Abstract
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.
Highlights
Aminoglycosides such as amikacin are currently used for the treatment of multidrug-resistant tuberculosis (MDR-TB)
Since the notion that aminoglycosides do not kill under acidic conditions arose during streptomycin’s halcyon days, we explored that drug’s activity at low pH in order to see if the pH effects were the same for the entire pharmacophore
At the Middlebrook broth pH of 6.8 as measured during the experiment, the amikacin Emax was 5.39 (95% confidence interval [CI], 4.91 to 5.63) log10 CFU/ml, the Hill slope (H) was 2.96, and the EC50 was 0.99 times the MIC (r2 ϭ 0.98)
Summary
Aminoglycosides such as amikacin are currently used for the treatment of multidrug-resistant tuberculosis (MDR-TB). Formal pharmacokinetic/pharmacodynamic (PK/PD) studies to identify amikacin exposures and dosing schedules that optimize Mycobacterium tuberculosis killing have not been performed. The optimal exposures and kill rates identified for log-phase M. tuberculosis will be optimal even for semidormant bacilli. We performed exposure-response and dose-scheduling studies in the hollow-fiber system model of tuberculosis using log-phase M. tuberculosis. The aminoglycoside exposures and dose schedules associated with maximal efficacy in the treatment of MDR-TB have been unexplored. In aminoglycoside treatment of Gram-negative bacilli, the peak concentration (Cmax)-to MIC ratio were found to be linked to efficacy, which led to a revolutionary overhaul of aminoglycoside regimens and dramatic improvement in clinical outcomes [6, 7]. The identified amikacin exposures associated with maximal kill are expected to be clinically relevant to MDR-TB patients
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