title: 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.
abstract: 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 50 mg/mL amikacin and 20 mg/mL fosfomycin; doses were separated by 24±2 hr. On day 3, patients received two blinded, randomized treatments (amikacin/fosfomycin and volume-matched placebo), separated by 2 hr. All treatments were administered with a single-patient, multitreatment nebulizer (Investigational eFlow(®) 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 24 hr after each dose.
  
  
  RESULTS
  Fifteen minutes after dosing with the 300/120 mg amikacin/fosfomycin combination, tracheal aspirate amikacin concentrations±SD were 12,390±3,986 μg/g, and fosfomycin concentrations were 6,174±2,548 μg/g (n=6). Airway clearance was rapid. Plasma concentrations were subtherapeutic; the highest observed amikacin plasma concentration was 1.4 μg/mL, and the highest observed fosfomycin plasma concentration was 0.8 μg/mL. Administration time was approximately 2 min/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.
authors.affiliation: 1 Cardeas Pharma , Seattle, WA.
authors.forename: A Bruce
authors.initials: AB
authors.lastname: Montgomery
authors.forename: Shirley
authors.initials: S
authors.lastname: Vallance
authors.forename: Tammy
authors.initials: T
authors.lastname: Abuan
authors.forename: Markus
authors.initials: M
authors.lastname: Tservistas
authors.forename: Andrew
authors.initials: A
authors.lastname: Davies
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000336:Aerosols; D000368:Aged; D000369:Aged, 80 and over; D000583:Amikacin / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D001991:Bronchitis / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D004311:Double-Blind Method; D004338:Drug Combinations; D016903:Drug Monitoring; D004867:Equipment Design; D005578:Fosfomycin / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009330:Nebulizers and Vaporizers; D053717:Pneumonia, Ventilator-Associated / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D012121:Respiration, Artificial / Q000009:adverse effects*; D014136:Tracheitis / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D014739:Victoria
chemical_list: D000336:Aerosols; D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D005578:Fosfomycin; D000583:Amikacin
keywords: aerosol delivery; amikacin; fosfomycin; ventilator; ventilator-associated pneumonia