Optimizing Vancomycin Therapy in Children

优化儿童万古霉素治疗

• 批准号: 10438596
• 负责人: Kevin James Downes
• 金额: $ 14.94万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-10 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10438596
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Adverse drug event; Age; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Area Under Curve; Bayesian Analysis; Bayesian Method; Biological Markers; Blood; Blood specimen; Cause of Death; Characteristics; Child; Childhood; Clinical; Clinical Pharmacology; Clinical Research; Clinical Trials; Clinical Trials Design; Communicable Diseases; Computer software; Creatinine; Critical Care; Critical Illness; Critically ill children; Data; Development; Development Plans; Dose; Drug Kinetics; Drug Monitoring; Ensure; Environment; Exhibits; Foundations; Future; Goals; Health; Hospital Mortality; Infection; Injury to Kidney; Intravenous; K-Series Research Career Programs; LCN2 gene; Lead; Measurement; Measures; Medicine; Mentors; Mentorship; Methods; Modeling; Nephrology; Outcome; Patients; Pediatric Hospitals; Pediatric Intensive Care Units; Pennsylvania; Pharmaceutical Preparations; Philadelphia; Pilot Projects; Plasma; Population; Prospective Studies; Prospective cohort; Public Health; Recording of previous events; Renal function; Research; Research Personnel; Research Proposals; Resistance development; Resources; Risk Factors; Safety; Sampling; Sepsis; Series; Serum; Specialist; Testing; Therapeutic; Time; Toxic effect; Training; Treatment Efficacy; Treatment Failure; Universities; Validation; Vancomycin; antimicrobial; antimicrobial drug; base; career; career development; cohort; control trial; design; dosage; drug clearance; effective therapy; high risk; improved; models and simulation; mortality; multidisciplinary; novel; novel marker; osteopontin; pediatric patients; pharmacokinetic model; pharmacokinetics and pharmacodynamics; pharmacometrics; post gamma-globulins; predictive modeling; prevent; prospective; research and development; skills; success; therapeutic target; urinary

PROJECT SUMMARY/ABSTRACT 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.

项目总结/文摘

项目成果

Optimizing Vancomycin Therapy in Critically Ill Children: A Population Pharmacokinetics Study to Inform Vancomycin Area under the Curve Estimation Using Novel Biomarkers.

在重症儿童中优化万古霉素治疗：一项种群药代动力学研究，可在曲线估计下使用新型生物标志物在曲线估计下为万古霉素区域提供信息。

• DOI: 10.3390/pharmaceutics15051336
• 发表时间: 2023-04-25
• 期刊: Pharmaceutics
• 影响因子: 5.4
• 作者: Downes KJ;Zuppa AF;Sharova A;Neely MN
• 通讯作者: Neely MN

Development and validation of a volumetric absorptive microsampling- liquid chromatography mass spectrometry method for the analysis of cefepime in human whole blood: Application to pediatric pharmacokinetic study.

用于分析人全血中头孢吡肟的体积吸收微量采样-液相色谱质谱法的开发和验证：在儿科药代动力学研究中的应用。

• DOI: 10.1016/j.jpba.2019.113002
• 发表时间: 2020
• 期刊: Journal of pharmaceutical and biomedical analysis
• 影响因子: 3.4
• 作者: Moorthy,GaneshS;Vedar,Christina;Zane,NicoleR;Downes,KevinJ;Prodell,JaniceL;DiLiberto,MaryAnn;Zuppa,AthenaF
• 通讯作者: Zuppa,AthenaF

Procalcitonin in Pediatric Sepsis: What Is It Good for?

• DOI: 10.1093/jpids/piab066
• 发表时间: 2021-07
• 期刊: Journal of the Pediatric Infectious Diseases Society
• 影响因子: 3.2
• 作者: K. Downes

Estimating renal function for drug dosing in critically ill patients with persistent inflammation, immunosuppression and catabolism syndrome.

评估患有持续性炎症、免疫抑制和分解代谢综合征的危重患者的肾功能以决定药物剂量。

• DOI: 10.1007/s11739-021-02770-4
• 发表时间: 2021
• 期刊: Internal and emergency medicine
• 影响因子: 4.6
• 作者: Downes,KevinJames;Barreto,ErinFrazee
• 通讯作者: Barreto,ErinFrazee

Return to School and COVID-19 Vaccination for Pediatric Solid Organ Transplant Recipients in the United States: Expert Opinion for 2021-2022.

• DOI: 10.1093/jpids/piab098
• 发表时间: 2022-02-23
• 期刊: Journal of the Pediatric Infectious Diseases Society
• 影响因子: 3.2
• 作者: Downes KJ;Statler VA;Orscheln RC;Cousino MK;Green M;Michaels MG;Muller WJ;Sharma TS;Danziger-Isakov LA;Ardura MI
• 通讯作者: Ardura MI