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

快速测定血液透析患者护理点万古霉素水平

• 批准号: 10398206
• 负责人: Martyn Darby
• 金额: $ 68.28万
• 依托单位: AFFINERGY, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398206
• 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; 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; detection limit; dosage; improved; instrument; large scale production; lateral flow assay; lot production; methicillin resistant Staphylococcus aureus; novel; patient population; performance tests; point of care; prototype; rapid test; resistant strain; scale up; stability testing; standard of care; verification and validation

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脏疾病，患有超过425,000个末期肾脏疾病 （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 （MRSA）HD患者的感染高100倍，败血病是此次的第二大死亡原因 人口。静脉通路现场是这些感染的最常见来源，并且由于很高 MRSA的概率，通常从经验上处理所有可疑的革兰氏阳性感染是HD 万古霉素患者。但是，万古霉素的治疗指数非常狭窄 受监控。万古霉素的半衰期从正常肾功能正常患者的6-12小时增加到100- 肾功能受损的患者200小时，去除循环的万古霉素数量可变 每次高清疗程中通过高速通量透析膜。不幸的是，仍然存在试用和错误给药策略 高清患者的护理标准，结果，在多达86％的地方发现了亚治疗浓度 高清患者。这通常会导致抗性霉素菌株的出现，并增加 治疗失败。为了维持高清患者的有效循环万古霉素浓度， 临床医生需要转移到经常的血清测量值。 目前使用竞争性免疫测定法来测量中央临床化学中的万古霉素水平 实验室。尽管这些方法具有足够的敏感性，但它们需要专业，昂贵的乐器，并且是 不在透析中心使用。相反，接受万古霉素的透析患者在先前有血液样本。 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 可以是48-72小时，在知道是否水平之前给患者服用下一个万古霉素剂量 应该调整。这将亚治疗剂量的持续时间扩大了2-3天，并促进了 已经脆弱的宿主中的抗性细菌菌株。为了解决这一技术障碍，Affinergy计划 开发出一个护理点的侧向流量测定法，该测定法可以经常启用，低复杂性，准确和 负担得起的万古霉素水平的监测。使用我们噬菌体展示的核心技术，我们有 已经确定了专有捕获的肽和检测试剂，该试剂与亚摩尔摩尔亲和力结合到 万古霉素。在第一阶段结束时，我们将拥有一个原型的横向流程测定法，其既定极限 定量。在第二阶段，我们将扩大评估的生产，优化性能特征，建立 存储条件并确定稳定性。最后，我们的评估将在透析患者人群中得到验证。 成功完成该项目将导致透析患者的治疗效率提高 万古霉素。