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

• 批准号: 10163177
• 负责人: Martyn Darby
• 金额: $ 67.94万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163177
• 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，超过42.5万人患有终末期肾病 (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 HD患者的耐甲氧西林金黄色葡萄球菌(MRSA)感染率高出100倍，败血症是该患者的第二大死亡原因 人口。静脉引流部位是这些感染的最常见来源，而且由于高 MRSA的可能性，对HD中所有可疑的革兰氏阳性感染进行经验性治疗是常见的做法 使用万古霉素的患者。然而，万古霉素的治疗指标非常狭窄，必须密切关注 被监视着。在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- 肾功能受损患者停用不同剂量的万古霉素治疗200小时 在每次HD治疗期间通过高通量透析膜。不幸的是，一种试错式的剂量策略仍然存在 HD患者的护理标准，因此，在高达86%的患者中发现亚治疗浓度 HD患者。这通常会导致出现对万古霉素耐药的菌株，并增加 治疗失败。因此，为了在HD患者中维持有效的循环万古霉素浓度， 临床医生需要改用频繁的血清检测。 竞争免疫分析目前被用于测量中心临床化学中的万古霉素水平 实验室。虽然这些方法有足够的敏感性，但它们需要专门的、昂贵的仪器，而且 不在透析中心使用。取而代之的是，接受万古霉素治疗的透析患者需要事先抽取血样 进行透析，然后送到参考实验室。因为参考实验室结果的周转时间 可以是48-72小时，患者在知道是否达到万古霉素水平之前给予下一剂量的万古霉素 应该进行调整。这将亚治疗剂量的持续时间延长了2-3天，并促进了 已经脆弱的宿主中的抗药性细菌菌株。为了解决这一技术障碍，AffinEnergy计划 开发一种护理点侧向血流分析，它将实现频繁、低复杂性、准确和 负担得起的万古霉素水平监测。使用我们的核心技术噬菌体展示生物扫描，我们有 已经鉴定了一种专有的捕获多肽和检测试剂，它与亚微摩尔亲和力结合到 万古霉素。在第一阶段结束时，我们将有一个原型侧向流动分析，其建立的限度为 量化。在第二阶段，我们将扩大我们的分析的生产，优化性能特征，建立 并确定储存条件和稳定性。最后，我们的分析将在透析患者群体中得到验证。 该项目的成功完成将提高透析患者的治疗效果。 万古霉素。