Antibiotics

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Antibiotics
Beliefs Opinions Evidence
Actions Outcomes Expectations

• Peter Davies BVSc, PhD
• College of Veterinary Medicine
• University of Minnesota

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Outline

• Links between AMU in animals and AMR in humans
• Actions and outcomes on AMU
• Expectations for FDA guidances 209/213
• What is coming next
• Antimicrobial use why and how to measure it
• European directions, further regulation

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Resistance to antimicrobials of human importance
has been generated in animals

• and is spread to humans with the potential to
  cause major harm and we..
• Must take action to minimize it!

• but the evidence that it has spread to humans
  and caused major harm is minimal or non-existent
  and..
• No action is required!

4
Action has been and will be taken!

• European ban on growth promotants
• Sweden 1987
• Denmark 2000
• EU 2006
• European initiatives on monitoring use
• Denmark 2000
• EU Directive 2011
• USA FDA Guidances 209/213..

5
FDA approves antibiotic labels for four purposes
in animals

• Disease treatment
• Disease control
• Disease prevention
• Growth promotion

Therapeutic Use CODEX, AVMA, FDA
FDA guidance 213 to remove AGP approvals by
December 2016
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Statement from US Surgeon-General (Public Health
Reports July-August, 2014)

• Antibiotic Resistance a Public Health Crisis
• Miracle drugs losing effectiveness
• Rising resistance in hospital and community
• Higher cost of treatment and worse outcomes
• 23,000 deaths per year
• 250,000 cases of C. difficile diarrhea
• Primary driver is antimicrobial use (AMU)
• Report did not mention animal use

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Statement from US Surgeon-General (Public Health
Reports July-August, 2014)

• Antibiotic Resistance a Public Health Crisis
• Miracle drugs losing effectiveness
• Rising resistance in hospital and community
• Higher cost of treatment and worse outcomes
• 23,000 deaths per year (0.89 of 2,596,993)
• 250,000 cases of C. difficile diarrhea
• Primary driver is antimicrobial use (AMU)
• Report did not mention animal use

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CDC Head Answers Your Questions on Antibiotic
ResistanceInterview with Dr. Tom Frieden, May
14, 2015

• Dr. Glatter Would you say that there is some
  contribution from the animal suppliers and from
  agriculture that leads to the problem of
  antibiotic resistance?
• Dr. Frieden We've certainly seen, with organisms
  such as Campylobacter jejuni and Salmonella,
  several species where use in animals seems to be
  associated with higher rates of drug resistance
  in animals and in people.

http//www.medscape.com/viewarticle/844241
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Food animal populations and infectious agents
pathways
Foodborne exposures
Food animal Populations
Occupational (direct) exposures
Environmental exposures
Humans
HUMAN RISK
Multihost organisms
ANIMAL RESERVOIRS
Host specific organisms
Wildlife Domestic Animals
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Antibiotic resistance threats in the USA(CDC, Am
Fam Physician. 2014 Jun 1589(12)938-941.)

• Urgent
• Clostridium difficile
• Carbapenem-resistant Enterobacteriaceae
• Drug-resistant N. gonorrhea
• Concerning
• Vancomycin-resistant S. aureus
• Erythromycin-resistant group A Streptococcus
• Clindamycin-resistant group B Streptococcus

• Serious
• Multidrug-resistant Acinetobacter
• Drug-resistant Campylobacter
• Fluconazole-resistant Candida
• ESBLproducing Enterobacteriaceae
• Vancomycin-resistant Enterococcus
• MDR Pseudomonas aeruginosa
• Non-typhoidal Salmonella
• Salmonella serotype Typhi
• Drug-resistant Shigella
• MRSA
• MDR Streptococcus pneumoniae
• Drug-resistant tuberculosis

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Antibiotic resistance threats in the USA(CDC, Am
Fam Physician. 2014 Jun 1589(12)938-941.)

• Urgent
• Clostridium difficile
• Carbapenem-resistant Enterobacteriaceae
• Concerning
• Vancomycin-resistant S. aureus

• Serious
• Multidrug-resistant Acinetobacter
• Drug-resistant Campylobacter
• ESBLproducing Enterobacteriaceae
• Vancomycin-resistant Enterococcus
• Non-typhoidal Salmonella
• MRSA

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Driving the discussion real concerns

• Vancomycin resistant enterococci (early 1990s)
• MDR Salmonella DT104 (mid 1990s)
• FQ resistant Campylobacter (1990s., poultry)
• Livestock associated MRSA (2004.)
• ESBL Enterobacteriaceae (2010 ., poultry)

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Driving the discussion hypothetical concerns
(Price et al., 2015, PNAS 1125554)

• There may be a vicious synergy of AMU in
  animals and in humans, whereby resistant bacteria
  that spill over to humans from livestock can
  ignite a blaze of resistant pathogens when
  medical AMU is high
• Elevated AMU on the farm can rapidly amplify
  resistance among human pathogens that find their
  way into livestock

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Pan-Sensitive Salmonella Isolates in the
USANARMS, 1997-2010 (courtesy of Craig Hedberg)

• Increase in pansusceptible isolates in humans
• No marked change in pigs or other animals

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Multidrug Resistance Among Salmonella Isolates
NARMS, 1997-2010 (courtesy of Craig Hedberg)

• Decrease in MDR Salmonella isolates in humans
• No marked change in pigs or other animals

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Percent Positive Salmonella Tests in the PR/HACCP
Verification Testing Program 1994 Baseline vs.
2011 USDA-FSIS
1994
2011
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Relative rates by year (compared with 19961998)
of lab-confirmed infections with Campylobacter,
STEC O157, Listeria, Salmonella, and Vibrio by
year (Foodborne Diseases Active Surveillance
Network, United States, 19962011)

• 20-30 reduction in Listeria, Campylobacter
• 50 reduction in Yersinia
• 0 change in Salmonella

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The signal vs. the noise!

