PediatRic sEpsiS induCed MODS: Relationship of Immune-phenotypes and antiBiotic Exposures (PRESCRIBE) study

小儿败血症诱发的 MODS：免疫表型与抗生素暴露的关系 (PRESCRIBE) 研究

基本信息

批准号：
10563839
负责人：
Kevin James Downes
金额：
$ 86.85万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-19 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10563839
关键词：
Age Anti-Inflammatory Agents Antibiotics Biological Blood Blood capillaries Blood specimen Child Childhood Clinical Critical Care Critical Illness Critically ill children Development Dose Double-Blind Method Drug Kinetics Enrollment Ensure Fever Functional disorder Granulocyte-Macrophage Colony-Stimulating Factor Immune Immune System Diseases Immune response Immunophenotyping Impairment Infection Inflammation Inflammation Mediators Inflammatory Response Knowledge Leukocytes Lower Respiratory Tract Infection Maintenance Measurement Measures Metagenomics Morbidity - disease rate Multicenter Trials Names Network Infrastructure Organ Outcome Perfusion Pharmaceutical Preparations Phenotype Placebo Control Population Production Recovery of Function Renal function Research Respiratory Failure Respiratory System Risk Sampling Sepsis Site Source Survivors Syndrome Testing Therapeutic Time Tissues Treatment outcome Weight adverse outcome anakinra high risk immunoregulation individualized medicine microbiome microbiome composition mortality next generation sequencing pathogenic bacteria pediatric sepsis pharmacokinetic model primary outcome randomized trial respiratory microbiome respiratory pathogen response secondary analysis septic simulation treatment optimization treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT Morbidity and mortality in children with sepsis and multi-organ dysfunction syndrome (MODS) are substantial. Timely delivery of effective antibiotic concentrations to the site of infection dictates treatment outcomes, but antibiotic pharmacokinetics (PK) are highly variable in septic children, frequently leading to sub- or supra- therapeutic antibiotic concentrations. To ensure optimal clinical and microbiologic outcomes, attainment and maintenance of safe and effective antibiotic concentrations throughout the treatment course are paramount. Despite this, antibiotic dosing in children with sepsis is based primarily by a child’s weight and kidney function, without regard to other sources of PK variability, while clinical measurement of antibiotic concentrations is performed for very few drugs. The host response to infection is a major driver of organ dysfunction and antibiotic PK variability in pediatric sepsis: hyperinflammation, as well as sepsis-induced immune dysfunction (i.e. immunoparalysis), are both common and exacerbate outcomes. Further, in critically ill children with respiratory failure, bacterial burden and composition of the respiratory tract microbiome impact both host inflammation and clinical outcomes. Understanding how the host immune response, antibiotic PK, and the microbiome interrelate, and influence clinical outcomes, is imperative to optimize treatment in pediatric sepsis. The Collaborative Pediatric Critical Care Research Network (CPCCRN) will perform two concurrent, double- blind, placebo-controlled RCTs to evaluate the impact of individualized immunomodulation (anakinra for hyperinflammation; GM-CSF for immunoparalysis) on organ function outcomes in pediatric sepsis-induced MODS. These trials (named PRECISE) provide a unique framework for evaluating the interplay between host immunophenotype (hyperinflammation, immunoparalysis), immunomodulation, and antibiotic PK/PD through our proposal. We will leverage PRECISE trials and CPCCRN infrastructure to evaluate sources of PK variability in children with sepsis and MODS, investigate how host immune responses longitudinally modulate antibiotic concentrations, and study how antibiotic concentrations impact organ dysfunction duration and the respiratory tract microbiome. In Aim 1, we will determine the influence of host immunophenotype and response to immunomodulation on antibiotic PK early (1A) and throughout the course (1B) of pediatric sepsis-induced MODS. Aim 2 focuses on understanding how antibiotic concentrations impact organ function outcomes in the context of immunomodulation in pediatric sepsis-induced MODS. Lastly, Aim 3 will quantify how antibiotic concentrations, immunophenotype and immunomodulation impact the respiratory tract microbiome over time in septic children with respiratory failure. By quantifying antibiotic concentrations and evaluating the drivers of antibiotic PK in sepsis in the context of immunomodulation, our proposal will facilitate development of individualized treatment strategies during sepsis-induced MODS.

项目概要/摘要脓毒症和多器官功能障碍综合征（MODS）儿童的发病率和死亡率很高。及时向感染部位提供有效浓度的抗生素决定了治疗结果，但是脓毒症儿童的抗生素药代动力学 (PK) 变化很大，经常导致亚或超确保最佳的治疗临床和微生物学结果、达到和在整个治疗过程中维持安全有效的抗生素浓度至关重要。尽管如此，败血症儿童的抗生素剂量主要取决于儿童的体重和肾功能，不考虑 PK 变异的其他来源，而抗生素浓度的临床测量是宿主对感染的反应是器官功能障碍的主要驱动因素。小儿脓毒症中抗生素 PK 的变异性：过度炎症以及脓毒症引起的免疫功能障碍（即免疫麻痹），在重症儿童中都是常见且恶化的结果。呼吸衰竭、细菌负荷和呼吸道微生物组的组成都会影响宿主了解宿主免疫反应、抗生素 PK 和临床结果。微生物组相互关联并影响临床结果，对于优化儿科败血症的治疗至关重要。儿科重症监护协作研究网络 (CPCCRN) 将同时进行两项双盲法、安慰剂对照随机对照试验，评估个体化免疫调节的影响（阿那白滞素过度炎症；GM-CSF 免疫麻痹）对小儿败血症引起的器官功能结果的影响 MODS。这些试验（名为 PRECISE）提供了评估宿主之间相互作用的独特框架。免疫表型（过度炎症、免疫麻痹）、免疫调节和抗生素 PK/PD 我们的提案将利用 PRECISE 试验和 CPCCRN 基础设施来评估 PK 来源。脓毒症和 MODS 儿童的变异性，研究宿主免疫反应如何纵向调节抗生素浓度，并研究抗生素浓度如何影响器官功能障碍的持续时间和在目标 1 中，我们将确定宿主免疫表型和反应的影响。儿科败血症引起的早期 (1A) 和整个病程 (1B) 中抗生素 PK 的免疫调节 MODS 目标 2 侧重于了解抗生素浓度如何影响器官功能结果。最后，目标 3 将量化抗生素在儿童脓毒症引起的 MODS 中的免疫调节作用。随着时间的推移，浓度、免疫表型和免疫调节会影响呼吸道微生物组通过量化抗生素浓度并评估导致呼吸衰竭的脓毒症儿童。在免疫调节的背景下脓毒症中的抗生素 PK，我们的建议将促进开发脓毒症诱发的 MODS 期间的个体化治疗策略。