Digestive Enhancers - The European Situation

Paul McMullin MVB DPMP MRCVS
E.Mail PaulMcMullin@poultry-health.com

Paper Presented: 2nd International Symposium on Turkey Diseases Berlin 24th-27th March 1999

............. Summary: Antibiotic digestive enhancers or "growth promoters" have been approved and used safely in Europe for over 30 years. This paper reviews recent events with respect to their approval and use. They provide benefits for the treated animals, the environment and society. These products exert their effect by moderating intestinal flora and thus allowing productivity closer to genetic potential and have no hormonal effect. In recent years they have come under concerted attack from a range of sources. Some people believe that their use in agriculture could reduce the efficacy of products used in human medicine. While much of the evidence for this is weak or lacking it must be accepted that human health is of paramount importance. Further research may well be required, however the unilateral assumption of a ban on the use of these products may have a series of unintended consequences. The balance of risk between continued use and suspensions (partial, temporary or permanent) needs to be carefully evaluated. Any antibiotic-alternatives need to fulfil the same criteria of safety, quality and efficacy as currently licensed products. They should also be capable of showing a microbiological/human health advantage if we are to use them. Serious questions with respect to equivalent hazards from imported materials need to be answered before any further suspensions are implemented.
   
............. Introduction:

Many antibiotics have been derived from natural bacterial populations. The natural bacterial population of the intestines of farm animals is extremely complex and variable among species, ages and types of animal. The use of low doses of a wide range of antibacterial compounds has been shown to significantly enhance digestion of nutrients in a range of species. The size of this effect varies with species and many other factors. That these compounds are exerting their effect by modulating the bacterial population is confirmed by the fact that they have no such effect when given by non-oral routes or in animals which are germ-free. To people unfamiliar with agricultural production systems this may seem a trivial use for antibacterials. The effects of such use are, however, far from trivial. They can have a significant benefit for animal welfare. Sometimes they act directly by helping control a specific disease such as necrotic enteritis in poultry, but they may also improve welfare by improving the utilisation of nutrients and reducing the volume or moisture of undigested material deposited in the animals environment. Wider environmental issues are also significant.

According to Dr J. Walton (1980) the ideal digestive enhancer must:

improve performance effectively/economically
not adversely affect normal gut flora
not be absorbed into edible tissue
not be mutagenic or carcinogenic
not promote Salmonella shedding
be non-toxic to: animal, human handlers, environment
have little therapeutic effect in human/veterinary med.
not cause cross-resistance
at actual use levels
not be involved with transferable drug resistance

  Antibiotic Resistance

Ability to resist the effects of antimicrobials has probably as long as bacteria and moulds have existed since many antimicrobials are synthesised naturally. Some species of bacteria are resistant to new antimicrobials which have never been used in agriculture, human or veterinary medicine. However certain species and strains are especially good at becoming resistant. Increasing resistance to tetracyclines in Salmonellae led to the Swann report (1969). This recommended that antibiotics used for treatment in man or animals should not be used for digestive enhancement/growth promotion. Many countries followed suit, but not US, because the benefits were considered to be uncertain and risk unproven. There has been increasing concern about antibiotic resistance in recent years, for various reasons. Among the medical reasons are worsening antibiotic resistance situation, especially in hospitals, no new antimicrobials licensed in 10 years, and more immuno-compromised and "Intensive care infections". There have also been political reasons, mainly related to the accession of Sweden and Finland to the EU and the fact that their derogation's to maintain their ban of the use of these products were running out. Many groups have investigated the subject with varying conclusions. For instance the only formal recommendation on the subject by the WHO meeting on antimicrobial resistance held in Berlin in 1997 was :

The use of any antimicrobial growth promotion in animals should be terminated if it is used in human medicine; or known to select for cross-resistance to antimicrobials used in human medicine. However, this approach has been "mutated" over the past year to include all products which themselves, or whose related products, might possibly someday be used in human medicine. This in effect amounts to a "back-door" blanket ban on all such use. The so-called "precautionary principle" has been used as the justification, given that current EU legislation does not allow for a blanket ban. Since these products have been in use for 20-40 years it is highly questionable whether any human health benefit will be achieved by a "retrospective precaution" such as this. The application of a precaution which is not, itself, zero-risk, should only occur after a careful analysis of the risks of the various options available. The application of a blanket ban on these products based on limited experience in a few countries, which are not typical of the rest of Europe, could have a number of unintended consequences. Enterococci are normal intestinal residents of both man and animals. The degree of transfer between the species is uncertain but they can cause serious disease in immuno-suppressed patients and in certain hospital environments. Vancomycin has become a popular treatment for enterococcal infections, especially in the US. There is a much better correlation between the medical use of vancomycin and resistance problems than there is with agricultural use of the related compound avoparcin. In spite of this, under a clause of directive 70/524 intended to protect public health, Denmark, and subsequently Germany, banned the use of Avoparcin in 1996. The EU Scientific Committee on Animal Nutrition did not support the Danish action yet the use of Avoparcin was suspended in 1997. As a result of this the association of feed additive manufacturers agreed to fund a multi-species multi-country survey of enterococcal resistance in food animals. This began in 1998 and is expected to last 2 years. Also in 1998 Denmark banned the use of Virginiamycin but once more SCAN did not support this action. In spite of this the EU has implemented a suspension of not just this compound but also Zinc Bacitracin, Tylosin and Spiramycin in January 1999 (with an option for countries to delay implementation to June 30th 1999). Only 2 digestive enhancers remain approved for poultry in the EU: Avilamycin (a compound related to this is under development for use in man) and Flavo-phospholipol. No other "alternatives" are formally approved as feed additives for poultry. The reader interested in this subject is referred to the HAN Foundation report (3) for a detailed discussion of the evidence for an against the human health risks associated with the use of these products in agriculture.

