ARCHIVE: Extended-Spectrum Beta-Lactamases (ESBL) in bacteria associated with animals - Defra Position
The guiding principle of Defra’s policy, with respect to antimicrobial resistance, is to seek to reduce the impact of antimicrobial resistance in organisms associated with animals on public health and animal health in a proportionate way, in conjunction with partners and in accordance with the Animal Health and Welfare Strategy.
ESBL producing E. coli – Background
Antimicrobial resistance is the ability of a microorganism to withstand an antimicrobial. ESBLs are enzymes that confer upon their host organism the ability to resist a wide range of therapeutic beta-lactam antimicrobials (i.e. penicillins and cephalosporins). One such group of enzymes is the CTX-M group which is divided into various types based on genetic structure. Please see the Question and Answer paper produced on this subject for more general information on ESBLs in Escherichia coli associated with animals.
The first isolation of an ESBL in Escherichia coli (E. coli) in GB in food producing animals was made by the Veterinary Laboratories Agency (VLA) in autumn 2004. It was recovered from calves that were being reared on a dairy farm in Wales. The gene encoding CTX-M-14 was identified in the isolates. Multiple visits to the farm for sampling and monitoring the prevalence of CTX-M-14 have been carried out by VLA staff. The prevalence of cattle testing positive for CTX-M-14 containing E. coli, among the herd, has continued to rise at each sampling visit, despite the measures taken since the initial finding in 2004. The source of the infection has not been determined but may have included: imported constituents of animal feed, direct or indirect transfer from human sources to livestock via environmental routes, contact with other livestock or development on the farm itself. The VLA has been working closely with the Health Protection Agency (HPA) from the time that it became clear that an unusual type of resistance had been identified. A joint letter with the HPA to the Veterinary Record was published on 5 February 2005 documenting the case.
The finding of Salmonella Typhimurium DT 104 in calves on the premises led to an investigation to find out if there was transfer of the CTX-M-14 enzyme from the E coli into the Salmonellas present on the farm. No evidence of this could be established following the most recent visit in October 2006. It is clear, however, that the resistance type has the ability to transfer between different strains of E. coli.
The second recorded case in UK livestock was identified in the south of England in July 2006, and was also detected as a result of investigations into the death of several calves. The situation, however, differed to that of the first case in that these animals had been part of a group of calves, sourced from 4 different premises and housed together at a veterinary referral centre. Susceptibility tests indicated that the E. coli isolate exhibited a multi-resistant phenotype and was found to possess the CTX-M-15 gene, a gene different from that found in the first case, but still conferring similar resistance to many penicillin and cephalosporin antimicrobials used in veterinary medicine. Further investigation on the premises has involved an attempt to establish the source of the ESBL. This work is currently ongoing and preliminary data indicate that the other ESBL types, but not CTX-M-15, have been detected in E. coli isolates from other animal species present on the premises. CTX-M enzymes have, however, been isolated from cattle on three of the four farms from which the original calves were obtained.
ESBL producing E. coli – Current Situation in food-producing animals in GB
Since July 2006, enhanced surveillance for ESBL containing E. coli
in clinical material submitted to the VLA has led to the identification
of further premises where these organisms have been detected in cattle.
The number of these premises makes the continued publication of the specific
details pertaining to each case impractical. Rather, Defra will continue
to provide a summary of the situation via this webpage, with further details
being made available via the peer-reviewed literature and other Government
publications, for example the VLA Monthly and Quarterly reports and the
Chief Veterinary Officer’s report, where appropriate.
Since July 2006 a further eight different cattle farms have been confirmed as having E. coli carrying ESBLs of the CTX-M type. 5 farms have CTX-M-15, two CTX-M-14 and one CTX-M-1. On one of the farms with CTX-M-15, the E coli serotype carrying the CTX-M-15 has been identified as serotype O25. Recent, preliminary findings indicate that approximately 10 further premises are likely to be positive for ESBL E. coli. Preliminary data suggest that E. coli carrying CTX-M enzymes are most numerous in south-west England. Closer examination of these cases and any potential epidemiological links is currently underway.
In addition to cattle, ESBL producing E. coli have also been identified from sheep and horses at a premises that was investigated following the detection of resistant organisms in calves at the same location. Some multi-resistant strains of E. coli from pigs have also been examined but, to date, ESBLs have not been identified in any porcine E. coli isolates in England and Wales.
