Continuous Therapeutic Drug Monitoring of Antibiotics in CRRT

CRRT 中抗生素的连续治疗药物监测

• 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
• 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

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.

摘要 适配子是基于寡核苷酸的受体，可以从大量的随机文库中分离出来 与小分子结合的寡核苷酸。在过去，我们的团队开发了系统的方法来裁剪 将适配子应用于特定应用，并将其转化为传感器，同时还验证它们是否可用于临床。我们的 基于电化学适配子(E-AB)的传感器的工作达到了顶峰，这是有史以来第一个通用的传感平台 能够实时监测活体内的药物。当用于闭环反馈控制时， 这一突破使我们能够控制清醒的、可行走的动物受试者血液中的药物水平 实时的。通过这里提出的研究计划，我们将把这一进展转化为临床应用。 重点对脓毒症所致急性肾损伤患者进行连续性肾脏替代治疗(CRRT)。 在美国，每三例医院死亡中就有一例是由败血症引起的，败血症是急性肾脏的主要原因。 医院中的伤害(AKI)和败血症导致的AKI导致重症监护病房(ICU)60%的死亡率。 由于肾功能大大降低，这些危重患者经常需要CRRT。这反过来又会导致 广为人知的(大)问题：如何适当地服用药物，包括挽救生命的抗生素 血流动力学不稳定的患者，药物清除率差异很大，变化很大。在这里我们 建议弥合解决这一问题所需的具体技术差距。 我们的工作重点将是E-AB传感器，它可以持续监测流出物中的药物消除 在CRRT期间产生，从而实时提供关于体外清除的完整信息。我们会 追求两组治疗窗口狭窄的抗生素，它们主要通过肾脏清除： 万古霉素和氨基糖苷类药物。与现有的治疗药物监测方案形成对比的是 在数小时的周转时间内，我们的方法将立即向临床医生返回可操作的信息， 它可以用来调整剂量。广泛的共识是，这样的信息将会改善 通过实现快速、准确和个性化的剂量调整，AKI的败血症CRRT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。接下来，我们将 通过在体外模型中安装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，使用传感器集连续监测两个血液上的药物水平 以及滤膜的流出侧。最后，我们将演示扩展的、实时的治疗药物 ICU真实患者透析液废液监测。在这项工作结束时，适配子传感器将 准备好接受CRRT治疗的脓毒症患者的临床试验。