Rationale: Observational studies suggest that high-dose isoniazid may be efficacious in treating multidrug-resistant tuberculosis. However, its activity against Mycobacterium tuberculosis (M.tb) with katG mutations (which typically confer high-level resistance) is not established. Objectives: To characterize the early bactericidal activity (EBA) of high-dose isoniazid in patients with tuberculosis caused by katG-mutated M.tb. Methods: A5312 was a phase IIA randomized, open-label trial. Participants with tuberculosis caused by katG-mutated M.tb were randomized to receive 15 or 20 mg/kg isoniazid daily for 7 days. Daily sputum samples were collected for quantitative culture. Intensive pharmacokinetic sampling was performed on Day 6. Data were pooled across all A5312 participants for analysis (drug-sensitive, inhA-mutated, and katG-mutated M.tb). EBA was determined using nonlinear mixed-effects modeling. Measurements and Main Results: Of 80 treated participants, 21 had katG-mutated M.tb. Isoniazid pharmacokinetics were best described by a two-compartment model with an effect of NAT2 acetylator phenotype on clearance. Model-derived maximum concentration and area under the concentration-time curve in the 15 and 20 mg/kg groups were 15.0 and 22.1 mg/L and 57.6 and 76.8 mg ⋅ h/L, respectively. Isoniazid bacterial kill was described using an effect compartment and a sigmoidal maximum efficacy relationship. Isoniazid potency against katG-mutated M.tb was approximately 10-fold lower than in inhA-mutated M.tb. The highest dose of 20 mg/kg did not demonstrate measurable EBA, except against a subset of slow NAT2 acetylators (who experienced the highest concentrations). There were no grade 3 or higher drug-related adverse events. Conclusions: This study found negligible bactericidal activity of high-dose isoniazid (15-20 mg/kg) in the majority of participants with tuberculosis caused by katG-mutated M.tb. Clinical trial registered with www.clinicaltrials.gov (NCT01936831).

中文翻译：

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高剂量异烟肼对 katG 突变介导的耐异烟肼结核病缺乏早期杀菌活性：一项随机 II 期临床试验。


理由：观察性研究表明，高剂量异烟肼可能有效治疗耐多药结核病。然而，其针对具有 katG 突变（通常赋予高水平耐药性）的结核分枝杆菌 (M.tb) 的活性尚未确定。目的：表征高剂量异烟肼对 katG 突变结核分枝杆菌引起的结核病患者的早期杀菌活性 (EBA)。方法：A5312 是一项 IIA 期随机、开放标签试验。患有由 katG 突变 M.tb 引起的结核病的参与者被随机每天接受 15 或 20 mg/kg 异烟肼治疗，持续 7 天。每日采集痰标本进行定量培养。第 6 天进行密集药代动力学采样。汇总所有 A5312 参与者的数据进行分析（药物敏感、inhA 突变和 katG 突变 M.tb）。 EBA 是使用非线性混合效应模型确定的。测量和主要结果：在 80 名接受治疗的参与者中，21 人患有 katG 突变结核分枝杆菌。异烟肼药代动力学最好通过两室模型来描述，该模型具有 NAT2 乙酰化表型对清除率的影响。 15 和 20 mg/kg 组中模型得出的最大浓度和浓度-时间曲线下面积分别为 15.0 和 22.1 mg/L 以及 57.6 和 76.8 mg·h/L。使用效应区室和 S 形最大功效关系来描述异烟肼细菌杀灭作用。异烟肼针对 katG 突变 M.tb 的效力比 inhA 突变 M.tb 低约 10 倍。 20 mg/kg 的最高剂量没有表现出可测量的 EBA，除了针对慢速 NAT2 乙酰化剂的子集（其经历了最高浓度）。没有发生 3 级或以上的药物相关不良事件。 结论：本研究发现，高剂量异烟肼（15-20 mg/kg）对大多数 katG 突变结核分枝杆菌引起的结核病参与者的杀菌活性可以忽略不计。在 www.clinicaltrials.gov 注册的临床试验 (NCT01936831)。