Biofilm antibiotic tolerance in periprosthetic joint infection

假体周围感染的生物膜抗生素耐受性

基本信息

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
项目类别：
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

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 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.

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调试（I＆D）是首选的方法来管理周围关节感染（PJI；感染TKA）。 I＆D大约有60％的失败案例。 I＆D的高衰竭率是生物膜对抗生素的高耐受性的结果。有很大的差距在Knowle中，生物膜如何产生抗生素耐受性，如何受到调节，并且没有策略在PJI中破坏了这种宽容。该提议的假设是细菌持续存在细菌在表型上对抗生素具有抗性，是导致这种耐受性的主要因素，高 I＆D的故障率。在其他慢性感染（IE结核和囊性纤维化）中，细菌持久性已被众所周知，以增加对抗生素的生物膜耐受性并防止感染的消除。证明细菌持久性存在于PJI生物膜中是制定治疗策略的第一步。目的包括在PJI生物膜中建立细菌持久性的存在并确定潜力降低生物膜抗生素耐受性的治疗策略，以进行以后的临床试验。初步结果提案表明，细菌持久性为生物膜抗生素耐受提供了重大贡献，并且这种耐受性与体外毒素 - 抗毒素表达的增加有关。在AIM 1中，临床研究将是完成以确定是否在临床样本上观察到这些相同的结果。在AIM 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，在动物模型中发达。在AIM 3中，一种新的抗生素ADEP4的效率不取决于活动将定量代谢或放射性细菌的正能状态。这将增加进一步的证据细菌持久性在PJI中的作用，并为以后的临床试验提供了另一种新的治疗策略。该研究计划与五年的职业发展计划紧密整合，Urish博士将在其中由跨科手术研究和临床研究人员的多学科团队指导，微生物学和生物统计学。根据已经存在的关系，方法论选择导师专业知识和精神上的先前初级调查人员的成功。心理团队是一个巨大的这项提案的力量会损害潜水员和免费的技能。为了实现他的训练整个提案期间安排的目标，课堂和会议的组合将为获得高级细菌遗传技术，分析及其其新技能的基础提供了基础应用于翻译的临床研究。共同产生的初步数据和心理将通过R01资助的研究，为Urish博士过渡到独立性的基础。