Assessment of MODS and Personalized Exposures of Antibiotics

MODS 评估和个性化抗生素暴露

• 批准号: 10298249
• 负责人: Kevin James Downes
• 金额: $ 80.14万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10298249
• 关键词: Achievement; Acquired Immunodeficiency Syndrome; Affect; Antibiotic Therapy; Antibiotics; Bacterial Infections; Biological Assay; Biological Markers; Blood; Cessation of life; Child; Childhood; Clinical; Clinical Data; Clinical Trials; Critically ill children; Data; Decision Trees; Development; Dose; Drug Kinetics; Drug Monitoring; Effectiveness; Enrollment; Epidemiology; Functional disorder; Funding; Future; Goals; Hour; Immune Tolerance; Immune response; Immunocompetent; Infection; Infrastructure; Intervention; Kidney; Knowledge; Laboratories; Measures; Modeling; Modification; Morbidity - disease rate; Multiple Organ Failure; National Institute of Child Health and Human Development; Nosocomial Infections; Organ; Organ failure; Outcome; Pediatric Intensive Care Units; Physiology; Population; Prospective Studies; Publishing; Reaction Time; Renal function; Research; Risk Factors; Sampling; Source; Strategic Planning; Therapeutic; Time; Toxic effect; United States National Institutes of Health; Vancomycin; Weight; adverse outcome; base; beta-Lactams; high risk population; immune function; immunological status; improved outcome; models and simulation; mortality; mortality risk; pediatric pharmacology; pharmacokinetic model; simulation; therapeutically effective; tool; trial comparing; vancomycin B

ABSTRACT Multiple organ dysfunction syndrome (MODS) affects as many 57% of critically ill children, with mortality rates as high 67% in those infected. The long-term goal of this proposal, Antibiotics in MODS: PersonaLizing Exposures (AMPLE), is to leverage the well-established infrastructure from our PARADIGM study (R01HD095976) to identify optimal antibiotic dosing strategies for this highly understudied, high-risk population. Infection is a common occurrence in children with MODS, either as an inciting insult or as a result of a new, nosocomial infection. However, management of children with MODS and infection is complicated by the development of immune paralysis (IP), which has deleterious effects on immune function. Unfortunately, antibiotic management strategies and how they should be modified as a function of host immune status are key knowledge gaps in pediatric MODS. Timely attainment of target antibiotic concentrations is a crucially important, modifiable intervention to increase survival in these children, yet we currently have limited data on antibiotic pharmacokinetics (PK) in children with MODS with which to develop personalized dosing strategies. We will quantify antibiotic PK in 400 subjects enrolled in the PARADIGM study, an ongoing, NIHfunded, 22- center, prospective study of the epidemiology and risk factors for IP in 1,400 children with MODS. The objectives of this application are to use samples and clinical data from PARADIGM subjects to characterize the variability of concentrations for the antibiotics most commonly used in pediatric MODS; to investigate the relationships between antibiotic target attainment and outcomes in pediatric MODS with and without IP; and to develop model-based dosing approaches that rapidly achieve and maintain target antibiotic concentrations. The central hypothesis of this proposal is that precision, PK-driven antibiotic dosing strategies can be developed that adequately account for organ dysfunction and immune function in children with MODS. We propose to pursue the following AIMs: 1) To create and evaluate sophisticated population PK models for the 6 most commonly used antibiotics in pediatric MODS. 2) To define antibiotic target windows outside of which children with MODS (with and without immunoparalysis) who are being treated for infection are at increased risk for death and prolonged organ failure. 3) To use simulations to identify dosing strategies that achieve and maintain antibiotic concentrations within defined therapeutic windows. The proposed studies will answer the following key questions about the pharmacology of pediatric MODS: 1) What proportion of children are under- or over- exposed using the current standard dosing approaches?, 2) How does MODS impact antibiotic PK and outcomes in children?, 3) How does IP impact necessary target concentrations in pediatric MODS? This research is expected to be significant as it will result in first-of-its kind data that are a crucial and a necessary step toward developing Precision Antibiotic Dosing strategies for children with MODS.

抽象的 多器官功能障碍综合征（MOD）影响了57％的重症儿童，死亡率 在被感染者中高67％。该建议的长期目标，mod中的抗生素：个性化 暴露（足够）是利用我们的范式研究中建立的基础设施 （R01HD095976）确定这种高风险的最佳抗生素剂量策略 人口。感染是Mods儿童的常见发生，无论是作为煽动侮辱还是结果 一种新的医院感染。但是，管理和感染的儿童的管理很复杂 免疫瘫痪（IP）的发展，对免疫功能产生有害影响。很遗憾， 抗生素管理策略及其应如何根据宿主免疫状态进行修改 小儿mod中的关键知识差距。及时达到靶抗生素浓度是至关重要的 重要的，可修改的干预措施以增加这些孩子的生存，但我们目前的数据有限 具有MOD的儿童的抗生素药代动力学（PK），可以使用该MOD制定个性化剂量策略。 我们将在范式研究中纳入的400名受试者中量化抗生素PK，这是一项正在进行的，Nihfund的22-- 中心，对1,400名MOD儿童的流行病学和IP风险因素的前瞻性研究。 该应用程序的目标是使用范式受试者的样本和临床数据 表征小儿mod中最常用的抗生素浓度的变异性；到 研究与和 没有IP；并开发基于模型的剂量方法，以迅速实现和维持靶抗生素 浓度。该提议的中心假设是精确，PK驱动的抗生素剂量 可以开发出充分说明儿童器官功能障碍和免疫功能的策略 与mods。我们建议追求以下目的：1）创建和评估复杂的人群PK 小儿mod中6种最常用的抗生素的模型。 2）定义抗生素目标窗口 在其中接受感染治疗的MOD（有和没有免疫分析）的儿童之外 死亡风险增加和器官延长。 3）使用模拟来识别剂量策略 在定义的治疗窗口内实现并保持抗生素浓度。提出的研究 将回答有关儿科mod的药理学以下关键问题：1） 儿童使用当前的标准给药方法不足或过度暴露？，2）mod如何如何 影响儿童的抗生素PK和结果吗？3）IP如何影响必要的目标浓度 小儿mods？这项研究有望具有重要意义，因为它将导致首个数据 至关重要的和必要的步骤，为有MOD的儿童制定精确的抗生素剂量剂量策略。