Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis

Abstract

Rationale: The effectiveness and safety of aztreonam lysine for inhalation (AZLI) in patients with cystic fibrosis (CF) on maintenance treatment for Pseudomonas aeruginosa (PA) airway infection was evaluated in this randomized, double-blind, placebo-controlled study.

Objectives: To evaluate the safety and efficacy of inhaled aztreonam lysine in controlling PA infection in patients with CF.

Methods: After randomization and a 28-day course of tobramycin inhalation solution (TIS), patients (n = 211; > or =6 yr; > or =3 TIS courses within previous year; FEV(1) > or = 25% and < or =75% predicted values) were treated with 75 mg AZLI or placebo, twice or three times daily for 28 days, then monitored for 56 days. The primary efficacy endpoint was time to need for additional inhaled or intravenous antipseudomonal antibiotics. Secondary endpoints included changes in respiratory symptoms (CF Questionnaire-Revised [CFQ-R] Respiratory Scale), pulmonary function (FEV(1)), and sputum PA density. Adverse events and minimum inhibitory concentrations of aztreonam for PA were monitored.

Measurements and main results: AZLI treatment increased median time to need for additional antipseudomonal antibiotics for symptoms of pulmonary exacerbation by 21 days, compared with placebo (AZLI, 92 d; placebo, 71 d; P = 0.007). AZLI improved mean CFQ-R respiratory scores (5.01 points, P = 0.02), FEV(1) (6.3%, P = 0.001), and sputum PA density (-0.66 log(10) cfu/g, P = 0.006) compared with placebo; no AZLI dose-response was observed. Adverse events reported for AZLI and placebo were comparable and consistent with CF lung disease. Susceptibility of PA to aztreonam at baseline and end of therapy were similar.

Conclusions: AZLI was effective in patients with CF using frequent TIS therapy. AZLI delayed time to need for inhaled or intravenous antipseudomonal antibiotics, improved respiratory symptoms and pulmonary function, and was well tolerated. Clinical trial registered with www.clinicaltrials.gov (NCT 00104520).

Trial registration: ClinicalTrials.gov NCT00104520.

Figures

Figure 1.

Study design and patient disposition. Patients were randomly assigned to treatment with aztreonam lysine for inhalation (AZLI)/placebo before they all began the open-label tobramycin inhalation solution (TIS) run-in; their reasons for discontinuing during the TIS run-in are displayed by randomization group. The 211 patients remaining in the study at baseline (Day 0) received at least one dose of AZLI/placebo and comprise the intent-to-treat (ITT) population. The category labeled “Met primary endpt” includes patients who met the primary efficacy endpoint, need for additional inhaled, or intravenous antibiotics. * Met primary endpoint in analyses of Day 84–100 data.

Figure 2.

Time to need for additional inhaled or intravenous antipseudomonal antibiotics to treat symptoms indicative of pulmonary exacerbation. The median time to antibiotic need is shown for both treatment groups (aztreonam lysine for inhalation [AZLI] vs. placebo, P = 0.007).

Figure 3.

Changes in Mean Cystic Fibrosis Questionnaire–Revised (CFQ-R) respiratory scores, FEV1, and Pseudomonas aeruginosa (PA) density in sputum. Child, teen, and adult CFQ-R respiratory scores were combined. The CFQ-R was not administered on Day 42. For CFQ-R respiratory, at Day 28, P = 0.021 for AZLI-BID versus placebo and P = 0.092 for AZLI-TID versus placebo. For FEV1 at Day 28, P = 0.006 for AZLI-BID versus placebo and P = 0.005 for AZLI-TID versus placebo. For PA density (log10 PA cfu/g sputum) at Day 28, P = 0.011 for AZLI-BID versus placebo and P = 0.031 for AZLI-TID versus placebo. BID = twice daily; TID = three times daily.