Macrolides and Moxifloxacin for Prevention of Exacerbations of Chronic Obstructive Pulmonary Disease (COPD)

Macrolides

In older studies, prophylactic, continuous use of antibiotics had no effect on the frequency of exacerbations in COPD (Francis et al 1960 & Francis et al. 1961). A study that examined the efficacy of chemoprophylaxis undertaken in winter months over a 5-year-period concluded that there was no benefit (Johnston et al. 1969).

However, more recent studies have shown that regular use of some antibiotics may reduce exacerbation rate. Therefore, there has been renewed interest in prophylactic antibiotics for patients with recurrent exacerbations (two or more per year), resulting in several placebo-controlled trials, with a macrolide being the most commonly prescribed agent. However, the benefits of antibiotic prophylaxis must be weighed against concerns about promoting antibiotic resistance and possible adverse effects. For most patients with COPD, we suggest not administering antibiotic prophylaxis.

Only carefully selected patients, such as those who continue to have frequent exacerbations in spite of optimal therapy for their COPD with bronchodilators and anti-inflammatory agents, should be considered for antibiotic prophylaxis. In such patients, we suggest prophylaxis with azithromycin. GOLD 2019 stated that azithromycin (given at 250 mg daily or at a lower dose of 250-500 mg three times per week) OR erythromycin (500 mg twice daily) for one year reduced the risk of exacerbations, compared to usual care (Seemungal et al 2008; Albert et al 2011 & Uzun et al 2014). UptoDate stated that 250 mg three times per week was oftenly used to reduce adverse effects, although this dose is less well studied.

When prophylactic antibiotics are prescribed, careful attention should be paid to contraindications, and patients should be closely monitored for adverse effects. Suspected bacterial exacerbations in patients on antibiotic prophylaxis should be treated with antibiotics that are from a different class than the prophylactic agent. Even if the regimen is successful in reducing exacerbations, interrupting treatment after 48-52 weeks should be considered. Interventions to prevent exacerbations of COPD that are unrelated to infection are discussed separately.

Azithromycin use was associated with an increased incidence of bacterial resistance, prologation of QTc intervals and impaired hearing tests (Albert et al 2011). Hearing should be assessed periodically as macrolides were associated with hearing loss in clinical trials. A post-hoc analysis suggests lesser benefit in active smokers (Han et al. 2014). There are no data showing efficacy or safety of chronic azithromycin treatment to prevent COPD exacerbations beyond one year of treatment.

Moxifloxacin

Although moxifloxacin has demonstrated efficacy for the prevention of COPD exacerbations, we generally reserve it for the treatment of serious pulmonary infections in order to reduce the risk of selecting fluoroquinolone-resistant bacteria and causing C. difficile infection.

Pulse therapy with moxifloxacin (400 mg/day for 5 days every 8 weeks) in patients with chronic bronchitis and frequent exacerbations had no beneficial effect on exacerbation rate overall. The recommendation is based on the randomised controlled trials conducted by Sethi et al. (2010), where moxifloxacin is given at 400 mg/day for 5 days every 8 weeks, for six cycles for a total duration of 48 weeks. The study revealed that:

• The patients who received moxifloxacin were less likely to have a COPD exacerbation in both the per-protocol analysis (OR 0.75, 95% CI 0.565-0.994) and in the intent-to-treat analysis (OR 0.81, 95% CI 0.645-1.008).
• A post-hoc analysis of per-protocol patients with purulent or mucopurulent sputum production at baseline showed a larger benefit with antibiotic prophylaxis (OR 0.55, 95% CI 0.36-0.84).
• Sustained emergence of moxifloxacin-resistant strains was not observed in sputum or in enteric flora.
• Gastrointestinal adverse effects were more frequent with moxifloxacin; however, C. difficile infections were not observed.

References:

1. UptoDate: Management of infection in exacerbations of chronic obstructive pulmonary disease
2.    UptoDate: Management of refractory chronic obstructive pulmonary disease
3.    Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD), 2019. Pocket Guide to COPD Diagnosis, Management, and Prevention: A Guide for Health Care Professionals.
4.    Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD), 2019. Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease.

All information accessed on 19 Sept 2019