Pharmacokinetic-Pharmacodynamic Determinants of Clinical Outcomes for Rifampin-Resistant Tuberculosis: A Multisite Prospective Cohort Study.
Pharmacokinetic-Pharmacodynamic Determinants of Clinical Outcomes for Rifampin-Resistant Tuberculosis: A Multisite Prospective Cohort Study.
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DOI：
10.1093/cid/ciac511
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发表时间：
2023-02-08
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耐利福平和/或耐多药结核病（RR/MDR-TB）治疗需要多种药物，结果仍然不理想。一些药物与改善结果有关。尚不清楚特定的药代动力学-药效学关系是否能预测结局。2016年6月至2018年7月，在坦桑尼亚、孟加拉国和俄罗斯联邦招募了接受当地治疗方案的肺RR/MDR-TB成人患者。在2周、4周和8周后采集血清，测定每种药物24小时内的浓度-时间曲线下面积（AUC 0 -24）。M.用最低抑菌浓度（MIC）法测定结核分离株的抑菌活性。通过调整的优势比（OR）和风险比（HR）评估个体药物AUC 0 -24/MIC目标，以获得有利的治疗结局，并评估至痰培养转换的时间。K-means聚类算法根据AUC 0 -24/MIC暴露量将最常见的多药治疗方案的队列分为4个聚类。在290例患者中，62例（21%）出现治疗失败，包括30例死亡。莫西沙星AUC 0 -24/MIC目标值为58与良好的治疗结局相关（OR，3.75; 95%可信区间，1.21-11.56; P = .022）;左氧氟沙星AUC 0 -24/MIC为118.3，氯法齐明AUC 0 -24/MIC为50.5，吡嗪酰胺AUC 0 -24为379 mg × h/L与培养转化较快相关（HR >1.0，P < .05）。其他个体药物暴露不具有预测性。通过AUC 0 -24/MIC聚类显示，多药暴露最低的患者的培养转化最慢。在RR/MDR-TB的多药方案中，血清药代动力学和M.结核病的MIC是可变的，但某些药物-氟喹诺酮类，吡嗪酰胺，氯法齐明-的定义参数是预测性的，应该优化，以改善临床结果。NCT 03559582。在一项多国家前瞻性队列研究中，采用标准化方案治疗利福平耐药/耐多药结核病，血清药代动力学和结核分枝杆菌最低抑菌浓度是可变的，但某些药物（氟喹诺酮类、吡嗪酰胺、氯法齐明）的参数可预测临床结局。
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. In a multicountry, prospective cohort treated with standardized regimens for rifampin-resistant/multidrug-resistant tuberculosis, serum pharmacokinetics and Mycobacterium tuberculosis minimum inhibitory concentrations were variable, yet parameters to certain drugs—fluoroquinolones, pyrazinamide, clofazimine—were predictive of clinical outcome.
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DOI：
10.1093/infdis/jiab101
发表时间：
2022-06-01
期刊：
The Journal of infectious diseases
影响因子：
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作者：
通讯作者：
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影响因子：
158.5
作者：
Conradie, Francesca;Diacon, Andreas H.;Spigelman, Melvin
通讯作者：
Spigelman, Melvin
影响因子：
11.8
作者：
Alffenaar, Jan-Willem C.;Gumbo, Tawanda;Migliori, Giovanni Battista
通讯作者：
Migliori, Giovanni Battista
影响因子：
11.5
作者：
Alsultan, Abdullah;Peloquin, Charles A.
通讯作者：
Peloquin, Charles A.
DOI：
10.5588/ijtld.17.0202
发表时间：
2017-10-01
影响因子：
4
作者：
Schnippel, K.;Firnhaber, C.;Sinanovic, E.
通讯作者：
Sinanovic, E.