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

• 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
• 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

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.

项目摘要/摘要 败血症和多器官功能障碍综合征（MOD）儿童的发病率和死亡率很大。 及时将有效的抗生素浓度输送到感染部位决定治疗结果，但 抗生素药代动力学（PK）在化粪池儿童中的变化很大，经常导致亚属或超质量 治疗性抗生素浓度。确保最佳的临床和微生物结果，成就和 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给药主要基于儿童的体重和肾功能， 不考虑其他PK可变性的来源，而抗生素浓度的临床测量是 进行的药物很少。宿主对感染的反应是器官功能障碍的主要驱动力和 小儿脓毒症的抗生素PK变异性：高炎症以及败血症诱导的免疫功能障碍 （即免疫分析）是常见和恶化的结果。此外，在重病的孩子中 呼吸衰竭，细菌燃烧和呼吸道微生物组的组成均影响宿主 炎症和临床结果。了解宿主免疫反应，抗生素PK和 微生物组相互关联并影响临床结果，必须优化小儿脓毒症的治疗。 协作小儿重症监护研究网络（CPCCRN）将执行两个并发双重 盲人，安慰剂控制的RCT评估个性化免疫调节的影响（Anakinra for Anakinra 高炎症； GM-CSF用于免疫分析）关于小儿败血症诱导的器官功能结果 mods。这些试验（命名精确）为评估主机之间的相互作用提供了独特的框架 免疫表型（高炎，免疫分析），免疫调节和抗生素PK/PD通过 我们的建议。我们将利用精确的试验和CPCCRN基础设施来评估PK的来源 败血症和mod儿童的变异性，研究宿主如何纵向调节宿主 抗生素浓度，并研究抗生素浓度如何影响器官功能障碍持续时间和 呼吸道微生物组。在AIM 1中，我们将确定宿主免疫表型和反应的影响 早期对抗生素PK的免疫调节（1A）和整个小儿脓毒症诱导的（1B） mods。 AIM 2专注于理解抗生素浓度如何影响器官功能结果 小儿脓毒症诱导的mod中免疫调节的背景。最后，AIM 3将量化抗生素 浓度，免疫表型和免疫调节会影响呼吸道微生物组随着时间的流逝而影响 化粪池儿童呼吸衰竭。通过量化抗生素浓度并评估 在免疫调节的背景下，败血症中的抗生素PK，我们的建议将促进 败血症引起的mod期间的个性化治疗策略。