Alternatives to antibiotics

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The following article is a special collaboration from AFMA (Animal Feed Manufacturers Association)
We thank their kind support.

The growth promoter is dead. Long live the “nutraceutical”! But what are they?, what do they do?, and, more importantly-do they work? In this first article of a series, we present the information needed to survive an antibiotic ban.

The stream of research papers on such topics as probiotics, prebiotics, organic acids, enzymes, herbs and spices has recently become a veritable torrent of data, covering everything from bacteria to Chinese herbal medicine. So what is the truth about “nutraceuticals”? Now that medical and consumer pressure is resulting in the systematic removal of low levels of antibiotics from animal feeds, especially in Europe, now is the time to explore the alternatives.

“Against” bacteria, “for” animals
Antimicrobial growth promoters allow animals to use their food more efficiently. The intestines of animals can be envisaged as complex ecosystems, a balance between the animals’ own intestinal cells, producing and secreting enzymes to digest food, and absorb the products, and of bacteria, which colonise the gut. The gut of the newborn animal or newly hatched bird is a sterile environment, which begins to develop, both in its physiology and microflora immediately the animal begins to ingest food. This is a critical time for the young animal, as exposure to pathogenic organisms now can easily lead to disease, at a time when the animal has little or no natural defences. In cattle, sheep and pigs, weaning is another crucial period. The natural immunoglobulin protection afforded by the mother through her milk has been removed, and the weanling’s own defence mechanisms are not yet fully formed.

Mode of action
At high, therapeutic levels, -lactam antibiotics andbantimicrobials work by a number of mechanisms. The bacitracin inhibit microbial cell wall synthesis; macrolides and streptogramins inhibit protein synthesis in bacteria; ionophores increase the permeability of cell membranes and quinoxalines act at the level of the target cell’s DNA, disrupting its ability to replicate. The effect of an antibiotic in vivo is not predicted easily by it’s molecular structure. Therapeutic doses of antibiotics kill bacteria. The much lower doses used as growth promoters in feed can still allow many of the beneficial bugs to grow, whilst themselves affecting the intestinal function of animals. It is only in more recent years, after their economic and health advantages at these levels have been allowed to revolutionise intensive animal production, that more light has been thrown on their modes of action, and these are diverse. The net effect is that less of the feed intake is wasted in maintaining the gut lining, and the surface for absorption of nutrients. Other effects include the sparing of glucose, by inhibiting bacterial lactic acid production; prevention of toxin production, which again spares amino acids and minerals, which otherwise would have been rendered unavailable to the animal.

Sound economic value

It is clear, from the experience of the past 50 years that in order to produce food cheaply, some sort of boost is needed, to help animals to realise their full (and ever improving) genetic potential, and as quickly as possible. Low feed conversion ratios (FCR), high daily weight gains, and shorter fattening times are traits that we have come to rely on for good economic returns. The consumers, in return, have become accustomed to cheap food, produced under conditions which are ethically acceptable, in terms of animal health and welfare. Now, it seems, the antibiotics which fulfilled these criteria will no longer be acceptable to them.

Ensuring safety and efficacy
Over the years the use of antibiotic growth promoters has not run wild and unchecked. As antibiotics were first used in veterinary and human medicine, it has always been a priority to prevent the use of low levels of antibiotics in animal feeds from transferring bacterial immunity to species pathogenic in animals or humans. For veterinary surgeons to allow this to continue unrestricted would be to shoot themselves in the foot. By 1995 some 90% of the antibiotics used in agriculture worldwide were estimated to be given as growth promoting and prophylactic agents rather than to treat infection (Khachatourians, 1998).However, on the basis of antibiotic used per kg liveweight, there is three times less use in animals than humans. It is obvious that, since some of them have been used in medicine, or are related to medicinal substances, there may be a risk of resistance or cross-resistance developing. As a result, the use of antimicrobials is legislated in the same way as other therapeutic drugs.

Who’s responsible for bacterial resistance?

In recent years, the public has become increasingly alarmed by the emergence and spread of antibiotic-resistant bacteria. It is true that microbial resistance to antibiotics is on the rise, and is even becoming something of a crisis in some countries’ health care. For bacteria to develop resistance to antibiotics, they must first receive exposure to them. The source of this, however, is disputed by scientists. Overuse of prescribed drugs in human and veterinary medicine, as well as their use as growth promoters in animals have all been blamed. The recommended levels of antimicrobials in feed were 5-10ppm in the 1950’s, but have increased by ten to twenty fold since then. Reports of bacteria resistant to the antibiotics used to control them (see “Birth of the superbugs”), despite world-wide legislation to control use, has eventually fuelled the downfall of antibiotic use to produce cheap meat under clean conditions. Consumers may still demand antibiotic treatment from doctors where it is ineffective, but they are no longer so keen to eat meat which has been raised with their help.

The verdict
Despite the arguments for using antibiotics at low levels in animal feed, the search for a pariah has become political. The public furore in the EU was to be quashed by drastic measures. Sweden was the first country to insist on a blanket ban on subtherapeutic doses of antibiotics used in animals. Denmark followed with a voluntary ban. The EU eventually succumbed to public pressure, ignoring the studied opinion of the Scientific Committee on Animal Nutrition, and has been sequentially adding to its list of banned substances in recent years, until only, monensin, salinomycin (both used as anticoccidials in poultry), avilomycin and flavomycin remain. These are not related to therapeutic antibiotics currently used in human medicine, and therefore are not considered to pose any immediate risk through animal feeds. However, a blanket ban in the EU is about to be enforced. This will have implications, not only for European producers, but also for eastern European States wishing to join the EU, which will have to comply with the regulations, and countries such as Thailand wishing to export animal products to it. The US is considering the case, and it is still possible that it will follow suit.

