As the world recently entered the 21st century, figures available from various census organisations offer some staggering facts. The world's population is increasing at the rate of close to a quarter of a million people per day, and this is already on top of a population count numbering close to 6.1 billion, with the projected figure for the year 2050 being around 9 billion inhabitants on the planet. There is no doubt that with this increase the pressures on countries to produce adequate supplies of food will also increase. This is already on top of almost 800 million people in the developing world not having enough to eat, and another 34 million people in the industrialised countries and countries in transition also suffering from chronic food insecurity (FAO, 2000).
In order to meet the food demands of the world, agriculture is continually being forced to intensify its' production practices, in particularly animal production systems. Up until recently rearing animals under intensive conditions was made in part possible through the routine use of in-feed medications where they prevented major outbreaks of disease and maintained growth performance. However with ever increasing public concern of animal welfare and food safety issues, and recent EU legislation, the use of previously considered safe feed grade antibiotics are now banned.
Antibiotics in agriculture
Since the 1950's the efficacy of incorporating in-feed antibiotics into animal rations could never be questioned, with benefits such as disease reduction, improved feed conversion and improved growth rates leading to greater economic return. However, effective as of July 1999 the European Union banned all but four drug related compounds for routine use in animal feed - the remaining compounds being avilamycin, flavophospholipidol, monensin and salinomycin. Although each of these remaining compounds are produced from respectable, highly regulated and legislated multinational companies, the future use of these is also under scrutiny. As recently as February this year the 41 member Council of Europe has called for a European-wide ban on the use of antibiotics in animal feed. Why is this so?
The scale and level of recent use of antibiotics in intensive animal production systems across the world could be described as enormous and staggering: between 100 to 1000 times in volume to that used in human applications. Of this about 90% of the antibiotics were used as prophylactic or growth promoting agents rather than for treating infections. This chronic overuse has contributed and promoted the emergence and selection of widespread antibiotic resistance within bacterial populations. There is now no doubt that microbial resistance to antibiotics is on the rise within animal production systems. Animals and humans share a large, interactive pool of bacteria that people can acquire by being in contact with animals or by eating foods that are tainted with bacteria from animals. The possibility of creating transborder resistance from animals to humans within bacterial populations stemming from overuse in agriculture is precisely the cornerstone as to why legislation has called for the resultant ban.
Challenge of antibiotic resistance
So is there justified concern for human safety and welfare, and these somewhat drastic measures that have been implemented?
Since the first antibiotic, penicillin, was discovered in 1929, antibiotics were considered the wonder drugs of the 20th century and would take the human race into our new millennium. They had transformed our ability to treat many infectious diseases that were previously killers. The period of the late 1940's and 1950's saw the discovery and introduction of compounds such as streptomycin and tetracycline, and the age of antibiotic chemotherapy came into full being.
However the signs were obvious very early on as to possible resistance by bacteria. Resistance to penicillin in some strains of staphylococci was recognised almost immediately after introduction of the drug (Today some 80% of all strains of staphylococcus aureus are resistant to penicillin), and this was just the beginning.
Now, more than 60 years after the discovery of penicillin, we find ourselves back to the future. It may as well be 1930 again, because many of the strains of bacteria we sought to eliminate, and indeed for a while seemed to have beaten, have re-emerged with a vengeance. Throughout the medical press you will find the concept of the "emergence" of new strains of superbugs. But, emergence is really regression, a frustrating return to the standard which prevailed universally in the previous century (JAMA, 1996). The human race must concede that presently the battle against bacteria has ultimately been lost.
Today we are bombarded in the popular press with scenarios of bacterial antibiotic resistance:
3 bacterial species capable of causing life-threatening illnesses, Enterococcus faecalis, Mycobacterium tuberculosis and Pseudomonas aeruginosa, already evade every antibiotic in the clinician's armamentarium, a stockpile of more than 100 drugs.
Since 1993, 90% of Salmonella typhimurium definitive type 104 isolates obtained from humans have been multidrug resistant.
Antibiotic resistant strain E.coli 0157 have been found in pig farmers, where pigs have been treated with apramycin and gentamycin.
Staphylococcus aureus, a major cause of hospital-acquired infections, is beginning to lack sensitivity to the once reliable antidote vancomycin, thus moving one step closer to becoming an unstoppable killer.
21stCentury Alternatives to assist in producing Healthy Animals
Because of the increasing demand for food by the world's population and the resultant need for an increase in intensively reared animals, there also comes a need to develop systems and products which will allow the continuance of being able to rear animals under these high stocking densities. Experience from some European countries has shown that the withdrawal of regular in-feed antibiotics can lead to an increase in costs as a result of reduced production efficiency, and at times have led to an increase in the actual usage of antibiotics to treat diseases, previously kept under control by subtherapeutic levels in-feed.
