Effect of azithromycin and clarithromycin therapy on pharyngeal carriage of macrolide-resistant streptococci in healthy volunteers: a randomised, double-blind, placebo-controlled study.

BACKGROUND Resistance to antibiotics is a major public-health problem, and studies that link antibiotic use and resistance have shown an association but not a causal effect. We used the macrolides azithromycin and clarithromycin to investigate the direct effect of antibiotic exposure on resistance in the oral streptococcal flora of healthy volunteers. METHODS Volunteers were treated with azithromycin (n=74), clarithromycin (74), or placebo (76) in a randomised, double-blind trial. Pharyngeal swabs were obtained before and after administration of study treatment through 180 days. The proportion of streptococci that were macrolide resistant was assessed and the molecular basis of any change in resistance investigated. Analyses were done on an intent-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00354952. FINDINGS The number of dropouts (n=20) was much the same in all groups until day 42; dropouts increased substantially at day 180 (105). Both macrolides significantly increased the proportion of macrolide-resistant streptococci compared with the placebo at all points studied, peaking at day 8 in the clarithromycin group (mean increase 50.0%, 95% CI 41.7-58.2; p<0.0001) and at day 4 in the azithromycin group (53.4%, 43.4-63.5; p<0.0001). The proportion of macrolide-resistant streptococci was higher after azithromycin treatment than after clarithromycin use, with the largest difference between the two groups at day 28 (17.4% difference, 9.2-25.6; p<0.0001). Use of clarithromycin, but not of azithromycin, selected for the erm(B) gene, which confers high-level macrolide resistance. INTERPRETATION This study shows that, notwithstanding the different outcomes of resistance selection, macrolide use is the single most important driver of the emergence of macrolide resistance in vivo. Physicians prescribing antibiotics should take into account the striking ecological side-effects of such antibiotics.