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Back to the future – Diagnostic considerations in a
growth promoters-free industry
Fabio Vannucci
Outline
• History
• EU experiences
o Disease incidence
• USA scenario
o Diagnostics
• USA and EU: compare/contrast
• Considerations for future scenarios
Overview
• Use of antimicrobial growth promoter (AGP)
- Late 1940s: Chickens fed with fermentation waste
from tetracycline production as a source of vit B12
OverviewHistory
- Better growth performance due to residual tetracycline: “Animal protein factor”
- Early 1950 (Cunha et al, Luecke et al):
o The effect of vitamin B12, animal protein factor and streptomycin on the growth of young pigs
• Use of antimicrobial growth promoter and antimicrobial resistance
OverviewHistory
- Inaction (UK and other EU countries): tylosin, spiramycin, avoparcin…
- Action (Sweden): consumers → Federation of Swedish Farmers → ban in 1986
- Mid 1960 (UK): Multi-drug-resistant salmonella
- “Sufficient sound basis for action”
- Recommendations for using on animal feed:
o Little or none application for therapeutic purposes in human or animals
o Not impair the efficacy of a prescribed therapeutic drugs through development of resistance
o Tylosin should be available only for therapeutic purposes
• Use of antimicrobial growth promoter and antimicrobial resistance
OverviewHistory
- Vancomycin (glycopeptide antimicrobial): discovered early 1960s
o 1980s: widely used in humans for treatment of resistant Gram positive bacteria
o 1993: Vancomycin resistant enterococci isolated from humans and animals (Bates et al 1993)
Not been used in food animal
o Cross-resistance with Avoparcin: commonly used for growth promotion in food animal
EU banned in 1997
- AGP termination
Sweden: 1986 Norway: 1995 Switzerland: 1999 Finland: 1999
Denmark: 2000 EU: 2006
OverviewEuropean experiences: disease incidence
• How to measure disease incidence (before/after AGP ban)?
- Indirect method for occurrence of disease
o Antimicrobial usage ONLY for therapeutic or preventive purposes (assumption after AGP ban)
o Recording antimicrobial usage for a given clinical syndrome
- Production data: mortality, ADG, Feed conversion
- Diagnostic data (lab accessions)
o High specificity but questionable sensitivity
o Confounders - emerging disease, surveillance, detection vs disease
OverviewEuropean experiences: disease incidence
• How to measure disease incidence (before/after AGP ban)?
Denmark
- Production data: mortality, ADG, Feed conversion
OverviewEuropean experiences: disease incidence
• How to measure disease incidence (before/after AGP ban)?
- Overall trends on antimicrobial consumption (therapeutic use)
Sweden Norway
OverviewEuropean experiences: disease incidence
• How to measure disease incidence (before/after AGP ban)?
- Overall trends on antimicrobial consumption (therapeutic use)
Denmark
Netherlands
OverviewEuropean experiences: disease incidence
• How to measure disease incidence (before/after AGP ban)?
- Age groups
Sweden (1986) – first 4 years after
o Increase post-weaning diarrhea
(> 1.5% mortality)
o 5-6 more days to reach 25 kg
o ↓ 1.5% feed efficiency in finishers
OverviewEuropean experiences: disease incidence
• How to measure disease incidence (before/after AGP ban)?
- Antimicrobial classes (Denmark)
OverviewEuropean experiences: disease incidence
• How to measure disease incidence (before/after AGP ban)?
- Antimicrobial classes (Netherlands)
Switzerland
OverviewEuropean experiences: disease incidence
• How to measure disease incidence (before/after AGP ban)?
