Macrolide antibiotics (including azithromycin) for cystic fibrosis.

backgroundCystic fibrosis (CF) is a life-limiting genetic condition, affecting over 90,000 people worldwide. CF affects several organs in the body, but airway damage has the most profound impact on quality of life (QoL) and survival. Causes of lower airway infection in people with CF are, most notably, Staphylococcus aureus in the early course of the disease and Pseudomonas aeruginosa at a later stage. Macrolide antibiotics, e.g. azithromycin and clarithromycin, are usually taken orally, have a broad spectrum of action against gram-positive (e.g. S aureus) and some gram-negative bacteria (e.g. Haemophilus influenzae), and may have a modifying role in diseases involving airway infection and inflammation such as CF. They are well-tolerated and relatively inexpensive, but widespread use has resulted in the emergence of resistant bacteria. This is an updated review.

objectivesTo assess the potential effects of macrolide antibiotics on clinical status in terms of benefit and harm in people with CF. If benefit was demonstrated, we aimed to assess the optimal type, dose and duration of macrolide therapy. SEARCH

methodsWe 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 last searched the Group's Cystic Fibrosis Trials Register on 2 November 2022. We last searched the trial registries WHO ICTRP and clinicaltrials.gov on 9 November 2022. We contacted investigators known to work in the field, previous authors and pharmaceutical companies manufacturing macrolide antibiotics for unpublished or follow-up data, where possible. SELECTION CRITERIA: We included randomised controlled trials of macrolide antibiotics in adults and children with CF. We compared them to: placebo; another class of antibiotic; another macrolide antibiotic; or the same macrolide antibiotic at a different dose or type of administration. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed risk of bias. We assessed the certainty of evidence using GRADE. MAIN

resultsWe included 14 studies (1467 participants) lasting 28 days to 36 months. All the studies assessed azithromycin: 11 compared oral azithromycin to placebo (1167 participants); one compared a high dose to a low dose (47 participants); one compared nebulised to oral azithromycin (45 participants); and one looked at weekly versus daily dose (208 participants). Oral azithromycin versus placebo There is a slight improvement in forced expiratory volume (FEV AUTHORS'

conclusionsAzithromycin therapy is associated with a small but consistent improvement in respiratory function, a decreased risk of exacerbation and longer time to exacerbation at six months; but evidence for treatment efficacy beyond six months remains limited. Azithromycin appears to have a good safety profile (although a weekly dose was associated with more gastrointestinal side effects, which makes it less acceptable for long-term therapy), with a relatively minimal treatment burden for people with CF, and it is inexpensive. A wider concern may be the emergence of macrolide resistance reported in the most recent study which, combined with the lack of long-term data, means we do not feel that the current evidence is strong enough to support azithromycin therapy for all people with CF. Future research should report over longer time frames using validated tools and consistent reporting, to allow for easier synthesis of data. In particular, future trials should report important adverse events such as hearing impairment or liver disease. More data on the effects of azithromycin given in different ways and reporting on our primary outcomes would benefit decision-making on whether and how to give macrolide antibiotics. Finally, it is important to assess azithromycin therapy for people with CF who are established on the relatively new cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies which correct the underlying molecular defect associated with CF (none of the trials included in the review are relevant to this population).