Multicenter Study of the Emergence and Genetic Characteristics of Pyrazinamide-Resistant Tuberculosis in China.
The aim of this study was to investigate the epidemiology of pyrazinamide (PZA) resistance and the associated risk factors as well as to evaluate the pncA gene loci as a marker for PZA resistance in China. A population-based multicenter study of pulmonary tuberculosis (TB) cases was carried out from 2011 to 2013 in four Chinese districts/counties with different geographic and socioeconomic features. Testing for multidrug-resistant tuberculosis (MDR-TB) and susceptibility to PZA was done by the proportion method on Lowenstein-Jensen medium and Bactec MGIT 960, respectively. Mutations in the pncA gene were identified by sequencing. Among 878 culture-positive cases, 147 (16.7%) were resistant to PZA, with a significantly higher proportion among MDR isolates than among the first-line drug-susceptible isolates (30.2% versus 7.7%; P < 0.001). In total, 136 isolates had a nonsynonymous pncA mutation, with a comparable diagnostic performance between Beijing family and non-Beijing family as well as between MDR-TB and first-line drug-susceptible TB. Furthermore, the mutations in isolates with high-level PZA resistance (MIC > 500 mg/liter) were observed mainly in three regions of the pncA gene (codons 51 to 76, codons 130 to 142, and codons 163 to 180). Patients with prior treatment history had a significantly higher risk for PZA monoresistance (odds ratio [OR], 2.86; 95% confidence interval [CI], 1.363 to 6.015) and MDR PZA resistance (OR, 6.47; 95% CI, 3.186 to 13.15), while the additional factors associated with MDR PZA resistance were the patient's age (OR, 1.02; 95% CI, 1.003 to 1.042), lung cavity (OR, 2.64; 95% CI, 1.296 to 5.391). These findings suggest that it is a priority to identify PZA resistance in MDR-TB and that a rapid molecular diagnostic test based on pncA mutations in the Chinese settings where MDR-TB prevalence is high should be developed.
Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China, and Key Laboratory of Public Health Safety (Fudan University), Ministry of Education, Shanghai, China.
Dange
D
Li
Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China, and Key Laboratory of Public Health Safety (Fudan University), Ministry of Education, Shanghai, China Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden yhu@fudan.edu.cn.
Yi
Y
Hu
Department of Microbiology, the Public Health Agency of Sweden, Solna, Sweden.
Jim
J
Werngren
Department of Microbiology, the Public Health Agency of Sweden, Solna, Sweden.
Mikael
M
Mansjö
Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China, and Key Laboratory of Public Health Safety (Fudan University), Ministry of Education, Shanghai, China.
Xubin
X
Zheng
Department of Infectious Diseases, Imperial College, London, United Kingdom.
Francis
F
Drobniewski
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden Department of Microbiology, the Public Health Agency of Sweden, Solna, Sweden.
Sven
S
Hoffner
Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China, and Key Laboratory of Public Health Safety (Fudan University), Ministry of Education, Shanghai, China.
Biao
B
Xu
D000328:Adult; D000367:Age Factors; D000368:Aged; D000581:Amidohydrolases / Q000235:genetics*; D000995:Antitubercular Agents / Q000627:therapeutic use*; D002681:China / Q000453:epidemiology; D003062:Codon; D003430:Cross-Sectional Studies; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development / Q000302:isolation & purification; D016017:Odds Ratio; D011718:Pyrazinamide / Q000627:therapeutic use*; D012307:Risk Factors; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy / Q000453:epidemiology* / Q000382:microbiology; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000453:epidemiology* / Q000382:microbiology
D000995:Antitubercular Agents; D003062:Codon; D011718:Pyrazinamide; D000581:Amidohydrolases; C487496:PncA protein, Mycobacterium tuberculosis