Two studies published last week highlight how a highly drug-resistant enteric pathogen is challenging clinicians and public health officials.
The studies, which appeared in The Lancet Infectious Diseases, describe an outbreak of different strains of multidrug-resistant (MDR) Shigella in Washington state and the emergence of an extensively drug-resistant (XDR) strain in England. Both studies suggest that drug-resistant Shigella presents a growing public health challenge that demands a coordinated response.
An outbreak in two at-risk groups
The first study, led by researchers with the University of Washington (UW) School of Medicine, describes an ongoing outbreak of shigellosis that began in Seattle and King County, Washington, in 2017 and accelerated after 2020.
Shigellosis is a gastrointestinal condition caused by one of the four species of Shigella bacteria: Shigella sonnei, S flexneri, S boydii, or S dysenteriae. Symptoms range from mild diarrhea to severe dysentery. Most cases are self-limiting, but antibiotics are frequently used to treat symptoms and reduce shedding, which can help limit transmission.
While shigellosis is commonly associated with exposure to food or water that has been contaminated by human feces and is known to spread in settings with overcrowding and poor sanitation, oral and anal sex has become a major route of transmission, particularly among men who have sex with men (MSM). In recent years, there have been a growing number of reports of strains of MDR and XDR Shigella spreading among networks of MSM.
Ferric Fang, MD, a senior author of the study and director of the clinical microbiology lab at Harborview Medical Center in Seattle, said clinicians at the hospital were well aware that there was transmission of drug-resistant Shigella among MSM in the area. But in 2020 they started to notice an increase in drug-resistant shigellosis cases in Seattle's homeless population, driven by a lack of sanitation—an issue that became worse when city officials closed public restrooms because of the COVID-19 pandemic.
"Especially during the pandemic, a lot of public facilities were closed that homeless people were used to using," Fang told CIDRAP News.
Over the course of the outbreak, it also became clear that different patterns of antibiotic resistance were emerging in the two populations, making treatment more challenging. The strains in the homeless population were largely susceptible to trimethoprim/sulfamethoxazole and azithromycin and resistant to ciprofloxacin, while the strains in MSM were resistant to trimethoprim/sulfamethoxazole and azithromycin but susceptible to ciprofloxacin. This led Fang and his colleagues to institute rapid diagnostic testing to quickly identify patients with shigellosis and develop a treatment algorithm based on the different risk factors in the two groups.
"We thought that this would be a convenient way to guide therapy," Fang said. "So we worked with our infectious disease clinicians to draw up a guideline, which was then disseminated to the clinics in the emergency department."
From MSM to homeless populations
The study provides a clearer picture of the patterns that emerged over the outbreak, and how those guidelines helped.
In their examination of isolates and other data from 171 patients treated at Harbor View Medical Center and UW Medical Center from May 1, 2017, to Feb 28, 2022, Fang and his colleagues found that 46% were MSM and 51% were people experiencing homelessness (PEH). Fifty-six patients were admitted to the hospital and 8 to an intensive care unit. Fifty-one percent of the isolates were MDR.
This is very much an emerging threat and something where our public health tools and therapeutic tools have significant limitations.
Whole-genome sequencing of the isolates revealed that the outbreak was primarily driven by the parallel emergence of multiple distinct lineages of S flexneri and S sonnei, both of which were first observed in the MSM population before spilling over into the homeless population. Of the 171 patients studied, 11 identified as both MSM and PEH.
"It's just an illustration of how these populations are fluid and they have interactions with each other," Fang said.
What the study also showed is that the use of rapid diagnostic tests and the development of risk-based treatment guidelines paid off. Data from 143 patients who received antibiotics showed that, despite high levels of multidrug resistance, 70% received appropriate antibiotic therapy. That was particularly important for homeless patients, who are frequently lost to follow-up.
"We figured out that our best bet was doing a rapid test with the patient still in the emergency room and then using our susceptibility patterns to target intervention while the patient was still there, because it was going to be our one shot at doing something for them," Fang said.
In addition, the genomic analysis linked the Seattle outbreaks to drug-resistant Shigella in other parts of the world. One of the S flexneri isolates from the Seattle outbreak was associated with an MDR strain from China, while the S sonnei isolates showed similarity to a strain driving a current outbreak of MDR Shigella in England.
"Both outbreaks showed epidemiological and phylogenomic similarity to strains previously reported in other countries, consistent with international dissemination of multidrug-resistant Shigella clones as a cause of resurgent infection," Fang and his co-authors wrote.
Two XDR strains in England
The outbreak in England provides the backdrop for the second study. Since 2009, England has seen a successive wave of sexually transmitted Shigella outbreaks in MSM driven by both MDR strains of S flexneri and S sonnei.
In January 2022, the UK Health Security Agency (HSA) reported an increase in XDR S sonnei infections with resistance to all but two antibiotic classes. Similar increases have been reported in other parts of Europe.
The emergence and the spread of XDR S sonnei among MSM in England motivated researchers with the HSA and the University of Liverpool to examine national surveillance data to see if an XDR strain of S flexneri might also be emerging. They were concerned about this prospect because XDR S sonnei harbors a mobile multidrug-resistance gene (blaCTX-M-27) that could potentially be shared with other Shigella species through horizontal transfer.
From Sep 1, 2015, to Jun 12, 2022, they identified 37 S flexneri isolates that harbored the blaCTX-M-27 gene, 26 of which were identified from September 2021 onward. Of those 26 isolates, 8 were XDR and 18 were MDR. All the cases occurred in adult men, and of the 13 patients who filled out questionnaires, 10 (77%) identified as gay men and 7 (54%) reported sexual contact in the weeks preceding symptom onset. Possible treatment failures were reported in 2 patients.
When the researchers analyzed the plasmids—the mobile pieces of DNA that carry antibiotic resistance genes—from the S flexneri isolates, they found "high similarity" to the plasmids characterized during the XDR S sonnei outbreak.
The study authors say their findings suggest links between the increase in the two XDR Shigella strains over the same period.
"The temporal correlation and similar epidemiological profile of the situations is suggestive of transmission of both strains of Shigella spp within overlapping sexual networks," they wrote.
Limiting the spread
Taken together, the two studies underscore the threat that drug-resistant Shigella presents both to individuals and the wider public. The UK study and reports from around the world highlight the rapid spread of highly resistant Shigella strains that complicate treatment among networks of MSM engaged in risky sexual behavior.
"With the potential for novel sexually transmitted Shigella spp. strains to disseminate internationally, a globally coordinated approach is needed to deliver effective public health interventions to limit the spread of this highly drug resistant pathogen," the UK authors wrote.
And as the Seattle outbreak shows, rising inequality and homelessness in cities are creating another population, with a different set of risk factors, that's vulnerable to this highly infectious pathogen.
Fang said they're both challenging public health problems that will require different strategies from public health officials. But he's concerned that it might not take much for Shigella infections to spread beyond these populations.
"You can't really expect an infectious disease to remain confined to a specific at-risk population," he said. "This is very much an emerging threat and something where our public health tools and therapeutic tools have significant limitations."
