Cefepime and continuous renal replacement therapy (CRRT): In vitro permeability of two CRRT membranes and pharmacokinetics in four critically ill patients

Abstract

Cefepime is a fourth-generation cephalosporin with a broad spectrum of antimicrobial activity against gram-positive and gram-negative micro-organisms. It is a useful option for treating infections in critically ill patients in intensive care due to its high degree of activity and its tolerability. The aim of this study was to characterize in vitro the permeability to cefepime of 2 membranes frequently used in continuous renal replacement therapies (CRRTs). An in vivo study was also carried out to determine the pharmacokinetics of cefepime in critically ill patients undergoing CRRT. In vitro procedures were conducted in 3 different fluids using polyacrylonitrile (AN69) or polysulfone (PS) membranes. Continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD) were simulated. Four male patients undergoing CVVH or continuous venovenous hemodiafiltration, who received 2000 mg of cefepime intravenously every 8 hours, entered the in vivo study. Prefilter and ultrafiltrate samples were collected, and concentrations of cefepime were measured using high-performance liquid chromatography. The sieving coefficient (Sc), defined as the fraction of drug eliminated across the membrane, and the saturation coefficient (Sa), defined as the fraction of drug diffused through the membrane to the dialysate fluid, were analyzed. Pharmacokinetic parameters were determined according to a noncompartmental analysis. The patients ranged in age from 18 to 75 years and weighed from 65 to 80 kg. By analyzing Sc and Sa values in the in vitro procedures, no differences were detected in the permeability of AN69 or PS membranes to cefepime in CVVH or CVVHD. Sc/Sa values were between 0.93 and 1.03 in Ringer's lactate and in bovine albumin-containing Ringer's lactate samples, but Sc/Sa values were lower in plasma samples (0.82-0.95). In the in vivo portion of the study, the patients' mean (SD) Sc/Sa value was 0.76 (0.21) and correlated well with the fraction unbound to proteins (0.79 [0.09]). Clearance by CRRT (mean [SD]) was 29.0 (16.8)% of the total clearance. Serum elimination t(1/2) was 4.6 (0.9) hours, and the volume of distribution at steady state was 0.6 (0.3) L/kg (mean [SD] values). Cefepime was significantly removed by CRRT. No significant differences were found in the Sc or Sa of cefepime between AN69 and PS membranes used in the CVVH or CVVHD procedures. The clearance of cefepime by CRRT must be considered when dosing critically ill patients.