Optimization of microdialysis experiments to study antibiotic disposition in children : lessons learnt

Introduction: Infants need effective antibiotics, but dosing is challenging due to variable pharmacokinetics. This study assessed cefazolin distribution at the target site in the subcutaneous tissue using microdialysis. Cefuroxime was evaluated as internal standard for catheter calibration, which offers advantages over standard methods. A clinical trial validated its feasibility. Methods: An observational study was conducted in children (2–15 years) undergoing minor elective surgery with prophylactic cefazolin (30 mg/kg IV bolus). Microdialysis catheters were placed subcutaneously (thigh/arm) to collect samples every 30–60 minutes for 6 hours. For calibration, the catheter was perfused with cefuroxime (20 µg/mL) during and cefazolin (100 µg/mL) at the end of the experiment. Antibiotic concentrations were measured using a validated LC-MS/MS method. Data analysis included Relative Recovery (RR) calculation and non-compartmental analysis (NCA) with PKanalix (MonolixSuite). Target attainment was defined as 100% fT[MIC for 4 hours (MIC: 2 mg/L for S. aureus). Results: Microdialysis was tolerated in all infants without adverse events. Sixty samples were collected from six patients (mean age 10 years, weight 33.7 kg). RR was above the advised 20%. Cefuroxime recovery was 21.77% ± 12.31%, and cefazolin 34.09% ± 15.52%, showing high inter- and lower intra-patient variability (RR: CFR 6.69%, CFZ 3.74%). The largest calibration-dependent RR difference (26.94%) significantly impacted cefazolin tissue concentration estimates. NCA results based on cefuroxime calibration were: AUC 207.08 hmg/L, Cl 5.12 L/h, Vd 8.33 L. Cefazolin calibration estimated AUC 119.32 hmg/L, Cl 8.96 L/h, Vd 19.92 L. Target attainment was achieved in 100% of patients. Conclusion: Microdialysis is a feasible, safe method for continuous sampling in infants. Cefuroxime and cefazolin showed differences in in vivo recovery, highlighting the importance of calibration methods choice in microdialysis studies. A larger trial is needed to better characterize cefazolin pharmacokinetics, variability, and optimise microdialysis studies in this vulnerable population.