Clinical failures in ventilator-associated pneumonia (VAP) caused by Gram-negative bacteria are common and associated with substantial morbidity, mortality, and resource utilization.
We assessed the safety and efficacy of the amikacin fosfomycin inhalation system (AFIS) for the treatment of Gram-negative bacterial VAP in a randomized double-blind, placebo-controlled, parallel group, phase 2 study between May 2013 and March 2016. We compared standard of care in each arm plus 300 mg amikacin/120 mg fosfomycin or placebo (saline), delivered by aerosol twice daily for 10 days (or to extubation if <10 days) via the investigational eFlow Inline System (PARI GmbH, Germany). The primary efficacy endpoint was change from baseline in the Clinical Pulmonary Infection Score (CPIS) during the randomized course of AFIS/placebo, using the subset of patients with microbiologically proven baseline infections with Gram-negative bacteria.
143 patients were randomized, 71 to AFIS, 72 to placebo. Comparison of CPIS change from baseline between treatment groups was not different (P=0.70). The secondary hierarchical endpoint of no mortality and clinical cure at Day 14 or earlier was also not significant (P=0.68) nor the hierarchical endpoint of no mortality and ventilator free days (P=0.06). Mortality was 17 (24%) in AFIS, 12 (17%) in placebo P=0.32. The AFIS group had significantly fewer positive tracheal cultures on Days 3 and 7 compared to placebo.
In this trial of adjunctive aerosol therapy compared to standard of care intravenous antibiotics in patients with Gram-negative VAP, AFIS was ineffective in improving clinical outcomes despite reducing bacterial burden.