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

基本信息

批准号：
10558711
负责人：
David Gagnon
金额：
$ 49.73万
依托单位：
MAINEHEALTH
依托单位国家：
美国
项目类别：
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/10558711
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 Biological Biological Response Modifier Therapy Blinded Brain Injuries Cardiopulmonary Resuscitation Caring Ceftriaxone Cell Separation Centers of Research Excellence Cephalosporins Clavulanate Clinical Clinical Data Clinical Pharmacists Clinical Trials Collaborations Coma Communities Critical Care Data Down-Regulation Enrollment Ensure Evaluation Feces Functional disorder Generations Genotype Goals Heart Arrest Inflammation Inflammatory Infrastructure Intervention Link Lung infections Maine Mediating Medical center Mentors Morbidity - disease rate Multi-Institutional Clinical Trial Neurological outcome Neurosciences Outcome Patients Pharmacodynamics Pharmacotherapy Pharmacy facility Placebo Control Placebos Pneumonia Pragmatic clinical trial Pre-Clinical Model Predisposition Production Prophylactic treatment Randomized Reporting Research Research Personnel Resistance Risk Rural Community Safety Sampling Sepsis Series 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 improvement heart rhythm immunoregulation improved improved outcome member metagenomic sequencing mortality natural hypothermia neuroprotection novel out-of-hospital cardiac arrest patient population placebo controlled trial pneumonia treatment prevent programs prophylactic prospective residence resistance gene respiratory examination rural disparities systemic inflammatory response

项目摘要

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.

抽象的院外心脏病复苏的昏迷患者中，高达 65% 发生早发性肺炎逮捕并与显着的发病率相关。肺炎和一般的心脏骤停与失控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，具有优异的抗菌谱，具有抗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 CD73 的表达，从而刺激腺苷的机制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性肺炎和 T 细胞介导的炎症通过有针对性的温度管理来治疗心脏骤停。我们的具体目标是：1）量化临床预防性使用头孢曲松钠对院外心脏骤停幸存者的微生物学影响有针对性的温度管理，2) 确定预防性头孢曲松是否抑制 T 细胞介导的通过增加 CD73/腺苷信号传导产生炎症。我们将进行单中心、前瞻性、在缅因州医疗中心进行的随机、三盲、安慰剂对照试验，测试了为期三天的疗程头孢曲松或安慰剂。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。我们的近期目标是开展务实的临床试验，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。该项目由缅因州医疗中心临床药剂师 David Gagnon 博士领导，他专门研究重症监护药房。 Gagnon 博士是一名重症监护常驻学者，也是一名早期职业调查员建立药物治疗研究计划。他与以下机构建立了卓有成效的研究合作该 COBRE 小组的其他成员，并将在该项目中接受一位资深临床研究人员的指导具有多中心临床试验经验，包括对肺部感染易感患者的研究（J. Zuckerman）和一位具有神经科学和病理生理学经验的药理学研究员（K. 豪斯克内希特）。该项目是 Gagnon 博士实现其长期目标的基础机会为心脏骤停幸存者建立有效的药物治疗方案，以改善功能和神经系统结果。作为这个主题相关的 COBRE 的组成部分，他将与同事合作相关研究提供协同影响，改善不同社区的心脏骤停护理。