Tissue-targeted Antibiotics for the Prevention of Surgical Site Infection

描述（由申请人提供）：疾病控制中心估计，每年有多达200万人在医院感染病毒，其中多达10万人死亡。大约1/4的医院相关感染（约50万）是手术部位感染。据报告，每一名手术部位感染的病人平均需要额外住院6.5天，造成3 000多美元的额外费用。因此，仅在美国，手术部位感染就代表着一个价值数十亿美元的问题。术后感染的风险仍然是医疗保健提供者严重关注的问题。选择性手术，如腹股沟疝修补术的感染率为0.5-4%，创伤或开放性骨折修补术的感染率高达20%。其他报告发现，由于阑尾炎或内脏穿孔，近一半的手术野受损病例发生感染。由于术后感染需要手术修复和/或特殊的医疗干预，预防需要医生大量的时间和精力。目前的抗感染策略采用围手术期预防性抗生素的系统管理。此外，冲洗液中经常含有抗生素；然而，很少有发表的报告支持这种做法的有效性。为了提高局部抗生素的疗效，提高临床医生预防手术部位感染的能力，出现了几种递送策略。材料，如水凝胶，骨水泥和聚合物珠浸渍抗生素，以提供局部释放机制，而脂质体递送已被用于增加全身性抗生素的时间过程。尽管各种各样的交付技术正在开发中，但很少有能够进入市场。因此，仍然需要一种同时满足1)持续释放和2)局部应用特性的抗生素给药机制。Affinergy Inc.正在开发位点特异性靶向肽，我们称之为界面生物材料（IFBMs），旨在结合治疗剂和目标底物（医疗设备或植入物）。利用噬菌体展示技术，可以利用随机噬菌体文库将肽序列定位到材料或分子上，在一次实验中可以检测数十亿个候选序列。通过将物质结合肽与治疗结合肽配对，我们产生了一种新的双功能肽，能够指导植入表面的生物活性。在目前的建议中，我们的目标是使用高亲和力肽直接将抗生素靶向组织，促进它们从手术部位的软组织快速吸收和持续释放。我们之前的工作已经确定了结合糖肽抗生素万古霉素的高亲和力肽。将这些肽与组织结合肽连接将产生一种新的基于肽的抗生素传递分子。作为一种平行递送方法，组织结合肽与含有抗生素的聚合物微颗粒的共价附着也被提出。公共卫生相关性：除了手术本身，感染可能是几乎任何手术干预过程中最重要的医学问题。在美国，每年大约有50万人遭受手术部位感染，这进一步加剧了与手术相关的风险、不适和成本。已经开发了一系列治疗方法来减少手术部位感染，但没有一种被证明是结论性的解决方案。在这里，我们建议开发一种新的基于肽的连接系统，直接靶向抗生素到手术部位组织。通过优化已有的组织和抗生素结合肽，Affinergy打算产生一种双功能抗生素递送系统，以增强手术后抗生素的局部保留和持续释放。该产品可以潜在地降低与此增加的医疗并发症相关的成本和患者痛苦。

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.