ESBL producing E. coli – Control of infection on-farm
The detection of the first case of an ESBL in E coli in UK livestock led to a consultation meeting, held in January 2005 between the Animal Health and Welfare Directorate General (AHWDG), Veterinary Medicines Directorate (VMD), VLA, HPA, Department of Health (DH), National Assembly for Wales Department for Environment, Planning and the Countryside (NAW DEPC), National Public Health Service Wales (NPHS Wales), Food Standards Agency (FSA), the farm owner and farm manager, and the farm’s private veterinary surgeon (PVS). It was agreed that there was a need for more information on the ESBL-producing strains of E. coli in both the animals and the environment on the farm and that further on-farm investigations should be carried out. Subsequent meetings of human and veterinary public health officials have been held in February and September 2006. Five visits to date have been made to the Welsh farm by VLA staff. Further measures that may be required are currently under discussion.
The ongoing investigations into the subsequent cases that have been detected are being carried out with the same objectives as initially planned for the first case in Wales. These include:
- Assist with control of endemic disease problems to minimise the need for use of antimicrobials on the farms;
- Advise, in conjunction with the PVS, on appropriate antimicrobial usage to treat the endemic disease problems currently affecting the herds;
- Assist with control of the ESBL E. coli and advise on practical measures to attempt to limit its spread and hasten its decline or elimination;
- Monitor how the situation is developing by collecting and testing samples collected during the visit;
- Investigate possible sources of the ESBLs, [though it should be noted that it is notoriously difficult to determine the source of a bacterial organism once secondary spread and multiplication have occurred, following a primary event at which an organism was introduced]; and
- Taking of samples to test for ESBL-resistance in any other significant pathogenic bacteria, including Salmonellae, present on the farms
Following discussions with stakeholders, including public health officials, it has not been thought appropriate to place restrictions on any animals on the farms involved for the following reasons:
- The E. coli strain types identified to date, are not known to be commonly associated with human infections. At this point, there is no evidence that ESBL E. coli identified in the human population have been acquired from animals or animal products.
- There has only been limited structured surveillance and limited testing of clinical veterinary diagnostic material for ESBLs. As a result, organisms containing these resistance genes may be present on many livestock premises not yet detected. This situation seems likely, thereby preventing the possibility of significantly restricting onwards transmission that might otherwise be achieved through the imposition of movement restrictions.
- Strains of E. coli can exist in the environment and often have the ability to colonise a number of different species. This aspect of the ecology of E. coli means that controlling its spread is extremely difficult owing to the many and varied potential routes of dissemination and environmental niches that it can occupy.
- The strains of ESBL E. coli identified are not known to be a significant cause of disease in animals - E. coli is naturally present in the intestinal tract of most healthy animals as a normal commensal organism.
ESBL producing E. coli – Public health implications
It is currently unclear what risk ESBL producing bacteria associated with animals pose to public health. CTX-M-14, the first of the CTX-M group to be identified in E. coli in UK livestock, is one of the more frequent CTX-M types internationally. However, both the strains of E. coli and the ESBL enzyme involved in the case in Wales, are different from the strains and the enzyme type that have been responsible for the majority of infections in humans in the UK over the past two years.
CTX-M-15 is the predominant enzyme type circulating in human ESBL isolates in the UK. This particular type of ESBL has been detected in E. coli from four separate cattle premises in England. One of these CTX-M-15 producing E. coli isolates has been identified as being of the O25 serotype. This serotype is often found among uropathogenic E. coli strains that cause disease in humans, although this specific O25 serotype strain is not known to be one of those commonly associated with human urinary-tract infections.
There is no evidence to suggest that O25 serotype E. coli are more resistant to standard on-farm hygiene precautions, and these bacteria are eliminated by the pasteurisation of milk. Following consultation with public health officials and colleagues from the FSA, it has been decided that additional precautions or on-farm restrictions are not required in this case.
Research to fully characterise the CTX-M types and E. coli serotypes involved in the most recent cases detected is ongoing. Investigations into the source of this ESBL- mediated resistance in animals are also currently underway.
There are collaborative studies between the HPA and VLA to determine whether any strains of the same type and enzyme type have caused disease in humans in the UK. As there is no evidence of human disease on these farms caused by this organism, farm workers have not been screened.
ESBL producing E. coli – Management of antimicrobial resistance issues within Defra
Management of antimicrobial resistance is shared between AHWDG and the VMD. ESBL E. coli do not cause a notifiable disease in animals and isolation of these organisms is not reportable. In fact, it is not clear at this stage if the resistant organisms are associated with any significant disease in animals or if it is merely a commensal (an organism that occurs naturally in the animal gut). We also do not know how long they have been on the farms or how widespread infection with this type of resistant organism is in cattle or other livestock in the UK, though a recent survey of cattle, sheep and pigs at slaughter in 2003 did not reveal the presence of any ESBLs in E. coli carried by these animals.
