Alternatives to Antibiotics - Dr. Cyril Gay, Senior National Program Manager, USDA Agricultural Research Service (ARS), from the 2017 NIAA Annual Conference, U.S. Animal Agriculture's Future Role In World Food Production - Obstacles & Opportunities, April 4 - 6, Columbus, OH, USA. More presentations at http://www.trufflemedia.com/agmedia/conference/2017_niaa_us_animal_ag_future_role_world_food_production

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

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

4. Secretary
Deputy Secretary
Chief Financial
Officer
General Counsel
Inspector
General
Executive
Operations
Chief Information
Officer
Director of
Communications
Forest Service
Natural Resource
Conservation Service
Under Secretary for
Natural Resources and
Environment
Farm Service Agency
Foreign Agricultural
Service
Risk Management
Agency
Under Secretary for
Farm and Foreign
Agricultural Services
Rural Utilities Service
Rural Business-
Cooperative Service
Rural Housing Service
Under Secretary for
Rural Development
Food and Consumer
Service
Under Secretary for
Food, Nutrition, and
Consumer Services
Food Safety and
Inspection Service
Under Secretary for
Food Safety
Agricultural Research
Service
National Institute for Food
and Agriculture
Economic Research
Service
National Agricultural
Statistics Service
Under Secretary for
Research, Education
and Economics
Assistant Secretary for Administration
Office of Civil Rights
Human Resources Management
Office of Operations
Administrative Law Judges
Judicial Officer
Board of Contract Appeals
Property and Procurement Management
OSDBU
Office of Congressional
Relations
Office Intergovernmental
Relations
Assistant Secretary for
Congressional Relations
Agricultural Marketing
Service
Animal and Plant Health
Inspection Service
Grain Inspection, Packers
and Stockyards
Administration
Assistant Secretary for
Marketing and
Regulatory Programs
2
Agricultural Research
Service
Animal and Plant Health
Inspection Service
Food Safety and
Inspection Service
Foreign Agricultural Service
National Institute for Food
and Agriculture

5. • Dr. Salmon’s research assistant, USDA BAI
• Discoverer of Salmonella
• Research on Cattle Tick Fever
• Water sanitation
• Comparative pathology
(1859 – 1934)
Theobald Smith, MD
(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
Bureau of Animal IndustryBureau of Animal Industry

6. Agricultural Research
Service
• In-house science research arm of USDA
• 1500+ scientists and post docs
• 6,500 + other employees
• 90+ laboratories
• 17 National Programs
• 1,000+ projects
• $1.1 billion annual budget

7. ARS National Programs
• Food Animal
Production
• Animal Health
• Arthropod Pests of
Animals and
Humans
• Aquaculture
• Water Quality &
Management
• Soil Resource Management
• Air Quality
• Global Change
• Rangeland, Pasture &
Forages
• Manure & Byproduct
Utilization
• Integrated Agricultural
Systems
• Bioenergy and Energy
Alternatives
Animal Production &
Protection
(~15%)
Natural Resources &
Sustainable Agricultural
Systems
(~20%)
• Plant, Microbial &
Insect Germplasm
Conservation &
Development
• Plant Biological &
Molecular
Processes
• Plant Diseases
• Crop Protection &
Quarantine
• Crop Production
• Methyl Bromide
Alternatives
Crop Production&
Protection
(~35%)
• Human Nutrition
• Food Safety
• New Uses, Quality
& Marketability of
Plant & Animal
Products
Nutrition, Food
Safety & Quality
(~30%)
8

8. ARS Mission
“Our mission is to conduct research to
develop and transfer solutions to agricultural
problems of high national priority . . .”

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

10. “But I would like to sound one note of warning.
Penicillin is to all intents and purposes non-
poisonous 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…..”
Alexander Fleming
Penicillin
Nobel Lecture, December 11, 1945
Antimicrobial Resistance (AMR)

11. 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.
Recommendations
http://www.oie.int/eng/A_AMR2013/Recommendations.htm

12. http://www.whitehouse.gov/the-press-office/2014/09/18/executivhttp://www.whitehouse.gov/blog/2014/09/18/pcast-releases-new-report-combating-antibiotic-resistance

13. 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-combating-antibiotic-res
http://www.whitehouse.gov/the-press-office/2014/09/18/executive-order-combating-
antibiotic-resistant-bacteria

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

16. USDA AMR Action Plan
Objective 1: Determine and/or model patterns,
purposes, and impacts of antibiotic use in food-
producing 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.

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

18. ad hocad hoc Group on prioritisation of diseases forGroup on prioritisation of diseases for
which vaccines could reduce antimicrobial usewhich vaccines could reduce antimicrobial use
in animalsin 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
April 21-23, 2015

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

20. 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 mass-
vaccination
2020

21. 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.
www.ars.usda.gov/alternativestoantibiotics
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

22. www.ars.usda.gov/alternativestoantibiotics

23. • 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
PrioritiesPriorities
ResearchResearch

24. PrioritiesPriorities
DevelopmentDevelopment
• 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

25. www.ars.usda.gov/alternativestoantibiotics

26. 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?

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

28. • 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
CONCLUSIONS
www.ars.usda.gov/alternativestoantibiotics

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

30. ConclusionsConclusions
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.

31. Thank you!Thank you!
cyril.gay@ars.usda.gocyril.gay@ars.usda.go
vv
www.usda.ars.govwww.usda.ars.gov