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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的总膝关节置换术（TKA）是医疗保险和感染的最大主要手术手术是TKA修订的最大原因。具有长期抗生素的灌溉和清创（I＆D）是首选管理周围关节感染（PJI；感染TKA）的方法。 I＆D在大约60％的案件中失败。 I＆D的高失效率是植入物上生物膜形成和随后的高公差的结果生物膜的抗生素。生物膜如何发展抗生素耐受性，它的知识存在很大差距受监管，没有破坏PJI承受能力的策略。该提议的假设是由毒素抗毒素系统调节的生物膜形成是负责形成的主要因素抗生素耐受生物膜。在其他慢性感染（IE结核和囊性纤维化）中，生物膜形成和抗生素耐受性已得到很好的认可，可降低抗生素功效。了解导致PJI中抗生素耐受生物膜发展的初始事件是发展的第一步治疗策略。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，生物膜的形成是抗生素耐受生物膜的发展。在AIM 1中，我们收集了PJI临床分离株的库，并将在这些分离株中确定结合和抗生素耐受生物膜形成的遗传和表型差异。在AIM 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，并与在体外和动物模型中，抗生素耐受性。这将为角色增加进一步的证据 PJI中抗生素耐受性生物膜的直接改善了治疗策略的发展。