P4. Macrolides

For patients with moderate-severe COPD and recurrent exacerbations, recent 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 12 month randomised controlled trial of erythromycin 250mg bd in patients with moderate COPD found a significantly reduced risk of exacerbation with a rate ratio of 0.65 (95% CI 0.49-0.86) (Seemungal 2008) [evidence level II].

A 12 month randomised controlled trial of azithromycin 250 mg daily vs. placebo was undertaken in patients with COPD who were using supplemental oxygen, or had received a course of systemic corticosteroids for respiratory problems in the past year, or had visited an Emergency Department for a COPD exacerbation within the past year, or had been hospitalised for a COPD exacerbation within the past year (Albert 2011). The study found that azithromycin significantly increased the median time to the first exacerbation, reduced exacerbation rates, and improved quality of life in some patients [evidence level II]. However, hearing loss was more common in a small proportion of patients, and more macrolide-resistant organisms were seen. Patients had been excluded from the study if they had resting tachycardia, prolonged corrected QT interval or use of medications that could prolong this, or hearing impairment. It was not clear from the study to what extent participants had other treatment for their COPD maximised. Azithromycin 500mg, three times per week, over 12 months, was associated with an almost halving of exacerbations (RR 0.58, 95% CI 0.42-0.79) in severe COPD patients, with CT chest being performed to exclude bronchiectasis. Patients had at least three admissions in the preceding 12 months. While on azithromycin, 1 in 5 experienced diarrhoea. Macrolide resistance assessment was limited by small numbers of sputum samples, and no oral flora assessment, but with an unexplained greater resistance in the placebo group rather than the azithromycin group. No audiometry was included in the study (Uzun 2014) [evidence level II].

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 0.43-0.89, 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.

Given the potential significant adverse effects of such regimens (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 antibiotic therapy. It should be noted that azithromycin is not available on the PBS for long term use.