Does Critical Illness Change Levofloxacin Pharmacokinetics?

Jason A. Roberts, Menino Osbert Cotta, Piergiorgio Cojutti, Manuela Lugano, Giorgio Della Rocca, Federico Pea

Levofloxacin is commonly used in critically ill patients for which existing data suggests non-standard dosing regimens should be used. The objective of this study was to compare the population pharmacokinetics of levofloxacin in critically ill and non-critically ill patients. Adult patients with a clinical indication for levofloxacin were eligible for participation in this prospective pharmacokinetic study. Patients were given 500 mg or 750 mg daily by intravenous administration with up to 11 blood samples taken on day 1 or 2 of therapy. Plasma samples were analysed and population pharmacokinetic analysis undertaken using Pmetrics®. Thirty-five patients (18 critically ill) were included. The mean (SD) age, weight and Cockcroft-Gault creatinine clearance for the critically ill and non critically ill patients were 60.3 (16.4) and 72.0 (11.6) years, 78.5 (14.8) and 70.9 (15.8) kg and 71.9 (65.8) and 68.2 (30.1) mL/min respectively. A two compartment linear model best described the data. Increasing creatinine clearance was the only covariate associated with increasing drug clearance. The presence of critical illness did not significantly affect any pharmacokinetic parameter. The mean (SD) parameter estimates were clearance 8.66 (3.85) L/h, volume of the central compartment 41.5 (24.5) L, intercompartmental clearance constants from central to peripheral 2.58 (3.51) L/h and peripheral to central compartments 0.90 (0.58) L/h. Monte Carlo dosing simulations demonstrated that achievement of therapeutic exposures was dependent on renal function, pathogen and MIC. Critical illness appears to have no independent effect on levofloxacin pharmacokinetics that cannot be explained by altered renal function.