Amikacin optimal exposures targets in the hollow fiber system model of tuberculosis.
Tawanda Gumbo M.D.
Srivastava, S., C. Modongo, C. W. Siyambalapitiyage Dona, J. G. Pasipanodya, D. Deshpande and T. Gumbo (2016). “Amikacin optimal exposures targets in the hollow fiber system model of tuberculosis.” Antimicrob Agents Chemother: 2016 Jul [Epub ahead of print].
Aminoglycosides such as amikacin are currently used for the treatment of multidrug-resistant tuberculosis (MDR-TB). However, formal pharmacokinetic/pharmacodynamics (PK/PD) studies to identify amikacin exposures and dosing schedules that optimize Mycobacterium tuberculosis (Mtb) killing have not been performed. It is believed that aminoglycosides do not work well under acidic conditions, which if true would mean poor sterilizing effect activity against semidormant bacilli at low pH. We performed time kill studies to compare the bactericidal effect of amikacin in log-phase growth bacilli versus sterilizing effect in semidormant bacilli at pH 5.8 in broth. In log-phase growth Mtb at normal pH versus semidormant Mtb at pH 5.8, the maximal kill (Emax) estimate and 95% confidence intervals (CI) were 5.39 (95% CI: 4.91-5.63) versus 4.88 (CI: 4.46-5.22) log10 CFU/mL, while the concentration mediating 50% of Emax (EC50) was 1.0 (CI: 0. 0.86-1.12) versus 0.60 (CI: 0.50-0.66) times MIC, respectively. Thus, the optimal exposures and kill rates identified for log-phase growth Mtb 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 growth Mtb. We recapitulated amikacin concentration-time profiles observed in lungs of patients treated over 28 days. The PK/PD index linked to Mtb kill was peak concentration (Cmax)-to-MIC ratio (r2>0.99), closely followed by the 0-24hour area under the concentration-time curve (AUC0-24)-to-MIC ratio (r2=0.98). The EC90 was a Cmax/MIC of 10.13 (95% CI: 7.73-12.48). The EC90 is the dosing target for intermittent therapy that optimizes cure in TB Programs for MDR-TB patients.