Transplacental Antibiotic Exposures in Newborn Infants

PROJECT SUMMARY/ABSTRACT Optimizing antibiotic use is a strategy for limiting toxicity risk and combating resistance. Maternally-administered intrapartum antibiotics expose the fetus via the placenta, and result in variable neonatal antibiotic concentrations at birth. In some cases, the same antibiotics administered intrapartum to mothers (ampicillin and gentamicin) are also administered to newborns after birth due to risk of neonatal sepsis. However, intrapartum antibiotic exposures are not integrated into postnatal antibiotic dosing recommendations, risking excessive cumulative exposures. Furthermore, pharmacokinetic (PK) data are lacking to inform the adequacy of some antibiotics used for intrapartum antibiotic prophylaxis (IAP) against neonatal Group B Streptococcus (GBS) disease. These lacking data influence current national sepsis risk stratification guidelines, and may lead to overestimation of overall sepsis risk and prompt unnecessary postnatal antibiotic use in newborns. The purpose of this study is to identify pharmacologically-based frameworks to safely optimize neonatal antibiotic use. Its specific aims are: (1A) to quantify maternally-administered ampicillin and gentamicin in maternal and umbilical cord blood; (1B) to characterize maternal and umbilical cord blood concentrations of second-line GBS IAP agents, vancomycin and clindamycin; and (2) to perform maternal-neonatal population PK modeling integrating intrapartum and postnatal ampicillin and gentamicin exposures. These Aims will focus on a newborn population lacking PK data, enriched with preterm infants, and will use both prospectively consented and opportunistically-scavenged samples. This study will directly address top NICHD research priorities: improving understanding of developmental pharmacokinetics in the perinatal period, and optimizing antibiotic use in order to promote neonatal therapeutic safety. These Aims will inform neonatal empiric antibiotic prescribing based on intrapartum antibiotic exposures – with potential to limit excessive antibiotic dosing and to optimize neonatal sepsis risk stratification. This career development award is designed to support the transition of Dr. Sarah Coggins, Instructor of Pediatrics the University of Pennsylvania and Attending Neonatologist at the Children’s Hospital of Philadelphia, into an independent clinician-investigator. This award will further assist her in achieving her long-term career goal of becoming an expert in antimicrobial pharmacology, and using her expertise to optimize the care of infants at risk for severe infections. In addition, this award will allow her to obtain the training, mentorship, and research experience necessary to successfully compete for future R01 grants in this arena. Dr. Coggins will receive advanced training and experiential learning in pharmacokinetic modeling, pharmacoepidemiology, and advanced statistical methods. The University of Pennsylvania and Children’s Hospital of Philadelphia provide a stellar research environment for this proposed study. This project will be guided by an outstanding mentorship team with a track record of successful collaboration and scholarship, including experts in neonatology, clinical pharmacology, infectious diseases, biostatistics, and epidemiology.