Population pharmacokinetics and optimized dosing of cefuroxime in critically ill patients

Abstract

Cefuroxime is a second-generation cephalosporin widely used in the intensive care unit (ICU). ICU patients have high variability in interpatient pharmacokinetics (PK), but the extent of this variation is unclear. We performed an observational PK study in ICU patients. The objective of this study was to gain knowledge on the PK of cefuroxime and investigate target attainment of currently clinically applied dosing regimens. To identify the most suitable regimen the time above the minimal inhibitory concentration of the unbound drug (%fT > MIC) was calculated for different minimal inhibitory concentrations (MICs) and estimated Glomerular Filtration rates (eGFRs). Twenty patients were included with an average age of 66 years and modification of diet in renal disease (MDRD) (not indexed by BSA) of 90 [60-117.5] mL/min. A two-compartment model best fitted the data, with eGFR as a covariate. Probability of target attainment (PTA) was 43% for a 1500-mg q8h bolus dosage for the EUCAST break point of 8 mg/L for a typical individual with a eGFR of 60 mL/min. Dosing continuously using 4.5 g/day obtained 100% PTA for a typical individual with a eGFR up to 120 mL/min.

Keywords: ICU; PK/PD; antibiotics; critical care medicine; intensive care; simulation.

FIGURE 1

Evaluation of various dosing regimens. Simulated pharmacokinetic curves, showing predicted cefuroxime (CXM) concentration (IPRED) converted to unbound concentrations vs. time for a typical patient, using various dosing regimens and different levels of glomerular filtration rates at the start and on the third day of treatment. Top row: 1500‐mg iv bolus every 8 h; middle row: 1500‐mg iv bolus at the start of the treatment followed by 1500 mg given with extended infusion during 4 h, every 8 h; bottom row: 1500‐mg iv bolus at the start of the treatment followed by 4500 mg given with continuous infusion every 24 h. left column: first dosing interval at the start of the treatment; right column: first dosing interval on the third day of treatment. The worst case scenario of the EUCAST break point of 8 mg/L for Enterobacterales has been highlighted by the red dashed line.

FIGURE 2

Probability of target attainment based on unbound concentrations for different dosing strategies for a typical individual with a fixed weight (85 kg), length (172 cm) and sex (M) based on our cohort for eGFR of 30 mL/min, 60 mL/min, 120 mL/min and 180 mL/min. Top row: 1500‐mg iv bolus every 8 h; middle row: 1500‐mg iv bolus at the start of the treatment followed by 1500 mg given with extended infusion during 4 h, every 8 h; bottom row: 1500‐mg iv bolus at the start of the treatment followed by 4500 mg given with continuous infusion every 24 h. left column: first dosing interval at the start of the treatment; right column: first dosing interval on the third day of treatment. The worst case scenario of the EUCAST break point of 8 mg/L for Enterobacterales has been highlighted.