PROJECT SUMMARY/ABSTRACT This Mentored Patient-Oriented Research Career Development Award will provide a structured environment with the training and expert mentorship needed to enable Dr. Angelique Boutzoukas to develop as an independent investigator and leader in the field of pediatric antimicrobial stewardship. Excess antibiotic use in preterm infants is common and causes morbidity and mortality. Identification of methods to safely limit unnecessary antibiotic exposures represents an urgent, unmet need in neonatal antibiotic stewardship. Due to differences in preterm infant physiology, current empiric ampicillin courses may provide prolonged levels of drug exposure beyond the intended duration. Dr. Boutzoukas hypothesizes that short-course empiric ampicillin (24 hours) will provide therapeutic exposures for 48 hours in select preterm infants, is safe, and represents a potential way to substantially reduce unnecessary antibiotic exposures in this population. Building on preliminary data, Dr. Boutzoukas aims to study the PK and safety of short-course ampicillin in preterm infants. She will accomplish this through population PK modeling and dosing simulation of ampicillin in preterm infants and conducting a pilot clinical trial to confirm that short-course ampicillin regimens provide the intended antibiotic exposures when accounting for post-discontinuation exposures. This work will advance the concept of post-discontinuation exposures, which may be applicable to other drugs and populations. Additionally, she will develop a novel desirability of outcome ranking endpoint that includes neonatal-specific outcomes and incorporates both the benefits and harms of antibiotic therapy in this population. This endpoint can be leveraged to study safety alongside efficacy and increase the efficiency of future neonatal clinical trials that compare antimicrobial regimens or durations. Dr. Boutzoukas is a pediatric infectious diseases physician with a proven commitment to patient-oriented research and a desire to acquire advanced skills in pharmacometrics, pediatric clinical trial conduct, and endpoint development and selection. The candidate’s short-term goals for the K23 program are to: 1) complete didactic training and practical experiences in population PK modeling and simulation; 2) characterize the PK of ampicillin in preterm infants and simulate optimal dosing regimens that account for post-discontinuation exposures; 3) obtain experiences in the conduct of interventional pediatric clinical trials; and 4) develop and apply a novel neonatal hierarchical ordinal endpoint to increase the efficiency of antibiotic trials in neonates. This proposal will capitalize on unique opportunities provided by the Duke Clinical Research Institute (Zimmerman, primary mentor; Cohen-Wolkowiez, co-mentor) and the University of North Carolina School of Pharmacy. The mentorship team assembled is uniquely qualified, with internationally recognized thought leadership in pediatric trial design and conduct, clinical pharmacology, and a successful history of mentorship of junior faculty. At the conclusion of this program, Dr. Boutzoukas will be well positioned to be an independent physician-scientist and leader in pediatric antibiotic stewardship research.

PROJECT NARRATIVE/PUBLIC HEALTH RELEVANCE Antibiotic exposures in preterm infants are common, but excess exposures can predispose to patient harm. Rigorous studies that aim to minimize unnecessary antibiotic exposures in this population are needed. This proposal seeks to minimize unnecessary exposure to ampicillin, the most commonly used antibiotic in preterm infants, and through the input of patients and families as well as neonatal experts, create a tool that can be used to study the outcomes of infants in future clinical trials that aim to reduce antibiotic exposures.