Consumers demand “natural” alternatives
Whatever the evidence, the fact remains that the tone has been set for public distrust and decisions made on the basis of politics and knee-jerk consumer reactions to information, led by the popular press and major supermarket chains. In this atmosphere, feed additives manufacturers are not to be outdone. If antibiotic growth promoters are to be removed completely, but it will inevitably be at a cost, either to the consumer, or to the producers, unless an effective replacement is found. Management practices can help to reduce the risks of widespread intestinal disorders, but cannot remove the problem completely, as the Scandinavian experiences have shown. Novel alternatives are already beginning to populate the gap, in an attempt to smooth the transition from cheap food to “safe” food. Although animal welfare is also a priority in consumer perceptions, the public is beginning to demand that this is achieved by some other route which is deemed “natural”, although all such products will still have to comply with the “Ten Commandments”, which were devised to control the use of antibiotics, but are equally relevant to any other growth promoting substance. This list was set out by John Walton (Lawrence, 1998) and has stood the test of time:

1. It must improve performance effectively and economically.
2. It must have little therapeutic use in human or veterinary medicine.
3. It must not cause cross-resistance to other antibiotics at actual use levels.
4. It must not be involved with transferable (infectious) drug resistance.
5. It must not cause deleterious disturbances of the normal gut flora.
6. It must not be absorbed from the gut into edible tissue.
7. It must not be mutagenic or carcinogenic.
8. It must not promote salmonella shedding.
9. It must not give rise to environmental pollution, being readily biodegraded.
10. It must be non-toxic to the animal and its human handlers.

New products are already available
In anticipation, research has been going on to find alternative growth promoting feed additives. Many have been available on the market for a number of years and yet more are under development. We are now confronted with a whole host of claims and different approaches to the problem of growing animals without using growth promoting antibiotics. There are now so many new approaches to using additives to improve weight gain and feed efficiency that there is an obvious need to review and explain what the products are, how they are purported to work, and how effective they appear to be. One problem which has already been encountered in compiling a comprehensive review is that there is not always enough data supplied by the manufacturers of all these new products to make an effective estimate of just what will be the eventual cost to the farmer of replacing antibiotics with any one, or a combination of products.

Enhancing digestion
There are two major concepts which appear time and again when assessing new feed additives which claim to be growth promoting. Firstly, natural substances which achieve similar effects to the classical antibiotic approach could be used (for example, substances which kill bacteria). Secondly, the animals’ own digestive processes could be enhanced. In the future it might be possible to genetically manipulate animals which can do this for themselves, so that the digestive system catches up with the genetic potential for growth. However, for now, it has to be achieved by other means. There are many ways in which this can be done, and this approach depends on the species in question. Two concepts which have been under research for many years are the use of enzymes and organic acids in the feed. Extra enzymes can add to the animals’ own digestive capacity, extending the period of breakdown of nutrients, so that is starts before the animals’ own enzymes have got the work. Organic acids can be used to stabilise the intestinal pH, preventing growth of pathogenic bacteria, encouraging the normal microflora, and ensuring that digestive enzymes can work at their maximal capacity.

Germs in white hats
Probiotics, which for a long time have been the subject of some controversy, are now coming into their own. The basic principle behind feeding live cultures of bacteria to animals is simple: if the gut is populated with enough of the bacteria which animals have naturally in the gut, then the colonisation and attachment of the bugs which suppress growth and feed conversion efficiency by causing diarrhoea will be impaired. Certain yeasts, too have long been hailed as having positive benefits for the growth of animals. In a similar vain, the animal’s own beneficial microflora can be encouraged, by aiming feed additives directly at them-the so-called prebiotics.

Herbs and spices
One of the more recently celebrated concepts is that of using herbs and spices, essential oils or the active substances contained therein. These, developed largely from the ancient art of Chinese herbal medicine, are evolving from being on the fringes of human nutrition to being more acceptable as means of promoting the growth of animals. They have many possible modes of action, not only being appetising to animals. Some herbs are well known to have antimicrobial effects, others have an astringent effect on the intestine, and can encourage efficient digestion.

Furthermore, with all these approaches, there is always the possibility of using combinations of these products, but this is really at a more embryonic stage of development. As with any new product, it is vital that positive economic returns are seen. Whatever the effects promised, the future without antibiotics may not necessarily be such a daunting place as was previously thought.
Birth of the “superbugs”
In any bacterial population, some individuals may be inherently insensitive to the antibiotics developed to control them. Since each type of antibiotics acts on a specific mechanism in the cell’s metabolism, which is regulated at the level of the cell’s DNA, when a mutation does occur that confers antibiotic resistance, that resistance will be specific to a particular group of antibiotics. Mutations can occur at the rate of one per million to one per billion cells. In the presence of an antibiotic, such individuals have the opportunity to grow, less inhibited by competition by non-resistant strains. Bacteria, however, carry the ability to transfer traits between and across species, via extra-chromosomal DNA fragments called plasmids and transposons. Genetic exchange by various mechanisms, including conjugative plasmids can result in antibiotic resistance passing between bacteria. This sort of resistance transfer can occur even in the absence of antibiotics.

Nutraceuticals in feed shall also have to comply with the ‘Ten Commandments” of John Walton.

Sarah Mellor

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