title: Polymyxin B in combination with meropenem against carbapenemase-producing Klebsiella pneumoniae: pharmacodynamics and morphological changes.
abstract: Combination therapy provides a useful therapeutic approach to overcome resistance until new antibiotics become available. In this study, the pharmacodynamics, including the morphological effects, of polymyxin B (PMB) and meropenem alone and in combination against KPC-producing Klebsiella pneumoniae clinical isolates was examined. Ten clinical isolates were obtained from patients undergoing treatment for mediastinitis. KPCs were identified and MICs were measured using microbroth dilution. Time-kill studies were conducted over 24 h with PMB (0.5-16 mg/L) and meropenem (20-120 mg/L) alone or in combination against an initial inoculum of ca. 106CFU/mL. Scanning electron microscopy (SEM) was employed to analyse changes in bacterial morphology after treatment, and the log change method was used to quantify the pharmacodynamic effect. All isolates harboured the blaKPC-2gene and were resistant to meropenem (MICs ≥8 mg/L). Clinically relevant PMB concentrations (0.5, 1.0 and 2.0 mg/L) in combination with meropenem were synergistic against all isolates except BRKP28 (polymyxin- and meropenem-resistant, both MICs >128 mg/L). All PMB and meropenem concentrations in combination were bactericidal against polymyxin-susceptible isolates with meropenem MICs ≤16 mg/L. SEM revealed extensive morphological changes following treatment with PMB in combination with meropenem compared with the changes observed with each individual agent. Additionally, morphological changes decreased with increasing resistance profiles of the isolate, i.e. increasing meropenem MIC. These antimicrobial effects may not only be a summation of the effects due to each antibiotic but also a result of differential action that likely inhibits protective mechanisms in bacteria.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA.
authors.forename: Rajnikant
authors.initials: R
authors.lastname: Sharma
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA.
authors.forename: Saloni
authors.initials: S
authors.lastname: Patel
authors.affiliation: Instituto Dante Pazzanese de Cardiologia, São Paulo, Brazil.
authors.forename: Cely
authors.initials: C
authors.lastname: Abboud
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA.
authors.forename: John
authors.initials: J
authors.lastname: Diep
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA.
authors.forename: Neang S
authors.initials: NS
authors.lastname: Ly
authors.affiliation: Division of Infectious Diseases, Detroit Medical Center, Wayne State University, Detroit, MI, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Pogue
authors.affiliation: Division of Infectious Diseases, Detroit Medical Center, Wayne State University, Detroit, MI, USA.
authors.forename: Keith S
authors.initials: KS
authors.lastname: Kaye
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Vic, Australia.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA. Electronic address: gaurirao@ad.unc.edu.
authors.forename: Gauri G
authors.initials: GG
authors.lastname: Rao
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015780:Carbapenems / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D007710:Klebsiella Infections / Q000382:microbiology*; D007711:Klebsiella pneumoniae / Q000166:cytology / Q000187:drug effects* / Q000302:isolation & purification; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D008855:Microscopy, Electron, Scanning; D011112:Polymyxin B / Q000494:pharmacology*; D013845:Thienamycins / Q000494:pharmacology*; D018440:beta-Lactam Resistance
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D013845:Thienamycins; D000077731:Meropenem; D011112:Polymyxin B
keywords: Combination; KPC carbapenemase; Klebsiella pneumoniae; Meropenem; Pharmacodynamics; Polymyxin B