# Long-Distance Spread of a Highly Drug-Resistant Epidemic Cholera Strain

Caroline Rouard, Louis Collet, Elisabeth Njamkepo, Claire Jenkins, Rosalie Sacheli, Thierry Benoit-Cattin, Julie Figoni, François-Xavier Weill

► To cite this version:

Caroline Rouard, Louis Collet, Elisabeth Njamkepo, Claire Jenkins, Rosalie Sacheli, et al., Long-Distance Spread of a Highly Drug-Resistant Epidemic Cholera Strain. New England Journal of Medicine, 2024, 391 (23), pp.2271-2273. 10.1056/NEJMc2408761. pasteur-04851774

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Submitted on 20 Dec 2024

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1 Long-distance spread of a highly drug-resistant epidemic cholera strain

2

3 Caroline Rouard, Pharm.D, Ph.D, caroline.rouard@pasteur.fr

4 Institut Pasteur, Université Paris Cité, Paris, France

5

6 Louis Collet, Pharm.D, Ph.D, l.collet@chmayotte.fr

7 Centre Hospitalier de Mayotte, Mamoudzou, France

8

9 Elisabeth Njamkepo, Ph.D, elisabeth.njamkepo-nguemkam@pasteur.fr

10 Institut Pasteur, Université Paris Cité, Paris, France

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12 Claire Jenkins, Ph.D, Claire.Jenkins@ukhsa.gov.uk

13 United Kingdom Health Security Agency, London, UK

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15 Rosalie Sacheli, Ph.D, R.Sacheli@chuliege.be

16 University Hospital Centre of Liege, University of Liege, Liege, Belgium

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18 Thierry Benoit-Cattin, Pharm.D, Ph.D, t.benoit-cattin@chmayotte.fr

19 Centre Hospitalier de Mayotte, Mamoudzou, France

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21 Julie Figoni, M.D, MPH, Julie.FIGONI@santepubliquefrance.fr

22 Santé Publique France, Saint-Maurice, France

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24 François-Xavier Weill, M.D, Ph.D, Professor, francois-xavier.weill@pasteur.fr

25 Institut Pasteur, Université Paris Cité, Paris, France

26

27 Corresponding author:

28 F-X.W., Unité des Bactéries pathogènes entériques, Institut Pasteur, Université Paris Cité, 28

29 rue du Dr Roux, 75015 Paris, France, francois-xavier.weill@pasteur.fr, Tel +33 1 45688345
30

31 **Key words:** Cholera, antimicrobial resistance, whole-genome sequencing, Africa, Middle

