Typhus has mutated to defeat antibiotics. Science is learning how to defeat these strains

Do you remember the story of Typhoid Mary, the cook who spread typhoid to about 100 people in the early 1900s, even though she showed no symptoms herself? She was confined to solitary confinement for 26 years because at that time there was no treatment that could cure this so-called “healthy carrier”.

Since then, we have developed powerful antibiotics that could have killed 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 epidemics worldwide and accounting for a larger percentage of the annual toll of 10 to 20 million cases and 100,000 deaths. And now science is fighting back, ramping up vaccine campaigns and devising more effective ways to detect typhoid cases.

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/ The New York Public Library

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The New York Public Library

“Typhoid Mary,” the cook believed to have infected about 100 people with the disease, as described in New York American, June 1909

Typhoid superbugs appeared around 1950

Some things about typhoid have not changed since the days of Typhoid Mary. The disease is caused by bacteria Salmonella enterica serovar Typhi (S Typhi). This strain of bacteria only infects humans – as far as we know – and is spread through contact with infected faeces. Symptoms include high fever, fatigue and digestive problems, which can eventually lead to internal bleeding and death.

Antibiotic-resistant typhoid first appeared on the scene around 1950. Since then, almost every time a new antibiotic with the potential to treat typhoid has been developed, a new strain has emerged that can defeat it.

“It’s back and forth. We’re developing new drugs, typhus is becoming resistant,” said Dr. Jason Andrews, an associate professor of infectious diseases at Stanford University. “It just happens over and over again, for 70 years now.”

The worst strain is called XDR – short for extensively drug resistant. It first appeared in Pakistan in 2016 and by 2019 had become the dominant strain in the country. It is also spreading to other countries, according to research published in June in The lanceolate microbe. That prevalence is what worries scientists like Andrews, the paper’s author. This is because there is only one oral antibiotic that can cure XDR typhus: 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 widespread use of azithromycin could lead to XDR becoming resistant to the drug.

A new vaccine could be the key to stopping XDR typhoid

So how can XDR be stopped? A 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 that the human immune system can recognize—to stimulate an immune response. and prevents typhoid infection even if it is resistant to antibiotics.

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

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

Now that the vaccine is no longer being tested, far more than 90,000 people have been vaccinated and preliminary results are outpacing 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 while the vaccine reduced the number of cases, it did not exactly lead to XDR. The vaccine has yet to make a breakthrough in the rate of XDR infections in Pakistan. “Before vaccination, 60 to 70% of typhoid infections [in Pakistan] were from XDR, and that continues to be the case even after the vaccination campaign,” says Dr. Farah Qamar of Aga Khan University, a Pakistani researcher who has worked on typhoid for more than a decade. Qamar says she expected XDR to start disappearing , because fewer cases means fewer antibiotics are prescribed, but that doesn’t seem to have happened.

To slow the spread of typhoid, we must first know where it is

So what’s the problem? One of the problems is that vaccine supplies are limited and it is not easy to know where it will have the greatest benefit. In an ideal situation, doses would be sent to regions with the highest number of XDR cases. However, current typhoid detection tools are not good enough to pinpoint such hotspots.

“The big challenge with typhoid is that it’s very difficult to diagnose, so we know it’s there, but we don’t really know how much of it there is,” says Dr. Kristen Ayemjoy, a professor of epidemiology at UC Davis. “Blood culture is the gold standard for typhoid diagnosis, and it’s not really that good. It has a sensitivity of only 60% – out of every 100 true cases you miss 40. It is also expensive and usually only available in referral hospitals and capital cities.”

In order to better count typhoid cases, scientists have developed a new tool, also reported in The lanceolate microbe in June, requiring only a drop of blood from a finger prick to detect the disease. Even if the blood is drawn for other reasons — such as looking for cases of COVID — the tool can still be used to detect typhoid. The hope is that this method will help determine what researchers call the “strength of infection” — how quickly typhus is spreading in a country.

“It’s the metric that’s actually much more relevant to public health planning because it tells you where cases are likely to increase.” This can be used to justify where to release the vaccine,” says Ayemjoy.

MSF helped introduce this tool in countries likely to have a lot of typhoid but insufficient data on its prevalence, such as South Sudan.

/ Jason Andrews

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Jason Andrews

An open sewer running past households in Vellore, India. Poor sanitation practices can lead to the rapid spread of typhoid fever, which can be contracted through contact with infected feces.

However, the complete elimination of typhoid requires dealing with the source of the epidemic – water and food contaminated with infected faecal matter. “There is a great need for improved water and sanitation, because if that doesn’t happen, we won’t be able to control typhoid or other such diseases,” says Qamar.

This has been done before. “Typhoid fever was a leading cause of morbidity in the United States in the 19th centuryth century after that it was almost eliminated city by city over a period of 10 years,” says Andrews. Simple measures such as connecting houses to proper sewage systems and clean water lines were sufficient.

Of course, infrastructure cannot be improved overnight. In the meantime, Andrews is optimistic that with better diagnostic data and effective vaccines, the further spread of antibiotic-resistant typhoid strains will be prevented.

“Vaccines are not enough to eliminate typhoid as we know it, but we hope they can reduce the incidence [of typhoid] to more manageable levels as we try to implement more permanent and effective elimination measures, such as clean water and sanitation.”

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