A TARGET SITE ANTIBIOTIC PHARMACOKINETIC MODEL: THE CASE OF THE MYSTERY OF BONE CONCENTRATIONS OF CEFUROXIME

Aim Prosthetic Joint Infections (PJI) are a common reason for prosthetic joint replacement in patients that underwent total hip or knee arthroplasty (THA/TKA). Per protocol, extensive antibiotic treatment follows. However, a clear understanding of the pharmacokinetics of antibiotics at bone target site is lacking. The aim is to analyse target site concentrations and use these concentrations in a pharmacokinetic model. This will lead to a better understanding of the kinetics of cefuroxime in non-standard matrices and could possibly optimise antibiotic dosing in PJI patients. Consequently, dose optimisation could lead to reduced risk of (re)-infection and adverse effects like renal-insufficiency and therefore lower health-care costs. Method As part of an ongoing prospective cohort study, PJI patients undergoing hip or knee revision in a one- or two-stage protocol treated with cefuroxime were included. During implant removal two samples of plasma, bone and synovial tissue were collected at 30-60 minutes and 90-120 minutes after start cefuroxime bolus infusion and one synovial fluid sample. Using a UltraPerformance Convergence Chromotography – quadruple mass spectrometry system (UPC 2 -MS/MS) the samples were analysed. Beforehand, bone and synovial tissue were pulverized acquiring a homogenate of cortical and cancellous bone for the bone tissue sample. Using nonlinear mixed effect modelling (NONMEM) software (Pirana©) a pharmacokinetic model was built. Results Mean bone concentrations (mg/L) of cefuroxime at 30-60 min after IV administration in the knee and hip are 21.29 (SD:11.86) and 19.06 (SD: 11.79) respectively and 8.23 (SD:4.90) and 9.67 (SD:9.75) respectively at 90-120 min after IV administration. The results mentioned here were collected during knee operations without blood void conditions. A two-compartment (central, bone) model best described the data. The kidney function (eGFR) was the only relevant covariate on the clearance of cefuroxime. Conclusions With the model were one step closer to solving the mystery of target site concentrations in bone of cefuroxime. On-going analysis of dosing schedules will show what the optimal dosing strategy is for PJI patients during and directly after surgery.