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.

总结/摘要 十分之一的美国成年人患有慢性肾脏疾病，超过425，000例终末期肾脏疾病 （ESRD）患者定期接受血液透析（HD）。耐甲氧西林S.金黄色 （MRSA）感染在HD患者中高出100倍，败血症是HD患者死亡的第二大原因。 人口静脉穿刺部位是这些感染的最常见来源， 由于MRSA的可能性，通常的做法是经验性地治疗HD中所有疑似革兰氏阳性感染 万古霉素患者然而，万古霉素具有非常窄的治疗指数，必须密切关注。 监测。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- 100小时。 肾功能受损患者200小时，清除了不同量的循环万古霉素 高通量透析膜。不幸的是，试验和错误的剂量策略仍然存在， HD患者的标准治疗，因此，在高达86%的患者中发现亚治疗浓度 HD患者。这通常导致万古霉素耐药菌株的出现，并增加了耐药率。 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， 临床医生需要转向频繁的血清测量。 竞争性免疫测定法目前用于在中心临床化学中测量万古霉素水平。 实验室虽然这些方法具有足够的灵敏度，但它们需要专门的昂贵仪器，并且 在透析中心不使用。相反，接受万古霉素的透析患者在接受万古霉素治疗前 进行透析，然后送到参考实验室。因为参考实验室的结果 可以是48-72小时，患者在知道水平是否 应该调整。这将亚治疗剂量的持续时间延长了2-3天，并促进了肿瘤细胞的生长。 在已经脆弱的宿主中产生耐药菌株。为了解决这一技术障碍，Affinergy计划 开发一种床旁侧流测定，其将能够实现频繁、低复杂性、准确和 万古霉素水平的监测。利用我们的噬菌体展示生物淘选核心技术，我们已经 已经确定了一种专有的捕获肽和检测试剂， 万古霉素在第一阶段结束时，我们将有一个原型侧流测定与确定的限制， 定量在第二阶段，我们将扩大检测试剂的生产规模，优化性能特征， 储存条件和测定稳定性。最后，我们的检测将在透析患者人群中进行验证。 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