Amikacin Optimal Exposure Targets in the Hollow-Fiber System Model of Tuberculosis.
Amikacin Optimal Exposure Targets in the Hollow-Fiber System Model of Tuberculosis.
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DOI：
10.1128/aac.00961-16
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发表时间：
2016-10
影响因子：
4.9
通讯作者：
Gumbo T
中科院分区：
文献类型：
--
作者：
Srivastava S;Modongo C;Siyambalapitiyage Dona CW;Pasipanodya JG;Deshpande D;Gumbo T
氨基糖苷类药物如阿米卡星目前用于治疗耐多药结核病（MDR-TB）。然而，尚未进行正式的药代动力学/药效学（PK/PD）研究，以确定优化结核分枝杆菌杀灭的阿米卡星暴露和给药方案。据信，氨基糖苷类不工作，以及在酸性条件下，如果是真的，这将意味着在低pH值下对semidorbacilli杀菌活性差。我们进行了时间杀菌研究，比较丁胺卡那霉素的杀菌效果在对数生长期的细菌与杀菌效果在semidorbacilli在pH 5.8的肉汤。在对数相M.结核病在正常pH值与半重度M。在pH 5.8的条件下，最大杀灭（Emax）估计值和95%置信区间（CI）分别为5.39（95% CI，4.91至5.63）和4.88（CI，4.46至5.22）log 10 CFU/ml，而介导50% Emax的浓度（EC 50）为1.0（CI，0. 0.86至1.12）与0.60（CI，0.50至0.66）倍的MIC。因此，确定了对数期M.结核病甚至对于半分枝杆菌也是最佳的。接下来，我们使用对数相M在结核病的中空纤维系统模型中进行了预防-反应和剂量调度研究。结核我们概括了阿米卡星的浓度-时间曲线观察到的患者的肺部治疗超过28天。与M.结核杆菌杀灭率的最大值是峰浓度（Cmax）与MIC之比（r2 > 0.99），紧随其后的是0 - 24 h浓度-时间曲线下面积（AUC 0 -24）与MIC之比（r2 = 0.98）。EC 90的Cmax/MIC比值为10.13（95% CI，7.73 - 12.48）。EC 90是间歇治疗的剂量目标，可优化耐多药结核病患者的结核病治疗方案。
Aminoglycosides such as amikacin are currently used for the treatment of multidrug-resistant tuberculosis (MDR-TB). However, formal pharmacokinetic/pharmacodynamic (PK/PD) studies to identify amikacin exposures and dosing schedules that optimize Mycobacterium tuberculosis killing have not been performed. It is believed that aminoglycosides do not work well under acidic conditions, which, if true, would mean poor sterilizing activity against semidormant bacilli at low pH. We performed time-kill studies to compare the bactericidal effect of amikacin in log-phase-growth bacilli with the sterilizing effect in semidormant bacilli at pH 5.8 in broth. In log-phase M. tuberculosis at normal pH versus semidormant M. tuberculosis at pH 5.8, the maximal kill (Emax) estimate and 95% confidence interval (CI) were 5.39 (95% CI, 4.91 to 5.63) versus 4.88 (CI, 4.46 to 5.22) log10 CFU/ml, while the concentration mediating 50% of Emax (EC50) was 1.0 (CI, 0. 0.86 to 1.12) versus 0.60 (CI, 0.50 to 0.66) times the MIC, respectively. Thus, the optimal exposures and kill rates identified for log-phase M. tuberculosis will be optimal even for semidormant bacilli. Next, we performed exposure-response and dose-scheduling studies in the hollow-fiber system model of tuberculosis using log-phase M. tuberculosis. We recapitulated the amikacin concentration-time profiles observed in lungs of patients treated over 28 days. The PK/PD index linked to M. tuberculosis kill was the peak concentration (Cmax)-to-MIC ratio (r2 > 0.99), closely followed by the area under the concentration-time curve from 0 to 24 h (AUC0–24)-to-MIC ratio (r2 = 0.98). The EC90 was a Cmax/MIC ratio of 10.13 (95% CI, 7.73 to 12.48). The EC90 is the dosing target for intermittent therapy that optimizes cure in TB programs for MDR-TB patients.