Usage of antibiotics in Europe, opportunities for Mexico

1. Usage of antibiotics in Europe, opportunities for Mexico F. Gautier Gautier Agro Consult

2. A challenging environment for the animals • Gastrointestinal disorders • Immune suppression • Diarrhea • Post weaning colibacillosis • Non-specific dysentery • Enteritis • Respiratory syndromes

3. Historically controlled by the usage of antibiotics • The three main uses of antibiotics in livestock are for growth promotion in general at sub-therapeutic levels, prophylaxis and to treat sick animals (Collignon 1999b; JETACAR 1999; WHO 2001). • All therapeutic and some prophylactic antibiotics are requiring a veterinary script to be used and withholding periods also apply. • Antibiotics used for growth promotion are generally classified as feed additives.

4. That is an efficient and common practice • Intensive animal production has depended on the use of therapeutic antibiotics and growth promoters for many years. • More than half of all antibiotics produced globally are used in animals. • In the USA alone, animal agriculture consumes 80% of all antibiotics used. • According to a first-ever estimate of the Food and Drug Administration (FDA), the amount of antibiotics sold for use in food animals in the USA was over 13,000 tons (29 million pounds) in 2009. • The overall national sales of veterinary antimicrobials in 10 European countrieswas approximately 3500 tons of active substance in 2007. • In 2009, French sales of veterinary antimicrobials were 1067 tons.

5. That is a potential risk • Resistance to antibiotics in food animals is well documented in the scientific literature (Danmap 2000). • Antibiotic use in animals, therefore, is a potential problem for human medicine because antibiotic resistant bacteria can pass through the food chain to people (JETACAR 1999, WHO 1997). • But also resistant bacteria can spread to the local environment (adjacent soil, air, and water) through the spreading of manure. • Some of these resistant bacteria are ‘super-bugs’ - multi-resistant bacteria for which there may be few or no therapeutic options available.

6. Are we ready for a world without antibiotics? • Carlet J, Collignon P, et al. in Society's failure to protect a precious resource: antibiotics. Lancet 2011 are predicting that we are entering an era where bacterial infections, such as bloodstream infections and ventilator-associated pneumonia, might no longer be successfully treated with antibiotics. • microorganisms are becoming extremely resistant to existing antibiotics, in particular Gram-negative rods (e.g., Escherichia coli, Salmonella spp, Klebsiellaspp, Pseudomonas aeruginosa, Acinetobacterspp), which are resistant to almost all currently available antibiotics in some settings. • Resistance can be combined with virulence, acting as a potentially deadly duo, as observed in the recent large epidemic outbreak of E. coli 0104:H4 in Europe. • The antibiotic pipeline has become extremely dry

7. How to act against this threat in our industry? • Based on the WHO recommendation if three basic principles of antibiotic use were adopted in the agriculture sector, most of the driving factors for unnecessary antibiotic resistance would be substantially reduced or eliminated. • This can be done without compromising the therapy of sick animals or the economic production of food animals. • These principles are: • Antibiotics should not be used as growth promoters. • The use of antibiotics for prophylactic purposes in animals should be kept to a minimum. The use of methods (other than antibiotics) to prevent infections should be expanded and developed. • Antibiotics that are ‘critical’ or ‘last-line’ for serious human infections should not be used in food production animals or agriculture.

8. Europe took the lead • Over the past 20 years the feed industry has, through legislation, consumer demands and supermarket pressure, been forced to change. • 1997 Avoparcin, belongs to glycopeptide class, a critically important group of antibiotics used in human medicine: Vancomycin. Vancomycin resistant enterococci (VRE bacteria commonly involved in fatal infections in hospitals) • 1999 Virginiamycin, belongs to streptogramin class, risk of cross resistance with antibiotic used in human medicine: Synercid used to treat Vancomycinresitant E. facium infections. • 2006 ban on all Antibiotic used as growth promoters • What’s next?

9. Be prepared for the next step! • 11 January 2013 - British conservative MP for Richmond Park and North Kingston, Zac Goldsmith has called for tougher controls on the use of antibiotics in livestock. • Speaking at a debate in Westminster, Goldsmith called on public health minister Anna Soubry to "lobby vigorously" for a ban on all routine, prophylactic, and non-therapeutic use of antibiotics. And for the government to give "significant consideration to the use of antibiotics on farms and to the link between farm use and resistance".

10. Alternative solutions • Solutions • Management and environment practices • Role of nutritionists • Diet digestibility • Improving gut health • Enzymes • Acidification of feed or water • Oligosaccharides • Vaccination • Bacteriophages • Plasma protein • Herbs and Spices, Essential oils

11. Plants may offer non-nutrient performance enhancing factors that benefit animal production; Greathead 2003 The benefit of plants?

12. What is herbal medicine • Herbal medicine (or "herbalism") is the study and use of medicinal properties of plants. • Most cultures have a tradition of using plants medicinally. In Europe, apothecaries stocked herbal ingredients for their medicines. • In the Latin names for plants created by Linnaeus, the word officinalis indicates that a plant was used in this way. For example, the marsh mallow has the classification Althaeaofficinalis, as it was traditionally used as an emollient to soothe ulcers. • Ayurvedic medicine and traditional Chinese medicine are other examples of medical practices that incorporate medical uses of plants.  • Modern medicine now tends to use the active ingredients of plants rather than the whole plants. The phytochemicals may be synthesized, compounded or otherwise transformed to make pharmaceuticals. • These phytochemicals are divided into (1) primary metabolites such as sugars and fats, which are found in all plants; and (2) secondary metabolites – compounds

13. Herbal medicine and secondary metabolites • Secondary metabolites • Function • Diversity • Not essential for the basic growth and development of plants • Impart flavor, color, aroma and fragrance to plants • 30,000 terpenoids • But play crucial roles in interactions between plants and their environment • Act as chemical weapons against micro-organism , herbivores, insect and other plants • 12,000 alkaloids • Several thousand phenylpropanoids • A variety of the compounds

14. Plants may offer non-nutrient performance enhancing factors that benefit animal production; Greathead 2003 Can we select some of these 50,000 secondary metabolites produced by plants FOR BETTER LIVESTOCK PERFORMANCE?

