When Qaurat al-Ain brought her fever-stricken daughter Mariam to a doctor in this city 90 miles east of Karachi, she assumed the one-year-old had a chest cold. The doctor prescribed antibiotics and sent her on her way, but the fever persisted. Another doctor tried antimalarial drugs, also to no avail. That’s when al-Ain got really worried—the fever had already lasted two weeks.

She sought a third opinion, and finally doctors at a specialized maternal and child care hospital in Hyderabad said her child likely had typhoid. That made sense: Pakistan is one of the few places where the bacterial infection remains endemic. Just over half a million people a year contract it here, often by consuming feces-contaminated food or water. Its hallmark symptom is a persistently high fever, and when left untreated it can cause intestinal perforation and fatal sepsis. “I remember having typhoid as a kid,” al-Ain says. “I just remember being out of school for a week, and other kids in my class having it, too.” But Mariam’s illness did not seem typical. “She would shake with fever chills for hours,” al-Ain recalls. “Seeing my baby like that was terrifying. It didn’t help that the doctors seemed so anxious, too.”

Mariam’s doctors, it turned out, had reason to be concerned: A blood test revealed the typhoid strain Mariam carried was resistant to five classes of antibiotics typically used to treat the infection. Although resistance to three classes of typhoid medication—formally known as “multidrug-resistant” typhoid—had become common in Pakistan in recent decades, this extreme level of resistance was much worse. Mariam’s infection was designated “extensively drug resistant,” or XDR—meaning it would only respond to one powerful, broad-spectrum class of antibiotics: azithromycin, which is considered the last line of defense against typhoid.

Mariam, who fell ill in November 2016, had the dubious distinction of becoming the second confirmed case of XDR typhoid in an outbreak that would soon roil much of southern Pakistan. Around the time Mariam was admitted to a hospital, another child was brought to the same ward and testing revealed the same affliction. The next week there were two more cases, and by the end of 2016 Hyderabad’s doctors had seen more than a dozen people with the extensively drug-resistant strain. Since then there have been more than 800 lab-confirmed cases, according to tracking by Aga Khan University (A.K.U.) in Karachi. And that number is widely considered an underestimate; many cases likely go undiagnosed or uncounted.

Infectious disease experts say Pakistan is in the grip of the world’s first outbreak of XDR typhoid, and they suspect the country’s abysmal sewage and water systems are the root cause for its spread. In most poor neighborhoods sewage lines do not exist, and where they do they are often faulty or broken, leaving potable water supplies vulnerable to contamination. Open sewage pools in areas throughout Hyderabad, even in the poshest neighborhoods in this sprawling city of six million people.

The XDR typhoid outbreak has crept across southern Pakistan and reached its largest city, Karachi. At first, government officials hoped it would remain small and burn out on its own. But it soon became clear they would need to launch an extensive vaccination campaign to battle the spread of the mutated strain.

A Shaky Start

A new typhoid vaccine, produced in neighboring India, was approved by the World Health Organization last year. It is more effective than its earlier counterparts and only requires a single dose. Health care workers have rushed to bring it to Hyderabad. Last month they kicked off a long-awaited campaign to vaccinate all children under age five in the city’s hardest-hit neighborhoods; the disease most often kills young kids who have not developed immunological defenses against it.

A four-year-old girl receives a typhoid vaccination in Hyderabad. Credit: Meher Ahmad

At the same time, researchers have been racing to understand the biological underpinnings of the XDR typhoid pathogen in the hopes of unraveling how it became so drug-resistant. A team of scientists from A.K.U. and colleagues from the Wellcome Sanger Institute in England have pored over Hyderabad’s typhoid-causing bacterium, and recently reported it developed its “superbug” powers by picking up DNA from another microbe—likely Escherichia coli. The team mapped cases and found the biggest clusters around the city’s sewage lines. Sadia Shakoor, an A.K.U. microbiology professor and co-author of the study, believes the pathogen likely mutated in those lines and spread when it seeped into the water supply.

But even though researchers have uncovered the “how” behind this outbreak, controlling its day-to-day spread remains a problem. At the beginning of this year 250,000 vials of vaccine reached Hyderabad, thanks to a Bill and Melinda Gates Foundation grant in collaboration with the U.S. Agency for International Development, which provided syringes. The vaccination effort has been underway for a little over a month, but Tahir Yousafzai, an infectious disease expert at A.K.U. and lead organizer of the vaccination campaign, says the work has run up against community opposition. Rumors are circulating about the vaccine itself, including talk that it is part of a foreign plot to poison Pakistan’s children, and vaccinators face refusals almost every day.

Suspicions surrounding public inoculation campaigns are not new in this country—years ago the Pakistani Taliban declared vaccination efforts part of a Western conspiracy against Islam. And in 2011, when it was discovered that a team of hepatitis vaccinators had aided U.S. intelligence efforts to locate Osama bin Laden, those rumors suddenly gained new credence in the eyes of many. Subsequently, distrust of vaccinators has become common across the country.

Two health workers knock on the door of a home in Hyderabad, hoping to administer typhoid vaccine to the children in the house. Credit: Meher Ahmad

Midway into their daily rounds, vaccinators Baktawar Memon and Jannath Rind recently knocked on doors in one Hyderabad neighborhood—only to be repeatedly turned away by parents. “This is medicine! It will help protect your children,” they yelled through the door at one home, but no one answered. They marked the house as a “refusal” on their clipboards, and by chalking a series of letters and numbers on the door.

Frequent migration in the region also means the XDR typhoid bacterium could potentially spread beyond areas contaminated with the raw sewage. But even without spread beyond southern Pakistan, Yousafzai says he is worried about the months and years ahead. Unless the vaccine’s use is standardized beyond an emergency campaign, he cautions, XDR typhoid could become endemic in Pakistan in the way multidrug-resistant typhoid was in decades past. “Our fear is that the mutant gene will prevail—that the antibiotics we have left will be rendered useless,” he says.

As for Mariam, she finally recovered from the resistant-typhoid strain weeks after being diagnosed. One recent afternoon al-Ain watched the toddler play on a tricycle. “I wouldn’t want any mother to watch her baby suffer like I did,” she says. Yet as XDR continues to spread, she knows many will.