The “new superbug” MCR—actually a gene, carried by gut bacteria, that confers resistance to the absolutely last-ditch antibiotic colistin—has been in the United States for at least a year, according to a new report.

The gene was first identified last year and caused a flurry of alarm when it was spotted for the first time in the U.S. in May, after being found in bacteria from people, animals and meat in more than 30 countries.

That first U.S. identification came from a just-diagnosed woman in Pennsylvania. But in a letter posted Monday by the journal Antimicrobial Agents and Chemotherapy, researchers from JMI Laboratories in Iowa say they have found a second instance of MCR that is more than a year old. It was found in a stored sample of E. coli that was collected in May 2015 in New York.

The new discovery confirms that the Pennsylvania case was not the first MCR-related infection in the U.S., but only the first to be found—making it a reasonable assumption that there are others that have not been identified yet.

Also, in both patients the bacteria harboring the gene were susceptible to other antibiotics—which raises the possibility that this new resistance factor may be less of an immediate health threat, and more like a time bomb with an unpredictably long fuse.

But along with new European research announced last week and a troubling new finding reported today, the U.S. discovery reinforces that for medicine and public health to protect the population from that time bomb going off—that is, from the arrival of completely untreatable infections—they will need to start doing a lot more looking for MCR than they do now.

New ‘First’ Case

Some details on the New York finding: JMI Laboratories is a private company that tests bacteria sent in by hospitals around the world. The testing is commissioned by antibiotics manufacturers who want to see how existing drugs are holding up, and to gauge the vulnerability of bacteria to new compounds. The system under which hospitals send in bacterial samples is called SENTRY; it has been drawing thousands of samples a year from almost 200 hospitals around the globe since 1997.

JMI holds on to samples after initial testing, and periodically does fresh research with them. The new publication draws on those collections of bacteria.

The researchers at JMI looked for colistin resistance in 21,006 E. coli and Klebsiella samples collected in 2014 and 2015; they found 390 that were resistant. Then they used PCR (a test that returns a genetic fingerprint resembling a bar code) to see whether those bacteria were resistant because they possessed the gene mcr-1. Nineteen of them were: eight collected in 2014 and 11 from 2015. The samples came from Belgium, Brazil, Germany, Hong Kong, Italy, Malaysia, Poland, Russia, and Spain, and a single one from New York.

Mariana Castanheira, PhD, one of JMI’s research directors, told me the lab doesn’t know anything yet about the patient the sample came from. “We know it was a gastrointestinal sample,” she said by phone, adding that the hospital where it was collected “is investigating the clinical history.”

The E. coli from the patient’s system also possessed ESBL resistance, meaning it would not have responded to penicillins or to cephalosporin antibiotics. But, Castanheira said, “It was susceptible to carbapenems, to nitrofurantoin, to fosfomycin, and to new compounds that have just been approved by the FDA.”

Rapid Spread

MCR resistance has generated so much concern because the gene mcr-1 resides on a plasmid, a small piece of DNA that can move freely from one bacterium to others. When resistance is plasmid-mediated, it spreads more quickly among bacteria than if it were passed down from one generation of bacteria to the next. Plus, resistance DNA carried on plasmids can stack up in bacteria like cards in a poker hand, rendering those bacteria resistant to multiple antibiotics even if they have never been exposed to the drugs.

Castanheira said her lab has not yet determined whether this mcr-1 is on a plasmid or not. “We’re working on that now, and we expect there will be another publication,” she said.

The new MCR finding reinforces the prediction made to me a few weeks ago by distinguished microbiologist Barry Kreiswirth of Rutgers, that as institutions scour their bacterial collections for any instance of the gene, more instances of MCR that have been in the U.S. for a while will be found.

“I think we can expect more cases are going to be reported,” Jean Patel, a microbiologist and the Deputy Director at the Centers for Disease Control and Prevention’s Office of Antimicrobial Resistance, told me. “Our best predictions right now are that they would just trickle in at a slow rate, because we think this is still a very rare event.”

What’s Next

To keep MCR from becoming more common, a few things are necessary. First is finding out where it is lurking, which requires more testing. Patel said most clinical labs don’t routinely test for colistin resistance. (In fact, the first MCR discovered in the U.S. was found only because the Department of Defense, which operates the outpatient clinic where the Pennsylvania woman was treated, had set up a special surveillance project.)

Recognizing that the gene is present would let the public health system push to increase infection prevention in hospitals, and also to avoid using colistin—because using a drug that bacteria are resistant to has the paradoxical effect of encouraging those bacteria to multiply. And when bacteria have acquired resistance to multiple drugs through plasmids, using any of those drugs can increase the spread of all of those resistance factors.

But news from Europe, released last Thursday in the journal Eurosurveillance and also today in Antimicrobial Agents and Chemotherapy, reinforces how complicated—and urgent—finding MCR may turn out to be.

The finding announced last week comes from a group of Belgian scientists who made news in January when they found more than 12 percent of 105 pigs and calves from different parts of Belgium were silently carrying mcr-1 in their feces. (Colistin is widely used in European agriculture, unlike the U.S., which has probably contributed to the spread of MCR resistance there.) Now they have gone back through the samples from that study, and discovered that some of the animals were also carrying a related gene that they have dubbed mcr-2.

The new gene was more common than mcr-1 in the E. coli samples taken from pigs: in 11 out of 53, compared to 7 out of 53. It also resides on a plasmid, and it appears to have genetic elements that make it more able to move between bacteria than mcr-1 does. However, it shares only about three-fourths of the genetic material of mcr-1. Thus, the scientists warned, the newly identified gene may be missed by the tests that countries are scrambling to set up to search for MCR.

And in a development that medicine has been braced for, Italian researchers say today that they have found yet another variant of the superbug gene, mcr-1.2, in a child hospitalized with leukemia in Florence. That variant, like mcr-1 and the newly named mcr-2, creates resistance to the very last-resort antibiotic colistin.

But what especially rang their alarm bells is that they found the gene in a strain of bacteria, Klebsiella pneumoniae, that was already resistant to the almost-last-resort antibiotic class, carbapenems, and to several other classes as well. Those bacteria are known by the acronym KPC, and since the early 2000s, they have spread through hospitals around the world. So the Italian discovery signals two things that medicine has feared: that MCR has landed in bacteria that are already good at spreading through healthcare, and that it has begun the process of stacking up in bacteria, alongside other resistance DNA, on the way to creating what could be a truly untreatable bug.