A sample-to-answer diagnostic for neonatal bloodstream infections

项目摘要 新生儿败血症是一种危及生命的疾病，在美国，每1,000名活产婴儿中约有2名受到影响， 25-30%的人无法生存。由新生儿血液感染引起，无论是在出生时， 不久之后，这种疾病的最初临床表现往往是非特异性的，可变的，有时是微妙的，而且经常是 是压力的常见症状因此，一个核心要求，既要规则在血流感染（BSI）和规则- BSI是微生物学证据;目前只能通过血液培养。培养， 然而，显示出两个主要弱点，这对结果至关重要， 抗菌剂：（1）周转时间较长，（2）假阴性结果的发生率较高， 母体抗生素和输入血量减少。由于时间对于最佳结果至关重要， 通常在微生物诊断之前用广谱（即非个性化） 抗生素，使大多数患者治疗不当，而那些没有治疗疾病的人 不必要的。因此，至关重要的是要推进创新的诊断方法， 培养，以促进尽快过渡到以证据为基础的决策过程。 在达到并超越了我们第一阶段的具体目标之后，第二阶段的建议侧重于开发一个 全自动新生儿病原体识别（Neo/PID）平台，实现“免提”识别 直接来自静脉切开术标本的临床上最流行的病原体，在大约2小时内， 文化的需要。第二阶段提出的诊断设备预计将产生深远的影响， 通过提供一种方法来开发循证一线干预措施，从而改善结果， 减少使用过多和不必要的抗菌药物。 为了在这一奋进中取得成功，我们组建了一个包括分析专家在内的一流团队 开发、人工核酸和自动诊断的实施。此外，我们还有 招募了临床微生物学、表面化学和病理学方面的关键顾问， 在诊断设备商业化方面经验丰富的企业家。我们将共同努力， 令人印象深刻的第一阶段结果，并开发一个自动化平台，致力于新生儿BSI，最终在一个 临床标本的性能评估研究。在实现我们的具体目标后，我们将开发 可部署的仪器/耗材，并验证我们的诊断，为关键的临床 审判

PROJECT SUMMARY Neonatal septicemia is a life-threatening disease that affects roughly 2 out of every 1,000 live births in the US, where 25-30% do not survive. Caused by an infection of the newborn bloodstream either at the time of birth or soon after, the disease’s initial clinical manifestations are often non-specific, variable, at times subtle, and often common to signs of stress. Thus a core requirement to both to rule-in a bloodstream infection (BSI) and to rule- out a BSI is microbiological evidence; which is currently only possible through blood-cultures. Cultures, however, display two major weaknesses which, crucial to outcome, delay the administration of the proper antimicrobials: (1) Long turnaround time of days and (2) high prevalence of false-negative results due to maternal antibiotics and a reduced input blood volume. As time is of essence for optimal outcomes, treatment is generally initiated prior to microbial diagnosis with a cocktail of broad spectrum (i.e. not personalized) 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 facilitate a transition to an evidence-based decision making process as soon as feasible. Having met our and exceeded our Phase I Specific Aims, this Phase II proposal focuses on development of a fully-automated neonatal pathogen identification (Neo/PID) platform enabling the ‘hands-free’ identification of the most clinically prevalent pathogens directly from phlebotomy specimens, in roughly 2 hours, without the need to culture. The Phase II proposed diagnostic device is expected to have profound impact, both by improving outcomes by providing a means to develop an evidence driven first-line intervention, and likewise by reducing the use of excessive and unnecessary antimicrobials. In order to succeed in this endeavor, we have assembled a top-notch team including experts in assay development, artificial nucleic acids, and the implementation of automated diagnostics. Additionally, we have enlisted key advisors in clinical microbiology, surface chemistry, and pathology as well as successful entrepreneurs experienced in the commercialization of diagnostic devices. Together, we will build upon our impressive Phase I results and develop an automated platform, dedicated to neonatal BSIs, culminating in a performance assessment study with clinical specimens. Having achieved our Specific Aims, we will develop deployable instrumentation/consumables and validate our diagnostic in preparation for the pivotal clinical trial.