Over 75,000 cases of pediatric severe sepsis occur in the US per year with mortality of 10-30%, and significant risk of new disability in survivors. Acute kidney injury (AKI) complicates 25% of pediatric severe sepsis, and is associated with further increased risk of mortality and disability. Dr. Fitzgerald?s goals are to define biomarker phenotypes and antibiotic exposures associated with septic AKI, to use these to improve pharmacologic models predicting vancomycin disposition, and test a strategy of personalized vancomycin prescribing and dose adjustments in a pilot trial with a goal of increased antibiotic efficacy and lower toxicity to the kidney. These results will inform future large interventional studies to reduce pediatric septic AKI, with the goal of allowing children with sepsis to lead longer, healthier lives free from disability, aligning with NIDDK?s mission. Candidate: Dr. Julie Fitzgerald, Assistant Professor of Pediatric Critical Care at The University of Pennsylvania Perelman School of Medicine (PSOM) and the Children's Hospital of Philadelphia, is focusing her research on patient-oriented clinical research in pediatric septic AKI. Dr. Fitzgerald?s immediate goals are to prospectively study septic AKI risk factors; obtain research training in the application of pharmacometrics to a specific pediatric critical illness and training in clinical trial implementation; and transition to research independence. Her long-term goal is to improve health and quality of life for children with sepsis through testing interventions to decrease sepsis-associated organ dysfunction. Dr. Fitzgerald?s career development plan includes coursework in pharmacology and clinical trial management; individualized expert mentoring; training by expert consultants in the proposed methodology; and completion of the proposed specific aims. Environment: The outstanding research infrastructure, educational resources, and expert mentorship at the candidate?s institution will support successful completion of the proposal. A research coordinator team will assist with subject recruitment and study procedures, and departmental statisticians will assist with analyses. Research: The study objectives are to define risk factors and biomarker phenotypes associated with septic AKI, and to use these to improve performance of pharmacologic models of vancomycin disposition. The objectives will be reached through the following specific aims: 1) to define biomarker phenotypes and vancomycin exposures associated with septic AKI, 2) to optimize vancomycin population pharmacokinetic model performance and identify targeted dosing strategies in silico, and 3) to determine the feasibility of a trial implementing personalized vancomycin pharmacokinetic models at the bedside. In a prospective cohort of critically ill children with severe sepsis, urine biomarkers, vancomycin concentrations, and medication exposure data will be collected and association with AKI measured. Optimal model-driven vancomycin dosing strategies will be derived through computer modeling, and the feasibility of implementing personalized model-driven vancomycin prescribing will be tested in a pilot interventional trial enrolling 20 children with severe sepsis.
Sepsis-associated acute kidney injury is a major source of morbidity and mortality in critically ill children, increasing the short-term risk of mortality and the risk of developing a new disability for those who survive. This proposal will evaluate urine biomarkers to improve early detection of those at risk for pediatric sepsis- associated acute kidney injury, determine potentially modifiable risk factors related to medication therapies for sepsis that are associated with risk of acute kidney injury progression, use these biomarkers and risk factors to improve pharmacologic models predicting appropriate antibiotic dosing, and test these new pharmacologic models for antibiotic dose adjustments in a pilot trial, which may lead to more effective antibiotic treatment in sepsis with lower risk of toxicity. These results will inform future interventional studies to target therapeutic strategies to reduce or prevent pediatric sepsis-associated acute kidney injury in those at high risk, with the ultimate goal of allowing children to lead longer, healthier lives free from disability.