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: 9293639
• 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/9293639
• 关键词: Address; Aftercare; Animal Model; Animals; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antitoxins; Bacteria; Biometry; Centers for Disease Control and Prevention (U.S.); Chronic; 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; bacterial genetics; base; career; career development; clinical practice; cost; improved; improved outcome; in vivo; joint infection; killings; knee replacement arthroplasty; mortality; multidisciplinary; mutant; novel therapeutic intervention; novel therapeutics; 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）是医疗保险和感染量最大的主要外科手术 是TKA翻修的最大原因。冲洗和清创（I&D）与长期抗生素是 治疗假体周围关节感染（PJI;感染性TKA）的首选方法。I&D失败率约为60% 例I&D的高失败率是生物膜对抗生素的高耐受性的结果。缺口较大 生物膜如何产生抗生素耐受性，它是如何被调节的知识，并且没有策略来 破坏PJI的耐受性。这个提议的假设是，细菌持久性，一个亚群的 细菌对抗生素的表型耐药是造成这种耐受性的主要因素， I&D故障率在其他慢性感染性疾病（如肺结核和囊性纤维化）中， 已经被公认为增加生物膜对抗生素的耐受性并防止感染的根除。 证明细菌持久性存在于PJI生物膜中是开发治疗策略的第一步。 目的包括确定PJI生物膜中细菌持久性的存在，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。初步结果显示， 一项提案证明细菌持留菌对生物膜抗生素耐受性提供了主要贡献， 这种耐受性与体外增加的毒素-抗毒素表达有关。在目标1中，将进行一项临床研究， 以确定在临床样品上是否观察到这些相同的结果。在目标2中，我们将 确定毒素-抗毒素系统在PJI生物膜抗生素耐受性中的作用， 开发在目标3中，一类新的抗生素ADEP 4的疗效不依赖于活性药物。 将量化代谢或正能量状态以根除细菌。这将进一步证明， PJI中细菌存留者的作用，并为以后的临床试验提供额外的新的治疗策略。 研究计划与五年职业发展计划紧密结合， 由骨科手术的多学科研究和临床研究人员组成的团队指导， 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 专业知识，并在指导以前的初级调查员方面取得成功。指导团队是一个巨大的 因为他们妥协了多样化和互补的技能组合。为了完成他的训练 目标，整个提案中安排的课程，研讨会和会议的组合将 提供基础，以获得先进的细菌遗传技术，分析，及其 应用于转化临床研究。生成的初步数据和指导将共同 为Urish博士的过渡到独立与R 01资助的研究创建一个基础。