Fluoroquinolone Resistance Mutation Detection Is Equivalent to Culture-Based Drug Sensitivity Testing for Predicting Multidrug-Resistant Tuberculosis Treatment Outcome: A Retrospective Cohort Study
Fluoroquinolone Resistance Mutation Detection Is Equivalent to Culture-Based Drug Sensitivity Testing for Predicting Multidrug-Resistant Tuberculosis Treatment Outcome: A Retrospective Cohort Study
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DOI：
10.1093/cid/cix556
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发表时间：
2017-10-15
影响因子：
11.8
通讯作者：
Mitnick, Carole D.
中科院分区：
文献类型：
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作者：
Farhat, Maha R.;Jacobson, Karen R.;Mitnick, Carole D.
背景。快速准确预测氟喹诺酮（FQ）耐药性的分子诊断有望改善耐多药结核病患者的治疗结果。然而，gyr基因的突变可以引起不同水平的体外FQ耐药，并且一些体外耐药仍然无法单独由gyr突变解释，但这些差异对治疗结果的影响尚不清楚。我们对172名耐多药/广泛耐药结核病患者进行了回顾性队列研究，并对各自痰液结核分离株的全gyrA和gyrB开放阅读框进行了测序。gyr突变被分为两类：一组编码高水平FQ抗性的突变，另一组编码中等抗性水平的突变。我们建立了Cox比例模型来评估gyr突变类型对死亡时间或治疗失败的影响，并在控制宿主和治疗因素的情况下，将其与体外FQ抗性进行比较。控制其他宿主和治疗因素，并与无gyr耐药突变的分离株患者进行比较，“高水平”gyr突变显著预测不良治疗结果，风险比为2.6（1.2-5.6）。我们观察到，“中等水平”的gyr突变为1.3(0.6-3.1)，死亡和治疗失败的风险没有达到统计学意义。gyr突变与基于培养的FQ药敏试验在预测死亡或治疗失败风险方面没有差异，可能更优。FQ基于分子的诊断试验可能比传统的药敏试验更好地预测治疗反应，并为个性化结核病治疗开辟道路。
Background. Molecular diagnostics that rapidly and accurately predict fluoroquinolone (FQ) resistance promise to improve treatment outcomes for individuals with multidrug-resistant (MDR) tuberculosis (TB). Mutations in the gyr genes, though, can cause variable levels of in vitro FQ resistance, and some in vitro resistance remains unexplained by gyr mutations alone, but the implications of these discrepancies for treatment outcome are unknown.Methods. We performed a retrospective cohort study of 172 subjects with MDR/extensively drug-resistant TB subjects and sequenced the full gyrA and gyrB open reading frames in their respective sputum TB isolates. The gyr mutations were classified into 2 categories: a set of mutations that encode high-level FQ resistance and a second set that encodes intermediate resistance levels. We constructed a Cox proportional model to assess the effect of the gyr mutation type on the time to death or treatment failure and compared this with in vitro FQ resistance, controlling for host and treatment factors.Results. Controlling for other host and treatment factors and compared with patients with isolates without gyr resistance mutations, "high- level" gyr mutations significantly predict poor treatment outcomes with a hazard ratio of 2.6 (1.2-5.6). We observed a hazard of death and treatment failure with "intermediate- level" gyr mutations of 1.3 (0.6-3.1), which did not reach statistical significance. The gyr mutations were not different than culture-based FQ drug susceptibility testing in predicting the hazard of death or treatment failure and may be superior.Conclusions. FQ molecular-based diagnostic tests may better predict treatment response than traditional drug susceptibility testing and open avenues for personalizing TB therapy.