Summary
In the European Union, the use of antimicrobial growth promoters (AGPs) in animal feed was banned from 1st January 2006. David Burch, based in the UK and AASV's e-Letter Section Editor on antimicrobial resistance, was asked to comment on the impact the ban would have on the EU pig industry. The EU ban is not an end game in itself but the first major step in a call for a worldwide ban on the use of antibiotics to promote livestock growth. David's report follows. (Harry Snelson, AASV Communications Director)
Introduction
The European Union now comprises 25 countries and produces approximately 240 million slaughter pigs/year, the second largest pig market after China and nearly two and a half times the US market. Antimicrobial feed premixes were divided into two groups, those that were used for growth promotion and as anticoccidials (Feed Additives) and were added to feed without a veterinary prescription and those used for therapy of diseases (Medicated Feed Premixes) which could only be added to feed with a veterinary prescription. From the 1st of January 2006, it is forbidden to use antimicrobial growth promoters (AGPs) in pig feed.
In the US, the majority of antimicrobial feed premixes are added to feed without a veterinary prescription but at specified levels. Often, low level use is for growth promotion, intermediate levels for prevention of disease and high levels for treatment. This is considered in the EU as a very 'free' use of antimicrobials and there is genuine concern that this potentially could lead to 'over use' and the unnecessary development of antimicrobial resistance. This resistance might be transmitted to man either by zoonotic infections (e.g. Salmonella spp or Campylobacter spp) or by commensal organisms carrying resistance plasmids, which if consumed, might pass resistance on to human gut flora and have an impact on the successful treatment of infections in man.
The initial concern was over the use of avoparcin, which is related to vancomycin and was used in humans for severe life-threatening infections caused by Enterococci spp especially in immuno-compromised patients, whether from infection (HIV) or from treatment for cancer or following transplant surgery. Vancomycin-resistant enterococci (VRE) were starting to emerge in man and it was thought that it could be related to the use of avoparcin in animals. In the US however, avoparcin was not approved for animal use yet VRE were found, primarily as a result of increased use in human medicine. The potential hazard of resistance transmission from animals to man via commensals is very difficult to quantify but with better genetic identification of bacteria within species, it is increasingly demonstrated to be a very low risk, especially for VRE as they are primarily associated with hospital-derived epidemic strains. However, to avoid the risk of this happening the EU banned a number of antimicrobial growth promoters in the 1990's under the 'precautionary principle', if they were related to human-use antibiotics, such as avoparcin (vancomycin), virginiamycin (quinupristin), tylosin and spiramycin (macrolides/erythromycin) and bacitracin (bacitracin). Other compounds, which had safety concerns and were thought to be potential carcinogens such as the nitroimidazoles, dimetridazole and ronidazole and the quinoxaline derivatives olaquindox and carbadox, were also banned from use.
From the 1st of January 2006 the remaining antibiotic growth promoters were also banned and these included avilamycin, flavophospholipol and the ionophores monensin for cattle and salinomycin for pigs. The ionophores will remain as prescription-free feed-additive anticoccidials for use in poultry. All of these compounds are not currently used in human medicine, so the decision can be questioned even further on a scientific risk-analysis/precautionary basis and is considered to be more politically based.
Denmark had voluntarily banned the use of growth promoters in pigs greater than 35kg bodyweight in March 1998 and in all pigs from January 2000, so this is the best documented model for what can be expected when growth promoters are withdrawn from the rest of the EU.
Growth promoters - their effects
Antimicrobial growth promoters have two major effects:-
1. To improve production i.e. to improve growth rate and feed conversion efficiency (FCE) by exerting an antimicrobial affect on commensal bacteria, hence their nutrient-sparing effect.
2. As antimicrobials, some AGPs have an effect against pathogenic organisms and can prevent primarily enteric diseases.
1. Improvement in production
Most growth promoters improve growth rate by about 30g/day, so in young pigs this can be 10% and in finishing pigs 3%. Similarly, FCE was improved by 0.1-0.2 or 4-10%.
