Azithromycin for Early Pseudomonas Infection in Cystic Fibrosis. The OPTIMIZE Randomized Trial

Abstract

Rationale: New isolation of Pseudomonas aeruginosa (Pa) is generally treated with inhaled antipseudomonal antibiotics such as tobramycin inhalation solution (TIS). A therapeutic approach that complements traditional antimicrobial therapy by reducing the risk of pulmonary exacerbation and inflammation may ultimately prolong the time to Pa recurrence.

Objectives: To test the hypothesis that the addition of azithromycin to TIS in children with cystic fibrosis and early Pa decreases the risk of pulmonary exacerbation and prolongs the time to Pa recurrence.

Methods: The OPTIMIZE (Optimizing Treatment for Early Pseudomonas aeruginosa Infection in Cystic Fibrosis) trial was a multicenter, double-blind, randomized, placebo-controlled, 18-month trial in children with CF, 6 months to 18 years of age, with early Pa. Azithromycin or placebo was given 3× weekly with standardized TIS.

Measurements and main results: The primary endpoint was the time to pulmonary exacerbation requiring antibiotics and the secondary endpoint was the time to Pa recurrence, in addition to other clinical and safety outcomes. A total of 221 participants (111 placebo, 110 azithromycin) out of a planned 274 were enrolled. Enrollment was stopped early by the NHLBI because the trial had reached the prespecified interim boundary for efficacy. The risk of pulmonary exacerbation was reduced by 44% in the azithromycin group as compared with the placebo group (hazard ratio, 0.56; 95% confidence interval, 0.37-0.83; P = 0.004). Weight increased by 1.27 kg in the azithromycin group compared with the placebo group (95% confidence interval, 0.01-2.52; P = 0.046). No significant differences were seen in microbiological or other clinical or safety endpoints.

Conclusions: Azithromycin was associated with a significant reduction in the risk of pulmonary exacerbation and a sustained improvement in weight, but had no impact on microbiological outcomes in children with early Pa. Clinical trial registered with clinicaltrials.gov (NCT02054156).

Keywords: Pseudomonas aeruginosa; clinical trial; eradication; pulmonary exacerbation.

Figure 1.

Participant flow diagram. ITT = intent to treat.

Figure 2.

Kaplan-Meier curve of the proportion of participants who remained free of pulmonary exacerbations from baseline to the end of follow-up. CI = confidence interval.

Figure 3.

Treatment effect estimates for time to pulmonary exacerbation among predefined subgroups. Although the data are not included in this figure because of the small number of patients, additional prespecified subgroup analyses were conducted among participants on commercial CFTR (cystic fibrosis transmembrane conductance regulator) modulators. An additional 5 participants (2 placebo and 3 azithromycin) initiated ivacaftor during the follow-up period, and an additional 18 participants (6 placebo and 12 azithromycin) initiated ivacaftor/lumacaftor during the follow-up. The exacerbation risk among azithromycin participants as compared with placebo was not statistically different between those using CFTR modulators (n = 19 placebo, n = 14 azithromycin; hazard ratio, 0.64; 95% confidence interval, 0.23–1.77) and those not using CFTR modulators (n = 91 placebo, n = 97 azithromycin; hazard ratio, 0.56; 95% confidence interval, 0.36–0.87). AZ = azithromycin; CI = confidence interval; Pa = Pseudomonas aeruginosa; PL = placebo; Sa = Staphylococcus aureus.

Figure 4.

(A) Percentage of participants with Pa-positive cultures over time. (B) Average change in weight over time. Error bars are 95% confidence intervals. CI = confidence interval; Pa = Pseudomonas aeruginosa.