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 isolate and 3 clinical isolates of A. baumannii. Minocycline susceptibility testing was performed with and without an efflux pump inhibitor, phenylalanine-arginine ␤-naphthylamide (PA␤N). The intracellular minocycline concentration was determined with and without polymyxin B (0.5 g/ml). Time-kill studies were performed over 24 h using approximately 10 6 CFU/ml of each strain with clinically relevant minocycline concentrations (2 g/ml and 8 g/ml), with and without polymyxin B (0.5 g/ml). The 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. A reduction in the minocycline MIC (>4؋) was observed in the presence of PA␤N. The intracellular concentration and in vitro bactericidal effect of minocycline were both enhanced by polymyxin B. With 2 minocyclinesusceptible strains, the bacterial burden in lung tissue at 24 h was considerably reduced by the combination compared to monotherapy with minocycline or polymyxin B. In addition, the combination prolonged survival of animals infected with a minocycline-susceptible strain. Polymyxin B increased the 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.A cinetobacter baumannii is a common nosocomial pathogen globally which has been implicated as an etiologic agent in ventilator-associated pneumonia, skin and skin structure infections (traumatic battlefield and other wounds), urinary tract infections, meningitis, and bacteremia (1). Over the past decades, infections due to increasingly resistant strains of Acinetobacter have emerged (2, 3). This is particularly alarming because there are very limited therapeutic options for these infections (4, 5). Multidrug-resistant strains of A. baumannii have been reported to adversely affect patient outcomes. Studies have found significantly higher rates of hospital mortality in patients infected with multidrug-resistant strains than in patients with susceptible strains (6, 7).Current treatment strategies for multidrug-resistant A. baumannii include combination therapy with tigecycline, minocycline, carbapenems, polymyxins, and even daptomycin (8-11). However, the rationale of using certain agents together in a combination is not well established. In this study, the combination of minocycline and polymyxin B was studied based on a mechanistically plausible approach. Resistance to the tetracycline class in A. baumannii is commonly mediated through the upregulation of efflux pumps loca...

Pharmacokinetics and Pharmacodynamics of Minocycline against Acinetobacter baumannii in a Neutropenic Murine Pneumonia Model

“…After being reconstituted with 1 ml of 50% methanol, 5-l portions of the samples were injected into the ultraperformance liquid chromatography (UPLC) system. The conditions and parameters of LC-MS/MS were described previously (9). The linear range of quantification was 0.0625 to 128 mg/liter.…”

“…For reference, there was a placebo (i.e., no-treatment) control group for each bacterial isolate. The bacterial burdens in lung tissues were determined at 0 h (baseline) and 24 h after the first dose of minocycline as described elsewhere (9,19). Briefly, after the animals were sacrificed by CO 2 asphyxiation, the lung tissues were harvested and homogenized in sterile saline.…”

“…A neutropenic murine pneumonia model was used to examine the in vivo bactericidal activity of minocycline. The experimental setup was as previously described (9,18). Briefly, female Swiss Webster mice between 20 and 25 g (Harlan, Indianapolis, IN) were rendered neutropenic by two doses of intraperitoneal cyclophosphamide prior to the experiment (150 mg/kg on day Ϫ4 and 100 mg/kg on day Ϫ1).…”

The New Metall-Beta-Lactamase’s Inhibitor Efficacy in a Model System in Vitro

“…К сожалению, в настоящее время ин-гибиторов МБЛ карбапенемрезистентных ми-кроорганизмов, разрешенных для применения в клинике, нет. Лечение таких нозокомиальных инфекций традиционными схемами неэффек-тивно; для терапии, как правило, подбирают комбинации антибиотиков из 2-3, а иногда и 4-х препаратов [22,26,29,33,36,37].…”

Correlation of Checkerboard Synergy Testing with Time-Kill Analysis and Clinical Outcomes of Extensively Drug-Resistant Acinetobacter baumannii Respiratory Infections

“…Additionally, minocycline-colistin was the only combination to have a bactericidal effect against all of the isolates tested by time-kill analysis. It is thought that polymyxins disrupt the efflux pumps, and therefore, an increased intracellular concentration of minocycline is obtained, leading to a synergistic interaction (15). Unfortunately, few of our patients received minocycline-colistin to treat an A. baumannii infection during this time period.…”