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.
Continuous Therapeutic Drug Monitoring of Antibiotics in CRRT Narrative: The dosing of drugs with a narrow therapeutic index in hemodynamically unstable patients, such as those on continuous renal replacement therapy (CRRT), is exceptionally challenging and necessitates a personalized approach tailored in real-time to each patient?s changing conditions. Building on our recent demonstrations of closed-loop feedback control over plasma drug levels in a living animal, we propose the development and validation of a first-in-class approach to performing real-time therapeutic drug monitoring of extracorporeal clearance in sepsis patients undergoing CRRT. This will enable the rapid, personalized adjustment of antibiotic dosing in grievously ill patients for whom the margin for therapeutic error is smallest.
