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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：
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
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/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

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.

摘要