In January, Columbia University revealed that four patients at its Irving Medical Center in New York had been sick with an unusual version of E. coli , a common gut bacterium. Although the news largely escaped attention in the media, it ricocheted through the world of infectious disease experts. E. coli is a relatively common bacterium and benign when it’s in the gut, where it usually lives, but in the wrong places—such as in lettuce or ground beef, or our bloodstream—it can turn deadly. When antibiotics prove ineffective against an E. coli infection, as many as half the patients with it die within two weeks.
That’s exactly why the Columbia E. coli was so worrying. Over the past decade or two, E. coli has developed resistance to one antibiotic after another. For some infected patients, their last hope is the antibiotic colistin, a toxic substance with potential side effects that include kidney and brain damage. The Columbia E. coli had a mutation in a gene, MCR-1, that confers a terrifying attribute: imperviousness to colistin.
“We’re looking to the shelf for the next antibiotic, and there’s nothing there,” says Erica Shenoy, associate chief of the infection control unit at Massachusetts General Hospital. “We’re facing the specter of patients with infections we can’t treat.”
Ever since an experimental miracle drug called penicillin was rushed to a Boston hospital in 1942 to save the lives of 13 victims of a nightclub fire, medical researchers have discovered more than 100 new antibiotics. We’ve needed each and every one of them—and they’re not enough. It’s not just E. coli . Drug-resistant strains of Staphylococcus , Enterobacteriaceae and Clostridium difficile have been steadily overcoming antibiotics; one study found that the number of deaths due to resistant infections quintupled between 2007 and 2015. Recently, treatment-resistant versions of the fungus Candida auris have shown up in hospitals in New York City and Chicago, killing half of infected patients.
The U.S. Centers for Disease Control and Prevention reports that 2 million people a year are sickened in the U.S. by bacteria or fungi resistant to major antibiotics, and that 23,000 die from them. “It’s probably a vast underestimate,” says Karen Hoffman, who heads the Association for Professionals in Infection Control and Epidemiology. “We don’t have a good reporting system for multiresistant organisms, so we don’t really know.” Studies suggest the cost to the U.S. health care system of treating patients with these hardy bugs tops $3 billion a year.
This grim trend is expected to accelerate. The World Health Organization predicts that worldwide death rates from drug-resistant microbes will climb from the current 700,000 per year to 10 million by 2050. At that point, they will have surpassed cancer, heart disease and diabetes to become the main cause of death in the human race. Before antibiotics, a small cut, tooth decay or routine surgery could lead to a life-threatening bacterial infection. Penicillin, the “miracle drug,” and other antibiotics changed all that, saving countless lives over the years. But the age of the miracle drug seems to be ending.
Doctors are learning how to identify and isolate the bugs that are already resistant in the hopes of avoiding large outbreaks. They are scrambling to tighten up on the use of antibiotics in an effort to slow the development of resistant strains. It’s too little, too late: The strategy will only buy us some time. At the moment, the oldest and weakest patients in hospitals are most affected, but the risks are spreading. “We’re seeing healthy young people with urinary tract and skin infections that we don’t have a pill for,” says Helen Boucher, an infectious disease specialist at Tufts Medical Center in Boston. “And we may not be able to perform organ transplants, and even routine surgeries like joint replacements. We should all be scared.”
Medical experts are pinning their hopes on entirely new strategies for dealing with infection. To find novel ways of killing bugs, they’re looking in exotic places—in viruses and fish slime and even on other planets. They’re using insights gained in genomics and other fields to come up with new technologies to kill bugs and keep them from spreading. And they are re-examining practices in hospitals and other spreading-grounds for bacteria, putting in place more holistic strategies for managing the bacteria in our bodies and in our hospitals and doctors’ offices.
The alternatives sound promising, but they are far off. It’s not clear that we can invent new weapons before the superbugs, like a zombie army at the gates, overwhelm our defenses.
“We need to make a huge investment in other approaches,” says Margaret Riley, a drug-resistance researcher at the University of Massachusetts. “And we need to make it 15 years ago.”
The New Bug-Hunters
Part of the problem with drug resistance is that microbes evolve with alarming speed into new species. Whereas a human needs 15 or more years to mature enough to have offspring, microbes like E. coli reproduce every 20 minutes. In a few years, they can go through evolutionary change that would have taken humankind millions of years to accomplish—change that can include acquiring genetic attributes that allow them to withstand drugs. A human on antibiotics is the perfect lab for developing resistant microbes. “Research shows that whenever a new antibiotic comes into use, we start to see the first resistant microbes emerge about a year later,” says Mass General’s Shenoy.
