Short-course inhaled amikacin therapy reduces the risk of VAP in patients who received recent invasive mechanical ventilation

03 Jan 2024

Ventilator-associated pneumonia (VAP) is a common nosocomial infection associated with significant morbidity, especially for patients in intensive care units (ICU).1 Previous clinical trials had evaluated the use of inhaled preventive antibiotics such as colistin, ceftazidime, and gentamicin in patients undergoing mechanical ventilation for 7 to 15 days with the goal of reducing the risk of VAP.2 To investigate the efficacy of short-term inhaled antibiotic therapy, the AMIKINHAL trial was conducted, which revealed a significant reduction in VAP associated with a 3-day course of inhaled amikacin when given after 72 hours of invasive mechanical ventilation.2

VAP is the dominant cause of nosocomial infection in ICUs worldwide, with incidence rates ranging between 1.9 to 3.8 cases per 1,000 ventilator days in the United States and exceeding 18 cases per 1,000 ventilator days in Europe.1,3 VAP affects up to  40% of patients on mechanical ventilation, which increases their risk of morbidity, mortality, extension of mechanical ventilation and hospital stays, dependence on antibiotic usage, and medical costs.1,4 Inhaled antibiotic therapy is highly preferred over intravenous antibiotic therapy as a prevention measure for VAP due to its rapid onset time, and high local concentrations with minimal toxicity.5 A meta-analysis suggested that the prophylactic administration of nebulized antibiotics to patients on mechanical ventilation may be beneficial in preventing VAP without increasing the risk of respiratory infection due to multidrug resistant-pathogens.5

The AMIKINHAL trial was a multicenter, double-blinded, placebo-controlled study, designed to assess the efficacy of inhaled amikacin in preventing VAP among patients undergoing invasive mechanical ventilation.2 847 adult patients who underwent invasive mechanical ventilation for at least 72 hours were recruited and randomized to receive a daily dose of inhaled amikacin 20mg/kg (n=417)  or inhaled placebo (n=430) for 3 days.2 The primary outcome was the first episode of VAP from randomization to day 28.2 Secondary outcomes included the incidence of VAP due to gram-negative bacteria with in vitro susceptibility to amikacin,  incidence of ventilator-associated events, duration of invasive mechanical ventilation and hospital stay, and mortality and safety outcomes at day 28.2

At day 28, a significantly lower incidence of VAP was observed in the amikacin arm compared to the placebo arm (15% vs. 22%; difference in restricted mean survival time to VAP=1.5 days; 95% CI: 0.6-2.5; p=0.004).2 In addition, the incidence of the first VAP episode due to gram-negative bacteria susceptible to amikacin in the placebo arm was double that of the amikacin arm (7% vs. 14%;  HR=1.9; 95% CI:1.1-2.8).2 Throughout the study period, the amikacin arm experienced a lower incidence of ventilator-associated events when compared to the placebo arm, including ventilator-associated conditions (defined as worsening oxygenation over 2 days after a stable or improvement period) (33% vs. 40%; HR=0.79; 95% CI:  0.64-0.99), infection-related ventilator-associated complications (defined as worsening oxygenation associated with signs of infection and initiation of antibiotic therapy) (18% vs. 26%; HR=0.66;  95% CI: 0.50-0.89), and possible VAP due to infection-related ventilator-associated complications (5% vs. 10%; HR=0.46; 95% CI:  0.27-0.78).2 The median duration of invasive mechanical  ventilation (9 days) and hospital stay (27 days) were identical  between the two arms, while the hospital mortality rate of the placebo arm was only slightly higher than that of the amikacin arm at day 28 (32% vs. 29%).2

Furthermore, amikacin demonstrated a tolerable safety profile with acceptable and manageable toxicities, with both treatment arms exhibiting comparable incidences of serious adverse events at day 28 (amikacin vs. placebo: 4% vs. 3%).2 The most common treatment-emergent adverse event (TEAE) was acute kidney injury, occurring in 4% and 8% of patients in the amikacin and the placebo arms, respectively (HR=0.47; 95% CI: 0.23-0.96).2

In conclusion, a 3-day course of inhaled amikacin demonstrated notable efficacy in minimizing the burden of VAP among adult patients who underwent invasive mechanical ventilation for at least 72 hours.2 The inhaled therapy was also well-tolerated among patients and remained consistent with previous studies.2

Get access to our exclusive articles.