The Danes noted a significant drop in growth rate in weaning pigs (<30kg bodyweight) of about 20g/day (427 to 407 g/day) as AGP use was reduced, but on average, maintained their performance in finisher pigs (>30kg bodyweight) (Callesen, 2002). Similarly there was a significant increase in mortality in weaners of 0.7% (2.9 to 3.6%) on a national basis but a non-significant effect on finishers of 0.2%.
2. Disease control effect
It has often been noted that in 'dirty' herds the response to growth promotion was higher than in 'clean/high health' herds.
The Danes also noticed an increased incidence of post-weaning diarrhoea in weaners (Larsen 2002) following the withdrawal of AGPs and a significant increase in treatments that carried on for over a year. Zinc oxide was also removed from use, although now it has been officially approved for use. In growers and finishers there was also an increase in diarrhoeas and treatments mainly associated with Lawsonia intracellularis but after six months the level of treatment subsided as the control of ileitis improved on the farms. Callesen (2002) reported that these problems affected about 37% of farms. Coincidentally, there was an increase in the use of therapeutic antimicrobials such as tetracyclines, tylosin, lincomycin and tiamulin and aminoglycosides (see Graph 1 and 2). Over 80% of the antimicrobial use in animals in Denmark is in pigs.
Graph 1. Antimicrobial and AGP usage - Pigs slaughtered in Denmark
(Source: Danmap 2004)
Post-weaning multi-systemic wasting syndrome (PMWS) started to appear in Denmark in 2001 and is probably responsible for the steady increase in therapeutic antimicrobial use since then.
Graph 2. Antimicrobial usage in Denmark by product group
(Source: Danmap 2004)
Key: TMP/S = Trimethoprim / sulphas; M,L,T = Macrolides, lincomycin and tiamulin
It is probably not surprising that this should happen as many AGPs had antimicrobial activity against a number of gut pathogens and therefore disease prevention effects (see Table 1).
Although AGPs were mostly not directly active against Escherichia coli, they seemed to reduce the incidence of post-weaning diarrhoeas to a certain extent. Many also had potent activity against Clostridium perfringens, which was probably of more significance in poultry production. Carbadox had potent activity against many enteric pathogens and is still available in the US. Tylosin's use changed in the EU from being a growth promoter to being an anti-ileitis medication and MLT group rose as therapeutics from 7-24 tonnes in Denmark as illustrated (see Graph 2). This change has already taken place in the UK with a rise of 37-70 tonnes (VMD, 2005) in the same time-period and probably in the rest of the EU, and although its use is expected to increase, it will not be quite so dramatic.
Salinomycin, which has been the major growth promoter for 'diarrhoea-problem' farms, will have an impact on removal this year. It has been shown to have activity against ileitis, as well as Brachyspira spp, which cause colitis and swine dysentery. In the UK, its removal has been highlighted as a potential cause of problems since November 2004 by the UK Pig Veterinary Society. Some farmers have tried to remove it and looked for alternatives, but many have gone back onto it and used it right up to December 2005.
A straw poll of the three major government veterinary investigation centres involved in pigs in the UK this last quarter, showed one had seen an increase of swine dysentery for most of the year, one had seen no change and the third had seen an increase this last quarter. It is expected to see an across-the-board increase in diarrhoea in 2006 in grower/finisher pigs primarily due to the removal of salinomycin. Many farms have switched already to tylosin for ileitis control, but where colitis and dysentery was controlled by salinomycin, they have remained on it as the effective alternatives, such as tiamulin, valnemulin and lincomycin are considerably more expensive.
The UK and a small number of other countries in the EU permit the therapeutic use of zinc oxide (3.1kgs/tonne of feed) for E.coli control and in those countries it is expected that increases in post-weaning problems will be limited. Recent work, which is part of an on-going three year programme in the UK, Nutwean (effects of nutrients on weaning) Agewean (effects of weaning age) and Gutwean (effect of gut development) have shown that none of the nutrient factors or organic acids etc, work as well as AGPs and zinc oxide in preventing coliform up growth and performance enhancement.
