Bedaquiline has been classified as a group A drug for the treatment of multidrug-resistant tuberculosis (MDR-TB) by the World Health Organization; however, globally emerging resistance threatens the effectivity of novel MDR-TB treatment regimens.

We analysed pre-existing and emerging bedaquiline resistance in bedaquiline-based MDR-TB therapies, and risk factors associated with treatment failure and death.

In a cross-sectional cohort study, we employed patient data, whole-genome sequencing (WGS) and phenotyping of Mycobacterium tuberculosis complex (MTBC) isolates. We could retrieve baseline isolates from 30.5% (62 out of 203) of all MDR-TB patients who received bedaquiline between 2016 and 2018 in the Republic of Moldova. This includes 26 patients for whom we could also retrieve a follow-up isolate.

At baseline, all MTBC isolates were susceptible to bedaquiline. Among 26 patients with available baseline and follow-up isolates, four (15.3%) patients harboured strains which acquired bedaquiline resistance under therapy, while one (3.8%) patient was re-infected with a second bedaquiline-resistant strain. Treatment failure and death were associated with cavitary disease (p=0.011), and any additional drug prescribed in the bedaquiline-containing regimen with WGS-predicted resistance at baseline (OR 1.92 per unit increase, 95% CI 1.15–3.21; p=0.012).

MDR-TB treatments based on bedaquiline require a functional background regimen to achieve high cure rates and to prevent the evolution of bedaquiline resistance. Novel MDR-TB therapies with bedaquiline require timely and comprehensive drug resistance monitoring.

贝达喹啉已被世界卫生组织列为治疗耐多药结核病 (MDR-TB) 的 A 组药物；然而，全球新出现的耐药性威胁着新型耐多药结核病治疗方案的有效性。

我们分析了基于贝达喹啉的耐多药结核病治疗中预先存在和新出现的贝达喹啉耐药性，以及与治疗失败和死亡相关的风险因素。

在一项横断面队列研究中，我们采用了患者数据、全基因组测序 (WGS) 和结核分枝杆菌复合体 (MTBC) 分离株的表型分析。我们可以从 2016 年至 2018 年期间在摩尔多瓦共和国接受贝达喹啉治疗的所有耐多药结核病患者中的 30.5%（203 名中的 62 名）检索基线分离株。这包括 26 名患者，我们还可以为其检索后续分离株。

在基线时，所有 MTBC 分离株都对贝达喹啉敏感。在有可用的基线和后续分离株的 26 名患者中，4 名 (15.3%) 患者携带在治疗中获得贝达喹啉耐药的菌株，而 1 名 (3.8%) 患者再次感染了第二种耐贝达喹啉菌株。治疗失败和死亡与空洞疾病相关（p=0.011），以及在含贝达喹啉的方案中开出的任何其他药物都与 WGS 预测的基线耐药性相关（OR 1.92 每增加一个单位，95% CI 1.15-3.21；p=0.012 ）。

基于贝达喹啉的耐多药结核病治疗需要功能性背景方案以实现高治愈率并防止贝达喹啉耐药性的演变。使用贝达喹啉的新型耐多药结核病治疗需要及时和全面的耐药性监测。