15. Function of Secondary Metabolites in Plants Secondary Metabolites Protection Attraction • Abiotic stress • UV • Biotic stress • Oxidation • Pollinating insects • Seed dispersing animals • Root nodule bacteria Defense Herbivores (insects, vertebrates) Competing plants Microbes (bacteria, fungi, viruses) • Repellence • Deterrence • Toxicity • Inhibition of germination • Inhibition of seedling growth • Growth inhibition • Toxicity According to M. Wink, 1999

16. Examples of Plant Secondary Metabolites and their proposed function Berberine Linalool Rutin Visual pollinator attractant Defense toxin Olfactory pollinator attractant Brassilexin DIMBOA Rotenone Insect feeding deterrent Antifungal toxin Defense toxin From Pichersky and Gang, 2000

17. Gut Health and Secondary Metabolites Host physiology Diet PROTECTION ATTRACTION Environmental factors Stress Microflora DEFENSE

18. Inflammation and Metabolic disorders • It is more and more clear that prolonged inflammation is inducing metabolic disorders • Sustained exposure to pathogens or pathogen-associated components, can disrupt systemic metabolic functions. • Similarly, chronic disturbance of metabolic homeostasis, such as occurs in « misnutrition », could lead to aberrant immune responses. • Metabolic disorders are characterized by abnormal cytokine production, increased acute-phase reactants and activation of a network of inflammatory signaling pathways. • TNF α more specifically is a pro-inflammatory cytokine that activates various signal transduction cascades. Hostamisligil, 2006

19. The Chronic inflammation circleof farm animals Host physiology Diet Oxidative stress Misnutrition Chronic inflammation Stress Immune dysfunction Inflammation Environmental factors Microflora

20. Effect of Curcumin on Metabolic disorders

21. Other interesting candidates • In addition to Curcumin, there are reports that other Secondary Metabolites may modulate inflammation pathways (Broadhurst et al. 2000; Talpur et al. 2005). • This may be because a significant structural homology exists between Curcumin, Cinnamaldehyde, Capsaicin, Piperine, Eugenol and Gingerol (Aggarwal 2010).

22. Other interesting candidates

23. Plants may offer non-nutrient performance enhancing factors that benefit animal production Greathead 2003 Application to capsicum

24. The Capsicum • There are about 22 species and more than 150 varieties of chilli in the world, five species were domesticated, the three most common being C. annuum, C. frutescens, C. chinense, followed by C. pubescens and C. baccatum var. pendulum. • Mexico being the homeland of Capsicum it has the highest genetic diversity of species available.

25. The Capsaicinoids

26. General biologic and physiologic effects of Capasaicinoids • Antioxydants [Materska, M.; Perucka, I. Antioxidant activity of the main phenolic compounds isolated from hot pepper fruit (Capsicum annuumL.). J. Agric. Food Chem. 2005, 53, 1750-1756.] • Gastroprotector [Mozsik, G.; Szolcsanyi, J.; Racz, I. Gastroprotection induced by capsaicin in healthy human subjects. World J. Gastroenterol. 2005, 11, 5180-5184.] • Effect on metabolism of energy [Ohnuki, K.; Niwa, S.; Maeda, S.; Inoue, N.; Yazawa, S.; Fushiki, T. CH-19 sweet, a non-pungent cultivar of red pepper, increased body temperature and oxygen consumption in humans. Biosci.Biotechnol. Biochem. 2001, 65, 2033-2036.] • Anti-inflammatory [Sancho, R.; Lucena, C.; Macho, A.; Calzado, M.A.; Blanco-Molina, M.; Minassi, A.; Appendino, G.; Muñoz, E. Immunosuppressive activity of capsaicinoids: capsiate derived from sweet peppers inhibits NF-κB activation and is a potent antinflammatory compound in vivo. Eur. J. Immunol.2002, 32, 1753-1763.] • Immunity enhancer [Kim D.K; Lillehoj, H.S; Lee, S.H; Jang, J.I; Bravo, D. (2010). High-throughput gene expression analysis of intestinal intraepithelial lymphocytes after oral feeding of carvacrol, cinnamaldehyde, or Capsicum oleoresin. Poultry Science, 89: 68-81. ] More Information on: • http://www.ethno-botanik.org/Capsicum/Capsicum-literature-scientific-publications.html

27. Research in Mexico on this hot topic • A program financed jointly by France and Mexico started. • This project will focus on the screening of different Mexican Capsicum for their health benefits effects on animals. • The objective of this research is to develop cost effective solutions to decrease chronic inflammatory status of animals submitted to stress.

28. An integrated approach to contribute to the improvement of gut health Decreased chronic oxidative stress and chronic inflammation Host physiology Diet PROTECTION ATTRACTION Environmental factors Stress Microflora DEFENSE

29. Conclusion • Over usage of antibiotics in livestock is a major worldwide concern. • Due to its specific and broad biologic activities, Capsicum could be used in antibiotic free diets to maintain health of livestock and profitability of this crucial industry. • A research program has started in order to select and to cultivate in Mexico the most cost effective variety of Capsicum for this purpose. • The University of Querétaro has developed special technologies in the selection and the cultivation of Capsicum rich in specifically active secondary metabolites that will be the corner stones of this ambitious research program. • Mexico may provide to the world and produce locally a solution to overcome one of the major today’s health concern.