Our present state of knowledge would suggest that it is not practically feasible to stop the spread of ESBL E. coli from these farms because we would expect the strain of E. coli to behave similarly to other types of E. coli, which can persist in the environment or circulate in animals for long periods and may be spread by wildlife and other vectors. On any farm identified, it may be reasonable to expect that this has already occurred to some extent.
The surveillance currently undertaken and the study of farms linked to the current incidents will provide further information that can be used to assist with the development of a rational, science-based policy for dealing with this type of event in the future. The gene encoding the CTX-M-14 ESBL enzyme has been found in several different strains of E. coli isolated from livestock on the farm involved in the first case, as well as on mobile genetic elements (plasmids) of different size. Molecular epidemiology suggests that there is a dynamic exchange of these genes between strains of E. coli in the intestinal and faecal flora of these animals. It is likely that the use of beta-lactams, as well as certain other antimicrobials that could co-select for linked genes on the same plasmid, will perpetuate the problem. Preliminary data from the second visit to the Welsh farm indicates persistence of several of the E. coli clones with the CTX-M determinant. Further gene sequencing and molecular analysis of the isolates obtained in all cases that have been identified, is planned.
There is a monitoring scheme across the VLA, which has been rolled out across the VLA’s Regional Laboratories in 2006, to screen for ESBLs in all E. coli isolates detected in clinical material submitted to regional laboratories. This will allow improved surveillance for ESBLs in food producing animals. The development of a protocol specifically for the investigation of such cases detected on UK farms is currently being prepared by the VLA lead on antimicrobial resistance.
The issue of the identification of an ESBL in E. coli in calves has been kept under review by the Defra Antimicrobial Resistance Co-ordination (DARC) Group. The membership of the group includes VMD, AHWDG Defra, Devolved Administrations (DAs), DH, FSA, HPA, Health Protection Scotland (HPS), Scottish Agricultural College (SAC) and VLA. In addition, a paper has been presented to the Department of Health’s Specialist Advisory Committee on Antimicrobial Resistance (SACAR) outlining the Defra position and the issue has been discussed by the Steering Group for Diseases and Infections in Animals (SGDIA).
ESBL producing E. coli – International Considerations
Some other European countries are also beginning to report the detection of ESBLs in bacteria isolated from livestock. The development of UK policy for dealing with ESBLs in bacteria associated with livestock will proceed taking into account the emerging position in Europe in both the medical and veterinary fields.
ESBLs and cephalosporin resistance in Salmonella species
Similarly to E. coli, resistance to third generation cephalosporins in Salmonella spp. can be the result of the acquisition of either of two different types of beta-lactamase enzymes – AmpC enzymes or ESBLs.
The VLA has had in place a screening programme for resistance to cephalosporins in Salmonella spp. for many years and in 2004 changes were made to enhance the surveillance to allow for the detection of resistance to third-generation cephalosporins and fluoroquinolones.
ESBLs have not so far been detected in Salmonella spp. recovered
from animals in England and Wales and there has only been one AmpC enzyme
detected. This was in a Salmonella Branderup isolate from a turkey
derived from an imported egg; the strain involved was indistinguishable
from a Canadian Salmonella Branderup isolate, also recovered
from turkeys. The results of VLA surveillance for third-generation cephalosporin
resistance in Great Britain, during 2005, are presented in table 1.
Additionally, abattoir surveillance of cattle, pigs and sheep in 2003 slaughtered in Great Britain, did not reveal the presence of any ESBLs or AmpC enzymes in Salmonella spp.
|Species||Year||No examined||ESBL positive||AmpC positive|
Table 1. Results of screening Salmonella spp. isolates for resistance to third-generation cephalosporins during 2005
A number of different ESBLs and AmpC enzymes have been detected in Salmonella
isolates from humans in the UK, including CTX-M enzymes and TEM enzymes.
Many of these infections appear to be travel-associated, though some were
acquired domestically. Third generation cephalosporin resistance is much
more prevalent in Salmonellas in some other parts of the world
than in the UK. For example, in the USA, multi-drug resistant S. Newport
has been affecting cattle and humans and these strains commonly carry
an AmpC enzyme. The ESBL enzyme TEM-52 has been detected in S. Blockley,
S. Virchow, S. Paratyphi B and S. Typhimurium PT 11 in poultry in Holland,
whilst CTX-M-9 has been detected in S. Virchow and S. Enteritidis in poultry
in Spain. These countries are cited by way of example; there are many
other reports from other countries. The reasons why the UK appears to
lag behind the rest of the world regarding the emergence of these types
of resistance has been the subject of debate.
Page last modified:
13 December, 2007
Page last reviewed: 13 December 2007