Phylogenomics and antimicrobial resistance of Salmonella Typhi and Paratyphi A, B and C in England, 2016-2019

Abstract

The emergence of antimicrobial resistance (AMR) to first- and second-line treatment regimens of enteric fever is a global public-health problem, and routine genomic surveillance to inform clinical and public-health management guidance is essential. Here, we present the prospective analysis of genomic data to monitor trends in incidence, AMR and travel, and assess hierarchical clustering (HierCC) methodology of 1742 isolates of typhoidal salmonellae. Trend analysis of Salmonella Typhi and S. Paratyphi A cases per year increased 48 and 17.3%, respectively, between 2016 and 2019 in England, mainly associated with travel to South Asia. S. Paratyphi B cases have remained stable and are mainly associated with travel to the Middle East and South America. There has been an increase in the number of S. Typhi exhibiting a multidrug-resistant (MDR) profile and the emergence of extensively drug resistant (XDR) profiles. HierCC was a robust method to categorize clonal groups into clades and clusters associated with travel and AMR profiles. The majority of cases that had XDR S. Typhi reported recent travel to Pakistan (94 %) and belonged to a subpopulation of the 4.3.1 (H58) clone (HC5_1452). The phenotypic and genotypic AMR results showed high concordance for S. Typhi and S. Paratyphi A, B and C, with 99.99 % concordance and only three (0.01 %) discordant results out of a possible 23 178 isolate/antibiotic combinations. Genomic surveillance of enteric fever has shown the recent emergence and increase of MDR and XDR S. Typhi strains, resulting in a review of clinical guidelines to improve management of imported infections.

Keywords: Paratyphi; Typhi; antimicrobial resistance; enteric fever; genomic; phylogeny.

Fig. 1.

Population pyramid of age and sex distribution of 1473 cases of enteric fever, from 2016–2019.

Fig. 2.

Travel of patients within 28 days of generating symptoms.

Fig. 3.

Antibiotic-resistance trends in S. Typhi, 2016–2019. Antibiotic-resistance trends of S. Typhi cases received between 2016 and 2019 based on the presence of AMR determinant markers. Categories are subdivided into antibiotic classes and strains are classified as β-lactams (Amoxicillin), extended β-lactamase producers (ESBL), multidrug resistant (MDR) and extremely drug resistant (XDR). With the exception of tetracycline, S. Typhi strains have increased resistance to all classes of antibiotics, including the increase of ESBL, MDR and XDR strains.

Fig. 4.

Trends of ciprofloxacin resistance in S. Typhi associated with travel to India, Pakistan, Bangladesh and Africa with y-axis showing the number of isolates. (a, b) Trends of resistance in S. Typhi cases received between 2016 and 2019 based on the presence of AMR determinant markers and subdivided into four main categories (Cip R, ciprofloxacin-resistant strains; ESBL, extended spectrum β-lactamase producing strains; MDR, multidrug resistant strains; XDR, extensively drug resistant strains) (a) and trends of ciprofloxacin resistance in S. Typhi associated with travel to India, Pakistan, Bangladesh and Africa (b). (c, d) Trends of MDR (c) and XDR (d) S. Typhi associated with travel to India, Pakistan, Bangladesh and Africa. Figures show an increase of S. Typhi Cip R, ESBL, MDR and XDR strains over time, with the largest increase in 2019 and with travel to Pakistan.

Fig. 5.

Neighbour-joining phylogeny of S. Typhi in association with year of receipt, AMR and travel. Phylogenetic tree of cgMLST analysis of S. Typhi strains generated using the neighbour-joining method and mapped against three categories: inner ring, travel; middle ring, AMR (XDR, extensively drug resistant strains; MDR, multidrug resistant strains; Cip R, ciprofloxacin-resistant strains; ESBL, extended-spectrum β-lactamase producing strains; Chlor R, chloramphenicol-resistant strains); outer ring, year. Multidrug resistance is predominantly associated with the HC5_1452 cluster associated with travel to Pakistan containing a sub-cluster of XDR strains (red dashed line box), predominantly occurring in 2019. Other smaller MDR clusters are distributed throughout the phylogeny and are associated with different regions of Africa (blue dashed line box).

Fig. 6.

Trends of ciprofloxacin resistance in S. Paratyphi A associated with travel to India, Pakistan and Bangladesh with y-axis showing the number of isolates. Trends of ciprofloxacin-resistant S. Paratyphi A cases received between 2016 and 2019 based on the presence of ciprofloxacin AMR determinant markers. The figure shows seasonal trends with the seasonal peak in September/October and the trough in June/July. Resistance is mainly associated with travel to India until the last quarter of 2019, where travel to Pakistan increases.

Fig. 7.

Neighbour-joining phylogeny of S. Paratyphi A in association with year of receipt, AMR and travel. Phylogenetic tree of cgMLST analysis of S. Paratyphi A strains generated using the neighbour-joining method and mapped against three categories: inner ring, travel; middle ring, AMR (Cip R, ciprofloxacin-resistant strains; ESBL, extended-spectrum β-lactamase producing strains); outer ring, year. The phylogeny shows multiple clusters of ciprofloxacin-resistant strains mainly associated with travel to India, Pakistan and Bangladesh. One strain falling into a cluster associated with travel to Bangladesh was seen in 2017 but has not been imported since (red dashed line box).

Fig. 8.

Neighbour-joining phylogeny of S. Paratyphi B in association with year of receipt, AMR and travel. Phylogenetic tree of cgMLST analysis of S. Paratyphi B strains generated using the neighbour-joining method and mapped against three categories: inner ring, travel; middle ring, AMR; outer ring, year. The phylogeny shows one main clade associated with travel to South America and one main clade associated with travel to the Middle East containing two sub-clusters mainly associated with travel to Pakistan. Resistance to ciprofloxacin occurs sporadically throughout the population.