- Clinical signs, age group, # days and animals treated
• Enteric pathogens after AGP ban
o Significant increase in diarrhea (nursery)
- Post-weaning diarrhea: β-hemolytic E. coli
- Spirochetal colitis (Brachyspira pilosicoli)
- Clinical ileitis
• ↓50-120g ADG
• ~ 7 additional days from weaning to 30Kg
OverviewEuropean experience: disease incidence
Weber et al (2016), 24th IPVS
1 days 5 days 2 weeks 3 weeks 5 weeks 10 weeks 28 weeks Adult
Escherichia coli
Brachyspiral colitis
Lawsonia intracellularis
Neonatal Nursery Finishing
Overview
Autolysis Non-autolysis
USA Scenario: Diagnostics
• Enterotoxigenic Escherichia coli (ETEC)
o Post-weaning diarrhea: β-hemolytic E. coli
o High morbidity and variable mortality
Overview
o Virulence
- Fimbria (F18, F4) + Enterotoxins (LT, STa, STb, EAST1, Stx2e, AIDA)
- Stx2e: Sudden death (CNS signs may be present)
USA Scenario: Diagnostics
• Enterotoxigenic Escherichia coli (ETEC)
OverviewUSA Scenario: Diagnostics
UMN-VDL: Enterotoxigenic E. coli 2010-2016 (n=2206)
Overview
F18F4
Neg
Others
(F41, F5, F6)
F18.LT
F18.STb
F18.STX2e
F4.LT
F4.STaF4.STb
F4. STa.STb
F4.LT.STa.STb
Weber et al (2016), 24th IPVS
USA Scenario: Diagnostics
UMN-VDL: Antimicrobial susceptibility (2006-2016)
Overviewβ-hemolyticE.coli
Ampicillin
Enrofloxacin
Trimethoprim/Sulpha
Gentamicin
Neomycin
Florfenicol
Sulpha
Oxytetracycline
Tiamulin
Chlortetracycline
USA Scenario: Diagnostics
• Brachyspiral colitis
Overview
“B. suanatina” Swine Swine dysentery-like
“B. hampsonii” Swine Swine dysentery-like
Strongly
β-hemolytic
Weakly
β-hemolytic
USA Scenario: Diagnostics
UMN-VDL: B. pilosicoli isolation (2011-2016)
Overview
0
1
2
3
4
5
6
7
8
9
NumberofB.pilosicoli
USA Scenario: Diagnostics
UMN-VDL: Antimicrobial susceptibility (2009-2013)
OverviewUSA Scenario: Diagnostics
Sweden: Antimicrobial susceptibility (AGP free scenario)
OverviewUSA Scenario: Diagnostics
• Proliferative enteropathy (ileitis): Lawsonia intracellularis
Overview
o Endemically distributed worldwide
o Classically affected growing-finishing pigs
0
10
20
30
40
50
60
70
2 5 7 10 13 16 19 22
weeks
0
10
20
30
40
50
60
70
5 7 10 13 16 19 22
weeks
FecalPCRSerology
o Clinical presentation (Acute/Chronic/Subclinical)
USA Scenario: Diagnostics
• Proliferative enteropathy (ileitis): Lawsonia intracellularis
o Clinical/subclinical PCR threshold to justify the treatment (?)
Overview
1.00E+00
1.00E+01
1.00E+02
1.00E+03
1.00E+04
1.00E+05
1.00E+06
1.00E+07
1.00E+08
1.00E+09
1.00E+10
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42
Log10Lawsoniaintracellularisbacteria/gfeces
Ct value
UMN-VDL
- One Log10 increase in LI load increases OR for a pig to have a low growth rate by 2 times
USA Scenario: Diagnostics
Overview
UMN-VDL: Lawsonia intracellularis PCR detection - 2013-2016 (n=3577)
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
10/3/2013 4/21/2014 11/7/2014 5/26/2015 12/12/2015 6/29/2016
Ctvalue
25%
34%
41%
USA Scenario: Diagnostics
Overview
UMN-VDL: Antimicrobial susceptibility
USA Scenario: Diagnostics
• Increasing of enteric bacterial infection (not much respiratory)
OverviewUSA and EU: compare/contrast
o Porcine Respiratory Disease Complex (PRDC)
- Success controlling primary triggers – vaccination, elimination
o Porcine Enteric Disease Complex (PEDC) – What the heck?
- Enteric bacteria as primary cause
- Synergism: Rotavirus – Clostridium perfringens, E.coli (?)
o Microbiome complexity
Overview
Europe United States
Weaning age 28-30 days 21 days
PRRS status Neg (some countries) Pos
Pig/farm density Low/variable High
Lawsonia vaccine usage Low Widely used
Carbadox Banned Widely used*
Zinc oxide Partial restrictions Widely used
USA and EU: compare/contrast
• Management/alternative strategies
• Systematic approach to measure disease incidence
• Scale matters
• AGP ban (EU)
– Enteric bacterial pathogens (diarrhea): When to act (?)
• Lawsonia PCR positive: “how much” to justify treatment (?) and for how long (?)
• Beta-hemolytic E coli with virulence factor + diarrhea
OutlineConsiderations for future scenarios
– Followed by additional regulation → Long term benefits
• Denmark (Yellow card regulations)
• Germany (DART, German Antibiotic Resistance Strategy)
• Netherlands (Netherlands Veterinary Medicines Authority - SDa)
Outline
• Talking about additional regulation…
Considerations on future scenarios
©2014 Regents of the University of Minnesota. All rights reserved.
The University of Minnesota is an equal opportunity educator and employer.
