Resistance to a Last-Ditch Antibiotic: Invisible Spread

Well, that escalated quickly.

Last night, the journal Lancet Infectious Diseases, which carried the initial report of resistance to the last-ditch drug colistin, published five letters from researchers announcing they too have found the MCR gene in additional countries: France; the Netherlands; and Algeria, Laos, and Thailand. Those are in addition to previous reports of the gene being found in bacteria from China (which started this story), Malaysia, Portugal (probably), Denmark, and the United Kingdom.

That’s 10 countries so far, and, sources say, more to come.

Brief catch-up: In November, researchers in China and the UK announced that they had identified this gene—which confers resistance to the last-resort antibiotic colistin—in bacteria recovered from live pigs and from retail meat, and bacterial samples stored from hospital patients. This is worrisome because, as waves of high-level antibiotic resistance have moved across the world, colistin has been the one drug that still worked.

One reason it still worked was that it is not a very good drug. It kills bacteria, but it is toxic to organs, and so human medicine had kept it on the shelf—and thus, bacteria had not developed much resistance to it. But it turns out that while medicine was conserving the drug carefully, agriculture—especially in China, but also in Europe and on other continents—was using it by the ton, pumping up the selective pressure that encourages bacteria to develop resistance in order to protect themselves. (If you’d like to catch up in more depth, the earlier posts are here, here and here.)

There are some things worth heeding in these new reports.

First, the gene—which is carried on several plasmids, free loops of DNA that can move among bacteria—has found a lot of homes: in these recent reports, in various strains of E. coli and multiple serotypes of Salmonella. As Lance Price, PhD, of the Milken Institute School of Public Health at George Washington University, told me a few days ago: “It’s almost like it possesses a universal key.”

Second, the bacteria carrying this gene are coming from many sources. In the Netherlands, it was found in the feces of Dutch residents who had traveled to China, Peru, Bolivia,  Tunisia, and Southeast Asia. In France, it was in packaged meats bought in three different areas of the country, and also in the dirt from a chicken farm in a fourth area. In Thailand, in people; in Algeria, in chickens; in Laos, pigs and also a pig farmer.

Third, in the reviews of existing collections of bacteria that produced these results, some of the authors also found colistin resistance even when the MCR gene was not present, reinforcing how widespread the use of the drug must be. (In the initial paper, the authors estimate international colistin use in agriculture at 11,942 metric tons this year; that’s 13,163 US tons, or 26.33 million pounds.)

Fourth, all of the authors of these reports are very clear that the trigger for the emergence of this resistance must be that vast use of this last-resort drug in agriculture, and call for immediate curbs to keep from making the problem worse.

Webb et al., who reported MCR in France: “Our findings, and those of others, reinforce the need to reconsider the use of in-feed colistin in veterinary medicine at a worldwide level. Stewardship efforts are needed to preserve the efficacy of antimicrobial drugs for society—both now and into the future.”

Olaitan et al., who found MCR in samples from Algeria, Laos and Thailand: “We anticipate that with the extensive use of colistin in animal production, including in Europe, plasmid-mediated colistin resistance has already spread worldwide, and this calls for prompt international action to restrict or ban the use of colistin in agriculture to avoid further spread of resistance.”

And finally, one of the letters to Lancet Infectious Diseases makes explicit a point that is present, but not emphasized, in the others: that this resistance factor, contained in bacteria that normally reside in the gut, is capable of spreading invisibly because it can be carried unknowingly by apparently healthy people. Hu et al. report that they identified the gene in 27 entries in a human microbiome database (3 complete gene sequences, 24 fragments, all from China, all taken before 2011). To be clear, the fecal samples that provided the sequences in that database would only have been taken from healthy people; these are not the kind of samples that are harvested in a hospital to help diagnose why someone is sick.

Those authors say: “These results suggest that the mcr-1 gene might have been in China for a long time and already spread to the healthy human gut, which is regarded as an antibiotic resistance gene reservoir, and a site with high horizontal gene transfer potential.”

They add: “We are concerned that the worldwide distribution of mcr-1 might be underestimated.”

There’s one more point to be made about these new findings, and the ongoing story of MCR. I’ll save that for a separate post.