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）：疾病控制中心估计，每年多达200万人在医院收缩感染，多达100,000人死亡。大约1/4的医院相关感染（〜500,000）是手术部位感染。对于每位患者，据报道，手术现场感染需要额外的6.5天住院时间，造成超过3,000美元的额外费用。因此，仅在美国，手术现场感染就代表了十亿美元的问题。术后感染的风险仍然是医疗保健提供者的严重关注。诸如腹股沟疝修复的选修手术的感染率为0.5-4％，创伤或开放性裂缝修复患者的率高达20％。其他报道已经观察到由于阑尾炎或内脏穿孔伴随的手术场中，几乎一半的所有病例中都有感染。由于术后感染需要手术修订和/或非凡的医疗干预，因此先发制人需要大量的医生时间和关注。当前的抗感染策略采用了围手术性预防性抗生素的全身性给药。另外，抗生素通常包括在灌溉液中。但是，很少有发布的报告支持这种做法的有效性。已经出现了几种分娩策略，以提高局部抗生素的功效，以提高临床医生预防手术部位感染的能力。材料，例如水凝胶，骨骼胶结和聚合物珠，已浸入抗生素以提供局部释放机制，而脂质体递送已被用来增加全身性抗生素的时间顺序。尽管正在开发各种各样的交付技术，但很少有人进入市场。因此，需要一种满足1）持续释放和2）局部应用的抗生素递送机制的需求。 Affinergy Inc.正在开发特定于现场的靶向肽，我们称其为界面生物材料（IFBMS），旨在结合治疗剂和靶标底物（医疗设备或植入物）。使用噬菌体显示技术，可以使用随机噬菌体库将肽序列靶向材料或分子，该培养基能够在一个实验中测试数十亿个候选序列。通过将材料结合肽与治疗性结合肽配对，我们产生了一种新型的双功能肽，能够在植入的表面引导生物学活性。在当前的建议中，我们旨在使用高亲和力肽直接靶向组织，从而促进其快速摄取并持续从外科部位的软组织中释放。我们以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联系起来会导致一种新型的基于肽的抗生素递送分子。作为一种平行的递送方法，此处还提出了组织结合肽与含有抗生素的聚合物胶片片的共价附着。公共卫生相关性：除了程序本身外，感染可能是几乎任何手术干预期间最重要的医学问题。每年在美国，大约有500,000人患有手术现场感染，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，这些治疗均未证明是一个结论性的解决方案。在这里，我们提出了一种新型基于肽的接头系统的开发，将抗生素直接靶向外科部位组织。通过优化已经掌握的组织和抗生素结合肽，Affinergy打算生成双功能抗生素递送系统，以增强手术后立即增强局部保留率并持续释放抗生素。该产品可能有可能降低与这种医疗并发症相关的成本和患者困扰。