Bacteria causing Typhoid fever are becoming increasingly resistant to the macrolide and quinone antibiotic classes, according to a study published in The Lancet Microbe. The largest genome analysis of Salmonella enterica serovar Typhi also reveals that resistant strains, mostly from South Asia, have spread to other countries nearly 200 times since 1990.
Typhoid fever is a global public health concern, causing 11 million infections and more than 100 000 deaths per year. While it is most prevalent in South Asia, making 70% of global cases, it also has significant impacts in sub-Saharan Africa, Southeast Asia, and Oceania, highlighting the need for a global response.
Typhoid fever infections are treatable with antibiotics, but their effectiveness is threatened by the emergence of resistant S. Typhi strains. Thus far, little is known about the rise and spread of resistant S. Typhi has so far been limited, with most studies based on small samples, prompting researchers led by Stanford University to conduct a wider spread study.
The study researchers genetically sequenced 3489 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 4169 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 7658 sequenced genomes were identified using genetic databases. Strains were classified as multidrug-resistant (MDR) if they contained genes giving resistance to classical front-line antibiotics ampicillin, chloramphenicol, and trimethoprim/sulfamethoxazole. The authors also traced the presence of genes conferring resistance to the crucially important macrolides and quinolones.
The analysis shows resistant S. Typhi strains have spread between countries at least 197 times since 1990. While these strains most often occurred within South Asia and from South Asia to Southeast Asia, East and Southern Africa, they have also been reported in the UK, USA, and Canada.
Since 2000, MDR S. Typhi has declined steadily in Bangladesh and India, and remained low in Nepal (less than 5% of Typhoid strains), though it has increased slightly in Pakistan. However, these are being replaced by strains resistant to other antibiotics.
For example, gene mutations giving resistance to quinolones have arisen and spread at least 94 times since 1990, with nearly all of these (97%) originating in South Asia. Quinolone-resistant strains accounted for more than 85% of S. Typhi in Bangladesh by the early 2000s, increasing to more than 95% in India, Pakistan, and Nepal by 2010.
Azithromycin resistance mutations have emerged at least seven times in the past 20 years. In Bangladesh, strains with these mutations emerged around 2013, and since then their population size has steadily increased. The findings add to recent evidence of the rapid rise and spread of S. Typhi strains resistant to third-generation cephalosporins, another class of antibiotics critically important for human health.
“The speed at which highly-resistant strains of S. Typhi have emerged and spread in recent years is a real cause for concern, and highlights the need to urgently expand prevention measures, particularly in countries at greatest risk. At the same time, the fact resistant strains of S. Typhi have spread internationally so many times also underscores the need to view typhoid control, and antibiotic resistance more generally, as a global rather than local problem.”
Dr Jason Andrews, Study Lead Author Stanford University
The authors acknowledge some limitations to their study. S. Typhi sequences are underrepresented in several regions, particularly 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 patterns of spread.
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. As S. Typhi genomes only cover a fraction of all typhoid fever cases, estimates of resistance-causing mutations and international spread are likely underestimated. These potential underestimate highlight the need to expand genomic surveillance to provide a more comprehensive window into the emergence, expansion, and spread of antibiotic-resistant organisms.