Macrolides and bronchiectasis: clinical benefit with a resistance price.

J. Stuart Elborn, MD Michael M. Tunney, PhD BRONCHIECTASIS IS A COMMON CONDITION. ALTHOUGH the true prevalence is unknown, the prevalence in the United States has been estimated to range from 4 per 100 000 in young adults to nearly 300 per 100 000 in persons75yearsandolder.Althoughbronchiectasisisapathological description, it describes a group of conditions of somewhat diverse etiology that result in impairment of innate immunityandchronic infection,whichinturnresult inbronchial damageanddilationof theairways. Ingeneral,whenreferring to the condition, cystic fibrosis (CF) is excluded for practical rather than scientific reasons and the condition is frequently identified as non–cystic fibrosis bronchiectasis. Adultswithbronchiectasisoftenhavechroniccoughandsputum production and frequently develop pulmonary exacerbations driven by infection. The cause of these events in bronchiectasis is not entirely clear, but they have an adverse effect on lung function, morbidity, and health-related quality of life (QOL). Treatment of patients with bronchiectasis is aimed atoptimizing lung functionandreducing the frequencyofpulmonary exacerbations. However, treatment approaches have beenextrapolatedfromotherrespiratorydiseasessuchaschronic obstructive pulmonary disease (COPD) and CF, because few randomizedcontrolledtrialshavebeenconductedtodetermine the specific treatment of bronchiectasis. In this issue of JAMA, the results of the BLESS (Bronchiectasis and Low-dose Erythromycin Study) and BAT (Bronchiectasis and Long-term Azithromycin Treatment) trials, providerobustevidenceforabeneficialeffectoflong-termmacrolide maintenancetherapyinpatientswithbronchiectasis.Giventhe paucityofevidence for treatments inbronchiectasis, theresults of these studies and the recently published EMBRACE trial arewelcome,because theyprovideagoodevidencebase foran effective therapy for bronchiectasis. In the BLESS trial, 117 patients with a diagnosis of bronchiectasiswere randomlyassigned to receiveerythromycin(400 mg) twice daily or placebo. In the BAT trial, 83 patients with bronchiectasis were randomly assigned to receive azithromycin (250 mg) daily or placebo. Patients recruited to the trials had experienced at least 2 (BLESS) or 3 (BAT) infective exacerbations in the year prior to study entry. Compared with placebo, the number of pulmonary exacerbations was significantly reduced by erythromycin in the BLESS trial (event rate, 1.29 vs 1.97; incidence rate ratio, 0.57 [95% CI, 0.42-0.77]; P=.003) and by azithromycin in the BAT trial (median number of exacerbations, 0 [interquartile range, 0-1] vs 2 [interquartile range, 1-3]; P .001) at the end of the 12-month treatment period. Furthermore, both macrolides were superior to placebo with respect to improving lung function, and azithromycin also demonstrated a significant improvement in disease symptoms and QOL. The results of these 2 studies confirm the results of the recently published EMBRACE trial, which reported a similar significant reduction in exacerbation frequency in patients who received azithromycin (500 mg) 3 times weekly for 6 months but no effect on lung function or QOL. A similar decrease in exacerbation frequency has also been reported for patients with COPD who received azithromycin (250 mg) daily. However, patients in the azithromycin group in the EMBRACE trial were more likely to have hearing decrements than those in the placebo group. A major concern with the use of long-term maintenance antibiotics in treatment of respiratory disease is the emergence of new pulmonary pathogens and increased antimicrobial resistance among the airway microbiota. In both the BLESS and the BAT studies, extensive culture microbiology and antimicrobial sensitivity testing were performed to address these issues. There was no difference in microbiological profile between macrolideand placebo-treated patients at baseline and after 1 year of treatment, suggesting that macrolide treatment did not result in the emergence of new pathogens. However, erythromycin significantly increased the proportion of macrolide-resistant commensal oropharyngeal streptococci, and azithromycin significantly increased macrolide resistance among respiratory pathogens including Haemophilus influenzae, Staphylococcus aureus, and Moraxella catarrhalis. These findings are consistent with previous data from studies involvingpatientswithCOPD andpatientswithCF linking long-termmacrolideexposurewithsignificantly increased resistanceamongrespiratorypathogensandoral flora.Furthermore,Malhotra-Kumaretal demonstrated thatasingle3-day course of azithromycin increases macrolide resistance among the oral streptococcal flora from healthy volunteers, with this effect lasting formore than180days.Thesestudiescollectively suggest that the commensal airway microbiota could act as a reservoirofresistanceforpotentiallypathogenicbacteria.Afur-