JAC Advance Access originally published online on December 21, 2006
Journal of Antimicrobial Chemotherapy 2007 59(2):277-284; doi:10.1093/jac/dkl485
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Ertapenem in critically ill patients with early-onset ventilator-associated pneumonia: pharmacokinetics with special consideration of free-drug concentration
1 Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, USA 2 Department of Pulmonary Medicine, Medical School Hannover, Hannover, Germany 3 Department of Pulmonary and Critical Care Medicine, University Otto-von-Guericke, Magdeburg, Germany 4 Department of Clinical Pharmacology, University Rostock, Rostock, Germany
Received 1 July 2006; returned 31 August 2006; revised 5 September 2006; accepted 3 November 2006
* Corresponding author. Tel: +49-511-532-3661; Fax: +49-511-532-3353; E-mail: burkhardt.olaf{at}mh-hannover.de
OBJECTIVES: Most information about pharmacokinetics of antimicrobial agents is obtained from studies in healthy volunteers. However, antibiotics are therapeutically used in infected patients with very different pharmacokinetic properties compared with healthy individuals.
PATIENTS AND METHODS: In a single-centre, prospective, open-label study, 17 adult critically ill patients with early-onset ventilator-associated pneumonia (VAP) were treated with 1 g of ertapenem infusion once a day. Blood and urine samples were collected before and at different time-points up to 24 h after medication on day 1. Concentrations of ertapenem in plasma were determined with a validated HPLC method. Free-drug concentrations were estimated using a two-class binding site equation.
RESULTS: The overall clinical success rate of the assessable cases was 66.7% (12/16). Pharmacokinetic parameters of ertapenem in our critically ill patients were clearly different when compared to those reported in the literature for healthy volunteers. The enhanced Vz (17 vs. 8 L) and CLTOT (43 vs. 20 mL/min) with resulting lower Cmax (90 vs. 253 mg/L) and AUC0–
(418 vs. 817 mg · h/L) values were mainly related to hypoalbuminaemia (range 9.2–25.6 g/L) in our patient population. A population pharmacokinetic analysis using the NONMEM program indicated creatinine clearance as a significant covariate for explaining the between-subject variability of ertapenem in the patient population. Estimated free plasma concentrations of ertapenem exceeded a MIC90 of 2 mg/L only for 6 h (25%) after infusion.
CONCLUSIONS: For an adequate dose adjustment of highly protein-bound drugs like ertapenem, knowledge of actual albumin concentrations is necessary. A shortening of the dosage interval or continuous infusion of ertapenem should be considered to ensure optimal free concentrations in critically ill patients with severe hypoalbuminaemia and normal renal function.
Keywords: protein binding , ICU patients , VAP
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