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Int J Antimicrob Agents. 2016 Dec;48(6):719-724. doi: 10.1016/j.ijantimicag.2016.07.024. Epub 2016 Sep 20.

Comparative pharmacodynamics of four different carbapenems in combination with polymyxin B against carbapenem-resistant Acinetobacter baumannii.

Author information

1
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.
2
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.
3
Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida.
4
Division of Infectious Diseases and Tropical Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
5
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
6
Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
7
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.

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 106 CFU/mL and 108 CFU/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 (Cmax concentrations 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 log10 CFU/mL reduction by 4 h against both strains at 106 CFU/mL, whereas maximum reductions against strain 03-149-1 at 108 CFU/mL were 1.0, 3.2, 2.2 and 3.3 log10 CFU/mL for ertapenem, doripenem, meropenem and imipenem, respectively. None of the combinations were capable of reducing 108 CFU/mL of N16870 by ≥2 log10 CFU/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.

KEYWORDS:

Acinetobacter baumannii; Carbapenem resistance; Polymyxins

PMID:
27773498
PMCID:
PMC5237376
DOI:
10.1016/j.ijantimicag.2016.07.024
[Indexed for MEDLINE]
Free PMC Article

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