The phylogeography and incidence of multi-drug resistant typhoid fever in sub-Saharan Africa

Se Eun Park^{1

2}, Duy Thanh Pham², Christine Boinett^{2

3}, Vanessa K Wong^{4

5}, Gi Deok Pak¹, Ursula Panzner¹, Ligia Maria Cruz Espinoza¹, Vera von Kalckreuth¹, Justin Im¹, Heidi Schütt-Gerowitt^{1

6}, John A Crump^{7

8

9

10}, Robert F Breiman^{11

12}, Yaw Adu-Sarkodie^{13

14}, Ellis Owusu-Dabo^{13

14}, Raphaël Rakotozandrindrainy¹⁵, Abdramane Bassiahi Soura¹⁶, Abraham Aseffa¹⁷, Nagla Gasmelseed^{18

19}, Karen H Keddy^{20

21}, Jürgen May^{22

23}, Amy Gassama Sow^{24

25}, Peter Aaby^{26

27}, Holly M Biggs^{7

8}, Julian T Hertz^{7

8}, Joel M Montgomery¹¹, Leonard Cosmas¹¹, Beatrice Olack²⁸, Barry Fields¹¹, Nimako Sarpong^{13

23}, Tsiriniaina Jean Luco Razafindrabe¹⁵, Tiana Mirana Raminosoa¹⁵, Leon Parfait Kabore²⁹, Emmanuel Sampo²⁹, Mekonnen Teferi¹⁷, Biruk Yeshitela¹⁷, Muna Ahmed El Tayeb¹⁸, Arvinda Sooka²⁰, Christian G Meyer^{30

31}, Ralf Krumkamp²², Denise Myriam Dekker^{22

23}, Anna Jaeger²², Sven Poppert³², Adama Tall²⁵, Aissatou Niang²⁵, Morten Bjerregaard-Andersen^{26

27}, Sandra Valborg Løfberg^{26

27}, Hye Jin Seo¹, Hyon Jin Jeon¹, Jessica Fung Deerin¹, Jinkyung Park¹, Frank Konings¹, Mohammad Ali^{1

33}, John D Clemens^{1

34

35}, Peter Hughes³⁶, Juliet Nsimire Sendagala³⁶, Tobias Vudriko³⁶, Robert Downing^{37

38}, Usman N Ikumapayi³⁹, Grant A Mackenzie^{39

40

41}, Stephen Obaro^{42

43

44}, Silvia Argimon⁴, David M Aanensen^{4

45}, Andrew Page⁴, Jacqueline A Keane⁴, Sebastian Duchene⁴⁶, Zoe Dyson⁴⁶, Kathryn E Holt⁴⁶, Gordon Dougan^{4

