Colistin Resistance: “The Pig is Out Of The Barn”

The scientists who this week reported dangerous drug resistance in seagulls aren’t the only researchers looking for mcr-1, the gene that confers protection against the last-resort antibiotic colistin.

Since the discovery of the gene was announced last November by English and Chinese researchers, microbiologists the world over have been scouring their “collections”—the thousands (or more) of bacterial isolates they keep in frozen storage—to see whether the sample banks contain any evidence that the gene has passed through. Almost 100 instances of finding the gene have been announced, many of them out of such collections, some from five or more years ago—and that has researchers quietly convinced that more are coming, and that MCR resistance may be more widely distributed than we know.

If their hunch is correct, then that would be trouble. MCR resistance resides in gut bacteria, chiefly E. coli, and can lurk in the intestines an undetermined period of time. Someone who unknowingly carries the bug could pass it to others in a chain of transmission that would go undetected until, in some unlucky person, an infection blooms.

Last weekend, MCR and the urgency of determining how far it has spread was the talk of the hallways at ASM Microbe, the largest infectious-disease conference of the year. During the conference, I grabbed some time with Barry Kreiswirth, a professor of medicine at Rutgers University and founding director of the Public Health Research Institute Center there. In the 2000s, Kreiswirth’s lab led the discovery of the last wave of dire superbugs to hit the United States: a form of the bacterium Klebsiella pneumoniae known as KPC because it was resistant to the formerly last-ditch drugs carbapenems. (Losing carbapenems made medicine take colistin, a very toxic antibiotic, off the shelf where medicine consigned it in the 1950s.)

Kreiswirth and his lab have made three of the almost 100 MCR discoveries made so far, all in China thanks to Chinese collaborators. They are now searching their collections to see whether there are domestic discoveries to be made. (I edited and condensed our conversation.)

Maryn McKenna:  You’re very accustomed to superbugs. Tell me why, from your perspective, the arrival of mcr-1 is alarming.

Barry Kreiswirth: The problem with resistance such as KPC, and now MCR, is that the resistance DNA is on mobile elements, plasmids. That’s a whole different game from stopping the spread of an infection from one person to another. Plasmids move. They move from one strain to another. They move from one bacterial species to another. You can have a person that has an E. coli and a Klebsiella in their gut, and those bacteria will actually swap their plasmids, from E. coli into Klebsiella and vice versa. Trying to control that type of epidemic is completely different. We don’t have a strategy, because you can’t stop plasmids moving.

MM: You have begun looking for this already?

BK: We have published three papers. The most striking one was, we had a colleague from China in my lab who, when he went back to China, took out any colistin-resistant strains and screened them for the presence of mcr-1, and found it. Now everyone is looking for mcr-1 genes retrospectively, and finding them. That means that there’s probably a fairly large reservoir out there of strains carrying mcr-1. But we don’t have a clue how big that reservoir is. We don’t know how much, we don’t know where. Why is this concerning? Because colistin, even though it’s not a very good drug, it’s still one of our salvage drugs for carbapenem resistance. If we lose that, we’ve lost another antibiotic, and we don’t have many. You know the old joke, the horse is out of the barn. In this case, the pig’s out of the barn.

We don’t have a clue how big that reservoir is. We don’t know how much, we don’t know where.

BK: China uses colistin in animal feedlots—which is sort of the history of antibiotic resistance; in the U.S. as well as in Europe, we have a history of using antibiotic remnants in animal feed, so that story is not new. But the Chinese don’t use colistin to treat [humans]. And because they don’t use it, they don’t test for resistance to it. The problem is, this is a global community, and other people do use colistin [in human medicine]. And you can’t stop strains or people moving from China to elsewhere.

MM: Where do you think the biggest concern should be now?

BK: My doomsday scenario is that someone in medicine is going to start thinking, Do we do high-risk procedures? Some of what we do now is remarkable. If you ever talk to the guys who do bone-marrow transplants, God. As one doctor said to me, “We kill the patient and then bring them back to life.” If 50 percent of liver transplant patients die of a bacterial infection, what’s the point?

MM: Aside from searching the bacterial collections that you hold—which by definition is looking backward, to when the samples were taken—what else could be done to define how much trouble we’re in?

BK: We don’t do a good job of screening healthy people [for pathogens], mainly because people don’t want to fund it. I would love to have a project where we could start screening. But those are difficult studies to do. They’re hard to get funded. There are a lot of logistics. For an example, my wife’s a nurse practitioner, and we tried to do a study of the prevalence of community-acquired MRSA. We made an attempt to go to doctors’ offices. But how do you do an [institutional consent] with 50 different offices? And then [obtain consent from] every patient that walks in? No one’s paying them to do that. For MCR, we hope to be able to screen liver transplant patients, bone-marrow transplant patients. When you consider how much those procedures cost, additional screening would be trivial. So that’s one intervention I think we could do.