Optimizing cloxacillin prophylaxis in hip and knee arthroplasty based on population pharmacokinetics of unbound plasma concentrations

OBJECTIVES: To characterize the population pharmacokinetics of unbound cloxacillin in patients undergoing total arthroplasty of the hip (THA) or knee (TKA), and to explore alternative dosing regimens for cloxacillin prophylaxis. METHODS: Plasma concentrations of total and unbound cloxacillin from 200 patients undergoing primary elective THA (n & 95) or TKA (n & 105) were analysed. Intravenous cloxacillin doses of 2 g were administered pre-surgery, and repeated after 2 and 6 hours. Samples (n & 496) were analysed using HPLC-MS/MS. Non-linear mixed-effects modelling was performed to develop a population pharmacokinetic model describing unbound cloxacillin exposure. Using this model, alternative prophylaxis regimens were explored with Monte Carlo simulations. RESULTS: A two-compartment model with non-linear protein binding adequately described the data. Estimated glomerular filtration rate (eGFR) and body weight (kg) were significant covariates on unbound cloxacillin clearance. In 13% of patients sampled at the end of surgery (n & 25/187), unbound cloxacillin <2 mg/L was observed. A model-predicted 18-22% (n & 36-43/200) of patients failed to sustain plasma levels ≥2 mg/L throughout the two-hour dosing interval with the current regimen. In contrast, a continuous 1 g/h infusion after a 1 g loading dose would ensure target attainment in >99% of patients, according to the model predictions. CONCLUSIONS: For many THA and TKA patients, the current cloxacillin prophylaxis regimen may fail to provide adequate target site concentrations during the entire surgical procedure. Transitioning to a prolonged infusion protocol could increase attainment of PK/PD targets without exceeding the currently recommended total perioperative dose amounts.