A Combination Coating for the Prevention of Perioperative Device Infections

描述(由申请人提供)： 相关性：在美国，每年对退伍军人和非退伍军人患者进行超过70万次初次髋关节和膝关节置换术以及另外120万例脊柱手术。在这些初级手术中，围术期设备相关感染约占2-3%，当考虑翻修手术时，这一数字高达17.5%。这些程序后的感染很难治疗，特别是在抗药性细菌已被确定为致病物种的情况下。这些耐药细菌可能以耐甲氧西林金黄色葡萄球菌(MRSA)、万古霉素耐药金黄色葡萄球菌(VRSA)或类似耐药菌株的形式存在。据估计，美国每年有近50万例退伍军人和非退伍军人医院感染金黄色葡萄球菌和耐甲氧西林金黄色葡萄球菌的病例。耐甲氧西林金黄色葡萄球菌病例数量的增加归因于细菌对传统抗生素治疗的耐药性不断增强。目的：本研究的目的是在绵羊动物模型中使用一种独特的硅(硅)聚合物释放的阳离子类固醇抗菌素-13(CsA-13)来对抗与常见骨科器械操作相关的耐药细菌菌株感染。这项工作的长期目标是减少设备相关感染的发生率，最大限度地减少住院所需时间，减少退伍军人医疗保健系统和患者的费用，并消除多阶段修订程序。假设：1)硅聚合物复合涂层中18%的CsA-13重量比(w/w)可防止多孔性涂层钛塞种植体从硅聚合物涂层中淋洗时引起的体内浮游MRSA感染。2)CsA-13抗菌剂的释放不会对塞式种植体多孔涂层区域内假体周围骨附着的速度和数量产生不利影响。程序：为了验证假设1，两个研究组将在磷酸盐缓冲盐水中挑战200×L 5x108个菌落形成单位的浮游MRSA。将多孔涂层钛(Ti)塞植入右侧股骨髁关节面，运行4周。感染控制组(第1组)将接受多孔涂层钛塞和MRSA悬浮液，以确保已产生感染信号。感染挑战赛(第2组)将收到一个钛塞子，上面涂有一层含有CsA-13抗菌剂(18%w/w)和MRSA混悬液的硅薄膜，以测试CsA-13的杀菌效果。为了验证假设2，将使用三组来评估CSA-13组合涂层的生物相容性-不使用MRSA来测试假设2。生物兼容性挑战(组3)将接受18%(w/w)CSA-13/Si涂层插头，以表征CSA-13对假体周围骨的影响。聚合物对照组(第4组)将接受硅涂层塞子(不含CsA-13)，以评估聚合物单独对邻近骨骼的影响，以区分 CsA-13来自硅上的骨骼附着。最后，生物相容性对照组(第5组)将只接受多孔涂层钛塞-不含CsA-13或硅，以证明骨骼附着在具有已建立的生物相容性的材料上。与假设1类似，塞子将被植入 并利用两个时间点评估生物相容性：4和 24周。研究结果的意义：这种抗菌药物组合涂层的成功有可能通过降低因围手术期设备相关感染而导致的初次和翻修手术的相关成本，显著改善退伍军人管理局的临床护理。这项研究还将大大提高退伍军人的生活质量，通过消除或显著限制退伍军人对围手术期器械相关感染的易感性，减少住院和康复所需的时间。

DESCRIPTION (provided by applicant): RELEVANCE: Annually, more than 700,000 primary hip and knee replacements and another 1.2 million spine surgeries are performed on VA and non-VA patients in the United States (US). Perioperative device-related infections compromise approximately 2-3% of these primary procedures and when considering revision surgeries, this number grows as high as 17.5%. Infections following these procedures are difficult to treat, especially in cases where antibiotic-resistant bacteria have been identified as the pathogenic species. These resistant bacteria may be present in the form of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant S. aureus (VRSA), or similar resistant bacterial strains. Estimates of veteran and nonveteran hospital acquired S. aureus and MRSA infections are reported at nearly 500,000 cases in the US each year. This increase in the number of MRSA cases has been attributed to the bacteria's evolving resistance toward conventional antibiotic therapy. OBJECTIVES: The objective of this study is to combat resistant bacterial strain infections associated with common orthopedic device procedures using a unique silicone (Si) polymer released cationic steroidal antimicrobial-13 (CSA-13) in a sheep animal model. The long-term goals of this work are to reduce the incidence of device-related infection, minimize the time required for hospitalization, decrease the expense incurred by the VA Health Care System and patient, and eliminate multiple-stage revision procedures. HYPOTHESES: 1) The 18% weight-to-weight ratio (w/w) CSA-13 in Si polymer combination coating will prevent infection caused by planktonic MRSA in vivo when eluted from the Si polymer coating on a porous coated titanium plug implant. 2) The rate and amount of periprosthetic skeletal attachment within the porous coated region of the plug implant will not be adversely affected by the release of the CSA-13 antimicrobial. PROCEDURES: To test Hypothesis 1 two study groups will be challenged with 200 ¿L of 5x108 colony forming units of planktonic MRSA in phosphate buffered saline. A porous coated titanium (Ti) plug will be implanted into the articulating surface of the right femoral condyle and run for 4 weeks. The infection control (Group 1) will receive a porous coated Ti plug and MRSA suspension to ensure that an infection signal has been generated. The infection challenge (Group 2) will receive a Ti plug coated with a thin film of Si containing the CSA-13 antimicrobial (18% w/w) and MRSA suspension to test the bactericidal efficacy of CSA-13. To test Hypothesis 2 three groups will be utilized to assess the biocompatibility of the CSA-13 combination coating- no MRSA will be used to test Hypothesis 2. The biocompatibility challenge (Group 3) will receive the 18% (w/w) CSA-13/Si coated plug to characterize the effects of CSA-13 on the periprosthetic bone. The polymer control (Group 4) will receive a Si coated plug (without CSA-13) to assess the effects of the polymer, alone, on the adjacent bone to distinguish the effects of CSA-13 from the Si on skeletal attachment. Finally, the biocompatibility control (Group 5) will receive only the porous coated Ti plug-without CSA-13 or Si to demonstrate skeletal attachment in a material with established biocompatibility. Similar to Hypothesis 1 the plug will be implanted in the right femoral condyle and two time points will be utilized to assess biocompatibility: 4 and 24 weeks. SIGNIFICANCE OF FINDINGS: The success of this antimicrobial combination coating has the potential to significantly improve VA clinical care by reducing costs associated with primary and revision surgeries caused by perioperative device related infections. This research would also greatly improve the veteran's quality of life and reduce the time required for hospitalization and rehabilitation by eliminating, or significantly limiting, the veteran's susceptibility to perioperative device related infections.