Multicenter Study of the Emergence and Genetic Characteristics of Pyrazinamide-Resistant Tuberculosis in China

Li, Dange; Hu, Yi; Werngren, Jim; Mansjö, Mikael; Zheng, Xubin; Drobniewski, Francis; Hoffner, Sven; Xu, Biao

doi:10.1128/aac.02687-15

Cited by 17 publications

(23 citation statements)

References 27 publications

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“…In our analysis, we found that 45% of isolates (95% CI, 37.7 to 52.5%) were PZA r . This finding correlates with the findings of many other studies conducted in the United States (38.0%) ( 24 ), South Africa (39.3% and 52.1%) ( 26 , 31 ), Belgium (43.4%) ( 13 ), Japan (53.0%) ( 32 ), Thailand (49%) ( 33 ), India (30.4%) ( 34 ), China (30.2%) ( 35 ), and Central Africa (50%) ( 36 ).…”

Section: Discussionsupporting

confidence: 91%

“…The mutations were diverse and scattered throughout the gene, which included substitution (both promoter and coding region), insertion, and deletion of a single nucleotide or a large DNA segment, causing a frameshift. In this study, we found 27 new mutations which were not previously described in the literature ( 14 , 35 , 45 – 48 ). Each of 52 different mutations was found in one isolate, which indicates that M. tuberculosis isolates acquire diverse mutations to develop PZA resistance.…”

Section: Discussionsupporting

confidence: 49%

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Pyrazinamide Susceptibility and pncA Mutation Profiles of Mycobacterium tuberculosis among Multidrug-Resistant Tuberculosis Patients in Bangladesh

Rahman

Ferdous

Ahmed

et al. 2017

Antimicrob Agents Chemother

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Pyrazinamide (PZA) is a frontline antituberculosis (anti-TB) drug used in both first- and second-line treatment regimens. However, due to complex laboratory requirements, the PZA susceptibility test is rarely performed, leading to a scarcity of data on susceptibility to PZA. Bangladesh is a country with a burden of high rates of both TB and multidrug-resistant TB (MDR-TB), but to our knowledge, published data on rates of PZA susceptibility (PZAs), especially among MDR-TB patients, are limited. We aimed to analyze the PZA susceptibility patterns of Mycobacterium tuberculosis isolates from MDR-TB patients and to correlate the pncA mutation with PZA resistance in Bangladesh. A total of 169 confirmed MDR M. tuberculosis isolates from a pool of specimens collected in a nationwide surveillance study were included in this analysis. All the isolates were tested for phenotypic PZA susceptibility in Bactec mycobacterial growth indicator tube (MGIT) culture medium, and the pncA gene was sequenced. We also correlated different types of clinical information and treatment outcomes with PZA susceptibility. We found that 45% of isolates were phenotypically PZA resistant. Sequencing of the pncA gene revealed a high concordance (82.2%) between the pncA gene sequence and the phenotypic assay results. A total of 64 different mutations were found, and 9 isolates harbored multiple mutations. We detected 27 new pncA mutations. We did not find any significant correlation between the different clinical categories, the genetic lineage, or treatment outcome group and PZA susceptibility. Considering the turnaround time, sequencing would be the more feasible option to determine PZA susceptibility, and further studies to investigate the MIC of PZA should be conducted to determine an effective dose of the drug.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 49%

Pyrazinamide Susceptibility and pncA Mutation Profiles of Mycobacterium tuberculosis among Multidrug-Resistant Tuberculosis Patients in Bangladesh

Rahman

Ferdous

Ahmed

et al. 2017

Antimicrob Agents Chemother

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“…Our present study also showed that there was no difference between pyrazinamide resistance in new cases versus in the previously treated cases. Patient's age and lung cavities were previously reported to be associated with pyrazinamide resistance in MDR-TB cases [22], however, the extent to which age affects pyrazinamide resistance among MDR-TB cases was smaller compared with the effects of cavities and treatment history. Unfortunately, we do not have chest X-ray information on cavitation.…”

Section: Discussionmentioning

confidence: 88%

“…One possible explanation is that the younger patients were recently infected with pyrazinamide resistant strains, while the elderly patients had reactivation of more remote infection, when pyrazinamide resistance levels were lower. Inadequate treatment, improper drug regimens, interrupted availability of drugs, or treatment for a very short period and an increased incidence of previous pyrazinamide exposure are possible causes for pyrazinamide resistance [21][22][23]. In one study conducted in Estonia and Latvia, findings were different as for the association between previous pyrazinamide usage and pyrazinamide resistance.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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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“… 12 , 14 The pnc A mutation frequency in PZA-resistant M. tuberculosis isolates varies between 46% and 97%. 19 , 20 , 21 , 22 , 23 , 24 This variability could be attributed to the unreliable results of PZA susceptibility testing, as mentioned above. Recent reviews reported that, globally, over 80% of PZA-resistant isolates harbor mutations in the pnc A gene and promoter, whereas up to 10% have no mutation or carry mutations not associated with phenotypic resistance.…”

Section: Introductionmentioning

confidence: 99%

Molecular analysis of pyrazinamide resistance in Mycobacterium tuberculosis in Vietnam highlights the high rate of pyrazinamide resistance-associated mutations in clinical isolates

Huy

Contamin

Hoa

et al. 2017

Emerging Microbes & Infections

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Pyrazinamide (PZA) is a key antibiotic in current anti-tuberculosis regimens. Although the WHO has stressed the urgent need to obtain data on PZA resistance, in high tuberculosis burden countries, little is known about the level of PZA resistance, the genetic basis of such resistance or its link with Mycobacterium tuberculosis families. In this context, this study assessed PZA resistance through the molecular analysis of 260 Vietnamese M. tuberculosis isolates. First-line drug susceptibility testing, pncA gene sequencing, spoligotyping and mycobacterial interspersed repetitive units-variable number of tandem repeats (MIRU-VNTR) typing were performed. Overall, the pncA mutation frequency was 38.1% (99 out of 260 isolates) but was higher than 72% (89 out of 123 isolates) in multidrug and quadruple-drug resistant isolates. Many different pncA mutations (71 types) were detected, of which 55 have been previously described and 50 were linked to PZA resistance. Among the 16 novel mutations, 14 are likely to be linked to PZA resistance because of their mutation types or codon positions. Genotype analysis revealed that PZA resistance can emerge in any M. tuberculosis cluster or family, although the mutation frequency was the highest in Beijing family isolates (47.7%, 62 out of 130 isolates). These data highlight the high rate of PZA resistance-associated mutations in M. tuberculosis clinical isolates in Vietnam and bring into question the use of PZA for current and future treatment regimens of multidrug-resistant tuberculosis without PZA resistance testing.

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Multicenter Study of the Emergence and Genetic Characteristics of Pyrazinamide-Resistant Tuberculosis in China

Cited by 17 publications

References 27 publications

Pyrazinamide Susceptibility and pncA Mutation Profiles of Mycobacterium tuberculosis among Multidrug-Resistant Tuberculosis Patients in Bangladesh

Pyrazinamide Susceptibility and pncA Mutation Profiles of Mycobacterium tuberculosis among Multidrug-Resistant Tuberculosis Patients in Bangladesh

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

Molecular analysis of pyrazinamide resistance in Mycobacterium tuberculosis in Vietnam highlights the high rate of pyrazinamide resistance-associated mutations in clinical isolates

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