By Stan Deresinski, MD, FACP, FIDSA
Clinical Professor of Medicine, Stanford University
SYNOPSIS: Administration of amikacin for three days beginning early in mechanically ventilated patients significantly reduces ventilator-associated pneumonia.
SOURCE: Ehrmann S, Barbier F, Demiselle J, et al; CRICS-TRIGGERSEP F-CRIN Research Networks. Inhaled amikacin to prevent ventilator-associated pneumonia. N Engl J Med 2023; Oct 25. doi: 10.1056/NEJMoa2310307. [Online ahead of print].
Ehrmann and colleagues performed a double-blind, randomized, placebo-controlled superiority trial to evaluate the efficacy of inhaled amikacin to prevent ventilator-associated pneumonia (VAP). Performed at 19 French intensive care units (ICUs), adults who were receiving mechanical ventilation for at least 72 hours, but no more than 96 hours, were enrolled. Exclusion criteria included existing VAP (suspected or proven), renal replacement therapy, renal impairment (glomerular filtration rate [GFR] < 30 cc/mL), the presence of a tracheostomy tube, imminent extubation, and systemic receipt of aminoglycosides. Patients were randomized to receive, by inhalation using a vibrating mesh nebulizer, 20 mg/kg amikacin or an equivalent volume of normal saline once daily for three consecutive days.
The diagnosis of VAP was made by a blinded adjudication panel. A first episode of gram-negative VAP by 28 days, the primary study outcome, occurred in 31/417 (7%) amikacin recipients and 61/430 (14%) in the placebo group. Analysis of the restricted mean survival time to the occurrence of VAP identified a difference of 1.5 days (95% confidence interval [CI], 0.6 to 2.5; P = 0.004).
In a secondary analysis, an infection-related complication associated with ventilator use occurred in 74 patients (18%) and 111 patients (26%), respectively (hazard ratio, 0.66; 95% CI, 0.50 to 0.89). The intervention was safe with, in particular, no evidence of nephrotoxicity. There were 20 deaths (74.3%) in the amikacin arm and 21 deaths (72.9%) in placebo recipients. Subsequent isolation of bacteria resistant to amikacin occurred in 10% in each group.
COMMENTARY
The development of pneumonia in mechanically ventilated patients is a potentially lethal event. Despite the ever-present difficulties in the accurate diagnosis of VAP, this study provides strong evidence of preventive benefit of the use of a brief course of inhaled amikacin in preventing this complication — although it was not sufficiently powered to examine outcomes such as length of stay and mortality.
Thus, a relatively simple, low-cost intervention provides significant benefit and should be routinely considered in appropriate patients. If implemented, it will be important to perform ongoing surveillance for the emergence of amikacin resistance.