Development and Evaluation of CRRT-Specific Precision Dosing Models to Optimize Beta-Lactam Treatment for Patients with Hospital-Acquired Pneumonia

开发和评估 CRRT 特异性精确剂量模型，以优化医院获得性肺炎患者的 β-内酰胺治疗

• 批准号: 10740095
• 负责人: Nathaniel James Rhodes
• 金额: $ 26.54万
• 依托单位: MIDWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-23 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740095
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Alveolar; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bronchoalveolar Lavage Fluid; Cessation of life; Clinical; Clinical Research; Critical Care; Critical Illness; Data; Development; Diagnostic; Dose; Drug Kinetics; Epithelium; Evaluation; Experimental Designs; Exploratory/Developmental Grant; Focus Groups; Funding; Future; Goals; Health; Health Care Costs; Hospital Mortality; Infection; Infrastructure; Injury to Kidney; Intensive Care Units; Klebsiella aerogenes; Klebsiella oxytoca; Klebsiella pneumoniae; Knowledge; Liquid substance; Literature; Lung; Measures; Mechanical ventilation; Medicine; Meropenem; Mission; Modeling; Nosocomial Infections; Nosocomial pneumonia; Online Systems; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Plasma; Pneumonia; Population; Pseudomonas aeruginosa; Public Health; Qualifying; Randomized, Controlled Trials; Recommendation; Regimen; Renal Replacement Therapy; Research; Research Infrastructure; Risk; Sampling; Scheme; Site; Statistical Models; Systems Biology; Translating; Translations; Treatment Failure; United States National Institutes of Health; Universities; Validity and Reliability; alveolar epithelium; antibiotic resistant infections; assay development; beta-Lactams; biobank; clinical efficacy; clinical risk; dose individualization; drug resistant pathogen; experience; high risk; improved; individual patient; innovation; mortality; mortality risk; novel; pathogen; pharmacodynamic model; pneumonia treatment; population based; predictive modeling; prospective; response; sample collection; tool; treatment optimization

Project Abstract Hospital-acquired pneumonia (HAP) caused by antibiotic-resistant pathogens such as Klebsiella aerogenes, Klebsiella pneumoniae, and Pseudomonas aeruginosa are responsible treatment failure and mortality rates up to 50% and 30%, respectively. Meropenem is a mainstay for the treatment of HAP, but antibiotic resistance continues to erode its clinical efficacy. Importantly, the efficacy of beta-lactams depends on achieving adequate pharmacokinetic-pharmacodynamic (PK/PD) exposures; however, many patients with HAP experience inadequate PK/PD because of changes in PK caused by critically illness. Precision Dosing strategies can overcome PK variability caused by critical illness, but Precision Dosing requires robust models; such models for critically ill patients who develop kidney injury and require continuous renal replacement therapy (CRRT) are currently lacking for HAP patients. Without Precision Dosing models to help guide antibiotic dosing, these vulnerable patients will continue to experience high rates of treatment failure and death. Whereas the status quo treatment of HAP patients requiring CRRT uses population-based dosing schemes, our proposal will innovate Precision Dosing (i.e., individualized) strategies for patients with HAP. We will leverage the infrastructure of the Successful Clinical Response In Pneumonia Therapy (SCRIPT) Systems Biology Center to robustly address the unmet needs of patients on CRRT. Our long-term goal is to develop Precision Dosing strategies that overcome PK variability caused by severe illness. The project objective is to utilize the infrastructure, samples, and data collected in SCRIPT to develop Precision Dosing models for HAP. Our central hypothesis is: (1) CRRT leads to variability in beta-lactam PK with standard “one-size-fits all” HAP dosing regimens which (2) increases the risk of clinical treatment failure in HAP, (3) requiring Precision Dosing schemes. The rationale for our study is that Precision Dosing is needed for CRRT patients with HAP and that these approaches must be translated clinically. In Aim 1, we will develop and qualify Precision Dosing models for meropenem in CRRT. In Aim 2, we will describe meropenem PK/PD target attainment in plasma and in the lung for patients requiring CRRT. In Aim 3, we will create a web-based dosing calculator for translation to practice. Our study will have a positive clinical impact by providing clinicians with the tools necessary to ensure that each patient’s dosing is optimized. This research is significant because it addresses a critical unmet need for optimized therapy. Upon completion, our study will have robustly characterized alveolar PK in CRRT patients, filling a gap in the rigor of prior research. We will have translated our Precision Dosing model predictions into actionable dosing regimens, which is innovative as no such calculators exist. Our Precision Dosing calculator will be evaluated in a future R01-funded randomized controlled trial.

项目摘要 由克雷伯菌等抗生素耐药病原体引起的医院获得性肺炎 (HAP) 产气杆菌、肺炎克雷伯菌和铜绿假单胞菌是治疗失败的原因 美罗培南是治疗 HAP 的主要药物，死亡率分别高达 50% 和 30%。 抗生素耐药性继续削弱其临床疗效，重要的是，β-内酰胺的疗效。 然而，取决于获得足够的药代动力学-药效学 (PK/PD) 暴露； HAP 患者由于危重病导致 PK 变化而出现 PK/PD 不足的情况。 精确给药策略可以克服危重疾病引起的 PK 变异性，但精确给药 需要稳健的模型；此类模型适用于出现肾损伤且需要的危重患者 目前 HAP 患者缺乏连续性肾脏替代治疗 (CRRT)，且缺乏精确性。 剂量模型有助于指导抗生素剂量，这些弱势患者将继续经历高风险 治疗失败率和死亡率（需要 CRRT 的 HAP 患者的现状治疗除外）。 使用基于人群的剂量方案，我们的建议将创新精确剂量（即个体化） 我们将利用成功临床反应的基础设施。 肺炎治疗 (SCRIPT) 系统生物学中心将有力地解决患者未满足的需求 我们的长期目标是开发克服 PK 变异性的精确剂量策略。 该项目的目标是利用收集到的基础设施、样本和数据。 在 SCRIPT 中开发 HAP 的精确剂量模型 我们的中心假设是：(1) CRRT 导致。 标准“一刀切”HAP 给药方案的 β-内酰胺 PK 的变异性 (2) 增加了 HAP 临床治疗失败的风险，(3) 需要精确剂量方案。 研究表明，患有 HAP 的 CRRT 患者需要精确剂量，并且这些方法必须 在目标 1 中，我们将开发并验证美罗培南的精确剂量模型。 在目标 2 中，我们将描述美罗培南在血浆和肺中的 PK/PD 目标实现情况。 在目标 3 中，我们将创建一个基于网络的剂量计算器，以便转化为实践。 我们的研究将通过提供必要的工具来产生积极的临床影响 确保每个患者的剂量得到优化 这项研究很重要，因为它解决了一个关键问题。 优化治疗的未满足需求完成后，我们的研究将具有强有力的肺泡 PK 特征。 在 CRRT 患者中，填补了先前研究的空白，我们将转化我们的精确剂量。 将模型预测转化为可行的剂量方案，这是创新的，因为我们不存在这样的计算器。 精确剂量计算器将在未来 R01 资助的随机对照试验中进行评估。