Read Caption
A cattle feedlot from the air. Photograph by Wongaboo (CC), Flickr.

Last-Ditch Drug Resistance: China and Europe Respond

I have a couple of pieces of news regarding the discovery of resistance to colistin, the last-resort antibiotic that is the only thing that works for some multi-drug resistant infections. Two are positive news, and the third is a corrective to some earlier reporting, and a revelation of how complex the antibiotic traffic between human and animal medicine can be.

The positive news first: Both Europe and China are moving to examine the use of colistin in agriculture. The European Medicines Agency has asked the European Commission to be allowed to examine whether colistin use should be restricted. And in China, the central government is studying whether it should ban the drug from agricultural use altogether.

Timothy Walsh, DSc, a British microbiologist who has been studying antimicrobial resistance in China’s agriculture and who collaborated with Chinese researchers on the blockbuster paper announcing the colistin discovery, told me: “The Chinese government have been very receptive” to concerns being expressed about colistin use. He added, “They are conducting a review now, to look at the impact of removing colistin from animal feed, and it is hoped in the next couple of weeks that they will indeed remove colisitin from animal feed.”

Quick update, if you’re coming to this fresh: Colistin is an old drug, first isolated in 1949, that languished on the shelf for decades but was recently revived. It it the only antibiotic that works against a growing category of serious infections; if widespread resistance to it developed, those infections, known as CREs, would become untreatable. In November, Walsh and his collaborators made the bombshell announcement in Lancet Infectious Diseases that they had found resistance to colistin in China, contained in a mobile genetic element that can reproduce and move freely among bacteria, and that its existence—in pigs, pork meat, and human patients—was due to colistin use in agriculture.

That news set off an international furor and also a hunt. The mcr-1 gene conferring this resistance was swiftly identified in stored bacterial samples in Denmark, and then England; the count is now up to 10 countries. (With more no doubt to come.)

That brings us up to date, and also to the corrective piece of news.

The early days of reporting about mobile colistin resistance gave the impression that it arose through China callously wasting a crucial drug. (This slots into China’s well-documented reputation for dubious food safety.) The message was that, unlike Europe and the United States, which have taken steps to control farm antibiotic use, China is allowing a free-for-all.

Turns out, it’s not that simple. The situation is not that agriculture, in China or elsewhere, is using up a drug that medicine has always needed. It’s more that medicine handed the drug to agriculture in the 1950s, and now wants it back.

View Images
Colistin use in agriculture in Europe in 2011 (expressed in a per-animal measure). Grpahic by the European Medicines Agency, original here.

You can see this most clearly in Europe. The EU has had the word’s strictest control on livestock antibiotics  since 2006, when it banned the routine micro-doses called growth promoters that make animals put on weight more quickly. Yet it is an abundant user of colistin. An eye-opening paper published last September lists colistin (and a related drug; both belong to the polymyxin class) as being used in “rabbits, pigs, broilers, veal and beef cattle, and meat-producing sheep and goats; furthermore, the antibiotic is used also in laying hens and dairy cattle, sheep and goats producing milk.” Of all the classes of antibiotics used in animals in Europe, the polymyxins were the 5th most-sold. That is all prophylaxis, to prevent the occurrence of diseases, which remained legal under the 2006 ban.

“Colistin is a survivor of the ban on antimicrobial growth promoters in Europe,” Boudewijn Catry, DVM, PhD, told me. Catry is the first author on that paper and the head of healthcare-associated infections and antimicrobial resistance at Belgium’s Scientific Institute of Public Health. He said that colistin gets so much use for two reasons: first, because it was so toxic in humans that it seemed medicine would never want it; and second, because other drugs were taken away from agriculture over the years precisely because medicine needed them preserved. Those other drugs include penicillin, the tetracyclines, and vancomycin, the last-resort drug for MRSA (agriculture used a close analog, avoparcin). Catry added: “When many compounds were banned, others were still possible to give in large quantities by the oral route, for prevention of major diseases, and colistin is one.”

Multi-drug resistant CREs began moving across the globe in the mid-2000s. There were different categories—the KPCs in the US, NDM in South Asia, OXA in the Mediterranean—but what they all had in common was resistance to carbapenems, essentially the last reliable, nontoxic drugs for highly resistant organisms. With nothing else left, human medicine was forced to turn back to colistin.

At that point, the European Union began re-evaluating the way that it had allowed agriculture to use the drug. In 2013, the European Medicines Agency recommended disallowing preventive use, and that recommendation has been chugging through the system since, without great urgency because resistance migrating from agriculture did not seem to be a problem. With the discovery of mobile colistin resistance, that has changed.

The MCR story is going to go on for a while, but right now, there are two important things to note. The first is that antibiotic control is porous. Colistin resistance is occurring in Europe because it entered agriculture through allowed preventive use; when the United States finalizes its long-awaited actions against growth promoters in 2016, it will allow preventive use too.

The second is that the progress of resistance is unpredictable. Medicine allowed agriculture to use avoparcin because it never thought vancomycin would be important; it allowed polymyxin use in agriculture because it never though it would need colistin either. It turns out both drugs are crucial. That seems to me a lesson that all antibiotics should be used conservatively. We never know what will arise next.

Previous posts in this series: