Development of a Unique Antibiofilm Therapy for Diabetic Foot Ulcer Infections

相关性：对于退伍军人管理局医疗系统内的患者，糖尿病足溃疡占很大比例 治疗和治疗。在糖尿病患者的所有并发症中，没有一种更常见，更昂贵，更 比脚部感染更复杂。当这些伤口被形成生物膜的细菌复杂化时，问题是 由于生物膜会导致慢性、难以治疗的感染，从而导致 发病率和截肢率。在感染的糖尿病足部溃疡和慢性伤口的病例中，最常见的两种 病原体培养为金黄色葡萄球菌(尤其是耐甲氧西林金黄色葡萄球菌(MRSA) 关注)和铜绿假单胞菌--容易形成生物膜的生物体。为了解决这些问题，我们 合成并开发了CZ化合物。CZS是获得专利的独一无二的一流系列 抗生物膜抗生素，减少抗药性发展的风险，分散和杀死成熟的生物膜。 它们还与传统抗生素协同工作，这不仅提供了解决 生物被膜相关感染的问题，但要改进目前的临床治疗。 目的：近期目标是测试一种创新的抗生物膜疗法的疗效，以治疗和 在糖尿病猪切除创面模型中预防生物膜相关感染。从长远来看，目标是翻译 这项技术用于在临床上检测CZ。合作伙伴：Larry Meyer，医学博士和Don Granger MD定期治疗VA患者-其中很大一部分人患有糖尿病足部溃疡-一次在活体动物中 收集数据后，我们的团队可以与FDA合作进行研究人员发起的研究并直接翻译 将减少发病率、成本、住院/就诊持续时间以及 我们退伍军人的康复。 假设：1)当用作局部凝胶时，CZ化合物将治疗和预防单一微生物和 糖尿病猪切除创面模型中耐甲氧西林金黄色葡萄球菌或铜绿假单胞菌的多菌生物膜相关感染。2)CZ 化合物将与目前临床上使用的抗生素协同作用，并将提高它们的能力 治疗和预防糖尿病猪切除中MRSA和铜绿假单胞菌引起的生物膜相关感染 伤口模型。 程序：目标1a：将重点放在体外对单菌和多菌生物膜的优化 耐甲氧西林金黄色葡萄球菌(MRSA)和铜绿假单胞菌。CZS的体外药效曲线有 这一点很重要，因为这意味着目标1b和目标2的成功将不会 完全依赖于目标1a的成功。然而，在目标1a中，我们建议进行体外分析 CZ技术优化剂量和凝胶配方，以消除单菌和多菌生物被膜。 目的1b：CZ对单菌和多菌生物被膜的体内疗效分析 将接种MRSA和/或铜绿假单胞菌的糖尿病猪切除创面的感染。目标2：意志 涉及与目标1b相同的猪模型，但将包括肠外给药的额外成分 传统抗生素联合局部CZ治疗。这种综合疗法的疗效将是 对单菌和多菌生物膜相关的MRSA和铜绿假单胞菌的感染进行测试。 研究结果的意义：这些研究将解决退伍军人医疗保健中的两个重要临床差距 和平民：1)针对并根除并发糖尿病足部溃疡的生物膜的定向方法 2)开发新的抗菌膜战略，以应对目前抗生素的全球威胁 抵抗。在这项提案中，将采取定向方法来测试独特的一流系列的有效性 抗生物膜抗生素降低了耐药风险，并已在体内试验，显示了它们的能力 治疗和预防生物被膜相关感染。长期目标是减少患者就诊的次数。 他们患有足部溃疡感染，降低了医疗成本，提高了退伍军人的生活质量。

RELEVANCE: For patients within the VA healthcare system, diabetic foot ulcers constitute a significant portion of treatment and therapy. Among all complications in patients with diabetes none is more common, costly and complex than foot infections. When these wounds are complicated by biofilm-forming bacteria, the problem becomes particularly challenging as biofilms contribute to chronic, difficult-to-treat infections that lead to morbidity and amputation. In cases of infected diabetic foot ulcers and chronic wounds, two of the most common pathogens cultured are Staphylococcus aureus (with methicillin-resistant S. aureus (MRSA) of particular concern) and Pseudomonas aeruginosa—organisms that readily form biofilms. To address these problems, we have synthesized and developed CZ compounds. CZs are a patented and unique first-in-class series of antibiofilm antibiotics with reduced risk of resistance development that disperse and kill well-established biofilms. They also work synergistically with traditional antibiotics, which provides the potential to not only address the problem of biofilm-related infections, but to improve current clinical treatments. OBJECTIVES: The immediate objective is to test the efficacy of an innovative antibiofilm therapy to treat and prevent biofilm-related infection in a diabetic pig excision wound model. Long-term, the objective is to translate this technology for testing CZs in the clinic. With the collaboration of Larry Meyer, MD, PhD and Don Granger MD who treat VA patients regularly—a large portion of which suffer from diabetic foot ulcers—once in vivo animal data is collected, our group can work with the FDA to perform investigator-initiated studies and directly translate the technology to the clinic to reduce morbidity, cost, duration of hospitalization/clinic visits, and the length of rehabilitation in our Veterans. HYPOTHESES: 1) When used as a topical gel, CZ compounds will treat and prevent monomicrobial and polymicrobial biofilm-related infection of MRSA or P. aeruginosa in a diabetic pig excision wound model. 2) CZ compounds will act synergistically with antibiotics that are currently used clinically and will improve their ability to treat and prevent biofilm-related infections caused by MRSA and P. aeruginosa in a diabetic pig excision wound model. PROCEDURES: Aim 1a: Will focus on in vitro optimization against monomicrobial and polymicrobial biofilms of methicillin-resistant Staphylococcus aureus (MRSA) and P. aeruginosa. In vitro efficacy profiles of CZs have been well-documented, which is important because this means that the success of Aim 1b and Aim 2 will not be solely dependent on the success of Aim 1a. Nevertheless, in Aim 1a we propose to perform in vitro analysis of the CZ technology to optimize dose and gel formulation to eradicate monomicrobial and polymicrobial biofilms. Aim 1b: Will involve in vivo analysis of CZ efficacy against monomicrobial and polymicrobial biofilm-related infections in diabetic pig excision wounds that will be inoculated with MRSA, P. aeruginosa or both. Aim 2: Will involve the same pig model as Aim 1b, but will include the additional component of parenteral administration of traditional antibiotics in combination with topical CZ treatment. The efficacy of this combined therapy will be tested against monomicrobial and polymicrobial biofilm-related infections of MRSA and P. aeruginosa. SIGNIFICANCE OF FINDINGS: These studies will address two important clinical gaps in Veterans' healthcare and civilians: 1) A directed approach that targets and eradicates biofilms that complicate diabetic foot ulcer infections and 2) the development of novel antibiofilm strategies that address the current global threat of antibiotic resistance. In this proposal, a directed approach will be taken to test the efficacy of a unique first-in-class series of antibiofilm antibiotics that have reduced risk of resistance, and have been piloted in vivo showing their ability to treat and prevent biofilm-related infection. The long-term goal is to reduce the number of clinic visits for patients who suffer from foot ulcer infections, lower healthcare costs and improve quality of life for our Veterans.