Critical Care: Original Research

Ceftriaxone to Prevent Early-Onset Pneumonia in Comatose Patients Following Out-of-Hospital Cardiac Arrest: A Pilot Randomized Controlled Trial and Resistome Assessment (PROTECT)

David J. Gagnon, Kristin M. Burkholder, Alexandra J. Weissman, et al

Chest 2025 Available online 28 August 2025 https://doi.org/10.1016/j.chest.2025.08.007

Background

Antibiotic prophylaxis following out-of-hospital cardiac arrest (OHCA) reduces early-onset pneumonia. However, it has an uncertain impact on mortality and noninfectious outcomes, with ongoing concerns about the subsequent development of antibiotic resistance.

Research Question

Does prophylactic ceftriaxone reduce the incidence of early-onset pneumonia without increasing the acquisition of antibiotic resistance genes after OHCA?

Study Design and Methods

Comatose survivors of OHCA treated with targeted temperature management without a clinical diagnosis of pneumonia at admission were randomized to receive ceftriaxone 2 g or matching placebo every 12 hours for 3 days. The primary outcome was early-onset pneumonia occurring ≤ 4 days following intubation confirmed by masked adjudicators. Abundance of antibiotic resistance genes recovered from rectal swabs before-and-after study drug administration were analyzed with metagenomic sequencing.

Results

A total of 411 participants were screened; 53 (13%) were randomized to treatment, and one participant withdrew, leaving 26 in each group in the final analysis. Early-onset pneumonia was diagnosed in 10 (38%) participants receiving ceftriaxone and 18 (69%) participants receiving placebo (risk ratio, 0.57; 95% CI, 0.21-1.001; P = .05). Open-label antibiotics were administered to 14 (54%) participants receiving ceftriaxone and 22 (85%) receiving placebo (risk ratio, 0.64; 95% CI, 0.43-0.94); most of the antibiotics were broad-spectrum agents (93% and 100%, respectively). After adjusting for differences in abundance of antibiotic resistance genes prior to study drug administration, participants randomized to receive ceftriaxone acquired significantly fewer antibiotic resistance genes to frequently used antibiotics in the ICU compared with those randomized to receive placebo (incidence risk ratio, 0.30; 95% CI, 0.13-0.70). Serious adverse drug effects were not reported in either treatment group.

Interpretation

This trial was inconclusive regarding the impact of ceftriaxone prophylaxis on reducing the incidence of early-onset pneumonia following OHCA. However, ceftriaxone was associated with less frequent administration of open-label antibiotics and reduced acquisition of antibiotic resistance genes to frequently used antibiotics in the ICU.

Clinical Trial Registration

ClinicalTrials.gov; No.: NCT04999592; URL: www.clinicaltrials.gov