Dr. Cyril Gay - Overview of Alternatives to Antibiotics in Agriculture


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Overview of Alternatives to Antibiotics in Agriculture - Dr. Cyril Gay, USDA, ARS, from the 2012 NIAA One Health Approach to Antimicrobial Resistance and Use Symposium, October 26-27, 2012, Columbus, OH, USA.

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Dr. Cyril Gay - Overview of Alternatives to Antibiotics in Agriculture

  1. 1. Alternatives to Antibiotics Cyril G. Gay, DVM, PhD Senior National Program Leader Animal Production and Protection Agricultural Research ServiceUnited States Department of Agriculture cyril.gay@ars.usda.gov
  2. 2. Antibiotic usage in food animals• Therapeutic - treatment of diseased animal• Prophylactic - disease prevention at times of stress when infection rates rise, such as shipping, weaning• Metaphylactic - therapeutic and prophylactic herd use in the face of a disease outbreak• Growth promotion – accelerate growth of healthy animals• Regardless of personal opinions: • Increasing concern with antibiotic resistance • Increased regulation – likely ban of some antibiotics• Examination of alternatives to conventional antibiotic use is warranted• Goal – improve animal health, welfare and production efficiency
  3. 3. www.ars.usda.gov/alternativestoantibiotics
  4. 4. OBJECTIVESThe objectives of this symposium was to 1) highlightpromising research results and novel technologiesthat provide alternatives to antibiotics, 2) assesschallenges associated with their commercializationand use, and 3) provide actionable strategies tosupport their development.
  5. 5. Symposium Organization Five Major Topics1. Alternatives to antibiotics: lessons from nature2. Immune modulation approaches3. The gut microbiome4. Alternatives to antibiotics for growth promotion5. Regulatory pathways to enable the licensing of alternatives to antibiotics
  6. 6. What are alternatives to antibiotics? Drugs, biologics, biotherapeutics, feed additivesHost derived antimicrobials, defensins, probiotics, prebiotics,bacteriocins, phytochemicals, acidifying agents, heavy metals,bacteriophages, bacteriophage lysins, small interfering RNAs,naturally occuring antibacterial lytic enzymes, recombinant andhyperimmune therapeutic antibodies, immune enhancers, Toll-like receptor agonists, cytokines. www.ars.usda.gov/alternativestoantibiotics
  7. 7. SESSION 1Alternatives to Antibiotics: Lessons from NatureThe aim of this session was to review novel biocontrolapproaches for preventing and/or treating bacterialpathogens (and where applicable viral and parasiticpathogens) in food animal production. www.ars.usda.gov/alternativestoantibiotics
  8. 8. Host derived antimicrobials “Innate host defense”• Present in all organisms Cellular defenses• Ancient Neutrophils Macrophages  Snake: cathelicidin NK-cells  Frog: plastrin  Insect: cecropin• Limited repertoire of molecules Effector molecules Enzymes• Rapid acting Host Defense Peptides Collectins• Broad specificity• Constitutive and stimulated secretion “The first line of defense against infection”
  9. 9. Chicken cathelicidin 2 (Cath-2) N• Cationic (+9)• 26 amino acids• AmphipathicRFGRFLRKIRRFRPKVTITIQGSARF-NH2  Hinge region  C Van Dijk et al., 2005 Xiao et al., 2006 Henk P. Haagsman Department of Infectious Diseases and Immunology, Utrecht University, The Netherlands
  10. 10. CATH-2 is produced by chicken heterophils HeterophilsMononuclear cells Giemsa Anti-CATH-2 Van Dijk et al., 2009a
  11. 11. Conclusions• Salmonella enteritidis infections of chickens result in accumulation of CATH-2 positive heterophils at the site of infection• CATH-2 is microbicidal against Gram (-), Gram (+) bacteria, yeasts and fungi• Truncated CATH-2 analogs are antimicrobial• CATH-2 and derived peptides induce cytokine production in a chicken macrophage cell line• CATH-2 dampens the LPS-induced inflammatory response• Prophylactic or therapeutic treatment of chickens with CATH-2 significantly reduced Salmonella survival in the crop
  12. 12. Bacteriophage HumanAnimal viruse.g., Influenza, HIV Poultry SwinePlant viruse.g., Tobacco mosaic virusBacteriophagee.g., T1, T2 Specific
  13. 13. Bacteriophage• Discovered by Felix d’Herelle in 1917• Infect and replicate in bacterial cells• Host specific infections• Must enter and exit bacterial host cell• Lytic cycle• Lysogenic cycle• DNA phage• RNA phage
