Ertapenem in critically ill patients with early-onset ventilator-associated pneumonia: pharmacokinetics with special consideration of free-drug concentration.
OBJECTIVE
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.


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 V(z) (17 vs. 8 L) and CL(TOT) (43 vs. 20 mL/min) with resulting lower C(max) (90 vs. 253 mg/L) and AUC(0-infinity) (418 vs. 817 mg x 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 MIC(90) 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.
Burkhardt
Olaf
O
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA. burkhardt.olaf@mh-hannover.de
Kumar
Vipul
V
Katterwe
Denise
D
Majcher-Peszynska
Jolanta
J
Drewelow
Bernd
B
Derendorf
Hartmut
H
Welte
Tobias
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000097:blood / Q000627:therapeutic use / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D003404:Creatinine / Q000652:urine; D016638:Critical Illness; D000077727:Ertapenem; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D053717:Pneumonia, Ventilator-Associated / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D011446:Prospective Studies; D016896:Treatment Outcome; D047090:beta-Lactams / Q000097:blood / Q000627:therapeutic use / Q000652:urine
D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D003404:Creatinine; D000077727:Ertapenem