Alternatives to Antibiotics

Alternatives to Antibiotics Cyril Gerard Gay, DVM, PhD Senior National Program Leader Animal Production and Protection Agricultural Research Service cyril.gay@ars.usda.gov

Presentation Outline 1. Agricultural Research Service 2. Antimicrobial Resistance 3. Alternatives to Antibiotics 4. Conclusion

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Bureau of Animal Industry (1850 1914) Daniel Elmer Salmon, DVM, Ph.D First class to be awarded a DVM in the U.S Director of the USDA Bureau of Animal Industries Eradicated Contagious Bovine Pleural Pneumonia Cattle Tick Fever Program Established federal meat inspection program Studied effect of animal diseases on public health Theobald Smith, MD Dr. Salmon s research assistant, USDA BAI Discoverer of Salmonella Research on Cattle Tick Fever Water sanitation Comparative pathology (1859 1934)

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Presentation Outline 1. Agricultural Research Service 2. Antimicrobial Resistance 3. Alternatives to Antibiotics 4. Conclusion

Antimicrobial Resistance (AMR) Alexander Fleming Penicillin Nobel Lecture, December 11, 1945 But I would like to sound one note of warning. Penicillin is to all intents and purposes nonpoisonous so there is no need to worry about giving an overdose and poisoning the patient. There may be an danger, though, in under dosage. It is not difficult to make microbes resistant to penicillin in the laboratory exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body..

Recommendations 13. To support relevant research to improve the understanding of the efficacy of current antimicrobial agents with the aim to prolong their usage while minimising the development of resistance, to develop new molecules and to find alternatives that could be used in animal production for antimicrobial agent substitutions. http://www.oie.int/eng/a_amr2013/recommendations.htm

http://www.whitehouse.gov/blog/2014/09/18/pcast-releasesnew-report-combating-antibiotic-resistance http://www.whitehouse.gov/the-pressoffice/2014/09/18/executive-order-combating-antibioticresistant-bacteria

Recommendation 3. Fundamental Research (1) Expand fundamental research relevant to developing new antibiotics and alternatives for treating bacterial infections. (2) Develop alternatives to antibiotics in agriculture. Goal 5: Research and Development: Incentivize development of therapeutics and diagnostics for humans and animals. 5.5 Establish and promote international collaboration and public-private partnerships to incentivize development of new therapeutics to counter antibiotic resistance including new, next-generation, and other alternatives to antibiotics; vaccines; and affordable, rapidly deployable, point-of-need diagnostics. http://www.whitehouse.gov/blog/2014/09/18/pcast-releases-new-report-combatingantibiotic-resistance http://www.whitehouse.gov/the-press-office/2014/09/18/executive-order-combatingantibiotic-resistant-bacteria

www.usda.gov/sites/default/files/documents/usda-antimicrobial-resistance-action-plan.pdf

USDA AMR Action Plan Objective 1: Determine and/or model patterns, purposes, and impacts of antibiotic use in foodproducing animals. Objective 2: Monitor antibiotic drug susceptibilities of selected bacterial organisms in food-producing animals, production environments, and meat and poultry. Objective 3: Identify feasible management practices, alternatives to antibiotic use, and other mitigations to reduce AMR associated with food-producing animals and their production environments.

Presentation Outline 1. Agricultural Research Service 2. Antimicrobial Resistance 3. Alternatives to Antibiotics 4. Conclusion

April 21-23, 2015 ad hoc Group on prioritisation of diseases for which vaccines could reduce antimicrobial use in animals Provide guidance on prioritisation of disease for which the use of already available and new vaccines could reduce antimicrobial use in animals, focusing the first step on pigs, poultry and fish Identify actions to improve utilisation of such vaccines To support the WHO Global Action Plan on AMR which makes provision for such approach

