A tenacious epidemic of extensively drug-resistant (XDR) typhoid in Pakistan is just one small genetic step away from becoming untreatable—and health experts expect it to spread worldwide.

“It’s a global concern at this point,” Dr. Eric Mintz, an epidemiologist at the Centers for Disease Control and Prevention told The New York Times. “Everything suggests this strain will survive well and spread easily—and acquiring resistance to azithromycin is only a matter of time.” Azithromycin is currently the only antibiotic remaining that treats the infection.

Typhoid fever, caused by Salmonella enterica serovar Typhi bacteria, is endemic to Pakistan, parts of which suffer from poor infrastructure, crowded urban areas, and insufficient access to healthcare. The epidemic caused by the XDR strain—the first of its kind—has been unfolding there since November 2016. It has now affected at least 850 people in 14 districts, according to the latest figures from the National Institute of Health in Islamabad and first reported by the Times. Prior to this epidemic, there were only four known, unrelated cases of such heavily drug-resistant typhoid, occurring in Iraq, Bangladesh, India, and Pakistan.

The XDR strain has already begun spreading outside of Pakistan, with a travel-related case appearing in the United Kingdom.

In a recent report on the strain’s emergence in the journal mBio, infectious disease experts established that it could withstand assaults from five classes of antibiotics used to treat typhoid. They concluded that the strain’s development was a “startling demonstration” of how easily S. Typhi can pick up genetic elements that confer drug resistance, “rendering it XDR and further narrowing treatment options.”

Antibiotics are the only effective treatment for typhoid fever, a systemic infection with varying severity that can become life-threatening. The infection is generally marked by fever, headache, nausea, loss of appetite, and constipation or sometimes diarrhea. The heaviest death tolls are in children younger than age four. About 2 to 5 percent of those infected can become chronic asymptomatic carriers, shedding the bacteria in their feces. The Salmonella Typhi bacteria are typically spread through food or water contaminated with feces.

Stinky squall

Researchers estimate that there are somewhere between 10 million to 20 million cases each year worldwide, leading to between 130,000 to 210,000 deaths. And that’s the case with antibiotic treatments largely still available and working.

“Most clinicians and clinical microbiologists today do not appreciate the lethality that typhoid fever exhibited in the pre-antibiotic era,” Myron Levine and Raphael Simon say. The vaccine researchers, both from University of Maryland School of Medicine, wrote a commentary recently on the “gathering storm” of XDR typhoid in Pakistan.

In the epidemic, researchers suspect leaking sewage lines were to blame for the creation and spread of the XDR strain. According to the Times, early disease mapping showed cases clustering around sewage lines in the city of Hyderabad. Researchers speculate that, within that seeping sewage, the aggressive MDR typhoid strain H58 encountered and picked up a circular piece of DNA (a plasmid) containing genes encoding additional drug resistance, likely from an E. coli strain or other enteric bacteria. This refuse rendezvous created the XDR strain.

With the epidemic well underway, health authorities have already begun a campaign to step up sanitation and hygiene efforts, such as making sure people boil drinking water and increase hand washing. Health authorities are also trying to get children vaccinated against the harmful germs.

As Levine and Simon note in their commentary, “we know how to impede amplified transmission of typhoid in most areas of endemicity, i.e., to treat water supplies and make them widely available and to improve sanitation and personal hygiene so that human feces do not contaminate water and food.” But, they note, such efforts “are expensive and require time to deploy, even if political will and financing are available.”

The recent spread of the XDR H58 is a “clarion call,” they conclude.

“Now is the time for global action to prevent a ‘gathering storm’ from becoming a ‘perfect storm’ and an enormous public health crisis.”