PediatRic sEpsiS induCed MODS: Relationship of Immune-phenotypes and antiBiotic Exposures (PRESCRIBE) study

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PROJECT SUMMARY/ABSTRACT Morbidity and mortality in children with sepsis and multi-organ dysfunction syndrome (MODS) are substantial. Timely delivery of effective antibiotic concentrations to the site of infection dictates treatment outcomes, but antibiotic pharmacokinetics (PK) are highly variable in septic children, frequently leading to sub- or supra- therapeutic antibiotic concentrations. To ensure optimal clinical and microbiologic outcomes, attainment and maintenance of safe and effective antibiotic concentrations throughout the treatment course are paramount. Despite this, antibiotic dosing in children with sepsis is based primarily by a child’s weight and kidney function, without regard to other sources of PK variability, while clinical measurement of antibiotic concentrations is performed for very few drugs. The host response to infection is a major driver of organ dysfunction and antibiotic PK variability in pediatric sepsis: hyperinflammation, as well as sepsis-induced immune dysfunction (i.e. immunoparalysis), are both common and exacerbate outcomes. Further, in critically ill children with respiratory failure, bacterial burden and composition of the respiratory tract microbiome impact both host inflammation and clinical outcomes. Understanding how the host immune response, antibiotic PK, and the microbiome interrelate, and influence clinical outcomes, is imperative to optimize treatment in pediatric sepsis. The Collaborative Pediatric Critical Care Research Network (CPCCRN) will perform two concurrent, double- blind, placebo-controlled RCTs to evaluate the impact of individualized immunomodulation (anakinra for hyperinflammation; GM-CSF for immunoparalysis) on organ function outcomes in pediatric sepsis-induced MODS. These trials (named PRECISE) provide a unique framework for evaluating the interplay between host immunophenotype (hyperinflammation, immunoparalysis), immunomodulation, and antibiotic PK/PD through our proposal. We will leverage PRECISE trials and CPCCRN infrastructure to evaluate sources of PK variability in children with sepsis and MODS, investigate how host immune responses longitudinally modulate antibiotic concentrations, and study how antibiotic concentrations impact organ dysfunction duration and the respiratory tract microbiome. In Aim 1, we will determine the influence of host immunophenotype and response to immunomodulation on antibiotic PK early (1A) and throughout the course (1B) of pediatric sepsis-induced MODS. Aim 2 focuses on understanding how antibiotic concentrations impact organ function outcomes in the context of immunomodulation in pediatric sepsis-induced MODS. Lastly, Aim 3 will quantify how antibiotic concentrations, immunophenotype and immunomodulation impact the respiratory tract microbiome over time in septic children with respiratory failure. By quantifying antibiotic concentrations and evaluating the drivers of antibiotic PK in sepsis in the context of immunomodulation, our proposal will facilitate development of individualized treatment strategies during sepsis-induced MODS.