ANTIMICROBIAL TECHNOLOGY TO ACTIVELY MITIGATE HYDROCEPHALUS SHUNT INFECTIONS LONG TERM

摘要 分流管放置在病人管理脑脊液（CSF）引流是不可缺少的医疗 然而，在实践中，他们很容易受到当地微生物菌群引起的感染，导致高死亡率， 发病率。分流器通常由富含碳或硅酮的聚合物制成，以保持期望的特性， 但这些惰性聚合物为入侵的皮肤植物群提供了一个有吸引力的避难所。缺乏自我- 保护特性无论是固有的还是与宿主的免疫系统相一致的，都使这些分流易于 感染大多数全身性抗生素不能穿透生物膜结构并成功地消除局部 器械感染使分流置换术（翻修术）成为唯一选择。修订程序，虽然 暂时有效的药物受到感染复发率高（约50%）的困扰。 为了解决上述挑战，旨在抵抗细菌感染的抗生素浸渍分流导管 已经开发了微生物定植，但缺乏其临床功效的明确证明。即使 广泛采用抗生素分流和严格的感染控制方案来管理CSF引流， 分流感染和相关临床后遗症的问题仍然存在。申请人已经认识到这一点 重要的，未满足的需求，并开发了一种旨在改善临床结果的新技术。的 申请人提出的解决方案可以有效地减少经皮器械上的微生物定植 表面长期不损害设备的物理性能， 大药厂 拟议的可行性研究的目标是评估新药物的安全性、有效性和稳健性。 临床前模型中的技术。提出了初步的设计改进，以确定原型与上级 通过短期和长期体外试验确定的抗微生物性能（包括广谱抗微生物性能）， 功效和细胞毒性）。随后，将评估抗菌有效性和安全性终点， 动物模型（家兔），以评价申报技术在安全缓解经皮 分流管感染体外和体内研究将包括适当的对照，包括未改性硅胶分流器， 抗生素浸渍分流导管（Medtronic ARESTM、Codman Bactiseal ™和Cook Spectrum ™）和 银洗脱导管。将对照对照（无涂层）分流管测量微生物定植的减少 导管在这些研究中。该项目概念验证阶段的预期成果将是 在体外和体内证明新技术的机械完整性、安全性和抗菌功效 vivo.可行性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.