Stanford University-led research has identified that bacteria causing typhoid fever are becoming progressively resistant to the antibiotics used to combat the infection.
The novel research included the largest ever genome analysis of Salmonella enterica serovar Typhi (S. Typhi), the bacteria that cause typhoid fever. The results illuminated that since 1990, resistant strains have spread to almost 200 countries worldwide, with the majority originating in South Asia.
The study is published in The Lancet Microbe journal.
The global burden of Typhoid fever
Typhoid fever causes 11 million infections and over 100,000 deaths annually, making it one of the most prominent global threats to human health and accounting for 70% of the disease burden worldwide. The condition is most common in South Asia but also affects sub-Saharan Africa, Southeast Asia, and Oceania.
Typhoid fever infections are predominantly treated with antibiotics; however, the effectiveness of the medications is decreasing over time due to the rise of resistant S. Typhi strains. Until now, examining the global prevalence of resistant S. Typhi has been limited.
Analysing resistant S. Typhi strains
The researchers conducted whole-genome sequencing on 3,489 S. Typhi isolates acquired from blood samples from people in Bangladesh, India, Nepal, and Pakistan who had confirmed cases of typhoid fever between 2014 and 2019. The team also sequenced 4,169 S. Typhi samples from over 70 countries between 1905 and 2018.
By employing genetic databases, the researchers discovered resistance-conferring genes in the 7,658 sequenced genomes. They classified strains as multidrug-resistant (MDR) if they comprised genes that drive resistance towards common antibiotics such as ampicillin, chloramphenicol, and trimethoprim/sulfamethoxazole. In addition, they analysed genes that cause resistance to two of the essential antibiotics for human health – macrolides and quinolones.
The results highlighted that resistant S. Typhi strains have disseminated across countries at least 197 times since 1990, with most occurring in South Asia, Southeast Asia, and East and Southern Africa. However, some were reported in the USA, UK, and Canada. MDR S. Typhi has reduced since 2000 in India, Bangladesh, and Nepal but has increased slightly in Pakistan but has been replaced by strains resistant to other antibiotics.
What antibiotics have been affected?
Gene mutations that cause resistance to quinolones were discovered 94 times since 1990, with 97% originating in South Asia. Moreover, in the early 2000s, quinolone-resistant strains accounted for over 85% of S. Typhi in Bangladesh, increasing to 95% in Pakistan, India, and Nepal by 2010.
Mutations that cause resistance to azithromycin were identified seven times throughout the past two decades and have increased dramatically in Bangladesh since emerging in 2013. The results build on recent findings of S. Typhi strains resistant to another vital class of antibiotics called third-generation cephalosporins.
Dr Jason Andrews, the lead author of the research from Stanford University, said: “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 fever control and antibiotic resistance more generally, as a global rather than local problem.”
Study limitations
The researchers noted that a limitation of their study was an underrepresentation of S. Typhi sequences in regions where typhoid fever is endemic, such as countries in sub-Saharan Africa and Oceania. Furthermore, sampling came from a small number of surveillance sites and may not represent the actual distribution of circulating strains as the S. Typhi genomes only cover a portion of typhoid fever cases. This means that estimates of resistance-causing mutations and international spread are potentially underestimated.
