Rapid assay to monitor vancomycin levels at the point of care in hemodialysis patients

快速检测血液透析患者护理点万古霉素水平

基本信息

批准号：
10058954
负责人：
Martyn Darby
金额：
$ 59.02万
依托单位：
AFFINERGY, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058954
关键词：
Address Adult Affinity American Binding Biological Biological Assay Blood Blood specimen Cause of Death Characteristics Chronic Kidney Failure Clinic Clinical Clinical Chemistry Complex Detection Development Dialysis patients Dialysis procedure Dose Early identification End stage renal failure Equipment Evaluation Failure Fostering Freezing Growth Guidelines Half-Life Hemodialysis Hour Immunoassay Impairment Infection Institutes Label Laboratories Lateral Libraries Life Liquid substance Measurement Measures Membrane Methodology Methods Monitor Outpatients Patients Peptide Synthesis Peptides Performance Personal Satisfaction Phage Display Phase Population Production Reader Reagent Renal function Reproducibility Risk Running Sampling Septicemia Serum Ships Site Source Specificity Specimen Staphylococcus aureus infection Technology Testing Therapeutic Therapeutic Index Time Toxic effect Treatment Efficacy Treatment Failure Validation Vancomycin Vancomycin Resistance Venous bacterial resistance base clinical care cross reactivity design dosage improved instrument large scale production lot production methicillin resistant Staphylococcus aureus novel patient population performance tests point of care prototype resistant strain scale up stability testing standard of care verification and validation

项目摘要

SUMMARY/ABSTRACT One in ten American adults suffer from chronic kidney disease, with over 425,000 end-stage renal disease (ESRD) patients receiving hemodialysis (HD) on a regular basis. The risk of methicillin-resistant S. aureus (MRSA) infections is 100-fold higher in HD patients, and septicemia is the second leading cause of death in this population. The venous access site is the most common source of these infections, and due to the high probabability of MRSA, it is common practice to empirically treat all suspected Gram-positive infections in HD patients with vancomycin. However, vancomycin has a very narrow therapeutic index that must be closely monitored. Vancomycin’s half-life increases from 6-12 hours in patients with normal kidney function up to 100- 200 hours in patients with impaired kidney function, with variable amounts of circulating vancomycin removed by high-flux dialysis membranes during each HD session. Unfortunately, a trial and error dosing strategy remains the standard of care for HD patients, and as a result, sub-therapeutic concentrations are found in up to 86% of HD patients. This often leads to the emergence of vancomycin-resistant strains and an increased rate of treatment failure. Thus, in order to maintain an effective circulating vancomycin concentration in HD patients, clinicians need to shift to frequent serum measurements. Competitive immunoassays are currently used to measure vancomycin levels in a central clinical chemistry lab. While these approaches have sufficient sensitivity, they require specialized, expensive instruments and are not in use at dialysis centers. Instead, dialysis patients receiving vancomycin have a blood sample drawn prior to dialysis, which is then sent to a reference laboratory. Because the turnaround time for reference lab results can be 48-72 hrs, patients are administered the next vancomycin dose prior to knowing whether or not levels should be adjusted. This expands the duration of sub-therapeutic dosing by 2-3 days and fosters growth of resistant bacterial strains in an already vulnerable host. To address this technical hurdle, Affinergy plans to develop a point-of-care lateral flow assay that will enable frequent, low complexity, accurate and affordable monitoring of vancomycin levels. Using our core technology of phage display biopanning, we have already identified a proprietary capture peptide and detection reagent that bind with submicromolar affinity to vancomycin. At the conclusion of Phase I, we will have a prototype lateral flow assay with established limits of quantitation. In Phase II, we will scale up production of our assay, optimize performance characteristics, establish storage conditions and determine stability. Finally, our assay will be validated in a dialysis patient population. Successful completion of this project will lead to improved therapeutic efficacy for dialysis patients receiving vancomycin.

摘要/摘要十分之一的美国成年人患有慢性肾病，其中终末期肾病患者超过 425,000 人 (ESRD) 定期接受血液透析 (HD) 的患者耐甲氧西林金黄色葡萄球菌的风险。 HD 患者的 MRSA（耐甲氧西林金黄色葡萄球菌）感染率高出 100 倍，败血症是该患者的第二大死因静脉通路部位是这些感染的最常见来源，并且由于感染率高。 MRSA 的可能性，根据经验治疗 HD 中所有疑似革兰氏阳性感染是常见做法然而，万古霉素的治疗指数非常窄，必须密切关注。监测发现，肾功能正常的患者中万古霉素的半衰期从 6-12 小时增加到 100-100 小时。肾功能受损患者 200 小时，去除不同量的循环万古霉素不幸的是，在每次 HD 治疗期间，仍需采用反复试验的剂量策略。 HD 患者的护理标准，因此，高达 86% 的药物浓度低于治疗浓度 HD 患者通常会出现万古霉素耐药菌株，并增加感染率。因此，为了维持 HD 患者有效的循环万古霉素浓度，牧师需要转向频繁的血清测量。竞争性免疫测定目前用于测量中心临床化学中的万古霉素水平虽然这些方法具有足够的灵敏度，但它们需要专门的、昂贵的仪器，并且透析中心不使用，相反，接受万古霉素的透析患者会事先抽取血样。进行透析，然后将其发送到参考实验室，因为参考实验室结果的周转时间。可能是 48-72 小时，在知道是否水平之前，给患者施用下一剂万古霉素应该调整，这将亚治疗剂量的持续时间延长 2-3 天，并促进生长。为了解决这一技术障碍，Affinergy 计划开发一种即时侧向层析检测，可实现频繁、低复杂性、准确和利用我们的噬菌体展示生物淘选核心技术，我们可以实现经济实惠的万古霉素水平监测。已经确定了一种专有的捕获肽和检测试剂，可以以亚微摩尔亲和力结合在第一阶段结束时，我们将有一个原型侧流测定，其限制为在第二阶段，我们将扩大检测的生产规模，优化性能特征，建立最后，我们的测定将在透析患者群体中进行验证。该项目的成功完成将提高接受透析治疗的患者的治疗效果万古霉素。