Antibiotic-binding Peptides for Biofilm Prevention on Ventriculoperitoneal Shunts

用于预防脑室腹腔分流术生物膜的抗生素结合肽

• 批准号: 7480552
• 负责人: PAUL T HAMILTON
• 金额: $ 27.36万
• 依托单位: AFFINERGY ,INC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7480552
• 关键词: Address; Affect; Affinity; Antibiotic Therapy; Antibiotics; Benign; Binding; Biocompatible Materials; Biological; Biological Assay; Biopolymers; Catheters; Cells; Ceramics; Cerebrospinal Fluid; Chemicals; Chemistry; Childhood; Class; Clinical Research; Combined Antibiotics; Condition; Creation of ventriculo-peritoneal shunt; Devices; Dose; Drug Delivery Systems; Ensure; Excision; Exhibits; Failure; Generations; Goals; Growth Factor; Healthcare Systems; Hydrocephalus; Immobilization; Implant; In Vitro; Infant; Infection; Infection prevention; Libraries; Localized; Mechanics; Mediating; Medical; Metals; Methods; Microbial Biofilms; Neonatal; Patients; Peptide Antibiotics; Peptides; Phage Display; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Physicians; Plastics; Polymers; Predisposition; Prevention; Prevention strategy; Procedures; Process; Public Health; Range; Rate; Repeat Surgery; Reporting; Research; Risk; Safety; Second Look Surgery; Series; Shunt Device; Silastic; Silicones; Skin; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Solutions; Source; Specific qualifier value; Specificity; Surface; Surgeon; System; Technology; Teflon; Testing; Therapeutic; Therapeutic Agents; Time; To specify; Vancomycin; Ventricular; antimicrobial; aqueous; base; biomaterial compatibility; cost; design; implant material; implantation; improved; in vivo; interfacial; lateral ventricle; lomustine/procarbazine/vincristine; microbial colonization; new technology; novel; novel therapeutics; point of care; prevent; programs; prototype

DESCRIPTION (provided by applicant): Ventriculoperitoneal (VP) shunts are used to treat pediatric and neonatal hydrocephalus in severe cases, representing approximately 1/3rd of affected infants. Due to the high susceptibility for infection and mechanical breakdown, the failure rate of VP shunts is around 30-40%. A need therefore exists to improve infection prevention for this procedure, likely by reducing microbial colonization and subsequent biofilm formation on the surface of these indwelling materials. The shunt itself is composed of a plastic valve, with silicone tubing leading from the lateral ventricle to a benign region where evacuated cerebrospinal fluid (CSF) can be reabsorbed. The majority of infection occurs within 2 months of implantation, and has been attributed to skin-dwelling flora. Therefore viscerally-derived infections are not typical. External ventricular drains (EVDs), which drain CSF externally, also exhibit similar infection rates from these sources. Current strategies to prevent infections represent a range of medical practices and technological advances. Systemic antibiotic administration is commonly used perioperatively but has been reported to exert a limited effect on infection rates. Using antibiotic impregnated materials for localized prevention of microbial colonization has become an exciting new prevention strategy validated through several clinical studies. The proposal here uses a novel antimicrobial approach, using high affinity peptide coatings to attach antibiotics noncovalently to VP shunt tubing. Affinergy has developed a range of peptides capable of binding implanted biomaterials, and therapeutic agents which we have termed interfacial biomaterials (IFBMs). During this Phase I research program we will attempt to optimize peptides which bind to the silicone tubing of a VP shunt, and combine this sequence with our known antibiotic-binding peptides against vancomycin. This plastic: vancomycin IFBM will be capable of delivering and retaining vancomycin on the plastic tubing of a VP shunt to prevent infection. Successful completion of this proposal will result in a prototype VP shunt coating capable of delivering bioactive vancomycin. Clinically, our IFBM-mediated delivery approach has several advantages including: 1) material and drug-binding modules can be interchanged for new therapeutic strategies; 2) peptide and antibiotic combinations can be applied to shunts at point-of-care, minutes before their implantation and 3) surgeons can choose any shunting materials or more than one class of antibiotics that best suit the patient rather than having one particular product with the antibiotic treatment. Successful completion of this Phase I program will result in a peptide-based antibiotic delivery prototype, ready for Phase II studies of in vivo efficacy and biocompatibility. PUBLIC HEALTH RELEVANCE: Because ventriculoperitoneal (VP) shunts exhibit a high rate of infection, there exists a strong need to enhance their ability to withstand microbial colonization. While current strategies involve impregnating these materials with antibiotics, new treatments will hopefully allow physicians to apply their choice of antibiotic on any VP shunt material. The coatings developed by Affinergy employ bifunctional, high-affinity peptides to attach therapeutic molecules to an implanted material surface. During this research program, we will generate a new coating, which attaches vancomycin to silicone VP shunts. Here, we will develop the peptide components, assemble the bifunctional coating molecules and test its antimicrobial efficacy in vitro. Completion of this Phase I program will result in a peptide-based antibiotic delivery prototype, ready for Phase II studies of in vivo efficacy and biocompatibility.

描述（由申请人提供）： 脑室腹膜（VP）分流用于治疗严重病例中的小儿和新生儿脑积水，约占受影响婴儿的1/3。由于对感染和机械故障的高度敏感性，VP分流器的故障率约为30- 40%。因此，需要改进该手术的感染预防，可能是通过减少这些留置材料表面上的微生物定植和随后的生物膜形成。分流器本身由一个塑料阀和硅胶管组成，硅胶管从侧脑室通向良性区域，排出的脑脊液（CSF）可以被重吸收。大多数感染发生在植入后2个月内，并归因于皮肤驻留植物群。因此，内脏来源的感染并不典型。脑室外引流（EVD）将CSF引流到外部，也显示出与这些来源相似的感染率。目前预防感染的战略代表了一系列医疗实践和技术进步。围手术期通常使用全身性抗生素给药，但据报道对感染率的影响有限。使用抗生素浸渍材料局部预防微生物定植已成为一种令人兴奋的新的预防策略，通过几项临床研究验证。该提案使用了一种新的抗菌方法，使用高亲和力肽涂层将抗生素非共价连接到VP分流管上。Affinergy开发了一系列能够结合植入生物材料的肽，以及我们称为界面生物材料（IFBM）的治疗剂。在该I期研究计划中，我们将尝试优化与VP分流器的硅胶管结合的肽，并将该序列与我们已知的抗万古霉素的抗生素结合肽联合收割机结合。这种塑料：万古霉素IFBM将能够输送万古霉素并将其保留在VP分流管的塑料管上，以防止感染。成功完成该提案将产生能够输送生物活性万古霉素的原型VP分流涂层。在临床上，我们的IFBM介导的递送方法具有以下几个优点：1）材料和药物结合模块可以互换用于新的治疗策略; 2）肽和抗生素组合可在护理点应用于分流器，植入前10分钟，以及3）外科医生可以选择任何分流材料或一种以上最适合患者的抗生素，而不是使用一种特定的产品，抗生素治疗。该I期项目的成功完成将产生基于肽的抗生素递送原型，为体内疗效和生物相容性的II期研究做好准备。公共卫生关系：由于脑室腹膜（VP）分流管的感染率很高，因此迫切需要增强其抵抗微生物定植的能力。虽然目前的策略涉及用抗生素浸渍这些材料，但新的治疗方法有望使医生能够在任何VP分流材料上应用他们选择的抗生素。Affinergy开发的涂层采用双功能，高亲和力肽将治疗分子附着到植入材料表面。在本研究项目期间，我们将生成一种新涂层，将万古霉素附着在硅胶VP分流管上。在这里，我们将开发肽组分，组装双功能涂层分子，并在体外测试其抗菌功效。完成这一第一阶段计划将导致肽为基础的抗生素输送原型，准备在体内疗效和生物相容性的第二阶段研究。