Long-Dreaded Superbug Found in Human and Animal in U.S.

A gene conferring resistance to the last-ditch drug colistin has been found in E. coli in the United States.

The antibiotic resistance factor MCR, which protects bacteria against the final remaining drugs of last resort, has been found in the United States for the first time—in a person, and separately, in a stored sample taken from a slaughtered pig.

Department of Defense researchers disclosed Thursday in a report placed online by the journal Antimicrobial Agents and Chemotherapy that a 49-year-old woman who sought medical care at a military-associated clinic in Pennsylvania last month, with what seemed to be a urinary tract infection, was carrying a strain of E. coli resistant to a wide range of drugs. That turned out to be because the organism carried 15 different genes conferring antibiotic resistance, clustered on two “mobile elements” that can move easily among bacteria. One element included the new, dreaded gene mcr-1.

The discovery “heralds the emergence of truly pan-drug resistant bacteria,” the DOD personnel, Patrick McGann of the Walter Reed Army Institute of Research and Kurt Schaecher of the Walter Reed National Military Medical Center, along with eight colleagues, write in the journal report.

Beth Bell, director of the National Center for Emerging and Zoonotic Infectious Diseases at the Centers for Disease Control and Prevention, said the CDC has begun working with the researchers and the Pennsylvania Department of Health to understand how the woman came to be carrying the highly resistant bacterium. (Later Thursday, Pennsylvania Governor Tom Wolf confirmed the case, and the CDC joint investigation, in a statement.)

The DOD researchers who described her case, who did not immediately respond to a request for comment, provided no other information on her case, except to say that she had not traveled in the previous five months, suggesting she did not pick up the bacterium outside the U.S.

“It is extremely concerning; this is potentially a sentinel event,” Bell said in a phone interview. “There is a lot that needs to be done in terms of contact tracing and field investigation, to have a sense of who else might have been exposed or might be carrying this resistant bacterium.”

Bell disclosed that the U.S. Department of Agriculture will shortly announce the first identification of MCR in the United States in an animal. It was found in a stored sample of pig intestine that was collected as part of the National Antimicrobial Resistance Monitoring System, a shared project of the CDC, USDA and Food and Drug Administration that looks for resistant foodborne bacteria in people, animals, and meat.

“We have been intentionally looking for this since MCR was first announced,” she said.

The Department of Health and Human Services subsequently confirmed the pig finding in a blog post Thursday afternoon.

The existence of MCR was reported for the first time just last November, in a report by British and Chinese researchers who said they had found the gene in people, animals, and meat in several areas of China. Subsequently it has been found in people, animals, or meat in at least 20 countries across the world.

MCR is so troubling because it confers protection against colistin, the last remaining antibiotic that works against a broad family of bacteria that have already acquired resistance to all the other antibiotics used against them. Colistin has worked up to this point because it is a toxic drug from the early days of the antibiotic era, seldom prescribed because of its side effects; because it was used so infrequently, bacteria had not adapted to it.

But because it is effective, agriculture adopted it instead, using it widely and legally for prevention of diseases in food animals. By the time the medical community discovered that it needed the drug back, resistance to colistin was already moving from agriculture into the human world.

Colistin is not actually used in animals in the United States, though it has been approved for use by the FDA. That makes the arrival of colistin resistance a mystery that will have to be plumbed through genetic sequencing.

Advocates who track antibiotic resistance, especially in agriculture, reacted to the news of U.S. colistin resistance by emphasizing the gravity this finding deserves.

“This shows that we are right on the verge of getting into the territory of routine bacterial infections being untreatable,” Steven Roach, the food safety program director at the Food Animal Concerns Trust, said by phone. “It underscores the failure of both the federal government and Congress, and the industry, to get a grasp of the problem. We can’t continue to drag our feet on taking needed action.”

The Pennsylvania woman’s diagnosis occurred thanks to a system set up within the DOD after MCR was discovered. Since last fall, any E. coli that was already resistant to a family of drugs known as ESBLs (extended-spectrum beta-lactams), as hers was, has been sent up the chain to Walter Reed, to be scrutinized for colistin resistance. That kind of systematic checking for antibiotic resistance, known as active surveillance, is rare in the United States. Most civilian surveillance systems are patchy; they focus only on foodborne illnesses, or rely on physicians or labs to report diagnoses, or draw from a few state health departments with already well-funded labs.

“This shows how much we need comprehensive surveillance, so that things are not discovered by accident,” Bell said. The CDC recently received additional funding under the Obama Administration’s national strategy for antibiotic resistance that will allow it to begin to set up regional lab networks. “We’ll be able to identify things systematically, identify clusters and begin contact investigations quickly,” she said.

“The first known case of MCR-1 in a U.S. patient underscores the urgent need for better surveillance and stewardship programs to combat antibiotic resistance,” agreed Dr. David Hyun, an infectious-disease specialist who is a senior officer in a long-running antibiotic resistance project at the Pew Charitable Trusts.

If there is any good news in the announcements of MCR’s appearance in the United States, it is that it has not, as yet, combined with other resistance genes into a completely untreatable organism. Bacteria acquire resistance genes like gamblers amassing a hand of cards, but the way the “cards” arrive is not step-wise—bad resistance, and then worse resistance, and then the worst—but randomly. What that means, in this case, is that the Pennsylvania E. coli possesses ESBL resistance (bad) and colistin resistance (worst)—but it remains susceptible to other intervening categories of drugs. (The stored pig sample has a yet different resistance pattern, colistin plus what is known as ASSuT, for the drug families represented by ampicillin, streptomycin, sulfas and tetracycline.)

But the random roulette of bacterial genetic recombination makes it more likely that an untreatable combination—of, for instance, colistin resistance plus carbapenem resistance, which the CDC has previously called “nightmare bacteria”—might occur. In fact, it already has occurred in patients in China, where MCR was first identified.

“We’re one step closer to carbapenem-resistant and colistin-resistant E. coli  bumping into each other in someone’s gut,” Lance Price, a molecular biologist and the director of the Antibiotic Resistance Action Center at George Washington University, said by phone. “It doesn’t matter in which direction the transfer takes place—if the carbapenem-resistant strain picks up colistin resistance, or if the colistin-resistant strain picks up carbapenem resistance. It’s double jeopardy.”

Once bacteria begin to collect resistance to multiple families of antibiotics, the speed and direction of their spread becomes hard to predict, because using any of the antibiotics to which they are resistant allows them to increase in number. (Not because the drugs affect the resistant bugs—they don’t—but because they kill susceptible organisms nearby, freeing up additional living space and food.) That makes it crucial to create surveillance systems that can identify them early.

The Department of Defense system that detected the Pennsylvania organism is a model for how surveillance ought to be carried out, Price said: “We need active surveillance for multi-drug resistant or high-priority resistant organisms, in animals and people, throughout the U.S.”

Previous coverage on Phenomena:

Feb. 1, 2016: Last-Ditch Antibiotic Resistance: What is the Role of Food?
Jan. 7, 2016: Last-Ditch Resistance: More Countries, More Dire Results
Jan. 6, 2016: Last-Ditch Drug Resistance: China and Europe Respond
Dec. 20, 2015: Last-Ditch Drug Resistance: An Early Warning And Chance to Act
Dec. 18, 2015: Resistance to a Last-Ditch Antibiotic: Invisible Spread
Dec. 15, 2015: More Countries Are Seeing a Last-Ditch Antibiotic Failing
Dec. 3, 2015: Apocalypse Pig Redux: Last-Resort Resistance in Europe
Nov. 21, 2015: Apocalypse Pig: The Last Antibiotic Begins to Fail

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