Bedaquiline resistance in patients with drug-resistant tuberculosis in Cape Town, South Africa: a retrospective longitudinal cohort study.
Bedaquiline resistance in patients with drug-resistant tuberculosis in Cape Town, South Africa: a retrospective longitudinal cohort study.
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南非开普敦耐药结核病患者的贝达喹啉耐药性：一项回顾性纵向队列研究。
DOI：
10.1016/s2666-5247(23)00172-6
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发表时间：
2023
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通讯作者：
VanRie,Anne
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作者：
Derendinger,Brigitta;Dippenaar,Anzaan;deVos,Margaretha;Huo,Stella;Alberts,Rencia;Tadokera,Rebecca;Limberis,Jason;Sirgel,Frik;Dolby,Tania;Spies,Claudia;Reuter,Anja;Folkerts,Megan;Allender,Christopher;Lemmer,Darrin;VanRie,Anne
背景贝达喹啉是一种挽救生命的结核病药物，正在全球范围内推广。尽管存在结核分枝杆菌耐药菌株的潜在来源，但面临结核病药物治疗方案较弱风险的人群仍是获得新药的优先对象。我们的目的是表征在贝达喹啉治疗期间持续培养呈阳性的个体的贝达喹啉耐药性。方法我们对培养阳性肺结核成人（年龄≥18岁）进行了一项回顾性纵向队列研究，这些成人在2016年1月20日至11月20日期间从南非开普敦的12个耐药结核病治疗机构接受了至少4个月的含贝达喹啉治疗方案。 2017 年。在基线（即开始贝达喹啉之前）和每月以程序方式收集痰液，以根据国家算法监测治疗反应。从使用贝达喹啉 4 个月或之后收集的痰中获得的最后一个分离株被指定为后续分离株。在 MGIT960 培养基（WHO 推荐的临界浓度 1 μg/mL）中对基线和后续分离株进行贝达喹啉表型药物敏感性测试。还进行了 Rv0678、atpE 和 pepQ 的靶向深度测序以及全基因组测序。结果显示，估计池中的 129 名患者中总共有 40 名 (31%) 符合本研究的资格。总体而言，通过贝达喹啉表型药物敏感性测试评估的 38 名患者中，3 名 (8%) 存在原发性耐药，18 名 (47%) 获得耐药（获得性或再感染），17 名 (45%) 在基线和随访时均易感。一些Rv0678和pepQ单核苷酸多态性和插入缺失与耐药性相关。尽管Rv0676c和Rv1979c中出现了变异，但这些变异与耐药性无关。靶向深度测序检测到全基因组测序未检测到的低水平变异；然而，全基因组测序已检测到没有变异的基因中没有一个。具有基线氟喹诺酮耐药性、氯法齐明暴露以及四种或更少有效药物的患者更有可能出现贝达喹啉耐药性增加。阻力增益主要是由于获取；然而，发生了一些耐药菌株的再感染。解释贝达喹啉耐药性增加（我们确定了危险因素）在这些经过程序治疗且持续培养呈阳性的患者中很常见。我们的研究强调了与实施救生新药相关的风险，并显示了贝达喹啉耐药性传播的证据。常规药敏试验应紧急伴随新药的扩大规模进行；然而，鉴于观察到的变异体的多样性，贝达奎林的快速药敏测试仍然具有挑战性。 资助来源：Doris Duke 慈善基金会、美国国家过敏和传染病研究所、南非医学研究理事会、国家研究基金会、佛兰德斯研究基金会、斯泰伦博斯大学医学健康科学学院、南非国家研究基金会、瑞士国家科学基金会和威康信托基金。
BackgroundBedaquiline is a life-saving tuberculosis drug undergoing global scale-up. People at risk of weak tuberculosis drug regimens are a priority for novel drug access despite the potential source ofMycobacterium tuberculosis-resistant strains. We aimed to characterise bedaquiline resistance in individuals who had sustained culture positivity during bedaquiline-based treatment.MethodsWe did a retrospective longitudinal cohort study of adults (aged ≥18 years) with culture-positive pulmonary tuberculosis who received at least 4 months of a bedaquiline-containing regimen from 12 drug-resistant tuberculosis treatment facilities in Cape Town, South Africa, between Jan 20, 2016, and Nov 20, 2017. Sputum was programmatically collected at baseline (ie, before bedaquiline initiation) and each month to monitor treatment response per the national algorithm. The last available isolate from the sputum collected at or after 4 months of bedaquiline was designated the follow-up isolate. Phenotypic drug susceptibility testing for bedaquiline was done on baseline and follow-up isolates in MGIT960 media (WHO-recommended critical concentration of 1 μg/mL). Targeted deep sequencing forRv0678, atpE, andpepQ, as well as whole-genome sequencing were also done.FindingsIn total, 40 (31%) of 129 patients from an estimated pool were eligible for this study. Overall, three (8%) of 38 patients assessable by phenotypic drug susceptibility testing for bedaquiline had primary resistance, 18 (47%) gained resistance (acquired or reinfection), and 17 (45%) were susceptible at both baseline and follow-up. SeveralRv0678andpepQsingle-nucleotide polymorphisms and indels were associated with resistance. Although variants occurred inRv0676candRv1979c, these variants were not associated with resistance. Targeted deep sequencing detected low-level variants undetected by whole-genome sequencing; however, none were in genes without variants already detected by whole-genome sequencing. Patients with baseline fluoroquinolone resistance, clofazimine exposure, and four or less effective drugs were more likely to have bedaquiline-resistant gain. Resistance gain was primarily due to acquisition; however, some reinfection by resistant strains occurred.InterpretationBedaquiline-resistance gain, for which we identified risk factors, was common in these programmatically treated patients with sustained culture positivity. Our study highlights risks associated with implementing life-saving new drugs and shows evidence of bedaquiline-resistance transmission. Routine drug susceptibility testing should urgently accompany scale-up of new drugs; however, rapid drug susceptibility testing for bedaquiline remains challenging given the diversity of variants observed.FundingDoris Duke Charitable Foundation, US National Institute of Allergy and Infectious Diseases, South African Medical Research Council, National Research Foundation, Research Foundation Flanders, Stellenbosch University Faculty of Medicine Health Sciences, South African National Research Foundation, Swiss National Science Foundation, and Wellcome Trust.