Informal genomic surveillance of regional distribution of Salmonella Typhi genotypes and antimicrobial resistance via returning travellers

Abstract

Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of typhoid fever, a systemic human infection with a burden exceeding 20 million cases each year that occurs disproportionately among children in low and middle income countries. Antimicrobial therapy is the mainstay for treatment, but resistance to multiple agents is common. Here we report genotypes and antimicrobial resistance (AMR) determinants detected from routine whole-genome sequencing (WGS) of 533 S. Typhi isolates referred to Public Health England between April 2014 and March 2017, 488 (92%) of which had accompanying patient travel information obtained via an enhanced surveillance questionnaire. The majority of cases involved S. Typhi 4.3.1 (H58) linked with travel to South Asia (59%). Travel to East and West Africa were associated with genotypes 4.3.1 and 3.3.1, respectively. Point mutations in the quinolone resistance determining region (QRDR), associated with reduced susceptibility to fluoroquinolones, were very common (85% of all cases) but the frequency varied significantly by region of travel: 95% in South Asia, 43% in East Africa, 27% in West Africa. QRDR triple mutants, resistant to ciprofloxacin, were restricted to 4.3.1 lineage II and associated with travel to India, accounting for 23% of cases reporting travel to the country. Overall 24% of isolates were MDR, however the frequency varied significantly by region and country of travel: 27% in West Africa, 52% in East Africa, 55% in Pakistan, 24% in Bangladesh, 3% in India. MDR determinants were plasmid-borne (IncHI1 PST2 plasmids) in S. Typhi 3.1.1 linked to West Africa, but in all other regions MDR was chromosomally integrated in 4.3.1 lineage I. We propose that routine WGS data from travel-associated cases in industrialised countries could serve as informal sentinel AMR genomic surveillance data for countries where WGS is not available or routinely performed.

Genomic profiling of antimicrobial resistance genes in clinical isolates of Salmonella Typhi from patients infected with Typhoid fever in India

“…4; Table S6 in Supplementary File 1). This is similar to the previously reported cases where the QRDR mutants were dominant in India (97%), Bangladesh (94%), Nepal (66%), Pakistan (94%), Myanmar (100%), Uganda (100%), and Nigeria (50%) 54 . The close examination of the tree exposed the genotype-based clustering in S. Typhi.…”

“…Population structure and QRDR mutation patterns. The genotyphi classification according to the scheme of Wong et al 50 (19/133) of Salmonella isolates obtained in India from January 1993 to December 2016 and probably emerged from South Asia and East Africa in the initial 1990s 54,55 . H58 lineage I (genotype 4.3.1.1) was present in 13.53% (18/133) of the isolates, whereas H58 lineage II (genotype 4.3.1.2) was dominant in the majority of the isolates (70/133, 52.63%).…”

Travel-Related Typhoid Fever: Narrative Review of the Scientific Literature

“…A recent study, which analyzed >500 isolates of S. typhi, found that the reduced susceptibility to fluoroquinolones is frequently (85%) associated with point mutations in the QRDR; however, the prevalence can vary depending on the geographical area:95% in South Asia, 43% in EastAfrica, and 27% in WestAfrica. Strains resistant to ciprofloxacin were mainly collected from patients diagnosed in India, accounting for 23% of the total Indian cases [67].…”

First Case of Typhoid Fever due to Extensively Drug-resistant Salmonella enterica serovar Typhi in Italy

“…After that, treatment of typhoid fever was based on third-generation cephalosporins, ceftriaxone for parenteral therapy and cefixime for oral therapy [3,6]. Resistance of S. Typhi to ceftriaxone remained rare until 2016, when a large outbreak of ceftriaxone-resistant cases was reported in Pakistan [7]. This XDR strain is the cause of the present epidemic and can be treated only with carbapenems and azithromycin.…”

“…An increase in typhoid fever cases was evidenced in Australia, Canada, Denmark, Taiwan, Ireland, the United Kingdom and the United States [4][5][6]. In most of these cases, diagnosis was made in subjects with a history of travel from Pakistan, where an outbreak of extensively drug resistant (XDR) S. Typhi cases began in November 2016 [7]. This led to the hypothesis that most of these diseases were an extension of the Pakistan epidemic.…”