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）：在严重病例中，使用心室（VP）分流器来治疗小儿和新生儿脑积水，约为受影响的婴儿的1/3。由于感染和机械崩溃的敏感性高，VP分流器的故障率约为30-40％。因此，存在需要改善此过程的预防感染，这可能是通过减少微生物定植和随后在这些留置材料表面形成的生物膜形成。分流本身由塑料阀组成，有机硅管从侧心通向良性区域，在该区域可以重新吸收疏散的脑脊液（CSF）。大多数感染发生在植入后的2个月内，并归因于皮肤植物群。因此，内脏衍生的感染不是典型的。外部耗尽CSF的外部室排水管（EVD）也表现出与这些来源相似的感染率。预防感染的当前策略代表了一系列医疗实践和技术进步。全身性抗生素给药通常在围手术期使用，但据报道对感染率产生有限的影响。使用抗生素浸渍的材料来局部预防微生物定植，已成为通过多项临床研究验证的令人兴奋的新预防策略。这里的提案使用一种新型的抗菌方法，使用高亲和肽涂层非折叠抗生素对VP分流管的抗生素。 Affinergy开发了一系列能够结合植入生物材料的肽和我们称为界面生物材料（IFBMS）的治疗剂。在此阶段I研究计划中，我们将尝试优化与VP分流器结合的肽，并将该序列与我们已知的抗生素结合肽与Vancomycin相结合。这种塑料：万古霉素IFBM将能够在VP分流器的塑料管上输送和保留万古霉素，以防止感染。该提案的成功完成将导致原型VP分流涂层能够输送生物活性万古霉素。从临床上讲，我们的IFBM介导的输送方法具有多个优点，包括：1）材料和药物结合模块可以互换用于新的治疗策略； 2）肽和抗生素组合可以在植入和植入之前的几分钟内将肽和抗生素组合应用于分流器，3）外科医生可以选择最适合患者而不是具有抗生素治疗的特定产品的任何分类材料或一类最适合患者的抗生素。该阶段I计划的成功完成将导致基于肽的抗生素递送原型，以便用于体内功效和生物相容性的II期研究。公共卫生相关性：由于心室（VP）分流表现出很高的感染率，因此有很大的需求以增强其承受微生物定殖的能力。尽管当前的策略涉及用抗生素浸渍这些材料，但新疗法有望使医生可以在任何VP分流材料上使用其选择抗生素。 Affinergy开发的涂层采用双功能，高亲和力的肽将治疗分子附着在植入物质表面上。在此研究计划中，我们将生成一个新的涂层，该涂层将万古霉素附加到有机硅副总裁分流器上。在这里，我们将开发肽成分，组装双功能涂层分子并在体外测试其抗菌功效。该阶段I计划的完成将导致基于肽的抗生素递送原型，准备进行体内功效和生物相容性的II期研究。