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Phenotypic and genotypic characterization of levofloxacin- and moxifloxacin-resistant Mycobacterium tuberculosis clinical isolates in southern China.

ABSTRACT: Background:Levofloxacin (LVX) and Moxifloxacin (MXF) are the cornerstones for treatment of multidrug-resistant tuberculosis (MDR-TB). China is one of the highest MDR- and fluoroquinolones (FQ)-resistant TB burdens countries. DNA gyrase encoded by gyr genes is the main target of FQ in Mycobacterium tuberculosis (MTB). The prevalence and molecular characterization of LVX- and MXF-resistant MTB strains from southern China were examined in this study. Methods:Drug susceptibility testing (DST) of 400 MTB clinical isolates was evaluated by proportion method on Löwenstein-Jensen (LJ) medium against ten drugs. The sequencing of entire gyrA and gyrB genes and multiplex PCR were performed to distinguish the prevalence of mutant types in Beijing and non-Beijing genotypes. Results:Three hundred and twenty-one out of four hundred (80.25%) drug-resistant isolates (resistant > one drug) were categorized as 83/321 (25.80%) MDR, 174/321 (54.20%) pre-XDR and 64/321 (19.93%) XDR-MTB. Overall, 303/400 (75.75%) LVX- and 292/400 (73.00%) MXF-resistant (R) MTB strains were identified. Two hundred seventy-one out of three hundred and three (89.43%) resistant strains carried mutations in gyrA and 91/303 (30.03%) in gyrB. Interestingly, 18 novel mutations were detected in gyrA and gyrB genes. Mutations at (A90, D94) and (T500, G510, G512) frequently existed in QRDR(s) of gyrA and gyrB respectively in 286/400 (71.50%) LVXRMXFR strains. The novel mutations in- and out-side the QRDR of gyrA (L105R, A126E, M127K, D151T, V165A) and gyrB (D461H, N499S, G520A) increased the sensitivity and consistency of genotypic tests. Notably, 25 LVXRMXFR strains were found with unknown resistance mechanisms. Conclusions:Mutations in QRDR(s) were concomitantly associated with Beijing and non-Beijing genotypes. The prevalence of resistance and cross-resistance between LVX and MXF in MTB isolates from southern China was immensely higher than other countries. Our valuable findings provide the substantial implications to improve the reliability of genotypic diagnostic tests relying on potential resistance conferring mutations in entire gyr genes.

SUBMITTER: Hameed HMA

PROVIDER: S-EPMC6940237 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Phenotypic and genotypic characterization of levofloxacin- and moxifloxacin-resistant <i>Mycobacterium tuberculosis</i> clinical isolates in southern China.

Hameed H M Adnan HMA Tan Yaoju Y Islam Md Mahmudul MM Guo Lingmin L Chhotaray Chiranjibi C Wang Shuai S Liu Zhiyong Z Gao Yamin Y Tan Shouyong S Yew Wing Wai WW Zhong Nanshan N Liu Jianxiong J Zhang Tianyu T

Journal of thoracic disease 20191101 11

<h4>Background</h4>Levofloxacin (LVX) and Moxifloxacin (MXF) are the cornerstones for treatment of multidrug-resistant tuberculosis (MDR-TB). China is one of the highest MDR- and fluoroquinolones (FQ)-resistant TB burdens countries. DNA gyrase encoded by <i>gyr</i> genes is the main target of FQ in <i>Mycobacterium tuberculosis</i> (MTB). The prevalence and molecular characterization of LVX- and MXF-resistant MTB strains from southern China were examined in this study.<h4>Methods</h4>Drug suscep ...[more]

