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

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 K-slope pharmacokinetic model relating the elimination rate constant (K-10) to renal function, as defined by creatinine clearance (CLCR), and central distribution volume (V-1) to total body weight (TBW). The final model was described by the following equations: K-10 = 0.0027 x CLCR + 0.071 h(-1) and V-1 = TBW x 0.21 liter/kg. The median inter-compartmental transfer constants K-12 and K-21 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 mu g/ml, 24.0 mu g/ml, and 26%, respectively. The independent validation group displayed a bias, precision, and coefficient of determination of -1.64 mu g/ml, 17.1 mu g/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 mu g/ml, respectively. This study provides a pharmacokinetic model capable of predicting cefepime concentrations in critically ill patients with VAP.