Population pharmacokinetics of cefazolin in neurosurgical antibiotic prophylaxis

Abstract

In neurosurgery, cefazolin (CFZ) is typically recommended at a dose of 2-gram within 60 minutes prior to surgical incision. However, due to the reported poor cerebrospinal fluid (CSF) penetration of CFZ, we conducted a population pharmacokinetic study to assess the adequacy of a 2-gram CFZ dosing regimen against the most common pathogens found in neurosurgical patients. If necessary, alternative CFZ dosing strategies were identified to achieve effective CSF concentrations. Adult patients undergoing neurosurgery were considered for inclusion in a prospective, observational, single-center study. After intravenous administration of CFZ 2-gram, blood and CSF samples were collected to determine CFZ concentrations. Population pharmacokinetic modeling of CFZ was performed using a non-linear mixed-effects approach and different dosing regimens were evaluated pharmacodynamically via Monte Carlo simulations. A total of 147 plasma and 42 CSF samples from 23 patients were analyzed. The median CFZ concentrations in plasma and CSF were 140.5 and 7.8 mg/L, respectively. The final model selected was a two-compartment model with an additional CSF compartment without covariates. The standard 2 g CFZ dose was inadequate in most cases. In contrast, intermittent administration of 1 g every hour following an initial bolus of 4-5 g, or continuous infusion at a rate of 1.625 g/h after a 6 g bolus provided better target attainment. The standard 2 g CFZ dose for neurosurgical antibiotic prophylaxis should be reassessed. The alternative dosing regimens proposed in this study warrant evaluation in future clinical trials.

Keywords: Antibiotic prophylaxis; Cefazolin; Monte Carlo simulations; Neurosurgery; Pharmacokinetics.