Defining Bedaquiline Susceptibility, Resistance, Cross-Resistance and Associated Genetic Determinants: A Retrospective Cohort Study.
Defining Bedaquiline Susceptibility, Resistance, Cross-Resistance and Associated Genetic Determinants: A Retrospective Cohort Study.
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DOI：
10.1016/j.ebiom.2018.01.005
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发表时间：
2018-03
期刊：
影响因子：
11.1
通讯作者：
Ndjeka N
中科院分区：
文献类型：
--
作者：
Ismail NA;Omar SV;Joseph L;Govender N;Blows L;Ismail F;Koornhof H;Dreyer AW;Kaniga K;Ndjeka N
贝达喹啉（BDQ）是一种新的药物批准用于联合治疗耐多药结核病（MDR-TB）。我们试图确定BDQ流行病学临界值（ECV），定义和评估对假定的耐药相关变异（RAV），微生物学结果和与氯法齐明（CFZ）的交叉耐药的解释标准。进行了一项回顾性队列研究。使用7 H9肉汤微量稀释法（BMD）和MGIT 960测定对BDQ的最小抑菌浓度（MIC）。使用全基因组测序对RAV进行遗传表征。采用ECOF法测定BDQ ECV，并与6个月培养转化状态和CFZ MIC进行比较。共分析了391株分离株。采用BMD测定敏感和中间类别的MIC分别为≤ 0.125 μg/ml和0.25 μg/ml，采用MGIT 960测定的MIC分别为≤ 1 μg/ml和2 μg/ml。在BDQ暴露患者中发生微生物学失败，这些患者具有非敏感BDQ MIC、Rv 0678突变和≤ 2种活性药物类别。Rv 0678 RAV不是CFZ抗性的主导机制，交叉抗性仅限于具有Rv 0678突变的菌株。定义了BDQ敏感性的标准，将有助于改善耐药性的早期检测。BDQ和CFZ之间的交叉耐药是一个新出现的问题，但在这项研究中，主要是在那些与Rv 0678突变。定义了BDQ敏感性标准，这将有助于改善BDQ耐药性的早期检测。具有非敏感BDQ MIC的人中发生了微生物学失败，Rv 0678突变和≤ 2种活性药物类别CFZ和BDQ之间的交叉耐药性主要在具有Rv 0678突变的患者分离株中观察到。本研究有力地定义了贝达喹啉的敏感性标准，并解决了遗传基础的不确定性。抗性和交叉抗性。提供了MGIT 960和肉汤微量稀释法的敏感性标准。我们的研究结果不支持早期的研究，表明选定的推定基因（pepQ和Rv 1979）在赋予抗性的作用，同时澄清Rv 0678基因突变体的作用。与氯法齐明的交叉耐药仅限于Rv 0678突变和贝达喹啉暴露的病例。此外，与Rv 0678突变是CFZ耐药主要原因的体外选择突变体不同，临床分离株似乎并非如此。
Bedaquiline (BDQ) is a novel agent approved for use in combination treatment of multi-drug resistant tuberculosis (MDR-TB). We sought to determine BDQ epidemiological cut-off values (ECVs), define and assess interpretive criteria against putative resistance associated variants (RAVs), microbiological outcomes and cross resistance with clofazimine (CFZ). A retrospective cohort study was conducted. Minimal inhibitory concentrations (MIC) to BDQ were determined using 7H9 broth microdilution (BMD) and MGIT960. RAVs were genetically characterised using whole genome sequencing. BDQ ECVs were determined using ECOFFinder and compared with 6-month culture conversion status and CFZ MICs. A total of 391 isolates were analysed. Susceptible and intermediate categories were determined to have MICs of ≤ 0.125 μg/ml and 0.25 μg/ml using BMD and ≤ 1 μg/ml and 2 μg/ml using MGIT960 respectively. Microbiological failures occurred among BDQ exposed patients with a non-susceptible BDQ MIC, an Rv0678 mutation and ≤ 2 active drug classes. The Rv0678 RAVs were not the dominant mechanism of CFZ resistance and cross resistance was limited to isolates with an Rv0678 mutation. Criteria for BDQ susceptibility are defined and will facilitate improved early detection of resistance. Cross- resistance between BDQ and CFZ is an emerging concern but in this study was primarily among those with an Rv0678 mutation. Criteria for BDQ susceptibility are defined which will facilitate improved early detection of BDQ resistance Microbiological failures occurred in those with a non-susceptible BDQ MIC, an Rv0678 mutation and ≤ 2 active drug classes Cross resistance between CFZ and BDQ was primarily observed in patient isolates with Rv0678 mutants This study robustly defines susceptibility criteria for bedaquiline and addresses uncertainties around the genetic basis of resistance and cross resistance. Susceptibility criteria are provided for MGIT 960 and broth microdilution. Our findings do not support earlier studies indicating a role for selected putative genes (pepQ and Rv1979) in conferring resistance whilst clarifying the role of mutants in the Rv0678 gene. Cross resistance with clofazimine was limited to cases with an Rv0678 mutation and bedaquiline exposure. Furthermore, unlike in-vitro selected mutants where Rv0678 mutation are the dominant cause of CFZ resistance, this does not appear to be true for clinical isolates.
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DOI：
10.5588/ijtld.14.0944
发表时间：
2015-08-01
影响因子：
4
作者：
Ndjeka, N.;Conradie, F.;Pillay, Y.
通讯作者：
Pillay, Y.
影响因子：
4.9
作者：
Keller, Peter M.;Hoemke, Rico;Boettger, Erik C.
通讯作者：
Boettger, Erik C.
影响因子：
13.6
作者：
Preiss L;Langer JD;Yildiz Ö;Eckhardt-Strelau L;Guillemont JE;Koul A;Meier T
通讯作者：
Meier T
影响因子：
158.5
作者：
Diacon, Andreas H.;Pym, Alexander;Dannemann, Brian
通讯作者：
Dannemann, Brian
影响因子：
14.8
作者：
Koul, Anil;Dendouga, Najoua;Andries, Koen
通讯作者：
Andries, Koen