title: Comparative pharmacodynamics of four different carbapenems in combination with polymyxin B against carbapenem-resistant Acinetobacter baumannii.
abstract: The objective of this study was to determine the comparative pharmacodynamics of four different carbapenems in combination with polymyxin B (PMB) against carbapenem-resistant Acinetobacter baumannii isolates using time-kill experiments at two different inocula. Two A. baumannii strains (03-149-1 and N16870) with carbapenem minimum inhibitory concentrations (MICs) ranging from 8 to 64 mg/L were investigated in 48-h time-kill experiments using starting inocula of 106CFU/mL and 108CFU/mL. Concentration arrays of ertapenem, doripenem, meropenem and imipenem at 0.25×, 0.5×, 1×, 1.5× and 2× published maximum serum concentration (Cmax) values (Cmaxconcentrations of 12, 21, 48 and 60 mg/L, respectively) were investigated in the presence of 1.5 mg/L PMB. Use of carbapenems without PMB resulted in drastic re-growth. All carbapenem combinations were able to achieve a ≥3 log10CFU/mL reduction by 4 h against both strains at 106CFU/mL, whereas maximum reductions against strain 03-149-1 at 108CFU/mL were 1.0, 3.2, 2.2 and 3.3 log10CFU/mL for ertapenem, doripenem, meropenem and imipenem, respectively. None of the combinations were capable of reducing 108CFU/mL of N16870 by ≥2 log10CFU/mL. Ertapenem combinations consistently displayed the least activity, whereas doripenem, meropenem and imipenem combinations had similar activities that were poorly predicted by carbapenem MICs. As doripenem, meropenem, or imipenem displayed similar pharmacodyanmics in combination, the decision of which carbapenem to use in combination with PMB may be based on toxicodynamic profiles if drastic discordance in MICs is not present.
authors: Laboratory for Antimicrobial Pharmacodynamics, NYS Center of Excellence in Bioinformatics & Life Sciences, Buffalo, NY, USA; School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA; California Northstate University College of Pharmacy.
authors: Justin R
authors: JR
authors: Lenhard
authors: Laboratory for Antimicrobial Pharmacodynamics, NYS Center of Excellence in Bioinformatics & Life Sciences, Buffalo, NY, USA; School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA.
authors: Jonathan S
authors: JS
authors: Gall
authors: Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida.
authors: Jurgen B
authors: JB
authors: Bulitta
authors: Division of Infectious Diseases and Tropical Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors: Visanu
authors: V
authors: Thamlikitkul
authors: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors: Cornelia B
authors: CB
authors: Landersdorfer
authors: Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
authors: Alan
authors: A
authors: Forrest
authors: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors: Roger L
authors: RL
authors: Nation
authors: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors: Jian
authors: J
authors: Li
authors: Laboratory for Antimicrobial Pharmacodynamics, NYS Center of Excellence in Bioinformatics & Life Sciences, Buffalo, NY, USA; School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA. Electronic address: btsuji@buffalo.edu.
authors: Brian T
authors: BT
authors: Tsuji
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015780:Carbapenems / Q000494:pharmacology*; D004347:Drug Interactions; D008826:Microbial Sensitivity Tests; D011112:Polymyxin B / Q000494:pharmacology*; D018440:beta-Lactam Resistance
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D011112:Polymyxin B
keywords: Acinetobacter baumannii; Carbapenem resistance; Polymyxins