Antibacterial action of penicillin against Mycobacterium avium complex

Abstract

<sec><title>INTRODUCTION</title>β-lactam antibiotics are promising treatments for Mycobacterium avium complex (MAC) lung disease. We hypothesized that benzylpenicillin has efficacy against MAC.</sec><sec><title>METHODS</title>Benzylpenicillin lung concentration–time profiles of seven doses in three dosing schedules were administered for 28 days using the hollow fiber system model of intracellular MAC (HFS-MAC). Data were analyzed using the inhibitory sigmoid maximal effect (Emax) model for each sampling day, while two ordinary differential equations (ODEs) were used for the wild-type and penicillin-resistant mutants.</sec><sec><title>RESULTS</title>Benzylpenicillin killed >2.1 log10 colony-forming unit (CFU)/mL below Day 0, better than azithromycin, ethambutol, and rifabutin. Efficacy was terminated by acquired resistance. Sigmoid Emax parameter estimates significantly differed between sampling days and were a poor fit. However, ODE model parameter estimates vs. exposure were a better fit. The exposure mediating Emax was 84.6% (95% CI 76.91–82.98) of time concentration exceeded the minimum inhibitory concentration (MIC). In Monte Carlo experiments, 24 million international units of benzylpenicillin continuous infusion achieved the target exposure in lungs of >90% of 10,000 subjects until an MIC of 64 mg/L, designated the susceptibility breakpoint.</sec><sec><title>CONCLUSIONS</title>Benzylpenicillin demonstrated a better bactericidal effect against MAC than guideline-recommended drugs before the development of resistance. Its role in combination therapy with other drugs with better efficacy than guideline-recommended drugs should be explored.</sec>