Population pharmacokinetics and dosing simulations of amoxicillin/clavulanic acid in critically ill patients

Objectives: The objective of this study was to investigate the population pharmacokinetics and pharmacodynamics of amoxicillin and clavulanic acid in critically ill patients. Methods: In this observational pharmacokinetic study, multiple blood samples were taken over one dosing interval of intravenous amoxicillin/clavulanic acid (1000/200 mg). 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-four blood samples were collected from 13 patients. For both amoxicillin and clavulanic acid, a two-compartment model with between-subject variability for both the clearance and the volume of distribution of the central compartment described the data adequately. For both compounds, 24 h urinary creatinine clearance was supported as a descriptor of drug clearance. The mean clearance of amoxicillin was 10.0 L/h and the mean volume of distribution was 27.4 L. For clavulanic acid, the mean clearance was 6.8 L/h and the mean volume of distribution was 19.2 L. Dosing simulations for amoxicillin supported the use of standard dosing regimens (30 min infusion of 1 g four-times daily or 2 g three-times daily) for most patients when using a target MIC of 8 mg/L and a pharmacodynamic target of 50% fT(>MIC), except for those with a creatinine clearance >190 mL/min. Dosing simulations for clavulanic acid showed little accumulation when high doses were administered to patients with high creatinine clearance. Conclusions: Although vast pharmacokinetic variability exists for both amoxicillin and clavulanic acid in intensive care unit patients, current dosing regiments are appropriate for most patients, except those with very high creatinine clearance.