Fosfomycin/tobramycin for inhalation in patients with cystic fibrosis with pseudomonas airway infection

Abstract

Rationale: Fosfomycin/tobramycin for inhalation (FTI), a unique, broad-spectrum antibiotic combination, may have therapeutic potential for patients with cystic fibrosis (CF).

Objectives: To evaluate safety and efficacy of FTI (160/40 mg or 80/20 mg), administered twice daily for 28 days versus placebo, in patients greater than or equal to 18 years of age, with CF, chronic Pseudomonas aeruginosa (PA) airway infection, and FEV(1) greater than or equal to 25% and less than or equal to 75% predicted.

Methods: This double-blind, placebo-controlled, multicenter study assessed whether FTI/placebo maintained FEV(1) % predicted improvements achieved following a 28-day, open-label, run-in course of aztreonam for inhalation solution (AZLI).

Measurements and main results: A total of 119 patients were randomized to FTI (160/40 mg: n = 41; 80/20 mg: n = 38) or placebo (n = 40). Mean age was 32 years and mean FEV(1) was 49% predicted at screening. Relative improvements in FEV(1) % predicted achieved by the AZLI run-in were maintained in FTI groups compared with placebo (160/40 mg vs. placebo: 6.2% treatment difference favoring FTI, P = 0.002 [primary endpoint]; 80/20 mg vs. placebo: 7.5% treatment difference favoring FTI, P < 0.001). The treatment effect on mean PA sputum density was statistically significant for the FTI 80/20 mg group versus placebo (-1.04 log(10) PA colony-forming units/g sputum difference, favoring FTI; P = 0.01). Adverse events, primarily cough, were consistent with CF disease. Respiratory events, including dyspnea and wheezing, were less common with FTI 80/20 mg than FTI 160/40 mg. No clinically significant differences between groups were reported for laboratory values.

Conclusions: FTI maintained the substantial improvements in FEV(1) % predicted achieved during the AZLI run-in and was well tolerated. FTI is a promising antipseudomonal therapy for patients with CF.

Figure 1.

Disposition of the patients with cystic fibrosis.

Figure 2.

Changes in FEV₁ % predicted, CFQ-R Respiratory Symptoms Scores, and Pseudomonas aeruginosa density in sputum. For each panel, observed mean (SE) change is presented during the open-label AZLI run-in period for the 119 patients randomized to FTI/placebo at baseline (Day 0). Imputed mean (SE) change is presented during the FTI/placebo period; data were imputed using the last observation carried forward method. P values are from ANOVA models (see Table 2), comparing change from Day 0 to Day 28; only significant values (P < 0.05) are shown. Relative change in FEV₁ % predicted at Day 0 was calculated as the percentage change from the value at Day −28, and at Days 14 and 28 was calculated as the percentage change from the value at Day 0. For each panel in the figure, change values at Day 14 and Day 28 were added to the Day 0 value for each group prior to being plotted, to allow the data to be displayed in continuous lines.