ANTIMICROBIAL TECHNOLOGY TO ACTIVELY MITIGATE HYDROCEPHALUS SHUNT INFECTIONS LONG TERM

摘要 在患者体内放置分流管以管理脑脊液(CSF)引流在医疗中是不可或缺的 然而，在实践中，他们很容易受到当地微生物群的感染，导致高死亡率和 发病率。分流管通常由富含碳或硅的聚合物制成，以保持所需的性能 但这些惰性聚合物为入侵的皮肤菌群提供了一个诱人的避难所。自我缺失-- 固有的或与宿主免疫系统协同的保护特性使这些分流更容易 感染。大多数全身性抗生素无法穿透生物膜结构并成功消除局部 设备感染使分流更换(翻修)成为唯一的选择。修订程序，尽管 暂时有效的是高复发率(~50%)的感染。 为了应对上述挑战，抗生素浸渍的分流导管意在抵抗 微生物定植已被开发出来，但其临床疗效尚无明确证据。即使在那之后 广泛采用抗生素分流和严格的感染控制方案来管理脑脊液引流 分流感染和相关的临床后遗症问题依然存在。申请者已经认识到了这一点 这是一项重要的、未得到满足的需求，并开发了一种旨在改善临床结果的新技术。这个 申请人提出的解决方案可以积极减少经皮设备上的微生物定植 表面长期使用，不会影响设备的物理性能，也不会使用有毒物质 制药公司。 拟议的可行性研究的目标是评估新的 临床前模型中的技术。提出了初步的设计改进，以确定具有更好性能的原型 通过短期和长期体外试验(包括广谱试验)确定的抗菌性能 有效性和细胞毒性)。随后，将对抗菌效果和安全终点进行评估 动物模型(兔)以评估拟议技术在安全缓解经皮损伤方面的潜力 分流感染。体外和体内研究将包括适当的对照，包括未改良的硅胶分流术， 抗生素浸渍分流导管(美敦力ARESTM、CodmanBactiseal和Cook Spectrum)和 银色洗脱导管。微生物定殖率的降低将与对照(无涂层)分流进行比较 这些研究中的导尿管。该项目概念验证阶段的预期结果将是 新技术在体外和体外的机械完整性、安全性和抗菌效果的论证 活着。可行性的论证将为该技术的进一步商业开发奠定基础。

ABSTRACT Shunts placed in patients to manage cerebrospinal fluid (CSF) drainage are indispensable in medical practice, however, they are susceptible to infection caused by local microflora leading to high mortality and morbidity. Shunts are generally made of carbon or silicone rich polymers to maintain desirable properties such as flexibility, but these inert polymers offer an attractive refuge for the invading skin flora. Absence of self- protective properties either inherently or in concert with the host’s immune system makes these shunts prone to infection. Most systemic antibiotics fail to penetrate the biofilm architecture and successfully eliminate local device infections leaving shunt replacement (revision) as the only option. Revision procedures, although provisionally effective are plagued by a high recurrence rate (~50%) of infection. To address the above-mentioned challenges, antibiotic impregnated shunt catheters intended to resist microbial colonization have been developed but clear demonstration of their clinical efficacy is absent. Even after wide spread adoption of antibiotic shunts and stringent infection control protocols to manage CSF drainage the problem of shunt infection and associated clinical sequelae persist. The applicants have recognized this important, unmet need and have developed a novel technology intended to improve clinical outcomes. The solution proposed by the applicants can actively reduce microbial colonization on transcutaneous device surfaces long term without compromising physical properties of the device and without the use of toxic pharmaceuticals. The goal of the proposed feasibility studies is to assess safety, efficacy and robustness of the new technology in pre-clinical models. Initial design refinement is proposed to identify prototypes with superior antimicrobial properties as determined by short-term and long-term in vitro tests (including broad spectrum efficacy and cytotoxicity). Subsequently, antimicrobial efficacy and safety end-points will be assessed in the animal model (rabbits) to evaluate the potential of the proposed technology in safely mitigating transcutaneous shunt infections. In vitro and in vivo studies will include appropriate controls including unmodified silicone shunts, antibiotic impregnated shunt catheters (Medtronic ARESTM, Codman Bactiseal and Cook Spectrum) and silver eluting catheters. Reduction in microbial colonization will be measured against control (uncoated) shunt catheter in these studies. The expected outcome of this proof-of-concept phase of the project will be the demonstration of mechanical integrity, safety and antimicrobial efficacy of the new technology in in vitro and in vivo. Demonstration of feasibility will set the stage for further commercial development of the technology.