Pharmacokinetic-pharmacodynamic rationale for cefepime dosing regimens in intensive care units

Roos, Juliana F., Bulitta, Jurgen, Lipman, Jeffrey and Kirkpatrick, Carl M. J. (2006) Pharmacokinetic-pharmacodynamic rationale for cefepime dosing regimens in intensive care units. Journal of Antimicrobial Chemotherapy, 58 5: 987-993. doi:10.1093/jac/dkl349

Author Roos, Juliana F.
Bulitta, Jurgen
Lipman, Jeffrey
Kirkpatrick, Carl M. J.
Title Pharmacokinetic-pharmacodynamic rationale for cefepime dosing regimens in intensive care units
Journal name Journal of Antimicrobial Chemotherapy   Check publisher's open access policy
ISSN 0305-7453
Publication date 2006
Sub-type Article (original research)
DOI 10.1093/jac/dkl349
Volume 58
Issue 5
Start page 987
End page 993
Total pages 7
Editor Alan P. Johnson
Place of publication Oxford, England
Publisher Oxford Univ Press
Collection year 2006
Language eng
Subject C1
320503 Clinical Pharmacology and Therapeutics
730101 Infectious diseases
Formatted abstract
(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.

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.


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 Cl only achieved a PTA expectation value of 75%.


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.
Keyword Beta-lactams
Critically Ill Patients
Probability Of Target Attainment
Infectious Diseases
Pharmacology & Pharmacy
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

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Created: Wed, 15 Aug 2007, 09:45:58 EST