Pharmacodynamics of meropenem and imipenem against Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa.
OBJECTIVE
To compare the pharmacodynamics of meropenem and imipenem, both administered as 500 mg every 6 hours, against populations of Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa.


METHODS
Ten thousand-subject Monte Carlo simulation.


METHODS
Variability in total body clearance (ClT), volume of distribution as calculated by the terminal elimination rate (Vdbeta), and minimum inhibitory concentration (MIC) distributions (Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, A. baumannii, P. aeruginosa) were derived from the literature for both meropenem and imipenem. For the free drug concentrations, the percentage of the dosing interval that the drug concentrations remain above the MIC (%T>MIC) for each carbapenem-bacteria combination was calculated for 10,000 iterations, substituting a different ClT, Vdbeta, fraction of unbound drug, and MIC into the equation each time based on the probability distribution for each parameter. Probabilities of attaining targets of 30%, 50%, and 100% T>MIC were calculated.


RESULTS
Meropenem free drug %T>MIC exposure was significantly greater than that of imipenem against Enterobacteriaceae and P. aeruginosa, whereas imipenem exposure was greater for A. baumannii. For both agents, free drug %T>MIC exposure was greatest against Enterobacteriaceae and less for A. baumannii and P. aeruginosa. Probabilities of target attainment for 30% and 50% T>MIC were similar between drugs for most bacteria. At 100% T>MIC, meropenem target attainments were greater than those of imipenem against Enterobacteriaceae and P. aeruginosa, and imipenem attainment was higher for A. baumannii.


CONCLUSIONS
The probability of attaining lower pharmacodynamic targets for most gram-negative bacteria is similar for these carbapenems; however, differences become apparent as the pharmacodynamic requirement increases. Further study of the benefits of achieving this pharmacodynamic breakpoint with a higher probability of attaining targets is necessary.
Kuti
Joseph L
JL
Center for Anti-Infective Research and Development, Hartford Hospital, Connecticut 06102, USA.
Florea
Naomi R
NR
Nightingale
Charles H
CH
Nicolau
David P
DP
D040981:Acinetobacter baumannii / Q000187:drug effects*; D015377:Cilastatin / Q000008:administration & dosage / Q000494:pharmacology; D018592:Cross-Over Studies; D004359:Drug Therapy, Combination; D004755:Enterobacteriaceae / Q000187:drug effects*; D006801:Humans; D015378:Imipenem / Q000008:administration & dosage / Q000494:pharmacology*; D007262:Infusions, Intravenous; D000077731:Meropenem; D008657:Metabolic Clearance Rate; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D013845:Thienamycins / Q000008:administration & dosage / Q000494:pharmacology*; D014018:Tissue Distribution
D013845:Thienamycins; D015377:Cilastatin; D015378:Imipenem; D000077731:Meropenem