Antibiotic-binding peptides for biofilm prevention on ventriculoperitoneal shunts

描述（由申请方提供）：脑室腹膜（VP）分流管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I期资助期间，我们鉴定了与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结合。我们证明了万古霉素：硅胶IFBM在VP分流管的塑料管上装载和输送万古霉素以预防感染的能力。此外，我们证明了万古霉素：硅胶IFBM的体外抗菌功效，并对肽进行了初步生物相容性试验。使用从PLGA：硅酮IFBM递送的装载万古霉素的微粒获得了类似的结果。在临床上，我们的IFBM介导的递送方法具有几个优点，包括：1）外科医生可以选择任何分流材料或最适合患者的多于一类抗生素，而不是具有抗生素治疗材料的特定产品; 2）肽和抗生素组合可在护理点应用于分流器，在植入前几分钟，以及3）药物结合模块可以互换用于新的治疗策略。该II期项目的成功完成将产生基于肽的抗生素递送原型，为进一步的体内疗效III期研究做好准备。公共卫生相关性：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，我们将继续测试能够将万古霉素输送至VP分流管的万古霉素：硅胶IFBM肽。在这里，我们将开发肽组分来连接替代抗生素，优化我们的领先IFBM用于产品开发，并进行更详尽的生物相容性测试，并在体内感染模型中测试其抗菌功效。该第二阶段计划的完成将产生基于肽的抗生素递送原型，为第三阶段研究做好准备，以继续将该IFBM推向开发。

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 the Phase I funding period, we identified peptides which bind to the silicone tubing of a VP shunt, and combined this sequence with our known antibiotic-binding peptides against vancomycin. We demonstrated the capability of this vancomycin:silicone IFBM to load and deliver vancomycin on the plastic tubing of a VP shunt to prevent infection. Further, we demonstrated the antimicrobial efficacy of the vancomycin:silicone IFBM in vitro and performed preliminary biocompatibility testing on the peptide. Similar results were obtained using vancomycin-loaded microparticle delivery from a PLGA:silicone IFBM. Clinically, our IFBM-mediated delivery approach has several advantages including: 1) 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 material; 2) peptide and antibiotic combinations can be applied to shunts at point-of-care, minutes before their implantation and 3) and drug-binding modules can be interchanged for new therapeutic strategies. Successful completion of this Phase II program will result in a peptide-based antibiotic delivery prototype, ready for further Phase III studies of in vivo efficacy. 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 continue testing of our vancomycin:silicone IFBM peptide capable of delivering vancomycin to VP shunts. Here, we will develop peptide components to attach alternative antibiotics, optimize our lead IFBM for product development and conduct more exhaustive biocompatibility testing, and test its antimicrobial efficacy in an in vivo infection model. Completion of this Phase II program will result in a peptide-based antibiotic delivery prototype, ready for Phase III studies to continue moving this IFBM into development.