Assessment of Minocycline and Polymyxin B Combination against Acinetobacter baumannii

ABSTRACT

Antimicrobial resistance among Acinetobacter baumannii is increasing worldwide, often necessitating combination therapy. The clinical utility of using minocycline with polymyxin B is not well established. In this study, we investigated the activity of minocycline and polymyxin B against 1 laboratory and 3 clinical isolates of A. baumannii. Minocycline susceptibility was performed with and without an efflux pump inhibitor, phenylalanine-arginine β-naphthylamide (PAβN). Intracellular minocycline concentration was determined with and without polymyxin B (0.5 μg/ml). Time-kill studies were performed over 24h using approximately 10⁶ CFU/mL of each strain with clinically relevant minocycline concentrations (2 μg/ml and 8 μg/ml), with and without polymyxin B (0.5 μg/ml). In vivo efficacy of the combination was assessed in a neutropenic murine pneumonia model. Infected animals were administered minocycline (50 mg/kg), polymyxin B (10 mg/kg) or both to achieve clinically equivalent exposures in humans. Reduction in minocycline MIC (≥ 4x) was observed in the presence of PAβN. Intracellular concentration and in vitro bactericidal effect of minocycline were both enhanced by polymyxin B. In 2 minocycline-susceptible strains, bacterial burden in lung tissue at 24h was considerably reduced by the combination group compared to monotherapy of minocycline or polymyxin B. In addition, the combination prolonged survival of animals infected with a minocycline-susceptible strain. Polymyxin B increased intracellular concentration of minocycline in bacterial cells and enhanced the bactericidal activity of minocycline, presumably due to efflux pump disruption. The clinical utility of this combination should be further investigated.