9 Tissue penetration of piperacillin-tazobactam in critically ill children – a microdialysis study

Introduction Critical illness may affect many pharmacokinetic (PK) processes. Research in adults suggests an impaired tissue penetration of beta-lactam antibiotics in critically ill patients compared to healthy individuals. Currently, data in critically ill children are lacking. This study aimed (1) to investigate the tissue penetration of piperacillin-tazobactam, a frequently used broad-spectrum beta-lactam/beta-lactamase inhibitor combination and (2) to assess the safety of microdialysis experiments in critically ill children. Methodology This pilot study included seven mechanically ventilated children (age range: 1 month - 13 years) receiving piperacillin-tazobactam (75 mg per kg bodyweight, based on the piperacillin component, every 6 h as a 30 min infusion). A microdialysis catheter (10 mm membrane) was inserted in the thigh muscle. Benzylpenicillin was used as internal standard for microdialysis calibration. During one or two dosing intervals, plasma and microdialysis samples were collected (max. stay of microdialysis catheter: 35 h). PK data were analyzed with non-compartmental PK analysis (Phoenix®, Certara). The tissue penetration was calculated by taking the ratio of the AUC(0-inf) in tissue and in plasma. Results In total, 12 dosing intervals were sampled. Median tissue penetration was 0.68 (IQR 0.55 – 0.84) for piperacillin and 1.10 (0.92 – 1.38) for tazobactam. The extrapolated part of the AUC(0-inf) accounted for less than 20% of the total AUC(0-inf). No adverse events occurred during microdialysis catheter insertion, microdialysis sampling, and catheter removal. Conclusion To the best of our knowledge, this study is the first to report on tissue penetration of piperacillin-tazobactam in critically ill children. Similarly to what was found in critically ill adult patients (septic shock cohort (Joukhadar 2001): mean 0.19 ± SE 0.03/post cardiac surgery cohort (Brunner 2000): mean 0.27 ± SE 0.04), the tissue penetration of piperacillin is impaired in critically ill children, albeit to a lesser extent than what has been reported in critically ill adults. These findings underscore the limitations of plasma as a surrogate for tissue exposure in critical illness. Contrary to general belief, this study shows that piperacillin and tazobactam have a different PK behavior, with a good tissue penetration of the beta-lactamase inhibitor. Microdialysis is a safe and feasible method for tissue pharmacokinetic research in critically ill children.