Amikacin inhaled once daily for 3 days after starting mechanical ventilation reduced the risk for developing ventilator-associated pneumonia, in a double-blind trial in critically ill patients.
Stephan Ehrmann, MD, PhD, Médecine Intensive Réanimation, Centre Hospitalier Régional Universitaire (CHRU), Tours. France, and colleagues of the Reva and CRICS-TRIGGERSEP F-CRIN research networks point out that ventilator-associated pneumonia is the most frequently occurring hospital-acquired lower-respiratory tract infection and the leading nosocomial infection worldwide, with mortality of up to 13%.
"Despite decades of research and implementation of preventive measures against ventilator-associated pneumonia—(including) reduced sedation and weaning protocols, patient positioning, management of the tracheal-tube cuff, and oral care—the burden of ventilator-associated pneumonia remains unacceptably high," Ehrmann and colleagues indicate.
The investigators posited, however, that there is a window of opportunity for a short course of prophylactic antibiotic, as the progression to overt pneumonia takes several days, with peak incidence occurring after 7 days of ventilation. They also considered that an inhaled antibiotic would be the most efficient, as it produces high concentrations in the tracheo-bronchial tree, lung parenchyma, and tracheal-tube biofilm.
What You Need to Know
The study suggests that inhaled amikacin, administered once daily for three days after initiating mechanical ventilation, can significantly reduce the risk of developing ventilator-associated pneumonia (VAP).
The researchers highlight the concept of a "window of opportunity" for prophylactic antibiotics, emphasizing the delayed progression to overt pneumonia after mechanical ventilation initiation.
The trial outcomes show a notable reduction in the incidence of ventilator-associated pneumonia and infection-related ventilator-associated complications with amikacin inhalation
The 3-day regimen was chosen with the expectation of efficacy, and that a short duration is less likely to promote development of antibiotic resistance. The regimen was initiated on the 3rd day of mechanical ventilation as sufficiently early for amikacin to control tracheobronchial spread of bacteria before pneumonia developed, and to further reduce antibiotic exposure from what might occur with earlier initiation.
"In our trial, the choice of a 3-day preventive therapy course represented a compromise between efficacy and feasibility on the basis of previous experience with inhaled amikacin and other forms of preventive antibiotic therapy in the ICU," Ehrmann and colleagues remarked.
The randomized, placebo-controlled trial comprised 417 patients assigned to receive 3 doses of inhaled amikacin 20mg/kg, and 430 to receive 0.9% saline inhalations. All were adults who had undergone invasive mechanical ventilation for between 72 and 96 hours. Exclusion criteria included suspected or confirmed ventilator-associated pneumonia, severe acute kidney injury without renal-replacement therapy, chronic kidney disease, a tracheostomy tube, extubation scheduled within 24 hours, or ongoing aminoglycoside antibiotic treatment.
In the 28-day follow-up, the investigators found ventilator-associated pneumonia occurred in 15% of the amikacin group and 22% in those receiving placebo. In addition, an infection-related ventilator associated complication occurred in 18% of the amikacin group and in 26% of the placebo group. The investigators reported trial-related serious adverse effects in 1.7% (7 patients) of the amikacin group and 0.9% (4 patients) in the placebo group.
The investigators note that the trial was not statistically powered to ascertain differences in other outcomes such as death or length of stay in the ICU. They also indicate that use of inhaled normal saline as placebo can be questioned, but assert that it is unlikely to increase risk for ventilator-associated pneumonia, and enabled the valuable blinded condition.
"The present trial shows that a 3-day course of amikacin at a dose of 20mg/kg of ideal body weight is effective in reducing the risk of ventilator-associated pneumonia with an effect size of the same extent as the pooled estimate of...previous, smaller, and mostly single-center trials," Ehrmann and colleagues conclude.
Ehrmann S, Barbier F, Demiselle J, et al. Inhaled Amikacin to Prevent Ventilator-Associated Pneumonia. N Engl J Med. Published online October 25, 2023. doi:10.1056/NEJMoa2310307