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Antimicrobial Agents and Chemotherapy, April 2009, p. 1476-1481, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01141-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Population Pharmacokinetics of High-Dose, Prolonged-Infusion Cefepime in Adult Critically Ill Patients with Ventilator-Associated Pneumonia{triangledown}

Anthony M. Nicasio,1 Robert E. Ariano,2 Sheryl A. Zelenitsky,2 Aryun Kim,1 Jared L. Crandon,1 Joseph L. Kuti,1 and David P. Nicolau1*

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut,1 Department of Pharmacy, St. Boniface General Hospital and Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada2

Received 25 August 2008/ Returned for modification 5 December 2008/ Accepted 19 January 2009

A population pharmacokinetic model of cefepime was constructed from data from adult critical care patients with ventilator-associated pneumonia (VAP). A total of 32 patients treated with high-dose cefepime, 2 g every 8 h (3-h infusion) or a renal function-adjusted equivalent dose, were randomized into two groups—26 for the initial model and 6 for model validation. Serum samples of cefepime were collected at steady state. Nonparametric adaptive grid population modeling was employed using a two-compartment Kslope pharmacokinetic model relating the elimination rate constant (K10) to renal function, as defined by creatinine clearance (CLCR), and central distribution volume (V1) to total body weight (TBW). The final model was described by the following equations: K10 = 0.0027 x CLCR + 0.071 h–1 and V1 = TBW x 0.21 liter/kg. The median intercompartmental transfer constants K12 and K21 were 0.780 h–1 and 0.472 h–1, respectively. Using these median parameter estimates, the bias, precision, and coefficient of determination for the initial model were 11.3 µg/ml, 24.0 µg/ml, and 26%, respectively. The independent validation group displayed a bias, precision, and coefficient of determination of –1.64 µg/ml, 17.1 µg/ml, and 62%, respectively. Time-concentration profiles were assessed for various dosing regimens, using 5,000-patient Monte Carlo simulations. Among the regimens, the likelihoods of 2 g every 8 h (3-h infusion) achieving free drug concentrations above the MIC for 50% of the dosing interval were 91.8%, 78.1%, and 50.3% for MICs of 8, 16, and 32 µg/ml, respectively. This study provides a pharmacokinetic model capable of predicting cefepime concentrations in critically ill patients with VAP.

* Corresponding author. Mailing address: Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102. Phone: (860) 545-3941. Fax: (860) 545-3992. E-mail: dnicola{at}harthosp.org

{triangledown} Published ahead of print on 2 February 2009.

Antimicrobial Agents and Chemotherapy, April 2009, p. 1476-1481, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01141-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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