A phase 2 study of aztreonam lysine for inhalation to treat patients with cystic fibrosis and Pseudomonas aeruginosa infection

Abstract

Summary. Background: Aztreonam lysine for inhalation (AZLI) is being developed for treatment of CF patients with Pseudomonas aeruginosa airway infection. Methods: This double-blind, randomized, placebo-controlled Phase 2 study evaluated the safety, tolerability and efficacy of 75 and 225 mg AZLI administered BID for 14 days using the eFlow 1 Electronic Nebulizer (Pari Innovative Manufacturers, Inc., Midlothian, VA). Patients were 13 years and older with FEV 1 ! 40% predicted, chronic P. aeruginosa infection, and had used no anti-pseudomonal antibiotics for 56 days. Results: Of 131 patients screened, 105 received AZLI or placebo. Mean age was 26 years and mean FEV 1 percent predicted was 77% at baseline. There was a statistically significant reduction, compared to placebo, in P. aeruginosa CFU density in each AZLI group at Days 7 and 14 (P < 0.001). The planned primary analysis, percent change in FEV 1 at Day 14, demonstrated no statistically significant difference. Post hoc analysis demonstrated significant increase in FEV 1 at Day 7 for the subset of patients with baseline FEV 1 < 75% predicted in the 225 mg AZLI group. Bronchodilator use was associated with greater improvement in FEV 1 , as well as greater reduction in P. aeruginosa bacterial density and higher plasma aztreonam concentrations in the 225 mg AZLI group. Adverse events were similar between placebo and AZLI although there was a trend toward

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

“…It is important to note that 46%, 32%, and 23% of patients in the 75-mg, 225-mg, and placebo dose groups, respectively, received bronchodilators; patients using bronchodilators had greater reductions of P. aeruginosa sputum loads and better improvement of lung function. The susceptibility pattern of the isolates did not change from day 0 to day 14 or 28 (303).…”

“…The study authors reported changes in P. aeruginosa sputum load and FEV 1 in comparison to values for the corresponding placebo group but not as a change from baseline, so the data summarized in Table 4 have been deduced from ClinicalTrials.gov registration data. The efficacies of two doses of aztreonam were compared in a placebocontrolled, randomized, phase II study (303). Patients were dosed with either 75 mg or 225 mg aztreonam twice daily for 14 days.…”

Potentiation Effects of Amikacin and Fosfomycin against Selected Amikacin-Nonsusceptible Gram-Negative Respiratory Tract Pathogens

“…The viscosity of tracheal aspirate samples makes measurements of the volume both inaccurate and nonreproducible; therefore, drug concentrations were measured per gram of sputum instead of per milliliter. To compare the MIC values, expressed in micrograms per milliliter, with the drug concentrations, expressed in micrograms per gram, we adopted the convention commonly used in studies of cystic fibrosis, in which tracheal aspirate samples are weighed and comparisons are conducted under the assumption that 1 g of sputum equals 1 ml (20,21). a GES, Guiana extended-spectrum ␤-lactamase; KPC, Klebsiella pneumoniae carbapenemase; OXA, oxacillin-hydrolyzing extended-spectrum ␤-lactamase; VIM, Verona integron-encoded metallo-␤-lactamase.…”

Pseudomonas aeruginosa Biofilm Formation in the CF Lung and Its Implications for Therapy

“…Nebulized tobramycin has been used for years as an effective anti-Pseudomonal therapy, and many other inhaled antibiotic formulation have been studied (Ryan, Singh et al 2011). Recently, Aztreonam Lysine for Inhalation has been approved in many countries for treatment of chronic CF lung infections, and studies have shown that use of this drug can improve quality of life and pulmonary function of CF patients, while decreasing P. aeruginosa burden and lower exacerbation severity (McCoy, Quittner et al 2008;Retsch-Bogart, Burns et al 2008;Anderson 2010;Bals, Hubert et al 2011). Work continues on other inhaled antibiotics, including aerosolized levofloxacin, fosfomycin/tobramycin, and inhalable dry powers of tobramycin and ciprofloxacin (Anderson 2010;Bals, Hubert et al 2011).…”