Although intuitively we always worry about creating drug resistance when using antibiotics, there is a surprising lack of well done studies that show a clear causal effect of antibiotic use on the development of subsequent drug resistance. A recent study in Lancet may however lead us to re-evaluate our use of macrolides in everyday practice.
Azithromycin and clarithromycin are two of the most commonly used macrolides for treating respiratory infections. Azithromycin has a long half-life, making it convenient for once daily dosing, while clarithromycin has a shorter half-life and needs to be given twice daily for 7 days. Theoretically, shorter drug exposure decreases the chance of developing resistance, and the higher tissue persistence of azithromycin should therefore confer more resistance. However, studies have shown conflicting results. In addition, we know that two different genes are largely responsible for resistance to macrolides in streptococci. The mef gene mediates active drug efflux and confers low to moderate resistance against macrolides. The erm(B) gene confers a high degree of resistance by changing the macrolide binding site on the bacterial ribosome.
This randomized, double-blind, placebo-controlled study compared the effects of a single course of azithromycin versus clarithromycin on the oral streptococcal flora of healthy volunteers. Pharyngeal swabs were obtained before and after the administration of the study treatment through 180 days (although subjects were not paid after day 42 and a significant withdrawal from the study occurred after this time). The primary outcome was a change in proportion of macrolide-resistant streptococci. Secondary outcomes involved genetic analysis of macrolide-resistant streptococci. Oral streptococcal flora harbors the same macrolide resistance genes seen in pathogenic streptococci; therefore, the results obtained from healthy subjects should be applicable to the patients we treat for streptococcal respiratory infections.
The results showed that a single course of either antibiotic caused an increase in macrolide-resistant streptococci compared with placebo, and this effect lasted for the entire duration of the study. Because the study was stopped after 180 days, it is not known whether this effect lasts even longer. In addition, azithromycin selected more resistant organisms in the early post-therapy phases, whereas clarithromycin selected for the higher resistance-conferring erm(B) gene.
These findings can easily be related to our own clinical experience. Think about how often we prescribe azithromycin along with nebulizers and steroids to patients admitted or seen in clinic for an asthma or COPD exacerbation. Some patients, over a 180-day period, may be given 2 or 3 courses of this antibiotic. Several questions arise: Do macrolides lose efficacy in the individual patient when administered more than once over a 6 month period? Should we be more discerning in our decision to prescribe antibiotics without clear evidence that bacterial respiratory infection is present? And, if we must administer an antibiotic, should we be alternating between antibiotic classes to treat frequent respiratory infections? At the very least, this study suggests that we should be asking our patients about their recent use of macrolides. A history of recent antibiotic use may alter our treatment decisions, improving individual outcomes and lessening resistance to these important antibiotics. Finally, when making the decision to give macrolides, we have to remember that the resistant streptococci that will inevitably arise in the individual will ultimately affect the rest of the hospital ward, clinic and the community at large.
Malhotra-Kumar S et al. “Effect of azithromycin and clarithromycin therapy on pharyngeal carriage of macrolide-resistant streptococci in healthy volunteers: a randomised, double-blind, placebo-controlled study.” Lancet 2007; 369: 482-490. http://sfx.med.nyu.edu/sfxlcl3?genre=article&id=pmid:17292768&_char_set=utf8