Biochemistry and Pharmacology - Research Publications

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Start date: 2010 × End date: 2019 × Author: Dougan, Gordon × Author: Duchene Garzon, Sebastian ×

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    Laboratory and molecular surveillance of paediatric typhoidal Salmonella in Nepal: Antimicrobial resistance and implications for vaccine policy
    Britto, CD ; Dyson, ZA ; Duchene, S ; Carter, MJ ; Gurung, M ; Kelly, DF ; Murdoch, DR ; Ansari, I ; Thorson, S ; Shrestha, S ; Adhikari, N ; Dougan, G ; Holt, KE ; Pollard, AJ ; Ryan, ET (PUBLIC LIBRARY SCIENCE, 2018-04)
    BACKGROUND: Children are substantially affected by enteric fever in most settings with a high burden of the disease, including Nepal. However pathogen population structure and transmission dynamics are poorly delineated in young children, the proposed target group for immunization programs. Here we present whole genome sequencing and antimicrobial susceptibility data on 198 S. Typhi and 66 S. Paratyphi A isolated from children aged 2 months to 15 years of age during blood culture surveillance at Patan Hospital, Nepal, 2008-2016. PRINCIPAL FINDINGS: S. Typhi was the dominant agent and comprised several distinct genotypes, dominated by 4.3.1 (H58). The heterogeneity of genotypes in children under five was reduced compared to data from 2005-2006, attributable to ongoing clonal expansion of H58. Most isolates (86%) were non-susceptible to fluoroquinolones, associated mainly with S. Typhi H58 lineage II and S. Paratyphi A harbouring mutations in the quinolone resistance-determining region (QRDR); non-susceptible strains from these groups accounted for 50% and 25% of all isolates. Multi-drug resistance (MDR) was rare (3.5% of S. Typhi, 0 S. Paratyphi A) and restricted to chromosomal insertions of resistance genes in H58 lineage I strains. Temporal analyses revealed a shift in dominance from H58 Lineage I to H58 Lineage II, with the latter being significantly more common after 2010. Comparison to global data sets showed the local S. Typhi and S. Paratyphi A strains had close genetic relatives in other South Asian countries, indicating regional strain circulation. Multiple imports from India of ciprofloxacin-resistant H58 lineage II strains were identified, but these were rare and showed no evidence of clonal replacement of local S. Typhi. SIGNIFICANCE: These data indicate that enteric fever in Nepal continues to be a major public health issue with ongoing inter- and intra-country transmission, and highlights the need for regional coordination of intervention strategies. The absence of a S. Paratyphi A vaccine is cause for concern, given its prevalence as a fluoroquinolone resistant enteric fever agent in this setting.
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    The phylogeography and incidence of multi-drug resistant typhoid fever in sub-Saharan Africa
    Park, SE ; Duy, TP ; Boinett, C ; Wong, VK ; Pak, GD ; Panzner, U ; Espinoza, LMC ; von Kalckreuth, V ; Im, J ; Schuett-Gerowitt, H ; Crump, JA ; Breiman, RF ; Adu-Sarkodie, Y ; Owusu-Dabo, E ; Rakotozandrindrainy, R ; Soura, AB ; Aseffa, A ; Gasmelseed, N ; Keddy, KH ; May, J ; Sow, AG ; Aaby, P ; Biggs, HM ; Hertz, JT ; Montgomery, JM ; Cosmas, L ; Olack, B ; Fields, B ; Sarpong, N ; Razafindrabe, TJL ; Raminosoa, TM ; Kabore, LP ; Sampo, E ; Teferi, M ; Yeshitela, B ; El Tayeb, MA ; Sooka, A ; Meyer, CG ; Krumkamp, R ; Dekker, DM ; Jaeger, A ; Poppert, S ; Tall, A ; Niang, A ; Bjerregaard-Andersen, M ; Lofberg, SV ; Seo, HJ ; Jeon, HJ ; Deerin, JF ; Park, J ; Konings, F ; Ali, M ; Clemens, JD ; Hughes, P ; Sendagala, JN ; Vudriko, T ; Downing, R ; Ikumapayi, UN ; Mackenzie, GA ; Obaro, S ; Argimon, S ; Aanensen, DM ; Page, A ; Keane, JA ; Duchene, S ; Dyson, Z ; Holt, KE ; Dougan, G ; Marks, F ; Baker, S (NATURE PORTFOLIO, 2018-11-30)
    There is paucity of data regarding the geographical distribution, incidence, and phylogenetics of multi-drug resistant (MDR) Salmonella Typhi in sub-Saharan Africa. Here we present a phylogenetic reconstruction of whole genome sequenced 249 contemporaneous S. Typhi isolated between 2008-2015 in 11 sub-Saharan African countries, in context of the 2,057 global S. Typhi genomic framework. Despite the broad genetic diversity, the majority of organisms (225/249; 90%) belong to only three genotypes, 4.3.1 (H58) (99/249; 40%), 3.1.1 (97/249; 39%), and 2.3.2 (29/249; 12%). Genotypes 4.3.1 and 3.1.1 are confined within East and West Africa, respectively. MDR phenotype is found in over 50% of organisms restricted within these dominant genotypes. High incidences of MDR S. Typhi are calculated in locations with a high burden of typhoid, specifically in children aged <15 years. Antimicrobial stewardship, MDR surveillance, and the introduction of typhoid conjugate vaccines will be critical for the control of MDR typhoid in Africa.