Population pharmacokinetics of linezolid in critically ill patients on renal replacement therapy: comparison of equal doses in continuous venovenous haemofiltration and continuous venovenous haemodiafiltration
Journal of Antimicrobial Chemotherapy February 2016 V.71 N.2 P.464-470
Roger, L. Muller, S. C. Wallis, B. Louart, G. Saissi, J. Lipman, J. Y. Lefrant, and J. A. Roberts
1Service des réanimations, Pôle Anesthésie Réanimation Douleur Urgence, CHU Nîmes, Place du Professeur Robert Debré, 30 029 Nîmes cedex 9, France
2Equipe d’Accueil 2992, Faculté de Médecine de Nîmes, Université de Montpellier, Chemin du Carreau de Lanes, Nimes, France
3Burns, Trauma & Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia
4Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
5Pharmacy Department, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
6Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
Few data are available to guide linezolid dosing during renal replacement therapy. The objective of this study was to compare the population pharmacokinetics of linezolid during continuous venovenous haemofiltration (CVVHF, 30 mL/kg/h) and continuous venovenous haemodiafiltration (CVVHDF, 15 mL/kg/h+15 mL/kg/h).
Patients requiring linezolid 600 mg iv every 12 h and CVVHF or CVVHDF were eligible for this prospective study. Seven blood samples were collected over one dosing interval and analysed by a validated chromatographic method. Population pharmacokinetic analysis was undertaken using Pmetrics. Monte Carlo simulations evaluated achievement of a pharmacodynamics target of an AUC from 0–24 h to MIC (AUC0-24/MIC) of 80.
Nine CVVHDF and eight CVVHF treatments were performed in 13 patients. Regimens of CVVHDF and CVVHF were similar. A two-compartment linear model best described the data. CVVHDF was associated with a 20.5% higher mean linezolid clearance than CVVHF, without statistical significance (P=0.39). Increasing patient weight and decreasing SOFA score were associated with increasing linezolid clearance. The mean (SD) parameter estimates were: clearance (CL), 3.8 (2.2) L/h; volume of the central compartment, 26.5 (10.3) L; intercompartmental clearance constants from central to peripheral, 8.1 (12.1) L/h; and peripheral to central compartments, 3.6 (4.0) L/h. Achievement of pharmacodynamic targets was poor for an MIC of 2 mg/L with the studied dose.
During CVVHF and CVVHDF, there is profound pharmacokinetic variability of linezolid. Suboptimal achievement of therapeutic targets occurs at the EUCAST breakpoint MIC of 2 mg/L using 600 mg iv every 12 h.