By Arzo Hamidi, PharmD, BCCCP
Clinical Pharmacy Specialist, Adult Critical Care, Rush University Medical Center, Chicago
SYNOPSIS: A short course of inhaled amikacin at therapeutic doses prevented the occurrence of ventilator-associated pneumonia without changes to duration of mechanical ventilation, length of stay, or mortality.
SOURCE: Ehrmann S, Barbier F, Demiselle J, et al. Inhaled amikacin to prevent ventilator-associated pneumonia. N Engl J Med 2023; Oct 25. doi: 10.1056/NEJMoa2310307. [Online ahead of print].
The Inhaled Amikacin vs. Placebo to Prevent Ventilator Associated Pneumonia (AMIKINHAL) trial was a multicenter, double-blind, randomized, controlled superiority trial. Adults intubated for at least 72 hours were included. Patients were excluded if they had suspected or confirmed ventilator-associated pneumonia (VAP), severe acute kidney injury without renal replacement therapy, chronic kidney disease, or tracheostomy tube; if extubation was planned in the next 24 hours; or if the patient was receiving systemic aminoglycoside therapy.
Patients received either inhaled amikacin 20 mg/kg of ideal body weight once daily for three days or inhaled placebo once daily for three days. The calculated sample size was 850 patients with 80% power with a two-sided alpha of 0.05. The primary outcome was a first episode of VAP at 28 days. The diagnosis was determined by a blinded committee using international guidelines based on a positive quantitative bacterial culture from a lung source and at least two of the following: leukocytosis, leukopenia, fever, or purulent secretions with a new infiltrate on chest X-ray. Secondary outcomes included incidence of VAP due to a gram-negative bacterium susceptible to amikacin, ventilator-associated events (VAE), number of days requiring mechanical ventilation, and number of days in the intensive care unit (ICU) and hospital.
The study included a total of 847 patients (417 in the amikacin group and 430 in the placebo group). Patients had a median age of 61 years, were mostly male (65%), had a median body mass index (BMI) of 29, and were mostly admitted for medical reasons. A mean of 1,625 mg ± 250 mg of inhaled amikacin was used. At 28 days, a first episode of VAP developed in 62 patients (15%) with amikacin vs. in 95 patients (22%) in the placebo group (P = 0.004). The first episode of VAP after randomization occurred after a median of 10 days (interquartile range [IQR], 7-16) vs. nine days (IQR, 7-12) in the amikacin and placebo groups, respectively.
The first VAP episode due to gram-negative bacteria was 7% in the amikacin group compared to 14% in the placebo group. VAE also were decreased with inhaled amikacin vs. placebo. Overall days of systemic antibiotics in either group were similar. The median number of days on mechanical ventilation was the same in both groups, as were the median lengths of stay in the ICU and hospital. Safety events and acute kidney injury development overall were low in both groups and not significantly different.
COMMENTARY
This study found that inhaled amikacin at therapeutic doses was associated with reducing the burden of VAP. However, before all patients on mechanical ventilation start receiving prophylactic antibiotics, there are several considerations.
First, this benefit might be at the cost of increasing the risk of drug resistance. The authors of the study mentioned that the short duration of inhaled amikacin for only three days was chosen to mitigate this risk. The impact of drug resistance is not measurable since it cannot be determined with a study that follows patients for 28 days.
Secondly, there is no explanation for the dose of amikacin used in the study. While 15 mg/kg once daily is a common dose used for systemic intravenous dosing, there is no standard dosing for inhaled strategies. There are few indications for amikacin to be used as monotherapy, which makes choosing a dose challenging for this route. Determining drug efficacy of this dosing strategy is difficult because serum amikacin levels cannot be measured to guide therapy, given that administration is local rather than systemic. The rate of acute kidney injury was not powered but was surprisingly lower in the amikacin group compared to the placebo group. No conclusion regarding the safety of inhaled amikacin can be drawn regarding this specific adverse effect based on these observations.
Finally, while there was a benefit seen with the primary outcome, ICU and hospital length of stay and duration of mechanical ventilation were no different. These patient-centered outcomes would help determine if this therapy should become common practice. In comparing this patient population to other ICU patients, the rate of VAP was higher than initially anticipated in the study design. Overall, these factors limit the generalizability and applicability of this study to all patients requiring mechanical ventilation.
