Prevention of Biofilm Related Infections Using a Novel, Broad Spectrum Antimicrob

描述（由申请人提供）：骨科植入物相关感染不仅对医疗保健系统成本高昂，而且影响全世界的患者。这些感染的主要原因是存在于自然界已建立的生物膜中的细菌，这些细菌在创伤时或随后的手术中污染开放性骨折部位。为了直接和局部地对抗和预防这些感染，已经研究了植入物的抗生素表面涂层。然而，由于微生物的抗生素耐药性不断发展，缺乏从植入物表面的长期洗脱特性，以及在许多情况下，对革兰氏阴性和革兰氏阳性细菌的活性谱有限，抗生素继续具有显著的局限性。因此，需要开发用于骨科植入物的新型抗菌涂层。在此，我们提出研究一种新的抗菌剂-阳离子类固醇抗菌剂-13（CSA-13）-其对革兰氏阴性和革兰氏阳性细菌具有上级广谱活性。我们打算使用CSA-13作为骨科固定板的表面涂层，以防止感染。为了在我们的实验设计中促进强感染信号，将在来自CDC生物膜反应器系统的试样上生长金黄色葡萄球菌的已建立的生物膜，后者提供了产生标准化生物膜的手段。将试样插入固定板下侧的凹槽中，并将固定板/试样作为一个单元直接放置在绵羊胫骨表面上。两组变量的评价; CSA-13涂层或未涂层和生物膜处理或未处理的植入物将确定这种新型抗菌涂层是否具有对抗和可能预防骨科生物膜植入物相关感染的潜力。此外，研究的第二阶段将使用氚作为CSA-13的放射性标记，以确定CSA-13对组织的局部和全身影响。通过闪烁计数和组织学分析，将确定CSA-13对组织和骨折愈合的影响。总之，所提出的实验设计用于首先分析新型CSA-13抗微生物剂对抗和预防由常见骨科病原体S.金黄色葡萄球菌，第二，以确定CSA-13是否对宿主组织和终末器官具有有害作用。我们希望，通过这些手段，以改善平民和军事创伤患者的骨科创伤护理。公共卫生相关性：矫形植入物相关感染不仅对医疗保健系统来说代价高昂，而且会损害个人生命，甚至可能导致截肢。如果要避免感染和植入物失效，细菌对抗生素的耐药性和抗生素用作植入物表面涂层时的局限性需要一种新的骨科植入物抗菌策略。因此，我们建议评价一种新型抗菌涂层CSA- 13作为植入物的表面涂层，以对抗和预防这些感染。我们希望这将给平民和军人患者一个更可靠的方法，避免严重污染伤口的感染。

DESCRIPTION (provided by applicant): Orthopaedic implant-related infections are not only costly to healthcare systems, but affect patients the world over. Contributing significantly to these infections are bacteria residing in established biofilms of nature that contaminate open fracture sites either at the time of trauma or during subsequent surgery. In an attempt to fight and prevent these infections, directly and locally, antibiotic surface coatings of implants have been investigated. However, antibiotics continue to have significant limitations due to evolving antibiotic resistance by microorganisms, a lack of long-term elution properties from implant surfaces and, in many instances, a limited spectrum of activity against Gram-negative and Gram-positive bacteria. Thus, novel antimicrobial coatings need to be developed for orthopaedic implants. Herein, we propose to investigate a novel antimicrobial - cationic steroid antimicrobial-13 (CSA-13) - which has superior broad-spectrum activity against Gram-negative and Gram-positive bacteria. We intend to use CSA-13 as a surface coating on orthopaedic fixation plates to prevent infection. To promote a strong infection signal in our experimental design, established biofilms of Staphylococcus aureus will be grown on coupons from the CDC biofilm reactor system, the latter provides a means to create standardized biofilms. The coupons will be inserted into a notch in the fixation plate on its underside and as a unit, the fixation plate/coupon will be placed directly onto the surface of the tibia of sheep. The evaluation of two sets of variables; CSA-13-coated or uncoated and biofilm-treated or untreated implants will determine if this novel antimicrobial coatings has the potential to fight and possibly prevent orthopaedic, biofilm implant-related infections. Furthermore, a second phase of the study will use tritium as a radiolabel on CSA-13 to determine the local and systemic effects of CSA-13 on tissue. By scintillation counting and histological analysis, the effects of CSA-13 on tissue and fracture healing will be determined. Taken together, the proposed experiments are designed to analyze first, the ability of the novel CSA-13 antimicrobial to fight and prevent orthopaedic implant-related infection promoted by a common orthopaedic pathogen, S. aureus, in an established biofilm and second, to determine if CSA-13 has detrimental effects on host tissue and end organs. We hope, by these means, to improve the orthopaedic trauma care of both civilian and military trauma patients. PUBLIC HEALTH RELEVANCE: Orthopaedic implant-related infections are not only costly to healthcare systems, but cripple individual lives and may even lead to amputation. Evolving bacterial resistance to antibiotics and the limitations of antibiotics when used as implant surface coatings, require a new antimicrobial strategy for orthopaedic implants if infection and implant failure are to be avoided. Therefore, we propose the evaluation of a novel antimicrobial coating-CSA- 13-as a surface coating for implants to fight and prevent these infections. We hope this will give civilian and military patients a more sure way of avoiding infection in grossly contaminated wounds.