How long should we maintain long‐term azithromycin treatment in cystic fibrosis patients?

We have read with interest the trial by Saiman et al., investigating the efficacy of azithromycin treatment in 146 Pseudomonas aeruginosa uninfected cystic fibrosis (CF) patients. Treatment resulted in a significant reduction in pulmonary exacerbations and a significant increase in weight gain after 12 months. However, the authors give no information about long-term treatment beyond 12 months. Up till now, azithromycin has been usedmainly as add-on treatment for chronicP. aeruginosa colonized CF patients. Nevertheless, the number of studies examining efficacy of azithromycin treatment in CF is limited, and the recommended dosage and duration of azithromycin treatment remains uncertain. A few randomized, placebo-controlled studies have shown a positive effect on pulmonary function, nutritional status and/or number of pulmonary exacerbations in both pediatric and adult CF patients. The longest duration of these studies is 12months. The only studywith a longer follow-up, an open retrospective study by TramperStranders et al. during 3 years, demonstrated a positive effect on FEV1% predicted in the first year after start of azithromycin, with a subsequent decline at the same rate as before therapy. Furthermore, placebo-controlled studies in P. aeruginosa colonized patients are limited. Only one trial studied the effect of azithromycin in a group of 185P. aeruginosa infected CF patients and found an improvement in FEV1 and a decreased number of pulmonary exacerbations in the azithromycin group after 6 months. Maintenance treatment with azithromycin was introduced in our center in 2004, as add-on therapy for chronically colonized P. aeruginosa CF patients who had experienced 2 or more pulmonary exacerbations in the past 6 months. Dosing schedule is 250mg three times a week in patients< 40 kg and 500mg three times a week in patients> 40kg. Most patients still continued this treatment, and this prompted us to question and reconsider its prolongation. We reviewed the medical files of all patients with chronic P. aeruginosa colonization (defined as having three or more positive cultures during at least 6 months follow-up), treated with azithromycin, age> 4 years and able to perform a reliable spirometry, and with a follow-up in our center of at least 3 years. Pulmonary function parameters (FEV1, FVC, and FEF25–75% predicted), body mass index (BMI) Z scores, and number of pulmonary exacerbations were analyzed at different time intervals: the year before azithromycin initiation, and the first, second and third year after azithromycin initiation. Pulmonary exacerbation was defined as increased cough, sputum, and/or dyspnea, requiring treatment with oral or intravenous antibiotics. Data were analyzed using SPSS 20.0 (SPSS, Inc., IBM, Chicago, IL). Pulmonary function values, BMI Z scores and number of pulmonary exacerbations were compared using student t tests. Statistical tests were two-sided and statistical significance was accepted at P< 0.05. A total of 50 patients were identified as having chronic P. aeruginosa colonization. Thirty one patients were started on azithromycin. Seven discontinued treatment prematurely after a median duration of 0.75 years (range 0.1–5.8), mainly due to gastro-intestinal adverse events. Three patients were excluded due to age< 4 years (one patient) or insufficient time of follow-up (two patients). Median age of patients was 29.6 years (range 13–47). Longest treatment duration was 7 years (median; range 4.5–8.6). Table 1 shows clinical characteristics of the patients. At the end of the first treatment year, no significant differences in pulmonary function parameters or BMI Z scores were found compared to the year before treatment start. However, the number of orally treated pulmonary exacerbations per patient decreased during the first treatment year (Fig. 1, P1⁄4 0.009), whereas no effect was seen on the more severe exacerbations, needing intravenous treatment (P1⁄4 0.13). The reduction of peroral antibiotic courses was not sustained in the second and third treatment year. In conclusion, in this single-center study, azithromycin treatment resulted in a reduction of orally treated