Ceftriaxone Immunomodulation and Antimicrobial Effects After Cardiac Arrest

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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.