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 (PAN). 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 PAN. 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...
Our modeling approach appeared to be robust in assessing the effectiveness of various combinations for KPC-producing isolates. Amikacin plus doripenem was the most effective combination in both in vitro and in vivo infection models. Empirical selection of combinations against KPCs may result in antagonism and should be avoided.
While there were no significant overall differences in readmission rates between the TOC and SOC groups, hospital readmissions were reduced in the subgroup of TOC patients who received both medication history-taking and reconciliation services and phone follow-up as TOC interventions.
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