A sample-to-answer diagnostic for neonatal bloodstream infections

项目总结 新生儿败血症是一种威胁生命的疾病，在美国，大约每1000名活产中就有2名受到影响。 在那里有25%-30%的人无法生存。在出生时或出生时由新生儿血液感染引起的 不久之后，这种疾病的最初临床表现通常是非特异性的、多变的、有时是微妙的，而且通常 这是压力征兆的共性。因此，既要统治血液感染(BSI)，又要统治- BSI是微生物学证据；目前只有通过血液培养才能做到这一点。文化， 然而，表现出两个主要弱点，这对结果至关重要，延误了适当的管理 抗菌药物：(1)周转时间长，(2)假阴性结果高，原因是 产妇使用抗生素和减少输血量。由于时间对于最佳结果至关重要，治疗 通常在微生物诊断之前用广谱鸡尾酒启动(即不个性化) 抗菌药，使大多数患者得到不适当的治疗，而那些没有患病的患者得到了治疗 不必要的。因此，至关重要的是推进创新的诊断方法，这些方法不依赖于 培养，以促进尽快过渡到基于证据的决策过程。 在达到并超过了第一阶段的特定目标后，第二阶段的建议重点是发展 全自动新生儿病原体识别(NEO/PID)平台，实现“免提”识别 临床上最流行的病原体直接从静脉采血标本中提取，在大约2小时内，没有 培养的需要。第二阶段拟议的诊断设备预计将产生深远影响，包括 通过提供一种发展证据驱动的一线干预的手段来改善结果，同样地 通过减少过量和不必要的抗菌剂的使用。 为了在这项工作中取得成功，我们组建了一支包括化验专家在内的一流团队 研发、人造核酸和自动化诊断的实施。此外，我们还有 聘请临床微生物学、表面化学和病理学方面的主要顾问，并取得成功 在诊断设备商业化方面经验丰富的企业家。共同努力，我们将在我们的 令人印象深刻的第一阶段成果，并开发一个自动化平台，专门用于新生儿BSI，最终以 使用临床标本进行性能评估研究。在实现了我们的具体目标后，我们将发展 可部署的仪器/消耗品，并验证我们的诊断，为关键临床做好准备 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.