Abstract

In this Leading article, we summarize current knowledge of the occurrence of the first and so far only transferable colistin resistance gene, mcr-1. Its location on a conjugative plasmid is likely to have driven its spread into a range of enteric bacteria in humans and animals. Screening studies have identified mcr-1 in five of the seven continents and retrospective studies in China have identified this gene in Escherichia coli originally isolated in the 1980s, while the first European isolate dates back to 2005. Based on the widespread use of colistin in pigs and poultry in several countries and the higher number of mcr-1-carrying isolates of animal origin than of human origin, it is tempting to assume that this resistance may have emerged in the animal sector. Whatever its origin, interventions to reduce its further spread will require an integrated global one-health approach, comprising robust antibiotic stewardship to reduce unnecessary colistin use, improved infection prevention, and control and surveillance of colistin usage and resistance in both veterinary and human medicine.

Initial observations

Whenever a novel antibiotic resistance emerges, there is a need to assess its potential clinical and public health impact. One newly reported resistance where such an assessment is clearly required is transferable plasmid-encoded resistance to colistin mediated by the mcr-1 gene. Colistin was introduced into clinical use in the 1950s, but due to its perceived nephrotoxicity and neurotoxicity, its use had greatly diminished by the 1980s, with the exception of nebulized administration to cystic fibrosis patients with lung infections and gut decontamination regimens used in intensive care.1 However, the increasing problem posed by MDR Gram-negative bacteria, coupled with a relative paucity of new antibiotics active against such strains, has led not only to a resurgence in the use of colistin, but the WHO has now included colistin in its list of critically important antibiotics.2 Although phenotypic resistance to colistin had been described prior to the discovery of mcr-1,3,4 such resistance was chromosomally encoded, and hence spread entailed either de novo emergence or clonal expansion of resistant isolates. However, in late 2015, a report was published that described for the first time transferable colistin resistance encoded by the mcr-1 gene located on a conjugative plasmid in Escherichia coli.5 This report was significant, not only for describing a novel mechanism of colistin resistance (production of a phosphoethanolamine transferase) that was transferable, but also for the finding of colistin-resistant E. coli in retail meat, pigs at slaughter and in infected humans. The observation that mcr-1-positive bacteria were more frequently observed in animals and food of animal origin led to the suggestion that this new resistance gene had spread from the veterinary to the human domain.5–7

The next steps

Following on from the publication of the nucleotide sequence of mcr-1, numerous research groups were able to rapidly screen archived bacterial DNA sequences for the presence of the gene. This resulted in a rash of reports of the detection of the mcr-1 gene in different countries on five continents: Asia (China,5,8–18 Cambodia,19 Japan,20 Laos,21 Malaysia,8,22,23 Taiwan,24 Thailand21 and Vietnam25–27), Europe (Belgium,28,29 Denmark,30 France,21,31–33 Germany,34 Great Britain,35,36 Italy,37,38 Lithunia,39 Poland,40 Portugal,8,41 Spain,42,43 Switzerland44 and The Netherlands45–47), Africa (Algeria,21 Egypt,48,49 Nigeria,21 South Africa50–52 and Tunisia53), South America (Argentina54,55 and Brazil56) and North America (Canada57 and the USA58) (Table 1). Although mcr-1 was initially identified in E. coli, several reports confirmed its presence in other Enterobacteriaceae, including Enterobacter aerogenes and Enterobacter cloacae,15Klebsiella pneumoniae,5,9Shigella somnei27 and the Salmonella enterica subsp. enterica serovars Anatum,47 Derby,31 1,4,[5],12:i:−,31 Java,47 Paratyphi B,31,36,47 Rissen,42 Schwartzengrund,47 Typhimurium8,35,36,41,42 and Virchow.35 The location of mcr-1 on mainly conjugative plasmids, which transfer in part at rather high frequencies,5 may explain its occurrence in different enterobacterial species. Plasmid analysis revealed that occasionally plasmids similar in structure to the original plasmid pHNSHP455 have been detected in Salmonella Typhimurium,36K. pneumoniae19 and E. coli.19,59 Other reports, however, detected mcr-1 on structurally diverse plasmids in E. coli.29,36,60 Many of the mcr-1-carrying plasmids also harbour other resistance genes, including ESBL genes and carbapenemase genes among others.10,11,16,28,29,32,34–37,60–63 The co-location of mcr-1 with other resistance genes on conjugative plasmids supports the co-transfer and the persistence of mcr-1 under the selective pressure imposed by the use of non-polypeptide antimicrobial agents. These findings were notable not only for the widespread geographical occurrence of a range of mcr-1-positive Gram-negative bacteria, but also for the fact that the mcr-1 gene was found in isolates dating from as long ago as the 1980s.14 Thus, the phenomenon of transferable colistin resistance had been around for more than 25 years, but without being detected. This suggests little previous clinical and public health impact over the previous decades since any major incidents or outbreaks would likely have triggered active laboratory investigations.

