Population pharmacokinetics and dosing simulations of cefuroxime in critically ill patients: Non-standard dosing approaches are required to achieve therapeutic exposures

Abstract

Objectives: To investigate the population pharmacokinetics of cefuroxime in critically ill patients. Methods: In this observational pharmacokinetic study, multiple blood samples were taken over one dosing interval of intravenous cefuroxime. Blood samples were analysed using a validated ultra HPLC tandem mass spectrometry technique. Population pharmacokinetic analysis and dosing simulations were performed using non-linear mixed-effects modelling. Results: One hundred and sixty blood samples were collected from 20 patients. CLCR ranged between 10 and 304 mL/min. A two-compartment model with between-subject variability on CL, V of the central compartment and V of the peripheral compartment described the data adequately. Twenty-four hour urinary CLCR was supported as a descriptor of drug CL. The population model for CLwas CL=θ1×CLCR/100, where θ1 is the typical cefuroxime CL in the population, which is 9.0 L/h. The mean V was 22.5 L. Dosing simulations showed failure to achieve the pharmacokinetic/pharmacodynamic target of 65% fT>MIC for an MIC of 8 mg/L with standard dosing regimens for patients with CLCR ≥50 mL/min. Conclusions: Administration of standard doses by intermittent bolus is likely to result in underdosing for many critically ill patients. Continuous infusion of higher than normal doses after a loading dose is more likely to achieve pharmacokinetic/pharmacodynamic targets. However, even continuous infusion of high doses (up to 9 g per day) does not guarantee adequate levels for all patients with a CLCR of ≥300 mL/min if the MIC is 8 mg/L.