Assessment of MODS and Personalized Exposures of Antibiotics

MODS 评估和个性化抗生素暴露

• 批准号: 10677658
• 负责人: Kevin James Downes
• 金额: $ 74.28万
• 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/10677658
• 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; Epidemiologic Factors; 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; Qualifying; Research; Risk Factors; Sampling; Source; Strategic Planning; Therapeutic; Time; Toxic effect; United States National Institutes of Health; Vancomycin; Weight; adverse outcome; beta-Lactams; high risk population; immune function; immunological status; improved outcome; models and simulation; mortality; mortality risk; pediatric pharmacology; pediatric sepsis; pharmacokinetic model; simulation; therapeutically effective; tool; trial comparing

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 (MODS) 影响多达 57% 的危重儿童，死亡率很高 感染者的比例高达 67%。该提案的长期目标，MODS 中的抗生素：个性化 Exposures (AMPLE) 是利用我们 PARADIGM 研究中完善的基础设施 (R01HD095976) 以确定针对这种高度研究不足的高风险的最佳抗生素剂量策略 人口。感染在患有 MODS 的儿童中很常见，无论是作为煽动性侮辱还是作为结果 新的院内感染。然而，患有 MODS 和感染的儿童的管理很复杂， 免疫麻痹（IP）的发展，对免疫功能产生有害影响。很遗憾， 抗生素管理策略以及如何根据宿主免疫状态对其进行修改 儿科 MODS 的关键知识差距。及时达到目标抗生素浓度是至关重要的 对于提高这些儿童的生存率来说，重要的、可修改的干预措施，但我们目前的数据有限 MODS 儿童的抗生素药代动力学 (PK)，用于制定个性化剂量策略。 我们将量化参加 PARADIGM 研究的 400 名受试者的抗生素 PK，这是一项正在进行的、由 NIH 资助的 22- 中心对 1,400 名 MODS 儿童的 IP 流行病学和危险因素进行了前瞻性研究。 该应用程序的目标是使用来自 PARADIGM 受试者的样本和临床数据 描述儿科 MODS 最常用抗生素浓度的变异性；到 调查抗生素目标达成与儿科 MODS 结局之间的关系 没有IP；并开发基于模型的给药方法，以快速实现和维持目标抗生素 浓度。该提案的中心假设是精确的、PK 驱动的抗生素剂量 可以制定充分考虑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标：1）创建和评估复杂的群体 PK 儿科 MODS 中 6 种最常用抗生素的模型。 2) 定义抗生素靶点窗口 除此之外，正在接受感染治疗的MODS（有或没有免疫麻痹）的儿童 死亡和长期器官衰竭的风险增加。 3) 使用模拟来确定给药策略 在规定的治疗窗口内达到并维持抗生素浓度。拟议的研究 将回答以下有关儿科 MODS 药理学的关键问题： 1) 使用当前标准剂量方法，儿童是否暴露不足或过度？, 2) MODS 如何 影响儿童的抗生素 PK 和结果？, 3) IP 如何影响抗生素的必要目标浓度 儿科MODS？这项研究预计将具有重要意义，因为它将产生首个此类数据 为 MODS 儿童制定精准抗生素剂量策略至关重要且必要的一步。

项目成果

Bioanalysis of six antibiotics from volumetric microsamples: a new tool for precision dosing in critically ill children.

对体积微量样品中的六种抗生素进行生物分析：危重儿童精确给药的新工具。

• DOI: 10.4155/bio-2023-0171
• 发表时间: 2024
• 期刊: Bioanalysis
• 影响因子: 1.8
• 作者: Takyi-Williams,John;Leino,AbbieD;Li,Ruiting;Downes,KevinJ;Zuppa,AthenaF;Bwint,Amanda;Wen,Bo;Sun,Duxin;Scheetz,MarcH;Pai,ManjunathP
• 通讯作者: Pai,ManjunathP

Making the case for precision dosing: visualizing the variability of cefepime exposures in critically ill adults.

论证精确给药：可视化危重成人头孢吡肟暴露的变异性。

• DOI: 10.1093/jac/dkad211
• 发表时间: 2023
• 期刊: The Journal of antimicrobial chemotherapy
• 作者: Chang,Jack;Liu,Jiajun;Alshaer,MohammadH;Venugopalan,Veena;Maranchick,Nicole;Peloquin,CharlesA;Rhodes,NathanielJ;Scheetz,MarcH
• 通讯作者: Scheetz,MarcH