It started with a routine procedure. Bill Warner was 54 when he went to the doctor for a test with a duodenoscope, a tiny tube that doctors put down his throat as part of an exam. Not long after, he started to get sick. Warner had contracted CRE, a deadly superbug that can get lodged in medical equipment and spread from patient to patient.
"Within a matter of months, he was just depleted," says Carla Warner, his widow. "He lost 60 pounds, and he got to the point where he didn't want to eat." Warner had worked as a concrete mixer truck driver, but soon he was no longer able to stand up.
Because CRE is a superbug—a type of bacteria that has evolved to resist almost all antibiotics—there were few options to fight the infection. One drug started to damage Warner's kidneys, so doctors couldn't use it. He was left taking a cocktail of two other antibiotics that made him vomit profusely. The drugs didn't work well. Warner was in the hospital almost continuously for eight months, in intense pain.
When he improved slightly, he went to physical therapy, attempting to get strong enough dress himself or bathe. But by the time he was allowed to go home, he was incontinent, could barely eat without a feeding tube, and had a bile drain in his abdomen. Periodically, Carla would rush him back to the hospital. "I would have to walk in and say, 'Bill, your fever's 102, we have to go back to the hospital'—and he would cry," she says. "And beg me not to take him."
He kept fighting, but the superbug won: Bill Warner died on November 24, 2013, just over 10 months after contracting CRE.
The head of the CDC calls CRE the "nightmare bacteria:" It kills up to half of the patients that contract it. In total, superbug infections from CRE, along with bacteria like MRSA and C. difficile, kill 23,000 people each year in the United States alone.
That number is projected to rise steeply in the coming years. If antibiotic resistance continues on its current trajectory, 10 million people around the world may die from common infections each year by 2050. That's more than the 8.2 million who are projected to die annually from cancer.
Colistin, one of the few drugs that still fights CRE, may be next to stop working as superbugs continue to evolve. The antibiotic, discovered in 1947, causes kidney damage and other problems, so when newer, safer drugs were created in the 1960s, doctors stopped prescribing it—except in cases, like Warner's, when other antibiotics fail. The drug's dangerousness and unpopularity means it works better: Because colistin hasn't been widely used, bacteria haven't evolved to resist it.
Last November, Chinese researchers announced that they had discovered—in pigs, raw pork meat, and a few people—a new strain of E. coli that even colistin can't kill. As the new superbug spreads, the last-resort drug may eventually no longer be an option.
It isn't the first time that scientists identified colistin-resistant bacteria, but this new discovery is a particularly nasty form. As the bacteria was exposed to colistin, it evolved a new gene called MCR-1 that makes it resistant to the drug. Because the gene happens to be on a plasmid—a tiny, portable piece of DNA—it can easily spread to other bacteria that happen to be next to it in a patient's gut or on equipment like a catheter.
"When we hear about genes on these mobile elements like this—these pieces of DNA—and in E. coli, we sort of brace ourselves because we know that's going to move around very quickly," says Dr. Lance Price, professor at George Washington University's Milken Institute School of Public Health and director of the school's Antibiotic Resistance Action Center.
It already has. Since November, other researchers have found MCR-1 in 20 other countries, from Denmark to Canada.
In China, however, colistin isn't used in medicine. But it is widely used by pig farmers. A low dose of the drug helps fatten up the pigs before they're turned into pork. Last year, China used about 12,000 tons of the drug. Like other antibiotics, the more colistin is overused (in humans or animals), the more likely it becomes that bacteria adapt to it, and it no longer works.
"Progression ... from extensive drug resistance to pan-drug resistance is inevitable and will ultimately become global," the researchers wrote when they talked about the discovery of MCR-1 in China.
In the worst-case scenario, the type of painful death that Bill Warner suffered could become commonplace, as this same sequence of events happens with more and more of the drugs we use to kill deadly bacteria.
One part of the solution will be new drugs. After penicillin was discovered in 1943, many other antibiotics followed, but around the turn of the millennium, many drug companies stopped trying to find more. Unlike other drugs that someone might take daily for years, the short course of antibiotics means they aren't very profitable. New laws, like the Gain Act in 2012, have tried to stimulate development of antibiotics by giving drug companies fast track to approval with the FDA, and offering an extra five years of exclusivity before the drug can be sold as a generic, so it's possible to make a bigger profit.
One report estimates that we'll need 15 new antibiotics a decade to stay ahead of quickly-adapting bacteria. An estimated 39 new antibiotics are in development now, but the success rate is low; only one in five are likely to make it to human testing.
A new technique may make success more feasible. For years, scientists have known that soil samples should be a good place to find new antibiotics, because microbes living there have naturally evolved ways to kill competitors like disease-causing bacteria. But if you take a sample into the lab, most microbes won't grow. The new approach brings the natural environment to the lab; a plastic chip of samples is surrounded by whatever the bacteria would live next to in the wild, so they can survive long enough to be tested and developed into new drugs.
