Ceftriaxone Immunomodulation and Antimicrobial Effects After Cardiac Arrest

心脏骤停后头孢曲松的免疫调节和抗菌作用

• 批准号: 10090069
• 负责人: David Gagnon
• 金额: $ 42.9万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-10 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10090069
• 关键词: Address; Adenosine; Affect; Amoxicillin; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antibiotic Prophylaxis; Antibiotic Resistance; Antibiotics; Antiinflammatory Effect; Antimicrobial Effect; Bacteremia; Bacterial Drug Resistance; Blinded; Brain Injuries; Cardiopulmonary Resuscitation; Caring; Ceftriaxone; Cells; Centers of Research Excellence; Cephalosporins; Clavulanate; Clinical; Clinical Data; Clinical Microbiology; Clinical Pharmacists; Clinical Trials; Collaborations; Coma; Communities; Critical Care; Data; Down-Regulation; Enrollment; Ensure; Evaluation; Feces; Foundations; Functional disorder; Generations; Genotype; Goals; Heart Arrest; Inflammation; Inflammatory; Infrastructure; Intervention; Link; Lung infections; Maine; Mediating; Medical center; Mentors; Microbiology; Morbidity - disease rate; Multi-Institutional Clinical Trial; Neurological outcome; Neurosciences; Outcome; Patients; Pharmacodynamics; Pharmacotherapy; Pharmacy facility; Placebos; Pneumonia; Pragmatic clinical trial; Pre-Clinical Model; Predisposition; Production; Prophylactic treatment; Randomized; Reporting; Research; Research Personnel; Resistance; Resuscitation; Risk; Rural Community; Safety; Sampling; Sepsis; Series; Shock; Signal Transduction; Sputum; Structure; Survivors; Syndrome; T-Cell Activation; T-Lymphocyte; Temperature; Testing; Therapeutic; Work; acute care; antimicrobial; bacterial resistance; bactericide; career; cytokine; early onset; experience; functional outcomes; heart rhythm; immunoregulation; improved; improved outcome; member; metagenomic sequencing; mortality; natural hypothermia; novel; out-of-hospital cardiac arrest; patient population; placebo controlled trial; pneumonia treatment; prevent; programs; prophylactic; prospective; residence; resistance gene; rural disparities; systemic inflammatory response

Abstract Early-onset pneumonia occurs in up to 65% of comatose patients resuscitated from out-of-hospital cardiac arrest and is associated with significant morbidity. Pneumonia, and cardiac arrest in general, is associated with uncontrolled systemic inflammation as part of the post-resuscitation cardiac arrest syndrome. Because inflammation and pneumonia may precipitate secondary brain injury, preventing them may improve outcomes. Ceftriaxone, a third-generation cephalosporin antibiotic, has an excellent anti-microbial spectrum, and has anti- inflammatory as well as potential neuroprotective effects. Our previous studies identified a novel cellular mechanism where ceftriaxone increases expression of CD73 on T lymphocytes, which stimulates adenosine production and decreases release of pro-inflammatory cytokines. Thus, we hypothesize that prophylactic ceftriaxone will reduce early-onset pneumonia and T cell-mediated inflammation in survivors of out-of-hospital cardiac arrest treated with targeted temperature management. Our specific aims are to: 1) quantify the clinical and microbiologic effects of prophylactic ceftriaxone in out-of-hospital cardiac arrest survivors treated with targeted temperature management, and 2) determine if prophylactic ceftriaxone suppresses T cell-mediated inflammation via increased CD73/adenosine signaling. We will conduct a single-center, prospective, randomized, triple-blinded, placebo-controlled trial at Maine Medical Center testing a three-day course of ceftriaxone or placebo. Because potential bacterial resistance is a concern with antibiotic prophylaxis, we will also evaluate bacterial resistomes in patient airway and gut. Our immediate goals are to conduct a pragmatic clinical trial, characterize a novel mechanism of action of ceftriaxone on T cell activity, and gain the experience, expertise, and infrastructure needed to conduct a multicenter clinical trial. This project is led by Dr. David Gagnon, a clinical pharmacist at Maine Medical Center who specializes in Critical Care Pharmacy. Dr. Gagnon is a Critical Care Scholar-in-Residence and is an early career investigator establishing a research program in pharmacotherapy. He has established fruitful research collaborations with other members of this COBRE group, and will be mentored in this project by an established clinical researcher with experience in multi-site clinical trials including study of patients with susceptibility to lung infections (J. Zuckerman) and a pharmacologist researcher with experience in neuroscience and pathophysiology (K. Houseknecht). This project is a foundational opportunity for Dr. Gagnon to work towards his long-term goal of establishing effective pharmacotherapy options for cardiac arrest survivors to improve functional and neurological outcomes. As a component of this thematically-linked COBRE, he will collaborate with colleagues on related studies to provide a synergistic impact to improve cardiac arrest care across diverse communities.

抽象的 早发肺炎发生在多达65％的昏迷患者中，从院外心脏复苏 逮捕，并与明显的发病率有关。肺炎和心脏骤停一般都与 不受控制的全身性炎症，作为后震动心脏骤停综合征的一部分。因为 炎症和肺炎可能会导致继发性脑损伤，以防止它们改善预后。 头孢曲松是第三代头孢菌素抗生素，具有极好的抗微生物光谱，并且具有抗 - 炎症以及潜在的神经保护作用。我们以前的研究确定了一种新颖的细胞 头孢曲松在T淋巴细胞上增加CD73的表达的机制，刺激腺苷 产生并减少促炎细胞因子的释放。因此，我们假设预防性 头孢曲松将减少院外幸存者的早发肺炎和T细胞介导的炎症 通过靶向温度管理治疗的心脏骤停。我们的具体目的是：1）量化临床 预防性头孢曲松对院外心脏骤停幸存者的微生物学作用 目标温度管理，2）确定预防性头孢曲松是否抑制了T细胞介导的 通过增加CD73/腺苷信号传导的炎症。我们将进行单一中心，潜在的 缅因州医学中心的随机，三盲，安慰剂对照试验测试为期三天的课程 头孢曲松或安慰剂。由于潜在的细菌耐药性是预防抗生素的问题，我们将 还评估患者气道和肠道中的细菌抗性。我们的直接目标是进行务实 临床试验是头孢曲松对T细胞活性的新型作用机理，并获得经验， 专业知识和基础设施需要进行多中心临床试验。 该项目由缅因州医疗中心的临床药剂师戴维·加格农（David Gagnon）博士领导，他专门从事 重症监护药房。 Gagnon博士是一位驻地重症监护学者，是早期职业调查员 建立药物治疗研究计划。他与 该毛病组的其他成员将由一位既定的临床研究人员在该项目中进行指导 具有多部位临床试验的经验，包括研究对肺部感染敏感的患者（J. Zuckerman）和具有神经科学和病理生理学经验的药理研究员（K. Houseknecht）。该项目是Gagnon博士实现其长期目标的基本机会 为心脏骤停幸存者建立有效的药物治疗选择，以提高功能和 神经学结果。作为这种主题链接的鞋底的组成部分，他将与同事合作 在相关研究中提供协同影响，以改善各种社区的心脏骤停护理。