Impact of augmented renal clearance (ARC) on the pharmacokinetics of linezolid: Advantages of continuous infusion from a PK/PD perspective

Abstract Objectives To assess the influence of renal function, specially the presence of augmented renal clearance (ARC) on the pharmacokinetics of linezolid in critically ill patients. The effect of continuous infusion on the probability of therapeutic success from a pharmacokinetic/pharmacodynamic (PK/PD) perspective was also evaluated. Methods Seventeen patients received linezolid (600 mg q12 h) as a 30-minute infusion and 26 as continuous infusion (50 mg/h). The PK parameters were calculated and the probability of PK/PD target attainment (PTA) was estimated by Monte Carlo simulation (MCS) for different doses administered by intermittent (600 mg q12 h or 600 mg q8h) or continuous infusion (50 mg/h or 75 mg/h). Results In patients without ARC the standard dose was adequate to attain the PK/PD target. However, linezolid clearance was significantly higher in ARC patients, leading to subtherapeutic concentrations. Continuous infusion (50 mg/h) provided concentrations (C) ≥2 mg/L in 70% of the ARC patients. MCS revealed that C ≥ 2 mg/L would be reached in >90% of patients receiving 75 mg/h. Conclusions ARC increases linezolid CL and leads to a high risk of underexposure with the standard dose. Continuous infusion increases the PTA, but an infusion rate of 75 mg/h should be considered to ensure C ≥ 2 mg/mL.