Antibiotics (azithromycin) to prevent COPD exacerbations (Review)

Jan 04, 2013

Azithromycin for Prevention of COPD Exacerbations

Azithromycin taken daily prevents exacerbations of chronic obstructive pulmonary disease (COPD exacerbations), but seems to also carry risks for cardiovascular death and hearing loss. The true balance of risks and benefits with use of azithromycin to prevent COPD exacerbations is unknown, but physicians who choose to prescribe azithromycin to prevent COPD exacerbations will take heart in a review article by Richard Wenzel, Alpha Fowler, and Michael Edmond in the July 26, 2012 New England Journal of Medicine, endorsing three-times-weekly azithromycin for people with recurrent COPD exacerbations without cardiovascular disease who meet certain criteria.

COPD Exacerbations and Lung Function Decline

The "average" patient with COPD experiences 1 - 2 acute exacerbations of COPD per year; however, this average masks a wide variation: many patients experience no COPD exacerbations to speak of, while others have them almost monthly. COPD exacerbations result in close to one million hospitalizations in U.S. hospitals per year, with up to half those patients staying in hospital longer than 9 days.

It's asserted that COPD exacerbations "accelerate the progressive decline in lung function associated with COPD," with each acute exacerbation increasing the rate of FEV1 decline by 2 mL per year in nonsmokers, and by 7 mL in smokers (from an average of 33 mL per year). This is based on epidemiologic studies [Vestbo, Donaldson]; again, these averages conceal a wide variation in FEV1 changes over time in people with COPD. (These two studies also show that many people with COPD don't experience an accelerated decline in FEV1 at all, contrary to medical conventional wisdom).

Bacteria (and Viruses) Cause Many COPD Exacerbations

Respiratory viral infections (with viruses like respiratory syncitial virus/RSV, picornaviruses, and influenza) have long been associated with COPD exacerbations. New research using advanced molecular testing has shown that bacteria are probably often responsible for COPD exacerbations. The airways of people with stable, controlled COPD are frequently colonized with bacteria like Hemophilus influenza; when these people experience COPD exacerbations, new bacterial strains can often be isolated, suggesting a new infection or disruption in the bacterial ecology of the airways is responsible.

Macrolide Antibiotics Treat COPD Exacerbations

Empiric antibiotics with macrolides, beta-lactams, or doxycycline have long been part of the established therapies for COPD exacerbations (since well before the advent of the modern clinical trial era). In most clinical trials testing macrolide antibiotics specifically, greater than 90% of patients treated with macrolides had an accelerated "clinical response" (a soft but consistently replicated finding).

Azithromycin Prevents COPD Exacerbations: The Evidence

The evidence for antibiotic prevention of COPD exacerbations stems mainly from a study we reviewed here, by Albert et al in NEJM 2011. Briefly, 1,142 patients with severe COPD were randomized to azithromycin 250 mg daily or placebo for one year. Those taking azithromycin had fewer COPD exacerbations during the year, a finding with the following contours:

A number needed to treat of 3 patients with azithromycin for one year to prevent one COPD exacerbation (0.35 fewer exacerbations per year).
A reduction of the exacerbation rate from 1.83 exacerbations per year (placebo) to 1.48 COPD exacerbations per year (azithromycin).
A delay in the time to first exacerbation of 92 days in the azithromycin group (174 vs 266 days).

Lung function (FEV1/spirometry/pulmonary function testing) was not a measured outcome. Dyspnea scores (SGRQ) improved in the azithromycin group by 2 points over placebo (with 4 points considered 'clinically signficant').

Risks of Azithromycin for COPD

Azithromycin taken regularly is potentially ototoxic (causes hearing loss), and authors of the Albert NEJM 2011 paper above reported an absolute 5% excess in hearing loss in the azithromycin-treated arm (25% vs. 20%). Most of the hearing loss was reversible with discontinuation of azithromycin, but a few people's were not. These rates of ototoxicity exceed the previously believed risks of azithromycin-induced hearing loss, which was limited to about 25 case reports, almost all of which reported reversible hearing loss.

Azithromycin is weakly pro-arrhythmogenic (causes abnormal heart rhythms). Azithromycin can prolong the QTc interval and in rare cases, induce the life-threatening heart arrhythmia known as torsades de pointes. A large retrospective study we reviewed here, by Ray NEJM 2012 suggested the chance of sudden cardiac death after an outpatient prescription for a short course of azithromycin was about 1 in 12,000 (by comparison, 1 in 30,000 controls--people taking other antibiotics, or no antibiotics--had sudden cardiac death during equivalent time periods).

However, most of the risk was concentrated in patients with heart disease: these patients had a risk for sudden cardiac death of 1 in 4,000 after a single outpatient azithromycin course. Excluding these patients, the risk was much lower, likely about 1 in 50,000 or 1 in 100,000 (these are broad estimates).

Notably, these calculated event rates were after single short antibiotic courses. The cardiovascular risks of taking daily azithromycin are not known.

As would be expected, daily azithromycin promotes the emergence of bacteria resistant to azithromycin. In the Albert NEJM 2011 trial, daily azithromycin reduced bacterial colonization of the airways overall, but induced very high rates (>80%) of antibiotic resistance among the bacterial strains isolated. What this might mean clinically or epidemiologically is unknown. As an example from another study, a single course of azithromycin in COPD patients resulted in more than half of the S. pneumonia strains isolated months later to be resistant to macrolides; these resistant strains could theoretically be spread to close (household) contacts.

Clinical Takeaway: The NEJM brand name and the reputations of these accomplished authors attached to this opinion piece will go far toward making azithromycin an accepted therapy for preventing COPD exacerbations. Whether the exacerbations prevented will outweigh the expected downsides (cardiovascular deaths, hearing loss, and antibiotic resistance), I guess we'll find out later.

They responsibly propose stringent limitations on who should receive azithromycin to prevent COPD exacerbations, such as:

At least 2 COPD exacerbations in the previous year
QTc < 450 msec on ECG, and not taking other QTc-prolonging drugs
No cardiovascular disease (heart failure, coronary artery disease, peripheral vascular disease, or cerebrovascular disease)
No hearing loss on formal audiology testing
A sputum culture negative for mycobacteria
Heart rate < 100 / min
ALT and AST < 3 times normal

Citing the observed pharmacokinetics of azithromycin, authors believe that daily azithromycin will result in unnecessarily high lung tissue levels, and that azithromycin 250 mg three times weekly (e.g., Monday, Wednesday, Friday) is their recommended approach. They suggest this may reduce the risk of adverse events, acknowledging this is not based on any outcomes data.

They advise 3-month follow-up visits with formal audiography and electrocardiography at each visit (looking for hearing loss and/or QTc prolongation, respectively), and watching for drug interactions with azithromycin. Needless to say, a patient with hearing loss or QTc prolongation should prompt further evaluation and likely, drug discontinuation.

Wenzel RP et al. Antibiotic Prevention of Acute Exacerbations of COPD. NEJM 2012;367:340-347.

Albert et al, [Azithromycin prevents COPD exacerbations], NEJM 2011.

Ray WA et al, [Azithromycin associated with cardiovascular deaths], NEJM 2012.