Tissue-targeted Antibiotics for the Prevention of Surgical Site Infection

用于预防手术部位感染的组织靶向抗生素

• 批准号: 7480572
• 负责人: Hanne Gron
• 金额: $ 28.33万
• 依托单位: AFFINERGY ,INC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7480572
• 关键词: Affinity; Animal Model; Antibiotic Prophylaxis; Antibiotics; Appendicitis; Area; Arginine; Aspartic Acid; Attention; Bacteriophages; Binding; Binding Proteins; Biocompatible Materials; Biological; Biopolymers; Blood Vessels; Bone Cements; Bone Transplantation; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Characteristics; Chemistry; Clinical; Connective Tissue; Contracts; Development; Distress; Drug Delivery Systems; Drug Kinetics; Effectiveness; Endothelial Cells; Exhibits; Fostering; Glycine; Glycopeptide Antibiotics; Goals; Growth Factor; Hand; Health Care Costs; Health Personnel; Hospitals; Hydrogels; Implant; In Vitro; Infection; Inguinal Hernia; Intervention; Irrigation; Length; Length of Stay; Libraries; Life; Link; Liposomes; Liquid substance; Literature; Localized; Malignant Neoplasms; Marketing; Mediating; Medical; Medical Device; Metals; Modeling; Normal tissue morphology; Open Fractures; Operative Surgical Procedures; Patients; Peptides; Perforation; Phage Display; Pharmaceutical Preparations; Phase; Physicians; Plastics; Polymers; Postoperative Period; Prevention; Procedures; Public Health; Publishing; RGD (sequence); Randomized; Range; Rate; Repeat Surgery; Reporting; Research; Rest; Risk; Science; Screening procedure; Second Look Surgery; Site; Solutions; Specific qualifier value; Specificity; Stainless Steel; Stents; Surface; System; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; To specify; Trauma; United States; Use Effectiveness; Vancomycin; Visceral; Week; Work; base; biomaterial compatibility; cost; day; design; desire; experience; improved; in vivo; innovation; interfacial; medical complication; nanoparticle; novel; peptide B; pre-clinical; preclinical study; prevent; programs; prophylactic; protein aminoacid sequence; prototype; repaired; research study; soft tissue; uptake

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.

描述（由申请人提供）：美国疾病控制中心估计，每年有多达 200 万人在医院感染，死亡人数多达 10 万人。大约 1/4 的医院相关感染（约 500,000 例）是手术部位感染。据报道，对于每位患者来说，手术部位感染平均需要额外住院 6.5 天，从而产生超过 3,000 美元的额外费用。因此，仅在美国，手术部位感染就造成了数十亿美元的问题。术后感染的风险仍然是医疗保健提供者严重关注的问题。腹股沟疝气修复术等选择性手术的感染率为 0.5-4%，而创伤或开放性骨折修复患者的感染率高达 20%。其他报告观察到，由于伴随阑尾炎或内脏穿孔，近一半的病例在受损手术区域出现感染。由于术后感染需要手术修复和/或特殊的医疗干预，因此需要医生投入大量时间和注意力。目前的抗感染策略采用围手术期预防性抗生素的全身给药。此外，冲洗液中通常含有抗生素；然而，很少有已发表的报告支持这种做法的有效性。已经出现了几种递送策略来增强局部抗生素的功效，从而提高临床医生预防手术部位感染的能力。水凝胶、骨水泥和聚合物珠等材料已浸渍抗生素，以提供局部释放机制，而脂质体递送已用于延长全身抗生素的时程。尽管有多种递送技术正在开发中，但很少有技术已进入市场。因此，仍然需要一种满足1)持续释放和2)局部应用这两个特征的抗生素递送机制。 Affinergy Inc. 正在开发位点特异性靶向肽，我们将其称为界面生物材料 (IFBM)，旨在结合治疗剂和目标基质（医疗设备或植入物）。利用噬菌体展示技术，可以使用随机噬菌体库将肽序列靶向材料或分子，能够在一次实验中测试数十亿个候选序列。通过将材料结合肽与治疗结合肽配对，我们产生了一种新型双功能肽，能够指导植入表面的生物活性。在当前的提案中，我们的目标是使用高亲和力肽将抗生素直接靶向组织，促进抗生素从手术部位软组织的快速摄取和持续释放。我们之前的工作已经鉴定出与糖肽抗生素万古霉素结合的高亲和力肽。将这些肽与组织结合肽连接将产生一种新型的基于肽的抗生素递送分子。作为一种平行递送方法，本文还提出了将组织结合肽共价连接到含有抗生素的聚合物微粒上。公共卫生相关性：除了手术本身之外，感染可能是几乎所有外科手术中最重要的医疗问题。在美国，每年约有 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、不适和费用。人们已经开发出一系列治疗方法来减少手术部位感染，但没有一种方法被证明是决定性的解决方案。在这里，我们建议开发一种新型的基于肽的连接系统，将抗生素直接靶向手术部位组织。通过优化现有的组织和抗生素结合肽，Affinergy 打算开发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。该产品可能会降低与这种增加的医疗并发症相关的成本和患者痛苦。