Acquisition of clofazimine resistance following bedaquiline treatment for multidrug-resistant tuberculosis

摘要

Objectives The aim of this study was to describe the prevalence of clofazimine (CFZ) resistance in a cohort of patients with multidrug-resistant tuberculosis (MDR-TB) in China. A further aim was to identify dynamic changes in CFZ susceptibility and its molecular mechanism after exposure to bedaquiline (BDQ) and/or CFZ. Methods The experimental setting was based on an MDR-TB cohort receiving BDQ-containing regimens. Sequential isolates were obtained from these patients. The CFZ and BDQ susceptibility of isolates were determined using the minimum inhibitory concentration (MIC) method. The fragments of Rv0678 and pepQ were sequenced. Results A total of 277 patients infected with MDR-TB were included in this study. CFZ resistance was noted in 23 isolates (23/277, 8.3%). The rate of acquired CFZ resistance (12/189, 6.3%) was significantly greater than that of primary resistance (11/88, 12.5%, p = 0.028). Out of 23 CFZ-resistant isolates, five (5/23) were BDQ-resistant and the other 18 (18/23) were susceptible to BDQ. Of note, nine out of 23 CFZ-resistant isolates had mutations within either of the target genes. Kaplan–Meier analysis demonstrated that the baseline CFZ resistance had no influence on time to culture conversion in this cohort ( p = 0.828). Acquired CFZ resistance emerged in eight patients (8/94, 8.5%) during treatment for MDR-TB, including three patients receiving regimens without CFZ. Conclusions The study results demonstrated a high rate of CFZ resistance among MDR-TB patients in China. Patients treated with BDQ-containing regimens achieved a comparable culture conversion rate regardless of baseline CFZ susceptibility. The presence of acquired CFZ resistance following BDQ treatment without a known mutation indicates that other mechanisms conferring cross-resistance to these two compounds may exist.