Evaluation of the need for dosing adaptations in obese patients for surgical antibiotic prophylaxis : a model-based analysis of cefazolin pharmacokinetics

Abstract

Background: Cefazolin is used as a prophylactic antibiotic to reduce surgical site infections (SSIs). Obesity has been identified as a risk factor for SSIs. Cefazolin dosing recommendations and guidelines are currently inconsistent for obese patients. As plasma and target-site exposure might differ, pharmacokinetic data from the sites of SSIs are essential to evaluate treatment efficacy: these data can be obtained via tissue microdialysis. This analysis was designed to evaluate the need for dosing adaptations in obese patients for surgical prophylaxis. Methods: Data from 15 obese (BMImedian ¼ 52.6 kg m 2) and 15 age- and sex-matched nonobese patients (BMImedian ¼ 26.0 kg m 2) who received 2 g cefazolin i.v. infusion for infection prophylaxis were included in the analysis. Pharmacokinetic data from plasma and interstitial space fluid (ISF) of adipose tissue were obtained and analysed simultaneously using nonlinear mixed-effects modelling. Dosing regimens were evaluated by calculating the probability of target attainment (PTA) and the cumulative fraction of response (CFR) for plasma and ISF using unbound cefazolin concentration above minimum inhibitory concentration 100% of the time as target (fT>MIC ¼ 100%). Dosing regimens were considered adequate when PTA and CFR were 90%. Results: Evaluation of cefazolin doses of 1 and 2 g with redosing at either 3 or 4 h by PTA and CFR in plasma and ISF found 2 g cefazolin with redosing at 4 h to be the most suitable dosing regimen for both obese and nonobese patients (PTA >90% and CFR >90% for both). Conclusions: This model-based analysis, using fT>MIC ¼ 100% as a target, showed that cefazolin dosing adaptations are not required for surgical prophylaxis in obese patients.