Typhoid fever is becoming immune to almost all antibiotics, causing great concern

Typhoid fever, which was once knocked down by simple pills, is standing up again. The bacterium Salmonella typhi now shows resistance to almost every antibiotic that doctors throw at it.

“The speed at which highly‑resistant strains of S. typhi have emerged and spread in recent years is a real cause for concern,” said Jason Andrews of Stanford University 

How typhoid resistance happens

Modern treatment depends on antibiotics killing the typhoid bacterium faster than it mutates. That race is tilting toward the microbe because antimicrobial resistance grows every time a course of drugs is cut short or the wrong medicine is prescribed.

Genomic work on 3,489 isolates from India, Pakistan, Nepal, and Bangladesh shows resistant typhoid strains replacing susceptible ones in only a few years.

Some of those isolates carry three mutations in the DNA‑gyrase genes that raise the ciprofloxacin dose needed a thousand‑fold, and remove a key outpatient option.

Third‑generation cephalosporins followed ciprofloxacin onto the front line in the early 2000s.

But now, a 2025 survey in Ahmedabad, India, has uncovered a cluster showing resistance to ceftriaxone, ampicillin, ciprofloxacin, and trimethoprim‑sulfamethoxazole. This marks “the largest hotspot of ceftriaxone‑resistant typhoid identified to date.”

A shrinking menu of antibiotics

Only azithromycin still works reliably by mouth. Laboratory monitoring in Pakistan found minimum inhibitory concentrations creeping upward, and a U.S. bulletin this year recorded the first two homegrown azithromycin‑resistant cases.

Typhoid resistance there comes from a single change in the AcrB efflux pump, which ejects the drug before it can act. That mutation has appeared at least seven separate times since 2013 according to whole‑genome timelines.

When azithromycin finally fails, intravenous carbapenems will be the fallback. Those drugs are expensive and scarce in many endemic regions, making hospitalization the only path to survival for many patients.

Typhoid vaccines on deck

Three typhoid vaccines are licensed worldwide, and the conjugate vaccine works in babies as young as six months.

The WHO “recommends introduction of typhoid conjugate vaccine in countries with a high burden of the disease,” a policy that is meant to cut cases before resistance spreads any wider.

Pakistan added the shot to its routine schedule in 2019 as the first nation to do so. Early surveillance suggests fewer childhood cases in vaccinated districts, which will buy time for antibiotic pipelines to catch up.

Economic models from India project that urban vaccination could prevent more than one‑third of typhoid deaths over the next decade.

That payoff grows if resistant strains keep rising, because every averted infection also avoids an expensive hospital stay.

Fueling antibiotic resistance

The same flights that move people, move pathogens. Genomic “family trees” trace at least 59 intercontinental jumps of resistant S. typhi since 1990, with most departures being from South Asia.

Once a strain lands, local water and sanitation gaps let it settle in. East Africa and Southeast Asia now report lineages that match South Asian ancestors, base pair for base pair.

Even countries with safe water see spillover. The CDC recorded about 450 culture‑confirmed typhoid cases in the United States in 2019, nearly all linked to recent travel.

Doctors there face a puzzle because routine empiric therapy may not cover the imported H58 lineage, which often resists five or more drugs. Rapid susceptibility testing, still unavailable in many clinics, is becoming a must‑have.

Typhoid resistance surveillance

Without continuous genomic surveillance, new resistant strains can spread silently across borders before health systems react.

A 2022 study tracked nearly 8,000 S. typhi genomes to map origins and movements, but this kind of data is still rare in low‑resource settings.

Health policy must keep pace with these shifts. Countries with rising resistance should not wait for full outbreaks before introducing vaccines or adjusting treatment protocols.

Rapid response depends on accurate, real‑time data and public health systems empowered to act on it.

What clinicians can do

Full 10 to 14 day azithromycin courses remain effective in most places, but follow‑up cultures are critical. Skipping the post‑treatment check risks silent carriers reseeding communities.

Where laboratories can measure ceftriaxone MICs, a rising trend should trigger public health alerts. Combination therapy, for example azithromycin plus meropenem in severe disease, can slow further resistance but raises costs.

Doctors also need to report every instance of typhoid resistance and treatment failure. Aggregated data guide updates to national formularies faster than peer‑reviewed studies can.

Big gains from basic safety measures

Researchers are trialing new oral β‑lactamase inhibitors that restore activity to cheap penicillins, but results are years away. Phage therapy and resistant‑bacteria “decoys” are on bench tops, and are promising but unproven.

Meanwhile, the biggest gains come from the basics. Safe water, sewer infrastructure, and reliable refrigeration cut typhoid risk more than any pill ever will.

Each dollar spent there pays back across multiple diseases, not just typhoid. That return on investment remains the strongest argument for governments that are watching health budgets tighten.

The study is published in the journal The Lancet Microbe.

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