The Role of Biofilm Formation in Antibiotic Tolerant Periprosthetic Joint Infection

生物膜形成在抗生素耐受性假体周围感染中的作用

• 批准号: 10188719
• 负责人: KENNETH L URISH
• 金额: $ 7.83万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188719
• 关键词: Address; Adhesions; Adhesives; Animal Model; Antibiotics; Attention; Bacteria; Bacterial Antibiotic Resistance; Binding; Cell Adhesion Molecules; Cells; Chronic Disease; Clinical; Complication; Cystic Fibrosis; DNA; DNA Sequence Alteration; Data; Debridement; Development; Diagnosis; Disease; Event; Evolution; Extracellular Matrix; Failure; Genes; Genetic; Goals; Gram-Negative Bacteria; Implant; In Vitro; Infection; Irrigation; Knowledge; Lead; Libraries; Measures; Mediating; Medicare; Metabolic; Metabolic Pathway; Methods; Microbe; Microbial Biofilms; Mutation; Operative Surgical Procedures; Orthopedics; Outcome; Pathogenesis; Patients; Pharmacology; Phenotype; Physicians; Play; Polysaccharides; Preparation; Process; Proteins; Relapse; Research Personnel; Residual state; Role; Scientist; Secondary to; Series; Staphylococcus aureus; Surface; System; Testing; Time; Toxin; Treatment Failure; Treatment outcome; Tuberculosis; United States; Work; alpha Toxin; antibiotic tolerance; antitoxin; career; chronic infection; comparative genomics; improved; improved outcome; joint infection; knee replacement arthroplasty; microbial; mortality; mutant; novel therapeutics; resistance mechanism; therapy development; 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 formation of biofilm on the implant and the subsequent 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 biofilm formation, regulated by toxin antitoxin systems, are a major factor responsible for the formation of antibiotic tolerant biofilm. In other diseases of chronic infection (ie tuberculosis and cystic fibrosis), biofilm formation and antibiotic tolerance have been well-recognized to decrease antibiotic efficacy. Understanding the initial events that lead to the development of antibiotic tolerant biofilm in PJI is the first step in developing treatment strategies. The aims include establishing the relationship between biofilm formation and antibiotic tolerance. Preliminary results in this proposal demonstrate that biofilm formation is a critical step in the development of antibiotic tolerant biofilm. In Aim 1, we have collected a library of PJI clinical isolates, and will identify genetic and phenotypic differences in binding and antibiotic tolerant biofilm formation in these isolates. In Aim 2, we will determine the role of toxin-antitoxin systems in PJI biofilm formation and association with antibiotic tolerance in vitro and in the animal model we have developed. This will add further evidence to the role of antibiotic tolerant biofilm in PJI to help direct improved the development of treatment strategies.

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）与长期抗生素是首选 治疗假体周围关节感染（PJI;感染性TKA）的方法。I&D在大约60%的情况下失败。 I&D的高失败率是种植体上形成生物膜和随后的高耐受性的结果 抗生素的生物膜。在生物膜如何产生抗生素耐受性方面， 调节，并且没有策略来破坏PJI中的这种耐受性。这一提议的假设是， 由毒素抗毒素系统调节的生物膜形成是导致 耐抗生素生物膜。在其他慢性感染性疾病（即肺结核和囊性纤维化）中，生物膜 已经充分认识到细菌的形成和抗生素耐受性会降低抗生素的功效。了解 导致PJI中抗生素耐受性生物膜发展的初始事件是发展抗生素耐受性生物膜的第一步。 治疗策略。目的包括建立生物膜形成与抗生素之间的关系 宽容该提案的初步结果表明，生物膜形成是生物降解的关键步骤。 抗生素耐受性生物膜的发展。在目标1中，我们收集了PJI临床分离株的文库，并将 鉴定这些分离株中结合和抗生素耐受性生物膜形成的遗传和表型差异。 在目标2中，我们将确定毒素-抗毒素系统在PJI生物膜形成中的作用，以及与PJI生物膜形成的相关性。 体外和我们开发的动物模型中的抗生素耐受性。这将进一步证明 抗生素耐药生物膜的PJI，以帮助直接改善治疗策略的发展。