Continuous Therapeutic Drug Monitoring of Antibiotics in CRRT

CRRT 中抗生素的连续治疗药物监测

基本信息

批准号：
10096440
负责人：
Sumit Mohan
金额：
$ 71.7万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10096440
关键词：
Acute Renal Failure with Renal Papillary Necrosis Adsorption Amikacin Aminoglycosides Animals Antibiotics Binding Binding Proteins Biological Assay Blood Cessation of life Clinical Clinical Trials Consensus Convection Critical Illness Data Development Dialysis procedure Diffuse Dose Drug Exposure Drug Kinetics Drug Monitoring Ensure Excision Feedback Filtration Frequencies Gold Hospitals Hour In Vitro Incidence Individual Infection Inferior Institutional Review Boards Intensive Care Units Kidney Laboratories Lead Libraries Life Liquid substance Measurement Measures Membrane Metabolic Clearance Rate Modality Modeling Monitor Oligonucleotides Outcome Patient Monitoring Patients Pharmaceutical Preparations Physiological Physiology Plasma Problem Solving Protocols documentation Rattus Renal Replacement Therapy Renal function Research Sampling Savings Sepsis Serum Side Technology Therapeutic Therapeutic Index Time Tobramycin Toxic effect Translating Validation Vancomycin Variant Whole Blood Work antimicrobial appropriate dose aptamer awake base clinical application design dosage drug clearance hemodynamics improved outcome in vitro Model individualized medicine mortality personalized approach programs rapid test receptor sensor septic septic patients small molecule temporal measurement tool validation studies wasting

项目摘要

Summary Aptamers are oligonucleotide-based receptors that can be isolated from the large libraries of random oligonucleotides to bind to small molecules. In the past, our team developed systematic approaches to tailor aptamers to specific applications and turn them into sensors, while also validating them for clinical use. Our work culminated in electrochemical aptamer-based (E-AB) sensors, the first ever general sensing platform capable of monitoring drugs in real time in the living body. When employed in closed-loop feedback control, this breakthrough enabled us to control the levels of drugs in the blood of awake, ambulatory animal subjects in real time. Via the research program proposed here, we will translate this progress into clinical applications focused on patients with sepsis-induced acute kidney injury on continuous renal replacement therapy (CRRT). One out of three hospital deaths in the USA are due to sepsis, sepsis is the leading cause of acute kidney injury (AKI) in hospitals, and sepsis-induced AKI results in a mortality rate in intensive care units (ICU) >60%. Due to greatly reduced renal function these critically ill patients often require CRRT. This, in turn, leads to a widely recognized (“big”) problem: how to appropriately dose medications, including life-saving antibiotics, in hemodynamically unstable patients with wildly divergent and highly variable drug clearance rates. Here we propose to bridge the specific gap in technology that is needed to solve this problem. The focus of our work will be on E-AB sensors that can continuously monitor drug elimination in effluent produced during CRRT, thus providing complete information on extracorporeal clearance in real time. We will pursue two antibiotic groups with narrow therapeutic windows that are predominantly cleared via the kidneys: vancomycin and the aminoglycosides. In a contrast to the existing therapeutic drug monitoring protocols with turnaround times of many hours, our approach will return immediately actionable information to the clinician, which can be used to adjust dosages. There is a broad consensus that such an information would improve outcomes in septic CRRT patients with AKI, by enabling rapid, accurate, and personalized dosing adjustment. We will first validate our E-AB sensors on matched whole blood and effluent clinical samples. Next, we will validate the applicability of our technology to CRRT monitoring by implementing sensors in an in vitro model simulating typical CRRT modalities, with sets of sensors monitoring drug levels continuously on both the blood and effluent sides of filtration membranes. Finally, we will demonstrate extended, real-time therapeutic drug monitoring in the spent dialysis fluids of real patients in the ICU. At the end of this work, aptameric sensors will be ready for clinical trials of their efficacy in the treatment of sepsis in patients on CRRT.

概括适体是基于寡核苷酸的受体，可以从大型随机数据库中分离出来过去，我们的团队开发了定制寡核苷酸的系统方法。适体到特定的应用并将它们转化为传感器，同时也验证它们的临床用途。工作的最终成果是基于电化学适体（E-AB）的传感器，这是第一个通用传感平台当用于闭环反馈控制时，能够实时监测生物体内的药物。这一突破使我们能够控制清醒、活动的动物受试者血液中的药物水平通过这里提出的研究计划，我们将把这一进展实时转化为临床应用。专注于接受连续肾脏替代治疗（CRRT）的脓毒症引起的急性肾损伤患者。在美国，三分之一的医院死亡是由于脓毒症，脓毒症是急性肾病的主要原因医院内的损伤（AKI），脓毒症引起的 AKI 导致重症监护病房（ICU）的死亡率 >60%。由于肾功能大大下降，这些危重患者通常需要 CRRT，这反过来又导致了 CRRT。广泛认可的（“大”）问题：如何在治疗中适当地服用药物，包括救生抗生素血流动力学不稳定的患者，其药物清除率差异很大且变化很大。提议弥合解决该问题所需的具体技术差距。我们的工作重点是 E-AB 传感器，它可以连续监测废水中药物的消除情况在 CRRT 期间产生，从而实时提供体外清除的完整信息。寻求两种治疗窗口狭窄且主要通过肾脏清除的抗生素组：与现有的治疗药物监测方案相反。周转时间长达数小时，我们的方法将立即向临床医生返回可操作的信息，可以用来调整剂量，人们普遍认为这样的信息会有所改善。通过实现快速、准确和个性化的剂量调整，改善脓毒症 CRRT 合并 AKI 患者的结果。我们将首先在匹配的全血和流出物临床样本上验证我们的 E-AB 传感器。通过在体外模型中实施传感器来验证我们的技术在 CRRT 监测中的适用性模拟典型的 CRRT 模式，使用多组传感器连续监测血液中的药物水平最后，我们将展示扩展的实时治疗药物。在这项工作结束时，适配体传感器将监测 ICU 中真实患者的用过的透析液。准备好进行其治疗 CRRT 患者脓毒症疗效的临床试验。