title: Polymyxin B in Combination with Rifampin and Meropenem against Polymyxin B-Resistant KPC-Producing Klebsiella pneumoniae.
abstract: Safe and effective therapies are urgently needed to treat polymyxin-resistant KPC-producing Klebsiella pneumoniae infections and suppress the emergence of resistance. We investigated the pharmacodynamics of polymyxin B, rifampin, and meropenem alone and as polymyxin B-based double and triple combinations against KPC-producing K. pneumoniae isolates. The rates and extents of killing with polymyxin B (1 to 128 mg/liter), rifampin (2 to 16 mg/liter), and meropenem (10 to 120 mg/liter) were evaluated against polymyxin B-susceptible (PBs) and polymyxin B-resistant (PBr) clinical isolates using 48-h static time-kill studies. Additionally, humanized triple-drug regimens of polymyxin B (concentration at steady state [Css] values of 0.5, 1, and 2 mg/liter), 600 mg rifampin every 12 or 8 h, and 1 or 2 g meropenem every 8 h dosed as an extended 3-h infusion were simulated over 48 h by using a one-compartment in vitro dynamic infection model. Serial bacterial counts were performed to quantify the pharmacodynamic effect. Population analysis profiles (PAPs) were used to assess the emergence of polymyxin B resistance. Monotherapy was ineffective against both isolates. Polymyxin B with rifampin demonstrated early bactericidal activity against the PBsisolate, followed by regrowth by 48 h. Bactericidal activity was sustained at all polymyxin B concentrations of ≥2 mg/liter in combination with meropenem. No two-drug combinations were effective against the PBrisolate, but all simulated triple-drug regimens showed early bactericidal activity against both strains by 8 h that was sustained over 48 h. PAPs did not reveal the emergence of resistant subpopulations. The triple-drug combination of polymyxin B, rifampin, and meropenem may be a viable consideration for the treatment of PBrKPC-producing K. pneumoniae infections. Further investigation is warranted to optimize triple-combination therapy.
authors.affiliation: Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo-State University of New York, Buffalo, New York, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Diep
authors.affiliation: Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo-State University of New York, Buffalo, New York, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Jacobs
authors.affiliation: Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo-State University of New York, Buffalo, New York, USA.
authors.forename: Rajnikant
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo-State University of New York, Buffalo, New York, USA.
authors.forename: Jenna
authors.initials: J
authors.lastname: Covelli
authors.affiliation: Kingman Regional Medical Center, Kingman, Arizona, USA.
authors.forename: Dana R
authors.initials: DR
authors.lastname: Bowers
authors.affiliation: Department of Medicine, Department of Microbiology and Immunology, The Witebsky Center for Microbial Pathogenesis, University at Buffalo-State University of New York, and Veterans Administration Western New York Healthcare System, Buffalo, New York, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Russo
authors.affiliation: Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo-State University of New York, Buffalo, New York, USA gaurirao@live.unc.edu.
authors.forename: Gauri G
authors.initials: GG
authors.lastname: Rao
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D011112:Polymyxin B / Q000494:pharmacology*; D012293:Rifampin / Q000494:pharmacology*; D013845:Thienamycins / Q000494:pharmacology*; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D001618:beta-Lactamases; D000077731:Meropenem; D011112:Polymyxin B; D012293:Rifampin
keywords: Klebsiella pneumoniae; carbapenemase; pharmacodynamics; polymyxin B; triple combination