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

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2024 · $783,342

## Abstract

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 fac...

## Key facts

- **NIH application ID:** 10869934
- **Project number:** 5R01HD110921-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Kevin James Downes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $783,342
- **Award type:** 5
- **Project period:** 2023-06-19 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10869934

## Citation

> US National Institutes of Health, RePORTER application 10869934, PediatRic sEpsiS induCed MODS: Relationship of Immune-phenotypes and antiBiotic Exposures (PRESCRIBE) study (5R01HD110921-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10869934. Licensed CC0.

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