Antibiotic-binding Peptides for Biofilm Prevention on Ventriculoperitoneal Shunts

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 mechanica l 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 inf ections 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 lo calized 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 noncov alently 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 optimiz e 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 stu dies 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 strat egies 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 att ach 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 molec ules 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.