Prevalence and molecular characterization of pyrazinamide resistance among multidrug-resistant Mycobacterium tuberculosis isolates from Southern China

Pang, Yu; Zhu, Damian; Zheng, Hao; Shen, Jing; Hu, Yan; Liu, Jie; Zhao, Yanlin

doi:10.1186/s12879-017-2761-6

Cited by 37 publications

(34 citation statements)

References 29 publications

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“…It is to be expected that the prevalence of resistance has increased, in line with the finding of higher prevalence among the younger group of patients, who on average have been infected more recently than older patients. The higher prevalence in more recent years from several sub-national studies in China [11][12][13][14] also support this expectation. Further studies of larger samples collected during more recent years and exploring the resistance by using of whole genome sequence may provide more accurate and deeper insights into the mechanism and associated factors of pyrazinamide resistance in China.…”

Section: Discussionmentioning

confidence: 56%

“…The reported prevalence of pyrazinamide resistance in MDR-TB isolates elsewhere varied substantially by country, ranging from 36.7 to 84.6% [17][18][19][20][21]. The range of previously reported proportions of pyrazinamide resistance in selected samples from China was 43.1-62.4% [11][12][13][14].…”

Section: Discussionmentioning

confidence: 94%

“…This partly explains the paucity of data on the prevalence of pyrazinamide resistance among MDR-TB patients in China. The available data show a large variation in pyrazinamide prevalence, which may be explained through inclusion of selected cases [11][12][13][14]. In this study, we analyzed pyrazinamide resistance, risk factors for resistance, and mutations in the pncA gene, among patients identified with MDR-TB in a nationally representative sample of TB patients in China.…”

Section: Introductionmentioning

confidence: 99%

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Value of pyrazinamide for composition of new treatment regimens for multidrug-resistant Mycobacterium tuberculosis in China

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Background: Pyrazinamide still may be a useful drug for treatment of rifampin-resistant (RR-TB) or multidrugresistant tuberculosis (MDR-TB) in China while awaiting scale up of new drugs and regimens including bedaquiline and linezolid. The level of pyrazinamide resistance among MDR-TB patients in China is not well established. Therefore, we assessed pyrazinamide resistance in a representative sample and explored determinants and patterns of pncA mutations. Methods: MDR-TB isolates from the 2007 national drug resistance survey of China were sub-cultured and examined for pyrazinamide susceptibility by BACTEC MGIT 960 method. pncA mutations were identified by sequencing. Characteristics associated with pyrazinamide resistance were analyzed using univariable and multivariable logbinominal regression. Results: Of 401 MDR-TB isolates, 324 were successfully sub-cultured and underwent drug susceptibility testing. Pyrazinamide resistance was prevalent in 40.7% of samples, similarly among new and previously treated MDR-TB patients. Pyrazinamide resistance in MDR-TB patients was associated with lower age (adjusted OR 0.54; 95% CI, 0.34-0.87 for those aged ≧60 years compared to < 40 years). Pyrazinamide resistance was not associated with gender, residential area, previous treatment history and Beijing genotype. Of 132 patients with pyrazinamide resistant MDR-TB, 97 (73.5%) had a mutation in the pncA gene; with 61 different point mutations causing amino acid change, and 11 frameshifts in the pncA gene. The mutations were scattered throughout the whole pncA gene and no hot spot region was identified. Conclusions: Pyrazinamide resistance among MDR-TB patients in China is common, although less so in elderly patients. Therefore, pyrazinamide should only be used for treatment of RR/MDR-TB in China if susceptibility is confirmed. Molecular testing for detection of pyrazinamide resistance only based on pncA mutations has certain value for the rapid detection of pyrazinamide resistance in MDR-TB strains but other gene mutations conferring to pyrazinamide resistance still need to be explored to increase its predictive ability .

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Value of pyrazinamide for composition of new treatment regimens for multidrug-resistant Mycobacterium tuberculosis in China

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“…6,8,9,26,30 In contrast, the substitution at position −11 of pncA usually possess negative PZase activity in PZA R strains. 40 While we identified one A−11G PZA R mutant having a deletion of C nucleotide at position −114 in the UFR of pncA showed PZase positive, that was completely divergent from five other PZase negative A−11G PZA R mutants, which proposes that C−114del might turn the impact of A−11G mutation and produced positive PZase activity in this PZA R strain. This needs to be further studied in the forthcoming studies.…”

Section: Discussionmentioning

confidence: 71%

Detection of Novel Gene Mutations Associated with Pyrazinamide Resistance in Multidrug-Resistant Mycobacterium tuberculosis Clinical Isolates in Southern China