  14. 14. Bacteriophage as an Intervention?• Felix d’Herelle explored using phage solutions to treat dysentery in humans• Phage solutions supplied to Russian soldiers during World War II• Republic of Georgia has been using phage therapy since the 1940s• In 2006, US FDA approved Listeria phage solution for using in ready-to-eat meat & poultry• In 2011, US FDA approved E. coli phage for using on food• Possible therapy for treating multi-drug- resistant strains of bacteria http://www.cfsan.fda.gov/~dms/opabacqa.html
  15. 15. Bacteriophage concerns?Restriction modification –degradation of phage DNA uponinfectionCRISPR – clustered regularlyinterspaced short palindromic repeatsImmunogenicity – antibodiesdeveloped against phage duringtreatmentResistance – mutations in bacterialgenes needed for adsorption andlysogenyLateral Gene Transfer – virulence Bacteriophage Resistance Mechanisms Labrie et al. Nat Rev Micro 8(5):317, 2010factors
  16. 16. Bacteriophage Gene Products• Phage genomics and proteomics to search for potential novel antimicrobials• Bacteriocins shown to reduce Campylobacter• Bacteriophage lytic enzymes • Amidase • Muramidase (Lysozyme) • Endopeptidase• Recombinant lytic enzymes (amidases) shown to be lytic against Clostridium perfringens Seal et al. Arch Virol• Challenges - Need efficient and cost- 156:25, 2011 effective expression system
  17. 17. SOME CONCLUSIONS FROM THE ATA SYMPOSIUM SESSION 1• Need to define the mechanism(s) of action!!!• Need to conduct scientific studies to determine the efficacy and safety of these products• Need to conduct studies under field conditions• Determine the product profile (label claims): treatment, prevention, or growth promotion?• Can these products be manufactured in a cost effective manner?• How will these products be administered?
  18. 18. SESSION 2 Immune Modulation Approaches to Enhance Disease Resistance and Treat Animal InfectionsThe aim of this session was to address novel drug-freealternative strategies to enhance innate defense mechanismsby modulation of innate immune pathways or activation ofconserved innate immune sensing molecules of the hostimmune system. www.ars.usda.gov/alternativestoantibiotics
  19. 19. Diversity of stimuli can bind host conserved recognition receptors (PRRs= Pattern Recognition Receptors) and stimulate immune response Innate sensing receptors PRRs TLRs NLRs RIG-1Bali Pulendran and David Artis. 2012,New Paradigms in Type 2 Immunity. Science 337, 431. Innate Immune Sensing: Conserved pattern recognition molecules, PRRs: Toll-Like Receptors, (TLRs), NOD-like receptors (NLRs ), Retinoic acid receptors (RIG-1) Conserved pattern recognition molecules, PRRs: Toll-Like Receptors, (TLRs), NOD-like
  20. 20. Recent studies have shown that dietary supplementation withphytonutrients such as safflower leaf, plum, anethol, mushroom,capsaicin, cinnamaldehyde, tumeric , garlic….enhance innateimmunity. Lee S. H. et al., 2008, 2009, 2010, 2011,2012 (30 papers)
  21. 21. Some phytochemicals (essential oils) interact with host PRRs and initiate inflammatory immune response PRRs and downstream signaling components are molecular targets for dietary intervention strategies using Bioactive phytochemicals to reduce PRR-mediated phytochemicals inflammation Innate immune response -Host resistance PAMPS -Wound healing (Pathogens, diets) PRRs: TLRs, NODs DAMPS(Necrotic cell products) Dysregulated immune response -Cancer Level of PRR - activation Atherosclerosis -Insulin Inflammation resistance
  22. 22. NUTRIGENOMICS Up regulated Down regulated 98 51 62 26 31 31 23 48 156 246 5 ppm 3 ppm 2 ppm Primary infection Secondary infectioncarvacrol cinnamaldehyde Capsicum oleor. E. Maxima E. Maxima KIM, DK et al., 2010. Poul Sci 89:68-81 Kim et al., 2011. PLoS One 6:e27712
  23. 23. SOME CONCLUSIONS FROM THE ATA SYMPOSIUM SESSION 2• Need veterinary immunological reagents to characterize function• What is the product profile (label claims): treatment, prevention, or disease resistance?• Need more basic research
