The clinical microbiology laboratory at Emory University Hospital in Atlanta processes more than 800 patient specimens every day. Samples of urine or stool arrive in stacks of petri dishes, sometimes by pneumatic tube straight from operating rooms. Most of the microbes the lab's technicians investigate are familiar creatures that can be dealt with by modern medicine. But in the fall of 2013, something puzzling appeared.
Lab director Eileen Burd and her staff of 36 work around the clock to figure out what kind of infections are making patients sick, and what drugs will work best to heal them. Three years ago, they tested a strain of the bacteria E. cloacae that infected a kidney transplant patient. The bug fought off a battery of antibiotics including colistin, the drug doctors rely on when no other antibiotics work. Colistin killed most of the germs, but a small colony survived.
This wasn't the first time a resistant bug had been found. But the fact the lab was even testing colistin against the microbe "signaled to me that this was a very resistant organism to begin with," Burd said. Discovered in 1949, colistin was later abandoned in most human medicine because of its toxic side effects, but doctors have been forced to employ it in recent years to treat infections where most other antibiotics fail.
For years scientists have warned that humanity is squandering antibiotics in medicine and agriculture. The drugs are frequently deployed against illnesses they don't even treat, or to make pigs, cows, and chickens grow faster. Reckless practices can speed the emergence of microbes that can't be killed by any drug we have. Cancer patients, premature babies, and organ recipients all rely on these medicines to fight off microbes when their own immune systems are weakened. Without effective antibiotics, a skin infection after a scraped knee could turn fatal.
Already, so-called superbugs kill at least 23,000 people in the U.S. every year and sicken 2 million. Globally, the number of deaths annually is 700,000, but that figure could spike to 10 million by 2050, according to a May report commissioned by the British government. That would make superbugs bigger killers than cancer.
While these bacteria and what they might do in 30 years are scary, what's more frightening is that some may have the biological equivalent of stealth technology: They appear to be treatable because diagnostics aren't sensitive enough to detect their resistance powers. That's precisely what Emory researchers found when they began investigating the strange organism that turned up in that kidney transplant patient.
Burd sent the sample to a colleague, microbiologist David Weiss, at Emory’s School of Medicine. “I called him and I said, ‘David, I think I’ve got something weird,’” she said.
Weiss is an academic researcher who can spend years untangling the inner workings of a single type of bacteria. Burd runs a workhorse hospital lab that delivers results to doctors in hours. They live in different worlds, and in many academic medical centers, the two would never cross paths. But a few years ago, Emory decided that bringing the Burds and Weisses of the world together would be essential to tackling the urgent problem of superbugs.
“The problem of antibiotic resistance threatens our entire medical system,” says Weiss, 39. “It’s only going to get worse before it gets better.”
Weiss traces his love of biology to childhood trips with his grandmother to the Central Park Zoo, where his favorite animal was the elephant. As he grew older, he became fascinated with nature's smallest life-forms. “How could it be that these little primitive single-celled organisms could do all these terrible things to us?” he asks.
Two years ago, he became director of the new Emory Antibiotic Resistance Center, which includes a network of 35 faculty members, a gaggle of students and postdocs, and more than $10 million a year in research grants. His lab is hidden in the forest on the edge of the university's campus, a short drive from the busy hospital. In the hallway outside the labs, graduate students leave their water bottles, thermoses, and half-eaten slices of pizza on top of a small fridge to avoid picking up pathogens they're studying. Inside, researchers conduct experiments with some of the trickiest bacteria there are.
The bugs evolve constantly, and scientists don’t fully understand all the ways they can defy medicines. “These organisms, because they replicate every 20 minutes and there’s untold trillions of them, are out ahead of us,” says Cliff McDonald, associate director for science at the Centers for Disease Control’s division of health-care quality promotion.
Since the unwelcome surprise inside that Emory transplant patient, another troubling development arose, this time in China. In November, researchers there identified a gene called MCR-1 that makes microbes resistant to colistin. MCR-1 wasn’t among the thousands of resistance genes scientists had already cataloged. When health authorities around the world went back and tested samples in storage, they found the new gene in at least 19 countries.
