title: pncA mutations are associated with slower sputum conversion during standard treatment of multidrug-resistant tuberculosis.
abstract: Despite the strong association between drug resistance and genetic mutations, the value of molecular diagnosis of drug resistance to guide the treatment of multidrug-resistant tuberculosis (MDR-TB) remains unclear. This is particularly relevant in resource-limited areas where it is difficult to perform drug susceptibility testing (DST). Here we investigated the association between drug susceptibility phenotypes and genotypes and treatment outcomes in patients with MDR-TB. This study enrolled 74 consecutive patients with confirmed MDR-TB between 2010 and 2011, and outcomes were followed-up over the 24-month treatment course. All of the isolates were tested for phenotypic susceptibility to second-line drugs using the Mycobacteria Growth Indicator Tube (MGIT)-based system, and genotypic mutations were assessed by DNA sequencing. Among the 74 MDR-TB isolates, 29 (39.2%) were resistant to fluoroquinolones and/or second-line injectable drugs, of which 21 (72.4%) harboured a mutation in drug resistance-related genes (gyrA, rrs or eis). In addition, 32 individuals (43.2%) also had pyrazinamide (PZA)-resistant isolates, with 28 (87.5%) containing the pncA mutation. By backward selection in the multivariate logistic regression and Cox proportional hazard models, PZA resistance and its related pncA gene mutation demonstrated a correlation with a lower likelihood of culture conversion at 8 weeks and treatment success. Meanwhile, the fluoroquinolone resistance-related gyrA gene mutation was negatively correlated with treatment success. DST for PZA and fluoroquinolones together with genetic information appears to provide a clinically useful indicator of the treatment outcome of MDR-TB in China.
authors.affiliation: Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China; Ministry of Education, Key Laboratory of Public Health Safety (Fudan University), China.
authors.forename: Xubin
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Zigong City Center for Disease Control and Prevention, Zigong City, Sichuan, China.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Ning
authors.affiliation: Department of Infectious Diseases, Imperial College, London, UK.
authors.forename: Francis
authors.initials: F
authors.lastname: Drobniewski
authors.affiliation: Shanghai integrated traditional Chinese and Western Medicine Hospital, Shanghai, China.
authors.forename: Jingyong
authors.initials: J
authors.lastname: Yang
authors.affiliation: Zigong City Center for Disease Control and Prevention, Zigong City, Sichuan, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Li
authors.affiliation: Zigong City Center for Disease Control and Prevention, Zigong City, Sichuan, China.
authors.forename: Zhengdong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China; Ministry of Education, Key Laboratory of Public Health Safety (Fudan University), China. Electronic address: yhu@fudan.edu.cn.
authors.forename: Yi
authors.initials: Y
authors.lastname: Hu
mesh_terms: D000328:Adult; D000581:Amidohydrolases / Q000235:genetics*; D000995:Antitubercular Agents / Q000008:administration & dosage*; D002681:China; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification*; D010641:Phenotype; D017422:Sequence Analysis, DNA; D013183:Sputum / Q000382:microbiology*; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000382:microbiology*
chemical_list: D000995:Antitubercular Agents; D000581:Amidohydrolases; C487496:PncA protein, Mycobacterium tuberculosis
keywords: China; Molecular diagnosis; Multidrug-resistant tuberculosis; Treatment