Research Project
7939582
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.
