Clinical Center on TB, Beijing Chest Hospital, Capital Medical University/ Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, 101149, P.R. China.
National Clinical Laboratory on Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, 101149, P.R. China.
Int J Infect Dis. 2021 Jan;102:392-396. doi: 10.1016/j.ijid.2020.10.081. Epub 2020 Oct 29.
We described the prevalence of clofazimine (CFZ) resistance in a multidrug-resistant tuberculosis (MDR-TB) cohort in China. We also aimed to identify dynamic changes in CFZ susceptibility and its molecular mechanism after exposure to bedaquiline (BDQ) and/or CFZ.
The experimental settings were conducted based on our MDR-TB cohort receiving BDQ-containing regimens. Sequential isolates were obtained from patients. CFZ and BDQ susceptibility of isolates were determined using the minimum inhibitory concentration (MIC) method. The fragments of Rv0678 and pepQ were sequenced.
A total of 277 patients infected with MDR-TB were included in our study. CFZ resistance was noted in 23 (23/277, 8.3%) isolates. 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 9/23) out of 23 CFZ-resistant isolates had mutations within either target genes. Kaplan-Meier analysis demonstrated that the baseline CFZ resistance had no influence on time to culture conversion in our cohort (P = 0.828). Acquired CFZ resistance emerged in eight (8/94, 8.5%) patients during treatment for MDR-TB, including three patients receiving regimens without CFZ.
Our results demonstrate the high rate of CFZ resistance among MDR-TB patients in China. Patients treated with BDQ-containing regimens achieve comparative culture conversion rate regardless of baseline CFZ susceptibility. The presence of acquired CFZ-resistance following BDQ treatment without known mutation indicates that other mechanisms conferring cross resistance to these two compounds may exist.
我们描述了中国耐多药结核病（MDR-TB）队列中氯法齐明（CFZ）耐药的流行情况。我们还旨在确定暴露于贝达喹啉（BDQ）和/或 CFZ 后 CFZ 敏感性的动态变化及其分子机制。
实验设置基于我们接受 BDQ 含药方案的 MDR-TB 队列。从患者中获得连续分离株。使用最小抑菌浓度（MIC）法测定分离株的 CFZ 和 BDQ 敏感性。测序 Rv0678 和 pepQ 片段。
本研究共纳入 277 例 MDR-TB 感染患者。23 株（23/277，8.3%）分离株出现 CFZ 耐药。获得性 CFZ 耐药率（12/189，6.3%）明显高于原发性耐药率（11/88，12.5%，P=0.028）。23 株 CFZ 耐药分离株中，5 株（5/23）对 BDQ 耐药，其余 18 株（18/23）对 BDQ 敏感。值得注意的是，23 株 CFZ 耐药分离株中有 9 株（9/23）在靶基因内发生突变。Kaplan-Meier 分析表明，基线 CFZ 耐药性对本队列的培养转换时间无影响（P=0.828）。在治疗 MDR-TB 期间，8 例（8/94，8.5%）患者出现获得性 CFZ 耐药，其中 3 例患者接受的方案不含 CFZ。
我们的研究结果表明，中国 MDR-TB 患者 CFZ 耐药率较高。接受含 BDQ 方案治疗的患者无论基线 CFZ 敏感性如何，均可获得相当的培养转换率。在没有已知突变的情况下，BDQ 治疗后出现获得性 CFZ 耐药性表明，可能存在赋予这两种化合物交叉耐药性的其他机制。