  24. 24. SESSION 3 The Gut Microbiome and Immune Development, Health and DiseaseRecent advances are demonstrating that the microbiota plays a keyrole in health and disease. The aim of this session was to attempt tocapture state-of-the-art results in farm animals and humans to assesshow microbiome analysis is helping to solve disease problems. www.ars.usda.gov/alternativestoantibiotics
  25. 25. Microbiome and Metagenomic Analysis Metatranscriptomics Metagenomics RNA 16s Survey DNAMicrobiome or Virome Metabolomics
  26. 26. Intestinal Microbiome• Bacteria, fungi, viruses, protozoa, helminths• Bacteria 1011 cells/gram • Firmicutes • Bacteroidetes • Proteobacteria• Bacteria primarily associated with mucus and macromolecular food matrix (fiber)• Composition varies • In different portions of GI • In different animals
  27. 27. Alternatives to antibiotics to modify microbiome• Science of nutrition • Science of disease • Improved feed • Prevent intestinal efficiency diseases • Improved growth • Reduce inflammation rates • Prevent colonization of • Assess alternative foodborne pathogens feeds • Reduce shedding of pathogens • Increase disease resistance
  28. 28. SOME CONCLUSIONS FROM THE ATA SYMPOSIUM SESSION 3• A number of the products discussed during the symposium impact the gut microbiome• Do we need to culture and characterize gut microorganisms or do we just need to identify them?• Do we need to just shift specific populations that are associated with beneficial effects or do we need to characterize the mechanisms by which gut microorganisms modulate disease and health traits• Need to integrate nutrition, health, and disease research
  29. 29. SESSION 4 Alternatives to Antibiotics to Promote Growth in Livestock, Poultry, and Aquaculture ProductionThe aim of this session was to explore novel approaches that canbe used as alternatives for antimicrobial growth promoters inpoultry, swine, ruminant, and aquaculture production. A key aim ofthis session was to improve knowledge on mechanisms of action ofthe growth-promoting characteristics of the proposed approaches. www.ars.usda.gov/alternativestoantibiotics
  30. 30. Alternatives to the Use of Antibiotic Growth Promotores in Ruminants S. Calsamiglia Dept. Ciència Animal i dels Aliments Universitat Autònoma de Barcelona
  31. 31. Intestinal Microbiota Associated with High Feed Conversion Efficiency in Chickens Rob Moore Australian Animal Health Laboratory CSIRO ANIMAL, FOOD AND HEALTH SCIENCESAlternatives to Antibiotics, September 2012
  32. 32. SOME CONCLUSIONS FROM THE ATA SYMPOSIUM SESSION 4• Need to understand mechanisms of action to maximize the effect of alternatives to antibiotics for growth promotion• The active ingredients needs to be defined to ensure quality and reproducibility of expected effect of the product under field condition• Current knowledge of mechanisms of action for growth promotion of certain alternatives to antibiotics may be greater than what we knew about antibiotics used for production
  33. 33. SESSION 5 Regulatory Pathways to Enable the Licensing of Alternatives to AntibioticsThe aim of this session was to review the regulatory pathways indifferent regions of the world to license alternatives to antibiotics.Regulatory challenges that are faced in taking new moleculesfrom discovery to commercial production was reviewed. Thissession also covered how to seek approval for labeling claims thatare new with specific focus on claims that a product is able toreduce the use of antibiotics www.ars.usda.gov/alternativestoantibiotics
  34. 34. SOME CONCLUSIONS FROM THE ATA SYMPOSIUM SESSION 5• Alternatives to antibiotics will be regulated as a drugs, biologics, feed additives, or possibly all of the above• Alternatives to antibiotics must be developed according to national and international standards and meet requirements for efficacy, safety, and quality• Regulatory processes are in place to enable and facilitate the licensing of alternatives to antibiotics• Need to engage regulatory agencies early in the process
  35. 35. GOING FORWARD• Need to link academia, government researchers, feed industry,pharmaceutical industry, regulatory agencies, and livestock industries• Stakeholders and scientific community need to define the scope ofthe research, development, and applications of alternatives toantibiotics
  36. 36. http://www.oie.int/eng/A_AMR2013/introduction.htm
  37. 37. www.ars.usda.gov/alternativestoantibiotics Thank you! cyril.gay@ars.usda.gov www.usda.ars.gov