Towards rapid measurement of antibiotics in critical care setting

在重症监护环境中快速测量抗生素

• 批准号: 10693403
• 负责人: Serge Cremers
• 金额: $ 67.62万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693403
• 关键词: Address; Affinity; Aminoglycosides; Antibiotic Resistance; Antibiotics; Binding Proteins; Biological; Biological Assay; Biosensor; Buffers; Calibration; Chemicals; Chromatography; Clinical; Clinical Chemistry; Complex; Consensus; Coupled; Critical Care; Critical Illness; Daptomycin; Decision Making; Devices; Dialysis procedure; Dose; Drug Kinetics; Drug Monitoring; Failure; Family; Fluoroquinolones; Foundations; Frequencies; Funding; Glycopeptides; Goals; Hospitalization; Hospitals; Immunoassay; Individual; Laboratories; Linezolid; Liquid substance; Measurement; Measures; Methods; Monitor; Nature; Oligonucleotides; Organ; Patients; Pharmaceutical Preparations; Physicians; Physiological; Plasma; Polymyxins; Preparation; Process; Property; Protocols documentation; Reagent; Regimen; Renal Replacement Therapy; Reporting; Sampling; Serum; Standardization; Surface; Technology; Testing; Therapeutic; Time; Ultrafiltration; Vancomycin; Variant; Whole Blood; Work; analytical method; aptamer; bacterial resistance; beta-Lactams; candidate validation; clinical decision-making; clinical practice; compare effectiveness; cost; cost effective; cross reactivity; design; graphene; nanomaterials; neglect; new chemical entity; receptor; response; sensor; small molecule; standard of care; theories

Summary: Delivering antibiotics (or other drugs) at effective and safe concentrations to unstable, critically ill hospitalized patients is a daunting problem – for example, for all six antibiotics that are the focus of this work, pharmacokinetic studies reveal truly wide discrepancies between predicted and actual active concentrations. While important strides have been made to help physicians make decisions that are most likely to help, and least likely to harm, an important cornerstone for such approaches is still missing: There are no clinically validated devices that can rapidly, accurately and precisely measure concentrations of drugs in a manner that would address the long turn- around-times and prohibitive cost of the central-laboratory-based approach to high-frequency therapeutic drug monitoring. We approach the problem systematically from the bottom up by building and validating at each step each of the components needed to overcome such barriers. As our first challenge (and our first Aim), we focus on high-quality receptors – well characterized and validated on their own – which could then be widely used and implemented by other groups in different formats, by simply being ordered “off the shelf”. We identified oligonucleotide-based receptors (aptamers) as such reagents. Building on our vast preliminary results, we delineate a process that will lead to isolation of sets of receptors, with each candidate validated on its own in a fluorescent format against gold-standard analytical methods in patient-derived fluids, under conditions that allow these simple sensors to be applied directly in mix-and-measure formats (e.g., dialysis effluents, ultrafiltered sera, and extracts from standard SPE columns). Our second challenge, exacerbated by the highly variable nature of samples collected from critically ill patients, is cross-reactivity and deviations from standardized conditions. We address these by identifying pairs of aptamers with orthogonal properties for each antibiotic: One of the aptamers will be used in biosensor modules (Aim 2) under strictly controlled conditions in conjunction with a commonly used nanomaterial (graphene) and validated on dialysis effluents and extracts from SPE columns (here, biosensors can be used without pre- purification) against gold-standard chromatographic methods. The other aptamer from the pair, from an unrelated family, will be comprehensively validated as the affinity component of extraction modules (Aim 3) on spiked commercial samples of sera and actual samples from critically ill patients. Through this approach, we will provide rigorously characterized, standardized components for analysis of polymyxins, fluoroquinolones, daptomycin, linezolid, and beta lactams, which will enable us (and others) to combine components into devices, either to be used at the bedside, or as cartridges in automatized analyzers. In either case, these will facilitate routine high-frequency drug monitoring outside of large, academic hospital settings. We expect to demonstrate one design of multi-modular devices by the end of this funding period.

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