Abstract
BackgroundPyrazinamide still may be a useful drug for treatment of rifampin-resistant (RR-TB) or multidrug-resistant 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.MethodsMDR-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 log-binominal regression.ResultsOf 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.ConclusionsPyrazinamide 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 .
Highlights
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
Patients and mycobacterial isolates A nationally representative sample of 3634 smear-positive pulmonary tuberculosis patients were included in the 2007 national drug resistance survey, of which 401 (11.0%) cases were identified as MDR-TB cases with the proportion method on Löwenstein-Jensen medium [1]
The 2007 national drug resistance survey was approved by the Tuberculosis Research Ethics Review Committee of the Chinese Center for Disease Control and Prevention and written informed consent was obtained from each participant
Summary
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. Its role in the longer MDR-TB regimen has been limited with the availability of new core drugs, such as bedaquiline and linezolid, its role in novel shorter regimens currently under trial but with promising outlooks, is pivotal. Anti-tuberculosis regimens consisting of moxifloxacin, pyrazinamide and other drugs for shortening treatment of multi-drug resistant tuberculosis were evaluated and used [2,3,4,5] before the new guideline was issued by WHO. In China group C agents including pyrazinamide may still be used to compose both longer and shorter regimen for drug resistant TB treatment
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