There’s little in the pharmaceutical pipeline to replace the antibiotics to which bugs are becoming resistant. That’s because development of a new antibiotic runs about $2 billion and takes about 10 years—with little hope of ending up with the sort of blockbuster drug that justifies such an investment. “The point of having a new antibiotic would be to use it as infrequently as possible, for as short a time as possible,” says Jonathan Zenilman, chief of the division of infectious diseases at Johns Hopkins Bayview Medical Center in Baltimore. “Why would a pharma company want to develop a drug for a market like that?”
Medical researchers are now searching for other approaches. One involves recruiting biologists with a flair for evolutionary theory into the war on bugs. In the 1990s, Riley started out at Harvard and Yale studying the ways viruses kill bacteria and bacteria kill one another. In 2000, a colleague casually asked her if the work had any application to human health. “I had never thought about that,” she says. “But suddenly everything clicked for me, and I became consumed by that question.”
Riley has since spent the past two decades looking into applying the warfare strategy of viruses to the problem of resistant infections in humans. Viruses called “phages,” which are basically chunks of genetic material wrapped in a protective protein, will pierce the cell wall of a bacterium and hijack its genetic machinery, turning the bacterium into a factory for making more viruses. Riley also studies how bacteria sometimes also kill other bacteria in the competition for food. A colony of bacteria will sometimes elbow out a competitor by producing poisonous proteins called “bacteriocins.”
Riley’s goal isn’t just to kill dangerous bacteria—it’s also to protect the beneficial ones. Of the roughly 400 trillion bacteria living in or on each of our bodies, the vast majority are helpful or benign—only one 10-thousandth of a percent of them are potentially harmful, she says. Commonly prescribed “broad spectrum” antibiotics like penicillin, ciprofloxacin and tetracycline don’t discriminate between good and bad bacteria—they wipe out them all. That not only helps lead to the emergence of resistant bacteria but also causes problems for patients.
“An antibiotic is like throwing an H-bomb at an infection,” Riley says. “You kill 50 percent or more of all the bacteria in the body, and a lack of healthy bacteria has been linked to obesity, depression, allergies and other problems.” Phages and bacteriocins, on the other hand, can in theory be tuned to take out a colony of infection-causing bacteria in a patient, all without harming the normal flora or creating a fertile breeding ground for resistant bugs.
ImmuCell, a biotech company in Portland, Maine, has developed a bacteriocin that treats dairy cows for mastitis, a disease that costs the dairy industry $2 billion a year. Riley says labs like hers can adapt phages and bacteriocins to target virtually any sort of human microbial infection too, with little risk of nurturing new resistance. “These are stable, hardy killing mechanisms that evolved 2 billion years ago,” she says.
Several clinical trials of phage therapy have already been successfully conducted in Poland, the nation of Georgia and Bangladesh. In the West, there have been successful phage trials for foot ulcers. No trials are underway for more serious infections, but a successful phage treatment of a critically multiresistant-infected patient in California in 2017 under Food and Drug Administration emergency rules has more researchers in the U.S. looking to develop phage treatments. One or more of these could move toward trials in the next few years, says Riley, including one for multi-resistant tuberculosis and another for pulmonary infections in cystic fibrosis patients. Bacteriocins are further behind. The U.S. government has promised to provide $2 billion for the effort to develop these alternatives, “but that’s not nearly enough,” she says.
Cancer researchers are widely investigating drugs that can boost immune systems, and these immunotherapies could be promising in helping weakened patients fight off resistant bugs that try to take hold. Researchers have produced human antibodies in cows and other animals that can be injected into patients. Boston’s Harvard-affiliated Brigham and Women’s Hospital, in an emergency effort, reported injecting a combination of antibodies and antibiotics to save a patient with a drug-resistant infection, but the results weren’t disclosed. Otherwise, little has been done to bring the approach to trials in infected patients. Researchers are also working on vaccines against resistant staph infections and other resistant bacteria, but these too are just research efforts. “These non-antibiotic treatments are still in the early stages of investigation,” says David Banach, who heads infection prevention at the UConn Health medical center in Farmington, Connecticut. “But we have to keep thinking of new approaches.”
Given the enormous urgency of the problem, why is it taking so long to move promising solutions toward trials and availability? Because there’s little money in it, says Tufts’ Boucher. The government is sinking billions into research, but the private investment to turn that research into manufactured drugs and devices has not materialized. Drug companies, says Boucher, have little prospect of profiting off a drug that isn’t likely to be taken by millions of people or fetch prices of tens of thousands of dollars per dose. “The economic model is broken,” she says.
Managing the Bugs
Although antibiotics are truly miracle drugs when they work, our current problems have arisen in part because medicine has relied too heavily on them. Doctors prescribe them for ear infections, sore throats and urinary tract infections. Surgeons use them to prevent postoperative infections. Because bacteria can develop resistance, antibiotics make the most sense as part of a holistic approach to managing the spread of bacteria and dealing with infections. As antibiotics begin to lose their usefulness, medical experts are now coming around to emphasizing many-pronged strategies for keeping the bugs at bay.