Global diversity and antimicrobial resistance of typhoid fever pathogens: Insights from a meta-analysis of 13,000 Salmonella Typhi genomes

Background: The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). Methods: This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. Results: Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal ‘sentinel’ surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (=3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has becomedominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. Conclusions: The consortium’s aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies

Global diversity and antimicrobial resistance of typhoid fever pathogens : insights from a meta-analysis of 13,000 Salmonella Typhi genomes

DATA AVAILABILITY : All data analysed during this study are publicly accessible. Raw Illumina sequence reads have been submitted to the European Nucleotide Archive (ENA), and individual sequence accession numbers are listed in Supplementary file 2. The full set of n=13,000 genome assemblies generated for this study are available for download from FigShare: https://doi.org/10.26180/21431883. All assemblies of suitable quality (n=12,849) are included as public data in the online platform Pathogenwatch (https://pathogen.watch). The data are organised into collections, which each comprise a neighbour-joining phylogeny annotated with metadata, genotype, AMR determinants, and a linked map. Each contributing study has its own collection, browsable at https://pathogen.watch/collections/all?organismId= 90370. In addition, we have provided three large collections, each representing roughly a third of the total dataset presented in this study: Typhi 4.3.1.1 (https://pathogen.watch/collection/ 2b7mp173dd57-clade-4311), Typhi lineage 4 (excluding 4.3.1.1) (https://pathogen.watch/collection/ wgn6bp1c8bh6-clade-4-excluding-4311), and Typhi lineages 0-3 (https://pathogen.watch/collection/ 9o4bpn0418n3-clades-0-1-2-and-3). In addition, users can browse the full set of Typhi genomes in Pathogenwatch and select subsets of interest (e.g. by country, genotype, and/or resistance) to generate a collection including neighbour-joining tree for interactive exploration.SUPPLEMENTARY FILES : Available at https://elifesciences.org/articles/85867/figures#content. SUPPLEMENTARY FILE 1. Details of local ethical approvals provided for studies that were unpublished at the time of contributing data to this consortium project. Most data are now published, and the citations for the original studies are provided here. National surveillance programs in Chile (Maes et al., 2022), Colombia (Guevara et al., 2021), France, New Zealand, and Nigeria (Ikhimiukor et al., 2022b) were exempt from local ethical approvals as these countries allow sharing of non-identifiable pathogen sequence data for surveillance purposes. The US CDC Internal Review Board confirmed their approval was not required for use in this project (#NCEZID-ARLT- 10/ 20/21-fa687). SUPPLEMENTARY FILE 2. Line list of 13,000 genomes included in the study. SUPPLEMENTARY FILE 3. Source information recorded for genomes included in the study. ^Indicates cases included in the definition of ‘assumed acute illness’. SUPPLEMENTARY FILE 4. Summary of genomes by country. SUPPLEMENTARY FILE 5. Genotype frequencies per region (N, %, 95% confidence interval; annual and aggregated, 2010–2020). SUPPLEMENTARY FILE 6. Genotype frequencies per country (N, %, 95% confidence interval; annual and aggregated, 2010–2020). SUPPLEMENTARY FILE 7. Antimicrobial resistance (AMR) frequencies per region (N, %, 95% confidence interval; aggregated 2010–2020). SUPPLEMENTARY FILE 8. Antimicrobial resistance (AMR) frequencies per country (N, %, 95% confidence interval; annual and aggregated, 2010–2020). SUPPLEMENTARY FILE 9. Laboratory code master list. Three letter laboratory codes assigned by the consortium.BACKGROUND : The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). METHODS : This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. RESULTS : Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal ‘sentinel’ surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. CONCLUSIONS : The consortium’s aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies.Fellowships from the European Union (funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 845681), the Wellcome Trust (SB, Wellcome Trust Senior Fellowship), and the National Health and Medical Research Council.https://elifesciences.org/am2024Medical MicrobiologySDG-03:Good heatlh and well-bein

Tenacious Endemic Typhoid Fever in Samoa

BACKGROUND: Typhoid fever has been endemic on the island nation of Samoa (2016 population, 195 979) since the 1960s and has persisted through 2019, despite economic development and improvements in water supply and sanitation. METHODS: Salmonella enterica serovar Typhi isolates from the 2 hospitals with blood culture capability and matched patient demographic and clinical data from January 2008 through December 2019 were analyzed. Denominators to calculate incidence by island, region, and district came from 2011 and 2016 censuses and from 2017-2019 projections from Samoa's Bureau of Statistics. Data were analyzed to describe typhoid case burden and incidence from 2008 to 2019 by time, place, and person. RESULTS: In sum, 53-193 blood culture-confirmed typhoid cases occurred annually from 2008 to 2019, without apparent seasonality. Typhoid incidence was low among children age < 48 months (17.6-27.8/105), rose progressively in ages 5-9 years (54.0/105), 10-19 years (60.7-63.4/105), and 20-34 years (61.0-79.3/105), and then tapered off; 93.6% of cases occurred among Samoans < 50 years of age. Most typhoid cases and the highest incidence occurred in Northwest Upolu, but Apia Urban Area (served by treated water supplies) also exhibited moderate incidence. The proportion of cases from short-cycle versus long-cycle transmission is unknown. Samoan S. Typhi are pansusceptible to traditional first-line antibiotics. Nevertheless, enhanced surveillance in 2019 detected 4 (2.9%) deaths among 140 cases. CONCLUSIONS: Typhoid has been endemic in Samoa in the period 2008-2019. Interventions, including mass vaccination with a Vi-conjugate vaccine coadministered with measles vaccine are planned

Global diversity and antimicrobial resistance of typhoid fever pathogens: Insights from a meta-analysis of 13,000 Salmonella Typhi genomes.

Peer reviewed: TrueFunder: Canadian Institutes of Health Research; FundRef: http://dx.doi.org/10.13039/501100000024Funder: National Institute for Health Research; FundRef: http://dx.doi.org/10.13039/501100000272Funder: Institut Pasteur and Santé Publique FranceFunder: Bill and Melinda Gates Foundation; FundRef: http://dx.doi.org/10.13039/100000865Funder: Indian Council of Medical Research; FundRef: http://dx.doi.org/10.13039/501100001411Funder: World Health Organization and Gavi, the Vaccine AllianceFunder: Department for Health and Social Care, the Department for International Development/Global Challenges Research Fund, the UK Medical Research Council, and the Wellcome TrustFunder: Wellcome; FundRef: http://dx.doi.org/10.13039/100010269BACKGROUND: The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). METHODS: This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. RESULTS: Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal 'sentinel' surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. CONCLUSIONS: The consortium's aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies. FUNDING: No specific funding was awarded for this meta-analysis. Coordinators were supported by fellowships from the European Union (ZAD received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 845681), the Wellcome Trust (SB, Wellcome Trust Senior Fellowship), and the National Health and Medical Research Council (DJI is supported by an NHMRC Investigator Grant [GNT1195210])

Global diversity and antimicrobial resistance of typhoid fever pathogens: Insights from a meta-analysis of 13,000 Salmonella Typhi genomes.

BACKGROUND: The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). METHODS: This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. RESULTS: Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal 'sentinel' surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. CONCLUSIONS: The consortium's aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies. FUNDING: No specific funding was awarded for this meta-analysis. Coordinators were supported by fellowships from the European Union (ZAD received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 845681), the Wellcome Trust (SB, Wellcome Trust Senior Fellowship), and the National Health and Medical Research Council (DJI is supported by an NHMRC Investigator Grant [GNT1195210])