47}, Florian Marks^{48

49}, Stephen Baker^{2

3

47}

Affiliations

¹ International Vaccine Institute, SNU Research Park, 1 Gwanak-ro, 1 Gwanak-gu, Seoul, 08826, Republic of Korea.
² The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, 764 Vo Van Kiet, Quant 5, Ho Chi Minh City, Vietnam.
³ Centre for Tropical Medicine and Global Health, University of Oxford, Old Road campus, Roosevelt Drive, Headington, Oxford, OX3 7FZ, UK.
⁴ Centre for Genomic Pathogen Surveillance, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
⁵ Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0QQ, UK.
⁶ Institute of Medical Microbiology, University of Cologne, 50923, Cologne, Germany.
⁷ Kilimanjaro Christian Medical Centre, P.O. Box 3010, Moshi, Tanzania.
⁸ Division of Infectious Diseases and International Health, Duke University Medical Center, Durham, NC, 27710, USA.
⁹ Duke Global Health Institute, Duke University, Durham, NC, 27708, USA.
¹⁰ Centre for International Health, University of Otago, Dunedin, 9054, New Zealand.
¹¹ Centers for Disease Control and Prevention, KEMRI Complex, Mbagathi Road off Mbagathi Way, P.O. Box 606-00621 Village Market, Nairobi, Kenya.
¹² Emory Global Health Institute, Emory University, 1599 Clifton Road, NE, Atlanta, GA, 30322, USA.
¹³ Kwame Nkrumah University of Science and Technology, P.O. Box PMB KNUST, Kumasi, Ghana.
¹⁴ Kumasi Centre for Collaborative Research in Tropical Medicine, Kwame Nkrumah University of Science and Technology, KCCR, UPO, PMB, KNUST, Kumasi, Ghana.
¹⁵ University of Antananarivo, BP 566, Antananarivo 101, Madagascar.
¹⁶ Institut Supérieur des Sciences de la Population, University of Ouagadougou, 03 B.P. 7118, Ouagadougou 03, Burkina Faso.
¹⁷ Armauer Hansen Research Institute, Jimma Road, ALERT Compound, P.O. Box 1005, Addis Ababa, Ethiopia.
¹⁸ Faculty of Medicine, University of Gezira, P.O. Box 20, Wad Medani, Sudan.
¹⁹ Faculty of Science, University of Hafr Al Batin, Al Jamiah, Hafr Albatin, 39524, Saudi Arabia.
²⁰ National Institute for Communicable Diseases, Private Bag X4, Sandringham, 2131 Johannesburg, South Africa.
²¹ Faculty of Health Sciences, University of the Witwatersrand, 1 Jan Smuts Avenue, Braamfontein, 2000, Johannesburg, South Africa.
²² Bernhard Nocht Institute for Tropical Medicine, Bernhard Nocht Str. 74, 20359, Hamburg, Germany.
²³ German Center for Infection Research, Hamburg-Borstel-Lübeck, Inhoffenstrabe 7, 38124, Braunschweig, Germany.
²⁴ Institute Pasteur de Dakar, 36 Avenue Pasteur, B.P. 220, Dakar, Senegal.
²⁵ Université Cheikh Anta Diop de Dakar, Dakar, B.P. 5005, Senegal.
²⁶ Bandim Health Project, Apartado, 8611004, Bissau codex, Bissau, Guinea-Bissau.
²⁷ Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, 5 Artillerivej, DK-2300, Copenhagen, Denmark.
²⁸ Kenya Medical Research Institute, Mbagathi Rd. P.O. BOX 54840-00200, Nairobi, Kenya.
²⁹ Schiphra Hospital, Ouagadougou 01, 01 B.P. 121, Burkina Faso.
³⁰ Institute of Tropical Medicine, Eberhard-Karls University Tübingen, Geschwister-Scholl-Platz, 72074, Tübingen, Germany.
³¹ Duy Tan University, 254 Nguyen Van Linh, Da Nang, Vietnam.
³² Swiss Tropical and Public Health Institute, University of Basel, Socinstrasse 57, Postfach, CH-4002, Basel, Switzerland.
³³ Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St., Baltimore, MD, 21205, USA.
³⁴ International Centre for Diarrheal Disease Research, Bangladesh (ICDDR,B), GPO Box 128, Dhaka, 1000, Bangladesh.
³⁵ University of California, Fielding School of Public Health, 650 Charles E. Young Dr. South, Center for Health Sciences, Los Angeles, CA, 90095-1772, USA.
³⁶ Medical Research Center (MRC)/Uganda Virus Research Institute (UVRI) & London School of Hygiene and Tropical Medicine (LSHTM) Uganda Research Unit, Plot 51-59 Nakiwogo Road, P.O. Box 49, Entebbe, Uganda.
³⁷ Uganda Virus Research Institute (UVRI), Plot 51-59 Nakiwogo Road, P.O. Box 49, Entebbe, Uganda.
³⁸ Public Health Emergency Operations Centre, Plot 6 Lourdel Road, Nakasero, PO Box 7272, Kampala, Uganda.
³⁹ Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, Atlantic Boulevard, Fajara, P.O. Box 273, Banjul, The Gambia.
⁴⁰ Murdoch Children's Research Institute, 50 Flemington Road Parkville Victoria, 3052, Melbourne, Australia.
⁴¹ Institut de Recherche en Santé, de Surveillance Epidemiologique et de Formations (IRESSEF), Arrondissement 4 Rue 2D1, BP 7325, Dakar, Senegal.
⁴² Division of Pediatric Infectious Diseases, University of Nebraska Medical Center, 42nd and Emile, Omaha, Nebraska, 68198, USA.
⁴³ University of Abuja Teaching Hospital, Gwagwalada, P.M.B 228, Abuja, Nigeria.
⁴⁴ Bingham University, P.M.B 005, KM 26 Abuja-Keffi Expressway Kodope, Karu, Nasarawa State, Nigeria.
⁴⁵ Big Data Institute, University of Oxford, Old Road Campus, Oxford, OX3 7LF, UK.
⁴⁶ Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, 30 Flemington Road, Parkville, Victoria, 3010, Australia.
⁴⁷ The Department of Medicine, The University of Cambridge, Box 157, Hills Road, Cambridge, CB2 0QQ, UK.
⁴⁸ International Vaccine Institute, SNU Research Park, 1 Gwanak-ro, 1 Gwanak-gu, Seoul, 08826, Republic of Korea. fmarks@ivi.int.
⁴⁹ The Department of Medicine, The University of Cambridge, Box 157, Hills Road, Cambridge, CB2 0QQ, UK. fmarks@ivi.int.

