Linezolid pharmacokinetics in critically ill patients with renal replacement therapy: comparison of equi-dose of continuous veno-venous haemofiltration with continuous veno-venous haemodiafiltration

Introduction

Linezolid is a commonly used antibiotic for difficult-to-treat Gram-positive infections for which little data is available to guide dosing for different types of renal replacement therapy.

Objectives

The objective of this study was to compare the population pharmacokinetics of linezolid during continuous venovenous haemofiltration (CVVHF, 30 mL.kg^-1.h^-1) and continuous venovenous haemodiafiltration (CVVHDF, 15 mL.kg^-1.h^-1 + 15 mL.kg^-1.h^-1). We then sought to perform Monte Carlo dosing simulations to determine doses that best achieve pharmacodynamic targets for these patients.

Methods

Patients with a clinical indication for linezolid and prescribed either CVVHF or CVVHDF were eligible for participation in this prospective pharmacokinetic study. Patients were administered 600 mg IV 12-hourly. Seven blood samples were collected over one dosing interval and analysed by a validated chromatographic method. Population pharmacokinetic analysis was undertaken using Pmetrics and Monte Carlo simulations evaluated achievement of a pharmacodynamics target of an area under the concentration-time curve from 0-24 hours to minimum inhibitory concentration (AUC_0-24/MIC) of 80.

Results

9 CVVHDF and 8 CVVHF were performed in 13 patients. Patient characteristics 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). Both increasing patient weight and decreasing SOFA score were associated with increasing linezolid clearance. The mean (SD) parameter estimates were clearance 3.8 (2.2) L/h, volume of the central compartment 26.5 (10.3) L, intercompartmental clearance constants from central to peripheral (Kcp) 8.1 (12.1) L/h and peripheral to central compartments (Kpc) 3.6 (4.0) L.h^-1. Achievement of pharmacodynamics targets was low for a MIC of 2 mg/L with the studied dose.

Conclusions

The present data indicates profound pharmacokinetic variability of linezolid during CVVHF and CVVHDF. Sub-optimal achievement of therapeutic targets occurs at the EUCAST breakpoint MIC of 2 mg/L using 600 mg IV 12-hourly.

Figure 1

The median observed linezolid concentration-time p.