Pediatric septic acute kidney injury: personalizing antibiotic dosing through understanding acute kidney injury risk factors and biomarker profiles

项目摘要/摘要 美国每年发生超过75,000例儿童严重脓毒症，死亡率为10%-30%，而且显著 幸存者有新的残疾风险。急性肾损伤(AKI)并发25%的儿童严重脓毒症， 与死亡和残疾风险进一步增加有关。菲茨杰拉德博士的目标是定义生物标记物 与败血症AKI相关的表型和抗生素暴露，以利用这些来改善药理学 预测万古霉素处置的模型，并测试个性化万古霉素处方和 在一项试点试验中进行剂量调整，目的是提高抗生素疗效并降低对肾脏的毒性。 这些结果将为未来减少儿童败血症AKI的大型介入研究提供信息，目标是 使败血症儿童能够活得更长、更健康、没有残疾，这与NIDDK的使命是一致的。 候选人：朱莉·菲茨杰拉德博士，加州大学儿科重症监护助理教授 宾夕法尼亚州佩雷尔曼医学院(PSOM)和费城儿童医院 她在儿科败血症AKI中以病人为中心的临床研究。菲茨杰拉德博士的近期目标是 前瞻性地研究败血症AKI的危险因素；获得药物计量学应用于 一种特殊的儿科危重疾病和临床试验实施方面的培训；以及向研究过渡 独立。她的长期目标是通过以下途径改善脓毒症儿童的健康和生活质量 测试减少败血症相关器官功能障碍的干预措施。菲茨杰拉德博士的职业发展 计划包括药理学和临床试验管理的课程；个性化的专家指导； 由专家顾问提供关于拟议方法的培训；完成拟议的具体目标。 环境：卓越的研究基础设施、教育资源和专家指导 候选人所在的院校将支持成功完成提案。一个研究协调小组将 协助受试者招募和研究程序，部门统计员将协助分析。 研究：研究目标是确定与脓毒症相关的危险因素和生物标记物表型 Aki，并利用这些来改进万古霉素处置的药理学模型的性能。这个 将通过以下具体目标实现目标：1)确定生物标记物表型和 与败血症AKI相关的万古霉素暴露，2)优化万古霉素群体药代动力学 建立性能模型并确定硅胶的靶向给药策略，以及3)确定试验的可行性 在床边实施个性化万古霉素药代动力学模型。在一个预期的队列中 有严重脓毒症、尿液生物标志物、万古霉素浓度和药物暴露的危重儿童 将收集数据并测量与AKI的关联性。模型驱动的万古霉素最优给药策略 将通过计算机建模导出，并实现个性化模型驱动的可行性 万古霉素处方将在一项试点干预试验中进行测试，该试验招募了20名患有严重脓毒症的儿童。

PROJECT SUMMARY/ABSTRACT 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.