JAC Advance Access published online on August 30, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl349
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1 School of Pharmacy, University of Queensland, Brisbane, QLD 4072, Australia
* To whom correspondence should be addressed. Objectives: (i) To develop a population pharmacokinetics (PK) model for cefepime in patients in intensive care units (ICUs). (ii) To assess the pharmacokinetic-pharmacodynamic profile of various cefepime dosing regimens and to assess their expected probability of target attainment (= PTA expectation value) against common ICU pathogens such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii. Methods: Thirteen ICU patients received cefepime 2 g 12 hourly intravenous (3 min). Twelve blood samples were taken on two occasions: (i) immediately after initial dose; and (ii) between days 3 and 6 after starting therapy. Population PK models were developed using NONMEM. Based on the final covariate model, Monte Carlo simulations were undertaken (n = 1000) to simulate free-drug concentrations of cefepime for two administration methods: (i) intermittent bolus administration (IBA); and (ii) continuous infusion (CI). Concentration-time profiles were evaluated by the probability of achieving free-drug concentration above the MIC for >65% of the dosing interval. Finally, using local MIC distributions of E. coli, K. pneumoniae, P. aeruginosa and A. baumannii the PTA expectation values for each dosing administration method were evaluated. Results: A three-compartment model with zero-order input best described the concentration-time data. The PTA expectation values for E. coli and K. pneumoniae were >90% in all CI doses but only when administered as 1 g every 6 h and higher daily doses for IBA. For the current treatment protocol, 2 g every 12 h, P. aeruginosa and A. baumannii achieved target concentrations of only 54% and 28%, respectively. For P. aeruginosa, a CI of at least 4 g/day was required to achieve a PTA expectation value >90% while for A. baumannii a 6 g/day CI only achieved a PTA expectation value of 75%. Conclusions: When given as IBA or CI for E. coli and K. pneumoniae, cefepime should be successful in achieving the bactericidal target. For P. aeruginosa higher doses of cefepime (>4 g/day) are required to achieve the required PTA expectation value. Cefepime fails to achieve the bactericidal target even when administered at high doses, e.g. 6 g/day, for A. baumannii.
Received May 25, 2006
Revised July 25, 2006
Accepted August 2, 2006
Original article
Pharmacokinetic-pharmacodynamic rationale for cefepime dosing regimens in intensive care units
Juliana F. Roos 1 *, Jurgen Bulitta 2, Jeffrey Lipman 3, and Carl M. J. Kirkpatrick 1
2 IBMP--Institute for Biomedical and Pharmaceutical Research, Paul-Ehrlich-Strasse, 19 D-90562 Heroldsberg, Nürnberg, Germany
3 Anaesthesiology and Critical Care, University of Queensland and Department of Intensive Care Medicine, Royal Brisbane Hospital, Brisbane, QLD 4029, Australia
Juliana F. Roos, E-mail: jroos{at}pharmacy.uq.edu.au
Abstract 
-lactams; critically ill patients; probability of target attainment.
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