PMID: 31903250

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Project description:We designed this study to determine the trend of moxifloxacin resistance among multidrug-resistant tuberculosis (MDR-TB) patients from 2007 to 2013 in China to inform the composition of multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment regimens. We assessed moxifloxacin resistance among MDR-TB isolates collected in national drug resistance surveys in 2007 and 2013 that included 3,634 smear-positive and 7,206 culture-positive pulmonary tuberculosis patients, respectively. Moxifloxacin susceptibility was examined by a Mycobacterium growth indicator tube (MGIT) 960 for the 2007 isolates, and by the minimum inhibitory concentration (MIC) method for the 2013 isolates, at both breakpoints 0.5 and 2.0 μg/mL. Risk factors were explored through multivariable log-binominal regression analysis. Mutations in gyrA and gyrB for part of the isolates were also studied through sequencing. Of 401 MDR strains isolated in 2007, moxifiloxacin resistance could be determined for 319 (79.6%): 41 (12.9%) and 10 (3.1%) were resistant at 0.5 and 2.0 μg/mL, respectively. Of 365 MDR strains isolated in 2013, 338 (92.6%) could be analyzed: 140 (41.4%) and 79 (23.4%) were resistant at 0.5 and 2.0 μg/mL. For patients in 2007, no characteristics were significantly associated with moxifloxacin resistance. For patients in 2013, patients aged ≥60 years (adjusted prevalence ratio [aPR], 1.46; 95% confidence interval [CI], 1.10 to 1.93) were more likely to have resistance at 0.5 μg/mL, whereas those residing in eastern China compared to those in central China had an increased risk of resistance at both 0.5 (aPR, 1.85; 95% CI, 1.38 to 2.48) and 2.0 μg/mL (aPR, 2.14; 95% CI, 1.35 to 3.40). Sequencing results were obtained for 245 and 266 MDR-TB isolates in 2007 and 2013, respectively. In total, 34 of 38 (89.5%) and 89 of 104 (85.6%) of 2007 and 2013 moxifloxacin-resistant (0.5 μg/mL) MDR-TB strains had mutations in the gyrA and gyrB gene, respectively. Asp94Gly was the most common mutation among 2007 (11 of 38, 28.9%) and 2013 isolates (24 of 104, 23.1%) and conferred high-level moxifloxacin resistance. Moxifloxacin resistance among MDR-TB patients in China increased from modest to high from 2007 to 2013. Moxifloxacin should be used carefully as a potentially effective drug for composing MDR/RR-TB regimens especially for elderly patients in China. Individual susceptibility testing especially rapid molecular-based assays should be conducted to confirm the susceptibility to moxifloxacin. IMPORTANCE China is one of the high-burden countries for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB). Moxifloxacin is one of the critical antituberculosis drugs for MDR/RR-TB treatment. Susceptibility to moxifloxacin is therefore very important to compose effective regimens and to provide protection against development of resistance of companion drugs such as bedaquiline and linezolid. There are, however, no nationally representative data on moxifloxacin resistance among MDR/RR-TB cases in China. Therefore, we assessed the resistance prevalence for moxifloxacin among MDR-TB strains isolated in national drug resistance surveys in 2007 and 2013 that covered 72 sites around the country. We demonstrate that the prevalence of moxifloxacin resistance in MDR-TB isolates increased from modest to high, which should prompt the national tuberculosis program to use moxifloxacin cautiously in second-line regimens to treat MDR/RR-TB unless susceptibility can be laboratory-confirmed.

Project description:BackgroundMultidrug-resistant tuberculosis (MDR-TB) remains a major public health problem in many high tuberculosis (TB) burden countries. Phenotypic drug susceptibility testing (DST) take several weeks or months to result, but line probe assays and Xpert/Rif Ultra assay detect a limited number of resistance conferring gene mutations. Whole genome sequencing (WGS) is an advanced molecular testing method which theoretically can predict the resistance of M. tuberculosis (Mtb) isolates to all anti-TB agents through a single analysis.MethodsHere, we aimed to identify the level of concordance between the phenotypic and WGS-based genotypic drug susceptibility (DS) patterns of MDR-TB isolates. Overall, data for 12 anti-TB medications were analyzed.ResultsIn total, 63 MDR-TB Mtb isolates were included in the analysis, representing 27.4% of the total number of MDR-TB cases in Latvia in 2012-2014. Among them, five different sublineages were detected, and 2.2.1 (Beijing group) and 4.3.3 (Latin American-Mediterranean group) were the most abundant. There were 100% agreement between phenotypic and genotypic DS pattern for isoniazid, rifampicin, and linezolid. High concordance rate (> 90%) between phenotypic and genotypic DST results was detected for ofloxacin (93.7%), pyrazinamide (93.7%) and streptomycin (95.4%). Phenotypic and genotypic DS patterns were poorly correlated for ethionamide (agreement 56.4%), ethambutol (85.7%), amikacin (82.5%), capreomycin (81.0%), kanamycin (85.4%), and moxifloxacin (77.8%). For capreomycin, resistance conferring mutations were not identified in several phenotypically resistant isolates, and, in contrary, for ethionamide, ethambutol, amikacin, kanamycin, and moxifloxacin the resistance-related mutations were identified in several phenotypically sensitive isolates.ConclusionsWGS is a valuable tool for rapid genotypic DST for all anti-TB agents. For isoniazid and rifampicin phenotypic DST potentially can be replaced by genotypic DST based on 100% agreement between the tests. However, discrepant results for other anti-TB agents limit their prescription based solely on WGS data. For clinical decision, at the current level of knowledge, there is a need for combination of genotypic DST with modern, validated phenotypic DST methodologies for those medications which did not showed 100% agreement between the methods.

Dataset Information

Phenotypic and genotypic characterization of levofloxacin- and moxifloxacin-resistant Mycobacterium tuberculosis clinical isolates in southern China.

Publications

Phenotypic and genotypic characterization of levofloxacin- and moxifloxacin-resistant <i>Mycobacterium tuberculosis</i> clinical isolates in southern China.

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