Last Line of Antimicrobial Defense Is Falling: Colistin Resistance Transmission

Actually, it’s sort of reached the rout stage. From China (don’t worry, I’ll translate from Science into English; boldface mine):

Background: Until now, polymyxin resistance has involved chromosomal mutations but has never been reported via horizontal gene transfer. During a routine surveillance project on antimicrobial resistance in commensal Escherichia coli from food animals in China, a major increase of colistin resistance was observed. When an E coli strain, SHP45, possessing colistin resistance that could be transferred to another strain, was isolated from a pig, we conducted further analysis of possible plasmid-mediated polymyxin resistance. Herein, we report the emergence of the first plasmid-mediated polymyxin resistance mechanism, MCR-1, in Enterobacteriaceae.

Methods: The mcr-1 gene in E coli strain SHP45 was identified by whole plasmid sequencing and subcloning. MCR-1 mechanistic studies were done with sequence comparisons, homology modelling, and electrospray ionisation mass spectrometry. The prevalence of mcr-1 was investigated in E coli and Klebsiella pneumoniae strains collected from five provinces between April, 2011, and November, 2014. The ability of MCR-1 to confer polymyxin resistance in vivo was examined in a murine thigh model.

Findings: Polymyxin resistance was shown to be singularly due to the plasmid-mediated mcr-1 gene. The plasmid carrying mcr-1 was mobilised to an E coli recipient at a frequency of 10−1 to 10−3 cells per recipient cell by conjugation, and maintained in K pneumoniae and Pseudomonas aeruginosa. In an in-vivo model, production of MCR-1 negated the efficacy of colistin. MCR-1 is a member of the phosphoethanolamine transferase enzyme family, with expression in E coli resulting in the addition of phosphoethanolamine to lipid A. We observed mcr-1 carriage in E coli isolates collected from 78 (15%) of 523 samples of raw meat and 166 (21%) of 804 animals during 2011–14, and 16 (1%) of 1322 samples from inpatients with infection.

Interpretation: The emergence of MCR-1 heralds the breach of the last group of antibiotics, polymyxins, by plasmid-mediated resistance. Although currently confined to China, MCR-1 is likely to emulate other global resistance mechanisms such as NDM-1. Our findings emphasise the urgent need for coordinated global action in the fight against pan-drug-resistant Gram-negative bacteria.

Before we get to what this means, a question for Lancet: why the fuck is this behind a paywall? This is really important. If there were a microbiological instance of when something should be made open access, this is definitely it. But I digress.

First, some background: polymyxins, including polymyxin E also known as colistin, are the last line of defense against antibiotic-resistant Gram-negative bacteria, such as E. coli, Klebsiella, and others. For regular readers, you might remember that I’ve referred to carbapenem antibiotics as the last line. That’s because the efficacy of colistin is debatable: some studies show a very good cure rate, others do not. It doesn’t help that colistin can have severe side effects such as kidney failure. Nonetheless, as carbapenem-resistance enterobacteriaceae (E. coli and pals, often referred to as ‘CRE’) increase, colistin is what we have.

Bacterial resistance to colistin has been seen, but its saving grace, such as it is, is that this resistance is not very transmissible. In other words, a colistin-resistant bacterial strain can spread, but it won’t transfer that resistance into another strain*.

Until this paper. This group, in China, discovered a plasmid (a bacterial mini-chromosome that can move to genetically different bacteria–think of it as a flash drive with EVIL) that has a gene mcr-1 that confers resistance to colistin. Unfortunately, this isn’t a ‘one-off’, bizarro finding: as the abstract above states, one in five farm animals has E. coli with mcr-1, and one percent of hospital isolates have mcr-1. Moreover, the authors note that at least three bacterial genomes already in Genbank have mcr-1 like genes (though we didn’t know this)–and these isolates were collected in Malaysia in September 2013. It’s out there. Worse, colistin is used widely in agriculture–yes, this is really fucking stupid. Here’s what I mean (boldface mine):

China is the world’s largest poultry and pig producer, and in 2014 produced 17.5 million tonnes and 56.7 million tonnes, respectively. Most of the production is for domestic consumption with about 10% for export. The global market value of veterinary drugs increased from US$8.7 billion in 1992 to $20.1 billion in 2010, and in 2018 is anticipated to reach $43 billion. China is also 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. In 2015, the European Union and North America imported 480 tonnes and 700 tonnes, respectively, of colistin from China. Colistin sulphate (together with other antibiotics) has also been used in farmed fish diets where it has been shown to improve health and promote growth. This increasingly heavy use of colistin could have resulted in high selective pressure in the veterinary environment and led to the acquisition of mcr-1 by E coli. We anticipate that the amount of colistin used in animal feed is likely to provide survival advantage for MCR-1-producer bacterial populations over colistin-sensitive bacterial populations. This usage pattern can also explain the apparently discrepant prevalence of mcr-1 between animal and human E coli isolates.

This is really bad news. It’s only a matter of time before it winds up elsewhere–which is what we’ve seen with almost every other form of plasmid-encoded resistance.

If this doesn’t convince people to get serious about the agricultural side of the problem, I don’t know what will.

I guess I shouldn’t quit my day job…

Update: It gets worse.

*It’s possible, but incredibly unlikely. Lots of biology and population dynamics suggest this, anyway…

Cited article: Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. 10.1016/s1473-3099(15)00424-7

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9 Responses to Last Line of Antimicrobial Defense Is Falling: Colistin Resistance Transmission

  1. A says:

    Hi, a Biologist here.

    Antibiotics themselves are dead. Long time ago. The future is in phages.

  2. eagle
    dolphin says:

    What about good ole’ raw garlic? To my knowledge, garlic was used as an antibiotic pre-penicillin and has not been shown to create resistant bacteria.

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