB/RIF Assay

2016 ◽  
Vol 8 (02) ◽  
pp. 096-100 ◽  
Author(s):  
Ramandeep Kaur ◽  
Neerja Jindal ◽  
Shilpa Arora ◽  
Shajla Kataria
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Surrogate Marker ◽  
Rpob Gene ◽  
Multidrug Resistant ◽  
Resistance Pattern ◽  
Resistance Mutations ◽  
Resistant Tuberculosis ◽  
Mdr Tb ◽  
Previously Treated Patients ◽  
User Friendly

ABSTRACT Background: Xpert MTB/RIF assay has revolutionized the diagnosis of tuberculosis (TB) by simultaneously detecting the bacteria and resistance to rifampicin (RIF), a surrogate marker for multidrug-resistant TB (MDR-TB) in <2 h. The RIF resistance pattern in Malwa region of Punjab, India, is not documented. Here, we report the epidemiology of RIF-resistant TB and mutations in rpoB gene of Mycobacterium tuberculosis (MTB). Materials and Methods: A total of 1612 specimens received between October 2013 and February 2015 were tested by Xpert MTB/RIF assay following manufacturer’s instructions. The results thus obtained were analyzed using SPSS version 20.0.0 (SPSS Inc., Chicago, IL, USA) statistical software. Result: RIF resistance was statistically higher in previously treated patients in comparison to the new patients (P = 0.006) and in patients with acid fast-Bacilli (AFB) positive smears to AFB-negative smears (P = 0.048). RIF resistance mutations in 130 specimens revealed frequency of E 73/130 (56%), B 28/130 (21.5%), D 18/130 (13.8%), A 11/130 (8.4%), and C 1/130 (0.7%) while in one specimen, mutation combination, i.e., mutations associated with more than one probe (A and B both) was present. Conclusion: Xpert MTB/RIF assay is a user-friendly screening tool for detection of MTB and RIF resistance from suspected TB/MDR cases in a shorter period of time. It could also serve as a useful technique to have simultaneous preliminary information regarding the mutation pattern of RIF resistance in MTB isolates.

scholarly journals Evolutionary trajectories and transmission dynamics of multidrug-resistant Mycobacterium tuberculosis in Tibet, China

2021 ◽  
Author(s):  
Qi Jiang ◽  
Hai-can Liu ◽  
Qing-yun Liu ◽  
Jody E. Phelan ◽  
Li Shi ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Phylogenetic Trees ◽  
Multidrug Resistant ◽  
Rifampicin Resistance ◽  
Whole Genome Sequencing Data ◽  
High Burden ◽  
Increased Risk ◽  
Mdr Tb ◽  
Resistant Strains ◽  
The Impact

ABSTRACTObjectiveTibet has the highest prevalence of both tuberculosis disease and multidrug-resistant tuberculosis (MDR-TB) in China. The circulated Mycobacterium tuberculosis strains from Tibet were sequenced to investigate the underlying drivers for the high burden of MDR-TB.MethodsUsing whole-genome sequencing data of 576 M. tuberculosis strains isolated from consecutive patients in Tibet, we mapped resistance-conferring mutations onto phylogenetic trees to determine their evolution and spread. The impact of drug resistance on bacterial population growth was assessed with a Bayesian (Skyline Plot) analysis. Multivariable logistic regression was used to identify risk factors for the development of rifampicin resistance.ResultsOf the 576 isolates, 284 (49.3%), 280 (48.6%), and 236 (41.0%) were, respectively, genetically resistant to isoniazid, rifampicin, or both (MDR-TB). Among the isoniazid- and rifampicin-resistant strains, the proportions in phylogenetically-inferred clusters were 77.8% (221/284) and 62.1% (174/280), respectively. Nearly half (47.2%, 134/284) of the isoniazid-resistant strains were in six major clades, which contained between 8 and 58 strains with katG S315T, katG S315N, or fabG1 promoter −15 C>T resistance mutations. These major clades exponentially expanded after emerging with isoniazid resistance and stabilized before evolving into MDR-TB twenty years later. Isoniazid-resistant isolates showed an increased risk of accumulating rifampicin resistance compared to isoniazid-susceptible strains, with an adjusted odds ratio of 3.81 (95% confidence interval 2.47-5.95).ConclusionHistorical expansion of isoniazid-resistant strains and their increased likelihood of acquiring rifampicin resistance both contributed to the high burden of MDR-TB in Tibet, highlighting the need to detect INH-resistant strains promptly and to control their transmission.

scholarly journals Prevalence of Multi-Drug Resistant Mycobacterium Tuberculosis in Khyber Pakhtunkhwa – A High Tuberculosis Endemic Area of Pakistan

2020 ◽  
Vol 69 (2) ◽  
pp. 133-137 ◽  
Author(s):  
SAJID ALI ◽  
MUHAMMAD TAHIR KHAN ◽  
ANWAR SHEED KHAN ◽  
NOOR MOHAMMAD ◽  
MUHAMMAD MUMTAZ KHAN ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Large Scale ◽  
Simple Random Sampling ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Drug Susceptibility Testing ◽  
Drug Resistant ◽  
Khyber Pakhtunkhwa ◽  
Mdr Tb

Anti-tuberculosis therapy involves the combination of drugs to hamper the growth of Mycobacterium tuberculosis (MTB). The emergence of multidrug-resistant tuberculosis (MDR-TB) is a global concern. Pakistan has been ranked 5th position in terms of a high burden of MDR-TB in the world. The aim of the current study was to investigate the prevalence of drug resistance in MTB in Khyber Pakhtunkhwa. Random samples were collected from 25 districts using the simple random sampling formula. All samples were processed in a biosafety level 3 laboratory for culture and drug susceptibility testing. Among 5759 presumptive tuberculosis (TB) cases, 1969 (34%) were positive. The proportion of TB was higher in females (39%) than males (29%), thus it represents a significant association between gender and tuberculosis (p < 0.05). People ages between 25 to 34 years were more likely to be infected with MTB (40%). Drug-resistant profile showed 97 (4.9%) patients were infected with MDR-TB. Streptomycin resistance was the highest and was observed in 173 (9%) isolates followed by isoniazid in 119 (6%) isolates. The lowest resistance was observed to pyrazinamide (3%). The prevalence of MDR-TB (10.4%) among patients that previously received anti-tuberculosis treatment is seemingly high. A large-scale drug resistance survey is required to evaluate the drug resistance for better management of tuberculosis.

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