Continuous Therapeutic Drug Monitoring of Antibiotics in CRRT

总结 适体是基于磷脂酰肌醇的受体，其可以从随机扩增的大文库中分离。 寡核苷酸与小分子结合。在过去，我们的团队开发了系统的方法来定制 适配体的特定应用，并把它们变成传感器，同时也验证它们的临床使用。我们 这项工作的高潮是基于电化学适体（E-AB）的传感器，这是有史以来第一个通用传感平台 能够在活体中真实的实时监测药物。当用于闭环反馈控制时， 这一突破使我们能够控制清醒的、能走动的动物受试者血液中的药物水平。 在真实的时间里。通过本文提出的研究计划，我们将把这一进展转化为临床应用 重点关注接受连续性肾脏替代治疗（CRRT）的脓毒症诱导急性肾损伤患者。 在美国，三分之一的医院死亡是由于脓毒症，脓毒症是急性肾衰竭的主要原因。 在医院中，脓毒症引起的急性肾损伤（阿基）导致死亡率> 60%，并且脓毒症引起的阿基导致重症监护室（ICU）中的死亡率> 60%。 由于肾功能大大降低，这些危重患者通常需要CRRT。这反过来又导致了 广泛认识到的（“大”）问题：如何适当剂量的药物，包括救生抗生素， 血流动力学不稳定的患者，药物清除率差异很大且变化很大。这里我们 建议弥合解决这一问题所需的具体技术差距。 我们工作的重点将是E-AB传感器，可以连续监测废水中的药物消除 在CRRT期间产生，从而提供真实的时间的体外清除率的完整信息。我们将 采用两种治疗窗较窄的抗生素组，主要通过肾脏清除： 万古霉素和氨基糖苷类。与现有的治疗药物监测协议相比， 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， 其可用于调节剂量。有一个广泛的共识，即这样的信息将改善 通过实现快速、准确和个性化的剂量调整，改善阿基脓毒症CRRT患者的结局。 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。接下来我们就 通过在体外模型中使用传感器，验证我们的技术对CRRT监测的适用性 模拟典型的CRRT模式，传感器组连续监测血液中的药物水平， 和过滤膜的流出侧。最后，我们将展示扩展的实时治疗药物 监测ICU中真实的患者的废透析液。在这项工作结束时，适体传感器将 准备进行CRRT治疗脓毒症患者疗效的临床试验。

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.