Microbiology, safety, and pharmacokinetics of aztreonam lysinate for inhalation in patients with cystic fibrosis.
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.
Gibson
Ronald L
RL
Department of Pediatrics, University of Washington, Children's Hospital and Regional Medical Center, Seattle, Washington 98105-0371, USA. ron.gibson@seattlechildrens.org
Retsch-Bogart
George Z
GZ
Oermann
Christopher
C
Milla
Carlos
C
Pilewski
Joseph
J
Daines
Cori
C
Ahrens
Richard
R
Leon
Kevin
K
Cohen
Morty
M
McNamara
Sharon
S
Callahan
Tracy L
TL
Markus
Richard
R
Burns
Jane L
JL
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
D000900:Anti-Bacterial Agents; D001398:Aztreonam