P4. Macrolides

For patients with moderate-severe COPD and recurrent exacerbations, trials have found that long-term low-dose oral macrolides reduce the number of patients experiencing an exacerbation and the frequency of exacerbations. The number needed to treat to prevent one exacerbation (NNT) was 8 (95% CI 5 to 18) (Herath 2018).

A systematic review of prophylactic macrolide treatment in severe COPD, which included 6 RCTs involving 1,485 COPD patients, showed that regular treatment of at least 6 months in duration results in a significant decrease in COPD exacerbations (RR 0.65 95% CI 0.43 to 0.89, p=0.01).  Participants treated with macrolides were more likely to experience non fatal adverse (gastrointestinal reactions, ototoxicity, rash, and liver injury) events compared to the placebo treated group (Yao 2013) [evidence level I].  However, prudence would suggest this treatment should be reserved for patients who have severe disease with recurrent exacerbations, in whom other treatments (for example: smoking cessation, pulmonary rehabilitation, vaccination and optimal use of other preventive pharmacotherapy known to reduce exacerbations) have been optimised.  Retrospective analysis of the trial by Albert et al found no evidence of treatment benefit among current smokers, with the greatest benefit seen in milder COPD and older patients (Han 2014).  Prospective data in predefined groups is required before any sub-group treatment recommendations can be made.

A Cochrane network meta-analysis of various prophylactic antibiotics for patients with COPD (12 studies, n=3,405 patients) found beneficial effects of macrolides for reducing exacerbations (hazard ratio 0.67, 95% credible interval 0.60 –0.75) compared to placebo and improving quality of life (mean difference in SGRQ of -2.30, 95% credible interval -3.61 to -0.99, although this difference did not reach the MCID) (Janjua 2021) [evidence level I]. No significant benefits were associated with use of long-term quinolones or tetracyclines, compared to placebo.

Since the publication of the above two systematic reviews, a further 12-month double-blind RCT comparing doxycycline 100mg daily to placebo has also demonstrated a lack of benefit of long-term doxycycline. The UK-based study recruited 222 patients with COPD and a history of exacerbations. Doxycycline did not reduce the exacerbation rate. Those receiving doxycycline experienced a deterioration in health status on the SGRQ by 5.2 points (95% CI 1.44 to 9, p=0.007) compared to the placebo group (Allinson 2023) [evidence level II].

Given the potential significant adverse effects of macrolides (including cardiac toxicity, ototoxicity, diarrhoea, and the development of antibiotic resistance which affects both the individual and the community), expert advice is recommended before starting long-term macrolide therapy. It should be noted that azithromycin is not available on the PBS for long term use.