South Asia as a Reservoir for the Global Spread of Ciprofloxacin-Resistant Shigella sonnei: A Cross-Sectional Study

Abstract

BackgroundAntimicrobial resistance is a major issue in the Shigellae, particularly as a specific multidrug-resistant (MDR) lineage of Shigella sonnei (lineage III) is becoming globally dominant. Ciprofloxacin is a recommended treatment for Shigella infections. However, ciprofloxacin-resistant S. sonnei are being increasingly isolated in Asia and sporadically reported on other continents. We hypothesized that Asia is a primary hub for the recent international spread of ciprofloxacin-resistant S. sonnei.Methods and FindingsWe performed whole-genome sequencing on a collection of 60 contemporaneous ciprofloxacin-resistant S. sonnei isolated in four countries within Asia (Vietnam, n = 11; Bhutan, n = 12; Thailand, n = 1; Cambodia, n = 1) and two outside of Asia (Australia, n = 19; Ireland, n = 16). We reconstructed the recent evolutionary history of these organisms and combined these data with their geographical location of isolation. Placing these sequences into a global phylogeny, we found that all ciprofloxacin-resistant S. sonnei formed a single clade within a Central Asian expansion of lineage III. Furthermore, our data show that resistance to ciprofloxacin within S. sonnei may be globally attributed to a single clonal emergence event, encompassing sequential gyrA-S83L, parC-S80I, and gyrA-D87G mutations. Geographical data predict that South Asia is the likely primary source of these organisms, which are being regularly exported across Asia and intercontinentally into Australia, the United States and Europe. Our analysis was limited by the number of S. sonnei sequences available from diverse geographical areas and time periods, and we cannot discount the potential existence of other unsampled reservoir populations of antimicrobial-resistant S. sonnei.ConclusionsThis study suggests that a single clone, which is widespread in South Asia, is likely driving the current intercontinental surge of ciprofloxacin-resistant S. sonnei and is capable of establishing endemic transmission in new locations. Despite being limited in geographical scope, our work has major implications for understanding the international transfer of antimicrobial-resistant pathogens, with S. sonnei acting as a tractable model for studying how antimicrobial-resistant Gram-negative bacteria spread globally.

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

“…South Asia has been shown to serve as a hub for dissemination of FQ-resistant S. sonnei clones around the globe (20), and our data suggest that the CA FQ-resistant SFr population also originated from the South Asian clade. Considering that no patients from the SFr outbreak cluster reported international travel (16), the introduced resistant clone could have been circulating locally prior to involvement in the outbreak.…”

“…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.…”

“…The lineages I to IV and Global III sublineage are outlined in gray based on lineage assignment by Holt et al [19]). The sublineage outlined in yellow includes the South Asian clade, described previously (20), and the isolates that clustered with it. The tree is unrooted.…”

Shigella Vaccine Development: Finding the Path of Least Resistance

“…Moreover, military personnel and other travelers from high-resource countries who visit these endemic settings are also at risk for acquiring Shigella infections and disseminating them upon returning home. The global spread of multidrug-resistant Shigella has been traced to the wide dissemination of single clones (7), and this ease of transmission threatens the ability to treat shigellosis with antibiotics that are effective, readily available, and affordable. Because of the limitations of current efforts to control the spread of Shigella, development of a Shigella vaccine is considered a public health priority.…”

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

“…Our previous work demonstrated that all cipR S. sonnei globally were clonal and emerged once from a single lineage that likely arose in South Asia 22 . Here, we describe the expansion of a single lineage III clade of cipR S. sonnei by providing phylo-temporal insights into its extant clonal dynamics using clinical samples obtained from children admitted to three paediatric facilities in Ho Chi Minh City (HCMC) between 2014 and 2016.…”