Table 1.

Isolation of bacteria carrying mcr-1

Bacteria Host Country Year(s) of isolation Reference(s) 
E. coli chicken meat, pork, pigs, humans China 2011–14 5 
K. pneumoniae human China 2014 5 
Unknown human microbiome China before 2011 8 
E. coli, K. pneumoniae humans China 2014–15 9,10 
E. coli chicken meat China 2014 11 
Unknown human microbiome China before 2011 12 
E. coli humans China 2015 13 
E. coli chickens China 1980–89, 2004, 2006, 2009–14 14 
E. aerogenes, E. cloacae humans China 2014 15 
E. coli humans China 2015 16 
E. coli human China 2015 17 
E. coli dogs, cats China 2016 17 
E. coli humans China 2015 18 
E. coli human Cambodia 2012 19 
E. coli cattle, pig Japan 2012–13 20 
E. coli humans, pigs Laos 2012 21 
E. coli pigs, chickens Malaysia 2013 8 
E. coli chickens, pig, water Malaysia 2013 22 
E. coli chickens, pig, human, chicken feed, water Malaysia 2013 23 
E. coli humans Taiwan 2010, 2012, 2014 24 
E. coli retail meat (beef, chicken, pork) Taiwan 2012–13, 2015 24 
E. coli humans Thailand 2012 21 
E. coli pigs and slaughterhouse environment Vietnam 2014–15 25 
E. coli chicken, pigs Vietnam 2013–14 26 
S. somnei human Vietnam 2008 27 
E. coli calves, piglets Belgium 2011–12 28 
E. coli pigs Belgium 2011–12 29 
E. coli human patient, imported chicken meat Denmark 2012–15 30 
E. coli humans France 2012 21 
Salmonella Derby sausage France 2013 31 
Salmonella Paratyphi B food of poultry origin France 2012 31 
Salmonella 1,4,[5],12:i:− boot swab from broiler farm France 2013 31 
E. coli veal calves France 2005–14 32 
E. coli pigs France 2011, 2013 33 
E. coli broilers France 2013–14 33 
E. coli turkeys France 2014 33 
E. coli pigs Germany 2010–11 34 
E. coli human Germany 2014 34 
E. coli humans Great Britain 2013–14 35 
Salmonella 1,4,[5],12:i:− humans Great Britain 2012, 2014–15 35 
Salmonella Typhimurium humans Great Britain 2015 35 
Salmonella Virchow human Great Britain 2014 35 
Salmonella Paratyphi B poultry meat, human Great Britain 2014–15 35 
E. coli pigs Great Britain 2015 36 
Salmonella Typhimurium pig Great Britain 2015 36 
E. coli humans Italy 2013–15 37 
E. coli humans Italy 2015 38 
E. coli European herring gull Lithuania 2016 39 
E. coli human Poland 2015 40 
Salmonella Typhimurium food sample Portugal 2011 8 
Salmonella Typhimurium retail meat (chicken, beef, pork) Portugal 2011–12 41 
E. coli turkeys Spain 2011, 2013–14 42 
Salmonella Typhimurium pigs Spain 2009–11 42 
Salmonella Rissen pigs Spain 2010 42 
E. coli humans Spain 2012–15 43 
E. coli river water Switzerland 2012 44 
E. coli vegetable from Asia Switzerland 2014 44 
E. coli humans (travellers) The Netherlands 2012–13 45 
E. coli retail chicken meat The Netherlands 2009, 2014 46 
E. coli broilers, turkeys, veal calves The Netherlands 2010–13 47 
Salmonella Java chicken meat The Netherlands 2010–15 47 
Salmonella Anatum turkey meat The Netherlands 2013 47 
Salmonella Schwartzengrund turkey meat The Netherlands 2015 47 
E. coli chickens Algeria 2015 21 
E. coli human Egypt 2015 48 
E. coli dairy cow Egypt 2014 49 
E. coli human Nigeria 2012 21 
E. coli humans South Africa 2014–16 50 
E. coli humans South Africa 2014–15 51 
E. coli chickens South Africa 2015 52 
E. coli chickens Tunisia 2015 53 
E. coli humans Argentina 2012–13, 2015–16 54 
E. coli kelp gulls Argentina 2012 55 
E. coli chickens, pigs Brazil 2012–13 56 
E. coli human Canada 2011 57 
E. coli ground beef Canada 2010 57 
