Macrolide antibiotics reduce exacerbations but increase antimicrobial resistance in non-cystic fibrosis bronchiectasis

The macrolide antibiotics erythromycin and azithromycin each appear to reduce exacerbations in patients with non-cystic fibrosis bronchiectasis but may also lead to increased antimicrobial resistance, according to two new studies in the March 27 Journal of the American Medical Association.

The Bronchiectasis and Low-dose Erythromycin Study (BLESS) randomly assigned 117 patients with non-cystic fibrosis bronchiectasis and a history of at least two infective exacerbations in the previous year to receive 400 mg of erythromycin twice daily (n=59) or placebo (n=58) for one year. At the study's end, protocol-defined pulmonary exacerbations were significantly lower in the erythromycin group than in the placebo group (mean, 1.29 vs. 1.97 per patient per year; incidence rate ratio, 0.57; P=0.003), as were 24-hour sputum production and measured decline in lung function. However, the proportion of macrolide-resistant oropharyngeal streptococci was also higher among patients taking erythromycin (median change, 27.7% vs. 0.04%; P<0.001).

In the Bronchiectasis and Long-term Azithromycin Treatment (BAT) study, 83 patients with non-cystic fibrosis bronchiectasis and at least three lower respiratory tract infections in the previous year were randomly assigned to receive 250 mg of azithromycin daily (n=43) or placebo (n=40) for one year. The analysis was modified intention-to-treat. At the end of the study, the azithromycin group had 0 mean exacerbations (interquartile range, 0 to 1) while the placebo group had 2 (interquartile range, 1 to 3) (P<0.001). Change in forced expiratory volume in the first second of expiration measured in three-month intervals increased in the azithromycin group but decreased in the placebo group. Forty percent of the azithromycin group and 5% of the placebo group reported gastrointestinal adverse events; no patients discontinued the study because of them. The macrolide resistance rate was 88% in the azithromycin group versus 26% in the placebo group.

The authors of an accompanying editorial noted that few previous randomized, controlled trials have examined macrolide treatment for non-cystic fibrosis bronchiectasis and said the current studies help provide “a good evidence base for an effective therapy for bronchiectasis.” However, they pointed out that both trials were limited because they focused only on antibiotic resistance in known pathogens and didn't use quantitative cultures to determine whether the decreased exacerbation rates in the macrolide groups were due to decreased total sputum bacterial load or decreased density in individual species.

The editorialists said that based on these trials, erythromycin and azithromycin both effectively reduce exacerbations in patients with bronchiectasis and yield similar rates of antibiotic resistance. “Macrolides offer an important and now evidence-based treatment for bronchiectasis and, if used carefully, may help to improve [quality of life] and reduce health care costs for patients with bronchiectasis,” they wrote.

They also pointed out, however, that macrolides can adversely affect hearing and liver function and can prolong the QTc interval. Physicians should consider macrolide therapy only in patients with non-cystic fibrosis bronchiectasis who have had at least two exacerbations in the previous year, they said. They recommended obtaining a sputum culture, performing an electrocardiogram, and testing hearing and liver function before starting treatment and periodically thereafter, and withholding or discontinuing macrolide therapy in patients with abnormal results. They also recommended careful monitoring of antibiotic resistance to common respiratory pathogens in individuals and community-wide.