title: 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 β-naphthylamide (PAβN). The intracellular minocycline concentration was determined with and without polymyxin B (0.5 μg/ml). Time-kill studies were performed over 24 h using approximately 10(6) 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). 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 PAβN. The intracellular concentration and in vitro bactericidal effect of minocycline were both enhanced by polymyxin B. With 2 minocycline-susceptible 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.
authors.affiliation: Department of Clinical Sciences and Administration, University of Houston College of Pharmacy, Houston, Texas, USA.
authors.forename: Dana R
authors.initials: DR
authors.lastname: Bowers
authors.affiliation: Department of Clinical Sciences and Administration, University of Houston College of Pharmacy, Houston, Texas, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Cao
authors.affiliation: Department of Clinical Sciences and Administration, University of Houston College of Pharmacy, Houston, Texas, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Clinical Sciences and Administration, University of Houston College of Pharmacy, Houston, Texas, USA.
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Ledesma
authors.affiliation: Rempex Pharmaceuticals, San Diego, California, USA.
authors.forename: Dongxu
authors.initials: D
authors.lastname: Sun
authors.affiliation: Rempex Pharmaceuticals, San Diego, California, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Lomovskaya
authors.affiliation: Department of Clinical Sciences and Administration, University of Houston College of Pharmacy, Houston, Texas, USA vtam@uh.edu.
authors.forename: Vincent H
authors.initials: VH
authors.lastname: Tam
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000472:pathogenicity*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D051379:Mice; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000627:therapeutic use*; D011014:Pneumonia / Q000188:drug therapy / Q000382:microbiology; D011112:Polymyxin B / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D008911:Minocycline; D011112:Polymyxin B