The candidate for this K23 Career Development Award, Kevin J. Downes, MD is a pediatric infectious diseases specialist with training in pediatric clinical pharmacology and a background in clinical research focusing on antimicrobial pharmacokinetics/pharmacodynamics (PK/PD) and antibiotic-associated acute kidney injury (AKI). Dr. Downes' long-term career goal is to become an independent investigator with expertise in both pharmacometrics and clinical trials. The proposed mentored research and career development plan promote this career goal by facilitating Dr. Downes' short-term goal to obtain didactic and experiential training in parametric and nonparametric population PK modeling and simulation, Bayesian adaptive control, and clinical trial design. He has assembled a strong team of mentors led by Athena Zuppa MD, MSCE (primary mentor) and Theoklis Zaoutis, MD, MSCE (co-mentor). His multidisciplinary mentorship team, comprised of national experts in clinical pharmacology, infectious diseases, nephrology, and critical care medicine, combined with the exceptional research environment of the Children's Hospital of Philadelphia and the University of Pennsylvania, will provide the resources and content expertise to ensure success of the proposed research and facilitate transition to academic independence. The proposed project seeks to improve the safety and efficacy of intravenous (IV) vancomycin administration in critically children by developing an approach to provide personalized, target-oriented vancomycin dosing. This proposal will involve a series of related prospective studies that will result in the development and implementation of an effective Bayesian dosing strategy to target vancomycin area under the curve (AUC24) in critically ill children.
Aim 1 will generate a population PK model for IV vancomycin, incorporating novel kidney injury biomarkers as covariates.
Aim 2 will identify the optimal sampling time to estimate AUC24 using Bayesian estimation (Aim 2A) and then validate the optimal sampling time (Aim 2B) in a separate cohort of children.
Aim 3 will pilot the feasability of Bayesian dosing to attain a targeted AUC24 goal in critically ill pediatric patients using real-time biomarker and vancomycin measurement and dosing adjustments. This proposal, combined with didactic training and strong mentorship in pharmacometrics and clinical research, will provide Dr. Downes with the foundation for an independent research career in pediatric clinical pharmacology and infectious diseases. This research will lead to development of future trials that investigate the ability of personalized antimicrobial dosing and selection to maximize treatment efficacy, decrease toxicity, and minimize the development of resistance in children receiving vancomycin. The skills learned during this career development award will be generalizable to the study of other antimicrobial agents and pediatric populations.

Public Health Relevance

Vancomycin is a commonly administered antibiotic in critically ill children, but it has a relatively narrow therapeutic window and there are currently no effective methods to prevent development of acute kidney injury (AKI) during therapy. This proposal seeks to improve the safety and efficacy of intravenous vancomycin administration in children by developing an approach to provide personalized, target-oriented vancomycin dosing in critically ill children, the population at highest risk for AKI and treatment failure. This research is highly relevant to public health as it aims to identify approaches to improve the health and safety of children requiring antibiotics for treatment of serious infections.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Mentored Patient-Oriented Research Career Development Award (K23)
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National Institute of Child Health and Human Development Initial Review Group (CHHD)
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Giacoia, George
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Children's Hospital of Philadelphia
United States
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Lavigne, Sondra; Fisher, Brian T; Ellis, Darcy et al. (2018) Posaconazole Administration in Hospitalized Children in the United States. J Pediatric Infect Dis Soc :
Downes, Kevin J; Fitzgerald, Julie C; Schriver, Emily et al. (2018) Implementation of a Pragmatic Biomarker-Driven Algorithm to Guide Antibiotic Use in the Pediatric Intensive Care Unit: the Optimizing Antibiotic Strategies in Sepsis (OASIS) II Study. J Pediatric Infect Dis Soc :
Downes, Kevin J; Ellis, Darcy; Lavigne, Sondra et al. (2018) The use of echinocandins in hospitalized children in the United States. Med Mycol :