Antibiotic drug exposures and endotracheal pharmacokinetics (DEEP)

The National Institute of Allergy and Infectious Diseases awarded the Children's Hospital of Philadelphia $889,516 on August 4, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to conduct the Antibiotic Drug Exposures and Endotracheal Pharmacokinetics (DEEP) study. The research aims to understand factors governing antibiotic delivery to the lower respiratory tract in critically ill children, examine how antibiotic concentrations relate to changes in the respiratory tract microbiome and host inflammation in severe bacterial lower respiratory tract infections, and develop optimal antibiotic dosing strategies for pediatric treatment. The Children's Hospital will enroll a subset of participants from an ongoing prospective multicenter cohort study of critically ill children with acute respiratory failure requiring mechanical ventilation, treating participants with cefepime or ceftriaxone with or without vancomycin, and simultaneously quantifying antibiotics in blood and tracheal aspirate samples. Through serial endotracheal sampling, the research team will utilize host and microbe metagenomic analysis to investigate how antibiotic exposures relate to respiratory tract microbiome structure, pathogen eradication, and host inflammation changes. This assistance type is a project grant. The work is performed in Philadelphia, Pennsylvania, with a period of performance extending from August 4, 2026, through July 31, 2031.

Abstract

The overall goals of this study are to understand factors that govern antibiotic delivery to the lower respiratory tract in critically ILL children, examine how antibiotic concentrations relate to changes in the respiratory tract microbiome and host inflammation in severe bacterial lower respiratory tract infections (LRTI), and develop optimal antibiotic dosing strategies for treatment of severe LRTI in children. Morbidity and mortality in children with severe LRTI are substantial. Antibiotics are crucial to the successful treatment of bacterial LRTI; yet, drug delivery to the respiratory tract is highly variable in critically ILL children leading to treatment failure, recurrent infection, and selection of resistant pathogens. To ensure optimal clinical and microbiologic outcomes, we need to understand the drivers of variability to maintain effective antibiotic concentrations at the site of infection. We must address this critical GAP so that optimal antibiotic dosing regimens can be developed to eradicate pathogens in the respiratory tract while minimizing the disruption of healthy microbial structure. This project, antibiotic drug exposures and endotracheal pharmacokinetics (DEEP), seeks to understand the drivers of drug delivery to the lower respiratory tract and investigate how antibiotic exposures relate to respiratory tract microbiome structure, pathogen eradication, and changes in host inflammation. We will leverage an ongoing, prospective, multicenter cohort study of critically ILL children with acute respiratory failure requiring mechanical ventilation (breath; R01AI182308) to accomplish our aims. We will enroll a subset of breath participants treated with ≥1 antibiotics (cefepime or ceftriaxone +/- vancomycin) and simultaneously quantify antibiotics in blood and tracheal aspirate (TA) samples. Through serial endotracheal sampling, we will utilize host/microbe metagenomic next generation sequencing (MNGS) to identify pathogens, describe the composition of the respiratory tract microbiome, and characterize host immune/inflammatory responses. In aim 1, we will characterize antibiotic transfer between blood and the lower respiratory tract among children with severe LRTI. This aim will define key associations between antibiotic dosing and variability in drug delivery to the lower respiratory tract. Aim 2 will determine how blood and respiratory tract antibiotic concentrations are associated with changes in the respiratory tract microbiome and host inflammation in children with severe bacterial LRTI. Our preliminary data demonstrate that certain patients clear LRTI pathogens and restore microbiome richness whereas others do not. We hypothesize that key concentrations drive these outcomes (not just drug selection). In aim 3 we will use model-informed personalized dosing (MIPD) approaches to define individualized dosing strategies that result in optimal microbiologic changes and inflammatory responses in children with severe LRTI. Understanding the factors that govern antibiotic delivery to the lower respiratory tract is novel and integrating antibiotic exposure data with metagenomic host-microbe profiling is innovative. Completion of our proposal will facilitate personalized antibiotic treatments for severe pediatric LRTI.