  The Precautionary Principle

The "Precautionary Principle" has been used as the justification for the recent suspensions. There is no universally agreed definition. At one extreme it might be "risk, no matter how small, is unacceptable". Although this may appear at first glance to be reasonable, it fails to take into account the complex web of interacting factors which make up real-life food production systems. Most importantly, it assumes that the precaution itself introduces no risk. There is no evidence that this will actually improve human health, but it will certainly reduce the already meagre profitability of European poultry companies, making it even more difficult to justify the investments required to further reduce the level of Salmonella infections. It is also likely to increase the proportion of poultry meat sourced from third countries, many of which have limited control programmes for food-borne infections and no or very lax controls on the use of antibiotics in food animals. Thus implementation of a ban on a European basis may actually be counter-productive in the things it is seeking to achieve! A full risk assessment of these issues should be able to take account of all such factors. The "Draft Guidelines on application of precautionary principle" issued by the EU Commission Consumer Affairs DG XXIV in October 1998 are to be welcomed (2) as a step forward. We await with interest confirmation that they are agreed and the basis of actions of both DGVI and , evidence of their application to the review of digestive enhancing antibiotics including those already suspended. It is widely accepted that antibiotics should be used prudently with a view to maximising their benefit and minimising risk to man. Suspensions/bans are acceptable where there is reasonable scientific evidence. However the balance of risk must be evaluated and be clearly favourable before a ban is introduced.

  Unanswered Questions

1. Have the human health risks associated with the suspension of the licenses of these (and, eventually, similar products) been fully evaluated and clearly shown to be less than those associated with their continued use?

2. How is it proposed to eliminate the equivalent threat arising from meat imported from third countries originating from animals treated with these products?

Swedish producers themselves acknowledge that they would not have been able to do without these products had they not previously instituted radical changes in their production systems to attempt to eradicate Salmonella infections (4). To force the rest of Europe rapidly down this route is likely to place European producers at a substantial disadvantage in competition with foreign producers not similarly burdened. This will lead to further reduced profitability of European agriculture with its inevitable effects on the ability to make the investments required to improve food safety and animal welfare. Increased imports from third countries will tend to reduce the European consumers influence on, and control of, issues such as animal welfare, food hygiene , residues. Because these products do not leave residues it will not be possible to enforce any ban on imports even if WTO rules allowed it. Concerns have also been expressed by veterinarians about indirect effects of product bans on the environment, animal welfare, animal disease and the need to use therapeutic medication (5,6,7,8).

  The RUMA Alliance

Vested interests on both sides of the "use of antimicrobials debate" have embarked on an intensive campaign to woo legislators and the public to their point of view over the past year. Some of these campaigns have concentrated more on building on uneducated prejudices and worries, rather than on presenting a balanced case. In the UK an organisation has come together to attempt to address the issues in a balanced fashion. The RUMA (Responsible Use of Medicines in Agriculture) Alliance, is formed by representatives of the various segments of agriculture, feed manufacture, pharmaceutical industry, veterinarians, food retailers and consumers. It has commissioned species sub-groups to produce papers to fulfil the following objectives.

"1. To review the use of antimicrobials in agriculture and to produce responsible use guidance for farmers.

2. To establish and communicate practical strategies by which the need to use antimicrobials might be reduced.

3. Ultimately to enable poultry producers to discontinue routine antimicrobial use without adversely affecting either the welfare of their animals or the viability of their business."

It is expected that the first papers arising from this process will be published shortly.

  Conclusions

Digestive enhancers exert their effect by moderating intestinal flora and thus allowing productivity closer to genetic potential, providing benefits for the environment animals, producers and consumers. Unilateral bans on these products may increase use of therapeutic antibacterials. Alternatives need to fulfil the same criteria as currently licensed products. The questions raised need to be answered before further suspensions are implemented.

  References

1. Anon (1997) The Medical Impact of the use of Antimicrobials in Food Animals. Report of a WHO Meeting, Berlin 13-17 October 1997
2. Belveze, H. (1998) Guidelines on the application of the precautionary principle.European Commission DG XXIV Consumer Policy and Consumer Health Protection 17th October 1998
3. Bezoen, A., van Haren, W., and Hanekamp, J.C. (1999) Emergence of a debate: AGP's and Public Health. Human Health and Antibiotic Growth Promoters: Reassessing the Risk. Heidelberg Appeal Nederland Foundation
4. Lundstrom, L (1999) Managing without Growth promotors. South West Broiler Conference, Cannington, Somerset, UK February 10th 1999
5. Sainsbury, D.W.B. (1999) EU Ban on four antibiotic feed additives Veterinary Record l 144 (3)80
6. Taylor, D.J.(1999) EU Ban on four antibiotic growth promoters Veterinary Record 144 (5)126
7. Thorp, B. McMullin, P.F. (1998) Antimicrobials Guidelines and "Mass Medication" Veterinary Record 143(7):203 (The BVPA guidelines are available on the Internet at http:\\www.bvpa.freeserve.co.uk\\microbia.htm)
8. Thorp, B., Cargill, P. (1999) Ban of digestive enhancers. Veterinary Record 144(1)27-28