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

项目摘要 克雷伯氏菌等耐药病原菌引起的医院获得性肺炎 产气菌、肺炎克雷伯菌和铜绿假单胞菌是治疗失败和 死亡率分别高达50%和30%。美罗培南是治疗HAP的主要药物，但 抗生素耐药性继续侵蚀其临床疗效。重要的是，β-内酰胺类药物的疗效 取决于获得足够的药代动力学-药效学(PK/PD)暴露；然而，许多 HAP患者由于危重疾病引起的PK改变，导致PK/PD不足。 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 需要健壮的模型；这样的模型适用于出现肾脏损伤并需要 HAP患者目前缺乏连续性肾脏替代治疗(CRRT)。没有精度 剂量模型有助于指导抗生素剂量，这些脆弱的患者将继续经历高 治疗失败率和死亡率。鉴于需要CRRT的HAP患者的治疗现状 使用基于人群的剂量方案，我们的提案将创新精确剂量(即个性化) HAP患者的治疗策略。我们将利用成功的临床响应的基础设施 肺炎治疗(SCRIPT)系统生物学中心大力解决患者未得到满足的需求 在CRRT上。我们的长期目标是开发克服PK变异性的精确给药策略 由严重疾病引起的。该项目的目标是利用收集的基础设施、样本和数据 在脚本中为HAP开发精确的剂量模型。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的可变性(2)增加了 HAP临床治疗失败的风险，(3)需要精确的剂量方案。我们的理由是 研究表明，CRRT合并HAP患者需要精确的剂量，这些方法必须 翻译成临床用的。在目标1中，我们将开发和鉴定美罗培南的精确剂量模型 CRRT。在目标2中，我们将描述美罗培南PK/PD在血浆和肺中的靶向性 需要CRRT的患者。在目标3中，我们将创建一个基于Web的剂量计算器，供翻译练习使用。 我们的研究将通过为临床医生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都是最优的。这项研究具有重要意义，因为它解决了一个关键的 对优化治疗的需求尚未得到满足。完成后，我们的研究将具有强有力的肺泡性PK特征 在CRRT患者中，填补了先前研究的严谨性空白。我们将会把我们的精准配料 将模型预测转化为可操作的剂量方案，这是创新的，因为没有这样的计算器。我们的 精确的剂量计算器将在未来由R01资助的随机对照试验中进行评估。

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.