New research by an international team of scientists has found strains of group A Streptococcus that are less susceptible to penicillin and other beta-lactam antibiotics, a finding they say is both surprising and worrisome.
The research, published this week in the Journal of Clinical Microbiology, identified 137 strains of Streptococcus pyogenes with mutations to a penicillin-binding-protein associated with decreased susceptibility to multiple beta-lactams. The analysis further found that the mutations appear to be geographically widespread, and that strains carrying the mutations have the ability to spread between patients.
Group A Streptococcus is most known for its ability to cause acute pharyngitis, also known as strep throat, which affects an estimated 600 million people a year globally. But it can also cause more serious and deadly infections like acute rheumatic fever (which can lead to rheumatic heart disease), scarlet fever, sepsis, and necrotizing fasciitis (flesh-eating disease), and is among the top 10 causes of death from infectious diseases.
Group A Streptococcus infections are typically treated with beta-lactam antibiotics, as they have been for decades. But the study authors warn the findings suggest clinicians may no longer be able to assume beta-lactams will work.
"This is really an important wake-up call that…the party may soon be over," said first study author James Musser, MD, PhD, chair of the department of pathology and genomic medicine at Houston Methodist Hospital. "This may be some important first steps to developing some higher-level resistance."
Universal susceptibility no longer a given
The findings are surprising, Musser said, because, for 70 years, microbiologists and clinicians have been taught that group A Streptococcus is universally susceptible to beta-lactam antibiotics. But in October 2019, a study came out identifying two clonally related and epidemiologically linked S pyogenes strains with mutations in the pbp2x gene and reduced susceptibility to ampicillin, amoxicillin, and cefotaxime.
That study prompted Musser and scientists from Sweden, Norway, Finland, Iceland, and Scotland to analyze a library of 7,025 S pyogenes genome sequences to see if they could find other strains with similar mutations. They focused on isolates from sequence types emm1, emm28, and emm89—which are the most common causes of strep throat and serious invasive group A Streptoccus infections in the United States and elsewhere.
"They're bad actors, numerically speaking, in human infections," Musser said.
Their analysis found 137 S pyogenes strains—roughly 2% of the strains analyzed—with mutations in the pbpx2 gene that alter the amino acid sequence in the bacteria, resulting in the replacement of one amino acid for another. These mutations likely arose from exposure to beta-lactam antibiotics.
"Although 2% sounds relatively low, the surprise, frankly, is that the number of mutations was so high, and that they [the isolates] were geographically widespread, not only in the United States but in Canada, the Nordic countries, and Scotland," Musser said.
When the researchers performed antimicrobial susceptibility testing on these isolates, testing them against penicillin, ampicillin, and four other beta-lactam antibiotics, they found reduced susceptibility compared with wild-type strains that lack the pbp2x mutation. They also found 16 instances in which strains of the same emm type had an identical mutation. And phylogenetic analysis of those strains revealed that they were clonally related—a finding Musser said suggests the mutations don't prohibit the organism from spreading among people and causing invasive infections.
"They don't cause what we call a detrimental fitness effect, so like the normal group A strep, these strains can spread quite well from person to person," he explained.
But the immediate clinical impact of these mutations, at this point, is unclear. While the mutation-harboring strains were less susceptible to beta-lactam antibiotics, they weren't resistant.
"They do not fulfill the laboratory definition of true resistance to these agents yet," Musser said. Moreover, he added, he and his colleagues don't know what kind of effect these mutation-harboring strains have on patients. But he's concerned about what might happen if some of the more contagious group A Streptococcus strains acquire the resistance mutations.
"If you had high-level resistance in a 'super-spreader,' we would have tremendous problems," he said.
Routine surveillance urged
Musser noted that since the group made this discovery, his lab has started doing routine surveillance for decreased susceptibility to beta-lactams in group A Streptococcus—something that most clinical microbiology labs don't do because of the dogma that beta-lactam susceptibility isn't an issue with the organism. And his co-authors, many of whom are diagnostic lab directors, are doing the same.
"We need to be much more vigilant in this arena," he said, adding that surveillance should be done not just on isolates from severe infections, but also on strep throat isolates. "All the strains we looked at in the study were from serious infections. We don't know what the extent of the problem is in the more common pharyngitis situation."
He also said the findings ultimately underscore the need for a group A Streptococcus vaccine, something that scientists have been working on, in fits and starts, for nearly 100 years. Those efforts have been hampered by the large variety of group A Streptococcus strains.
"We desperately need an efficacious vaccine against group A Streptococcus, because at the end of the day, that's going to be the real solution," he said. "It's the only reasonable long-term approach to controlling this organism."
See also:
Jan 29 J Clin Microbiol abstract
