Capable of causing invasive infections, Streptococcus pyogenes (Group A strep) has been susceptible to beta-lactam antibiotics for more than a half century.
Ominously, researchers investigating an upsurge of Group A strep cases in Seattle found a mutated strain that confers resistance to ampicillin and other beta-lactam drugs.
“Our results suggest the potential for emergence of clinically significant beta-lactam resistance in Group A streptococcus,” Kirsten Vannice, PhD, MHS, said recently in Atlanta at the CDC Epidemic Intelligence Service (EIS) conference.
Commonly associated with strep throat, S. pyogenes also can cause invasive disease in vulnerable populations.
“Group A strep is not a benign disease, with severe manifestations like sepsis and necrotizing fasciitis,” Vannice said. “Fortunately, severe morbidity and mortality from Group A strep is preventable with widely available antibiotics.”
Penicillin and amoxicillin are the first-line antibiotics used, with clindamycin often added for invasive disease to suppress bacterial toxins.
“While resistance has been seen in Group A strep for clindamycin and other antibiotics, [it] has remained susceptible for beta-lactams for over 50 years,” she says.
Other bacteria that are resistant to beta-lactams like penicillin and ampicillin have acquired a way to protect the cell walls these antibiotics typically bind to and break down.
“An intact cell wall is essential for cell survival,” Vannice said. “When a beta-lactam binds to the cell wall, synthesis is inhibited, and [this] leads to bacterial cell death.”
After repeated exposures to antibiotics due to recurrent infections, a medical aide (Patient A) at a homeless shelter and a homeless person (Patient E) were infected with a novel strain of Group A strep.1 Genomic analysis showed a “first-step mutation” that conferred resistance to ampicillin.
However, it could not be determined whether one of the cases transmitted to the other or whether both were infected by another source.
“The mutation could have developed in one of those patients or it could have developed elsewhere and then was transmitted within the community,” Vannice says. “What we do know from this cluster is that this mutation developed within a very short time frame, within the last one or two years.”
The old axiom of “use it and lose it” speaks to the historical trend of antibiotic use eventually selecting out bacterial resistance that renders the drug ineffective.
However, the case was unusual in that it represents the first report of emerging Group A strep resistance to the time-honored beta-lactam class of antibiotics.
The mutation was found when investigators were contacted about an upsurge in infections with Group A strep at an area hospital.
They conducted whole-genome sequencing and antimicrobial susceptibility testing on a convenience sample of strep isolates recovered from sterile sites or wounds of patients at Hospital A during June 2017 to March 2018.
Fifty-two of the 267 isolates were genetically sequenced and subtyped, revealing two “nearly identical isolates” identified as emm43.4, she said. These isolates had a point mutation predictive of resistance.
“This mutation was located within the pbp2x gene at the same site that is known to reduce beta-lactam susceptibility in other strep species, including S. pneumoniae,” she said.
Indeed, the isolates were eight times higher than the minimum inhibitory concentration (MIC) susceptibility breakpoint for ampicillin and two times higher for cefotaxime compared to control strains without the mutation.
Both patients had received multiple courses of beta-lactams in the preceding three years due to recurrent strep infections.
“Patient A repeatedly received beta-lactam and other antibiotics courses, including ampicillin,” she says. “Patient E had three culture-confirmed infections with streptococcal species in 2017 alone.”
An IV drug user, Patient E had a history of wound and skin infections.
“We identified this concerning mutation in two patients whose complex medical histories predisposed them to repeat antibiotics,” she said.
Patient E was treated so often that he was sometimes prescribed antibiotics empirically, and his adherence to completing a course of treatment was unknown.
“These are precisely the kind of situations where we are most concerned about developing antibiotic resistance,” Vannice says. “Our findings suggest that the novel mutation identified in two Group A strep isolates was responsible for reduced ampicillin susceptibility.”
The mutation was more of a warning, as no other similar cases were found and there were no reports of treatment failure and waning immunity.
“We need to reduce infections such as Group A strep among people experiencing homelessness within the broader goal of reducing homelessness itself,” she said.
“This includes educating individuals at high risk about ways to prevent disease transmission, ensuring easy access to wound care, and, most importantly, improving the conditions that lead to skin breakdown and susceptibility to pathogens.”
Fortunately, the resistance mechanism revealed by whole genome analysis is not on an S. pyogenes plasmid that could be transmitted to other bacteria.
“This resistance mechanism is a point mutation. So, theoretically, this bacteria developed a slight advantage, and it could proliferate and spread from person to person,” said Jeffrey Duchin, MD, health officer for Seattle and King County. “But it is not a plasmid-borne resistance mechanism, so it won’t be spreading readily from bacteria to bacteria or across species.”
The research had limitations, but it appears there was no transmission within the hospital that prompted the investigation by reporting the increase in cases. Nor was the mutation responsible for the increase. It was serendipitously revealed by the investigation.
“To address antibiotic resistance, we need to be ahead of the bacteria. I think that is the importance of this investigation,” said Denise Cardo, MD, director of the CDC division of healthcare quality promotion.
- Vannice V, Ricaldi J, Nanduri S, et al. Group A Streptococcus Bacteremia Isolates with a Penicillin-Binding Protein 2x Gene Mutation Conferring Reduced Susceptibility to Ampicillin — Seattle, Washington, 2017–2018. CDC EIS Conference. Atlanta, April 29–May 2, 2019.