Hameed¹,

Tan²,

Islam³

et al. 2020

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is a cornerstone of modern tuberculosis regimens. This study aimed to investigate the performance of genotypic testing of pncA + upstream region, rpsA, panD, Rv2783c, and clpC1 genes to add insights for more accurate molecular diagnosis of PZA-resistant (R) Mycobacterium tuberculosis. Methods: Drug susceptibility testing, sequencing analysis of PZA-related genes including the entire operon of pncA (Rv2044c-pncA-Rv2042c) and PZase assay were performed for 448 M. tuberculosis clinical isolates. Results: Our data showed that among 448 M. tuberculosis clinical isolates, 113 were MDR, 195 pre-XDR and 70 XDR TB, while the remaining 70 strains had other combinations of drugresistance. A total of 60.04% (269/448) M. tuberculosis clinical isolates were resistant to PZA, of which 78/113 were MDR, 119/195 pre-XDR and 29/70 XDR TB strains. PZA R isolates have predominance (83.3%) of Beijing genotype. Genotypic characterization of Rv2044c-pncA-Rv2042c revealed novel nonsynonymous mutations in Rv2044c with negative PZase activity which led to confer PZA R. Compared with phenotypic data, 84.38% (227/269) PZA R strains with mutations in pncA + upstream region exhibited 83.64% sensitivity but the combined evaluation of the mutations in rpsA 2.60% (7/269), panD 1.48% (4/269), Rv2783c 1.11% (3/269) and Rv2044c 0.74% (2/269) increased the sensitivity to 89.59%. Fifty-seven novel mutations were identified in this study. Interestingly, a frameshift deletion (C−114del) in upstream of pncA wt nullified the effect of A−11G mutation and induced positive PZase activity, divergent from five PZase negative A−11G PZA R mutants. Twenty-six PZA R strains having wild-type-sequenced genes with positive or negative PZase suggest the existence of unknown resistance mechanisms. Conclusion: Our study revealed that PZA R rate in MDR and pre-XDR TB was markedly higher in southern China. The concomitant evaluation of pncA + UFR, rpsA, panD, Rv2783c, and Rv2044c provides more dependable genotypic results of PZA resistance. Fifty-seven novel mutations/indels in this study may play a vital role as diagnostic markers. The upstream region of pncA and PZase regulation are valuable to explore the unknown mechanism of PZA-resistance.

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“…In addition, some genetic mutations might not necessarily lead to a drug resistance phenotype. 32,33 The pncA mutation rate in PZA-resistant strains varies among different regions, eg, 45.7% in Brazil, 34 70.6% in Iran, 35 75.0% in Taiwan, 36 88% in Chongqing, 23 and 94.1% in Sweden. 37 In this study, 89.52% of the PZAresistant strains harboured pncA mutations.…”

Section: Discussionmentioning

confidence: 99%

Pyrazinamide Resistance and Mutation Patterns Among Multidrug-Resistant Mycobacterium tuberculosis from Henan Province

Shi¹,

Su²,

Zheng³

et al. 2020

IDR

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This study was designed to identify the phenotypic and genotypic characteristics of pyrazinamide (PZA) resistance among multidrug-resistant Mycobacterium tuberculosis (MDR-TB) from Henan and to evaluate the efficacy of pncA, rpsA, and panD mutations in predicting PZA resistance. Materials and Methods: A total of 152 MDR strains were included in this study. The Bactec MGIT system was used to determine PZA susceptibility for all strains. The pncA, rpsA, and panD genes were sequenced to identify any mutations, and the sequences were then aligned with the sequence of standard strain H37Rv. Moreover, the correlations between PZA-resistant phenotypes and treatment outcomes were analysed. Results: Of the152 strains, 105 had a PZA-resistant phenotype, and 102 harboured the pncA mutation. The PZA resistance rate was higher in the strains with resistance to all four firstline drugs and those that were pre-extensively drug-resistant (pre-XDR) and extensively drug-resistant (XDR). A total of 100 different pncA mutation patterns were identified, including 80 point mutations and 20 insertions/deletions, and 32 new pncA mutation patterns were detected. In this study, 13 strains had multiple mutations. Of the11 PZA-resistant strains without pncA mutations, two harboured the rpsA mutation, and one harboured the panD mutation. With PZA susceptibility results as the reference, single-gene pncA sequencing had sensitivity of 89.52% and specificity of 89.36%. With the combination of rpsA and panD, the sensitivity increased to 92.38%, and the specificity remained the same. No significant differences were observed in the sputum smear/culture conversion rate between PZAresistant patients and PZA-sensitive patients. However, PZA resistance was related to the time to sputum smear/culture conversion (P = 0.018). Conclusion: The combination of pncA, rpsA, and panD was beneficial for the timely diagnosis of PZA resistance and could provide a laboratory basis for customizing treatment regimens for MDR-TB patients.

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Prevalence and molecular characterization of pyrazinamide resistance among multidrug-resistant Mycobacterium tuberculosis isolates from Southern China

Cited by 37 publications

References 29 publications

Value of pyrazinamide for composition of new treatment regimens for multidrug-resistant Mycobacterium tuberculosis in China

Value of pyrazinamide for composition of new treatment regimens for multidrug-resistant Mycobacterium tuberculosis in China

<p>Detection of Novel Gene Mutations Associated with Pyrazinamide Resistance in Multidrug-Resistant <em>Mycobacterium tuberculosis</em> Clinical Isolates in Southern China</p>

<p>Pyrazinamide Resistance and Mutation Patterns Among Multidrug-Resistant <em>Mycobacterium tuberculosis</em> from Henan Province</p>

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