ID Consult

Amoxicillin Failure in Strep Throat

Apair of newly detected actions of Group A streptococci may offer clues as to why penicillin and amoxicillin often fail to eradicate streptococcal pharyngitis in children and adults, and why cephalosporins or macrolides may be better treatment options.

Penicillin failure in eradicating strep throat has been increasingly documented beginning in the 1980s, rising from just 5% in the 1950s to approximately 35% today. My colleague Dr. Janet R. Casey and I have published a series of articles over the years documenting this phenomenon, as have other researchers worldwide. In 2004, Dr. Casey and I conducted two separate meta-analyses demonstrating the clear superiority of cephalosporins—mainly azithromycin and clarithromycin—over penicillin in treating strep throat, both in children (Pediatrics 2004;113:866–82) and adults (Clin. Infect. Dis. 2004;38:1526–34).

Traditional antibiotic resistance does not appear to be the reason. In fact, there is absolutely no in vitro resistance of group A streptococci (GAS) to penicillin or amoxicillin (or cephalosporins).

Some people have theorized that the inadvertent inclusion of strep carriers in many of the studies explains the eradication failure with penicillin, but that has never made sense to me. Why would such inclusion have increased since the 1950s? In fact, the opposite has happened: Efforts have been made in more recent studies to exclude carriers. Our meta-analyses showed that the failure rate remained pretty much rocksolid at 35%, even when we looked at only the 12 most recent studies that did a fantastic job of excluding carriers.

I think the answer lies in considering mechanisms of “resistance” beyond those involving a particular bacterium resisting a particular drug in a test tube. There are two newly appreciated phenomena that I categorize as “in vivo resistance” because they result from a fundamental interaction with the host and can't be measured by a lab test.

About 5 years ago, several researchers published studies showing that streptococci were capable of entering and living inside the epithelial cells of the upper respiratory tract, a process dubbed “internalization.” Prior to that time, GAS was thought to be a strictly extracellular pathogen.

Then, just last year, Dr. Edward L. Kaplan of the University of Minnesota and his associates showed for the first time that internalization was a likely explanation for the treatment failure of penicillin and amoxicillin, which are incapable of penetrating the cell wall. In contrast, erythromycin and azithromycin, which enter cells easily, were the most effective at GAS eradication while the first-generation cephalosporin cephalothin and clindamycin had intermediate efficacy (Clin. Infect. Dis. 2006;43:1398–406).

A second mechanism of in vivo resistance, known as “coaggregation,” was first described in 2004 by Dr. Eric R. LaFontaine and his associates at the University of Toledo (Ohio). They found that the pathogens Streptococcus pyogenes and Moraxella catarrhalis colonize overlapping regions of the human nasopharynx, and that M. catarrhalis can dramatically increase the adherence of S. pyogenes to human epithelial cells (Infect. Immun. 2004;72:6689–93).

Subsequent to that paper, my laboratory group completed a study in which we confirmed Dr. LaFontaine's finding regarding coaggregation of S. pyogenes with M. catarrhalis, and also for the first time demonstrated the same phenomenon with S. pyogenes and Haemophilus influenzae.

With coaggregation, the GAS bacteria acquire the ability to attach themselves to the M. catarrhalis or H. influenzae that already colonize the throat at various times during childhood and adulthood (H. influenzae is about 5–6 times more common than M. catarrhalis). While these two organisms have long been known to become pathogenic in certain settings, we are now realizing that they also may serve to enhance the attachment of GAS to throat cells.

Indeed, coaggregation is a likely explanation for why some children—such as those more frequently colonized with M. catarrhalis or H. influenzae—are more vulnerable to strep throat than others. Moreover, it also explains our finding that an individual who is colonized with one of those two organisms and then is exposed to streptococcus has a 10-fold increased likelihood of developing strep throat.

It also helps explain the differential treatment effect of penicillin/amoxicillin versus other antibiotic classes. Both M. catarrhalis and H. influenzae produce beta-lactamase, which inactivates penicillin and amoxicillin. Cephalosporins, on the other hand, have greater activity in the presence of beta-lactamase, while macrolides such as azithromycin are completely immune to the enzyme.

Thus, it appears that beta-lactamase production, a well-described mechanism for in vitro antimicrobial resistance, is being enhanced by this additional coaggregation mechanism.

Based on this new information, my practice now uses cephalosporins as first-line treatment for strep throat. Cephalexin is a good option because it's generic, and it's first-generation, so it is not as broad-spectrum. We prescribe it twice daily for 10 days.

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