The use of azithromycin and clarithromycin clearly raises the proportion of macrolide-resistant organisms in the oral flora for a period of at least 6 months, reported Surbhi Malhotra-Kumar, Ph.D., of the University of Antwerp, Belgium, and associates.
This finding establishes that “macrolide use is the single most important driver of the emergence of macrolide resistance in human beings,” the researchers said.
Many studies in the past have demonstrated a clear relation between antibiotic use and resistance, but to date none of those studies have shown a definite causal effect.
Neither have any studies linked antibiotic exposure within an individual to later resistance in that individual.
Dr. Malhotra-Kumar and associates used subjects' oral commensal streptococcal flora, which harbors the same macrolide resistance genes as pathogenic strep organisms do, as a model to study the effects of azithromycin and clarithromycin exposure on antibiotic resistance.
In their double-blind trial, 224 healthy volunteers were randomly assigned to receive once daily azithromycin for 3 days, twice daily clarithromycin for 7 days, or placebo.
Samples of oral strep flora were then taken from the subjects' tonsils and posterior pharyngeal wall before treatment and on several occasions afterward for up to 180 days.
Immediately after treatment, the mean proportion of macrolide-resistant streptococci dramatically increased in both active treatment groups. This effect was not seen in the placebo group.
Resistance peaked at the fourth day for azithromycin and the eighth day for clarithromycin, the investigators said (Lancet 2007;369:482–90).
The proportion of resistant streptococci remained increased for both drugs through the final follow-up at 6 months, “which emphasises that the commensal flora could serve as a reservoir of resistance for potentially pathogenic bacteria,” they noted.
Although the study was able to reach definitive results after 6 months, a longer follow-up period “would have enabled us to define the time needed for the resistant oral flora to revert to baseline levels,” Dr. Malhotra-Kumar and associates said.
“In view of the consequences of antibiotic use seen here, physicians should take into account the striking ecological side-effects of antibiotics when prescribing such drugs to their patients,” the researchers added.