@phdthesis{01HYHWGNBENJWVMATE5HWF9T5Z,
  abstract     = {{For most antibiotic therapies, the target site is outside the plasma compartment and located in the tissue. The lack of knowledge concerning the influence of growth, development, and disease-related factors on the tissue distribution of antibiotics complicates the dosing of antibiotics in children. Especially children who are critically ill could be at risk for underdosing and subtherapeutic target site concentrations if dosing is only guided by the drug concentrations in plasma. This hypothesis is based on data from adult research, as no tissue pharmacokinetic (PK) data has been gathered in critically ill children yet. However, tissue PK research is practically and ethically more challenging than performing PK research in plasma. Microdialysis is currently considered the gold standard technique for studying drug disposition in the interstitial compartment. An appropriate juvenile animal model could help circumvent the practical and ethical difficulties of tissue PK research in children. In recent years, the young pig has been proposed as a suitable model for studying PK in the child. 

This research project aimed to investigate the influence of critical illness and sepsis on antibiotic tissue distribution in children, using piperacillin-tazobactam, a broad-spectrum beta-lactam antibiotic, as a model compound. First, the currently available data on pediatric drug tissue distribution from previous studies in children was summarized (Chapter 3). No microdialysis data in healthy children are available and only four studies (of which one case report) described the antibiotic tissue distribution in diseased or surgical pediatric populations. Microdialysis has clearly not convincingly found its way into pediatric drug research yet. This could be a consequence of the unavailability of experimental protocols adapted to children and unexplored safety and feasibility concerns. Therefore, an experimental protocol to measure piperacillin and tazobactam in muscle tissue was optimized with the use of in vitro and in vivo experiments in septic and healthy piglets and critically ill children admitted to the pediatric intensive care unit (PICU) (Chapter 4). Multiple-day microdialysis was successfully applied in both study populations, without the occurrence of serious adverse events. The relative recovery (RR) data demonstrated the impact of the study subject, disease state, and experimental setting on the microdialysis performance and the need for proper method validation in the target study population. Additionally, a large interoccasion variability of RR was observed.  

In piglets, drug tissue concentrations were obtained in healthy and septic conditions (Chapter 5). For piperacillin-tazobactam, a lower tissue penetration (i.e. AUC tissue to plasma ratio) in septic piglets (mean ± SD: 0.90 ± 0.21) compared to healthy piglets (mean ± SD: 1.12 ± 0.54) was observed. In six critically ill children, the median tissue penetration of piperacillin amounted to 0.82 (IQR 0.65 – 0.86) (Chapter 6). This translates to a reduction of antibiotic tissue penetration in critically ill children of approximately 20% compared to healthy individuals when assuming a value of approximately one in healthy circumstances. However, considering that a proportion of the PICU population is even more critically ill than the patients included in our study, the effect of critical illness on the tissue penetration of piperacillin is potentially more pronounced in these patients. Interestingly, both in the piglet and pediatric study, tazobactam was distributed more easily into the tissue than piperacillin. This stands in contrast to the belief that beta-lactamase inhibitors and their accompanying beta-lactam antibiotics have similar PK properties. Importantly, the research findings and clinical implications from both PK studies varied according to the applied microdialysis methodology.  

In conclusion, this research project was the first to explore the tissue distribution of beta-lactam antibiotics in critically ill children. Even though microdialysis appeared to be safe in critically ill children, the technique remains methodologically challenging and many methodological uncertainties remain. Both the piglet and the pediatric study demonstrated reduced antibiotic tissue penetration in diseased individuals. Therefore, clinicians should recognize the limitations of plasma drug concentrations as a surrogate for antibiotic tissue penetration at the target site in the critically ill child. The results and experiences from these pilot studies should encourage researchers and clinicians to set up more large-scale tissue PK studies on piperacillin-tazobactam and other important antibiotics in this population. As tissue PK data is currently only obtained in research settings and plasma concentrations are readily available, future studies should focus on identifying predictors for impaired drug penetration from plasma to tissue.}},
  author       = {{Hermans, Eline}},
  keywords     = {{microdialysis,tissue pharmacokinetics,pediatric pharmacology,juvenile animal models,pediatric intesive care,sepsis,antibiotics}},
  language     = {{eng}},
  pages        = {{283}},
  publisher    = {{Ghent University. Faculty of Medicine and Health Sciences}},
  school       = {{Ghent University}},
  title        = {{Studying antibiotic tissue distribution using microdialysis : from piglets to critically ill children}},
  year         = {{2024}},
}