Journal
INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS
Volume 62, Issue 5, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ijantimicag.2023.106970
Keywords
Tissue pharmacokinetics; Microdialysis; Pediatric sepsis; Juvenile animal model; Piperacillin-tazobactam
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This study explored the feasibility and performance of microdialysis experiments in septic piglets and children, and found that microdialysis is a safe and applicable method for measuring tissue drug concentrations.
Objectives: Knowledge on the tissue penetration of piperacillin-tazobactam in children with sepsis is lack -ing. In this study, the feasibility and performance of microdialysis experiments were explored in septic piglets and children as part of a translational research project.Methods: Multiple-day microdialysis investigations were performed in muscle tissue of 22 piglets (of which 11 were septic) and 6 children with sepsis. An in vitro experiment preceded the (pre)clinical trials to derive optimal experimental settings and calibration technique. Linear mixed-effects models quanti-fied the impact of sepsis on relative recovery (RR) and intercatheter, interindividual, interoccasion, and residual variability.Results: In vivo microdialysis was well tolerated in piglets and children, with no significant adverse events reported. Using identical experimental settings, lower RR values were recorded in healthy and septic piglets (range: piperacillin, 17.2-29.1% and tazobactam, 23.5-29.1%) compared with the in vitro experiment (piperacillin, 43.3% and tazobactam, 55.3%), and there were unacceptably low values in chil-dren with sepsis ( < 10%). As a result, methodological changes were made in the pediatric trial. Realistic tissue concentration-time curves were derived in piglets and children. In piglets, sepsis reduced the RR. The greatest contributors to RR variability were residual ( > 40%) and interoccasion ( > 30%) variability. The internal standard method was the preferred calibration technique in both piglets and children.Conclusions: Microdialysis is a safe and applicable method for the measurement of tissue drug concen-trations in piglets and children. This study demonstrated the impact of experimental settings, sepsis, and target population on individual RR.(c) 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.
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