Drug-Resistant Typhoid Is Spreading Across Borders, Genomes Reveal a Global Pattern

Typhoid fever has long been treated as a disease of poor sanitation and limited access to clean water. It remains responsible for an estimated 11 million infections and more than 100,000 deaths each year. Most cases occur in South Asia, which carries about 70 percent of the global burden.

For decades, antibiotics have kept typhoid manageable. But the bacterium behind the disease, Salmonella enterica serovar Typhi, has been steadily changing.

A large international team has now traced those changes at the genetic level. Their findings show that drug resistance in typhoid has not appeared just once or twice. It has emerged repeatedly, spread across borders, and in many places replaced strains that were once easier to treat.

The study was published in The Lancet Microbe in August 2022.

Building a Global Genetic Map

To understand how resistance developed and moved, researchers sequenced the genomes of 3,489 Salmonella Typhi isolates collected between 2014 and 2019 in Bangladesh, Nepal, Pakistan, and India. These samples came from large surveillance projects that enrolled children and adults with blood culture confirmed typhoid.

The team then combined these new sequences with 4,169 previously collected genomes from more than 70 countries, dating as far back as 1905.

In total, 7,658 bacterial genomes were analyzed.

Each genome acts like a historical record. By comparing small genetic differences, known as single nucleotide polymorphisms, scientists can build evolutionary trees. These trees show how strains are related and help estimate when new lineages appeared.

One Lineage Dominates

About 71 percent of the newly sequenced isolates belonged to a lineage known as 4.3.1, often called H58. This lineage has been associated with multidrug resistance for several decades and has become globally dominant.

When placed into a global phylogenetic tree, most South Asian isolates clustered together. This pattern suggests that the region has played a central role in shaping modern typhoid evolution.

The researchers identified 29 distinct genotypes among the new samples. While H58 was the most common, several non H58 lineages also circulated widely in South Asia.

The Rise and Fall of Multidrug Resistance

Multidrug resistant typhoid, defined as resistance to ampicillin, chloramphenicol, and trimethoprim sulfamethoxazole, first appeared in the 1970s.

From 2000 onward, the proportion of multidrug resistant isolates declined in Bangladesh and India. Nepal maintained a relatively low and stable proportion. Pakistan, however, showed a different pattern, with an increase linked to a new form of resistance.

Globally, 26.8 percent of the 7,657 analyzed isolates carried genes associated with multidrug resistance. Nearly all of these belonged to the H58 lineage.

In earlier decades, resistance genes were often carried on plasmids, which are mobile DNA elements. Over time, many H58 strains integrated these resistance genes into their chromosomes. This shift allows resistance to be passed down more stably from one generation of bacteria to the next.

Fluoroquinolone Resistance Becomes Common

As older first line drugs lost effectiveness, fluoroquinolones became widely used in the 1990s. By the 2010s, however, resistance to these drugs had become common in South Asia.

Mutations in specific regions of the bacterial genome, known as quinolone resistance determining regions, reduce susceptibility to fluoroquinolones. These mutations affect genes such as gyrA and parC, which are involved in DNA replication.

The study found that mutations in these regions had arisen independently at least 94 times over the past three decades. Nearly all of these events occurred in South Asia.

From 2010 onward, strains carrying multiple mutations became more frequent. More than 10 percent of all isolates had three such mutations, which are associated with high level resistance.

Among the newly sequenced samples, 437 were triple mutants. Most belonged to a sublineage circulating in India and Nepal.

Extensively Drug Resistant Typhoid in Pakistan

In 2016, Pakistan reported an outbreak of extensively drug resistant, or XDR, typhoid. These strains were resistant not only to first line drugs and fluoroquinolones, but also to third generation cephalosporins.

Genetically, these strains belong to a subgroup of H58 and carry additional resistance genes on an IncY plasmid.

