An automated platform for direct-from-specimen identification of pathogens common in endocarditis

项目总结 感染性心内膜炎(IE)是一种危及生命的疾病，每年影响大约45,000名美国人。IE是 以心内膜表面的微生物植被为特征的，会导致严重的心脏损害和 持续性血流感染(BSI)导致败血症。如果不及时治疗，IE是致命的。在以下标准中 建立IE，最有效地治疗患者，血培养是鉴定病原体必不可少的。 然而，文化表现出两个主要的弱点，推迟了适当的抗菌剂的使用： (1)周转时间长达数天甚至数周，以及(2)由于以下原因之一而导致的假阴性结果的高流行率 用抗生素进行前处理或存在难以培养的病原体。因为时间对于最优是至关重要的 结果并发症最少，通常在诊断前用广谱的鸡尾酒开始治疗。 光谱(即非靶向)抗菌药，导致大多数患者治疗不当， 没有不必要的疾病治疗。因此，至关重要的是推进创新的诊断方法， 它们不依赖于培养，以便迅速过渡到个性化的抗微生物干预措施。 为了解决这一未得到满足的需求，HelixBind将开发第一个能够识别 在2小时内诱发IE的病原体。我们的方法特别适合于检测挑剔 与IE相关的病原体和不可培养的病原体，目前的诊断标准往往无法 侦测到。HelixBind的快速(抗药性和病原体识别)诊断平台利用多个新的 从样本到答案的创新，直接从样本准确地描述感染的特征。见过面 我们的和超过了我们第一阶段的特定目标，在这个第二阶段的提案中，我们将专注于开发一个完全- 自动化测试，快速/IE，使最临床流行的病原体和 直接从采血标本中提取与IE相关的耐药基因。快速/IE预计将有一个 通过使医生能够应用个性化和循证干预，产生深远的临床影响 在几个小时内，而不是几天内；最终改善结果和抗菌管理。 为了在这项工作中取得成功，我们组建了一支自动化开发专家团队 由具有病理学、传染病和临床专业知识的世界级顾问为诊断提供支持 微生物学。我们将共同努力，在我们成功的第一阶段基础上，提供一种自动化的、专门的 到IE，在与我们的临床合作伙伴合作的盲目研究中达到顶峰。已经实现了我们的特定目标 目标，我们将开始在国际标准化组织13485质量体系下的验证和确认工作，规模制造， 并完成监管审批的临床试验。

PROJECT SUMMARY Infective Endocarditis (IE) is a life-threatening disease that affects roughly 45,000 Americans annually. IE is characterized by microbial vegetations on the endocardial surface which induce serious heart damage and persistent bloodstream infections (BSIs) leading to sepsis. Left untreated IE is fatal. Among the criteria to establish IE and treat patients most effectively, blood cultures are indispensable to identify the etiologic agent. Cultures, however, display two major weaknesses which delay the administration of the proper antimicrobials: (1) High turnaround time of days or even weeks and (2) high prevalence of false-negative results due to either pre-treatment with antibiotics or the presence of difficult to culture pathogens. As time is of essence for optimal outcomes with minimal complications, treatment is often initiated prior to diagnosis with a cocktail of broad spectrum (i.e. not targeted) antimicrobials, leaving the majority of patients treated inappropriately and those without the disease treated unnecessarily. It is therefore critical to advance innovative diagnostic approaches, which do not rely on culturing, in order to rapidly transition to personalized antimicrobial interventions. To address this unmet need, HelixBind will develop the first culture-free diagnostic assay capable of identifying pathogens which induce IE in under 2 hours. Our approach is particularly suited to the detection of fastidious pathogens and unculturable pathogens associated with IE, which today’s diagnostic standard frequently fail to detect. HelixBind’s RaPID (Resistance and Pathogen Identification) diagnostic platform leverages multiple novel innovations from sample-to-answer to accurately characterize infections directly from specimen. Having met our and exceeded our Phase I Specific Aims, in this Phase II proposal we will focus on development of a fully- automated test, RaPID/IE, enabling the ‘hands-free’ identification of the most clinically prevalent pathogens and resistance genes associated with IE directly from phlebotomy specimens. RaPID/IE is expected to have a profound clinical impact by enabling the physician to apply a personalized and evidence-driven intervention within a few hours, rather than days; ultimately improving both outcomes and antimicrobial stewardship. In order to succeed in this endeavor, we have assembled a team of experts in the development of automated diagnostics supported by world-class advisors with expertise in pathology, infectious diseases, and clinical microbiology. Together, we will build upon our successful Phase I and deliver an automated assay, dedicated to IE, culminating in a blinded study in collaboration with our clinical partners. Having achieved our Specific Aims, we will begin verification and validation efforts under an ISO 13485 Quality System, scale manufacturing, and complete clinical trials for regulatory clearance.