PMID: 30504848
PMCID: PMC6269545
DOI: 10.1038/s41467-018-07370-z

The phylogeography and incidence of multi-drug resistant typhoid fever in sub-Saharan Africa

Se Eun Park et al. Nat Commun. 2018.

. 2018 Nov 30;9(1):5094.

doi: 10.1038/s41467-018-07370-z.

Authors

Affiliations

¹ International Vaccine Institute, SNU Research Park, 1 Gwanak-ro, 1 Gwanak-gu, Seoul, 08826, Republic of Korea.
² The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, 764 Vo Van Kiet, Quant 5, Ho Chi Minh City, Vietnam.
³ Centre for Tropical Medicine and Global Health, University of Oxford, Old Road campus, Roosevelt Drive, Headington, Oxford, OX3 7FZ, UK.
⁴ Centre for Genomic Pathogen Surveillance, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
⁵ Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0QQ, UK.
⁶ Institute of Medical Microbiology, University of Cologne, 50923, Cologne, Germany.
⁷ Kilimanjaro Christian Medical Centre, P.O. Box 3010, Moshi, Tanzania.
⁸ Division of Infectious Diseases and International Health, Duke University Medical Center, Durham, NC, 27710, USA.
⁹ Duke Global Health Institute, Duke University, Durham, NC, 27708, USA.
¹⁰ Centre for International Health, University of Otago, Dunedin, 9054, New Zealand.
¹¹ Centers for Disease Control and Prevention, KEMRI Complex, Mbagathi Road off Mbagathi Way, P.O. Box 606-00621 Village Market, Nairobi, Kenya.
¹² Emory Global Health Institute, Emory University, 1599 Clifton Road, NE, Atlanta, GA, 30322, USA.
¹³ Kwame Nkrumah University of Science and Technology, P.O. Box PMB KNUST, Kumasi, Ghana.
¹⁴ Kumasi Centre for Collaborative Research in Tropical Medicine, Kwame Nkrumah University of Science and Technology, KCCR, UPO, PMB, KNUST, Kumasi, Ghana.
¹⁵ University of Antananarivo, BP 566, Antananarivo 101, Madagascar.
¹⁶ Institut Supérieur des Sciences de la Population, University of Ouagadougou, 03 B.P. 7118, Ouagadougou 03, Burkina Faso.
¹⁷ Armauer Hansen Research Institute, Jimma Road, ALERT Compound, P.O. Box 1005, Addis Ababa, Ethiopia.
¹⁸ Faculty of Medicine, University of Gezira, P.O. Box 20, Wad Medani, Sudan.
¹⁹ Faculty of Science, University of Hafr Al Batin, Al Jamiah, Hafr Albatin, 39524, Saudi Arabia.
²⁰ National Institute for Communicable Diseases, Private Bag X4, Sandringham, 2131 Johannesburg, South Africa.
²¹ Faculty of Health Sciences, University of the Witwatersrand, 1 Jan Smuts Avenue, Braamfontein, 2000, Johannesburg, South Africa.
²² Bernhard Nocht Institute for Tropical Medicine, Bernhard Nocht Str. 74, 20359, Hamburg, Germany.
²³ German Center for Infection Research, Hamburg-Borstel-Lübeck, Inhoffenstrabe 7, 38124, Braunschweig, Germany.
²⁴ Institute Pasteur de Dakar, 36 Avenue Pasteur, B.P. 220, Dakar, Senegal.
