Synovial Fluid and Joint Sepsis

滑液和关节败血症

• 批准号: 9402991
• 负责人: Noreen J Hickok
• 金额: $ 54.05万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9402991
• 关键词: Acute suppurative arthritis due to bacteria; Amikacin; Animal Disease Models; Anti-Bacterial Agents; Antibiotic Therapy; Antibiotics; Arthritis; Bacteria; Biochemical; Characteristics; Clinical; Coagulation Process; Data; Debridement; Diagnosis; Effectiveness; Ensure; Excision; Exhibits; Family suidae; Fibrin; Human; In Situ; In Vitro; Infection; Irrigation; Joint Capsule; Joints; Local Anti-Infective Agents; Mediating; Metabolic; Methicillin; Methicillin Resistance; Microbial Biofilms; Microbiology; Microbubbles; Microscopic; Modeling; Musculoskeletal Diseases; Necrosis; Operative Surgical Procedures; Orthopedics; Pain; Patients; Permeability; Pharmaceutical Preparations; Physics; Prevention; Protease Inhibitor; Proteins; Recurrence; Rupture; Sepsis; Staphylococcus aureus; Staphylococcus epidermidis; Surface; Surgeon; Synovial Fluid; Synovial joint; Testing; Tissues; Treatment Efficacy; Ultrasonography; antimicrobial; base; combat; cost; crosslink; effective therapy; in vivo; joint destruction; joint infection; joint injury; mortality; neutrophil; novel therapeutics; prevent; protein aggregation; septic; success

ABSTRACT In 2013, more than 20,000 patients in the US were diagnosed with joint infection. Despite surgical intervention with debridement of necrotic tissue, aggressive lavage with antiseptic solutions, and systemic antibiotic treatment, the mortality rate exceeds 11% and recurrence is common. Furthermore, the aggressive treatments damage the joint ensuring later arthritis. Once bacteria access the joint capsule, our preliminary data suggest that bacterial contaminants become recalcitrant to antibiotic treatments due to formation of large bacterial aggregates that can be floating or loosely associated with tissues. We propose to develop new treatments that disrupt and prevent re-formation of bacterial aggregates in septic joints to allow effective antibacterial treatment. To attack this problem, we propose three specific aims: Specific Aim 1: To inhibit bacterial aggregate formation in synovial fluid through treatment with drugs that alter protein aggregation. We hypothesize that inhibition of aggregation will allow antibiotic access and increased effectiveness. Specific Aim 2: To permeabilize synovial fluid aggregates using ultrasound-mediated microbubble rupture in an ex vivo model of the joint. We hypothesize that microbubble cavitation will permeabilize aggregates to increase antibiotic efficacy towards bacteria within the clump. Specific Aim 3: To eradicate joint infection, in vivo, through combined microbubble/drug/antibiotic treatments. We will test the hypothesis that joint infections may be treated more effectively by the local application of microbubble cavitation in the presence of agents from Specific Aim 1 and amikacin. To attack this problem, we have assembled a team of experts in orthopaedic infection, animal models of disease, ultrasound physics, musculoskeletal disease together with a practicing orthopaedic surgeon specializing in joint infection. The success of our proposed approach will lead to higher treatment success rates, so that the pain, cost, suffering and mortality associated with joint infections will be markedly reduced.

摘要 2013年，美国有2万多名患者被诊断为关节感染。尽管做了手术 通过清创坏死组织、用消毒液进行侵入性灌洗以及全身干预 抗生素治疗，死亡率超过11%，复发很常见。此外，咄咄逼人的 治疗会损害关节，从而导致日后的关节炎。一旦细菌进入关节囊，我们的初步研究 数据表明，细菌污染物对抗生素治疗变得顽固，因为形成了 可以漂浮或松散地与组织结合的细菌聚集体。我们建议开发新的 破坏和防止脓毒症关节中细菌聚集体重新形成的治疗方法，以使有效 抗菌治疗。针对这一问题，我们提出了三个具体目标：具体目标1：抑制 通过用改变蛋白质聚集的药物治疗，在滑液中形成细菌聚集体。我们 假设抑制聚集将允许抗生素的获得和有效性的提高。特定目标 2：体外超声介导的微泡破裂对滑液聚集体的通透性 关节的模型。我们假设微泡空化会使集合体的渗透性增加 对菌丛内细菌的抗生素效果。具体目标3：在体内根除关节感染， 通过微泡/药物/抗生素联合治疗。我们将检验这样的假设：关节感染 在药剂存在的情况下，局部应用微泡空化可更有效地治疗 来自特定的目标1和阿米卡星。为了解决这个问题，我们组建了一个骨科专家团队 传染病，疾病的动物模型，超声物理学，肌肉骨骼疾病与练习 专门研究关节感染的整形外科医生。我们提议的方法的成功将导致更高的 治疗成功率，因此与关节感染相关的疼痛、费用、痛苦和死亡率将 明显减少。