Typhoid fever may be uncommon in developed countries, but this ancient threat, considered to have existed for millennia, remains a threat in our modern world.

According to new research, the bacterium that creates typhoid fever is developing widespread drug resistance and rapidly replacing susceptible strains.

Antibiotics are currently the only effective treatment for typhoid, which is caused by the bacterium Salmonella enterica serovar Typhi (S Typhi). Nonetheless, the bacterium's resistance to oral antibiotics has grown and spread over the last three decades.

Researchers discovered a recent increase in extensively drug-resistant (XDR) Typhi after sequencing the genomes of 3,489 S Typhi strains contracted from 2014 to 2019 in Nepal, Bangladesh, Pakistan, and India.

XDR Typhi is resistant not only to first-line antibiotics such as ampicillin, chloramphenicol, and trimethoprim/sulfamethoxazole but also to newer antibiotics such as fluoroquinolones and third-generation cephalosporins. Worse, these strains are rapidly spreading around the world.

While the majority of XDR Typhi cases are from South Asia, researchers have documented nearly 200 cases of international spread since 1990.

The majority of strains were exported to Southeast Asia, as well as East and Southern Africa, but typhoid superbugs were also discovered in the United Kingdom, the United States, and Canada.

The first XDR typhoid strain was discovered in Pakistan in 2016. It had become the dominant genotype in the country by 2019.

Most XDR typhoid strains have traditionally been treated with third-generation antimicrobials such as quinolones, cephalosporins, and macrolides.

Scientists have been advising about drug-resistant typhoid for years, but this is the most comprehensive genome analysis of the bacterium to date.

However, by the early 2000s, mutations that confer quinolone resistance accounted for more than 85% of all cases in Bangladesh, India, Pakistan, Nepal, and Singapore. Simultaneously, cephalosporin resistance was spreading.

Today, only one oral antibiotic remains azithromycin, a macrolide. And this medication may not be effective for much longer.

The new study discovered that mutations that confer azithromycin resistance are now spreading, threatening "the efficacy of all oral antimicrobials for typhoid treatment." While XDR S Typhi has not yet adopted these mutations, if they do, we are in big trouble.

Future outbreaks can be mitigated to some level with typhoid conjugate vaccines, but if global access to these shots is not expanded, the world may soon face another health crisis.

South Asia may be the main hub for typhoid fever, accounting for 70% of all cases, but if COVID-19 has taught us anything, it is that disease variants are easily spread in our modern, globalized world.

To avoid this, health experts argue that countries should increase access to typhoid vaccines and invest in new antibiotic research. According to one recent study in India, vaccinating children against typhoid in urban areas could prevent up to 36% of typhoid cases and deaths.