Linezolid pharmacokinetic/pharmacodynamic profile in critically ill septic patients: intermittent versus continuous infusion

Pharmacokinetics and pharmacodynamics are significantly altered in critically ill septic patients and the risk of prolonged periods with concentrations below the minimum inhibitory concentration (MIC) and of low area under the serum concentration-time curve/MIC (AUC/MIC) ratios is of concern. We compared the pharmacokinetic/pharmacodynamic (PK/PD) profile of linezolid administered by intermittent or continuous infusion in critically ill septic patients. Patients were divided into two groups: intermittent infusion (Group I) (600 mg/12 h); or continuous infusion (Group C) (300 mg intravenous loading dose +900 mg continuous infusion on Day 1, followed by 1200 mg/daily from Day 2). Linezolid serum levels were monitored for 72h and microbiological data were collected. The clinical outcome was monitored. Sixteen patients completed the study. MICs of susceptible pathogens were 2 mg/L for 80% of the isolates. In Group I, linezolid trough serum levels (C-min) varied widely and were below the susceptibility breakpoint (4 mg/L) during the study period; in 50% of patients Cmin was <1 mg/L. In Group C, mean linezolid serum levels were more stable and, starting from 6 h, were significantly higher than Cmin levels observed in Group I and were always above the susceptibility breakpoint. Time that the free drug concentration was above the MIC (T-free > MIC) of > 85% was more frequent in Group C than in Group I (P < 0.05). Finally, with continuous infusion it was possible to achieve AUC/MIC values of 80-120 more frequently than with intermittent infusion (P < 0.05). According to PK/PD parameters, continuous infusion has theoretical advantages over intermittent infusion in this population of patients. (C) 2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.