Table 2: Infections for which new or improved vaccines would significantly reduce the need for antibiotic use in swine Key syndrome Primary pathogen(s) (disease) Antibiotic use Commercial* vaccine exists Major constraints to use of vaccine / vaccine development Vaccine research priority Systemic (respiratory) Respiratory Streptococcus suis High Yes Strain coverage too narrow Lack of cross-protection Poor immunogenicity due to being a capsule based vaccine Haemophilus parasuis Medium Yes Serotype specific with variable crossprotection Maternal antibody interference Pasteurella multocida (for pneumonic disease) High No No vaccine with approved label claim for pneumonia (There is a vaccine for atrophic rhinitis) Mycoplasma hyopneumoniae High Yes Does not completely prevent lung lesions Animals continue to shed pathogen Diagnostics not always accurately done Actinobacillus pleuropneumoniae Porcine Reproductive and Respiratory Syndrome virus (secondary bacterial infections) Swine Influenza Virus (secondary bacterial infections) Enteric neonatal Escherichia coli High for the syndrome, Low for E. coli Enteric (weaners/finishers) High Yes Limited coverage Good immunity only if serotype specific Sub-unit vaccine which affords crossprotection High Yes Strain coverage limited High virus mutation rate Modest cross-protection Vaccine evasion High Yes Strain matching Vaccine-associated enhanced respiratory disease (VAERD) Lack of cross-protection Efficacy in piglets limited Yes Maternal vaccine provides effective lactogenic immunity Coverage of enterotoxigenic E. coli may occasionally need to be updated Escherichia coli High Yes Maternal antibody interference Short window for induction of immunity Lawsonia intracellularis High Yes Other pathogens in the syndrome (Brachyspira) not included Antibiotic-free window for vaccination required (live attenuated oral vaccine) Brachyspira spp B. hyodysenteriae, B. pilosicoli Medium-high No Low current research investment as changes in husbandry largely eliminated the disease Technical barriers to vaccine development High Medium High Low High High High Low High Low (see also Brachyspira) High Rotaviruses (secondary bacterial infections) High Yes Reasons limiting wider adoption unknown High

Outcome Vaccine research could have a significant impact, particularly if it addressed the following four priority gaps: Maternal antibody interference Cross-protection or inclusion of relevant strains in vaccine formulations Occurrence of immunological interference in multivalent vaccines Innovative delivery systems to enable massvaccination 20

What are alternatives to antibiotics? Alternatives to antibiotics are broadly defined as any substance that can be substituted for therapeutic drugs that are increasingly becoming ineffective against pathogenic bacteria, viruses or parasites. Gay C.G., Seal B.S., Lillehoj H.S., Donovan D.M. (2014) Alternatives to Antibiotics: Recent Scientific Advancements. OIE Conference Booklet, Ed. 2014: Responsible and Prudent Use of Antimicrobial Agents for Animals; 74-75 www.ars.usda.gov/alternativestoantibiotics

www.ars.usda.gov/alternativestoantibiotics

Priorities Research Discovery of antibiotic alternatives with defined mechanisms of action Discovery of antibiotic alternatives that are not only safe, but effective Discovery of antibiotic alternatives for the prevention or treatment of infectious diseases Discover antibiotic alternatives that are less susceptible to antimicrobial resistance Discover antibiotic alternatives to maintain the health of animals throughout their production cycle

Priorities Development Clear regulatory pathways Business incentives to invest in the development of new and innovative products: feed additives versus drugs and biologics Antibiotic alternatives are very distinct molecules, with different effects, doses and mechanisms of action, and need to be developed accordingly Conducting a general evaluation of the effect of antibiotic alternatives on production performance is difficult but paramount in achieving commercial success

www.ars.usda.gov/alternativestoantibiotics

Questions A paradigm shift for antimicrobial drug discovery: bactericidal, bacteriostatic, or new approaches that target virulence or modulate the host response? Broad spectrum versus narrow spectrum? Definition of drugs versus biologics? Co-development of interdependent products? Achieving disease resistance outcomes?

Session 1: Vaccines Program Session 2: Microbial-Derived Products Session 3: Phytochemicals Session 4: Immune-Related Products Session 5: Innovative Drugs, Chemicals, and Enzymes Session 6: Regulatory Pathways www.ars.usda.gov/alternativestoantibiotics

CONCLUSIONS Defining the mechanisms of action of alternatives to antibiotics is paramount to enable their effective use A portfolio of alternatives to antibiotics may need to be considered to achieve optimum health and disease management for different animal production systems There is a need to integrate nutrition, health, and disease research Regulatory support and new approaches to enable the licensing of antibiotic alternatives Public-private partnerships to advance the research, development, and commercialization antibiotic alternatives www.ars.usda.gov/alternativestoantibiotics

Presentation Outline 1. Agricultural Research Service 2. Antimicrobial Resistance 3. Alternatives to Antibiotics 4. Conclusion

Conclusions 1. Technological advances are providing new research tools and opportunities that afford scientists a hitherto unprecedented ability to solve 21st century problems 2. Scientific discovery is delivering promising new tools and technologies to take on seemingly intractable diseases 3. There is a need to establish public-private partnerships to develop veterinary medical countermeasures that are designed for a specific purpose.

Thank you! cyril.gay@ars.usda.gov www.usda.ars.gov