Last-Ditch Resistance: More Countries, More Dire Results

The frantic international hunt triggered by the discovery of genetically mobile resistance to colistin, a last-resort antibiotic, is producing many more findings this evening. The resistance factor is showing up in more countries, but, much more important, it has combined in some bacterial samples with genes conferring resistance to other potent drugs, creating bacteria that look effectively untreatable.

These disclosures are made in letters from research groups in a number of countries that are being published by the journal Lancet Infectious Diseases at 11:30pm London time, which is 6:30pm East Coast time here in the US. They represent evidence that this drug resistance, which was driven by agricultural use of colistin during the years that human medicine did not make use of it, is an imminently serious issue for human health.

“We’re watching our demise in real time,” Lance Price, PhD, a prominent resistance microbiologist and founder of the Antibiotic Resistance Action Center at George Washington University, who not involved in any of the research, told me. “I guess this is one of the advantages of next-generation DNA sequencing, is we can watch ourselves fall apart.”

Here’s a quick way to think about what follows. It’s natural to imagine that antibiotic resistance proceeds step-wise; that in the leapfrog between bug and drug, bacteria gain resistance to one drug, and then the next toughest drug presented to them, and then a last-resort drug after that. But in the wild, the way bacteria accumulate resistance DNA is more like being dealt cards in a hand of poker: one might have a 3, a 5, and a Jack, while another has a King, a Queen and a 10.

In these papers published tonight, researchers are finding bacteria that already possess colistin resistance— call it the Ace—and are accumulating the rest of a winning hand. Only, what looks like winning would be losing, for us. Here are the details:

Laurent Poirel and colleagues in Switzerland have identified an E. coli strain, recovered from an 83-year-old Swiss man who was hospitalized last month, that possesses both colistin resistance and also VIM resistance to the carbapenems, the family of antibiotics that was considered the last and toughest before colistin. The colistin-resistance gene shared a plasmid with genes conferring resistance to chloramphenicol, flofenicol and co-trimoxazole. The authors warn, “Such accumulation of multidrug resistance traits may correspond to an ultimate step toward pandrug resistance.”

Our data suggest that the advent of untreatable infections has already arrived.

Marisa Haenni and collaborators in France and Switzerland queried the Resapath network in France, which conducts surveillance for antibiotic resistance in animals, found that 21 percent of bacterial samples 21 percent of bacterial samples 21 percent of bacterial samples collected from veal calves on French farms between 2005 and 2014 carried the signal of mobile colistin resistance, the gene mcr-1. There were 106 positive samples (out of 517) and they came from 94 different farm properties. On seven of those isolates, the mcr gene lived alongside ones for ESBL resistance—that’s to penicillins and to the first three generations of cephalosporin drugs—and also genes for resistance to sulfa drugs and tetracycline.

Linda Falgenhauer and collaborators in the Reset consortium in Germany examined the sequences of 577 isolates taken from human patients and livestock and from the environment since 2009. They identified four carrying the mcr-1 gene, three from humans and one from a hog. The three from swine also possessed ESBL resistance; the one from the human was also carbapenem-resistant (KPC-2). One of the swine samples dated back to 2010. They say, somberly: “Our data suggest that the advent of untreatable infections has already arrived, as every colistin-resistant isolate described in this study is also resistant to either third-generation cephalosporins or to carbapenems.”

Surbi Malhotra-Kumar and colleagues at the University of Antwerp examined 105 E. coli strains collected from piglets and calves in 2011 in Belgium that had previously been identified as colistin-resistant. They found mcr-1 in 13 of themfound mcr-1 in 13 of themfound mcr-1 in 13 of them, and also found that it is being carried on a different plasmid than those identified in China and in Denmark. They descrcibe this as “a marked presence of mcr-1 in animal pathogenic bacteria in Europe, an indication that this is already a truly global phenomenon”— and also note that the 92 resistant strains that did not contain mcr might indicate other transferable colistin resistance that has not yet been identified.

In a separate letter, the same research group and several Vietnamese collaborators report mcr-1 in nine out of 24 E. colinine out of 24 E. coli collected from chickens and pigs in two provinces in Vietnam. One isolate contained resistance to eight additional drug families. They also screened 112 ESBL E. coli from three hospitals in Hanoi, but, they report, did not find any mcr.

Nicole Stoesser and colleagues from England and collaborators in Virginia and Bangkok examined sequences from a database of E. coli and Klebsiella collected in North America, Europe and Southeast Asia between 1967 and 2012, and found only a single isolate carrying mcr. It was taken frmo a child hospitalized in Cambodia in 2012, and also possessed ESBL resistance.

In Japan, Satowa Suzuki and collaborators from several institutions say they scoured the sequences of  1,747 plasmid genomes from Gram-negative bacteria, originally taken from human patients and livestock and from the environment, and found five animal isolates carrying mcr, but no human ones. None carried other resistance genes. They also examined a separate database of E. coli from livestock and, out of 9.308, found only two carrying mcr—but 88 others that were colistin-resistant.

And in the eighth letter, Mauro Petrillo and colleagues of the European Union’s Molecular Biology and Genomics Unit present a hypothesis for how the mcr-1 gene is being acquired.

There are some important leads in these reports: that mcr is in more countries,  is appearing on different plasmid backbones, and, apparently, seems more common in animals than in humans in the locations where it has been found. That may suggest, as the CDC said last month, that molecular analysis allowed this to be identified relatively earlier than other dire resistance factors have been in the past.

But the discovery that colistin resistance is combining in the same plasmids with other resistance genes should especially raise alarm bells. That indicates that using any of those drugs—some of which are very common—could amplify this resistance and and increase its spread. It signals that, as serious as mobile colistin resistance appeared at first, it is even more complex and more urgent.

Previous posts in this series:

• Nov. 21, 2015: Apocalyse Pig: The Last Antibiotic Begins to Fail
• Dec. 3, 2015: Apocalypse Pig Redux: Last-Resort Resistance in Europe
• Dec. 15, 2015: More Countries Are Seeing a Last-Ditch Antibiotic Failing
• Dec. 18, 2015: Resistance to a Last-Ditch Antibiotic: Invisible Spread
• Dec. 20, 2015: Last-Ditch Drug Resistance: An Early Warning And Chance to Act
• Jan. 6, 2016: Last-Ditch Drug Resistance: China and Europe Respond