The international spread of drug-resistant Shigella sonnei

By Neha MathurApr 12 2023Reviewed by Lily Ramsey, LLM

In a recent study published in the Nature Communications Journal, researchers examined the international dissemination of the outbreak of extensively drug-resistant Shigella sonnei (S. sonnei) strain transmitted via men who have sex with men (MSM) in the United Kingdom (UK).

Study: The evolution and international spread of extensively drug resistant Shigella sonnei. Image Credit: TatianaShepeleva/Shutterstock.com

Background

S. sonnei, the causal agent of shigellosis, a gastrointestinal (GI) infection, exhibited multidrug resistance (MDR) in the 1960s.

Since it causes high levels of morbidity and mortality in lower to middle-income countries (LMIC), the World Health Organisation (WHO) recommends ciprofloxacin (an antibiotic) for empirical treatment of shigellosis.

After S. sonnei acquired resistance to ciprofloxacin, the WHO raised the urgency for new antibiotics against this microbe.

XDR S. sonnei strains resist all commonly recommended empiric and alternative antibiotics, e.g., first-line antimicrobials, such as ciprofloxacin, azithromycin, extended-spectrum β-lactam antibiotics, such as ceftriaxone, trimethoprim-sulfamethoxazole, and ampicillin. This subtype previously caused periodic outbreaks in some countries but did not spread widely like its MDR predecessors.

From 2015 to 2019, when the coronavirus disease 2019 (COVID-19) pandemic began, S. sonnei was resistant to both azithromycin and ciprofloxacin transmitted via MSM in the UK. During the pandemic, its case numbers dramatically declined. However, S. sonnei resurged in late 2021 to cause an outbreak that likely involved multiple countries.

About the study

In the present study, researchers used genomic epidemiology to study the evolutionary trajectory of S. sonnei and the foundation of its XDR genotype.

In addition, they explored the extent of dissemination of representatives of all S. sonnei subclades, including those assigned a single nucleotide polymorphism (SNP) address by the United Kingdom Health Security Agency (UKHSA), across UK, France, Belgium, Australia, and the United States of America (USA).

The lineage with SNP address 1.1.1.1.377 became XDR, and the researchers examined the outbreak at the 10-SNP threshold. For consistency with the prior report, they referred to the 1.1.1.1.377 SNP linkage cluster as t10.377.

Results

The researchers analyzed 3,304 isolates from five countries, and their genomic epidemiological analyses uncovered a global connection for the recent UK XDR outbreak.

Analysis of eight isolates from the UK revealed that all carried an identical plasmid with the bla_CTX-M-27 gene called p893816. Isolates from France and Australia also matched this plasmid from the UK.

Recently, a study showed that this plasmid inhibited the host SOS response to very low inhibitory concentrations of ciprofloxacin. While p893816 was present in most BAPS 5 isolates, its 2018 ancestor carrying a low-fitness cost resistance plasmid was found previously in an S. flexneri 3a isolate from Australia.

It seems likely that this plasmid will continue to spread via horizontal gene transfer (HGT) to other microbial species and Shigella serotypes among MSMs.

Of the 2,895 S. sonnei isolates analyzed in this study, the t10.377 cluster constituted 483 S. sonnei isolates. The team analyzed these 483 isolates alongside 475 CipR.MSM5 isolates originating from France, Australia, the USA, and Belgium. They constructed an SNP-based phylogeny and further divided this population into BAPS clusters.

This analysis favored the notion that the evolution pattern of MSM-related S. sonnei was structured temporally (not geographically). Further, it revealed that the CipR.MSM5 genotype and the BAPS 5 cluster likely emerged in 2014 and 2018, respectively.

A monophyletic lineage of S. sonnei carrying the bla_CTX-M-27 gene was circulating intercontinental across regions historically considered low-risk for shigellosis. Moreover, these isolates correlated with phenotypic ceftriaxone resistance.

Conclusions

Both MDR and XDR Shigella strains have evolved to become problematic within the MSM community, likely due to excessive antibiotic use to treat sexually transmitted diseases (STDs).

For instance, MSM have been using azithromycin for STD treatment, which led MSM-related Shigella to acquire mph(A) and erm(B) antimicrobial resistance (AMR) genes.

In the high-risk MSM community, Shigella strains acquire genes through horizontal gene transfer (HGT) from the commensal gut microbiota to hone their AMR repertoire.

Accordingly, MDR S. sonnei, e.g., the BAPS5 lineage, is causing outbreaks throughout the global MSM community. It is a global public health concern, which raises the risk of treatment failure and the advent of pan-drug-resistant S. sonnei strains.

The study results highlighted the threat of horizontal transfer of AMR genes and sexually transmissible enteric infections (STEIs) in MSM and beyond. Thus, it is critical to share relevant genomic surveillance data continuously across the globe.