Colistin - The Latest European Antibiotic Resistance Challenge02 March 2016
Europe appears to have been thrown into turmoil following the release of a paper by Liu and colleagues (2015), describing the emergence of a plasmid-mediated colistin resistance mechanism, mcr-1 gene, in China, writes David Burch, Veterinarian, Octagon Services Ltd, UK.
This gene was found in animals, meat products and potentially transmitted to man, causing infections there.
In 2014, the Chinese researchers found this resistant gene in Escherichia coli in 20.9 per cent of pigs at slaughter, on 22.3 per cent of retail pork samples and 28 per cent of chicken samples.
Worringly, they also found the resistance gene in E. coli from 13 out of 902 human patients (1.4 per cent) and in Klebsiella pneumoniae from a further 3 out of 420 patients (0.7 per cent).
Most animal E. coli do not colonise the human gut, but E. coli can be quite promiscuous, and so animal types can pass on plasmids (genetic material that can contain the resistant genes) via conjugation to the human E. coli.
They can also pass plasmids on to other bacteria found in the gut, such as Klebsiella.
So why is this important? Colistin is an old drug and was dropped in human medicine for being toxic when injected some 40 years ago. As a result, it was primarily left as an animal health only antibiotic.
With the widespread use of antibiotics in man to protect patients from infection, this has allowed surgery and medicine to progress to our current level of development.
However, this has been at a cost – the development of antibiotic resistance.
So for some infections, like E. coli, Klebsiella and Pseudomonas spp, once these have developed resistance to more widely used drugs, there is almost nothing left, so they started using colistin again – as a last resort.
It is also used orally in man for gut decontamination in intensive care along with other powerful antibiotics, to reduce complications and also by inhalation to control Pseudomonas infections in patients with cystic fibrosis.
Following the identification of the mcr-1 colistin resistance gene and the recognition of its spread, many countries have started looking for it and have found it in Asia, Latin America and it seems the authorities in Europe were put on ‘red alert’.
An extensive search has taken place to see if the gene had arrived or occurred in the EU, and if it was here, how extensively had it spread?
EU survey results
Denmark was the first to report. It examined 3,000 E. coli and found the gene in five samples of chicken meat, two of which had been imported and in one human case.
The UK looked at 24,000 isolates of various bacteria and found it in fifteen samples (0.06 per cent). Twelve were in Salmonella and three isolates of resistant E. coli were found in two human patients.
The UK also checked past samples and found one isolate of resistant E. coli in a caecal sample from a pig and two in clinical pig cases; the number tested was not reported.
In poultry, they found three colistin-resistant Salmonella in 53 isolates, but they did not have the same mcr-1 gene for resistance.
The Netherlands reported on tests on 3274 Salmonella from humans, animals and food and found it in three (0.09 per cent) poultry isolates.
Belgium looked at 52 calf isolates and 53 pig isolates of E. coli, which were already colistin resistant, but only six (11.5 per cent) of the calf and seven (13.2 per cent) of the pig isolates carried the mcr-1 gene.
These countries are all comparatively low users of colistin in animals, with under 7.8 tonnes of active substance (ESVAC, 2015).
France, a user of larger amounts of colistin, examined 8,684 Salmonella from various species and found four (0.05 per cent) positive. France also tested 517 extended-spectrum beta lactamase (ESBL) resistant calf E. coli (resistant to third and fourth generation cephalosporins) and found 106 were positive.
The calf E. coli were taken in the period from 2005-14, an estimated pool of 8,617 isolates, so approximately 1.2 per cent of isolates were carriers, which is the highest yet and the earliest isolate was 2005.
Calves, especially reared for veal, do use a lot of antibiotics and diarrhoea can be a major problem. France uses a moderate amount of colistin at 42.4 tonnes (ESVAC, 2015).
Germany is a high user of colistin at 124.7 tonnes but it also has the largest pig population in the EU.
They examined 577 isolates of Gram negative bacteria (this includes bacteria such as E. coli, Salmonella, and Klebsiella species, but they were not specified) from humans, animals and the environment.
Three isolates (0.5 per cent) from swine were positive, with one from as early as 2010, and one isolate (0.17 per cent) came from a human clinical case. This isolate was also carbapenem resistant. Spain is another high user at 149 tonnes and has reported the finding of 6 isolates carrying the mcr-1 gene out of 561 (1.1 per cent) samples of lymph node (salmonella) and pooled faeces samples from pigs (E. coli) and 3 isolates of E.coli from 122 (2.5 per cent) turkey pooled faecal samples.
The mcr-1 resistant gene is here in the EU already and the earliest isolate recorded was from 2005.
The country surveys are very variable but overall from 49,041 isolates tested, 163 isolates (0.33 per cent) were positive.
Generally, the low and moderate users (DK, UK, NL, B, FR) have a very low mcr-1 positive rate in overall surveys (0.07 per cent). This compares very favourably with China where 20-28 per cent of animal and meat samples were positive.
The special trials are also of interest, even those selecting for either ESBL or carbapenem resistance have found an increased percentage of resistant mcr-1 genes, which highlights the potential of resistance development in higher use species like calves.
From the Belgian work, only about 12 per cent of colistin resistance is associated with the mcr-1 gene, so one can see why it was overlooked for so long.
There is already a carbapenem/colistin resistant E. coli, presumably in a German hospital case. The concern is that hospitals can propagate resistant genes and cross-infect other patients.
There are only five human isolates out of a 508 million EU population so far, so a very small proportion of carriers have been identified but it is likely the search will be intensified and the southern countries, where carbapenem resistance is highest, may report more.
At present, the prevalence of mcr-1 colistin resistance is extremely low in most countries and can be considered a very low risk. The gene has been around in the EU from at least 2005 and is not reportedly causing many problems in human medicine, so far.
What about the future?
There are calls already to voluntarily ban colistin use in animals, and the European Medicines Agency (EMA) will be reviewing the situation shortly.
It could be considered an over-reaction to suspend colistin in veterinary medicine at this stage, especially in low use countries, before the EMA reports, but responsible use, i.e. using it as a last resort antibiotic and using suitable alternatives first, would help reduce colistin resistance selection and spread, and minimise any potential jeopardy to human treatments.