Bacteria that cause typhoid fever are becoming increasingly resistant to some of the most important antibiotics for human health, according to a study published in The lancet microbe log. The largest genome analysis of Salmonella enterica serovar Typhi (S. Typhi) also reveals that resistant strains — almost all of them native to South Asia — have spread to other countries nearly 200 times since 1990.
Typhoid fever is a global public health problem, causing 11 million infections and more than 100,000 deaths each year. While it is most prevalent in South Asia – which accounts for 70% of the global burden of disease – it is also having significant impacts in Sub-Saharan Africa, Southeast Asia and Oceania, highlighting the need for a global response.
Antibiotics can be used to successfully treat typhoid fever infections, but their effectiveness is threatened by the emergence of resistant S. Typhi strains. Analysis of the emergence and spread of resistant S. typhi has so far been limited, with most studies being based on small samples.
The authors of the new study performed whole-genome sequencing on 3,489 S. Typhi isolates obtained from blood samples collected between 2014 and 2019 from people in Bangladesh, India, Nepal and Pakistan with confirmed cases of typhoid fever. A collection of 4,169 S. Typhi samples isolated from more than 70 countries between 1905 and 2018 was also sequenced and included in the analysis.
Resistance conferring genes in the 7,658 sequenced genomes were identified using genetic databases. Strains were classified as multidrug resistant (MDR) if they contain genes conferring resistance to classical first-line antibiotics ampicillin, chloramphenicol and trimethoprim/sulfamethoxazole. The authors also identified the presence of genes conferring resistance to macrolides and quinolones, which are among the most important antibiotics for human health.
The analysis shows that resistant S. Typhi strains have spread between countries at least 197 times since 1990. While these strains were most common in South Asia and from South Asia to Southeast Asia, East and South Africa, they have also been reported in the UK, US and Canada.
Since 2000, MDR S. typhi has steadily declined in Bangladesh and India, and has remained low in Nepal (less than 5% of typhoid strains), although it has increased slightly in Pakistan. However, these are being replaced by strains that are resistant to other antibiotics.
For example, since 1990 there have been gene mutations resistant to quinolones and these have spread at least 94 times, almost all (97%) of which originated in South Asia. Quinolone-resistant strains accounted for more than 85% of S. Typhi in Bangladesh in the early 2000s, rising to more than 95% in India, Pakistan and Nepal in 2010.
Mutations that cause resistance to azithromycin – a commonly used macrolide antibiotic – have occurred at least seven times in the past 20 years. In Bangladesh, tribes with these mutations arose around 2013 and their population size has steadily increased since then. The findings add to recent evidence of the rapid emergence and spread of S. Typhi strains resistant to third-generation cephalosporins, another class of antibiotics critical to human health.
The rate at which highly resistant strains of S. Typhi have emerged and spread in recent years is a real cause for concern and underlines the need to urgently expand prevention measures, especially in countries with the highest risk. At the same time, the fact that resistant strains of S. Typhi have spread internationally so often also underscores the need to view typhoid control and antibiotic resistance more broadly as a global rather than a local problem.†
dr. Jason Andrews, lead author of the Stanford University study
The authors acknowledge some limitations to their study. There remains an under-representation of S. Typhi sequences from different regions, especially many countries in sub-Saharan Africa and Oceania where typhoid is endemic. More sequences from these regions are needed to improve understanding of timing and distribution patterns.
Even in countries with better sampling, most isolates come from a small number of surveillance sites and may not be representative of the distribution of circulating strains. Since the genomes of S. Typhi cover only a fraction of all cases of typhoid fever, estimates of resistance-causing mutations and international distribution are likely underestimated. This potential underestimation highlights the need to expand genomic surveillance to provide a more comprehensive picture of the emergence, expansion and spread of antibiotic-resistant organisms.
da Silva., et al† (2022) The International and Intercontinental Spread and Expansion of Antimicrobial Resistance Salmonella Typhi: a genomic epidemiological study. the lancet† doi.org/10.1016/S2666-5247(22)00093-3