This randomised placebo controlled trial is the first study of the long term use of low dose azithromycin in young patients with CF. The results showed that treatment for 12 months with oral azithromycin given 3 days a week led to a significant reduction in the number of pulmonary exacerbations requiring courses of antibiotics. Importantly, most of the patients enrolled in the trial were not infected with P aeruginosa, providing evidence that the beneficial effect of azithromycin could be observed at an early stage of lung disease in CF.
The first suggestion that long term macrolide therapy might be of interest in CF was based on the results of low dose erythromycin treatment in patients with diffuse panbronchiolitis.
Following the preliminary report of a pilot study with patients infected with P aeruginosa
, several randomised placebo controlled trials were conducted in CF.18
Wolter and colleagues performed a 3 month parallel group trial in 60 CF adult patients (mean age 27.9 years) with a daily dose of 250 mg azithromycin.19
They reported that subjects randomised to azithromycin maintained pulmonary function and experienced a reduced number of pulmonary exacerbations. Saiman and colleagues conducted a 6 month parallel group trial in 185 adult patients infected with P aeruginosa
with a dose of 250 or 500 mg azithromycin given 3 days a week.10
They reported improvement in pulmonary function and decreased rates of pulmonary exacerbation in the azithromycin group. So far, no parallel group trial in CF children has been reported. Equi and colleagues conducted a 15 month crossover trial in 41 young patients with CF (mean age 13.8 years) with a daily dose of 250 or 500 mg azithromycin.20
They reported a significant though modest group response in FEV1
to azithromycin. It is important to point out that many of their patients were infected with P aeruginosa
and that they did not analyse their results by microbiological status (that is, absence or presence of P aeruginosa
On the basis of these studies, we selected for the present trial a long term treatment period (12 months) with low dose azithromycin (250 mg or 500 mg adjusted to patient body weight and given only 3 days a week) in young patients with CF. The groups were well matched, with most of the patients not being infected with P aeruginosa. The drug was well tolerated, with good adherence to treatment and similar minor adverse events in the two groups.
We found no difference in the primary end point of change in FEV1
. The results showed that the placebo group did not experience an overall decline in FEV1
over the 12 month study period. This observation can be explained by the early stage of the lung disease in the population studied. Indeed, the mean (SD) FEV1
% predicted values at baseline were 84.5 (18.4)% in the placebo group and 86.5 (25.9)% in the azithromycin group. These values were higher than the baseline FEV1
values reported in the other trials mentioned above (60% in the study by Equi and colleagues, 68.3% and 70.6% in the study by Saiman and colleagues, and 62.3% and 50.9% in the study by Wolter and colleagues.10,19,20
In a study reported several years ago, Davis et al
observed that a higher initial FEV1
was associated with a greater rate of decline and, among patients with an initial FEV1
>60% predicted, younger subjects had a faster decline than did older subjects.21
Similar conclusions could not be drawn from our results as no significant changes in lung function could be documented in our young CF study population. Certainly, the constant improvement in therapeutic strategies should contribute to reduce the decline in lung function in children. The study protocol did not include measurements of mid‐expiratory flow between 25% and 75% of FVC. Indeed, from other reports on longitudinal analysis of pulmonary function decline in CF, it is most likely that this functional parameter would not have provided different information.22
Another important consideration for analysis of the pulmonary function test results in our population is the large variation in individual FEV1
measurements gathered during the trial. Intra‐individual variability in spirometry has been reported by several authors in patients with CF, mainly in children.23
When the response group was analysed, virtually no decline in the linear trend of FEV1
could be observed in the placebo group, and no significant improvement was found in FEV1
% predicted after 12 months of treatment with azithromycin. Similar findings were also observed for FVC. Interpretation of these data cannot exclude the possibility that the treatment was not continued long enough to detect changes in FEV1
in the final measurements.
Another possibility would be that the study was not adequately powered to document significant differences in FEV1 % predicted after 12 months of treatment with either azithromycin or placebo. With a hypothesis of a 5% difference in change in FEV1 % predicted between the two groups, the estimated sample size would have been 67 patients per group. However, there was no significant relative change from baseline in FEV1 % predicted measured at month 12 in the placebo group. This can be explained by the fact that the patients were young and had mild lung disease, and that nearly 80% were not infected with P aeruginosa. With regard to the sample size, we were able to include 82 patients by the closure of enrolment in June 2003. The main reason was an inaccurate estimation of CF physician attitude regarding the use of azithromycin when the study was conceived and designed. Indeed, the rate at which this drug has been adopted by practitioners has increased rapidly over the past years, most likely because of its potential anti‐inflammatory effects and the absence of significant adverse events related to azithromycin in any of the trials reported to date. Considering the number of patients enrolled in the present trial, the power to statistically detect a difference of 5% in change in FEV1 % predicted between the two groups was estimated to be 72%. Therefore, because of the insufficient number of patients, no clear conclusion with regard to the effect on lung function parameters such as FVC and FEV1 can be drawn from the study.
