Sterilizing Effect of Ertapenem-Clavulanate in a Hollow-Fiber Model of Tuberculosis and Implications on Clinical Dosing
Sterilizing Effect of Ertapenem-Clavulanate in a Hollow-Fiber Model of Tuberculosis and Implications on Clinical Dosing
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DOI：
10.1128/aac.02039-16
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发表时间：
2017-09-01
影响因子：
4.9
通讯作者：
Gumbo, Tawanda
中科院分区：
文献类型：
--
作者：
van Rijn, Sander P.;Srivastava, Shashikant;Gumbo, Tawanda
目前正在探索碳青霉烯类药物用于治疗耐多药结核病（MDR-TB），特别是与克拉维酸联合使用。由于每天需要多次肠胃外剂量以及缺乏对灭菌效果最佳剂量的了解，临床使用受到限制。我们的目标是确定与最佳灭菌效果相关的厄他培南暴露量，然后设计临床使用的每日一次剂量。我们利用结核病的中空纤维系统模型对 8 种不同剂量的厄他培南与克拉维酸联合进行了为期 28 天的暴露反应研究。在预定时间点对系统进行采样，以验证浓度-时间曲线并确定总细菌负荷。抑制性 S 形最大效应 (E-max) 模型用于确定总细菌负荷与药物暴露之间的关系，并确定最佳暴露量。与文献相反，厄他培南-克拉维酸盐组合表现出良好的微生物杀灭和灭菌效果。在一项剂量分割中空纤维研究中，疗效与厄他培南浓度持续高于 MIC 的 24 小时给药间隔百分比 (%T-MIC) 相关。我们基于蒙特卡罗方法对 10,000 名耐多药结核病患者进行了计算机辅助临床试验模拟，以确定达到或超过 %T-MIC >= 40% 的剂量和时间表。我们确定每天一次 2 g 静脉注射剂量即可达到 96% 患者的目标。该剂量的厄他培南敏感性断点 MIC 确定为 2 毫克/升。厄他培南剂量为每天一次 2 g，最适合在耐多药结核病患者的灭菌效果 II 期研究中进行测试。
Carbapenems are now being explored for treatment of multidrug-resistant tuberculosis (MDR-TB), especially in conjunction with clavulanate. Clinical use is constrained by the need for multiple parenteral doses per day and the lack of knowledge of the optimal dose for sterilizing effect. Our objective was to identify the ertapenem exposure associated with optimal sterilizing effect and then design a once-a-day dose for clinical use. We utilized the hollow-fiber system model of tuberculosis in a 28-day exposure-response study of 8 different ertapenem doses in combination with clavulanate. The systems were sampled at predetermined time points to verify the concentration-time profile and identify the total bacterial burden. Inhibitory sigmoid maximum-effect (E-max) modeling was used to identify the relationship between total bacterial burden and the drug exposure and to identify optimal exposures. Contrary to the literature, ertapenem-clavulanate combination demonstrated good microbial kill and sterilizing effect. In a dose fractionation hollow-fiber study, efficacy was linked to percentage of the 24-h dosing interval of ertapenem concentration persisting above MIC (%T-MIC). We performed 10,000 MDR-TB patient computer-aided clinical trial simulations, based on Monte Carlo methods, to identify the doses and schedule that would achieve or exceed a %T-MIC of >= 40%. We identified an intravenous dosage of 2 g once per day as achieving the target in 96% of patients. An ertapenem susceptibility breakpoint MIC of 2 mg/liter was identified for that dose. An ertapenem dosage of 2 g once daily is the most suitable to be tested in a phase II study of sterilizing effect in MDR-TB patients.