The new analysis shows how quickly this strain expanded. By 2018, XDR organisms had eclipsed non XDR H58 strains in Pakistan.

Phylodynamic modeling, which estimates changes in effective population size over time, revealed a rapid rise in the XDR population after 2016. As this resistant group expanded, less resistant strains declined.

Azithromycin Resistance Emerges

Azithromycin has been one of the last widely available oral treatments for typhoid. The study identified mutations in the acrB gene that confer resistance to this drug.

These mutations appeared independently at least seven times. Most cases were detected in Bangladesh beginning around 2013.

In Bangladesh, the effective population size of azithromycin resistant H58 strains has steadily increased since their emergence. So far, strains combining XDR and azithromycin resistance have not been identified in this dataset.

Tracking International Spread

The researchers reconstructed the timing and location of strain movements using dated phylogenetic trees.

They identified at least 197 introduction events between countries over the past 30 years. Of these, 138 occurred within continents and 59 crossed continental boundaries.

The majority involved antimicrobial resistant strains.

The H58 lineage appears to have emerged around 1984. Analyses of genetic diversity and geographic distance pointed to the Indian subcontinent as the most probable origin.

From there, resistant strains spread within South Asia and into Southeast Asia, East Africa, Southern Africa, and beyond. Travel related cases were also identified in the United Kingdom and the United States.

In many locations, once a resistant strain arrived, it became locally established and replaced susceptible strains.

Repeated, Independent Evolution

One striking finding is how often resistance has arisen independently.

Fluoroquinolone resistance mutations appeared at least 94 separate times. Azithromycin resistance mutations appeared at least seven times. These events were not limited to a single lineage.

This pattern suggests strong selective pressure from antibiotic use. When similar drugs are widely used across a region, different bacterial populations can evolve similar solutions.

The study also shows that resistance is not confined to the dominant H58 lineage. Several non H58 genotypes acquired resistance genes and spread regionally.

Shifting Treatment Landscape

While multidrug resistance to older drugs appears to be declining in parts of South Asia, it has been replaced by resistance to newer antibiotics.

In some African regions, multidrug resistant strains remain common or are increasing. This variation highlights how local antibiotic use and public health conditions shape bacterial evolution differently across regions.

The rapid expansion of XDR typhoid in Pakistan demonstrates how quickly a new resistant clone can dominate.

Implications for Control

The findings suggest that decisions about typhoid control cannot rely only on local data at a single moment in time.

Because resistant strains frequently move across borders, a country with low resistance today may face different conditions within a few years.

The study emphasizes the importance of genomic surveillance. Sequencing allows public health authorities to detect emerging resistance early and to track its spread.

Vaccination is another key tool. Typhoid conjugate vaccines have shown effectiveness in preventing disease. Introducing vaccines before resistance becomes widespread may help reduce transmission and limit the expansion of resistant strains.

Limitations and Gaps

Although this analysis includes the largest collection of Salmonella Typhi genomes to date, some regions remain underrepresented. Parts of sub Saharan Africa and Oceania contributed relatively few sequences.

Most isolates were also drawn from specific surveillance sites, which may not capture the full diversity of circulating strains.

Because genome sequences represent only a fraction of all infections, estimates of resistance emergence and international transfer likely represent lower bounds.

A Global Pattern in a Local Disease

Typhoid fever is often described as a disease of local infrastructure. Yet its bacterial evolution shows a global pattern.

Over the past 30 years, antimicrobial resistant Salmonella Typhi strains have repeatedly emerged in South Asia. Many have crossed borders and continents. Once introduced into new settings, they have often expanded and replaced susceptible strains.

This dynamic underscores that antibiotic resistance is not confined by national boundaries. The genetic record shows that the bacterium moves with people, adapts to drug pressure, and establishes itself wherever conditions allow.

Understanding this pattern is essential for designing control strategies that anticipate change rather than respond to it after the fact.

The research was first published in The Lancet Microbe on August 01, 2022.