Longitudinal Assessment of Beta-lactam Antibiotic Exposure in in Critically Ill Children with Sepsis in the PICU to Predict Dosing Requirements

对 PICU 中脓毒症危重儿童的 β-内酰胺抗生素暴露进行纵向评估以预测剂量需求

• 批准号: 9752320
• 负责人: John S Bradley
• 金额: $ 63.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-28 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752320
• 关键词: Abdomen; Acute Renal Failure with Renal Papillary Necrosis; Admission activity; Anatomy; Anti-Bacterial Agents; Antibiotics; Bacterial Infections; Biological Markers; Bladder; Blood Volume; Capillary Leak Syndrome; Cardiac Output; Catheters; Child; Clinical; Clinical Microbiology; Clinical Trials; Comorbidity; Complex; Computer Simulation; Critically ill children; Dose; Drug Exposure; Drug Kinetics; Excretory function; Exposure to; Extravasation; FDA approved; Genetic; Guidelines; Hospitalization; IV Fluid; Immune; Infant; Infection; Intravenous; Kidney; LCN2 gene; Laboratories; Lead; Legal patent; Life; Liquid substance; Malignant Neoplasms; Measurement; Measures; Mediastinal; Mediating; Meropenem; Microbiology; Modeling; Monobactams; Morbidity - disease rate; Organ; Patient Care; Pediatric Intensive Care Units; Perfusion; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Physiological; Physiology; Plasma; Pleural; Population; Prospective Studies; Recovery; Renal function; Research; Resuscitation; Risk; Risk Estimate; Safety; Secondary to; Sepsis; Sepsis Syndrome; Septic Shock; Shock; Specific qualifier value; TIMP2 gene; Techniques; Testing; Therapeutic; Time; Time trend; Tissues; Toxic effect; Toxicant exposure; Trauma; Tubular formation; United States; Urine; Variant; antimicrobial; antimicrobial drug; base; beta-Lactams; classification trees; clinical efficacy; clinically relevant; drug distribution; glomerular filtration; high risk; longitudinal analysis; mortality; mortality risk; neonate; novel; off-patent; pathogen; patient subsets; pharmacodynamic model; pharmacokinetic model; post gamma-globulins; regression trees; standard of care; tool; trend

Project Summary Bacterial sepsis and septic shock are among the most common causes of admission to pediatric intensive care units (PICU) in the United States. Morbidity and mortality remain high for neonates, infants and children with increasingly complicated comorbidities (cancer, trauma, complex genetic and anatomic anomalies) with many being immune compromised from breaches in anatomic barriers with catheters (intravenous, bladder, pleural/mediastinal space, abdominal) as well as secondary to immune-ablative and immune-suppressive therapy. All children who present to the PICU with sepsis syndrome receive empiric antimicrobial therapy. Currently, doses of antimicrobial agents used for children in the PICU are based on pharmacokinetic descriptions of drug distribution and elimination in children without severe infections; this population is usually excluded from participation in FDA mandated clinical trials for safety and efficacy of new antibacterial agents. For infants and children with bacterial sepsis, attaining an antimicrobial drug exposure that is adequate for microbiologic and clinical cure is essential for survival. In these children, dramatic and rapid changes in kidney function during the first days of hospitalization for sepsis based on changes in cardiac output and organ perfusion can lead to increased or decreased renal elimination of antibiotics. Additional reasons for inadequate antibiotic exposure include leakage of fluids and antibiotics into tissues (capillary leak syndrome) and changes in circulating blood volume following massive intravenous fluid resuscitation (up to 100 mL/kg), not uncommon in septic shock. We plan to analyze antibiotic exposure and renal function in critically ill children receiving FDA-approved doses of a standard-of-care (SOC), generic beta-lactam antibiotic with broad spectrum antibacterial activity, meropenem, focusing on each of the first 3 days of admission, when the most dramatic alterations in physiology occur. By measuring plasma and urine concentrations in 50 children daily for the first 3 days in the PICU, we can define the adequacy of beta-lactam exposure with current SOC therapy. We will create pharmacokinetic-pharmacodynamic models, that can allow us to analyze physiologic factors, renal toxicity and function, sepsis scores, and laboratory tests/biomarkers that may be associated with subtherapeutic or potentially toxic exposures. Ultimately, we plan to present new antibiotic dosing guidelines for children with sepsis in the PICU, with the potential to optimize daily dosing to save lives and decrease sepsis-mediated morbidity.

项目概要 细菌性败血症和感染性休克是儿科重症监护室最常见的原因之一 美国的儿科重症监护病房 (PICU)。新生儿、婴儿和儿童的发病率和死亡率仍然很高 日益复杂的合并症（癌症、创伤、复杂的遗传和解剖异常） 由于导管（静脉内、膀胱、 胸膜/纵隔间隙、腹部）以及继发于免疫消融和免疫抑制 治疗。所有因败血症综合征而进入 PICU 的儿童均接受经验性抗菌药物治疗 治疗。目前，PICU儿童使用的抗菌药物剂量是根据药代动力学确定的。 描述未发生严重感染的儿童的药物分布和消除情况；这个人群通常是 被排除在 FDA 授权的新抗菌药物安全性和有效性临床试验之外。 对于患有细菌性败血症的婴儿和儿童，获得的抗菌药物暴露量为 充分的微生物学和临床治愈对于生存至关重要。在这些孩子身上，戏剧性和 因脓毒症住院的第一天，根据心脏变化，肾功能发生快速变化 输出量和器官灌注可导致肾脏消除抗生素的增加或减少。额外的 抗生素暴露不足的原因包括液体和抗生素渗漏到组织中（毛细血管渗漏 综合征）和大量静脉液体复苏后循环血量的变化（最多 100 mL/kg），在感染性休克中并不罕见。 我们计划分析接受 FDA 批准剂量的危重儿童的抗生素暴露和肾功能 具有广谱抗菌活性的标准护理 (SOC)、通用 β-内酰胺抗生素， 美罗培南，重点关注入院前 3 天的每一天，此时 生理发生。通过在试验的前 3 天每天测量 50 名儿童的血浆和尿液浓度 在 PICU，我们可以定义当前 SOC 治疗中 β-内酰胺暴露的充分性。我们将创造 药代动力学-药效学模型，可以让我们分析生理因素、肾毒性和 功能、脓毒症评分以及可能与亚治疗或亚治疗相关的实验室测试/生物标志物 潜在的有毒暴露。最终，我们计划为患有以下疾病的儿童提出新的抗生素剂量指南 PICU 中的脓毒症，有可能优化每日剂量以挽救生命并减少脓毒症介导的 发病率。