Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia, USA.
Kibong'oto Infectious Diseases Hospital, Sanya Juu, Tanzania.
Clin Infect Dis. 2023 Feb 8;76(3):497-505. doi: 10.1093/cid/ciac511.
Rifampin-resistant and/or multidrug-resistant tuberculosis (RR/MDR-TB) treatment requires multiple drugs, and outcomes remain suboptimal. Some drugs are associated with improved outcome. It is unknown whether particular pharmacokinetic-pharmacodynamic relationships predict outcome.
Adults with pulmonary RR/MDR-TB in Tanzania, Bangladesh, and the Russian Federation receiving local regimens were enrolled from June 2016 to July 2018. Serum was collected after 2, 4, and 8 weeks for each drug's area under the concentration-time curve over 24 hours (AUC0-24). Quantitative susceptibility of the M. tuberculosis isolate was measured by minimum inhibitory concentrations (MICs). Individual drug AUC0-24/MIC targets were assessed by adjusted odds ratios (ORs) for favorable treatment outcome, and hazard ratios (HRs) for time to sputum culture conversion. K-means clustering algorithm separated the cohort of the most common multidrug regimen into 4 clusters by AUC0-24/MIC exposures.
Among 290 patients, 62 (21%) experienced treatment failure, including 30 deaths. Moxifloxacin AUC0-24/MIC target of 58 was associated with favorable treatment outcome (OR, 3.75; 95% confidence interval, 1.21-11.56; P = .022); levofloxacin AUC0-24/MIC of 118.3, clofazimine AUC0-24/MIC of 50.5, and pyrazinamide AUC0-24 of 379 mg × h/L were associated with faster culture conversion (HR >1.0, P < .05). Other individual drug exposures were not predictive. Clustering by AUC0-24/MIC revealed that those with the lowest multidrug exposures had the slowest culture conversion.
Amidst multidrug regimens for RR/MDR-TB, serum pharmacokinetics and M. tuberculosis MICs were variable, yet defined parameters to certain drugs-fluoroquinolones, pyrazinamide, clofazimine-were predictive and should be optimized to improve clinical outcome.
NCT03559582.
利福平耐药和/或耐多药结核病（RR/MDR-TB）的治疗需要多种药物，且治疗结果仍不理想。一些药物与改善结果有关。目前尚不清楚特定的药代动力学-药效学关系是否可以预测治疗结果。
2016 年 6 月至 2018 年 7 月，从坦桑尼亚、孟加拉国和俄罗斯联邦接受当地方案治疗的患有肺 RR/MDR-TB 的成年人入组。在每个药物的 24 小时 AUC0-24 时，收集治疗后第 2、4 和 8 周的血清，以测量药物的浓度-时间曲线下面积（AUC0-24）。通过最低抑菌浓度（MIC）测量结核分枝杆菌分离株的定量药敏性。通过调整有利治疗结果的优势比（OR）和痰培养转化时间的风险比（HR），评估个体药物 AUC0-24/MIC 目标。K-均值聚类算法根据 AUC0-24/MIC 暴露将最常见的多药方案队列分为 4 个簇。
在 290 名患者中，有 62 名（21%）治疗失败，包括 30 例死亡。莫西沙星 AUC0-24/MIC 目标值为 58 与有利的治疗结果相关（OR，3.75；95%置信区间，1.21-11.56；P=.022）；左氧氟沙星 AUC0-24/MIC 为 118.3，氯法齐明 AUC0-24/MIC 为 50.5，吡嗪酰胺 AUC0-24 为 379 mg×h/L 与更快的培养转化相关（HR>1.0，P<.05）。其他个体药物暴露情况没有预测作用。按 AUC0-24/MIC 聚类显示，药物暴露最低的患者培养转化最慢。
在 RR/MDR-TB 的多药方案中，血清药代动力学和结核分枝杆菌 MIC 存在差异，但某些药物（氟喹诺酮类、吡嗪酰胺、氯法齐明）的确定参数具有预测性，应加以优化以改善临床结果。
NCT03559582。
