Srivastava Shashikant, Modongo Chawanga, Siyambalapitiyage Dona Chandima W, Pasipanodya Jotam G, Deshpande Devyani, Gumbo Tawanda
Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, USA.
Division of Infectious Diseases, University of Pennsylvania, Philadelphia, Pennsylvania, USA Botswana-University of Pennsylvania Partnership, Gaborone, Botswana.
Antimicrob Agents Chemother. 2016 Sep 23;60(10):5922-7. doi: 10.1128/AAC.00961-16. Print 2016 Oct.
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 (r(2) > 0.99), closely followed by the area under the concentration-time curve from 0 to 24 h (AUC0-24)-to-MIC ratio (r(2) = 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.
诸如阿米卡星之类的氨基糖苷类药物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)研究来确定能优化结核分枝杆菌杀灭效果的阿米卡星暴露量和给药方案。据信氨基糖苷类药物在酸性条件下效果不佳,如果真是这样,那就意味着在低pH值下对半休眠杆菌的杀菌活性较差。我们进行了时间杀灭研究,以比较阿米卡星在对数生长期细菌中的杀菌效果与在肉汤中pH值为5.8时对半休眠细菌的杀菌效果。在正常pH值下的对数期结核分枝杆菌与pH值为5.8时的半休眠结核分枝杆菌中,最大杀灭量(Emax)估计值及95%置信区间(CI)分别为5.39(95%CI,4.91至5.63)log10CFU/ml对4.88(CI,4.46至5.22)log10CFU/ml,而介导50%Emax的浓度(EC50)分别为MIC的1.0(CI,0.86至1.12)倍对0.60(CI,0.50至0.66)倍。因此,为对数期结核分枝杆菌确定的最佳暴露量和杀灭率对半休眠杆菌也是最佳的。接下来,我们在结核病中空纤维系统模型中使用对数期结核分枝杆菌进行了暴露-反应和给药方案研究。我们重现了接受28天治疗的患者肺部观察到的阿米卡星浓度-时间曲线。与结核分枝杆菌杀灭相关的PK/PD指数是峰浓度(Cmax)与MIC之比(r(2)>0.99),紧随其后的是0至24小时浓度-时间曲线下面积(AUC0-24)与MIC之比(r(2)=0.98)。EC90是Cmax/MIC比为10.13(95%CI,7.73至12.48)。EC90是优化耐多药结核病患者结核病治疗方案中治愈效果的间歇治疗给药目标。