Horizontal antimicrobial resistance transfer drives epidemics of multiple Shigella species

Abstract

Horizontal gene transfer has played a role in developing the global public health crisis of antimicrobial resistance (AMR). However, the dynamics of AMR transfer through bacterial populations and its direct impact on human disease is poorly elucidated. Here, we study parallel epidemic emergences of multiple Shigella species, a priority AMR organism, in men who have sex with men to gain insight into AMR emergence and spread. Using genomic epidemiology, we show that repeated horizontal transfer of a single AMR plasmid among Shigella enhanced existing and facilitated new epidemics. These epidemic patterns contrasted with slighter, slower increases in disease caused by organisms with vertically inherited (chromosomally encoded) AMR. This demonstrates that horizontal transfer of AMR directly affects epidemiological outcomes of globally important AMR pathogens and highlights the need for integration of genomic analyses into all areas of AMR research, surveillance and management.

Persistent transmission of shigellosis in England is associated with a recently emerged multi-drug resistant strain ofShigella sonnei

“…and evidence that strains harbouring mobile resistance-conferring plasmids can spread intercontinentally through sexual transmission [5], therapy guided according to susceptibility testing should be a priority. Previous studies have discussed the role of AMR in driving transmission of shigellosis in the MSM community, and azithromycin resistance is regarded as a marker for isolates associated with sexual transmission among MSM [5,17]. During the peak of MSM transmission in 2014, only one of the four Shigella sonnei clades (clades 1-4) associated with MSM transmission was resistant to ciprofloxacin [16].…”

“…Genome-derived serotyping and AMR-conferring genes and SNPs was performed using the GeneFinder tool (https://github.com/phe-bioinformatics/gene_finder) [21,28]. Resistance to streptomycin, tetracycline, the sulphonamides and trimethoprim in Shigella species is high, and trends have been consistent for many years [5,[15][16][17]28]. We therefore focused our AMR analysis on the presence of genomic makers of resistance to macrolides (specifically ermB and mphA) and fluroquinolones (specifically mutations in the quinolones resistance determining regions (QRDR) of gyrA and parC), as the trends in resistance to these clinically relevant classes of antimicrobials fluctuated during the study period (data not shown).…”

“…Whole genome sequencing (WGS) studies have been used to determine factors driving the emergence and transmission of Shigella spp. and have demonstrated that certain community outbreaks of shigellosis in the UK belonged to prolonged, global epidemics [5,[15][16][17][18]. These analysis have shown that lineages of S. flexneri serotypes 3a and 2a have exhibited intercontinental spread via sexual transmission in GBMSM networks, and subsequently acquired multiple antimicrobial resistance (AMR) determinants [5,17].…”

“…and have demonstrated that certain community outbreaks of shigellosis in the UK belonged to prolonged, global epidemics [5,[15][16][17][18]. These analysis have shown that lineages of S. flexneri serotypes 3a and 2a have exhibited intercontinental spread via sexual transmission in GBMSM networks, and subsequently acquired multiple antimicrobial resistance (AMR) determinants [5,17]. Within the S. sonnei population, Baker et al (2018) [16] defined four clades associated with transmission in GBMSM communities, all within lineage III the dominant extant lineage both in the UK and globally [19,20].…”

“…These analysis have shown that lineages of S. flexneri serotypes 3a and 2a have exhibited intercontinental spread via sexual transmission in GBMSM networks, and subsequently acquired multiple antimicrobial resistance (AMR) determinants [5,17]. Within the S. sonnei population, Baker et al (2018) [16] defined four clades associated with transmission in GBMSM communities, all within lineage III the dominant extant lineage both in the UK and globally [19,20]. A two-year population-level study of all cultured Shigella isolates in the state of Victoria, Australia (2016-2018) identified 2 predominant MSM lineages circulating [21]; the S. flexneri 2a lineage described above and an MDR S. sonnei clade associated with reduced susceptibility to azithromycin, trimethoprim-sulfamethoxazole and ciprofloxacin.…”