Ventilator-associated pneumonia (VAP) is a serious complication of mechanical ventilation that has persisted despite decades of research and preventive measures, such as reducing sedation and weaning protocols, positioning patients appropriately, managing the tracheal-tube cuff, and providing oral care. Some researchers have proposed the use of inhaled antibiotics, but data have been limited.
In 2018, a meta-analysis evaluated prophylactic antibiotics administered via the respiratory tract to prevent ventilator-associated pneumonia (VAP) in mechanically ventilated (MV) patients. From six trials involving 1,158 patients, it was found that these antibiotics significantly reduced VAP occurrences compared to placebo (OR 0.53; 95% CI 0.34-0.84), especially when given via nebulization (OR 0.46; 95% CI 0.22-0.97). However, intratracheal instillation showed no significant difference (OR 0.57; 95% CI 0.28-1.15). ICU mortality rates and VAP from multidrug-resistant pathogens were unaffected by antibiotic prophylaxis. The study concluded that nebulized antibiotics may offer a way to decrease VAP in MV patients. However, further investigation was needed before accommodating this modality within the standards of critical care practices .
A new French study that was published in NEJM on October 25, 2023, examined the effectiveness of inhaled amikacin in preventing ventilator-associated pneumonia over 28 days in critically ill adults on invasive mechanical ventilation for at least 72 hours. Using a multicenter, double-blind, randomized trial, 417 patients received inhaled amikacin, while 430 received a placebo for three days. The primary outcome showed a significant reduction in the development of ventilator-associated pneumonia in the amikacin group (15%) compared to the placebo group (22%) with a difference in restricted mean survival time to ventilator-associated pneumonia, 1.5 days; 95% confidence interval [CI] 0.6 to 2.5; P=0.004. However, slightly more severe adverse effects were noted in the amikacin group, though not conclusively significant .
Given this new data, should we alter our practice and begin administering inhaled amikacin on the fourth day of mechanical ventilation?
To answer this question, let's first analyze the primary outcome. As you see, the authors reported difference in restricted mean survival (RMST) time which is a new statistical measure for me, and I had to look it up. When you have two or more groups in a study (e.g., treatment group vs. control group), the difference in their RMSTs gives a measure of the treatment effect. It tells you how much longer, on average, individuals in one group remain free from the event compared to those in another group, up to that specified time point. Our study reported a difference in RMST of 1.5 days between a treatment and control group, it would mean that, on average, individuals in the treatment group remained free from ventilator-associated pneumonia for 1.5 days longer than those in the control group, within the time frame considered.
Inhaled amikacin has shown a clear benefit in terms of reduction of VAP occurrences, but other measures, such as mortality or length of stay, would have supported the intervention benefit more. Unfortunately, the study was not powered to investigate these patient-centered outcomes. Also, one may question the possibility of increased risk of VAP with the use of 0,9% saline as placebo, but this is very unlikely.
A possible advantage of preventive inhaled antibiotics at the population level could be to lower the need for systemic antibiotics and thus reduce the antibiotic-resistance selection pressure, which is a potential long-term drawback of preventive antibiotic therapy. However, this objective was not within the scope of the trial.
The use of amikacin had some serious adverse effects, such as a higher rate of resistance in the expiratory limb filter and bronchospasm, but they were not statistically significant. Surprisingly, the rate of acute kidney injury was lower for those who used inhaled amikacin (4% versus 8%).
To sum up, amikacin could be a viable option for preventing VAP in patients who are on mechanical ventilation for longer than 72 hours. However, more evidence on patient-centered outcomes is required before this method is adopted in our practice.
Póvoa FCC, Cardinal-Fernandez P, Maia IS, Reboredo MM, Pinheiro BV. Effect of antibiotics administered via the respiratory tract in the prevention of ventilator-associated pneumonia: A systematic review and meta-analysis. J Crit Care. 2018 Feb;43:240-245. Link
Ehrmann S, Barbier F, Demiselle J, Quenot JP, Herbrecht JE, Roux D, Lacherade JC, Landais M, Seguin P, Schnell D, Veinstein A, Gouin P, Lasocki S, Lu Q, Beduneau G, Ferrandiere M, Plantefève G, Dahyot-Fizelier C, Chebib N, Mercier E, Heuzé-Vourc'h N, Respaud R, Gregoire N, Garot D, Nay MA, Meziani F, Andreu P, Clere-Jehl R, Zucman N, Azaïs MA, Saint-Martin M, Gandonnière CS, Benzekri D, Merdji H, Tavernier E; Reva and CRICS-TRIGGERSEP F-CRIN Research Networks.. Inhaled Amikacin to Prevent Ventilator-Associated Pneumonia. N Engl J Med. 2023 Oct 25. Link