Friday, April 19, 2024
4/19/2024
¿ 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.
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