Population pharmacokinetic evaluation of cefuroxime in perioperative antibiotic prophylaxis during and after cardiopulmonary bypass.

AIMS: The purpose of this study was to explore pharmacokinetic and pharmacodynamic aspects of a contemporary dosing scheme of cefuroxime as perioperative prophylaxis in cardiac surgery using cardiopulmonary bypass (CPB). METHODS: Cefuroxime plasma concentrations were measured in 23 patients. A 1.5-g dose of cefuroxime was administered at start of surgery and CPB, followed by 3 additional doses every 6 hours postoperative. Drug levels were used to build a population pharmacokinetic model. Target attainment for Staphylococcus aureus (2-8 mg/L) and Escherichia coli (8-32 mg/L) were evaluated and dosing strategies for optimization were investigated. RESULTS: A dosing scheme of 1.5 g cefuroxime preoperatively with a repetition at start of CPB achieves plasma unbound concentrations of 8 mg/L in almost all patients during surgery. The second administration is critical to provide this level of coverage. Simulations indicate that higher unbound concentrations up to 32 mg/L are reached by a continuous infusion rate of 1 g/h after a bolus of 1 g. In the postoperative phase, most patients do not reach unbound concentrations above 2 mg/L. To improve target attainment up to 8 mg/L, the continuous application of cefuroxime with infusion rates of 0.125-0.25 g/h is simulated and shown to be an alternative to bolus dosing. CONCLUSION: Dosing recommendations for cefuroxime as perioperative antibiotic prophylaxis in cardiac surgery are sufficient to reach plasma unbound concentration to cover S. aureus during the operation. Target attainment is not achieved in the postoperative period. Continuous infusion of cefuroxime may optimize target attainment.

Physiologically based pharmacokinetic evaluation of cefuroxime in perioperative antibiotic prophylaxis.

AIMS: Adequate plasma concentrations of antibiotics during surgery are essential for the prevention of surgical site infections. We examined the pharmacokinetics of 1.5 g cefuroxime administered during induction of anaesthesia with follow-up doses every 2.5 hours until the end of surgery. We built a physiologically based pharmacokinetic model with the aim to ensure adequate antibiotic plasma concentrations in a heterogeneous population. METHODS: A physiologically based pharmacokinetic model (PK-Sim® /MoBi® ) was developed to investigate unbound plasma concentrations of cefuroxime. Blood samples from 25 thoracic surgical patients were analysed with high-performance liquid chromatography. To evaluate optimized dosing regimens, physiologically based pharmacokinetic model simulations were conducted. RESULTS: Dosing simulations revealed that a standard dosing regimen of 1.5 g every 2.5 hours reached the pharmacokinetic/pharmacodynamic target for Staphylococcus aureus. However, for Escherichia coli, >50% of the study participants did not reach predefined targets. Effectiveness of cefuroxime against E. coli can be improved by administering a 1.5 g bolus immediately followed by a continuous infusion of 3 g cefuroxime over 3 hours. CONCLUSION: The use of cefuroxime for perioperative antibiotic prophylaxis to prevent staphylococcal surgical site infections appears to be effective with standard dosing of 1.5 g preoperatively and follow-up doses every 2.5 hours. In contrast, if E. coli is relevant in surgeries, this dosing regimen appears insufficient. With our derived dose recommendations, we provide a solution for this issue.