Abstract Body: Background
Antibiotic prophylaxis after out-of-hospital cardiac arrest (OHCA) reduces early-onset pneumonia (EOP) but no study has used microbiome analysis to evaluate its effect on antibiotic resistance. The objective of this trial was to assess the effects of prophylactic ceftriaxone after OHCA on EOP and antibiotic resistance gene acquisition.
Methods
This single center, blinded, placebo-controlled trial randomized patients ≥18 years of age who were comatose after OHCA due to any initial heart rhythm and treated with targeted temperature management (TTM) to ceftriaxone 2g intravenously every 12 hours or placebo for three days. The primary outcome was clinical EOP diagnosed by blinded adjudicators occurring <4 days after resuscitation. Secondary outcomes included broad-spectrum antibiotic treatment, ICU- and mechanical ventilator-free days, antibiotic spectrum coverage score, mortality, and cerebral performance category (CPC) at six months. Antibiotic resistance genes to macrolides, beta-lactams, fluoroquinolones, sulfamethoxazole-trimethoprim, and vancomycin were isolated from rectal swabs before and after study drug administration and were identified using high-throughput metagenomic sequencing.
Results
Four hundred eleven patients were screened and 53 (13%) were randomized; one subject withdrew consent leaving 52 (13%) evaluable patients (26 in each group). Most cardiac arrests were witnessed (63%) with a shockable initial heart rhythm (51%); median time to ROSC was 25 minutes. Ceftriaxone reduced clinical EOP (38% vs. 69%; RR 0.6, 95% CI 0.3-0.9; p=0.03), broad-spectrum antibiotic exposure (50% vs. 85%; RR 0.6, 95% CI 0.4-0.9; p=0.02) and antibiotic spectrum coverage score (20 [0, 43] vs. 53 [17, 80]; p=0.02), while increasing days alive and free from the ICU (16 [0, 24] vs. 0 [0, 0] days; p=0.02) and mechanical ventilator (25 [0, 26] vs. 0 [0, 6] days; p=0.02). In-hospital mortality (42% vs. 73%; p=0.05) and functional outcome (CPC 1 [1, 3] vs. 3 [1, 3]; p=0.7) were similar. Collectively, patients in the ceftriaxone group acquired fewer antibiotic resistance genes (99 vs. 142 genes) with a lower proportion of antibiotic resistance genes targeting commonly prescribed antibiotics (24% vs. 43%; RR 0.6, 95% CI 0.4-0.8; p=0.003) compared to placebo.
Conclusion
Prophylactic ceftriaxone reduces EOP and may decrease antibiotic resistance gene acquisition through reduced exposure to broad spectrum antibiotics. Its effects on other clinical outcomes are uncertain.