Ceftriaxone Immunomodulation and Antimicrobial Effects After Cardiac Arrest

摘要 早发性肺炎发生在高达65%的从院外心脏复苏的昏迷患者中 逮捕，并与显着的发病率。肺炎和一般的心脏骤停与 不受控制的全身炎症是复苏后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，预防它们可能会改善预后。 头孢曲松是第三代头孢菌素类抗生素，具有良好的抗菌谱， 炎症以及潜在的神经保护作用。我们之前的研究发现了一种新的细胞 头孢曲松增加T淋巴细胞上CD 73表达的机制，其刺激腺苷 产生并减少促炎细胞因子的释放。因此，我们假设， 头孢曲松将减少院外幸存者的早发性肺炎和T细胞介导的炎症 心脏骤停治疗有针对性的温度管理。我们的具体目标是：1）量化临床 预防性头孢曲松对院外心脏骤停存活者的微生物学作用 目标温度管理，和2）确定预防性头孢曲松是否抑制T细胞介导的 炎症通过增加的CD 73/腺苷信号传导。我们将开展一项单中心前瞻性研究， 一项在缅因州医学中心进行的随机、三盲、安慰剂对照试验， 头孢曲松或安慰剂。由于潜在的细菌耐药性是抗生素预防的一个问题，我们将 还评估患者气道和肠道中的细菌耐药性。我们的近期目标是进行一次务实的 临床试验，表征头孢曲松对T细胞活性的新作用机制，并获得经验， 进行多中心临床试验所需的专业知识和基础设施。 该项目由大卫加尼翁博士领导，他是缅因州医学中心的临床药剂师，专门从事 重症监护药房加尼翁博士是一名重症监护住院学者，也是一名早期职业调查员 建立药物治疗的研究项目。他建立了富有成效的研究合作， 这个COBRE小组的其他成员，并将在这个项目中由一个既定的临床研究人员指导 具有多中心临床试验的经验，包括对肺部感染易感性患者的研究（J. Zuckerman）和具有神经科学和病理生理学经验的药理学家研究员（K。 Houseknecht）。这个项目是一个基础性的机会，博士.加尼翁朝着他的长期目标， 为心脏骤停幸存者建立有效的药物治疗方案，以改善功能和 神经学结果。作为这个主题相关的COBRE的一部分，他将与同事合作， 在相关的研究，以提供协同影响，以改善心脏骤停护理在不同的社区。

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.