A Randomized Double-Blind Placebo-Controlled Dose-Escalation Phase 1 Study of Aerosolized Amikacin and Fosfomycin Delivered via the PARI Investigational eFlow® Inline Nebulizer System in Mechanically Ventilated Patients

Background: This clinical trial evaluated the pharmacokinetics and safety/tolerability of amikacin/fosfomycin solution using a vibrating plate nebulizer, in mechanically ventilated patients with ventilator-associated tracheobronchitis (VAT) or ventilator-associated pneumonia (VAP). Methods: Nine adult patients were consented to receive three escalating doses of a combination of 50mg/mL amikacin and 20mg/mL fosfomycin; doses were separated by 242hr. On day 3, patients received two blinded, randomized treatments (amikacin/fosfomycin and volume-matched placebo), separated by 2hr. All treatments were administered with a single-patient, multitreatment nebulizer (Investigational eFlow((R)) Inline Nebulizer System; PARI Pharma GmbH, positioned in the inspiratory limb tubing between the ventilator and the patient. The nebulizer remained in-line until all treatments had been delivered. Concentrations of amikacin and fosfomycin were measured in tracheal aspirate and plasma samples obtained during the 24hr after each dose. Results: Fifteen minutes after dosing with the 300/120mg amikacin/fosfomycin combination, tracheal aspirate amikacin concentrations +/- SD were 12,390 +/- 3,986g/g, and fosfomycin concentrations were 6,174 +/- 2,548g/g (n=6). Airway clearance was rapid. Plasma concentrations were subtherapeutic; the highest observed amikacin plasma concentration was 1.4g/mL, and the highest observed fosfomycin plasma concentration was 0.8g/mL. Administration time was approximately 2min/mL. No adverse effects on respiratory rate, peak airway pressures, or oxygenation were observed during or following drug or placebo administration. Conclusions: High tracheal aspirate concentrations of amikacin and fosfomycin were achieved in mechanically ventilated patients with VAT or VAP after aerosolized administration with an inline nebulizer system. Airway clearance was rapid. No adverse respiratory effects were noted during or following drug administration.