The Problem
A 57-year-old male with a history of chronic obstructive pulmonary disease (forced expiratory volume in 1 second, 26%) and history of alcoholism presents to you for shortness of breath and increasing productive cough. He is currently on budesonide/formoterol, tiotropium, and albuterol inhalers as well as albuterol/ipratropium nebulizers. He has had four exacerbations this year for which you have treated with doxycycline and steroids. His alcoholism is in remission, but he has a 60 pack-year history of cigarette smoking and currently smokes one pack daily. On examination, his oxygen saturations are 90%, he is afebrile, and he has diffuse coarse airway sounds and expiratory wheezes. You prescribe doxycycline and a steroid taper with refills. You wonder if daily antibiotics would prevent future exacerbations.
The Question
In patients with severe COPD, does the use of daily antibiotics decrease the frequency of COPD exacerbations?
The Search
You open PubMed, enter "COPD" and "antibiotics" and limit to "randomized control trial."
The Evidence
"Azithromycin for Prevention of Exacerbations of COPD" (N. Engl. J. Med.2011;365:689-98).
• Design and Setting: Randomized, placebo-controlled clinical trial conducted at 17 sites that are associated with 12 academic centers in the United States.
• Participants: Potential subjects had to be at least age 40 years; have had a clinical diagnosis of COPD, a smoking history of at least 10 pack-years, an FEV1/FVC ratio of less than 70% and a post-bronchodilator response of less than 80%; be using continuous supplemental oxygen or had received systemic glucocorticoids within the previous year; had visited an emergency room or had been hospitalized for an acute exacerbation of COPD; and had not had an acute exacerbation of COPD for at least 4 weeks before enrollment. Potential subjects were excluded if they had asthma; had a corrected QT (QTc) interval greater than 450 msec; used medications that prolong QTc interval or were associated with torsades de pointes (except amiodarone); or had hearing impairment documented by audiometric testing.
• Intervention: Subjects were randomized to receive azithromycin, 250 mg by mouth once per day; or an identical-appearing placebo. Medication or placebo was given for 1 year.
• Outcomes: The primary outcome was the time to the first acute exacerbation of COPD. A COPD acute exacerbation was defined as "a complex of respiratory symptoms (increased or new onset) of more than one of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics or systemic steroids." Secondary outcomes included quality of life, nasopharyngeal colonization (i.e., Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus species, and Moraxella species), and hearing changes as measured by audiometry.
• Results: A total of 1,142 subjects were randomized. Of those in the azithromycin arm, 495 (89%) subjects completed the 12-month follow-up, compared with 502 (90%) of those in the control arm. The risk of COPD exacerbations was significantly lower in the azithromycin group (P less than .001). The hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63-0.84; P less than .001). Median time to first exacerbation was longer in the azithromycin group (266 vs. 174 days; P less than .001). The rate of acute COPD exacerbations per patient-year were 1.48 and 1.83 in the azithromycin and placebo groups, respectively (rate ratio; 0.83; 95% CI: 0.72-0.95). The number needed to -treat to prevent one exacerbation was 2.86. No significant differences were observed in quality of life and no differences were observed in the death rate between the two groups. An audiogram-confirmed hearing decrement occurred in 142 of the participants receiving azithromycin (25%), compared with 110 of those receiving placebo (20%) (P = .04). Among subjects who were colonized at baseline, the prevalence of macrolide resistance did not differ between the groups. Azithromycin decreased the rate of colonization, compared with placebo (12% vs. 31%, P less than .001). However, among subjects colonized during the study, the incidence of macrolide resistance was 81% in the azithromycin group and 41% in placebo (P less than .001). Adherence to the study medication was 67% in the azithromycin group and 67% in the placebo group (P = .84).
Our Critique
This was a well-conducted clinical trial, providing insights about a potentially useful intervention for preventing COPD exacerbations among our higher-risk patients. Impressively, azithromycin increased the median time to an exacerbation by almost 100 days. The number needed to treat to prevent one exacerbation was a 2.86. Azithromycin decreased the rate of colonization but increased the likelihood that colonizing bacteria will be macrolide-resistant. The authors suggest that the presence of colonizing bacteria did not increase the likelihood of a COPD exacerbation. Although hearing loss was observed (macrolides are potentially ototoxic), investigators observed that baseline level of hearing returned among 32% of subjects who continued their medication. Patients should be made aware of this risk and monitoring decisions should be made before starting therapy. In the present study, audiometry was performed at baseline, and at 3 and 12 months, or whenever a patient reported worsening hearing or tinnitus.