²⁵ Université Cheikh Anta Diop de Dakar, Dakar, B.P. 5005, Senegal.
²⁶ Bandim Health Project, Apartado, 8611004, Bissau codex, Bissau, Guinea-Bissau.
²⁷ Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, 5 Artillerivej, DK-2300, Copenhagen, Denmark.
²⁸ Kenya Medical Research Institute, Mbagathi Rd. P.O. BOX 54840-00200, Nairobi, Kenya.
²⁹ Schiphra Hospital, Ouagadougou 01, 01 B.P. 121, Burkina Faso.
³⁰ Institute of Tropical Medicine, Eberhard-Karls University Tübingen, Geschwister-Scholl-Platz, 72074, Tübingen, Germany.
³¹ Duy Tan University, 254 Nguyen Van Linh, Da Nang, Vietnam.
³² Swiss Tropical and Public Health Institute, University of Basel, Socinstrasse 57, Postfach, CH-4002, Basel, Switzerland.
³³ Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St., Baltimore, MD, 21205, USA.
³⁴ International Centre for Diarrheal Disease Research, Bangladesh (ICDDR,B), GPO Box 128, Dhaka, 1000, Bangladesh.
³⁵ University of California, Fielding School of Public Health, 650 Charles E. Young Dr. South, Center for Health Sciences, Los Angeles, CA, 90095-1772, USA.
³⁶ Medical Research Center (MRC)/Uganda Virus Research Institute (UVRI) & London School of Hygiene and Tropical Medicine (LSHTM) Uganda Research Unit, Plot 51-59 Nakiwogo Road, P.O. Box 49, Entebbe, Uganda.
³⁷ Uganda Virus Research Institute (UVRI), Plot 51-59 Nakiwogo Road, P.O. Box 49, Entebbe, Uganda.
³⁸ Public Health Emergency Operations Centre, Plot 6 Lourdel Road, Nakasero, PO Box 7272, Kampala, Uganda.
³⁹ Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, Atlantic Boulevard, Fajara, P.O. Box 273, Banjul, The Gambia.
⁴⁰ Murdoch Children's Research Institute, 50 Flemington Road Parkville Victoria, 3052, Melbourne, Australia.
⁴¹ Institut de Recherche en Santé, de Surveillance Epidemiologique et de Formations (IRESSEF), Arrondissement 4 Rue 2D1, BP 7325, Dakar, Senegal.
⁴² Division of Pediatric Infectious Diseases, University of Nebraska Medical Center, 42nd and Emile, Omaha, Nebraska, 68198, USA.
⁴³ University of Abuja Teaching Hospital, Gwagwalada, P.M.B 228, Abuja, Nigeria.
⁴⁴ Bingham University, P.M.B 005, KM 26 Abuja-Keffi Expressway Kodope, Karu, Nasarawa State, Nigeria.
⁴⁵ Big Data Institute, University of Oxford, Old Road Campus, Oxford, OX3 7LF, UK.
⁴⁶ Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, 30 Flemington Road, Parkville, Victoria, 3010, Australia.
⁴⁷ The Department of Medicine, The University of Cambridge, Box 157, Hills Road, Cambridge, CB2 0QQ, UK.
⁴⁸ International Vaccine Institute, SNU Research Park, 1 Gwanak-ro, 1 Gwanak-gu, Seoul, 08826, Republic of Korea. fmarks@ivi.int.
⁴⁹ The Department of Medicine, The University of Cambridge, Box 157, Hills Road, Cambridge, CB2 0QQ, UK. fmarks@ivi.int.

