Targeting the CSF microbiota to optimize CSF shunt infection treatment

 描述（由申请方提供）：脑脊液（CSF）分流术可使脑积水儿童存活并避免持续性脑损伤，脑积水是儿童神经功能障碍的常见原因。 然而，CSF分流引起新的慢性手术问题。 初次放置后，CSF分流器通常需要因机械故障进行手术翻修。 翻修是随后CSF分流道感染的主要风险因素。 脑脊液分流管感染的治疗需要手术切除脑脊液分流管，根据从传统培养中恢复的微生物量身定制两周的静脉注射抗生素，以及第二次手术放置新的脑脊液分流管。 尽管有这种积极的治疗，再感染率从20%到25%不等。 提高对感染机制的理解对于有效治疗每年诊断的2，000多例CSF分流感染至关重要。 我们和其他人已经表明，与首次或随后的再感染相关的患者，医疗或手术风险因素很少。 然而，间接证据确实指出了微生物或微生物群的复杂环境在CSF分流感染中的作用，而不是单一感染微生物-这表明潜在需要一种新的范式。 拟议的R 01研究计划代表了一种新的范式-表征脑积水手术过程中CSF中的微生物群，从最初的分流放置到感染翻修。 我们组建了一个拥有独特专业知识的团队，采取创新方法来解决我们对分流脑积水微生物群的理解中的关键差距。 我们将使用高通量测序对CSF分流感染中检测到的可培养和不可培养微生物DNA进行表征，使用细菌DNA PCR定量对CSF中的总细菌载量进行定量，并在可行的情况下使用显微镜描述这些微生物的生长情况。 我们还将利用我们的单中心经验和现有的多中心合作开展这项前瞻性观察性多中心研究，在所有CSF分流术时收集临床数据和样本。 该申请涉及三个具体目标。 在目标1中，我们将确认在初始CSF分流器放置时不存在微生物群。 在目标2中，我们将确定CSF分流微生物群的进展及其与CSF分流感染的相关性。 在目标3中，我们将确定在连续分流手术中显著改变CSF微生物群的手术方法。 这种模式代表了标准CSF分流管理的偏离，对于实质性提高我们治疗CSF分流感染的能力和降低目前不可接受的高CSF分流感染和再感染率至关重要。 这些关键研究将直接为针对该微生物群的新型预防和/或治疗策略的开发提供信息。

 DESCRIPTION (provided by applicant): Cerebrospinal fluid (CSF) shunt placement allows children with hydrocephalus, a common cause of neurological disability in children, to survive and avoid ongoing brain injury. However, CSF shunts cause new chronic surgical problems. After initial placement, CSF shunts often require surgical revision for mechanical failure. Revisions are the major risk factor for subsequent CSF shunt infections. CSF shunt infection treatment requires surgical removal of the CSF shunt, two weeks of intravenous antibiotics tailored to the organism recovered from conventional culture, and a second surgery to place a new CSF shunt. Despite this aggressive treatment, re-infection rates range from 20 to 25%. An improved understanding of the mechanisms of infection is critical to effectively treat over 2,000 CSF shunt infections diagnosed each year. We and others have shown that there are surprisingly few patient, medical, or surgical risk factors associated with either a first or subsequent re-infection. Indirect evidence does, however, point to a role in CSF shunt infection for a complex milieu of microorganisms, or microbiota, rather than a single infecting organism - suggesting the potential need for a new paradigm. The proposed R01 research plan represents a novel paradigm - characterizing the microbiota in CSF across the surgical course of hydrocephalus, from the time of initial shunt placement to revision to infection. We have assembled a team with unique expertise to undertake an innovative approach to address the critical gap in our understanding the microbiota of shunted hydrocephalus. We will characterize the culturable and non-culturable microbial DNA detected in CSF shunt infection using high-throughput sequencing, quantify total bacterial load in CSF using bacterial DNA PCR quantitation, and where feasible use microscopy to describe how these organisms are growing. We will also capitalize upon our single center experience and existing multicenter collaborations to conduct this prospective observational multicenter study collecting clinical data and samples at the time of all CSF shunt surgeries. The application addresses three specific aims. In Aim 1, we will confirm the absence of microbiota at the time of initial CSF shunt placement. In Aim 2, we will determine the progression of CSF shunt microbiota and its association with CSF shunt infection. In Aim 3, we will determine surgical approaches that significantly alter the CSF microbiota across successive shunt surgeries. This paradigm represents a departure from standard CSF shunt management and is critical to substantively advancing our ability to treat CSF shunt infections and reduce the current unacceptably high rates of CSF shunt infection and re-infection. These critical studies will directly inform development of novel prevention and/or treatment strategies that target that microbiota.