Periods of relative stability in lung disease expression are classically punctuated by exacerbations of symptoms.24
In the present study the group randomised to receive azithromycin had a significant decrease in the number of pulmonary exacerbations, which paralleled the reduced number of additional courses of antibiotics received by the patients. These results confirm the data reported by the two other double blind, placebo controlled studies performed in adult patients.10,19
Possible explanations for the efficacy of low dose long term macrolide antibiotic therapy in patients with CF include the antibacterial role of these molecules. Azithromycin is an erythromycin derived 15‐membered ring azalide, structurally modified to permit enhanced intracellular accumulation with greater tissue penetration, as well as increased intracellular and extracellular antimicrobial activity.25
However, in the present study, no significant differences were found in the number of positive cultures for the common CF pathogens at months 6 and 12 between the two groups. These results may be explained at least in part by the young age of the patients. Only three patients in the placebo group acquired P aeruginosa
. No recent detection of Staphylococcus aureus
could be documented in the azithromycin group compared with two in the placebo group (one methicillin sensitive and one methicillin resistant).
The significant difference in the incidence of acute exacerbations between the study groups is an important and, most likely, clinically relevant measure of respiratory benefit in CF patients. The protocols of most therapeutic trials in CF are designed to see if lung function improves. But patients may still benefit even if functional parameters do not change. Interestingly, Saiman and coworkers recently provided additional information on the various effects of azithromycin among the 185 CF participants enrolled in the US trial.10
Their main objective was to describe the heterogeneity of the treatment response in terms of changes in lung function and frequency of pulmonary exacerbations. They showed that participants treated with azithromycin in whom the pulmonary function did not improve still experienced clinical benefits with a reduction in the number of pulmonary exacerbations. These results, which share similarities with our present data, suggest that analysis of changes in FEV1
may not be the most adequate marker for assessing clinical benefits in young CF patients. Despite the well know difficulty of defining a pulmonary exacerbation in CF, the association of new findings or changes in clinical status and antibiotic intervention may be considered as a valuable marker of acute degradation of CF lung disease.26
Clearly, response to treatment in patients with CF needs to be monitored by both functional and exacerbation parameters.
The reduced number of pulmonary exacerbations requiring courses of antibiotics documented in the present study with young CF patients may relate to the anti‐inflammatory properties of azithromycin. A growing body of experimental and clinical evidence indicates that low dose macrolide antibiotics express anti‐inflammatory and tissue reparative effects that are distinct from their antibacterial properties.27
The structure of the 15‐membered ring macrolides promotes interaction of the drug with phospholipids in the plasma and intracellular organelle membranes, thereby interfering with the regulation of signalling pathways involved in the various components of the inflammatory response.28,29
Among their numerous effects, macrolides have been reported to inhibit the release of pro‐inflammatory mediators, to limit the pulmonary influx of neutrophils, to regulate mucus secretion, and to alter the formation of the biofilm matrix. In CF, there is currently no direct demonstration of the anti‐inflammatory action of macrolides.30
Saiman and colleagues found that sputum neutrophil elastase activity increased in the placebo group over 6 months but remained the same in the azithromycin group.10
By contrast, Equi and colleagues could not document any changes in airway interleukin (IL)‐8 and neutrophil elastase concentrations in the subgroup of patients who produced sputum.20
This discrepancy can be explained by the difficulty in obtaining reliable measurements of inflammatory mediators in the sputum of CF patients. Information obtained in other chronic inflammatory pulmonary conditions is therefore of interest. In diffuse panbronchiolitis, decreased levels of IL‐8 were reported in the bronchoalveolar lavage fluids of patients treated with macrolides.31
Improvement in clinical symptoms of corticosteroid dependent patients with asthma and a reduction in corticosteroid dosage with concomitant macrolide therapy have also been reported in several studies.7
In conclusion, the results of this randomised controlled trial show the beneficial effect of long term use of low dose azithromycin in young patients with CF, even in the absence of infection with P aeruginosa. This benefit was associated with a significant reduction in the occurrence of pulmonary exacerbations requiring additional courses of antibiotics, and may be seen in the absence of changes in lung function. The lower incidence of acute exacerbations in patients receiving azithromycin is an important and clinically relevant measure of beneficial effect. Long term use of azithromycin with sub‐antimicrobial doses may therefore be considered as a therapeutic strategy to slow pulmonary deterioration in CF, possibly through reduction of the inflammatory burden of the disease, although this remains to be better investigated. Additional trials will be needed to evaluate further the efficacy and safety of prolonged use (>1 year) of macrolide antibiotics in children. These trials should be monitored by both relevant clinical and functional parameters.