In 2015, using the new device, researchers at Northeastern University discovered the first new class of antibiotics in 30 years. Called teixobactin, the antibiotic was found in soil from Maine, and researchers hope to bring it to market in five or six years. More importantly, the same technique can be used to find other new antibiotics in the soil or in samples from the ocean.
Others are trying to find ways to make existing antibiotics more effective. A startup called Spero, which raised $30 million in February, makes a drug delivery platform that weakens the cell wall around bacteria so antibiotics can break through, even if the bacteria would otherwise resist treatment.
"The Potentiator platform is 'upcycling' existing antibiotics and putting them to new uses to address the growing epidemic of antibiotic resistance," says CEO Ankit Mahadevia. "With this platform, we can extend and enhance the utility of many classes of existing drugs."
Another solution, based on compounds discovered in the ocean, does something similar, blocking the resistance mechanisms of bacteria so older antibiotics can work again. Researchers from the Woods Hole Oceanographic Institution believe there may be many other ocean-based solutions waiting for discovery.
"The ocean covers 71% of the planet and is woefully unexplored chemically," says Kristen Whalen, a research associate at WHOI. "Bacteria have been engaging in 'chemical warfare' for millennia...it is time we investigated marine bacteria for new compounds that can help us in the fight against human pathogens."
Whalen is at the beginning of a drug discovery process for something called a pump blocker, which patients would take to disable the part of the bacteria that's resistant to antibiotics. Then they'd take an old-school antibiotic. "I'm proposing that we don't throw out our stockpile of antibiotics," Whalen says.
At Tel Aviv University, researchers are using Crispr—the new, precise gene-editing tool—to take resistance genes out of some bacteria, and make other bacteria more sensitive to antibiotics. The system could be used in hospitals to stop the spread of the worst pathogens.
The best solution to antibiotic resistance, though, is to just use the drugs less often—both in agriculture and in medicine—something that's already happening in places like Scandinavia. The U.S., on the other hand, has a long way to go. "In the United States, we talk a lot about shifting away from antibiotics, but if you look at drug use trends, it's going up," says Price. "Despite all this conversation, the latest numbers from the FDA say the food animal producers are using more antibiotics. And that's despite actual production being flat or even decreasing."
In a plan released in May 2015, the Obama administration called for food producers to stop using antibiotics to make animals grow faster. But they can still use the drugs to prevent disease, something Price says is a mistake.
"They've left this giant loophole, which is routine disease prevention," he says. "They're putting antibiotics into the feed of animals or their water, on a regular basis, to prevent an infection that may or may not occur. And if they do occur, they're occurring because of the way they're raising them."
If animals were raised differently than the status quo on factory farms—crowded into dirty cages, eating cheap feed, and piglets taken from their mothers almost immediately—they'd be less likely to get sick. Some countries, like Denmark—the world's second largest pork producer—have made these adjustments, as have premium producers in the United States.
Doctors will also have to use antibiotics differently; it's still common, for example, to get a prescription for an antibiotic before the doctor actually knows which bacteria is making you sick. Rapid diagnostics are beginning to change that. If doctors can identify specific bacteria, they can avoid prescribing drugs that are overkill for that particular infection. The less that more powerful drugs are used, the longer they'll be effective before bacteria evolve.
Clinics are also working to prescribe antibiotics less often, and trying to educate a public that still believes that the drugs can help cure viruses, or that it's okay to stop taking antibiotics before a prescription is used up—something that itself can help create superbugs. If all the bacteria aren't killed, it's easier for the surviving bugs to mutate drug-resistant genes.
Hygiene is another critical factor; in Bill Warner's case, the medical equipment that gave him CRE could have been designed and sterilized differently. In a hospital or clinic, something as simple as medical staff washing hands can make a big difference. One study calculated that a tiny 5% increase in hand hygiene at hospitals could prevent four potentially fatal MRSA infections (and save the hospital $200,000 in medical costs).
Despite the potential of these changes, Price says we'll still need new antibiotics in the short term. "We've sort of backed ourselves into a corner on this," he says. "We've been squandering antibiotics for years in human medicine, and in animal production. I don't think new drugs are the ultimate solution, but we have gotten ourselves into a position where we need new drugs. What we need in conjunction with new drugs—and I think more importantly than new drugs—is better stewardship in humans and in animals."
That stewardship will have to happen on a global scale to work, dramatically shifting both agriculture and medicine. In places like India, it's possible to get some antibiotics over the counter, leading to widespread overuse; some antibiotic manufacturers dump their waste into nearby rivers, helping build superbugs in the wild. And whenever that happens in one country, the bacteria can easily spread to the rest of the world.
"Basically, the two keys are reducing antibiotic use and increasing hygiene, preventing the spread of bacteria," Price says. "If we do both of those things, we could make our antibiotics last, I think, for generations. But as long as we have countries and companies that are squandering antibiotics ... we're going to always have superbugs to deal with."