Tissue-targeted Antibiotics for the Prevention of Surgical Site Infection

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DESCRIPTION (provided by applicant): The Centers for Disease Control estimates that as many as 2 million people contract infections in hospitals each year, with as many as 100,000 deaths. Approximately 1/4 of hospital related infections (~500,000) are surgical site infections. For each single patient, surgical site infections have been reported to require a median 6.5 additional days of hospital stay, incurring over $3,000 in extra costs. Therefore, in the United States alone, surgical site infection represents a billion dollar problem. The risk of postoperative infection remains a serious concern for healthcare providers. Elective surgeries such as inguinal hernia repair exhibit infection rates of 0.5-4%, with rates rising as high as 20% for trauma or open fracture repair patients. Other reports have observed infections in nearly half of all cases in compromised surgical fields due to concomitant appendicitis or visceral perforation. Because post-operative infection requires surgical revision and/or extraordinary medical intervention, preemption requires considerable physician time and attention. Current anti-infection strategies employ systemic administration of peri-operative prophylactic antibiotics. In addition, antibiotics are often included in irrigation fluid; however few published reports support the effectiveness of this practice. Several delivery strategies have emerged to enhance the efficacy of local antibiotics to improve clinicians' ability to prevent surgical site infections. Materials, such as hydrogels, bone cements, and polymer beads have been impregnated with antibiotics to provide a local release mechanism, while liposomal delivery has been used to increase the time-course of systemic antibiotics. Despite a wide array of delivery technologies under development, very few have made their way to market. A need therefore remains for an antibiotic delivery mechanism that satisfies both characteristics of 1) sustained release and 2) localized application. Affinergy Inc. is developing site-specific targeting peptides, which we have termed interfacial biomaterials (IFBMs) designed to bind a therapeutic agent and a target substrate (medical device or implant). Using phage display technology, peptide sequences can be targeted to a material or molecule using a randomized phage library, capable of testing billions of candidate sequences in one experiment. By pairing a material-binding peptide with a therapeutic-binding peptide, we generate a novel bifunctional peptide, capable of directing biological activity on an implanted surface. In the current proposal, we aim to target antibiotics directly to tissues using high-affinity peptides fostering their rapid uptake and sustained release from the soft tissues of a surgical site. Our previous work has identified high-affinity peptides that bind the glycopeptide antibiotic vancomycin. Linking these peptides with tissue-binding peptides will give rise to a novel peptide-based antibiotic delivery molecule. As a parallel delivery approach, covalent attachment of tissue- binding peptides to polymeric micoparticles containing antibiotic is also proposed here. PUBLIC HEALTH RELEVANCE: Apart from the procedure itself, infection is perhaps the most important medical concern during virtually any surgical intervention. Approximately 500,000 people suffer from surgical site infections in the US each year, further compounding the risks, discomfort and costs associated with surgery. A range of treatments have been developed to reduce surgical site infections, none of which have proven to be a conclusive solution. Here we propose the development of a novel peptide-based linker system, targeting antibiotic directly to surgical site tissue. By optimizing the tissue and antibiotic-binding peptides already in hand, Affinergy intends to generate a bifunctional antibiotic delivery system to enhance the localized retention and sustained release of antibiotics immediately following surgery. This product could potentially reduce the costs and patient distress associated with this added medical complication.