Resistance to antibiotics: new information concerning colistin

Colistin is an antibiotic used in veterinary medicine, particularly for treating colibacillosis infections in the livestock sector.

In human medicine, colistin has long been avoided in therapeutic protocols because of renal toxicity. Since the global spread of resistance to last-generation cephalosporins and carbapenems, colistin has again come to be prescribed as an antibiotic for the treatment of severe human infections involving bacteria resistant to all other therapeutic options.

Because of the renewed interest for colistin in human medicine, the scientific and medical community became concerned about the risk of the selection of resistance to colistin in humans, following its use in animals. Recent opinions published by both the European Medicines Agency (EMA) and ANSES recommended that colistin should not yet be included in the list of critically important antibiotics used in veterinary medicine, whose use requires supervision. In particular, the absence of a mechanism for transferring resistance to colistin between bacteria was a powerful scientific argument.

November 2015: description of the first transferable mechanism for resistance to colistin

On 18 November 2015, the first transferable mechanism for resistance to colistin (the mcr-1 gene) was described in China in pigs and chickens, in meat sold at retail, and also among bacterial strains isolated in humans¹. The prevalence of this plasmidic gene has been estimated at approximately 20% in animals and around 1% in humans.

The publication of the genetic sequence of the mcr-1 gene led several institutes to seek it in other bacterial collections around the world. To date, in Europe, the mcr-1 gene has been detected in bacterial strains of Escherichia coli and/or Salmonella enterica, by the European Reference Laboratory for Antimicrobial Resistance (DTU, Denmark)², by the reference laboratory at Public Health England³ and by the four ANSES laboratories involved in the monitoring of animal antimicrobial resistance⁴. In all these collections, the prevalence of the mcr-1 gene is particularly low.

Moreover, no alarming increase in resistance to colistin in bacteria isolated from the poultry or pork sectors has been reported by the various ANSES surveillance networks in recent years.

On 17 December 2015, additional data on the distribution of the mcr-1 gene in other world collections were published^4,5,6,7,8. They confirm the low prevalence of this gene in humans and provide additional information about its molecular structure.

Several studies are under way on this topic and several questions remain currently unanswered. They concern, most importantly:

• the prevalence of the mcr-1 gene in the different sectors, animals and humans, in France, in Europe and in the world. The different sampling programmes from the bacterial collections studied lead to the conclusion that the gene can be detected, but not yet at levels of prevalence validated from an epidemiological point of view;
• how long the mcr-1 gene has been circulating in animal and human bacterial flora. Most of the published data relate to relatively recent strains (post-2010). The length of time the gene has been circulating in livestock sectors is an important element of assessment in risk analysis;
• the levels of resistance to colistin (low or high) of bacteria possessing the mcr-1 gene, which directly affect its therapeutic impact. Also, the mcr-1 gene is not present in all colistin-resistant bacteria, which raises the question of the role played by this mechanism in a broader explanation of this resistance;
• the possibilities (or not) of co-selection of the mcr-1 gene by the use of antibiotics other than colistin, such as those widely used in veterinary medicine (e.g. tetracyclines, sulfonamides) or those of critical importance to humans and plasmid-mediated (last-generation cephalosporins);
• the diversity of the molecular characteristics of genetic supports (types of plasmids) and bacterial clones carrying the mcr-1 gene, on which depend the different capabilities of diffusion between bacterial species, between animal species, and from animals to humans.

A new risk analysis is necessary related to the use of colistin

The recently published scientific information on bacterial resistance to colistin will need to be taken into account in a new analysis of the risks related its use, especially in veterinary medicine.

In this context, EMA has decided to convene its Antimicrobial Advice Ad Hoc Expert Group to revise its Opinion on the use of colistin in veterinary medicine, published in 2013. This Group includes experts from ANSES.

For many years now, ANSES has played a key role in surveillance and alerts concerning phenomena of antimicrobial resistance in the animal world, and in connection with the possible consequences for public health. This work is carried out thanks to the responsiveness of all the schemes it runs, of regulatory monitoring at the slaughterhouse and in food, and in the framework of the activity of the Salmonella and Résapath networks that were set up several decades ago in France. In parallel, ANSES-ANMV, through its involvement with EMA and its annual survey on the consumption of veterinary antibiotics, provides essential data on the exposure of animals to antibiotics, which it is useful to compare with the levels of resistance observed.

ANSES will therefore revise the risk assessment it undertook in its scientific opinion (Opinion No 2015-SA-0118 (PDF) (in French), on the classification of colistin as a veterinary antibiotic of critical importance.