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06 Dec 2023

Landmark Salmonella Typhi genomic study provides crucial insights into regional and global antimicrobial resistance (AMR) patterns

An estimated 2.2 billion people globally do not have access to clean water, sanitation and hygiene, posing a risk for typhoid fever infection. Salmonella Typhi, the bacterium that causes typhoid fever, has shown increased and extreme resistance to drugs. Indeed, decades-long reliance on antimicrobials for its treatment, along with overuse and misuse of the medication, have resulted in antimicrobial resistance (AMR) — a serious public health challenge.

In an international, landmark study on Salmonella Typhi, researchers from the Doherty Institute joined nearly 200 scientists from around the world to understand the differences in variants of the Typhi bacteria and their resistance to antimicrobial agents globally. As part of this Global Typhoid Genomics Consortium, researchers collectively analysed the genomes of 13,000 Typhi samples from 110 countries under an open data-sharing model, making it one of the largest and most unique studies in bacterial genomics.

University of Melbourne’s Dr Danielle Ingle, NHMRC Emerging Leadership Fellow at the Doherty Institute, co-author of the paper and member of the Steering Committee of the Global Typhoid Genomics Consortium, said the research sheds light on Salmonella Typhi's genetic diversity and AMR patterns globally, revealing some concerning trends.

“The study highlights the wide variation between countries and regions in terms of which variants of the Salmonella Typhi bacteria are present and which antimicrobial agents they have evolved resistance to. Most studies have focussed on a multidrug-resistant lineage called H58; however, by combining data from different countries, we showed that other countries have their own local variants that have evolved to be equally drug-resistant,” said Dr Ingle.

The results show that more than 85 per cent of typhoid infections in South Asian countries are caused by ciprofloxacin non-susceptible Salmonella Typhi, and that this non-susceptibility is also becoming common in some African countries. Importantly, the data show that resistance can emerge in whichever Salmonella Typhi variants are present in a local setting. So, whilst international transmission does occur, and can contribute to the spread of resistance between countries, all countries are at risk of evolving resistant variants and local monitoring is important wherever typhoid disease occurs.

Whether these strains can spread to neighbouring countries or have done so already remains unknown. The lack of widespread surveillance means that first-line WHO-recommended drugs, like ciprofloxacin, are likely to be used in areas where resistance is already present but still undetected, which may lead to prolonged disease, greater chances of transmission and severe complications, such as intestinal perforations.

The infectious disease community has watched anxiously since the emergence of an extensively drug-resistant (XDR) typhoid variant in Pakistan in 2016. This variant is resistant to all oral drugs except azithromycin and has caused outbreaks across Pakistan, prompting emergency use of new typhoid conjugate vaccines (TCVs), and more recently, the introduction of TCV into the national immunisation program.  

This study confirms that XDR typhoid has not yet become established in other regions. Alarmingly, it did identify variants that are resistant to both ciprofloxacin and ceftriaxone, and azithromycin resistance mutations arising in multiple different bacterial variants across South Asia.

The lead author of the study, Dr Megan Carey, a Postdoctoral Research Fellow at the London School of Hygiene and Tropical Medicine, said the study demonstrates the power of collective genomic data sharing and analyses for a high-priority bacterial pathogen but also underscored extensive gaps.

“This analysis paints a worrying picture of the increasing prevalence and severity of antimicrobial resistance (AMR) in Salmonella Typhi globally, as we are running out of viable treatment options for typhoid fever, particularly in South Asia,” said Dr Carey.

“This large-scale study demonstrates the enormous power of collective genomic data sharing and analysis. We hope that it will encourage policymakers to consider implementing preventative interventions, like typhoid conjugate vaccines, to reduce the global incidence of typhoid fever and limit the emergence and spread of AMR.”

Peer review: Carey M, et al. Global diversity and antimicrobial resistance of typhoid fever pathogens: Insights from a meta-analysis of 13,000 Salmonella Typhi genomes. eLife (2023). DOI: 10.7554/eLife.85867

Funding: European Union, Wellcome Trust and NHMRC