Clin Microbiol Infect. 2021 Apr 22:S1198-743X(21)00169-5. doi: 10.1016/j.cmi.2021.04.001. Online ahead of print.
OBJECTIVES: Little is known about how additional second-line drug resistance emerges during multidrug resistant tuberculosis(MDR-TB) treatment. The present study aimed to investigate the influence of microevolution, exogenous reinfection and mixed-infection on second-line drug resistance during the recommended two-year MDR-TB treatment.
METHODS: MDR-TB patients were enrolled between 2013-2016 in a multi-centre prospective observational cohort study and followed for two years until treatment completion. Whole genome sequencing (WGS) was applied for serial Mycobacterium tuberculosis isolates from study participants throughout the treatment, to study the role of microevolution, exogenous reinfection and mixed-infection in the development of second-line drug resistance.
RESULTS: Of the 286 enrolled MDR-TB patients, 63(22.0%) Mycobacterium tuberculosis isolates developed additional drug resistance during MDR-TB treatment, including 5(1.7%) that fulfilled the criteria of extensively drug-resistant TB. By comparing WGS data of serial isolates retrieved from the patients throughout treatment, 41(65.1%) of the cases of additional second-line drug resistance were due to exogenous reinfection, 18(28.6%) were caused by acquired drug resistance, i.e. microevolution, while the remaining 4(6.3%) were caused by mixed-infections with drug-resistant and drug-susceptible strains. In multivariate analysis, previous TB treatment[adjusted hazard ratio(aHR)2.51, 95% confidence interval(CI)1.51-4.18], extensive disease on chest X-ray(aHR3.39, 95%CI2.03-5.66) and type 2 diabetes mellitus (aHR4.00, 95%CI2.22-7.21) were independent risk factors associated with the development of additional second-line drug resistance.
CONCLUSIONS: A large proportion of additional second-line drug resistance emerging during MDR-TB treatment was attributed to exogenous reinfection, indicating the urgency of infection control in health facilities as well as the need of repeated drug susceptibility testing throughout MDR-TB treatment.