There's only one drug left to fight this "human killer," and now it's starting to fail

Salmonella enterica serovar Typhi (S. typhi) Image source: Microbewriter - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=106822321

Typhoid fever may be rare in developed countries, but this ancient threat, which may have existed before the Christian era, remains dangerous to the modern world. According to a new study published in The Lancet Microbe, the pathogen that causes typhoid fever, Salmonella enterica serovar Typhi (S. typhi), is evolving extensive drug resistance and rapidly replacing strains that are not resistant.

S. typhi, also known as Salmonella typhi, is one of more than 2,400 serotypes of Salmonella enterica. It infects humans and causes typhoid fever, which kills about 200,000 people each year. Currently, antibiotics are the only effective treatment for typhoid fever. However, over the past three decades, this "human killer" has become increasingly resistant to oral antibiotics.

The researchers sequenced the genomes of 3,489 S. typhi strains isolated from Nepal, Bangladesh, Pakistan, and India between 2014 and 2019. This largest analysis of Salmonella typhi genomes to date found that the number of extensively drug-resistant (XDR) typhoid strains has increased in recent years.

Not only are XDR typhoid strains impervious to first-line antibiotics such as ampicillin, chloramphenicol, and trimethoprim/sulfamethoxazole, they are also increasingly resistant to newer-generation antibiotics, such as fluoroquinolones and third-generation cephalosporins.

Worse still, these strains are spreading rapidly around the world.

Most XDR typhoid strains come from South Asia, and researchers have identified nearly 200 events of international spread since 1990. Most strains have been exported to Southeast Asia, East Africa, and South Africa, but typhoid superbugs have also been found in the United Kingdom, the United States, and Canada.

The global spread of different types of typhoid strains after 1990. The yellow arrows indicate XDR typhoid strains. Image source: paper

“The increasing rate at which highly resistant S. typhi strains emerge and spread has become a real concern in recent years and highlights the urgency of scaling up prevention measures in countries most at risk,” said Jason Andrezw, an infectious disease expert at Stanford University in the United States.

In 2016, the first XDR typhoid strain was identified in Pakistan. By 2019, this strain had become the predominant genotype circulating in the country.

Historically, most strains of XDR typhoid have struggled with third-generation antibiotics such as quinolones, cephalosporins, and macrolides. Until the early 2000s, 85% of strains in Bangladesh, India, Pakistan, and Singapore had mutations that conferred resistance to quinolones. At the same time, resistance to cephalosporins also began to emerge.

There is only one effective oral antibiotic left: the macrolide azithromycin. But it may not last long.

New research has found that mutations that cause azithromycin resistance are also spreading, "a situation that threatens all oral antimicrobial drugs for treating typhoid fever." Although these mutations have not yet appeared in XDR typhoid strains, if they do, we will face a very serious situation.

If left untreated, 20% of typhoid cases are fatal, and today, approximately 11 million cases occur each year.

Vaccination with conjugate typhoid vaccines can go some way toward preventing future typhoid outbreaks, but if these vaccines are not rolled out globally, the world could soon be on the brink of another health crisis. The conjugate typhoid vaccine, which consists of the Vi antigen associated with a tetanus toxoid protein, was first prequalified by WHO in December 2017 and is prioritized for use in countries with the highest burden of typhoid disease or high levels of antimicrobial resistance. The other two typhoid vaccines available are an injectable vaccine based on purified antigens and an oral live attenuated vaccine capsule.

"The recent emergence of XDR and azithromycin-resistant typhoid strains makes it even more urgent to rapidly expand preventive measures, including the use of typhoid conjugate vaccines, in countries where typhoid fever is endemic," the authors wrote. "Such measures are necessary in these countries because the level of antibiotic resistance among isolates is already high, but given the propensity for international spread, we should not limit the promotion of typhoid conjugate vaccines to these countries alone."

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South Asia may be the epicenter of typhoid fever, with 70% of cases occurring there. But if the coronavirus pandemic has taught us anything, it’s that our modern world is globalized and disease variants can spread easily. To prevent that, health experts are urging countries to expand typhoid vaccinations and invest in new antibiotic research. One study in India, for example, estimated that 36% of typhoid illness and death could be prevented if urban children were vaccinated against the disease.

Pakistan is leading the way, becoming the first country in the world to offer routine typhoid vaccinations, and last year, more than a million children were vaccinated, prompting health experts to urge more countries to follow suit.

Antibiotic resistance is one of the leading causes of death worldwide, claiming more lives than AIDS and malaria combined. But if vaccines are available, we have the best weapon to prevent the next pandemic.

There is no time to waste.

Source: Research Circle (ID: keyanquan)

By: CARLY CASSELLA

Original link:

https://www.sciencealert.com/a-medieval-killer-is-rapidly-becoming-resistant-to-more-antibiotics

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