Development of a Unique Antibiofilm Therapy for Diabetic Foot Ulcer Infections

开发治疗糖尿病足溃疡感染的独特抗菌膜疗法

• 批准号: 9334624
• 负责人: Dustin Lee Williams
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9334624
• 关键词: Address; Amputation; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteria; Chronic; Clinic; Clinic Visits; Clinical; Clinical Treatment; Collaborations; Communities; Complex; Development; Diabetes Mellitus; Diabetic Foot; Diabetic Foot Ulcer; Doctor of Philosophy; Dose; Excision; Family suidae; Foot Ulcer; Formulation; Gel; Goals; Growth; Health Care Costs; Healthcare; Healthcare Systems; Hospitalization; Impaired wound healing; In Vitro; Infection; Infectious Skin Diseases; Lead; Legal patent; Length; Methicillin Resistance; Microbial Biofilms; Microbiology; Modeling; Morbidity - disease rate; Motivation; Names; Nomenclature; Organism; Patients; Pilot Projects; Production; Pseudomonas aeruginosa; Quality of life; Regimen; Rehabilitation therapy; Reporting; Research Personnel; Resistance; Resistance development; Risk; Series; Staphylococcus aureus; Technology; Testing; Therapeutic; Translating; Veterans; Work; Wound Healing; animal data; chronic wound; clinical care; cost; design; diabetic; efficacy testing; foot; improved; in vivo; innovation; killings; methicillin resistant Staphylococcus aureus; novel; parenteral administration; pathogen; prevent; success; wound

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.

相关性：对于VA医疗保健系统中的患者，糖尿病足溃疡构成了重要部分 治疗和治疗。在糖尿病患者的所有并发症中，没有任何并发​​症更常见，成本高昂，并且 复杂的比脚感染。当这些伤口因生物膜形成细菌而变得复杂时，问题 由于生物膜有助于导致慢性，难以治疗的感染，因此变得特别具有挑战性 发病率和截肢。在感染糖尿病足溃疡和慢性伤口的情况下，最常见的两个 培养的病原体是金黄色葡萄球菌（特定于甲氧西林的金黄色葡萄球菌（MRSA） 关注）和铜绿假单胞菌 - 易于形成生物膜的原生物。为了解决这些问题，我们 已经合成并开发了CZ化合物。 CZ是专利且独特的一流系列 抗生素抗生素降低了耐药性发展的风险，这些抗生素分散并杀死了良好的生物膜。 它们还与传统抗生素协同作用，这不仅可以解决问题 与生物膜相关感染的问题，但要改善当前的临床治疗。 目的：直接目标是测试创新抗体膜治疗的效率，以治疗和 在糖尿病猪切除伤口模型中预防生物膜相关感染。长期，目标是翻译 这项用于在诊所测试CZ的技术。与拉里·迈耶（Larry Meyer）的合作，医学博士，博士和唐·格兰杰（Don Granger） 定期治疗VA患者的医学博士（其中很大一部分患有糖尿病足溃疡）在体内动物 收集数据，我们的小组可以与FDA合作以进行研究者发起的研究并直接翻译 诊所的技术降低发病率，成本，住院/诊所就诊持续时间以及长度 我们的退伍军人康复。 假设：1）当用作局部凝胶时，CZ化合物将治疗并预防单粒细胞和 糖尿病性猪切除伤口模型中MRSA或铜绿假单胞菌的多因素生物膜相关感染。 2）CZ 化合物将与目前在临床上使用的抗生素协同作用，并将提高其能力 治疗和预防由MRSA和铜绿假单胞菌引起的生物膜相关感染在糖尿病性猪切除中 伤口模型。 程序：AIM 1A：将重点介绍针对针对单粒和多型生物膜的体外优化 耐甲氧西林金黄色葡萄球菌（MRSA）和铜绿假单胞菌。 CZ的体外效率概况具有 有充分的文献记录，这很重要，因为这意味着AIM 1B和AIM 2的成功不会是 仅取决于目标1a的成功。然而，在AIM 1A中，我们建议对 CZ技术以优化剂量和凝胶配方为放射性单粒细胞和多菌菌生物膜。 AIM 1B：将涉及针对单粒和多因素生物膜相关的CZ效率的体内分析 糖尿病猪的感染将被MRSA，铜绿假单胞菌或两者兼而有之。目标2：意志 涉及与AIM 1B相同的猪模型，但将包括父母给药的其他组成部分 传统的抗生素与局部CZ治疗结合使用。这种合并疗法的效率将是 针对MRSA和铜绿假单胞菌的一单星和多粒生物膜相关感染进行了测试。 发现的意义：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）一种针对和放射性生物膜的定向方法，使糖尿病足溃疡复杂化 感染和2）开发新型抗生素策略，以解决当前的全球抗生素威胁 反抗。在此提案中，将采用一种定向方法来测试独特的第一类系列的效率 抗生素抗生素的抗生素降低了耐药的风险，并已在体内驾驶 治疗和预防与生物膜相关的感染。长期目标是减少患者的诊所就诊次数 患有足部溃疡感染，降低医疗保健成本并改善退伍军人生活质量的人。