• Dr. Peter Davies
• Dr. Connie Gebhart
• Dr. Julio Alvarez
AknowledgementsAcknowledgements
Fabio Vannucci
vannu008@umn.edu

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Dr. Fabio Vannucci - Diagnostic Considerations in a Growth-Promoter Free Industry - Back to the Future

  • 1. Back to the future – Diagnostic considerations in a growth promoters-free industry Fabio Vannucci
  • 2. Outline • History • EU experiences o Disease incidence • USA scenario o Diagnostics • USA and EU: compare/contrast • Considerations for future scenarios Overview
  • 3. • Use of antimicrobial growth promoter (AGP) - Late 1940s: Chickens fed with fermentation waste from tetracycline production as a source of vit B12 OverviewHistory - Better growth performance due to residual tetracycline: “Animal protein factor” - Early 1950 (Cunha et al, Luecke et al): o The effect of vitamin B12, animal protein factor and streptomycin on the growth of young pigs
  • 4. • Use of antimicrobial growth promoter and antimicrobial resistance OverviewHistory - Inaction (UK and other EU countries): tylosin, spiramycin, avoparcin… - Action (Sweden): consumers → Federation of Swedish Farmers → ban in 1986 - Mid 1960 (UK): Multi-drug-resistant salmonella - “Sufficient sound basis for action” - Recommendations for using on animal feed: o Little or none application for therapeutic purposes in human or animals o Not impair the efficacy of a prescribed therapeutic drugs through development of resistance o Tylosin should be available only for therapeutic purposes
  • 5. • Use of antimicrobial growth promoter and antimicrobial resistance OverviewHistory - Vancomycin (glycopeptide antimicrobial): discovered early 1960s o 1980s: widely used in humans for treatment of resistant Gram positive bacteria o 1993: Vancomycin resistant enterococci isolated from humans and animals (Bates et al 1993) Not been used in food animal o Cross-resistance with Avoparcin: commonly used for growth promotion in food animal EU banned in 1997 - AGP termination Sweden: 1986 Norway: 1995 Switzerland: 1999 Finland: 1999 Denmark: 2000 EU: 2006
  • 6. OverviewEuropean experiences: disease incidence • How to measure disease incidence (before/after AGP ban)? - Indirect method for occurrence of disease o Antimicrobial usage ONLY for therapeutic or preventive purposes (assumption after AGP ban) o Recording antimicrobial usage for a given clinical syndrome - Production data: mortality, ADG, Feed conversion - Diagnostic data (lab accessions) o High specificity but questionable sensitivity o Confounders - emerging disease, surveillance, detection vs disease
  • 7. OverviewEuropean experiences: disease incidence • How to measure disease incidence (before/after AGP ban)? Denmark - Production data: mortality, ADG, Feed conversion
  • 8. OverviewEuropean experiences: disease incidence • How to measure disease incidence (before/after AGP ban)? - Overall trends on antimicrobial consumption (therapeutic use) Sweden Norway
  • 9. OverviewEuropean experiences: disease incidence • How to measure disease incidence (before/after AGP ban)? - Overall trends on antimicrobial consumption (therapeutic use) Denmark Netherlands
  • 10. OverviewEuropean experiences: disease incidence • How to measure disease incidence (before/after AGP ban)? - Age groups Sweden (1986) – first 4 years after o Increase post-weaning diarrhea (> 1.5% mortality) o 5-6 more days to reach 25 kg o ↓ 1.5% feed efficiency in finishers
  • 11. OverviewEuropean experiences: disease incidence • How to measure disease incidence (before/after AGP ban)? - Antimicrobial classes (Denmark)
  • 12. OverviewEuropean experiences: disease incidence • How to measure disease incidence (before/after AGP ban)? - Antimicrobial classes (Netherlands) Switzerland
  • 13. OverviewEuropean experiences: disease incidence • How to measure disease incidence (before/after AGP ban)? - Clinical signs, age group, # days and animals treated
  • 14. • Enteric pathogens after AGP ban o Significant increase in diarrhea (nursery) - Post-weaning diarrhea: β-hemolytic E. coli - Spirochetal colitis (Brachyspira pilosicoli) - Clinical ileitis • ↓50-120g ADG • ~ 7 additional days from weaning to 30Kg OverviewEuropean experience: disease incidence Weber et al (2016), 24th IPVS 1 days 5 days 2 weeks 3 weeks 5 weeks 10 weeks 28 weeks Adult Escherichia coli Brachyspiral colitis Lawsonia intracellularis Neonatal Nursery Finishing
