pncA mutations are associated with slower sputum conversion during standard treatment of multidrug-resistant tuberculosis

•Clinical value of phenotypic and genotypic drug susceptibility testing in MDR-TB is proposed.•Mutations in designated genes and loci are consistent with phenotypic results.•Pyrazinamide and fluoroquinolone phenotypic resistance is associated with treatment outcome.•Genetic mutation in pncA gene indicates poor treatment outcome.•Susceptibility testing for pyrazinamide is necessary before treating MDR-TB.

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.