PMID: 30504848
PMCID: PMC6269545
DOI: 10.1038/s41467-018-07370-z

Abstract

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1**
The phylogenetic context of *Salmonella* Typhi isolated in sub-Saharan Africa. Maximum likelihood tree outlining the phylogenetic structure of 249 S. Typhi isolates unique to this study (highlighted by the blue points) combined with 2,057 global S. Typhi isolates. The tree is adjacent to three concentric circles highlighting associated metadata. The inner most circle represents the three most predominant genotypes (colour coded according to top of key), the middle circle represents the geographical sub-regions of Africa from where the S. Typhi organisms were isolated (colour coded according to top of key), and the outer circle (blue) again highlights the organisms unique to this study. The scale bar indicates the number of substitutions per variable site

**Fig. 2**
The distribution of multi-drug resistant *Salmonella* Typhi isolated in Africa. Map of the African continent showing the locations of the field sites from where the S. Typhi organisms were isolated for this study. Countries in which multi-drug resistant (MDR) S. Typhi were isolated are coloured in red, countries in which MDR S. Typhi were not isolated are coloured in grey. Pie charts correspond with the proportion of the main genotypes isolated (see key), with the number of isolates from each location in the centre

**Fig. 3**
The phylogenetic structures of the major *Salmonella* Typhi genotypes in sub-Saharan Africa. a Maximum likelihood tree of genotype 4.3.1 S. Typhi isolates from this study in the context of other global genotype 4.3.1 S. Typhi isolates; the two distinct sub-lineages are labeled at the base of the tree. 4.3.1 S. Typhi isolates from this study (Kenya, Tanzania, and Uganda) are highlighted in corresponding coloured branches and circles at the tip of each tree. The first coloured bar shows the MDR phenotypes of study isolates. The second coloured bar outlines the continents and African regions where 4.3.1 S. Typhi have been detected. Scale bar indicates the number of substitutions per variable site; nodes of the tree have been collapsed for better visualization. b Maximum clade credibility tree (reconstructed using BEAST2) of genotype 3.1.1 S. Typhi isolates from this study in the context of other global genotype 3.1.1 S. Typhi isolates. Tree shows a phylogeographical reconstruction of genotype 3.1.1 S. Typhi isolates in West Africa. Branches are weighted by the support for the location changes; thicker branches have higher support. Branches and nodes are coloured according to the location that had the highest posterior probability values for some nodes of the tree. The scale bar indicates the number of substitutions per variable site per year

**Fig. 4**
The antimicrobial gene distribution within sub-Saharan African *Salmonella* Typhi. Maximum likelihood phylogenetic tree of 249 S. Typhi isolates from this study with corresponding metadata including genotype, location, antimicrobial resistance genes (AMR), and plasmids (see keys). Countries where S. Typhi isolates were isolated are highlighted by coloured circles at the tip of the branches. The three major genotypes and sub-regions of the Africa continent are shown by the coloured bars; present AMR genes are shown in red. The scale bar indicates the number of substitutions per variable site

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The phylogeography and incidence of multi-drug resistant typhoid fever in sub-Saharan Africa

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The phylogeography and incidence of multi-drug resistant typhoid fever in sub-Saharan Africa

Authors

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Abstract

Conflict of interest statement

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