The spread of sexually transmissible drug-resistant shigellosis: A genomic epidemiology study

Abstract

Background: Shigellosis, caused by Shigella bacteria, is a leading cause of diarrhoeal disease globally. In the last two decades, Shigella circulation in high-income countries has expanded from being a sporadic travel-associated illness to also being an endemic sexually transmissible illness (STI) among men who have sex with men (MSM). We aimed to characterise the nature and drivers of this multimodal Shigella transmission in a high-income setting. Methods: Shigella sonnei isolates were collected from 138 laboratories across 15 UK health regions. Cases that had recent travel to Africa, Asia, or Latin America and the Caribbean were defined as high-risk travel-associated. Presumptive MSM (pMSM) cases were defined as men aged 16-60 without recent high-risk travel history. Non-pMSM were defined as cases that were defined not pMSM or high-risk travel. We implemented phylodynamic and geospatial modelling on national genomic surveillance data of S. sonnei (N=3,514 isolates) collected in the United Kingdom between 2004 and 2020 to quantitate and compare geospatial spread and transmission intensity of S. sonnei across demographic groups (the primary outcome of this study). We also determined the relative influence of antimicrobial resistance on pathogen dynamics in these demographic groups and evaluate the emergence of an extensively drug-resistant S. sonnei clade (n= 468) collected in England between 2016 and 2021 as a secondary analysis. Findings: Isolates were collected from September 20th, 2004 to February 28th, 2020. Of these isolates, 1,197 came from pMSM, 1,269 from non-pMSM, and 1,048 from high-risk travel, respectively. We find that sexually transmitted S. sonnei spread more rapidly (i.e. had a greater mean pairwise spatial distance after < 2·5 years of evolutionary time: pMSM (117·4 km (95% Confidence Interval (CI): 100·7-132·5)), non-pMSM (45·8 kilometre (km) (95% CI: 32·6-62·1), p-value = <0·0001) and transmitted more intensely (100 more transmission chains for a given population size (95% CI: 41-171), p-value = <0·002) than other domestically acquired S. sonnei. Sexually transmitted shigellosis also had greater annual case growth (115%, 95% Credible Interval (CrI): 108-123) compared to high-risk travel transmission. The relative fitness of azithromycin resistance among pMSM was greater (171% relative growth, 95% CrI: 159-184) than in either non-pMSM or high-risk travel demographics, and that declines of azithromycin fitness in sexual transmission networks coincided with changes in treatment policies for gonorrhea.. Interpretation: These results demonstrate the distinct and intensifying sexual transmission of shigellosis, highlighting the urgent need to address sexually transmissible shigellosis as a distinct health threat. Traditional interventions for enteric diseases, such as handwashing and food hygiene practices, are not likely to affect sexual transmission of shigellosis, highlighting a critical gap in public health management. The development of alternative interventions to address this public health threat is urgently needed. Furthermore, the unequivocal evidence of bystander resistance driven by treatment guidelines in a syndemic setting underscores the need to better manage antimicrobial stewardship across pathogens at a public health level.