Author:
Srivastava Shashikant,Modongo Chawanga,Siyambalapitiyage Dona Chandima W.,Pasipanodya Jotam G.,Deshpande Devyani,Gumbo Tawanda
Abstract
ABSTRACTAminoglycosides 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 optimizeMycobacterium tuberculosiskilling 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-phaseM. tuberculosisat normal pH versus semidormantM. tuberculosisat 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) log10CFU/ml, while the concentration mediating 50% ofEmax(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-phaseM. tuberculosiswill 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-phaseM. tuberculosis. We recapitulated the amikacin concentration-time profiles observed in lungs of patients treated over 28 days. The PK/PD index linked toM. tuberculosiskill 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 EC90was aCmax/MIC ratio of 10.13 (95% CI, 7.73 to 12.48). The EC90is the dosing target for intermittent therapy that optimizes cure in TB programs for MDR-TB patients.
Funder
HHS | National Institutes of Health (NIH)
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
31 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献