32 East

33

34 **Word count:** 459

35

36 Disclosure: Supported by Institut Pasteur and Santé Publique France.
TO THE EDITOR: In 2018-2019, Zimbabwe experienced a cholera outbreak with over 10,000 suspected cases caused by a highly drug-resistant (HDR) seventh pandemic Vibrio cholerae El Tor (7PET) strain.¹ This strain belonged to the AFR13 sublineage, which was introduced into East Africa from South Asia in 2013-2014.¹ The Zimbabwean strain contained an IncC plasmid (pYA00120881) carrying 14 antimicrobial drug resistance (AMR) genes and the outbreak isolates were resistant to tetracycline, ciprofloxacin, and third-generation cephalosporins in particular.¹ Fortunately, this HDR strain resistant to two of the three antibiotics recommended for cholera treatment (doxycycline, ciprofloxacin, azithromycin)¹ did not spread further. In Yemen² in 2018 — after two years of intense circulation (> 2 million suspected cholera cases) of an AFR13 7PET strain essentially susceptible to antibiotics — the outbreak isolates became HDR after acquiring the IncC plasmid pCNRVC190243 containing a set of AMR genes different from that of pYA00120881. From 2019 onwards, all Yemeni outbreak isolates were resistant to azithromycin (presence of the plasmid-borne mph(A), mph(E), and msr(E) genes), ciprofloxacin (mutations of the chromosomal gyrA and parC genes), and third-generation cephalosporins (presence of the plasmid-borne extended-spectrum beta-lactamase bla<sub>PER-7</sub> gene).² In 2022, this HDR strain was identified in cholera cases in southern and eastern Lebanon.³ Using the cholera surveillance systems of several European countries and genomic analyses (Supplementary Appendix) on the bacterial isolates (Tables S1 to S4), we were able to show that this HDR AFR13 7PET strain has now spread to Eastern Africa (Figure 1). In 2023, this strain was isolated from three European travelers returning from Kenya at different times of the year. In March 2024, this HDR strain was isolated in Mayotte — a French island located off the coast of Southeastern Africa — initially from patients coming from Tanzania or the Comoros subsequently from patients contaminated locally. A major cholera outbreak, with 12,120 cases, was reported in Kenya⁴ between October 2022 and October 2023. In Tanzania⁵, the
number of cholera cases has been increasing since the start of 2024, with 3,032 cases as of May 26 2024, and in the Comoros⁵, after a lull of more than 20 years, a cholera outbreak began in February 2024, with 7,335 cases as of May 26 2024. This HDR strain has probably contributed to the increase in cholera notifications in these countries, but the extent of its involvement remains to be confirmed in the absence of AMR phenotype data. These findings argue for a strengthening of laboratory capacity for the rapid diagnosis and surveillance of cholera (including the regular antimicrobial susceptibility testing of 7PET isolates) in East Africa. We would also argue more specifically for real-time trans-border surveillance of this emerging HDR AFR13 7PET strain as the potential acquisition of an additional tetracycline resistance gene by this strain would jeopardize oral antibiotic treatment of the infections it causes.

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**Figure 1. Maximum-likelihood phylogeny of 1,523 seventh pandemic Vibrio cholerae O1 El Tor isolates, including 17 recently obtained highly-drug resistant isolates.** Blue arrows represent the three genomic waves and the black arrow indicates the acquisition of the *ctxB7* allele. The double slash (//) indicates an artificial shortening of this branch for visualization. The color coding in the first column shows the geographic origins (GEO) of the isolates, and African sublineages (AFR1, AFR3–AFR15) are shown on the right. A magnification of the AFR13 sublineage (red square) is shown on the right with red text indicating the 17 highly drug-resistant isolates studied. For each genome, its name (or accession number), the country in which contamination occurred and the year of sample collection are indicated at the tip of the branch. The acquisitions of the two IncC plasmids are indicated. Scale bars indicate the number of nucleotide substitutions per variable site. Blue values correspond to bootstrap values ≥85% for the main nodes.

86
87 References

88 1. Mashe T, Domman D, Tarupiwa A, et al. Highly Resistant Cholera Outbreak Strain in
89 Zimbabwe. N Engl J Med 2020;383(7):687-9.

90 2. Lassalle F, Al-Shalali S, Al-Hakimi M, et al. Genomic epidemiology reveals multidrug
91 resistant plasmid spread between *Vibrio cholerae* lineages in Yemen. Nat Microbiol
92 2023;8(10):1787-98.

93 3. Fayad AA, Rafei R, Njamkepo E, et al. An unusual two-strain cholera outbreak in
94 Lebanon, 2022-2023: a genomic epidemiology study. Nat Commun 2024;15(1):6963.

95 4. World Health Organization. Multi-country outbreak of cholera, External situation report
96 #8 - 2 November 2023 [Internet]. 2023. Available from:
97 https://www.who.int/publications/m/item/multi-country-outbreak-of-cholera--external-
98 situation-report--8---2-november-2023 (accessed 11 Jul 2024).

99 5. World Health Organization. Multi-country outbreak of cholera, External situation report
100 #15 - 19 June 2024 [Internet]. 2024 Available from:
101 https://www.who.int/publications/m/item/multi-country-outbreak-of-cholera--external-
102 situation-report--15---19-june-2024 (accessed 11 Jul 2024).

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104