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Antimicrobial Agents and Chemotherapy, October 2009, p. 4483-4489, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00430-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Population Pharmacokinetics of Ceftazidime in Intensive Care Unit Patients: Influence of Glomerular Filtration Rate, Mechanical Ventilation, and Reason for Admission

Bernard Georges,^1,3 Jean-Marie Conil,^1,3 Thierry Seguin,^1,3 Stéphanie Ruiz,^1,3 Vincent Minville,^1,3 Pierre Cougot,¹ Jean-François Decun,¹ Hélène Gonzalez,¹ Georges Houin,² Olivier Fourcade,^1,3 and Sylvie Saivin^2,3*

Anesthésie Réanimation, CHU Rangueil, TSA 50032, 31059 Toulouse, France,¹ Laboratoire de Pharmacocinétique et Toxicologie Clinique, Institut Fédératif de Biologie, 330 Avenue de Grande Bretagne, TSA 40031, 31059 Toulouse Cedex 9, France,² GRCB 48, IFR 31, Institut Louis Bugnard, CHU Rangueil, TSA 50032, 31059 Toulouse, France³

Received 30 March 2009/ Returned for modification 10 June 2009/ Accepted 15 July 2009

The aim of this study was to develop a population-pharmacokinetic model of ceftazidime in intensive care unit patients to include the influence of patients' characteristics on the pharmacokinetics. Forty-nine patients for model building and 23 patients for validation were included in a randomized study. They received ceftazidime at 2 g three times a day or as 6 g per day continuously. A NONMEM pharmacokinetic model was constructed, and the influences of covariates were studied. The model was validated by a comparison of the predicted and observed concentrations. A final model was elaborated from the whole population. Total clearance (CL) was significantly correlated with the glomerular filtration rate (GFR) calculated by modification of the diet in renal disease (MDRD), the central volume of distribution (V1) with intubation, and the peripheral volume of distribution (V2) with the reason for admission. The mean pharmacokinetic parameters were as follows: CL, 5.48 liters/h, 40%; V1, 10.48 liters, 34%; V2, 32.12 liters, 59%; total volume, 42.60 liters, 45%; and intercompartmental clearance, 16.19 liters/h, 42%. In the polytrauma population (mechanically ventilated), the time above the MIC at steady state never corresponds to 100% for discontinuous administration, and the target concentration of five times the MIC was reached with a 6-g/day dose only for patients with an MDRD of <150 ml/min. We showed that the GFR-MDRD, mechanical ventilation, and the reason for admission may influence the achieved concentrations of ceftazidime. Our model allows the a priori dosing to be adjusted to the individual patient.

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* Corresponding author. Mailing address: Laboratoire de Pharmacocinétique et Toxicologie Clinique, Institut Fédératif de Biologie, 330 Avenue de Grande Bretagne, TSA 40031, 31059 Toulouse Cedex 9, France. Phone: 33 5 67 69 03 67. Fax: 33 5 67 69 03 84. E-mail: saivin.s{at}chu-toulouse.fr

Published ahead of print on 27 July 2009.

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Antimicrobial Agents and Chemotherapy, October 2009, p. 4483-4489, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00430-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.