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

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.Ceftazidime is a broad-spectrum cephalosporin generally used in the treatment of severe Pseudomonas aeruginosa infections. Since ceftazidime exhibits time-dependent killing of gram-negative bacteria in vitro or in critically ill patients, studies involving continuous administration of cephalosporin confirm that the steady-state concentration in blood should be four to five times higher than the bacterial MIC (6, 27). When the MIC is not available, the European breakpoint is used to calculate the target concentration (8). In patients with sepsis syndrome, ceftazidime plasma concentrations after a 2-g dose of ceftazidime every 8 h or 4 g by continuous infusion may be inadequate (42).Intensive care unit (ICU) patients represent a highly heterogeneous population ranging from young trauma patients to elderly medical patients and postsurgical patients. This heterogeneity is well known to produce high variability in pharmacokinetic parameters, as was previously demonstrated for the clearance and the total volume of distribution (15, 26, 36). Ceftazidime pharmacokinetics in critically ill patients is altered by an increased volume of drug distribution and a longer elimination half-life (16).In order to determine interindividual pharmacokinetic variability and the influence of some patient characteristics on the pharmacokinetics of ceftazidime, we conducted a population pharmacokinetic study to develop and validate a model to enable an adequate individual dosing strategy to be put in place (3). We used rich data collected in a prospective study comparing continuous infusion versus intermittent administration of ceftazidime, along with the demographic, clinical, and biological characteristics of these ICU patients. This study used the nonlinear mixed-effect model as implemented in the NONMEM program for pharmacostatistical analysis (4).