Last Antibiotic Begins to Fail 

A new gene that makes bacteria highly resistant to a last-resort class of antibiotics has been found in people and pigs in China - including in samples of bacteria with epidemic potential, researchers said on Wednesday.

Researchers from several Chinese, British and US universities announced in the journal Lancet Infectious Diseases that they have identified a new form of resistance, to the very last-ditch drug colistin—and that it is present in both meat animals and people, probably comes from agricultural use of that drug, can move easily among bacteria, and may already be spreading across borders.

"All use of polymyxins must be minimized as soon as possible and all unnecessary use stopped," said Laura Piddock, a professor of microbiology at Britain's Birmingham University who was asked to comment on the finding.

To understand why, it’s necessary to know a little bit about colistin. It is an old drug: It was first introduced in 1959. It has been on the shelf, without seeing much use, for most of the years since, because it can be toxic to the kidneys. And precisely because it hasn’t been used much, bacteria have not developed much resistance to it. It remains effective.

(From around that time: Here’s a great story that Jason Gale of Bloomberg wrote about colistin, and one I wrote for Nature about CREs. A long series of posts I wrote for WIRED about the discovery of NDM and the bitter political fights over its apparent origin in India can be found  here. Of note, one of the discoverers of NDM is one of the authors of this new research.)

This suggests "an alarming potential" for it to spread and diversify between bacterial populations, they said.

Which, apparently, is how it is being used in China—but not only in China. From the paper:

China is… one of the world’s highest users of colistin in agriculture. Driven largely by China, the global demand for colistin in agriculture is expected to reach 11,942 tonnes per annum by the end of 2015 (with associated revenues of $229·5 million), rising to 16,500 tonnes by the year 2021, at an average annual growth rate of 4·75%. Of the top ten largest producers of colistin for veterinary use, one is Indian, one is Danish, and eight are Chinese. Asia (including China) makes up 73·1% of colistin production with 28·7% for export including to Europe.

This suggests "the progression from extensive drug resistance to pandrug resistance is inevitable," they said.

"(And) although currently confined to China, mcr-1 is likely to emulate other resistance genes ... and spread worldwide."

Here’s what they found. The gene they discovered, which directs colistin resistance and which they dubbed MCR-1, was present:

• in  78 (15 percent) of 523 samples of raw pork and chicken meat
• in 166 (21 percent) of 804 pigs in slaughterhouses
• and in 16 (1 percent) of 1,322 samples from hospital patients with infections. 

Piddock and others said global surveillance for mcr-1 resistance is now essential to try to prevent the spread of polymyxin-resistant bacteria.

China is one of the world's largest users and producers of colistin for agriculture and veterinary use.

And, of most concern: The MCR-1 gene that creates this resistance is contained on a plasmid, a small piece of DNA that is not part of a bacteria’s chromosome. Plasmids move freely around the bacterial world, hopping from one bacterium to another; in the past, they have transported resistance DNA between bacterial species, facilitating resistance’s rapid movement around the globe. This gene, the authors predict, will be able to do that as well.

In Europe, 80 percent of polymixin sales - mainly colistin - are in Spain, Germany and Italy, according to the European Medicines Agency's Surveillance of Veterinary Antimicrobial Consumption (ESVAC) report.

“Pan-drug resistance,” to be clear, means that nothing at all will work—that infections are untreatable by any known compound.

They found a high prevalence of the mcr-1 gene in E coli samples from animals and raw meat. Worryingly, the proportion of positive samples increased from year to year, they said, and mcr-1 was also found in 16 E.coli and K.pneumoniae samples from 1,322 hospitalized patients.

MCR, this new colistin resistance, different from VRSA is the role that agriculture seems to be playing in its evolution and dispersal. There are two problems here. First, that thousands to millions of animals are getting the drug, which exponentially expands the opportunities that favor resistance. And second, that projects such as the Chinese one that allowed the new gene to be discovered are rare—so colistin resistance could begin moving, from animals and into people, without being noticed. 

"One of the few solutions to uncoupling these connections is limitation or cessation of colistin use in agriculture," they said. "Failure to do so will create a public health problem of major dimensions."