Macrolide Antibiotics for Prevention of Chronic Obstructive Pulmonary Disease Exacerbations: Are We There Yet?
Authors: Marcos I. Restrepo, Antonio Anzueto
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Chronic obstructive pulmonary disease (COPD) exacerbations are associated with significant morbidity and mortality (1). Among the major goals of COPD treatment is the prevention of exacerbations (2). Clinical studies have shown that long-term continuous or intermittent use of antibiotics reduces COPD exacerbation frequency and extends the time to the next event (3, 4). Among antibiotic classes, macrolides are highlighted on the basis of well-designed randomized controlled trials (5–8). Although macrolides are known to have not only antibacterial but also antiinflammatory, immunomodulatory, and antiviral effects (9, 10), the mechanisms responsible for their clinical efficacy in preventing COPD exacerbations are unclear.

In contrast to the beneficial effects, long-term use of macrolides has potential adverse events. Some studies have described changes in nasal bacteria flora increasing the prevalence of macrolide-resistant bacteria (5, 11); and hearing loss has been described as well (5). At the same time, there are controversial reports regarding the cardiac safety of chronic macrolide use. Although some studies have suggested an increased risk of cardiac arrhythmias (12) and increased heart attacks in patients over age 65 years (13), a review concluded that these cardiac effects are more likely to be present in patients with other coexisting risk factors (14); therefore, the authors concluded that there is need for electrocardiographic monitoring at the time of initiation of macrolide therapy and for a short time thereafter (14). Therefore, to balance the risk–benefit ratio, it is critical to better identify patients who are more likely to benefit from the use of long-term macrolide therapy.

In a large pivotal study, Albert and colleagues (5) reported the use of 12-month treatment with daily azithromycin in the prevention of COPD exacerbations. In this study, the addition of azithromycin to standard therapy was associated with a 27% decrease in the frequency of exacerbations and an increase in the median time to exacerbation (266 vs. 174 d, respectively; P < 0.001). Their initial unadjusted analyses suggested that the efficacy of azithromycin in reducing COPD exacerbations may differ as a function of age, smoking status, concomitant inhaled therapy, oxygen use, and disease severity (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stage). In the June 15 issue of the Journal, Han and colleagues reported the results of a secondary analysis of this cohort, to determine the treatment effect of azithromycin in specific patient subpopulations (15). The data reported in this study were the results of a comprehensive analysis that took into consideration potentially relevant confounders such as the use of various concomitant therapies, clinical characteristics, disease severity, and the type of COPD exacerbations. These investigators report that azithromycin (250 mg daily) had greater efficacy in older patients and milder GOLD stages, with little evidence of treatment effect among current smokers. They also found no difference in efficacy by sex, history of chronic bronchitis, oxygen use, or concomitant COPD therapy. Azithromycin was most effective in preventing exacerbations that required both antibiotics and steroid treatment.

We congratulate the COPD Clinical Research Network, and the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health, for funding and conducting relevant clinical studies that attempt to improve the treatment of patients with COPD. We also believe that the authors should be recognized for their efforts to better characterize subgroups of patients who might be able to respond to and benefit from this pharmacological approach. However, this analysis raises more questions than it answers.

First, what is the appropriate azithromycin dose? In this study, patients received azithromycin at 250 mg daily. In contrast, most clinical studies in COPD and other respiratory conditions have used 250 mg three times per week, in an attempt to minimize some of the potential side effects listed previously (16). The development of bacterial resistance is a major concern, in view of the large patient population affected by COPD. Therefore, the widespread use of macrolides, particularly azithromycin, has the potential to substantially influence antimicrobial resistance rates of a large range of respiratory microbes (11). In this study the incidence of resistance to macrolides on the part of respiratory pathogens isolated from nasopharyngeal swabs was significantly increased in the group of patients receiving azithromycin compared with the placebo arm (5). Collateral damage may need to be addressed before recommending the widespread use of macrolides; one approach could be to study intermittent use of macrolides during high-risk periods for COPD exacerbations, such as the winter months.

Second, what kind of patients with COPD should be given azithromycin? The investigators reported that azithromycin had greater efficacy for older patients and those at milder GOLD stages. It seems contradictory to give azithromycin to patients with milder COPD; they constitute the group with fewer COPD exacerbations and the one most likely to benefit from other medications. In addition, older patients with COPD have more comorbid conditions compared with younger individuals. It is therefore likely that these patients will be at greater risk for cardiovascular complications when exposed to macrolides because of other coexisting risk factors, increasing their morbidity and possible associated cardiovascular mortality if caution is not exercised during macrolide treatment.

Third, where does azithromycin fit in the current treatment guidelines for the management of COPD and prevention of exacerbations? At present, the use of long-acting bronchodilators (long-acting antimuscarinic agents [LAMAs] and long-acting β agonists [LABAs]) with or without inhaled corticosteroids (ICSs) is the pivotal therapy for patients with COPD, and the use of these medications is associated with a significant decrease in COPD exacerbations (1, 2). In this study, the protocol allowed “all concomitant COPD therapies” to be used during macrolide therapy. However, there was wide variability in the medications that patients received. Although 49% patients at baseline were using LAMAs, LABAs, and ICSs (5), it is unclear whether these medications were continued during the study period and what other medications were added.

Fourth, the investigators report that azithromycin-treated patients received less antibiotics and corticosteroids, suggesting that this therapy was more effective in preventing more severe exacerbations. This is an interesting observation pertaining to a specific group of patients, but other studies using LAMAs and LABAs plus ICSs have also reported associated differences in the use of antibiotics and or corticosteroids (17). Until a prospective randomized controlled study is done that takes into consideration all COPD pharmacological interventions and also provides guidelines on how to use corticosteroids and/or antibiotics during the exacerbations, we cannot conclude that using azithromycin prevents “more severe exacerbation.”

In conclusion, we have not yet arrived at our destination, although clinical studies conducted over the last decade have indicated that treatment with long-term or intermittent antibiotics may have a beneficial effect by reducing the frequency of COPD exacerbations and extending the time to the next event. The analysis by Han and colleagues (15) identified a subgroup of patients that could benefit from this intervention. Therefore, we need to conduct additional prospective clinical studies to test these hypotheses taking into consideration the potential risks of adverse events and development of bacterial resistance.