South Asia as a reservoir for the global spread of ciprofloxacin resistantShigella sonnei

Abstract

59Background 60 Antimicrobial resistance is a major issue in the Shigellae, particularly as a specific multidrug resistant 61 (MDR) lineage of Shigella sonnei (lineage III) is becoming globally dominant. Ciprofloxacin is a 62 recommended treatment for Shigella infections. However, ciprofloxacin resistant S. sonnei are being 63 increasingly isolated in Asia, and sporadically reported on other continents. 64 Methods and Findings 65Hypothesising that Asia is the hub for the recent international spread of ciprofloxacin resistant S. 66 sonnei, we performed whole genome sequencing on a collection of contemporaneous ciprofloxacin 67 resistant S. sonnei isolated in six countries from within and outside of Asia. We reconstructed the 68 recent evolutionary history of these organisms and combined these data with their geographical 69 location of isolation. Placing these sequences into a global phylogeny we found that all ciprofloxacin 70 resistant S. sonnei formed a single clade within a Central Asian expansion of Lineage III. Further, our 71 data show that resistance to ciprofloxacin within S. sonnei can be globally attributed to a single clonal 72 emergence event, encompassing sequential gyrA-S83L, parC-S80I and gyrA-D87G mutations. 73

Dissecting the molecular evolution of fluoroquinolone-resistant Shigella sonnei

“…We confirmed that global FQr S. sonnei are clonal and likely emerged in South Asia around early 2007. This finding is in agreement with a wealth of epidemiological data citing the rise of FQr S. sonnei since 2007 9 . It is notable that the second and third mutations ( parC -S80I, gyrA -D87G) were acquired rapidly in the last two decades, coinciding with a sharp increase in the use of FQ during this period, when these drugs became routinely prescribed for shigellosis 6,41 .…”

“…Our previous analysis of 70 representative FQr S. sonnei suggested that they emerged as a single clone (nested within CenAsiaIII) in South Asia and subsequently radiated internationally 9 . Here, we utilised a collection of 411 internationally isolated S. sonnei , including 265 contemporary isolates sequenced for the purpose of this study (Table 1).…”

“…This investigation centring on the international dissemination of FQr S. sonnei was performed by combining WGS data from our previous investigations with an additional 265 isolates sequenced for this study 9,11 . This resulted in a collection of 411 S. sonnei isolates (Bhutan, n = 71; Vietnam, n = 24; Thailand, n = 8; Cambodia, n = 1; Ireland, n = 20; Australia, n = 85; France, n = 97; England, n = 91; global references, n = 14).…”

“…The isolates from shigellosis endemic countries (Bhutan, Vietnam, Thailand, Cambodia) are mostly FQr and sourced from multiple diarrhoeal surveillance studies in the respective countries. Institutional review board (IRB) approval and informed consent for these studies have been described previously 9 . Isolates from shigellosis non-endemic regions were collected from public health laboratories (Ireland, Australia, England, France), and these were mostly isolated from adults with recent travel histories.…”

“…We recently demonstrated that the extant FQr S. sonnei population, now reported worldwide, likely emerged from a single common ancestor in South Asia, the descendants of which moved across Asia prior to intercontinental dissemination 9 . Despite the significance of these findings, our inferences were derived from limited sampling, consisting of genome sequences generated from 70 FQr S. sonnei isolates.…”