Categories: Sanger Science20 February 20183.9 min read

Sequencing a superbug: How typhoid became extensively drug-resistant

By: Gordon Dougan and Elizabeth Klemm, Wellcome Sanger Institute and the Department of Medicine, University of Cambridge
Date: 20:02:18

Reprinted from the Take on Typhoid website,

The bacteria that causes typhoid fever, Salmonella Typhi, is a smart one.

I know this because our laboratory has been sequencing the DNA of S. Typhi strains that infect people around the world, and we have found evidence for an accelerating evolution of resistance to antibiotics.

After antibiotics were first introduced to treat typhoid in the 1940s, typhoid’s mortality rate plummeted from around 26 percent to just 1 percent. But within 20 years the first cases of typhoid resistant to chloramphenicol—one of the three first-line treatments for typhoid appeared signaling a battle between antibiotic and bacteria. Typhoid strains resistant to all three first-line treatments, which are known as multidrug-resistant (MDR) typhoid strains were quick to follow those resistant to only one antibiotic. And when doctors began using second-line antibiotics (more modern but expensive versions) such as fluoroquinolones, typhoid followed with resistance against those drugs, too.

A particular agressive strain (actually a genetic clone) of MDR typhoid, H58, first emerged in the 1990s. This H58 strain has grabbed our attention because, while other MDR typhoid strains have mostly remained in the local area where they first appeared, H58 has quickly spread across the globe. Currently, the majority of all global MDR typhoid strains can be classified as H58. It’s a quick learner that is able to not only evolve more easily, but also multiply and spread more rapidly than other typhoid strains.

The global prevalence of H58 typhoid strains, 2017

The global prevalence of H58 typhoid strains, 2017

Recently, the world saw yet another evolution of the H58 strain. In November 2016, doctors in Sindh, Pakistan, observed cases of a novel H58 S. Typhi strain that was resistant to not only the three first-line antibiotics and fluoroquinolones, but also a third-generation cephalosporin called ceftriaxone. This new strain is classified as extensively drug-resistant (XDR) typhoid. It is only susceptible to a limited number of antibiotics, which can be expensive and difficult to access, especially for low- and middle-income countries.

In an effort to learn more about this new XDR typhoid, our team, working closely with outstanding collegues in Pakistan, quickly went to work to sequence its DNA — research that was recently published in mBio. We found three concerning issues. First, we found that S. Typhi has the ability to transform from MDR to XDR in a single step. By acquiring just one highly mobile DNA molecule (plasmid) from another bacteria such as E. coli, MDR H58 typhoid in any location can potentially become XDR typhoid.

Second, we found that the new XDR strain is an end product of a global chain of antibiotic resistant bacteria. The plasmid that created XDR typhoid is present in a variety of diverse geographic settings across the globe, and once created, XDR typhoid rapidly reproduces itself. This is a concerning development because previous reports of XDR typhoid have been sporadic and isolated, while this particular strain has already caused large-scale outbreaks and is spreading within and outside Pakistan. It has already been carried as far as the United Kingdom.

Finally, our findings confirm the fact that the antibiotic arsenal for typhoid treatment is fading. We can no longer rely on antibiotics to treat typhoid fever. We need to shift our paradigm away from treatment and toward prevention.

Fortunately, we now have a promising new preventative tool. Typhoid conjugate vaccines are a newly WHO-prequalified class of typhoid vaccines that, compared to older typhoid vaccines, are longer-lasting, require fewer doses, and can be given to children as young as 6 months of age. Because they can be given to young children, countries can include typhoid conjugate vaccines in routine immunization programs, developing widespread immunity to typhoid and stopping dangerous strains like H58 from spreading and evolving. When implemented alongside improvements in water, sanitation, and hygiene, these vaccines can have the power to take on typhoid for good.

Typhoid may be smart, but we know how to outsmart it. We just have to act now.

This blog is reposted from Take on Typhoid website,

About the Author:
Professor Gordon Dougan is a Group Leader at the Wellcome Sanger Institute and University of Cambridge Department of Medicine.

Elizabeth Klemm is a postdoctoral researcher in Gordon Dougan's research group at the Wellcome Sanger Institute.

Related publication:
Elizabeth Klemm et al. (2018) Emergence of an extensively drug-resistant Salmonella enterica Serovar Typhi clone harboring a promiscuous plasmid encoding resistance to Fluoroquinolones and third-generation Cephalosporins. mBioDOI: 10.1128/mBio.00105-18

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