Biofilm antibiotic tolerance in periprosthetic joint infection

假体周围感染的生物膜抗生素耐受性

• 批准号: 10076032
• 负责人: KENNETH L URISH
• 金额: $ 0.08万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10076032
• 关键词: Address; Aftercare; Animal Model; Animals; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Toxins; Biometry; Centers for Disease Control and Prevention (U.S.); Chronic Disease; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Collaborations; Complication; Cystic Fibrosis; Data; Debridement; Development Plans; Diagnosis; Disease; Educational workshop; Failure; Foundations; Funding; Future; Gene Expression; Genes; Genetic Techniques; Goals; Implant; In Vitro; Infection; Irrigation; Knock-out; Knowledge; Literature; Measures; Medicare; Mentors; Messenger RNA; Metabolic; Metabolic Pathway; Metabolism; Methodology; Methods; Microbe; Microbial Biofilms; Microbiology; Mus; Operative Surgical Procedures; Orthopedic Surgery procedures; Orthopedics; Outcome; Patients; Peptide Hydrolases; Pharmacology; Phenotype; Physicians; Play; Population; Recurrence; Relapse; Replacement Arthroplasty; Research; Research Personnel; Residual state; Ribosomal RNA; Role; Sampling; Schedule; Scientist; Secondary to; Staphylococcus aureus; Sterility; Surface; System; Testing; Therapeutic; Time; Toxin; Training; Treatment Cost; Treatment outcome; Tuberculosis; Virulence; Wood material; Work; antibiotic tolerance; antitoxin; bacterial genetics; base; career; career development; chronic infection; clinical practice; cost; improved; improved outcome; in vivo; joint infection; knee replacement arthroplasty; mortality; multidisciplinary; mutant; novel therapeutic intervention; novel therapeutics; persistent bacteria; prevent; skills; success; symposium; transcriptome sequencing; treatment strategy

Abstract Total knee arthroplasty (TKA) is the largest major surgical procedure by volume for Medicare, and infection is the largest reason for TKA revision. Irrigation and debridement (I&D) with long-term antibiotics is the preferred method to manage periprosthetic joint infection (PJI; infected TKA). I&D fails in approximately 60% of cases. The high failure rate of I&D is a result of the high tolerance of biofilm to antibiotics. There is a large gap in knowledge in how biofilm develops antibiotic tolerance, how it is regulated, and there are no strategies to disrupt this tolerance in PJI. The hypothesis of this proposal is that bacterial persisters, a subpopulation of bacteria phenotypically resistant to antibiotics, are a major factor responsible for this tolerance and the high failure rate of I&D. In other diseases of chronic infection (ie tuberculosis and cystic fibrosis), bacterial persisters have been well-recognized to increase biofilm tolerance to antibiotics and prevent eradication of the infection. Demonstrating bacterial persisters are present in PJI biofilm is the first step in developing treatment strategies. The aims include establishing the presence of bacterial persisters in biofilm of PJI and identify potential therapeutic strategies to decrease biofilm antibiotic tolerance for later clinical trials. Preliminary results in this proposal demonstrate bacterial persisters provide a major contribution to biofilm antibiotic tolerance, and that this tolerance is associated with increased toxin-antitoxin expression in vitro. In Aim 1, a clinical study will be completed to determine whether these same results are observed on clinical samples. In Aim 2, we will determine the role of toxin-antitoxin systems in PJI biofilm antibiotic tolerance in the animal model we have developed. In Aim 3, the efficacy of a new class of antibiotics, ADEP4, that is not dependent on active metabolism or a positive energy state to eradicate bacteria will be quantified. This will add further evidence to the role of bacterial persisters in PJI and offer an additional new therapeutic strategy for later clinical trials. The research plan is tightly integrated with a five-year career development plan where Dr. Urish will be mentored by a multidisciplinary team of research and clinical investigators in orthopaedic surgery, microbiology, and biostatistics. Mentors were selected based on already existing relationships, methodological expertise, and success in mentoring previous junior investigators. The mentoring team is a tremendous strength in this proposal as they compromise a diverse and complimentary skill set. To achieve his training objectives, a combination of classes, workshops, and conferences scheduled throughout the proposal will provide the foundation to acquire new skills in advanced bacterial genetic techniques, analysis, and their application into translational clinical studies. Together, the generated preliminary data and mentoring will create a foundation for Dr. Urish’s transition to independence with R01 funded research.

抽象的 全膝关节置换术 (TKA) 是医疗保险和感染领域规模最大的主要外科手术 是TKA翻修的最大原因。使用长期抗生素进行冲洗和清创 (I&D) 是 处理假体周围感染（PJI；受感染的 TKA）的首选方法。 I&D 的失败率约为 60% 案例。 I&D 的高失败率是生物膜对抗生素高度耐受的结果。差距较大 关于生物膜如何产生抗生素耐受性、如何对其进行调节的知识，并且没有策略可以 破坏 PJI 的这种耐受性。该提议的假设是细菌持续存在，是细菌的一个亚群 细菌对抗生素具有表型耐药性，是造成这种耐药性和高耐药性的一个主要因素。 I&D 的失败率。在其他慢性感染疾病（即结核病和囊性纤维化）中，细菌持续存在 已被广泛认为可以增加生物膜对抗生素的耐受性并防止根除感染。 证明 PJI 生物膜中存在细菌持久存在是制定治疗策略的第一步。 目的包括确定 PJI 生物膜中细菌持续存在的情况并确定潜在的 降低生物膜抗生素耐受性的治疗策略，用于以后的临床试验。本次初步结果 该提案表明细菌持续存在对生物膜抗生素耐受性做出了重大贡献，并且 这种耐受性与体外毒素-抗毒素表达增加有关。在目标 1 中，将进行一项临床研究 完成以确定是否在临床样本上观察到这些相同的结果。在目标 2 中，我们将 在我们的动物模型中确定毒素-抗毒素系统在 PJI 生物膜抗生素耐受性中的作用 发达。在目标 3 中，一类新型抗生素 ADEP4 的功效不依赖于活性药物 新陈代谢或消灭细菌的正能量状态将被量化。这将增加进一步的证据 细菌持续存在在 PJI 中的作用，并为以后的临床试验提供额外的新治疗策略。 该研究计划与五年职业发展计划紧密结合，Urish 博士将在该计划中 由骨科研究和临床研究人员组成的多学科团队指导， 微生物学和生物统计学。导师的选择是基于现有的关系、方法论 专业知识，并成功指导以前的初级研究人员。导师团队是一个巨大的 该提案的优势在于他们妥协了多样化和互补的技能。为了实现他的训练 整个提案中安排的课程、研讨会和会议的组合将 为获得先进细菌遗传技术、分析及其相关新技能奠定基础 应用于转化临床研究。生成的初步数据和指导将共同 通过 R01 资助的研究为 Urish 博士向独立过渡奠定基础。