ANTIMICROBIAL TECHNOLOGY TO ACTIVELY MITIGATE HYDROCEPHALUS SHUNT INFECTIONS LONG TERM

抗菌技术可主动缓解长期脑积水分流感染

• 批准号: 10081483
• 负责人: Marion Walker
• 金额: $ 38.82万
• 依托单位: THROMBODYNE, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10081483
• 关键词: Acute; Address; Adoption; Animal Model; Antibiotic Therapy; Antibiotics; Architecture; Binding; Biological Availability; Blood - brain barrier anatomy; Candida albicans; Carbon; Catheters; Cell Line; Cerebrospinal Fluid; Cessation of life; Chemistry; Chronic; Clinical; Copper; Deposition; Devices; Disease; Dose; Drainage procedure; Electroplating; Ensure; Environment; Evaluation; Exposure to; Feasibility Studies; Goals; Healthcare Systems; Hydrocephalus; Immune system; In Vitro; Infection; Infection Control; Invaded; Knowledge; Lead; Measures; Mechanics; Medical; Medical Device; Methods; Microbial Biofilms; Modeling; Modification; Morbidity - disease rate; Mycoses; Neurons; Oryctolagus cuniculus; Outcome; Output; Patients; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Polymers; Pre-Clinical Model; Procedures; Property; Protocols documentation; Pseudomonas aeruginosa; Recurrence; Research Personnel; Safety; Shunt Device; Silicones; Silver; Staphylococcus aureus; Staphylococcus epidermidis; Surface; Techniques; Technology; Thick; antimicrobial; clinical efficacy; commercialization; cooking; cytotoxicity; design; efficacy study; experimental study; flexibility; head-to-head comparison; improved; in vitro testing; in vivo; lead candidate; mechanical force; microbial colonization; microbiota; mortality; new technology; novel strategies; pathogen; phase 1 study; physical property; prevent; product development; prototype; skin microbiota; technology development

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.

抽象的 在医疗领域，为患者放置分流管以管理脑脊液 (CSF) 引流是必不可少的 然而，在实践中，它们很容易受到当地微生物群落的感染，从而导致高死亡率和 分流器通常由富含碳或硅的聚合物制成，以保持所需的特性，例如。 作为灵活性，但这些惰性聚合物为入侵的皮肤菌群提供了一个有吸引力的避难所。 固有的或与宿主免疫系统协同的保护特性使得这些分流容易发生 大多数全身抗生素无法穿透生物膜结构并成功消除局部感染。 然而，设备感染使分流器更换（修订）成为唯一的选择。 暂时有效的方法受到高感染复发率（~50%）的困扰。 为了解决上述挑战，抗生素浸渍分流导管旨在抵抗 微生物定植已经被开发出来，但即使在之后也没有明确的临床疗效证明。 广泛采用抗生素分流术和严格的感染控制方案来管理脑脊液引流 申请人已经认识到分流感染和相关临床后遗症的问题仍然存在。 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。 申请人提出的解决方案可以主动减少经皮装置上的微生物定植 长期表面不会影响设备的物理性能，也不使用有毒物质 药品。 拟议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 提出了临床前模型中的技术改进，以确定具有优越性的原型。 通过短期和长期体外测试（包括广谱 随后，抗菌功效和安全性终点将在 动物模型（兔子）评估所提出的技术在安全减轻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器， 抗生素浸渍分流导管（Medtronic ARESTM、Codman Bactiseal 和 Cook Spectrum）和 将对照对照（未涂层）分流器测量微生物定植的减少。 这些研究中的导管。该项目概念验证阶段的预期结果将是 在体外和体内展示新技术的机械完整性、安全性和抗菌功效 可行性论证将为该技术的进一步商业开发奠定基础。