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 儿童败血症和多器官功能障碍综合征(MODS)的发病率和死亡率是相当高的。 及时将有效的抗生素浓度输送到感染部位决定了治疗结果，但 败血症儿童的抗生素药代动力学(PK)变化很大，经常导致低于或超过... 治疗性抗生素浓度。为了确保最佳的临床和微生物学结果，实现和 在整个治疗过程中保持安全和有效的抗生素浓度是至关重要的。 尽管如此，败血症儿童的抗生素剂量主要是基于儿童的体重和肾功能， 不考虑PK变异性的其他来源，而临床测量的抗生素浓度是 只为很少的毒品表演。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：高炎症和脓毒症引起的免疫功能障碍 (即免疫麻痹)既是常见的，也是恶化的结果。此外，在患有严重疾病的儿童中 呼吸衰竭、细菌负荷和呼吸道微生物群的组成对两个宿主都有影响 炎症和临床结果。了解宿主免疫反应、抗生素PK和 微生物群相互关联并影响临床结果，是优化儿童败血症治疗的当务之急。 协作性儿科危重护理研究网络(CPCCRN)将同时进行两项 盲法、安慰剂对照RCT评估个体化免疫调节的影响(Anakinra用于 高炎症；GM-CSF用于免疫麻痹)对儿童脓毒症患者器官功能结局的影响 MODS。这些试验(名为PRECISE)为评估宿主之间的相互作用提供了一个独特的框架 免疫表型(炎症、免疫麻痹)、免疫调节和抗生素PK/PD通过 我们的提议。我们将利用精确试验和CPCCRN基础设施来评估PK的来源 脓毒症和MODS儿童的变异性，研究宿主免疫反应是如何纵向调节的 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 呼吸道微生物群。在目标1中，我们将确定宿主免疫表型和反应的影响 抗生素PK早期(1A)和全程(1B)对小儿败血症的免疫调节作用 MODS。目标2侧重于了解抗生素浓度如何影响器官功能结果 儿科脓毒症致多器官功能障碍综合征的免疫调节背景。最后，目标3将量化抗生素如何 浓度、免疫表型和免疫调节随着时间的推移影响呼吸道微生物群 败血症合并呼吸衰竭的儿童。通过量化抗生素浓度和评估 在脓毒症抗生素PK免疫调节的背景下，我们的建议将促进 脓毒症致多器官功能障碍综合征的个体化治疗策略。