Testing the effects of combining azithromycin with inhaled tobramycin for P. aeruginosa in cystic fibrosis: a randomised, controlled clinical trial

Abstract

Rationale: Inhaled tobramycin and oral azithromycin are common chronic therapies in people with cystic fibrosis and Pseudomonas aeruginosa airway infection. Some studies have shown that azithromycin can reduce the ability of tobramycin to kill P. aeruginosa. This trial was done to test the effects of combining azithromycin with inhaled tobramycin on clinical and microbiological outcomes in people already using inhaled tobramycin. We theorised that those randomised to placebo (no azithromycin) would have greater improvement in forced expiratory volume in one second (FEV₁) and greater reduction in P. aeruginosa sputum in response to tobramycin.

Methods: A 6-week prospective, randomised, placebo-controlled, double-blind trial testing oral azithromycin versus placebo combined with clinically prescribed inhaled tobramycin in individuals with cystic fibrosis and P. aeruginosa airway infection.

Results: Over a 6-week period, including 4 weeks of inhaled tobramycin, the relative change in FEV₁ did not statistically significantly differ between groups (azithromycin (n=56) minus placebo (n=52) difference: 3.44%; 95% CI: -0.48 to 7.35; p=0.085). Differences in secondary clinical outcomes, including patient-reported symptom scores, weight and need for additional antibiotics, did not significantly differ. Among the 29 azithromycin and 35 placebo participants providing paired sputum samples, the 6-week change in P. aeruginosa density differed in favour of the placebo group (difference: 0.75 log₁₀ CFU/mL; 95% CI: 0.03 to 1.47; p=0.043).

Conclusions: Despite having greater reduction in P. aeruginosa density in participants able to provide sputum samples, participants randomised to placebo with inhaled tobramycin did not experience significantly greater improvements in lung function or other clinical outcomes compared with those randomised to azithromycin with tobramycin.

Keywords: bacterial Infection; cystic fibrosis; respiratory Infection.

Figure 1

Study design schematic. The study consisted of three visits during the 6-week randomised period. Participants were randomly allocated 1:1 to receive oral AZM (500 mg) or placebo three times per week throughout the 6-week period. Two weeks post-randomisation, participants started their usual inhaled TOB solution or powder two times per day for 4 weeks while continuing on study drug (AZM or placebo, see online supplemental material for details) to complete the 6-week study. Participants completing the study were offered optional, additional participation in an 8-week open-label period. AZM, azithromycin; TOB, tobramycin.

Figure 2

Overview of the study population. Individuals screened, randomised, length of follow-up and included in the analytical populations. AZM, azithromycin; m-ITT, modified intention-to-treat; Pa, Pseudomonas aeruginosa; PP, per-protocol.

Figure 3

Pulmonary function outcomes: (A) mean relative (%) change from baseline in FEV₁ litres and (B) mean absolute change from baseline in ppFEV₁. Error bars are 95% CIs. AZM, azithromycin; FEV₁, forced expiratory volume in one second; ppFEV₁, forced expiratory volume in one second; TOB, tobramycin.

Figure 4

Mean relative (%) change from baseline in FEV₁ litres (unadjusted estimates) among prespecified subgroups. AZM, azithromycin; FEV₁, forced expiratory volume in one second.

Figure 5

Microbiologic outcomes: (A) mean change from baseline in Pa density in log₁₀ CFU/mL and (B) mean P. aeruginosa density in log₁₀ CFU/mL. Error bars are 95% CIs. AZM, azithromycin; Pa, Pseudomonas aeruginosa; TOB, tobramycin.