Scientists uncover genetic cause behind typhoid's antibiotic resistance

The genetic cause behind a strain of typhoid's resistance to five classes of antibiotics has been uncovered by scientists at the Wellcome Sanger Institute and their collaborators at Public Health England and Aga Khan University, Pakistan. There is currently a major outbreak of typhoid fever in Pakistan, and there was a case in the UK following air travel, which has been isolated and treated. This study shows the typhoid strain causing the outbreak acquired an additional piece of DNA to become resistant to multiple antibiotics, including a third-generation antibiotic.

The results, published today (20 February) in mBio suggest that treatment options are running out for typhoid, and there is an urgent need for preventative strategies including vaccines.

Typhoid fever is a bacterial infection caused by the bacterium Salmonella enterica serovar Typhi. It is highly contagious, and spreads through a human population in areas with poor water sanitation when contaminated food or water is consumed. Symptoms include fever, stomach pain, headache and constipation or diarrhea, and if left untreated it can become fatal.

Currently, an outbreak of drug-resistant typhoid is spreading through Pakistan and an emergency vaccination campaign is underway.

The outbreak began in November 2016, and was immediately recognized and reported to provincial public health authorities in Pakistan, where investigation into possible sources and control measures including use of a vaccine are ongoing. Public health alerts helped physicians recognize cases of typhoid that were resistant to ceftriaxone, an antibiotic reserved to treat multidrug-resistant infections. This strain was resistant to five antibiotics in total, a higher level of resistance than previously seen. The doctors treated the infections with the few remaining antibiotic options.

In the spring of 2017, collaborators Professor Rumina Hasan and Dr Sadia Shakoor from the Aga Khan University in Pakistan contacted the Wellcome Sanger Institute to genetically analyze the outbreak. Sanger Institute scientists performed whole genome sequencing of typhoid samples from Pakistan to investigate the genetic cause behind its high level of antibiotic resistance.

The team discovered that the typhoid outbreak was caused by strain H58, a strain known to be associated with multidrug resistance. When researchers looked further, they found this strain of H58 had gained an extra strand of bacterial DNA - a plasmid - that encoded for additional antibiotic resistance genes. The typhoid possibly picked up the plasmid from E. coli.

Scientists at Public Health England identified a strain of typhoid with the same high levels of resistance from an individual in the UK who had recently returned from Pakistan. Genomic comparison revealed that it was identical to the outbreak strain, meaning the outbreak had reached the UK, where it has been isolated and treated.

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."

Dr Elizabeth Klemm, co-first author from the Wellcome Sanger Institute, said: "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."

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."