The Role of Biofilm Formation in Antibiotic Tolerant Periprosthetic Joint Infection

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)是首选 方法处理假体周围关节感染(PJI；感染TKA)。在大约60%的案例中，I&D失败。 I&D的高失败率是植入物上形成生物膜和随后的高耐受性的结果 从生物膜到抗生素。关于生物被膜如何产生抗生素耐受性，它是如何产生的，在知识上有很大的差距 在PJI中，没有任何策略可以破坏这种容忍。这项提议的假设是 生物膜的形成受毒素抗毒素系统的调节，是形成的一个主要因素。 耐抗生素生物膜。在其他慢性感染疾病(如结核病和囊性纤维化)中，生物被膜 众所周知，细菌的形成和耐药会降低抗生素的疗效。了解 导致PJI耐抗生素生物被膜发展的最初事件是发展的第一步 治疗策略。目的包括建立生物被膜形成和抗生素之间的关系。 宽容。初步研究结果表明，生物膜的形成是生物膜形成的关键步骤。 耐药生物膜的研究进展。在目标1中，我们收集了PJI临床分离菌的文库，并将 确定这些分离株在结合和耐药生物膜形成方面的遗传和表型差异。 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 在体外和我们开发的动物模型中，抗生素耐受性。这将为这一角色增加进一步的证据 PJI对抗生素耐药生物膜的研究有助于指导改进治疗策略的制定。

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.