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

项目总结/摘要 脓毒症和多器官功能障碍综合征（MODS）患儿的发病率和死亡率很高。 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， 抗生素药代动力学（PK）在脓毒症儿童中变化很大，经常导致亚或超 抗生素治疗浓度。为了确保最佳的临床和微生物学结果， 在整个治疗过程中维持安全和有效的抗生素浓度是至关重要的。 尽管如此，脓毒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变异性的其他来源，而抗生素浓度的临床测量是 很少的药物。宿主对感染的反应是器官功能障碍的主要驱动因素， 儿科脓毒症的抗生素PK变异性：炎症过度以及脓毒症诱导的免疫功能障碍 (i.e.免疫麻痹）是常见和恶化的结果。此外，在重症儿童中， 呼吸衰竭、细菌负荷和呼吸道微生物组的组成影响两种宿主 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，对于优化儿科败血症的治疗至关重要。 合作儿科重症监护研究网络（CPCCRN）将进行两个同时，双- 采用盲法、安慰剂对照随机对照试验，评价个体化免疫调节（阿那白滞素对 炎症过度; GM-CSF用于免疫麻痹）对儿科脓毒症诱导的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（过度炎症、免疫麻痹）、免疫调节和抗生素PK/PD， 我们的提议我们将利用PRECISE试验和CPCCRN基础设施评价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 呼吸道微生物组在目标1中，我们将确定宿主免疫表型和应答的影响 免疫调节对儿科脓毒症诱导的早期（1A）和整个过程（1B）抗生素PK的影响 MODS。目标2的重点是了解抗生素浓度如何影响器官功能结果， 免疫调节在儿科脓毒症诱导的MODS中的作用。最后，目标3将量化抗生素 浓度、免疫表型和免疫调节随时间推移影响呼吸道微生物组， 败血症患儿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，脓毒症中的抗生素PK，我们的建议将促进 脓毒症诱导的MODS期间的个体化治疗策略。

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.