Ceftriaxone Prevents Ventilator-Associated Pneumonia After Brain Injury

PHOENIX — Administering ceftriaxone prophylactically in the intensive care unit (ICU) reduced the risk of ventilator-associated pneumonia (VAP) among patients with an acute brain injury, a randomized double-blind trial conducted in France found.

Confirmed incidence of early VAP, occurring from the second to the seventh day of mechanical ventilation, was lower at 14% in a cohort of patients who received an early dose of ceftriaxone compared with 32% for patients assigned a saline placebo (HR 0.60, 95% CI 0.38-0.95), showed data presented by Claire Dahyot-Fizelier, MD, PhD, of the University of Poitiers, France, at the Society of Critical Care Medicine Critical Care Congress.

By 28 days, the risk of developing all kinds of VAP remained lower in those who had received a single administration of the antibiotic (20% vs 36%; HR 0.62, 95% CI 0.42-0.98), according to findings from the PROPHY-VAP trial, which were simultaneously published in Lancet Respiratory Medicine.

“The PROPHY-VAP trial confirms the protective effect of a single dose of 2 g of ceftriaxone without application of [selective digestive tract decontamination] in brain-injured patients,” said Dahyot-Fizelier.

“Ventilator-associated pneumonia is the first cause of infection in ICU patients, and a brain-injured patient [is] particularly exposed to the early onset of VAPs,” she told the audience, adding that VAP increases morbidity and mortality, increases secondary insults in brain-injured patients, increases exposure to antibiotics and mechanical ventilation, and is associated with longer ICU and hospital stays and higher costs.

Indeed, in the trial, the group of patients assigned to ceftriaxone had a lower mortality rate (15% vs 25%; HR 0.62, 95% CI 0.39-0.97) and more ICU-free days (34 vs 26) and hospital-free days (23 vs 8).

In an accompanying comment, Michael Klompas, MD, of Harvard Medical School and Harvard Pilgrim Health Care Institute in Boston, encouraged caution when interpreting results, noting that “these findings differ from those of previous randomized trials, which did not report significant impacts on length of stay or mortality.”

“In addition, the study was underpowered to assess antibiotic resistance, particularly over the long term, and did not evaluate the potential impact of widespread and sustained antibiotic prophylaxis on the broader ICU and hospital populations,” he added. “Furthermore, it is not clear whether and how these results will generalize to ICUs with different prevailing flora and antibiotic resistance profiles.”

The PROPHY-VAP investigators found that three patients developed Clostridium difficile infection during the course of the trial, two in the placebo group and one in the ceftriaxone group. Of the 115 participants who received rectal swabs, two patients in the ceftriaxone group showed an extended spectrum beta-lactamase-producing Enterobacteriaceae acquired during the ICU study.

A total of 194 adverse events were recorded during the trial, with 90 severe events seen — 39 in the intervention group and 51 within the placebo group. No adverse events were attributed to ceftriaxone and all were the result of the patient’s initial condition. Similarly, no microbiological impact was attributed to ceftriaxone treatment, which is promising for reducing the emergence of bacterial resistance.

Even so, the authors acknowledged that they had not monitored changes in digestive microbiota.

Ceftriaxone is a third-generation cephalosporin with a long half-life, enabling efficacy for 24 hours without another injection.

PROPHY-VAP was conducted at the ICUs of eight French university hospitals. A total of 345 patients were randomized in the trial after meeting criteria for a brain injury, a Glasgow Coma Scale score of 12 or less, and a likely need for mechanical ventilation for more than 48 hours after their initial brain injury.

Patients in the intervention group were given a single, 30-minute long administration of 2 g ceftriaxone, while patients in the placebo group were given saline. Patients were assessed for VAP several times a day until day 28 during the ICU stay.

Of the patient population, 48% were women, while the average age was 56 in the intervention group and 57 years in the placebo group. The main brain injuries represented were subarachnoid hemorrhage (approximately 40% of the cohort), brain trauma (28%), and hemorrhagic stroke (22%). Over 60% of the patients in both cohorts scored a 4-8 on the Glasgow Coma Scale.

Limitations to the study included a lack of monitoring for VAP preventive measures in participating ICUs. Additionally, the impact of early ceftriaxone administration on other health outcomes, outside of VAP, was not measured.

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