An Integrated Device for Rapid Bacteremia Diagnosis from Whole Blood

 描述(申请人提供)：细菌引起的血液感染是美国主要的死亡原因，几乎占所有医院死亡的50%。鉴于这种疾病占所有ICU使用量的25%，它不仅是致命的，而且是迄今为止代价最高的 疾病给美国的医疗体系带来了巨大的损失，每年造成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，目前的现实情况是麻烦的：虽然适当的治疗方案很容易获得，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实施以发挥最大益处。这在很大程度上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”，这些药物成本高、效果差、增加了并发症，并显著增加了耐药病原体的流行率。我们已经开发并通过临床标本验证了病原体鉴定(PID)试验，它允许直接从血液中鉴定90%的导致菌血症的病原体，从而消除“培养障碍”。我们的PID分析采用了独特的样品制备方法，并创新地使用了具有无与伦比的动力学和目标检测能力的合成核酸类似物。该应用专注于将整个工作流程自动化到一个完全集成的、样本到答案的消耗品中，从而能够在不到2小时的时间内直接从静脉采血样本中完全自动化地识别病原体。我们预计，我们提出的PID系统将产生深远的临床影响，包括提供一种手段，比目前可能的更快地开发假说驱动的一线干预天数，并通过减少过度和不必要的抗菌药使用。为了在这项工作中取得成功，我们组建了一支顶尖的团队，其中包括化验开发、合成核酸类似物、样本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，我们还聘请了临床微生物学、表面化学和核酸类似物领域的关键战略顾问，以及在诊断设备商业化方面经验丰富的成功企业家。我们将共同努力，在令人印象深刻的初步结果的基础上，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进行一项性能评估研究，使用临床标本。在实现我们的特定目标后，我们将开发可部署的仪器/消耗品，并验证我们的诊断，为关键的临床试验做准备。

 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.