E. coli human USA 2016 58 
Bacteria Host Country Year(s) of isolation Reference(s) 
E. coli chicken meat, pork, pigs, humans China 2011–14 5 
K. pneumoniae human China 2014 5 
Unknown human microbiome China before 2011 8 
E. coli, K. pneumoniae humans China 2014–15 9,10 
E. coli chicken meat China 2014 11 
Unknown human microbiome China before 2011 12 
E. coli humans China 2015 13 
E. coli chickens China 1980–89, 2004, 2006, 2009–14 14 
E. aerogenes, E. cloacae humans China 2014 15 
E. coli humans China 2015 16 
E. coli human China 2015 17 
E. coli dogs, cats China 2016 17 
E. coli humans China 2015 18 
E. coli human Cambodia 2012 19 
E. coli cattle, pig Japan 2012–13 20 
E. coli humans, pigs Laos 2012 21 
E. coli pigs, chickens Malaysia 2013 8 
E. coli chickens, pig, water Malaysia 2013 22 
E. coli chickens, pig, human, chicken feed, water Malaysia 2013 23 
E. coli humans Taiwan 2010, 2012, 2014 24 
E. coli retail meat (beef, chicken, pork) Taiwan 2012–13, 2015 24 
E. coli humans Thailand 2012 21 
E. coli pigs and slaughterhouse environment Vietnam 2014–15 25 
E. coli chicken, pigs Vietnam 2013–14 26 
S. somnei human Vietnam 2008 27 
E. coli calves, piglets Belgium 2011–12 28 
E. coli pigs Belgium 2011–12 29 
E. coli human patient, imported chicken meat Denmark 2012–15 30 
E. coli humans France 2012 21 
Salmonella Derby sausage France 2013 31 
Salmonella Paratyphi B food of poultry origin France 2012 31 
Salmonella 1,4,[5],12:i:− boot swab from broiler farm France 2013 31 
E. coli veal calves France 2005–14 32 
E. coli pigs France 2011, 2013 33 
E. coli broilers France 2013–14 33 
E. coli turkeys France 2014 33 
E. coli pigs Germany 2010–11 34 
E. coli human Germany 2014 34 
E. coli humans Great Britain 2013–14 35 
Salmonella 1,4,[5],12:i:− humans Great Britain 2012, 2014–15 35 
Salmonella Typhimurium humans Great Britain 2015 35 
Salmonella Virchow human Great Britain 2014 35 
Salmonella Paratyphi B poultry meat, human Great Britain 2014–15 35 
E. coli pigs Great Britain 2015 36 
Salmonella Typhimurium pig Great Britain 2015 36 
E. coli humans Italy 2013–15 37 
E. coli humans Italy 2015 38 
E. coli European herring gull Lithuania 2016 39 
E. coli human Poland 2015 40 
Salmonella Typhimurium food sample Portugal 2011 8 
Salmonella Typhimurium retail meat (chicken, beef, pork) Portugal 2011–12 41 
E. coli turkeys Spain 2011, 2013–14 42 
Salmonella Typhimurium pigs Spain 2009–11 42 
Salmonella Rissen pigs Spain 2010 42 
E. coli humans Spain 2012–15 43 
E. coli river water Switzerland 2012 44 
E. coli vegetable from Asia Switzerland 2014 44 
E. coli humans (travellers) The Netherlands 2012–13 45 
E. coli retail chicken meat The Netherlands 2009, 2014 46 
E. coli broilers, turkeys, veal calves The Netherlands 2010–13 47 
Salmonella Java chicken meat The Netherlands 2010–15 47 
Salmonella Anatum turkey meat The Netherlands 2013 47 
Salmonella Schwartzengrund turkey meat The Netherlands 2015 47 
E. coli chickens Algeria 2015 21 
E. coli human Egypt 2015 48 
E. coli dairy cow Egypt 2014 49 
E. coli human Nigeria 2012 21 
E. coli humans South Africa 2014–16 50 
E. coli humans South Africa 2014–15 51 
E. coli chickens South Africa 2015 52 
E. coli chickens Tunisia 2015 53 
E. coli humans Argentina 2012–13, 2015–16 54 
E. coli kelp gulls Argentina 2012 55 
E. coli chickens, pigs Brazil 2012–13 56 
E. coli human Canada 2011 57 
E. coli ground beef Canada 2010 57 
E. coli human USA 2016 58 