Areas of concern that have also been highlighted, since the EU regulatory activity on antibiotics, have been hygiene and management factors in the rearing of densely stocked animals. We now find scenarios where pigs and poultry are increasingly raised under "all in - all out" systems, preventing the cross-contamination of animals with disease between subsequent batches. This has been coupled with the routine use of disinfectants between batches, to assist in clearing the housing of any residual pathogens. It is also recently noted that a leading U.K. company has taken an additional step in management by making claim to be the first company to have animal feed manufacturing facility that is biosecure, thus preventing the introduction of organisms such as Salmonella sp. to the animals via feed.
However the sector receiving the greatest attention since the banning of routine use of in-feed antibiotics, is that of non-pharmaceutical feed additives/growth promoters. Within a period of 9 months the animal health industry has been presented with an array of products under various categories which assist in preventing disease, improving growth rates and increasing feed efficiency. The alternatives currently available can be generally categorised as follows;
NATURAL PLANT EXTRACTS
Whilst the initial 5 categories have been used with varying degrees of success for a number of years now, and at times have shown to have synergistic effects with antibiotics and other non-pharmaceutical feed additives, an area of rapid interest has been that of the natural plant extracts or 'botanicals'.
Whilst 'botanicals' or 'herbs' have a colourful history for their medicinal properties, dating back to the ancient Egyptians, Chinese, Indians and Greeks, it is still interesting to note that some 25% of our modern medicines can be traced back to plant origin. Successful examples of these include aspirin from willow, dioxin from digitalis, ephedrine from ma huang, and are produced under very regulated conditions and subjected to stringent legislation procedures.
The appeal to feed manufacturers to incorporate natural compounds with promises of growth promotion, increased feed efficiency, disease resistance and lack of withdrawal times is undeniable. However, the use of botanicals in animal feed is in its' infancy and is very much non-regulated, and this includes all other non-pharmaceutical additives. Any claim by non-pharmaceutical feed additives for disease treatment or prevention, may render the product to be considered a "drug" in some countries, and even without "drug" claims not all products can be included in animal feeds unless they are also considered generally recognised as safe (GRAS), prior sanctioned or approved as a feed additive. There generally has been a lack of data on the traceability, safety and residues of non-pharmaceutical feed additives, with the long term viability of these products and intensive animal production systems at risk unless more research and effort is focused in these areas and developing confidence in the minds of animal feed manufacturers and ultimately the consumer of animal derived products.
One such U.K. based company, Meriden Animal Health Ltd., whom have been involved in the development and marketing of a plant extract based non-pharmaceutical feed additive, have taken the view from the outset of their development that legislative control may eventually be implemented to regulate these types of products. In order to comply with any future legislative requirements Meriden Animal Health's work, which has focused on the herb Oregano, has been structured in a manner whereby the protocol adopted at each phase of development was similar to that expected when introducing pharmaceutical products to the market. The commercial product developed, now available worldwide, is marketed under the brand name "Orego-StimÂ®".
Activity of Oregano Oil
If you have ever observed microbiologists or chemists swabbing down their research stations, you may have wondered why they use the pungent solution phenol. They use it because it fights and kills germs. Most people associate oregano with its use as a herb or flavour on pizza, or frequent reference in ancient Egyptian and Greek text for treating gastrointestinal disorders and retarding food spoilage. What explains this historical use to some extent is through modern analytical techniques it is shown that oil of oregano in fact share two very effective phenols, carvacrol and thymol - known antiseptic compounds. In fact carvacrol and thymol work together with synergistic effect. Oil of oregano is the premier natural antiseptic and possesses a wide range of microbial killing powers.
It should be noted that there are perhaps as many as 40 different species of oregano, and not all species of oregano possess significant levels of phenols to express antimicrobial activity. Members of the genus Origanum are characterised by the existence of chemical differences, with respect to both essential oil content and composition. As a result the total phenol content of their essential oils range from traces up to 95%, even between plants of the same species. The variation in the chemical composition of Origanum oils has a bearing on the level of their antimicrobial properties.
The variety of oregano shown to have the highest composition of phenols is the Greek variety Origanum vulgare ssp. hirtum, which after analysis by gas chromatography - mass spectrometry (GC-MS) has detected 79.6% carvacrol and 2.5% thymol and significant levels of their biosythetic precursors g-terpinene and r-cymene. Additional to these, a further 30 compounds were also detected which add to the efficacy of the oregano oil through the synergistic effect the additional compounds have with the phenols. The efficacy of the natural oregano oil has been shown to be more potent than synthetic types - probably due to the fact that synthesis so far has been unable to exactly re-create carvacrol, coupled with synthetic reproduction of all the active compounds is probably impossible and certainly prohibitively expensive.
The mode of action of phenols against organisms such as bacteria is through its' toxic effect on the bacterial cell wall, by denaturing and coagulating the protein within the cell wall structure. Once the cell wall structure is disrupted, altered, and increasing its permeability this allows for leakage of cellular constituents, resulting in water unbalance and death.
What is of great significance is in contrast to antibiotic growth promoters, there is no evidence of bacterial resistance from using oregano. Also the inhibitory effect of oregano on bacteria is not through the transfer of any chromosomes, thus there is no risk of increasing the bacterial resistance to such important substances as penicillin, streptomycin, etc. The components in oregano oil are classified by the FDA as GRAS.
