title: Microbiology, safety, and pharmacokinetics of aztreonam lysinate for inhalation in patients with cystic fibrosis.
abstract: BACKGROUND
  Aztreonam lysinate for inhalation (AI) is a novel monobactam formulation being investigated for pulmonary Pseudomonas aeruginosa infections in patients with cystic fibrosis (CF).
  
  
  METHODS
  Pre-clinical studies investigated the pre- and post-nebulization activity of AI and its activity in the presence of CF sputum. A double-blind, placebo-controlled, dose-escalation trial determined pharmacokinetics and tolerability of AI in subjects with CF. Single daily escalating doses of AI 75, 150, or 225 mg, or placebo were self-administered using an eFlow Electronic Nebulizer. Sputum samples were collected up to 4 hr and blood samples up to 8 hr post-dose.
  
  
  RESULTS
  AI activity against multiple CF isolates was retained after nebulization via eFlow, and activity was not inhibited by CF sputum. All 12 adult subjects and 11/12 adolescents tolerated all AI doses. One patient had an asymptomatic FEV1 decrease > 20% with the 150 mg dose. Median aztreonam sputum concentrations in adults 10 min after AI 75, 150, and 225 mg were 383, 879, and 985 microg/g, respectively. Median sputum concentrations in adolescents 10 min after AI 75, 150, and 225 mg were 324, 387, and 260 microg/g, respectively. Systemic exposure to AI was low. Plasma pharmacokinetics in adults receiving AI 75 mg were Cmax = 419 ng/g, Tmax = 0.99 hr, t1/2 = 2.1 hr. Aztreonam concentrations in sputum were at or above the MIC50 for at least 4 hr post-dose.
  
  
  CONCLUSIONS
  These data support the continued development of AI for treatment of pulmonary infections in patients with CF.
authors.affiliation: Department of Pediatrics, University of Washington, Children's Hospital and Regional Medical Center, Seattle, Washington 98105-0371, USA. ron.gibson@seattlechildrens.org
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Gibson
authors.forename: George Z
authors.initials: GZ
authors.lastname: Retsch-Bogart
authors.forename: Christopher
authors.initials: C
authors.lastname: Oermann
authors.forename: Carlos
authors.initials: C
authors.lastname: Milla
authors.forename: Joseph
authors.initials: J
authors.lastname: Pilewski
authors.forename: Cori
authors.initials: C
authors.lastname: Daines
authors.forename: Richard
authors.initials: R
authors.lastname: Ahrens
authors.forename: Kevin
authors.initials: K
authors.lastname: Leon
authors.forename: Morty
authors.initials: M
authors.lastname: Cohen
authors.forename: Sharon
authors.initials: S
authors.lastname: McNamara
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Callahan
authors.forename: Richard
authors.initials: R
authors.lastname: Markus
authors.forename: Jane L
authors.initials: JL
authors.lastname: Burns
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001398:Aztreonam / Q000493:pharmacokinetics* / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000378:metabolism* / Q000382:microbiology*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D013183:Sputum / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001398:Aztreonam