On May 27, as Americans were preparing for the long Memorial Day weekend, U.S. authorities announced they had detected MCR-1 in a Pennsylvania patient’s urinary tract infection and, separately, in a sample from a pig intestine. The bacteria remained susceptible to some other drugs, just not colistin. But the gene is particularly scary because it can spread swiftly to other types of bacteria, imbuing new strains with resistance traits. If it reaches a bug like CRE (carbapenem-resistant enterobacteriaceae), the highly resistant bacteria that the head of the CDC has called a "nightmare bacteria," resulting infections could be untreatable.
Back at Emory, the type of resistance uncovered in the kidney transplant patient didn't generate the same alarming headlines, in part because it was a bug that can't spread its resistance power as easily to other types of bacteria. But their findings, published in the journal Nature Microbiology in May, raise a different concern: that routine diagnostics can miss superbugs, incorrectly labeling them as susceptible to treatment.
The sample from the patient turned out to have an unusual form of resistance: A small population of the bugs survived treatment with colistin even though they were genetically identical to ones that were vulnerable to the drug. More concerning still, the resistant bacteria flourished in mice without any treatment, actually reproducing faster as a result of the rodents' own immune response.
Victor Band, a fifth-year graduate student in Weiss's lab, said the small population of resistant bacteria begins to expand when the mouse's immune system tries to fight the infection. Nature's chemical defenses killed some of the bugs but made the surviving ones stronger. Colistin had the same effect.
"It’s almost like a stacked deck against the drug," Weiss said. How could doctors treat an infection that behaves that way in a human patient? "It’s a conundrum." (Under medical privacy rules, the fate of the original human patient infected was not disclosed.)
After analyzing the initial strain from Emory, Weiss’s lab got several similar bugs from the freezers of the Georgia Emerging Infections Program, a collaboration among Emory, the CDC, and the state's health department. For 25 years, the program has been tracking unusual or important pathogens circulating in hospitals, the community, and the food supply.
They found a similar strain of E. cloacae with a small subpopulation that colistin couldn’t kill. But the standard lab tests indicated that this strain was susceptible to antibiotics. The superbug was masquerading as a more vulnerable microbe.
To be sure, antibiotics still remain effective most of the time. But science has blind spots: "We should be most concerned, I think, about the problems we don’t even know about,” Weiss says. "Those are the ones that can really creep up on you.”
It's hard to tell how often antibiotics fail, but such cases aren't unheard of. Even a bacterium considered "susceptible" to a particular drug may not respond to the treatment up to 10 percent of the time, though other medicines will often still work. The kind of phenomenon Weiss’s team identified might explain mysterious treatment failures. They’re currently investigating how prevalent such strains may be through a network of other U.S. hospitals.
The weird bug that Burd flagged to Weiss could have easily been shelved in another hospital. To better understand what kind of novel pathogens are circulating, Emory plans to set up a new lab capable of more closely examining unusual specimens from hospital patients. The goal is to "not to lose something that’s really interesting and let it slip through our fingers,” Weiss says.
The government is waking up to the same need, albeit on a broader scale. Stronger surveillance, improved diagnostics, and accelerated research are central elements of the National Action Plan for Combating Antibiotic-Resistant Bacteria, published by the White House in March 2015. That document, just 15 months old, makes no mention of colistin resistance, or the MCR-1 gene. They weren’t on the radar last year.
But the CDC is ramping up to fight superbugs. Armed with $160 million from Congress, the agency plans to equip about eight labs around the country to test resistant bacteria discovered in hospitals and clinics. They should start operating in the fall. It’s also trying to improve the capabilities of state public health departments to track superbugs. “We need to have a robust system for seeing, understanding what’s out there, in terms of what’s making people sick," says Beth Bell, director of the CDC’s National Center for Emerging and Zoonotic Infectious Diseases.
In the meantime, Emory’s superbug hunters will continue to search for strange organisms passing through the hospital lab. “It takes somebody recognizing that something is odd,” Burd says, "and then kind of knowing or figuring out what to do with it."
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