Villellas Cristina, Coeck Nele, Meehan Conor J, Lounis Nacer, de Jong Bouke, Rigouts Leen, Andries Koen
Janssen Research and Development, Beerse, Belgium.
Institute of Tropical Medicine, Antwerp, Belgium.
J Antimicrob Chemother. 2017 Mar 1;72(3):684-690. doi: 10.1093/jac/dkw502.
Resistance-associated variants (RAVs) in Rv0678 , a regulator of the MmpS5-MmpL5 efflux pump, have been shown to lead to increased MICs of bedaquiline (2- to 8- fold) and clofazimine (2- to 4-fold). The prevalence of these Rv0678 RAVs in clinical isolates and their impact on treatment outcomes are important factors to take into account in bedaquiline treatment guidelines.
Baseline isolates from two bedaquiline MDR-TB clinical trials were sequenced for Rv0678 RAVs and corresponding bedaquiline MICs were determined on 7H11 agar. Rv0678 RAVs were also investigated in non-MDR-TB sequences of a population-based cohort.
Rv0678 RAVs were identified in 23/347 (6.3%) of MDR-TB baseline isolates. Surprisingly, bedaquiline MICs for these isolates were high (> 0.24 mg/L, n = 8), normal (0.03-0.24 mg/L, n = 11) or low (< 0.03 mg/L, n = 4). A variant at position -11 in the intergenic region mmpS5 - Rv0678 was identified in 39 isolates (11.3%) and appeared to increase the susceptibility to bedaquiline. In non-MDR-TB isolates, the frequency of Rv0678 RAVs was lower (6/852 or 0.7%). Competition experiments suggested that rifampicin was not the drug selecting for Rv0678 RAVs.
RAVs in Rv0678 occur more frequently in MDR-TB patients than previously anticipated, are not associated with prior use of bedaquiline or clofazimine, and in the majority of cases do not lead to bedaquiline MICs above the provisional breakpoint (0.24 mg/L). Their origin remains unknown. Given the variety of RAVs in Rv0678 and their variable effects on the MIC, only phenotypic drug-susceptibility methods can currently be used to assess bedaquiline susceptibility.
Rv0678是MmpS5-MmpL5外排泵的一个调节因子，其耐药相关变异（RAVs）已被证明会导致贝达喹啉的最低抑菌浓度（MICs）升高（2至8倍）以及氯法齐明的MICs升高（2至4倍）。这些Rv0678 RAVs在临床分离株中的流行情况及其对治疗结果的影响是贝达喹啉治疗指南中需要考虑的重要因素。
对两项贝达喹啉耐多药结核病临床试验的基线分离株进行Rv0678 RAVs测序，并在7H11琼脂上测定相应的贝达喹啉MICs。还在一个基于人群队列的非耐多药结核病序列中研究了Rv0678 RAVs。
在347株耐多药结核病基线分离株中的23株（6.3%）中鉴定出Rv0678 RAVs。令人惊讶的是，这些分离株的贝达喹啉MICs较高（>0.24mg/L，n = 8）、正常（0.03 - 0.24mg/L，n = 11）或较低（<0.03mg/L，n = 4）。在39株分离株（11.3%）中鉴定出基因间区域mmpS5 - Rv0678中-11位的一个变异，该变异似乎增加了对贝达喹啉的敏感性。在非耐多药结核病分离株中，Rv0678 RAVs的频率较低（6/852或0.7%）。竞争实验表明利福平不是选择Rv0678 RAVs的药物。
Rv0678中的RAVs在耐多药结核病患者中出现的频率比之前预期的更高，与之前使用贝达喹啉或氯法齐明无关，并且在大多数情况下不会导致贝达喹啉的MICs高于临时断点（0.24mg/L）。它们的起源仍然未知。鉴于Rv0678中存在多种RAVs及其对MIC的可变影响，目前只有表型药敏方法可用于评估贝达喹啉敏感性。
