Does the Overuse of Macrolides Lead to Antibiotic Resistance?

March 12, 2007

MortarCommentary By: Danise Schiliro, PGY-3

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

One Response to Does the Overuse of Macrolides Lead to Antibiotic Resistance?

  1. Neal Steigbigel on March 21, 2007 at 1:29 pm

    Re: the very nice note in the blog on bacterial resistance to the macrolides.
    The evidence that the emergence of antibiotic usage is related to the amount used as medication for man and animals is overwhelming and applies to the macrolides as well.That data on the emergnce of antibiotic resistance as related to the amount used medically has been known and growing since the 1950′s when it was first vigorously demonstated and championed by Maxwell Finland, M.D. at Harvard and the Boston City Hospital. Finland was one of the major “fathers” of the modern discipline of infectious diseases.
    It has been shown over ensuing years that the emergence of antibiotic resistance (encoded by genes for resistance mechanisms) is the result of the selective pressure by antibiotic use on microbial populations that harbor minor populations that already carry those genes, thereby enriching (by elimination of the sensitive strains) the resistant strains. Antibiotics themselves are rarely mutagenic; the flouroquinolones are exceptional in that they may occasionally be mutagenic.The antibiotic resistance genes seemed to have originated (probably by spontaneous mutation) in microbial strains that produced the antibiotic in question and therefore needed the resistance mechanism to survive its own armament for competition in the environment. Those resistance genes then jumped across to other species, gaining a foothold as a minor population, then later to be enriched by the selective pressure of medicinal use in man or animals. When the resistance is enriched by selective pressure within one microbial species it is called “clonal” or “vertical” expansion of the resistance. When the resistance gene jumps across species (by conjugation, transduction, transformation or transposition) and then is expanded by selective pressure that is called “polyclonal “or “horizontal “expansion.
    Regarding the emergence of bacterial resistance to the macrolides as related to medical use, which is substantial, the chapter on the “Macrolides and Clindamycin” that I have been writing for many years in the editions of the Mandell’s textbook, “Principles and Practice of Infectious Diseases” (last edition 2005, that chapter authored by Sumathi Sivapalasingam, M.D., and me; Sumathi is Assistant Professor of Medicine here at NYUSOM in our Div of ID ) details that, especially for S. pneumo, Group A strept and S. aureus.
    Neal H. Steigbigel, M.D.

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