Work conducted on Origanum vulgare ssp. hirtum at Aristotle University, in Greece, indicates it is highly effective against both gram-positive and gram-negative, especially against 2 strains of Escherichia coli and Staphylococcus aureus and against single strains of Salmonella typhimurium, Pseudomonas aeroginosa, Bacillus subtilis and Rhizobium leguminosum. Carvacrol has also been shown to possess antifungal and bacteriacidal activity against the food-borne pathogen Bacillus cereus, and antioxidant activity. Moreover, the complete essential oil extracted from Origanum vulgare ssp. hirtum have also exhibited high cytotoxic activity against cell lines derived from human cancers, and anticoccidial activity against Eimeria tenella, E. acervulina, E. necatrix, E. mivati and E. bruneti. Other research conducted on oregano species indicate a wide range of antibacterial properties, similar to other phenolic compounds.
The routine test used to assess the effectiveness of antimicrobial agents is to determine the Minimum Inhibitory Concentration (MIC). Whilst this test is an in vitro evaluation, it is a good indicator of effectiveness in vivo. The aim is to determine the concentration of active substance that will inhibit the growth of bacteria, i.e. 100% inhibition at a known concentration in micrograms per ml. As an example, some of the current antibiotic growth promoters exhibit MIC between 0.03 to 180 micrograms per mil against bacteria such as E. Coli, Pseudomonas and Enterobacter sp.
Although even at this low concentration the level of inhibition can range from 40 to 100%. In the case of Origanum vulgare ssp. hirtum, MIC values between 0.05 and 250 micrograms per ml have produced a 100% inhibition against similar strains of bacteria.
Orego-Stim is a patented product (European patent 96922166.2-2107 0835120 EP Bulletin 99/20 19/05/99 applies) and is the result of 12 years research and development including a plant breeding programme that produced the hybrid variety of oregano, Origanum vulgare ssp. hirtum, and extensive in vitro and in vivo trials to assess the efficacy of the product.
Each year a crop of this hybrid variety of oregano is harvested, with the resultant leaf and flower components then subjected to a process of steam distillation, giving rise to a quantity of pure oil of Origanum. The pure oil is then analysed using the GC-MC technique to quantify the levels of predominantly carvacrol and thymol, along with the remainder of the compounds. To complete the manufacture of Orego-Stim, the pure oil is applied at a concentration of 5% to 2 types of bases giving rise to Orego-Stim Liquid 5% and Orego-Stim Powder 5%.
The manufacture of Orego-Stim is conducted under a GMP system, and conforms to ISO accreditation, ensuring uniformity and each batch produced is fully traceable.
Orego-Stim is included in animal feed diets as a feed flavour and appetite enhancer that has some interesting added benefits linked to the antimicrobial and antioxidant properties of the pure oil of oregano. The effectiveness of Orego-Stim is demonstrated in a number of published studies. Predominantly, Orego-Stim is included in Poultry diets at the rate of 150gms-300gms per tonne of feed for the Orego-Stim Powder 5% and 150ml-300ml per 1000 litres of drinking water for the Orego-Stim Liquid 5%, and in pigs the rates of inclusion are 250gms-500gms per tonne of feed for the Orego-Stim Powder 5% and 250ml-500ml per 1000 litres of drinking water for the Orego-Stim Liquid 5%. Whilst it is felt probable that this active compound will demonstrate benefits in all livestock classes eg. coccidiosis in lambs and calves, most studies have concentrated upon swine and poultry. A series of trial papers relating to efficacy studies for Orego-Stim in pigs and poultry are available from Meriden Animal Health Ltd.
Because of the increasing awareness to food safety by consumers, particularly in light of recent food scares such as the BSE, Dioxin and GMO crisis, Meriden Animal Health Ltd. has also attempted to establish confidence in feed/premix manufacturers and consumers towards Orego-Stim by conducting additional non-performance studies to assess the safety of the product. This work entailed feeding Orego-Stim at the maximum inclusion level versus a commercial control, whereby no Orego-Stim was included, in diets until slaughter, to pigs under surveillance at a University of Leeds trial farm in the U.K. and to poultry at the Swedish Agricultural University.
Various cuts of meat were taken from both the treatment and control groups and forwarded to the Camden and Chorleywood Food and Drinks Research Organisation, whereby they were then subjected to a Free Description test by a panel of assessors. From the results it was established that there were no differences in quality (flavour, odour, texture) between the treatment and control samples of meat, and more importantly there were no 'herbal' notes detected within the meat giving credence to previous research that the compounds within Orego-Stim are not absorbed beyond the boundaries of the gastro-intestinal tract of animals fed Orego-Stim.
Research studies relating to Orego-Stim will continue to be an ongoing process, as an increasing number of benefits are becoming more evident with its rapid development in markets throughout the world. This further work will enable Meriden Animal Health Ltd. to complement the existing studies along with meeting the demands that may be required by any future legislation, providing a safe and reliable product that meet the demands of the animal feed industry for the challenges that lie ahead in ultimately producing clean food for the world's population.
Related Article: Efficacy of Origanum Essential Oils in Sows and Their Piglets Feeds