A patient arrives at a clinic with high fever, headache and abdominal discomfort. The diagnosis is typhoid fever. But there is a complication. The bacterium causing the infection may no longer respond to an antibiotic that doctors once relied upon. The culprit is Salmonella enterica serovar Typhi, commonly known as S. Typhi.
How did a bacterium that could once be treated with familiar antibiotics become so difficult to tackle? And why has India become an important part of this story?
What is typhoid fever?
First identified in 1884, S. Typhi is a bacterium that can live and multiply inside human cells. Interestingly, humans are its only known reservoirs.
The bacterium spreads through what scientists call the faecal-oral route. When food or water becomes contaminated with faecal matter from an infected person, someone consuming it can become infected. Once inside the body, the bacterium travels through the digestive system, enters intestinal tissues and can spread to other organs, causing serious illness.
For decades, antibiotics have been central to treating typhoid. But over time, S. Typhi has developed ways of surviving some of these medicines.
The evolution of antibiotic resistance
There was a time when doctors could treat typhoid using antibiotics such as chloramphenicol, ampicillin and co-trimoxazole. But as S. Typhi developed resistance to these older drugs, doctors needed other options.
One of these was ciprofloxacin, an antibiotic belonging to the fluoroquinolone family. It works by interfering with the enzymes bacteria need to copy their DNA and multiply. For a while, fluoroquinolones became important medicines for treating typhoid. But another problem was emerging.
In India, the widespread use of these antibiotics was followed by a major shift in resistance patterns. Resistance to older drugs began declining, while resistance to fluoroquinolones became increasingly common.
Why did this happen?
An important part of the explanation is antimicrobial selection pressure, which occurs when antibiotic use favours bacteria that can survive treatment. Think of repeatedly weeding a garden. The easily killed weeds disappear, while the hardier ones survive and continue growing. Over time, the garden may become dominated by weeds that are harder to remove.
Something similar happens with bacteria. Random genetic changes, called mutations, occur as bacteria reproduce and some mutations may make them less vulnerable to an antibiotic. When that antibiotic is used, susceptible bacteria are killed or prevented from multiplying, while resistant ones can survive and reproduce.
Importantly, antibiotics do not teach bacteria how to become resistant. Rather, they create conditions in which bacteria already carrying resistance-related changes have an advantage.
What changes inside S. Typhi?
The answer lies partly in the bacterium’s DNA. The antibiotic ciprofloxacin targets two enzymes, DNA gyrase and topoisomerase IV, which help bacteria copy their DNA. But certain mutations in the genes responsible for these enzymes can make it harder for the antibiotic to work.
The genes gyrA and parC, among others, are particularly important as even a single mutation may reduce the bacterium’s susceptibility to ciprofloxacin, while additional mutations can lead to higher levels of resistance.
A genomic study of 133 S. Typhi samples from India found that almost 97% carried mutations associated with fluoroquinolone resistance. But resistance is not only about what happens inside individual bacteria. Once resistant strains multiply and spread, the problem becomes much larger.
The curious case of H58
An interesting example comes from Bengaluru. Between July 2016 and June 2017, researchers at St John’s Medical College Hospital collected S. Typhi isolates from patients with enteric fever. Their study found that approximately 96% were not susceptible to fluoroquinolones.
Among them was a resistant strain belonging to a lineage called H58. It carried three mutations associated with fluoroquinolone resistance and accounted for around 18% of the enteric fever cases in the study. Interestingly, this strain was genetically related to resistant strains previously identified in India and Nepal.
This shows that resistance is not just about individual bacteria developing mutations. Resistant strains can multiply, circulate among people and spread across geographical boundaries. But there is another twist to this story.
Is everything becoming resistant?
We often imagine antibiotic resistance as a one-way process. Once bacteria become resistant to one antibiotic, they keep accumulating resistance until eventually no medicines work. But S. Typhi in India tells a more complicated story.
A 2026 systematic review and meta-analysis examining S. Typhi isolates collected across India between 1977 and 2024 revealed some interesting patterns.
Multidrug resistance, defined as resistance to chloramphenicol, ampicillin and co-trimoxazole, declined dramatically from approximately 65% in 1990–94 to nearly zero in samples collected from 2020 onward.
Meanwhile, fluoroquinolone resistance rose from approximately 2% in 1990–94 to 85% in 2015–19, before declining somewhat in more recent years. Resistance to several other antibiotic groups remained comparatively low.
Why would resistance to some antibiotics decline while resistance to others becomes widespread?
One possible explanation brings us back to selection pressure. When patterns of antibiotic use change, the advantage of carrying certain resistance mutations can also change. Some mutations may even slow bacterial growth or reproduction, creating a biological trade-off.
In other words, antibiotic resistance is not necessarily a ladder that bacteria steadily climb towards resistance to every drug. It is more like a changing landscape, shaped by antibiotic use, bacterial genetics and transmission.
Why is India an important setting?
Several interconnected factors make India an important setting for understanding typhoid and antibiotic resistance.
Typhoid transmission remains closely linked to unsafe drinking water, inadequate sanitation and poor food hygiene. These conditions allow the bacterium to continue spreading. At the same time, limited access to diagnostic tests such as blood cultures means doctors sometimes need to prescribe antibiotics without knowing exactly which bacterium is responsible or which medicine will work. Antibiotics can also be obtained without prescriptions in some settings.
Together, these conditions create opportunities for infections to spread and resistant bacteria to survive. However, India is a large and diverse country. The 2026 meta-analysis found variations in resistance patterns across states and noted that many available samples came from major cities. National estimates, therefore, may not reflect what is happening everywhere.
Can vaccination change the equation?
So far, this story has focused on treating infections. But what if we could prevent some of them in the first place? Vaccines cannot remove resistance genes already present in bacteria. But by preventing infections, they can reduce the need for antibiotics and the selection pressure that favours resistant strains.
Typhoid conjugate vaccines (TCVs) offer one way of doing this. In Navi Mumbai, local health authorities introduced a single-dose typhoid conjugate vaccine through a municipal campaign. An evaluation found an estimated vaccine effectiveness of 83.7% among children aged nine months to 14 years.
Vaccination, alongside improvements in water, sanitation, diagnostics and appropriate treatment, can therefore play an important role in reducing infections and antibiotic resistance.
From India to the world
Interestingly, the story of resistant S. Typhi does not stop at national borders. After all, bacteria do not need a passport or visa to cross borders.
As people travel, resistant strains can travel with them. Studies have identified closely related S. Typhi strains causing infections in countries thousands of kilometres apart.
This brings us back to the patient who arrived at the clinic with a fever. Whether an antibiotic works for that patient is connected to much more than the infection itself. It is shaped by decades of antibiotic use, changes in bacterial DNA, the spread of resistant strains and the conditions in which people live and receive healthcare.
The story of typhoid in India reminds us that antibiotic resistance is neither inevitable nor a simple, one-way process. Understanding how resistance changes, and preventing infections in the first place, are both essential to keeping our antibiotics effective for longer.
Niveditha A M is a first year PhD student in Infection Biology at NCBS, Bengaluru. Her research explores the complex interactions between Mycobacterium tuberculosis and the host immune system. She is also passionate about making infectious disease research accessible to the public through science communication.