  • 16. • Enterotoxigenic Escherichia coli (ETEC) o Post-weaning diarrhea: β-hemolytic E. coli o High morbidity and variable mortality Overview o Virulence - Fimbria (F18, F4) + Enterotoxins (LT, STa, STb, EAST1, Stx2e, AIDA) - Stx2e: Sudden death (CNS signs may be present) USA Scenario: Diagnostics
  • 17. • Enterotoxigenic Escherichia coli (ETEC) OverviewUSA Scenario: Diagnostics
  • 18. UMN-VDL: Enterotoxigenic E. coli 2010-2016 (n=2206) Overview F18F4 Neg Others (F41, F5, F6) F18.LT F18.STb F18.STX2e F4.LT F4.STaF4.STb F4. STa.STb F4.LT.STa.STb Weber et al (2016), 24th IPVS USA Scenario: Diagnostics
  • 19. UMN-VDL: Antimicrobial susceptibility (2006-2016) Overviewβ-hemolyticE.coli Ampicillin Enrofloxacin Trimethoprim/Sulpha Gentamicin Neomycin Florfenicol Sulpha Oxytetracycline Tiamulin Chlortetracycline USA Scenario: Diagnostics
  • 20. • Brachyspiral colitis Overview “B. suanatina” Swine Swine dysentery-like “B. hampsonii” Swine Swine dysentery-like Strongly β-hemolytic Weakly β-hemolytic USA Scenario: Diagnostics
  • 21. UMN-VDL: B. pilosicoli isolation (2011-2016) Overview 0 1 2 3 4 5 6 7 8 9 NumberofB.pilosicoli USA Scenario: Diagnostics
  • 22. UMN-VDL: Antimicrobial susceptibility (2009-2013) OverviewUSA Scenario: Diagnostics
  • 23. Sweden: Antimicrobial susceptibility (AGP free scenario) OverviewUSA Scenario: Diagnostics
  • 24. • Proliferative enteropathy (ileitis): Lawsonia intracellularis Overview o Endemically distributed worldwide o Classically affected growing-finishing pigs 0 10 20 30 40 50 60 70 2 5 7 10 13 16 19 22 weeks 0 10 20 30 40 50 60 70 5 7 10 13 16 19 22 weeks FecalPCRSerology o Clinical presentation (Acute/Chronic/Subclinical) USA Scenario: Diagnostics
  • 25. • Proliferative enteropathy (ileitis): Lawsonia intracellularis o Clinical/subclinical PCR threshold to justify the treatment (?) Overview 1.00E+00 1.00E+01 1.00E+02 1.00E+03 1.00E+04 1.00E+05 1.00E+06 1.00E+07 1.00E+08 1.00E+09 1.00E+10 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 Log10Lawsoniaintracellularisbacteria/gfeces Ct value UMN-VDL - One Log10 increase in LI load increases OR for a pig to have a low growth rate by 2 times USA Scenario: Diagnostics
  • 26. Overview UMN-VDL: Lawsonia intracellularis PCR detection - 2013-2016 (n=3577) 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 10/3/2013 4/21/2014 11/7/2014 5/26/2015 12/12/2015 6/29/2016 Ctvalue 25% 34% 41% USA Scenario: Diagnostics
  • 28. • Increasing of enteric bacterial infection (not much respiratory) OverviewUSA and EU: compare/contrast o Porcine Respiratory Disease Complex (PRDC) - Success controlling primary triggers – vaccination, elimination o Porcine Enteric Disease Complex (PEDC) – What the heck? - Enteric bacteria as primary cause - Synergism: Rotavirus – Clostridium perfringens, E.coli (?) o Microbiome complexity
  • 29. Overview Europe United States Weaning age 28-30 days 21 days PRRS status Neg (some countries) Pos Pig/farm density Low/variable High Lawsonia vaccine usage Low Widely used Carbadox Banned Widely used* Zinc oxide Partial restrictions Widely used USA and EU: compare/contrast • Management/alternative strategies • Systematic approach to measure disease incidence • Scale matters
  • 30. • AGP ban (EU) – Enteric bacterial pathogens (diarrhea): When to act (?) • Lawsonia PCR positive: “how much” to justify treatment (?) and for how long (?) • Beta-hemolytic E coli with virulence factor + diarrhea OutlineConsiderations for future scenarios – Followed by additional regulation → Long term benefits • Denmark (Yellow card regulations) • Germany (DART, German Antibiotic Resistance Strategy) • Netherlands (Netherlands Veterinary Medicines Authority - SDa)
  • 31. Outline • Talking about additional regulation… Considerations on future scenarios
  • 32. ©2014 Regents of the University of Minnesota. All rights reserved. The University of Minnesota is an equal opportunity educator and employer. • Dr. Peter Davies • Dr. Connie Gebhart • Dr. Julio Alvarez AknowledgementsAcknowledgements Fabio Vannucci vannu008@umn.edu