Diagnosis and Tracking of Spinal Staphylococcus aureus Orthopaedic Implant Infections

脊柱金黄色葡萄球菌骨科植入物感染的诊断和追踪

• 批准号: 10554426
• 负责人: Cheryl Lynne Ackert-Bicknell
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-24 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10554426
• 关键词: Anatomy; Antibiotic Therapy; Antibodies; Antibody titer measurement; Antibody-Producing Cells; Antigens; B-Cell Activation; Benchmarking; Biological; Biological Assay; Blood; Blood Tests; Blood specimen; Body Temperature; C-reactive protein; Cell Culture Techniques; Cell secretion; Circulation; Clinical; Collecting Cell; Complex; Complication; Cultured Cells; Data; Death Rate; Devices; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic tests; Disadvantaged; Early Intervention; Environment; Erythrocyte Sedimentation Rate; Fever; Goals; Harvest; Immune response; Immunoassay; Immunoglobulin G; Immunoglobulin-Secreting Cells; Implant; In Vitro; Infection; Infectious Agent; Infectious Skin Diseases; Joint Prosthesis; Knee; Learning; Liquid substance; Masks; Measurement; Measures; Methods; Microbial Biofilms; Monitor; Morbidity - disease rate; Musculoskeletal; Neurologic Symptoms; Nomograms; Operative Surgical Procedures; Organism; Orthopedics; Outcome; Pain; Patients; Peripheral Blood Mononuclear Cell; Polymers; Postoperative Period; Practice Guidelines; Property; Rapid diagnostics; Reaction; Sampling; Second Look Surgery; Serum; Serum Markers; Site; Spinal; Staphylococcus aureus; Staphylococcus aureus infection; Surface; Surgical Wound Infection; Temperature; Testing; Therapeutic; Therapeutic Intervention; Time; Vertebral column; White Blood Cell Count procedure; Whole Blood; Work; antimicrobial; cost; cytokine; diagnostic accuracy; diagnostic tool; diagnostic value; experience; extracellular; foot; implant associated infection; implantation; in vivo; joint infection; novel; pathogen; prognostic; response; spine bone structure; standard of care; success; treatment guidelines; treatment response; usability

Spinal infections are a serious complication of vertebral implantation surgery with a death rate as high as 20% in the first year. Challenging to identify, especially in the early stages, they are typically diagnosed after becoming well established when the patient is experiencing significant pain and permanent vertebral damage. Here, we propose to explore the early immune response to these infections, focusing on Staphylococcus aureus, (S. aureus), the most frequent and serious among the multiple pathogens that cause spinal implant infections. Our goal is to develop a new way to diagnose spinal implant infections that will: 1) be usable early in the infection's course, 2) cost less than current approaches, 3) require only a routine blood sample, and 4) be capable of monitoring therapeutic success. Most patients have high circulating levels of S. aureus-specific antibodies, and these levels increase with infection, but remain elevated long after the infection has been resolved. To provide a more sensitive diagnostic tool and at the same time create a simple measure for monitoring therapeutic success, we propose to measure the antibodies produced by circulating Antibody- Secreting Cells (ASC) that are present in the blood while the infection is ongoing and rapidly decline thereafter. ASC can be harvested from whole blood, washed free of serum antibodies, and cultured in vitro for a short time. These cultured cells will secrete newly synthesized antibodies, as well as the cytokines, yielding “medium enriched for newly synthesized antibodies” or MENSA, for short. Antibody titers of MENSA fluid against antigens for specific pathogens and the cytokines being secreted can be measured using a multiplex immunoassay. In this proposal, we hypothesize that the diagnosis and monitoring of treatment response due to spine related S. aureus infection is feasible utilizing pathogen-specific antibodies secreted by ASC, and that the antigenic signatures will be distinct compared to other musculoskeletal infections. To test this hypothesis, we will examine MENSA antibody and cytokine levels in patients with a known or suspected infection associated with previously placed spinal orthopedic implants. We will determine if MENSA antibodies alone or in combination with cytokines can discriminate between patients with S. aureus infections or infections due to other pathogens. Accuracy will be determined by comparing to the clinical gold standard of bacterial culture. We will also determine if we can use MENSA to track the response to treatment for S. aureus infection. This study is focused on S. aureus as we can diagnosis this pathogen via culture, giving us a benchmark for accuracy, even though 48% of the time, the infectious agent in spine infections cannot be determined by culture. This study is a proof-of-concept study that can be expanded to other pathogens that are complex to diagnose while also monitoring treatment when direct culture methods become impractical. The goal of this work is the creation of simple, inexpensive, rapid diagnostic method that can lead to earlier interventions and better outcomes for spinal infections patients.

脊柱感染是椎体植入手术的严重并发症，死亡率高达20% 在第一年。为了识别，特别是在早期阶段，他们通常在 当患者经历显著疼痛和永久性椎骨损伤时， 在这里，我们建议探讨这些感染的早期免疫反应，重点是葡萄球菌 aureus，（S.金黄色葡萄球菌），是引起脊柱植入物的多种病原体中最常见和最严重的 感染.我们的目标是开发一种诊断脊柱植入物感染的新方法，该方法将：1）早期可用， 感染的过程，2）成本低于目前的方法，3）只需要一个常规的血液样本，和4） 能够监测治疗的成功。大多数患者有高水平的S循环。金黄色特有的 抗体，这些水平随着感染而增加，但在感染后很长一段时间内仍然升高。 解决了提供更灵敏的诊断工具，同时创建一个简单的测量方法， 监测治疗成功，我们建议测量循环抗体产生的抗体- 分泌细胞（ASC）是存在于血液中，而感染正在进行，并迅速下降之后。 ASC可以从全血中收集，洗涤除去血清抗体，并在体外培养短时间。 时间这些培养的细胞将分泌新合成的抗体，以及细胞因子，产生“培养基 富含新合成的抗体”或简称MENSA。MENSA液体的抗体滴度 特异性病原体的抗原和分泌的细胞因子可以使用多重免疫分析仪（multiplex 免疫测定法在这个建议中，我们假设，诊断和监测治疗反应，由于 spine related S.利用ASC分泌的病原体特异性抗体，金黄色葡萄球菌感染是可行的， 与其它肌肉骨骼感染相比，抗原特征将是不同的。为了验证这个假设， 我们将检查已知或疑似感染患者的MENSA抗体和细胞因子水平 与先前放置的脊柱矫形植入物相关。我们将确定是否单独使用MENSA抗体或 联合细胞因子可以区分S.金黄色葡萄球菌感染或感染由于 其他病原体。通过与细菌培养的临床金标准进行比较，确定准确度。 我们还将确定我们是否可以使用MENSA来跟踪对S.金黄色葡萄球菌感染。这 研究的重点是S.因为我们可以通过培养来诊断这种病原体， 准确性，即使48%的时间，脊柱感染中的感染因子不能通过 文化这项研究是一项概念验证研究，可以扩展到其他复杂的病原体， 当直接培养方法变得不切实际时，诊断同时也监测治疗。这个目标 工作是创造简单，廉价，快速的诊断方法，可以导致早期干预， 对脊柱感染患者有更好的疗效。