The future

Increases in infections due to MDR Gram-negative bacteria, particularly those resistant to carbapenems, are likely to lead to greater reliance on colistin for treatment until new antibiotics with activity against these bacteria become available. In terms of assessing the future risk, a number of factors need to be considered, many of which will require active surveillance and research. Clearly the relative contribution of resistance in animals, food, the environment and humans (both colonized and infected patients) needs delineation if we are to fully understand the underlying epidemiology. Such knowledge is essential if we are to devise rational interventions aimed at reducing or even halting the future spread of colistin resistance. This will require a multidisciplinary approach: molecular biology is needed to better understand the inter-strain/species spread of plasmids containing mcr-1 and to seek its presence in the gut microbiome of both animals and humans; surveillance of the prevalence of colistin resistance and usage in both veterinary and human medicine and the associations between them (including the use of other antibiotics to which colistin-resistant bacteria are also resistant) are needed to inform antibiotic prescribing and stewardship policies to optimize clinical outcomes while trying to minimize resistance; and classical surveillance activities are also needed to identify risk factors in both human and animal populations to inform policy and intervention strategies.

Finally, an important factor in dealing with problems of antibiotic resistance is the dissemination of information. The current issue of the Journal of Antimicrobial Chemotherapy contains numerous articles on various aspects of colistin resistance and efficacy. They include: two newly developed real-time PCR assays for diagnosis;64,65 a report about the veterinary sector as the most likely origin of mcr-1;6 the evaluation of antibacterial activities of colistin, rifampicin and meropenem combinations against NDM-1-producing K. pneumoniae;66 reports about the isolation of E. coli carrying mcr-1 from a pig farm in Belgium;29 the isolation of mcr-1-positive E. coli from humans and retail meats between 2010 and 2015 in Taiwan;24 the detection of mcr-1 in E. coli and S. enterica serovars from livestock and meat in the Netherlands;47 the finding of mcr-1 in S. enterica from retail meat in Portugal;41 a report about mcr-1 in S. enterica serovars and E. coli from a pig farm in Great Britain;36 the detection of the mcr-1 gene in human and food isolates of S. enterica and E. coli in England and Wales;35 the emergence of mcr-1-positive commensal E. coli in a long-term care facility in Italy;38 a mcr-1-positive Shigella sonnei isolated in Vietnam in 2008;27 the co-location of mcr-1 and an ESBL gene on the same plasmid in S. enterica;63 the presence of mcr-1-positive E. coli in wild birds;39,55 and the presence of E. coli carrying mcr-1 in Poland.40 In addition, there is a paper reporting a high rate of colistin dependence in Acinetobacter baumannii from hospitals in Korea.67 Moreover, a report of a pharmacokinetic/pharmacodynamic model based on in vitro time–kill data for predicting the in vivo PK/PD index of colistin has been published in this journal recently.68 Hopefully, this level of generation and dissemination of new information is indicative of the response of the international research community to the threat posed by colistin resistance and the need to develop interventions to control its future spread.

Transparency declarations

None to declare.

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