People with cystic fibrosis suffer from chest infections, often caused by the bacteria Pseudomonas aeruginosa. This bacteria is resistant to nearly all antibiotics that can be taken by mouth. Macrolide antibiotics, e.g. azithromycin, have no direct killing effect on Pseudomonas aeruginosa, but they may reduce the activity of these bacteria. We have included ten randomised controlled trials with a total of 959 participants in this review. Eight of these trials compared azithromycin (a macrolide antibiotic) to placebo and two compared different doses of azithromycin. Four trials in children and adults (549 participants) showed significant improvements in lung function after treatment with azithromycin compared to placebo at six months; although data from later time points are not so clear. Patients treated with azithromycin were about twice as likely to be free of pulmonary exacerbation; needed fewer oral antibiotics and had fewer instances of Staphylococcus aureus in cultures from their lungs and airways. Adverse events were not common and not obviously associated with azithromycin, although there was an increase in resistance to macrolides. Most studies used a three times a week dosing schedule. Taking a high weekly dose was linked to an increase in mild gastrointestinal adverse events. Further multicentre studies are needed to look at the long-term effects of this antibiotic treatment, especially for infants diagnosed through newborn screening.
This review provides evidence of improved respiratory function after six months of azithromycin. Data beyond six months were less clear, although reduction in pulmonary exacerbation was sustained. Treatment appeared safe over a six-month period; however, emergence of macrolide resistance was a concern. A multi-centre trial examining long-term effects of this antibiotic treatment is needed, especially for infants recognised through newborn screening.
Macrolide antibiotics may have a modifying role in diseases which involve airway infection and inflammation, like cystic fibrosis.
To test the hypotheses that, in people with cystic fibrosis, macrolide antibiotics:
1. improve clinical status compared to placebo or another antibiotic;
2. do not have unacceptable adverse effects.
If benefit was demonstrated, we aimed to assess the optimal type, dose and duration of macrolide therapy.
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings.
We contacted investigators known to work in the field, previous authors and pharmaceutical companies manufacturing macrolide antibiotics for unpublished or follow-up data (May 2010).
Latest search of the Group's Cystic Fibrosis Trials Register: 29 February 2012.
Randomised controlled trials of macrolide antibiotics compared to: placebo; another class of antibiotic; another macrolide antibiotic; or the same macrolide antibiotic at a different dose.
Two authors independently extracted data and assessed risk of bias. Seven groups were contacted and provided additional data which were incorporated into the review.
Ten of 31 studies identified were included (959 patients). Five studies with a low risk of bias examined azithromycin versus placebo and demonstrated consistent improvement in forced expiratory volume in one second over six months (mean difference at six months 3.97% (95% confidence interval 1.74% to 6.19%; n = 549, from four studies)). Patients treated with azithromycin were approximately twice as likely to be free of pulmonary exacerbation at six months, odds ratio 1.96 (95% confidence interval 1.15 to 3.33). With respect to secondary outcomes, there was a significant reduction in need for oral antibiotics and greater weight gain in those taking azithromycin. Adverse events were uncommon and not obviously associated with azithromycin, although a once-weekly high dose regimen was associated with more frequent gastrointestinal adverse events. Treatment with azithromycin was associated with reduced identification of Staphylococcus aureus on respiratory culture, but also a significant increase in macrolide resistance.