JAC Advance Access originally published online on August 30, 2006
Journal of Antimicrobial Chemotherapy 2006 58(5):987-993; doi:10.1093/jac/dkl349
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Pharmacokinetic-pharmacodynamic rationale for cefepime dosing regimens in intensive care units
1 School of Pharmacy, University of Queensland Brisbane, QLD 4072, Australia 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
Received 25 May 2006; returned 5 July 2006; revised 25 July 2006; accepted 2 August 2006
*Corresponding author. Tel: +61-7-33469718; Fax: +61-7-33651688; E-mail: jroos{at}pharmacy.uq.edu.au
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.
Keywords: ß-lactams , critically ill patients , probability of target attainment
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