Conclusions
It is expected to see a small decrease in performance and an increase in diarrhoeas in weaners and grower/finisher pigs following the withdrawal of AGPs in the EU. It is not expected to be as marked as in Denmark, as adjustment to diets etc have already been made and changes in therapeutic use of antimicrobials have to a certain extent already taken place.
In those countries, which have zinc oxide approved for use, post-weaning diarrhoeas are not expected to be a problem but in other countries, a small increase, similar to Denmark, can be anticipated.
In growers and finishers, the switch to tylosin for ileitis control has already largely happened, although a small increase will still occur following the withdrawal of salinomycin.
It is also anticipated that there will be an increase in colitis caused by B. pilosicoli and swine dysentery caused by B. hyodysenteriae and in some areas in the UK it is already being reported.
Will the removal of growth promoters have the desired effect of reducing antimicrobial use overall in animals? This will be difficult to determine. Firstly there has been a substantial amount of switching of antimicrobials e.g. from tylosin as a growth promoter to tylosin as a therapeutic, as well as a switch originally from carbadox and olaquindox to other swine dysentery therapeutics such as tiamulin and lincomycin. Secondly PMWS has spread throughout most of the EU and there has been a consequent increase in antimicrobial use to control secondary bacterial infections as indicated in Denmark. It must be a concern, though, that there has been an increase in most of the main antimicrobial families for therapeutic use following the AGP ban in Denmark.
Will the ban of AGPs impact antimicrobial resistance transfer to man? The Danes have shown a substantial reduction in antimicrobial resistance in the commensal Enterococci faecium to avoparcin and virginiamycin (see Graph 3). Initially they saw a fall in macrolide (tylosin) resistance but the latest data shows there has been an increase in 2004. In healthy human samples, they have seen an increase in both virginiamycin and macrolide resistant E. faecium but not to vancomycin, which remains very low as before. Not surprisingly, there has been no major reduction in resistance to therapeutic antimicrobials reported in zoonotic bacteria or E. coli from pigs.
Graph 3. Antimicrobial resistance - effect on E. faecium in pigs
(Source: Danmap 2004)
Key: TMP/S = Trimethoprim / sulphas; M,L,T = Macrolides, lincomycin and tiamulin
Although macrolides are not the treatment of choice for E. faecium infections in especially immuno-compromised patients, if there is a continued increase in the level of resistance it may add to the pressure to further restrict their use in veterinary medicine. In 2006 the WHO and OIE will be meeting to review the use of antimicrobials in humans and animals and which families of antimicrobial are critical for medical and veterinary use. Macrolides, as well as fluoroquinolones and 3rd generation cephalosporins are currently on both the FDA and WHO human critical product lists and in the US we saw in 2005 the withdrawal of the fluoroquinolone, enrofloxacin, from oral therapy in poultry, which is a concern from a veterinary perspective. The EU are expected to take the line that there is no need to make further restrictions on veterinary medicinal products as a risk assessment on antimicrobial resistance issues is part of their regulatory procedures, however the FAO has supported the WHO call 'for a ban on the use of antibiotics to promote livestock growth'. This may have a future impact on the US swine industry.
References:
Callesen, J. (2002) Effects of termination of AGP-use on pig welfare and productivity. In Proceedings of World Health Organisation's Symposium 'Beyond Antimicrobial Growth Promoters in Food Animal Production' Foulum, Denmark, pp 43-46
Larsen, P.B. (2002) Consequences of termination of AGP use for pig health and usage of antimicrobials for therapy and prophylaxis. In Proceedings of World Health Organisation's Symposium 'Beyond Antimicrobial Growth Promoters in Food Animal Production' Foulum, Denmark, pp 51-55
Danmap 2004 (2005) Use of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from food animals, food and humans in Denmark.
VMD (Veterinary Medicines Directorate) (2005) Sales of antimicrobial products authorised for use as veterinary medicines, antiprotozoals, antifungals, growth promoters and coccidiostats, in the UK - 2004.
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