麻豆传媒

A short course of an inhaled antibiotic helped prevent the incidence of ventilator-associated pneumonia in the intensive care unit (ICU), a randomized trial in France showed.

In critically ill patients intubated for between 3 to 4 days, administration of amikacin (Arikayce) reduced the rate of first ventilator-associated pneumonia compared with an inhaled placebo (15% vs 22% at 28 days), with a difference in restricted mean survival time to pneumonia of 1.5 days (95% CI 0.6-2.5, P=0.004).

Infection-related ventilator-associated complications also developed in fewer of the patients treated with the 3-day amikacin course (18% vs 26%, respectively; HR 0.66, 95% CI 0.50-0.89), and serious adverse event rates associated with the intervention were low, reported Stephan Ehrmann, MD, PhD, of the University of Tours in France, and coauthors in the .

Mechanically ventilated patients in the ICU are at high risk for bacterial pneumonia, a common and often deadly source of hospital-acquired infection that develops in up to 40% following intubation.

"Microaspirations around the tracheal-tube cuff and the formation of biofilm lead to progressive bacterial spread in the tracheobronchial tree, ultimately leading to pneumonia," the group wrote. "Ventilator-associated pneumonia is a disease with an attributable mortality of up to 13% and contributes to increased systemic antibiotic consumption, duration of mechanical ventilation and ICU lengths of stay, and costs."

Ehrmann and colleagues posited that limiting enrollment to within 72- to 96-hours of invasive mechanical ventilation may have enabled amikacin to control tracheobronchial spread before pneumonia onset. The aminoglycoside antibacterial is currently in the U.S. under limited use for refractory non-tuberculosis mycobacterial lung disease associated with Mycobacterium avium complex.

"Inhaled antibiotics for a short period of time is enticing!" said Shyoko Honiden, MD, MS, of the Yale School of Medicine in New Haven, Connecticut, who was not involved in the research.

"This gets around the concerns around prolonged antibiotic exposure and the risk of antibiotic resistance," she told 麻豆传媒 via email. "Timing is everything in the ICU. This study helps to better define the patient population where this strategy is beneficial: those who are still intubated at 72 hours -- not too early, not too late."

On the other hand, the researchers noted that as only 22% of patients in the study "had tracheal bacterial colonization at the time of randomization, later intervention, such as after day 4 or 5, may deserve evaluation" as well.

The so-called trial was conducted across 19 ICUs in France from 2017 to 2021. Data analysis included 847 participants without suspected or confirmed ventilator-associated pneumonia in the double-blind study, which had a primary outcome of first episode of ventilator-associated pneumonia at 28 days.

In a 1:1 ratio, patients were randomized to receive either once-daily inhaled amikacin (20 mg/kg of ideal body weight) or placebo (0.9% sodium chloride at an equal volume) via a vibrating mesh nebulizer for 3 consecutive days. Over 80% in each arm received their planned nebulizations.

About two-thirds of patients enrolled were male, and the average age was just above 60 years. The most common diagnoses upon admission were infection (30-33%), respiratory failure (24-25%), and cardiac arrest (8-10%). More than three-fourths were receiving systemic antibiotic therapy at randomization.

Treatment with the inhaled antibiotic also led to fewer ventilator-associated conditions versus placebo (33% vs 40%; HR 0.79, 95% CI 0.64-0.99) and fewer first episodes of ventilator-associated pneumonia caused by gram-negative bacteria known to be susceptible to amikacin (7% vs 14%).

Serious adverse events considered related to the interventions were low, at 1.7% in the amikacin group and 0.9% in the control group. In the amikacin-treated patients, these included obstruction of the tracheal tube and brochospasms. Acute kidney injury at 28 days was significantly lower in the antibiotic arm (4% vs 8%, P=0.03).

Limitations included that the trial was not powered to assess outcomes such as death or length of hospital or ICU stay, and that certain patient populations -- those with severe acute kidney injury without renal-replacement therapy and chronic kidney disease -- were among the exclusion criteria.

Honiden encouraged further research among these populations and in those with pre-existing lung disease, where bacterial colonization rates might be greater.

"It remains to be seen whether other inhaled antibiotics with a more favorable kidney toxicity profile might be an option for those patients. I suspect they might be," she said. "This is a higher-risk and more fragile group of patients -- in whom substantial prior antibiotic exposure often exists -- where the 'price' of [ventilator-associated pneumonia] may be substantially higher."

Comment