Reduced Susceptibility of Mycobacterium tuberculosis to Bedaquiline During Antituberculosis Treatment and Its Correlation With Clinical Outcomes in China.

Abstract

We aimed to assess the proportion of multidrug-resistant tuberculosis (MDR-TB) cases with initial bedaquiline (BDQ) resistance, monitor the dynamics of BDQ susceptibility of Mycobacterium tuberculosis isolates during therapy, and correlate susceptibility with MDR-TB patient clinical outcomes in China. A retrospective, cohort study of MDR-TB patients was conducted, with positive cultures collected from cases at 13 sites. Patients with nontuberculous mycobacterial infection during anti-TB therapy were excluded. BDQ minimal inhibitory concentrations (MICs) were determined using a 7H9 Middlebrook broth-based microdilution method. Mutations that conferred BDQ resistance were detected via Sanger sequencing. A total of 277 patients receiving BDQ treatment were studied, with BDQ resistance noted in isolates from 2.2% (6/277) of MDR-TB cases, sputum conversion observed in 5 cases, and culture conversion observed in 138 cases within 2 weeks. Another 15 and 30 isolates were excluded from final analysis due to failures in obtaining subcultures and serial isolates, respectively. Of 94 cases that yielded serial isolates, 11 exhibited reduced BDQ susceptibility, while 3 of 5 cases with acquired resistance failed to culture-convert. Sequence analysis revealed that 6 of 11 BDQ-resistant isolates harbored Rv0678 mutations; no mutations were detected in 3 other BDQ resistance-associated genes. No significant intergroup difference in culture conversion time was observed. MDR-TB patients in China exhibited a low initial BDQ resistance rate. MDR-TB cases with acquired BDQ resistance were at greater risk of treatment failure relative to initially BDQ-resistant cases. Rv0678 mutations accounted for BDQ resistance in this cohort.