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: 10557161
• 负责人: Sumit Mohan
• 金额: $ 68.97万
• 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/10557161
• 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; Critical Illness; Data; Development; Dialysis procedure; Dose; Drug Exposure; Drug Kinetics; Drug Monitoring; Ensure; Excision; Feedback; Filtration; Frequencies; 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; Protocols documentation; Rattus; Renal Replacement Therapy; Renal function; Research; Sampling; Sepsis; Serum; Side; Technology; Therapeutic; Therapeutic Index; Time; Tobramycin; Toxic effect; Translating; Validation; Vancomycin; Variant; Whole Blood; Work; antimicrobial; appropriate dose; aptamer; awake; clinical application; clinical trial readiness; design; dosage; drug clearance; experimental study; hemodynamics; improved outcome; in vitro Model; individualized medicine; mortality; personalized approach; programs; rapid test; receptor; sensor; septic; septic patients; small molecule; 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.

总结