TACTIC Study: Tissue Penetration of Antibiotics in CriTically Ill Children

Pathophysiological alterations during critical illness, such as severe sepsis and septic shock, frequently alter the pharmacokinetics (PK) and pharmacodynamics (PD) of beta-lactam antibiotics. In pediatric critical care, these changes are further complicated by ongoing physiological growth and developmental changes in drug absorption, distribution, metabolism, and excretion. Although research in critically ill children has demonstrated that standard intravenous dosing regimens often fail to achieve target plasma concentrations, plasma levels alone do not necessarily reflect drug disposition at the actual site of infection. For extracellular pathogens, the target site of infection corresponds to the interstitial fluid (ISF) of tissues. Studies in adult septic populations suggest that subtherapeutic antibiotic concentrations in ISF may contribute to treatment failure, even when total plasma concentrations appear adequate. Data regarding antibiotic tissue disposition in pediatric intensive care unit (PICU) patients remain extremely limited. This monocentric, prospective, observational pharmacokinetic study utilizes in vivo microdialysis to directly quantify unbound tissue concentrations of three hydrophilic beta-lactam antibiotics-piperacillin-tazobactam, meropenem, and amoxicillin-clavulanic acid-in the ISF of skeletal muscle in critically ill pediatric patients.

The study will be conducted as follows:

• Microdialysis Probe Insertion and Placement: Under continuous analgosedation, a 63 Microdialysis Catheter (M Dialysis AB, Solna, Sweden; 20 kDa molecular weight cut-off, 10 mm membrane length) is inserted into the vastus lateralis muscle of the anterolateral thigh using a steel guidance needle.

• Perfusion and Calibration: The probe is continuously perfused with 0.9% physiological saline at a fixed flow rate via microinfusion precision pumps. After an equilibration period, in vivo probe recovery is determined using both retrodialysis and internal standard methods:

• Retrodialysis: Performed prior to drug administration by perfusing the target antibiotic through the probe (2 x 30-minute intervals) to calculate relative recovery based on drug loss across the membrane.

• Internal Standard Method: An internal calibrator (penicillin G for piperacillin-tazobactam and amoxicillin-clavulanic acid; cefuroxime for meropenem) is added to the perfusate solution to continuously monitor recovery throughout the experiment.

• Biological Sampling: Following calibration, dialysate fractions are collected over designated time intervals across one or two antibiotic dosing cycles (representing early-dose and steady-state conditions). Paired blood samples are drawn concurrently from an existing intra-arterial or central venous catheter to quantify total plasma antibiotic levels. Unbound fractions in plasma are separated using ultrafiltration.

• Analytical and Pharmacokinetic Modeling: Microdialysate and plasma drug concentrations are measured using high-performance liquid chromatography-mass spectrometry (HPLC-MS). Population pharmacokinetic modeling (non-linear mixed-effects modeling) and Monte Carlo simulations will be applied to derive PK parameters and evaluate PK/PD target attainment in the ISF in muscle.