Ethambutol Optimal Clinical Dose and Susceptibility Breakpoint Identification by Use of a Novel Pharmacokinetic-Pharmacodynamic Model of Disseminated Intracellular Mycobacterium avium

摘要

Ethambutol, together with a macrolide, is the backbone for treatment of disseminated Mycobacterium avium disease. However, at the standard dose of 15 mg/kg of body weight/day, ethambutol efficacy is limited. In addition, susceptibility breakpoints have consistently failed to predict clinical outcome. We performed dose-effect studies with extracellular M. avium as well as with bacilli within human macrophages. The maximal kill rate (Emax) for ethambutol against extracellular bacilli was 5.54 log10 CFU/ml, compared to 0.67 log10 CFU/ml for intracellular M. avium, after 7 days of exposure. Thus, extracellular assays demonstrated high efficacy. We created a hollow-fiber system model of intracellular M. avium and performed microbial pharmacokinetic-pharmacodynamic studies using pharmacokinetics similar to those of ethambutol for humans. The Emax in the systems was 0.79 log10 CFU/ml with 7 days of daily therapy, so the kill rates approximated those encountered in patients treated with ethambutol monotherapy. Ratio of peak concentration to MIC (Cmax/MIC) was linked to microbial kill rate. The Cmax/MIC ratio needed to achieve the 90% effective concentration (EC90) in serum was 1.23, with a calculated intramacrophage Cmax/MIC ratio of 13. In 10,000 patient Monte Carlo simulations, doses of 15, 50, and 75 mg/kg achieved the EC90 in 35.50%, 76.81%, and 86.12% of patients, respectively. Therefore, ethambutol doses of ≥50 mg/kg twice a week would be predicted to be better than current doses of 15 mg/kg for treatment of disseminated M. avium disease. New susceptibility breakpoints and critical concentrations of 1 to 2 mg/liter were identified for the determination of ethambutol-resistant M. avium in Middlebrook broth. Given that the modal MIC of clinical isolates is around 2 mg/liter, most isolates should be considered ethambutol resistant.