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: 10522146
• 负责人: Serge Cremers
• 金额: $ 69.72万
• 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/10522146
• 关键词: Address; Affinity; Aminoglycosides; Antibiotics; Binding Proteins; Biological; Biological Assay; Biosensor; Buffers; Chemicals; Clinical; Clinical Chemistry; Complex; Coupled; Critical Care; Critical Illness; Daptomycin; Decision Making; Devices; Dialysis procedure; Dose; Drug Kinetics; Drug Monitoring; Ensure; Failure; Family; Fluoroquinolones; Foundations; Frequencies; Funding; Glycopeptides; Goals; Gold; 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; Resort; Sampling; Serum; Standardization; Surface; Technology; Testing; Therapeutic; Time; Variant; Whole Blood; Work; analytical method; aptamer; bacterial resistance; base; beta-Lactams; clinical decision-making; clinical practice; compare effectiveness; cost; cost effective; cross reactivity; design; graphene; nanomaterials; receptor; response; sensor; small molecule; standard of care; theories; tool

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.

概括： 以有效且安全的浓度输送抗生素（或其他药物），以至不稳定，重病住院治疗 患者是一个艰巨的问题 - 例如，对于这项工作的重点，药代动力学的所有六种抗生素 研究揭示了预测和实际的主动浓度之间的真正差异。虽然很重要 已取得了长足的进步，以帮助医生做出最有可能提供帮助，最不可能伤害的决定， 这种方法的重要基石仍然缺少：没有临床验证的设备可以 快速，准确，准确，精确地测量药物的浓度，以解决长期转交的方式 大约是在高频治疗药物的基于中央实验室的方法的禁止成本 监视。我们通过构建和在每个步骤进行验证从自然而然地解决问题 克服此类障碍所需的每个组件。 作为我们的第一个挑战（也是我们的第一个目标），我们专注于高质量的接收器 - 表征和验证 独自 被订购“从架子上”。我们将基于寡核苷酸的受体（适体）确定为这种试剂。 在我们广泛的初步结果的基础上，我们描绘了一个过程，该过程将导致隔离接收器集合， 每位候选人都以荧光格式自行验证，以针对金标准的分析方法 在允许将这些简单传感器直接应用于混合量的条件下，患者来源的流体 格式（例如，透析效应，超过滤的血清和从标准SPE柱中提取）。 我们的第二个挑战，因重病患者收集的样本的高度可变性质加剧， 是交叉反应性，偏离了标准化条件。我们通过识别一对 每种抗生素具有正交特性的适体：一种适体将用于生物传感器模块 （目标2）在严格控制的条件下与常用的纳米材料（石墨烯）和 对透析作用和SPE色谱柱提取物进行了验证（此处可以使用生物传感器，而无需预先 纯化）针对金色标准色谱法。这对的另一个适体来自一个无关的 家族将被全面验证为提取模块的亲和力成分（AIM 3） 来自重症患者的血清和实际样品的商业样本。 通过这种方法，我们将提供严格特征的标准化组件，以分析 多碳素，氟喹诺酮，daptomycin，linezolid和beta lactams，这将使我们（和其他）能够达到 将组件组合到设备中，要么在床边使用，要么将其用作自动分析仪中的墨盒。 无论哪种情况，这些都将有助于常规高频药物监测大型学术医院外 设置。我们希望在此资金期结束时展示一种多模块化设备的设计。