Antibiotic Resistance of Typhoid-Causing Bacteria Spreads Globally

The bacteria that cause Typhoid fever are becoming increasing resistant to antibiotics, according to new research published tonight in The Lancet.

This largest ever genome sequencing study of the bacteria Salmonella enterica serovar Typhi (S Typhi) found strains have been developing resistance to 2 major antibiotics, macrolides and quinolones.

"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,” said Dr. Jason Andrews, the lead author of the study.

Typhoid fever is considered a global public health concern, causing an estimated 11 million infections and 100000 deaths each year. Antibiotics are typically effective against typhoid fever, but their efficacy is limited by the rise of S Typhi antimicrobial resistance.

Other studies of the rise and spread of antibiotic-resistant S Typhi were limited by theor relatively small sample sizes. This study analyzed more than 7500 S Typhi genomes, performing whole-genome sequencing on 3489 S Typhi blood sample isolates.

The samples were obtained from people with confirmed cases of typhoid fever in Bangladesh, India, Nepal, and Pakistan. Typhoid fever is most prevalent in South Asia, accounting for 70% of its global disease burden. The study found that resistant strains of S Typhi largely originated in South Asia, but have since spread to other areas nearly 200 times since 1990.

The final analysis included 4169 S Typhi samples previously isolated from 1905-2018 across more than 70 countries. Using genetic databases, the investigators identified resistance-conferring genes in a total of 7658 sequenced genomes. The isolates were considered multidrug-resistant if they were resistant to the typical front-line antibiotics ampicillin, chloramphenicol, and trimethoprim/sulfamethoxazole. Additionally, gene resistance to macrolides and quinolones was included, as these antibiotics are considered critical to human health.

The investigators found that since 2000, multidrug-resistant S Typhi remained low in Nepal, steadily declined across Bangladesh and India, and slightly increased in Pakistan. However, these strains are being replaced by new S Typhi strains resistant to other antibiotics.

Quinolone resistance in S Typhi was found to have risen and spread at least 94 times since 1990, with 97% of these strains originating in South Asia. By the early 2000s, these quinolone-resistant strains accounted for over 85% of S Typhi in Bangladesh. By 2010, the quinolone-resistant strains represented more than 95% of S Typhi in India, Pakistan, and Nepal.

Antibiotic-resistant mutations to the widely used azithromycin were found to have emerged at least 7 times in the last 20 years. S Typhi strains with azithromycin-resistance have steadily increased since they were first identified in 2013.

The resistant strains were most prevalent in South Asia, Southeast Asia, and East and Southern Africa. However, they were also identified in the UK, US, and Canada.

“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,” Andrews said.