Introduction and establishment of fluoroquinolone-resistant Shigella sonnei into Bhutan

Abstract

Shigella sonnei is a major contributor to the global burden of diarrhoeal disease, generally associated with dysenteric diarrhoea in developed countries but also emerging in developing countries. The reason for the recent success of S. sonnei is unknown, but is likely catalysed by its ability to acquire resistance against multiple antimicrobials. Between 2011 and 2013, S. sonnei exhibiting resistance to fluoroquinolones, the first-line treatment recommended for shigellosis, emerged in Bhutan. Aiming to reconstruct the introduction and establishment of fluoroquinolone-resistant S. sonnei populations in Bhutan, we performed whole-genome sequencing on 71 S. sonnei samples isolated in Bhutan between 2011 and 2013.We found that these strains represented an expansion of a clade within the previously described lineage III, found specifically in Central Asia. Temporal phylogenetic reconstruction demonstrated that all of the sequenced Bhutanese S. sonnei diverged from a single ancestor that was introduced into Bhutan around 2006. Our data additionally predicted that fluoroquinolone resistance, conferred by mutations in gyrA and parC, arose prior to the introduction of the founder strain into Bhutan. Once established in Bhutan, these S. sonnei had access to a broad gene pool, as indicated by the acquisition of extended-spectrum β-lactamase-encoding plasmids and genes encoding type IV pili. The data presented here outline a model for the introduction and maintenance of fluoroquinolone-resistant S. sonnei in a new setting. Given the current circulation of fluoroquinolone-resistant S. sonnei in Asia, we speculate that this pattern of introduction is being recapitulated across the region and beyond.

Ciprofloxacin facilitates the transfer of XDR plasmids from commensalE. coliinto epidemic fluoroquinolone-resistantShigella sonnei

“…IncI and IncB/O plasmids belong to the IncI-complex (IncI, IncB/O, IncK, IncZ), which have comparable antisense RNA plasmid replication control mechanisms 69 . Our results concur with previous reports that proposed a commonality of IncI-complex plasmids associated with the bla CTX-M element in S. sonnei from countries at various stages of economic development 21,47,70–74 . The reasons for these specific plasmid-host combinations remain elusive; however, we found that IncI and IncB/O plasmids displayed the highest in vitro conjugation efficiencies compared to other ESBL-encoding plasmids.…”

“…To date, cipR S. sonnei has been reported in children across Asia 16,17 , as well as homeless individuals and men-who-have-sex-with-men (MSM) in Canada, the US, Taiwan, and the UK 14,18–20 . Of further concern is the observation that cipR S. sonnei have the ability to acquire resistance to second-line alternative drugs such as ceftriaxone 21 , which further limits alternative treatment options.…”

Recent Outbreaks of Shigellosis in California Caused by Two Distinct Populations of Shigella sonnei with either Increased Virulence or Fluoroquinolone Resistance

“…The genomes of CA S. sonnei isolates were compared with the genomes of global S. sonnei clones reported by previous studies (see Data Set S1, sheet 2, in the supplemental material) (19–21) using genome-wide SNP analysis. The isolates from the aforementioned studies (188 total) were selected based on following criteria: (i) to represent all lineages as per Holt et al (19), (ii) different clades described by authors (Global III, Central Asia III), and (iii) various ciprofloxacin resistance mutations.…”

Genomic epidemiology of Shigella in the United Kingdom shows transmission of pathogen sublineages and determinants of antimicrobial resistance

“…sonnei 7 , 8 , 15 , 17 . In addition to these horizontally-acquired AMR determinants, chromosomal mutations in the Quinolone Resistance Determining Region (QRDR) (that confer resistance to ciprofloxacin, the recommended treatment for shigellosis) 18 have also been reported in shigellae isolated from Asia, Latin America, and high-income nations 7 , 11 , 14 , 19 . Ciprofloxacin-resistant Shigella were recently recognised by the World Health Organisation as one of the top dozen agents for which new antimicrobials are urgently needed.…”