Drug-Resistant Typhoid Is Spreading Across The World

Typhoid fever, an infection that has stalked humans for thousands of years, is quietly staging a dangerous comeback. New research shows the bacterium behind the disease is rapidly evolving resistance to nearly every widely used oral antibiotic.

Typhoid is caused by Salmonella enterica serovar Typhi, known as S. Typhi. For decades, antibiotics have kept the disease largely under control in many parts of the world, but experts warn this safety net is now fraying at an alarming pace.

Rising Tide of Drug Resistance

A major genomic study published in 2022 analyzed 3,489 S. Typhi samples collected between 2014 and 2019. The strains came from patients in Nepal, Bangladesh, Pakistan and India, the region where most of the world’s typhoid cases occur.

Researchers found a sharp rise in extensively drug-resistant (XDR) typhoid. These strains no longer respond to frontline antibiotics such as ampicillin, chloramphenicol and trimethoprim-sulfamethoxazole, treatments that once dramatically reduced deaths.

XDR S. Typhi is also increasingly resistant to newer antibiotics, including fluoroquinolones and third-generation cephalosporins. The study authors warned that these highly resistant strains are gradually displacing more susceptible lineages across South Asia.

Jason Andrews, an infectious disease specialist at Stanford University who was involved in the research, described the pace of evolution and spread as “a real cause for concern,” emphasizing the need to strengthen prevention efforts in regions with the highest disease burden.

Global Spread Beyond South Asia

Although South Asia remains the epicenter of the problem, XDR typhoid is no longer confined to one region. Since 1990, scientists have documented nearly 200 international transmission events involving drug-resistant strains, often linked to travel and migration.

Most exported strains have been detected in Southeast Asia and parts of East and Southern Africa. However, health authorities have also identified highly resistant typhoid strains in high-income countries, including the United Kingdom, the United States and Canada.

The first confirmed outbreak of XDR typhoid was reported in Pakistan in 2016. Within just a few years, by 2019, this resistant genotype had become the dominant strain circulating in the country, demonstrating how rapidly a successful variant can spread once established.

Historically, physicians turned to newer antimicrobial agents such as quinolones, cephalosporins and macrolides when older drugs lost effectiveness. However, by the early 2000s, quinolone-resistance mutations already accounted for more than 85% of typhoid cases in several Asian countries.

Azithromycin Under Growing Threat

Today, azithromycin remains the last widely available oral antibiotic that is still considered reliably effective against typhoid fever. Unfortunately, evidence suggests that this final line of defense is also beginning to weaken.

The 2022 study identified an increasing number of mutations associated with azithromycin resistance. These genetic changes have been detected in multiple countries, indicating that S. Typhi is continuing to evolve under the selective pressure created by antibiotic use.

For now, azithromycin-resistance mutations have not fully merged with the XDR genetic background. Researchers warn that if such a combination emerges and spreads, treatment options could become severely limited, particularly in low-resource settings where access to injectable antibiotics may be restricted.

Untreated typhoid fever can be life-threatening, with mortality rates approaching 20%. Global estimates suggest there were more than 13 million typhoid cases worldwide in 2024, highlighting the scale of the threat if effective treatments continue to lose their effectiveness.

Vaccines as a Critical Lifeline

As antibiotic resistance grows, vaccines are becoming an increasingly important tool in the fight against typhoid fever. Typhoid conjugate vaccines (TCVs) can protect young children and significantly reduce community transmission when widely implemented.

Researchers argue that expanding access to these vaccines is now an urgent priority, particularly in countries where antimicrobial resistance is already widespread. At the same time, they stress that vaccination strategies should not be limited only to high-risk regions because resistant strains can easily cross international borders.

A 2021 modeling study conducted in India estimated that routine TCV immunization in urban areas could prevent up to 36% of typhoid cases and deaths. Such reductions would not only save lives but also reduce pressure on healthcare systems and slow the spread of antibiotic resistance.

Pakistan has emerged as one of the first countries to incorporate TCVs into its routine childhood immunization program. A growing number of other nations are now introducing or planning similar vaccination campaigns.

Race to Prevent Another Crisis

As of April 2025, the World Health Organization had prequalified four typhoid conjugate vaccines. According to the U.S. Centers for Disease Control and Prevention, these vaccines are increasingly being incorporated into national immunization programs in countries where typhoid remains endemic.

Public health experts emphasize that vaccination alone will not solve the problem. Expanded vaccine coverage must be accompanied by investment in new antibiotics, improved surveillance systems and genomic sequencing programs capable of detecting emerging resistant strains before they spread widely.

Antimicrobial resistance is already among the leading causes of death worldwide, claiming more lives each year than HIV/AIDS or malaria. The resurgence of drug-resistant typhoid illustrates how quickly decades of medical progress can be undermined.

Experts note that the COVID-19 pandemic demonstrated how rapidly infectious threats can spread in an interconnected world. Strengthening sanitation infrastructure, improving access to clean water, expanding vaccination programs and accelerating antibiotic development are all considered essential components of a long-term response.

The study on XDR typhoid, published in The Lancet Microbe, has prompted renewed calls for coordinated international action. Without decisive intervention, health authorities warn that a disease that is largely preventable and treatable today could once again become a major global killer.