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系统来说代价高昂，而且会影响世界各地的患者。这些感染的重要原因是存在于已建立的自然界生物膜中的细菌，这些细菌在创伤时或在随后的手术中污染开放的骨折部位。为了直接和局部地对抗和预防这些感染，已经对植入物的抗生素表面涂层进行了研究。然而，由于微生物不断产生的抗生素耐药性，植入物表面缺乏长期的洗脱特性，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范围有限，抗生素仍然具有很大的局限性。因此，需要开发用于骨科植入物的新型抗菌涂料。在此，我们建议研究一种新型抗菌剂-阳离子类固醇抗菌剂-13(CSA-13)，它对革兰氏阴性和革兰氏阳性菌具有优异的广谱活性。我们打算使用CsA-13作为骨科固定钢板的表面涂层，以防止感染。为了在我们的实验设计中促进强烈的感染信号，已建立的金黄色葡萄球菌生物膜将在CDC生物膜反应器系统的优惠券上生长，后者提供了一种创建标准生物膜的手段。将优惠券插入固定板底部的凹槽中，作为一个单元，将固定板/优惠券直接放置在绵羊胫骨的表面上。对两组变量的评估：CsA-13涂层或未涂层以及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抗击并可能预防骨科生物膜植入物相关感染的潜力。此外，该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。综上所述，拟议的实验旨在首先分析新型CSA-13抗菌剂在已建立的生物膜中对抗和预防由常见骨科病原体金黄色葡萄球菌促进的骨科植入相关感染的能力，然后确定CSA-13是否对宿主组织和末端器官产生有害影响。我们希望通过这些手段，改善对平民和军事创伤患者的骨科创伤护理。公共卫生相关性：与骨科植入物相关的感染不仅会给医疗系统带来高昂的成本，而且会削弱个人的生命，甚至可能导致截肢。细菌对抗生素的耐药性以及抗生素用作植入物表面涂层时的局限性，要求为骨科植入物制定新的抗菌策略，以避免感染和植入物失败。因此，我们建议评估一种新型的抗菌涂层-CSA-13-作为植入物的表面涂层来对抗和预防这些感染。我们希望这将为平民和军人患者提供一种更可靠的方法，避免在严重污染的伤口上感染。

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.