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: 9912728
• 负责人: KENNETH L URISH
• 金额: $ 16.6万
• 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/9912728
• 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.

摘要 全膝关节置换术(TKA)是医疗保险中容量最大的主要外科手术，也是感染 是TKA修订的最大原因。使用长期抗生素的冲洗和清创(I&D)是 处理假体周围关节感染的首选方法(PJI；感染的TKA)。大约60%的I&D失败 案子。I&D的高失败率是由于生物膜对抗生素的高度耐受性造成的。有一个很大的差距 在关于生物被膜如何形成抗生素耐受性、如何调节它的知识方面，目前还没有策略来 破坏PJI中的这种容忍。这一提议的假设是细菌持续存在，即细菌的亚群 细菌对抗生素的表型抗药性是导致这种耐受性和高耐受性的主要因素 其他慢性感染性疾病(如结核病和囊性纤维化)、细菌持久者的I&D失败率 已经被公认为可以增加生物膜对抗生素的耐受性，防止感染的根除。 证明PJI生物膜中存在细菌持久性是制定治疗策略的第一步。 目的包括确定PJI生物膜中细菌持续体的存在并确定潜在的 降低生物膜对抗生素耐受性的治疗策略，用于以后的临床试验。这方面的初步结果 提案表明，细菌持续体对生物膜抗生素耐受性有重大贡献，而且 这种耐受性与体外毒素-抗毒素表达的增加有关。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生物被膜抗生素耐受中的作用 发展起来的。在目标3中，一种新的抗生素ADEP4的疗效不依赖于活性 消除细菌的新陈代谢或正能量状态将被量化。这将增加更多的证据 细菌持久剂在PJI中的作用，为以后的临床试验提供了另一种新的治疗策略。 研究计划与乌里什博士将担任的五年职业发展计划紧密结合在一起 在整形外科多学科研究和临床研究人员团队的指导下， 微生物学和生物统计学。导师的选择是基于已经存在的关系、方法 专业知识，并成功地指导了以前的初级调查人员。指导团队是一支巨大的 这项提议的优势在于他们妥协了多样化和互补性的技能组合。为了完成他的训练 目标，在整个提案中安排的课程、研讨会和会议的组合将 为获得先进的细菌基因技术、分析和他们的新技能提供基础 在转化型临床研究中的应用。总而言之，生成的初步数据和指导将 通过R01资助的研究，为乌里什博士向独立的过渡奠定基础。