title: Pharmacokinetics and pharmacodynamics of imipenem during continuous renal replacement therapy in critically ill patients.
abstract: The pharmacokinetics of imipenem were studied in adult intensive care unit (ICU) patients during continuous venovenous hemofiltration (CVVH; n=6 patients) or hemodiafiltration (CVVHDF; n=6 patients). Patients (mean+/-standard deviation age, 50.9+/-15.9 years; weight, 98.5+/-15.9 kg) received imipenem at 0.5 g every 8 to 12 h (total daily doses of 1 to 1.5 g/day) by intravenous infusion over 30 min. Pre- and postmembrane blood (plasma) and corresponding ultrafiltrate or dialysate samples were collected 1, 2, 4, and 8 or 12 h (depending on dosing interval) after completion of the drug infusion. Drug concentrations were measured using validated high-performance liquid chromatography methods. Mean systemic clearance (CL(S)) and elimination half-life (t1/2) of imipenem were 145+/-18 ml/min and 2.7+/-1.3 h during CVVH versus 178+/-18 ml/min and 2.6+/-1.6 h during CVVHDF, respectively. Imipenem clearance was substantially increased during both CVVH and CVVHDF, with membrane clearance representing 25% and 32% of CL(S), respectively. The results of this study indicate that CVVH and CVVHDF contribute to imipenem clearance to a greater degree than previously reported. Imipenem doses of 1.0 g/day appear to achieve concentrations adequate to treat most common gram-negative pathogens (MIC up to 2 microg/ml) during CVVH or CVVHDF, but doses of 2.0 g/day or more may be required to adequately treat and prevent resistance in pathogens with higher MICs (MIC=4 to 8 microg/ml). Higher doses should only be used after consideration of potential central nervous system toxicities or other risks of therapy in these severely ill patients.
authors.affiliation: University of Colorado Health Sciences Center, Department of Clinical Pharmacy, School of Pharmacy, Campus Box C-238, 4200 East Ninth Avenue, Denver, CO 80262, USA. doug.fish@uchsc.edu
authors.forename: Douglas N
authors.initials: DN
authors.lastname: Fish
authors.forename: Isaac
authors.initials: I
authors.lastname: Teitelbaum
authors.forename: Edward
authors.initials: E
authors.lastname: Abraham
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015377:Cilastatin / Q000008:administration & dosage / Q000627:therapeutic use; D016638:Critical Illness; D004359:Drug Therapy, Combination; D005260:Female; D017583:Hemodiafiltration; D006440:Hemofiltration; D006801:Humans; D015378:Imipenem / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D007676:Kidney Failure, Chronic / Q000188:drug therapy / Q000628:therapy; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D017582:Renal Replacement Therapy
chemical_list: D000900:Anti-Bacterial Agents; D011480:Protease Inhibitors; D015377:Cilastatin; D015378:Imipenem