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

项目摘要 细菌性脓毒症和脓毒性休克是儿科重症监护最常见的原因之一 PICU（美国）新生儿、婴儿和儿童的发病率和死亡率仍然很高， 越来越复杂的合并症（癌症、创伤、复杂的遗传和解剖异常）， 对导管（静脉内，膀胱， 胸膜/纵隔空间，腹部）以及继发于免疫消融和免疫抑制 疗法所有因脓毒症综合征到PICU的儿童均接受经验性抗菌药物治疗。 疗法目前，在PICU中用于儿童的抗菌药物的剂量是基于药代动力学 描述没有严重感染的儿童中的药物分布和消除;这一人群通常是 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，达到抗菌药物暴露 足够的微生物和临床治愈是生存所必需的。在这些孩子身上，戏剧性的， 根据心脏指标的变化，在因脓毒症住院的第一天肾功能的快速变化 输出和器官灌注可导致抗生素的肾消除增加或减少。额外 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容量的变化（高达 100 mL/kg），在感染性休克中并不少见。 我们计划分析接受FDA批准剂量的重症儿童的抗生素暴露和肾功能 标准治疗（SOC），具有广谱抗菌活性的通用β-内酰胺抗生素， 美罗培南，集中在入院的前3天，当最戏剧性的变化， 生理发生。通过测量50名儿童在最初3天的血浆和尿液浓度， PICU，我们可以确定当前SOC治疗的β-内酰胺暴露的充分性。我们将创建 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、脓毒症评分和可能与亚治疗或 潜在的毒性暴露。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。

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.