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Wellcome Sanger Institute scientists uncover secret of multi-drug resistant typhoid sweeping through Pakistan

A drug-resistant strain of typhoid has hit Pakistan
A drug-resistant strain of typhoid has hit Pakistan

The strain has even reached the UK - but the case was isolated and treated

Elizabeth Klemm, of Wellcome Sanger Institute, Picture: Phil Mynott
Elizabeth Klemm, of Wellcome Sanger Institute, Picture: Phil Mynott

An extensively drug-resistant strain of typhoid is spreading through Pakistan and treatment options are running out.

The strain even reached the UK through air travel, but the case was isolated and treated.

Now scientists at the Wellcome Sanger Institute and their collaborators at Public Health England and Aga Khan University in Pakistan have identified the genetic cause behind the strain’s resistance to five classes of antibiotics.

Their research showed it had acquired an additional piece of DNA, enabling it to become resistant to more antibiotics, including a third-generation antibiotic.

The results, published in mBio, suggest treatment options are running out and there is an urgent need for preventative strategies including vaccines.

Professor Gordon Dougan, a senior author from the Wellcome Sanger Institute and University of Cambridge Department of Medicine, said: “We have used genetic sequencing to uncover how this particular strain of typhoid became resistant to several key antibiotics. Sporadic cases of typhoid with these levels of antimicrobial resistance have been seen before, but this is the first time we’ve seen an ongoing outbreak – which is concerning.”

An emergency vaccination campaign is under way in Pakistan, where the outbreak began in November 2016.

It was immediately recognised and reported to provincial public health authorities in the country, and investigation into possible sources and control measures continue.

While public health alerts help doctors recognise cases of typhoid resistant to ceftriaxone, a drug reserved to treat multidrug-resistant infections, this strain was resistant to five antibiotics – the highest seen. The doctors have been using the few remaining antibiotic options available to them.

Prof Rumina Hasan and Dr Sadia Shakoor from the Aga Khan University contacted the Wellcome Sanger Institute in spring 2017 to seek genetic analysis of the outbreak.

The Hinxton-based Institute’s scientists performed whole genome sequencing of typhoid samples from Pakistan and discovered the outbreak was caused by strain H58, which is known to be associated with multi-drug resistance.

But this strain had gained an extra strand of bacterial DNA – a plasmid – that encoded for additional antibiotic resistance genes.

It is possible that typhoid strain picked up the plasmid from E.coli.

Dr Elizabeth Klemm, co-first author from the Wellcome Sanger Institute, added: “Antibiotic resistance has been mounting in typhoid for decades. This outbreak was caused by a multidrug-resistant strain that had gone a step further and acquired an extra piece of DNA encoding additional genes for antibiotic resistance. We therefore classified this strain of typhoid as extensively drug-resistant. This is the first time we have seen an outbreak of extensively drug-resistant typhoid.”

Typhoid fever is a bacterial infection caused by the bacterium Salmonella enterica serovar Typhi, which is related to the bacteria that cause salmonella food poisoning.

Highly contagious, it spreads in areas with poor water sanitation when contaminated food or water is consumed. Symptoms include fever, stomach pain, headache and constipation or diarrhoea. If left untreated, it can be fatal.

Scientists at Public Health England found the same strain in an individual who had recently returned to the UK from Pakistan. Genomic comparison confirmed it was identical. The case was isolated and treated.

Dr Charlie Weller, Wellcome’s head of vaccines, said: “The treatment options for typhoid are running out. It’s time we focus on prevention, in addition to treatment.

“Vaccines offer another way to tackle drug resistant infections and we have a unique opportunity to address typhoid with a new typhoid conjugate vaccine that has been recently prequalified by the World Health Organisation.”

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