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Typhoid mutated to beat antibiotics. Science is learning how to beat those strains

Scanning electron micrograph of <em data-stringify-type="italic">Salmonella typhi</em>, the parasite that causes typhoid fever (in yellow-green, attached to another bacterial cell.
Science Source
Scanning electron micrograph of Salmonella typhi, the parasite that causes typhoid fever (in yellow-green, attached to another bacterial cell.

Do you remember the story of Typhoid Mary – the cook who spread typhoid to as many as 100 people in the early 1900s even though she herself showed no symptoms? She was confined to isolation for 26 years because, at the time, there weren't any treatments that could cure this so-called "healthy carrier."

Since then we've developed powerful antibiotics that could have wiped out Mary's typhoid and that have been used to successfully treat many millions with the disease.

But the ancient disease of typhoid has adapted to modern times. New antibiotic-resistant strains are on the rise, fueling outbreaks across the world and making up a greater percentage of the yearly toll of 10 to 20 million cases and 100,000 deaths. And now science is fighting back by ramping up vaccine campaigns and figuring out more efficient ways to find cases of typhoid.

"Typhoid Mary," the cook believed to have infected some 100 people with the disease, as depicted in the <em>New York American, </em>June, 1909.
/ The New York Public Library
The New York Public Library
"Typhoid Mary," the cook believed to have infected some 100 people with the disease, as depicted in the New York American, June, 1909.

Typhoid superbugs made their debut around 1950

Some things about typhoid are unchanged from the days of Typhoid Mary. The disease is caused by the bacteria Salmonella enterica serovar Typhi (S Typhi). This strain of bacteria only infects humans – as far as we know – and spreads through contact with infected feces. Symptoms include high fever, fatigue and digestive problems, which can eventually result in internal bleeding and death.

Antibiotic-resistant typhoid first appeared on the scene around 1950. Since then, nearly every time a new antibiotic with the potential to cure typhoid is developed, a new strain emerges that can beat it.

"It's this back and forth. We develop new drugs, typhoid becomes resistant," says Dr. Jason Andrews, associate professor of infectious diseases at Stanford University. "It's just happened over and over again, now for 70 years."

The worst strain is called XDR – short for extensively drug resistant. It first emerged in Pakistan in 2016 and by 2019 became the dominant strain in the country. It's also spread to other countries, according to research published in June in The Lancet Microbe. This spread is what concerns scientists like Andrews, an author of the paper. That's because there is only one oral antibiotic that can cure XDR typhoid: azithromycin, which was approved for medical use in 1988 and is one of the most commonly prescribed antibiotics on the market. But researchers are concerned that the widespread use of azithromycin could lead XDR to become resistant to the drug.

A new vaccine could be the key to stopping XDR typhoid

So how can XDR be stopped? One relatively new weapon in the typhoid arsenal is a vaccine that the World Health Organization recommended for use in 2018. It's called Typbar, and it combines two types of antigens – parts of the bacteria the human immune system can recognize – to stimulate an immune response and prevent infection from typhoid, even if it's resistant to antibiotics.

Last year the results of three trials for the vaccine were published, each demonstrating roughly 80% effectiveness in preventing typhoid infection among about 90,000 total children vaccinated in areas where XDR typhoid is rampant.

And there's been even more good news since the vaccine has been widely used in not only Pakistan but also in Liberia, Zimbabwe and Nepal.

Now that the vaccine is no longer in trials, far more than 90,000 people have been vaccinated, and the preliminary results outpace the trial data. "The vaccination campaign in Pakistan was about 95% effective [at preventing typhoid infection]," says Dr. Kathy Neuzil, director of the Center for Vaccine Development and Global Health at the University of Maryland.

But even though the vaccine has brought down the number of cases, it hasn't exactly kayoed XDR. The vaccine hasn't yet been able to make a dent in the rate of XDR infections in Pakistan. "Before vaccination, 60 to 70% of typhoid infections [in Pakistan] were from XDR and that's continuing to be the case even after the vaccination campaign," says Dr. Farah Qamar of Aga Khan University, a Pakistani researcher working on typhoid for over a decade. Qamar says she would have expected XDR to start going away because fewer cases means fewer antibiotics are being prescribed, but that doesn't seem to have happened.

To slow the spread of typhoid, we first need to find out where it is

So what's the problem? One issue is that supply of the vaccine is limited and it's not easy to figure out where it'll do the most good. In an ideal situation, doses would be sent to regions with the highest number of XDR cases. However, current tools for detecting typhoid aren't good enough to pinpoint such hot spots.

"The big challenge with typhoid is that it's very difficult to diagnose, so we know that it's there, but we don't actually know how much of it there is," says Dr. Kristen Aiemjoy, professor of epidemiology at UC Davis. "Blood culture is the gold standard diagnostic for typhoid and it's actually not that great. It only has a sensitivity of 60% – out of every 100 true cases, you're missing 40. On top of that, it's expensive and is typically only available in reference hospitals and capital cities."

To better count cases of typhoid, scientists have developed a new tool, also reported in The Lancet Microbe in June, that only requires a drop of blood from a finger prick to find the disease. Even if the blood was drawn for other reasons – like looking for COVID cases – the tool can still be used to detect typhoid. The hope is that this method will help determine what researchers refer to as the "force of infection" – how quickly typhoid is spreading in a country.

"That's the metric that is actually much more relevant to public health planning, because that tells you where cases are likely to increase. This can be used to justify where to roll out the vaccine," says Aiemjoy.

Doctors Without Borders has helped introduce this tool in countries that likely have a lot of typhoid but poor data on its prevalence, like South Sudan.

Open sewage running alongside households in Vellore, India. Poor sanitation practices can lead to rapid spread of typhoid, which can be contracted by contact with infected feces.
/ Jason Andrews
Jason Andrews
Open sewage running alongside households in Vellore, India. Poor sanitation practices can lead to rapid spread of typhoid, which can be contracted by contact with infected feces.

Getting rid of typhoid completely, however, requires dealing with the source of outbreaks –water and food contaminated with infected fecal matter. "There is very much a need for improved water and sanitation, because unless that happens, we will not be able to control typhoid or other similar diseases," says Qamar.

This has been done before. "Typhoid was a leading cause of morbidity in the United States in the 19th century then was nearly eliminated city by city over a period of 10 years," says Andrews. Simple measures like connecting houses to proper sewage systems and clean water lines were all it took.

Infrastructure of course can't be improved overnight. In the meantime, Andrews is optimistic that with better diagnosis data and the effective vaccines, antibiotic-resistant strains of typhoid will be prevented from spreading further.

"The vaccines aren't enough to eliminate typhoid as we know it, but hopefully they can knock down incidence [of typhoid] to more manageable levels, while we try to institute more permanent and effective measures for elimination, like clean water and sanitation."

Copyright 2022 NPR. To see more, visit https://www.npr.org.

Max Barnhart
Max Barnhart is the 2022 AAAS Mass Media Science and Engineering Fellow at NPR. He is a 5th year Ph.D. candidate and science journalist studying the evolution of heat stress resistance in sunflowers at the University of Georgia.