An Integrated Device for Rapid Bacteremia Diagnosis from Whole Blood

 描述（由申请人提供）：在美国，细菌引起的血流感染是导致死亡的主要原因，占所有医院死亡人数的近50%。考虑到这种疾病占所有ICU使用的25%，它不仅致命，而且是迄今为止最昂贵的 疾病给美国医疗保健系统带来了每年300亿美元的经济负担。考虑到疾病发展的速度，早期和有针对性的抗生素治疗是改善患者预后的最关键因素。然而，目前情况的现实是令人烦恼的：虽然适当的治疗方案是现成的，但由于缺乏及时的信息，靶向抗生素治疗很少在疾病的时间进程中足够早地进行，以获得最大的益处。这主要是由于目前的诊断标准需要多个耗时的培养步骤，最终导致诊断延迟长达2-5天。因此，医生经常求助于经验性设计的广谱抗生素“鸡尾酒”，其成本密集，效果较差，增加并发症，并显著增加耐药病原体的流行。我们开发了一种病原体鉴定（PID）检测试剂盒，并对临床标本进行了验证，该试剂盒可直接从血液中鉴定>90%的菌血症诱导病原体，从而消除了“培养障碍”。我们的PID检测采用了独特的样品制备方法，结合了具有无与伦比的动力学和靶点检测能力的合成核酸类似物的创新使用。该应用程序专注于将整个工作流程自动化为一个完全集成的样品到答案消耗品，从而能够在2小时内直接从采血标本中完全自动识别病原体。我们预计，我们提出的PID系统将产生深远的临床影响，无论是通过提供一种手段来开发一个假设驱动的一线干预天比目前可能更快，并通过减少过度和不必要的使用抗菌药物。为了在这一奋进中取得成功，我们组建了一支一流的团队，包括检测开发、合成核酸类似物、样品到答案诊断的设计和实施以及生物医学仪器方面的专家。此外，我们还招募了临床微生物学、表面化学和核酸类似物方面的关键战略顾问，以及在诊断设备商业化方面经验丰富的成功企业家。我们将共同建立在我们令人印象深刻的初步结果的基础上，并开发一种自动化和无培养的PID系统，最终与塔夫茨医学中心合作，对临床标本进行性能评估研究。在实现我们的特定目标后，我们将开发可部署的仪器/耗材，并验证我们的诊断，为关键临床试验做准备。

 DESCRIPTION (provided by applicant): Bloodstream infections caused by bacteria are a leading cause of death in the US and accounts for almost 50% of all hospital deaths. Given that this disease accounts for 25% of all ICU usage, it is not only fatal but it is by far the costliest disease to the American healthcare system, inducing an economic burden of $30B annually. Considering the rate at which the disease develops, early and targeted antibiotic treatment is the most crucial factor for improving patient outcome. The reality of the current situation, however, is troublesome: while proper treatment options are readily available, targeted antibiotic therapy is seldom administered early enough in the disease's time course to be of maximal benefit due to a lack of timely information. This is largely due to current diagnostic standards which require multiple time-consuming culturing steps, ultimately leading to a diagnostic delay as long as 2-5 days. As a consequence, physicians often resort to empirically designed broad-spectrum antibiotic 'cocktails' which are cost-intensive, less effective, increase complications, and significantly increase the prevalence of drug resistant pathogens. We have developed and validated with clinical specimens a Pathogen Identification (PID) assay that allows species-level identification of >90% of bacteremia-inducing pathogens directly from blood, thus removing the "culturing barrier". Our PID assay employs a unique sample-preparation methodology combined with the innovative use of a synthetic nucleic acid analogue with unmatched kinetics and target detection capabilities. This application focuses on the automation of the entire workflow into a fully-integrated, sample-to-answer consumable enabling the completely automated identification of pathogens directly from phlebotomy specimens, in under 2 hours. We anticipate that the PID system we propose will have a profound clinical impact, both by providing a means to develop a hypothesis driven first-line intervention days faster than currently possible and by reducing the excessive and unnecessary use of antimicrobials. In order to succeed in this endeavor, we have put together a top-notch team including experts in assay development, synthetic nucleic acid analogues, the design & implementation of sample-to-answer diagnostics, and biomedical instrumentation. Additionally, we have enlisted key strategic advisors in clinical microbiology, surface chemistry, and nucleic acid analogues as well as successful entrepreneurs experienced in the commercialization of diagnostic devices. Together, we will build upon our impressive initial results, and develop an automated and culture-free PID system culminating in a performance assessment study with clinical specimens in collaboration with Tufts Medical Center. Having achieved our Specific Aims, we will develop deployable instrumentation/consumables and validate our diagnostic in preparation for the pivotal clinical trial.