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: 10464246
• 负责人: Cheryl Lynne Ackert-Bicknell
• 金额: $ 20.71万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10464246
• 关键词: Anatomy; Antibiotic Therapy; Antibodies; Antibody titer measurement; Antibody-Producing Cells; Antigens; B-Cell Activation; Benchmarking; Biological Assay; Blood; Blood Circulation; Blood Tests; Blood specimen; Body Temperature; C-reactive protein; Cell Culture Techniques; Clinical; Complex; Complication; Cultured Cells; Data; Death Rate; Devices; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic tests; Disadvantaged; Early Intervention; Environment; Erythrocyte Sedimentation Rate; Fever; Foot joint structure; Genus staphylococcus; Goals; Gold; Harvest; Immune response; Immunoassay; Immunoglobulin G; Immunoglobulin-Secreting Cells; Implant; In Vitro; Infection; Infectious Agent; Infectious Skin Diseases; Joint Prosthesis; Knee; Lead; Liquid substance; Masks; Measurement; Measures; Methods; Microbial Biofilms; Microbiology; 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; Sampling; 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; base; 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

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.

脊柱感染是椎骨植入手术的严重并发症，死亡率高达20％ 在第一年。具有挑战性的识别，尤其是在早期阶段，通常会在 当患者遭受重大疼痛和永久性椎体损害时，变得良好。 在这里，我们建议探索对这些感染的早期免疫响应，重点是葡萄球菌 金黄色葡萄球菌（金黄色葡萄球菌），是导致脊柱植入物的多种病原体中最常见和严重的 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：1） 感染的过程2）成本低于当前方法，3）仅需要常规的血液样本，4） 能够监测疗法成功。大多数患者的金黄色葡萄球菌特异性水平高。 抗体，这些水平随着感染而增加，但在感染后很长时间保持升高 解决。提供更敏感的诊断工具，同时为 监测理论的成功，我们建议测量循环抗体产生的抗体 在感染正在进行并随后迅速下降时，存在于血液中的分泌细胞（ASC）。 ASC可以从全血收集，无血清抗体洗涤，并在体外培养短暂培养 时间。这些培养的​​细胞将秘密合成抗体以及细胞因子，产生“培养基” 富含新合成的抗体”或mensa，用于简短。 可以使用多路复用 免疫测定。在此提案中，我们假设诊断和监测治疗反应 使用ASC分泌的病原体特异性抗体，与脊柱相关的金黄色葡萄球菌感染是可行的， 与其他肌肉骨骼感染相比，抗原性特征将是不同的。为了检验这一假设， 我们将检查已知或怀疑感染的患者的MESA抗体和细胞因子水平 与先前放置的脊柱骨科关联。我们将确定单独的mensa抗体还是 结合细胞因子可以区分金黄色葡萄球菌感染或由于 其他病原体。与细菌培养的临床黄金标准相比，将确定精度。 我们还将确定是否可以使用Mensa跟踪对金黄色葡萄球菌感染的治疗反应。这 研究的重点是金黄色葡萄球菌，因为我们可以通过培养诊断这种病原体，从而为我们提供了基准 准确性，即使有48％的时间，脊柱感染中的传染剂也不能由 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。目标的目标 工作是创建简单，廉价，快速诊断的方法，可以导致较早的干预措施，并且 脊柱感染患者的更好结果。