• Salmonella prevalence in animals at harvest is
  not driving Salmonella incidence in people
• Trends in AMR in Salmonella in animals are not
  driving trends in AMR in Salmonella in humans
• Does not mean there is no contribution
• Does suggest it may not be major
• Reduced AMR in humans due to reduced Salmonella
  risk from meat?

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What about MRSA?(Methicillin resistant S.
aureus)

• From 1961 emerged rapidly to be a major problem
  of chronically ill in health care institutions
• Resistance linked to antimicrobial use in
  hospitals
• Hospital Associated MRSA (HA-MRSA)
• The truth prior to 1995
• Not a concern for broader community
• No epidemiologic role of animal reservoirs

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Holland an issue emerges!

• Very low MRSA prevalence
• Intensive screening and typing with sma1 PFGE
• Search and destroy policy isolation/decoloniza
  tion
• 2004 6mo girl screened before heart surgery
• MRSA isolate not typable with Sma1 PFGE
  Tetracycline resistant
• 2 other screening isolates not typable by Sma1
  PFGE also linked to pigs Novel MLST type ST398
  Tetracycline resistant
• Studies of MRSA prevalence in pigs, farmers and
  pork
• 39 of market hogs positive for ST398 MRSA
• Pig farmers had 760x higher MRSA prevalence than
  general public

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ST398 (livestock associated) MRSAGenerally
accepted facts

• Occurs in livestock in many countries
• Pigs, cattle, avian, horse, ..?
• High MRSA prevalence in livestock farmers,
  veterinarians, slaughter plant workers
• 20-50 in farmers (vs. 0.5 - 2 in population)
• Mainly LA-MRSA
• Long term persistence can occur in some people
• Secondary transmission to family members
• Clinical infections can occur some severe

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Diversity of MRSA in pigs globally
ST398 t011, t108 t034, t567 gt30 spa types
ST5 t002
ST9 t899 t337
Not all livestock associated MRSA are ST398
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The role of antimicrobial use in the emergence of
LA-MRSA?

• MecA gene codes resistance to all beta lactams
• Long term use of beta lactams in food animals
• Therapeutic vs. non-therapeutic uses
• Role of antimicrobial growth promotants
• Most are not beta lactams
• Tetracycline resistance
• LA-MRSA emergence in horses (no tet use)
• Newer injectable products
• Long acting cephalosporins

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Growth promotants as the culprit?MRSA cases in
Denmark (all types)
MRSA ST398 Detected in DK
MRSA ST398 Detected in NL
Ban of AGP in nurseries
Ban of AGP In finishers
DANMAP 2010
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Selective pressures (Aarestrup 2010) Law of
unintended consequences?

• Tetracyclines MSSA in pigs also resistant
• Zinc resistance in MRSA
• 74 of ST398 MRSA had high resistance to zinc
• Zinc resistance gene on MecA cassette
• All MSSA susceptible to zinc
• Widespread use of zinc since AGP ban
• Prevention of enteric disease in weaned pigs
• USA (120 S. aureus isolates - unpublished)
• All MSSA and MRSA tested were tetracycline
  resistant
• Zn All MSSA susceptible MRSA resistant (one
  farm)

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Summary of MRSA/MSSA in pigs in USA
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Changes and expectations

• Outcomes of EU changes
• FDA guidances 209/213
• What might we expect
• How do we measure it?

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Expectations for banning of AGP in Denmark and EU

• Reduction of antibiotic use in food animals
• Minimal impact on production
• Reduction of antibiotic resistance
• Animal isolates
• Human isolates
• Reduced risk to human health
• Zoonotic and foodborne pathogens
• Commensal organisms and animal pathogens

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Response of Danish producers (2004)

• Increased enteric disease in weaned pigs
• Increased weaning age by more than 3 days
• Reduced ration density (protein/energy)
• Practiced limit feeding where possible
• Added ZnO and organic acids to diets
• Utilized more therapeutic antimicrobials

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Aggregate antimicrobial use in Danish swine
industry
Avoparcin ban and ban on vet sales
AGP ban F N

• Lowest use was in 1999 before weaned pig ban
• Replacement of AGP with therapeutic use

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AMR in Salmonella in pigs DANMAP 2004/2012
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(No Transcript)
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Timeline of EU/Dutch events(Speksnijder et al,
2015)
Goals to reduce AMU are arbitrary and not linked
to measurable public health outcomes
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AMU per kg biomass of pig meat, poultry meat and
cattle meat produced in 10 EU countries (2005
data)
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Gross sales of veterinary antimicrobials in the
Netherlands (Speksnijder et al, 2015)
Reduced AMU is the goal!
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Expectations for successpost FDA 209/213?

• Is compliance success?
• What does success look like?
• Does less use success?
• Residues
• Resistant foodborne pathogens
• Other resistant organisms
• Public health measures?

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Residue violations in market hogsUnheralded
success!

• 1978 violative residues (USDA)
• 5.6 for antibiotics
• 9.7 for sulfonamides
• 2011 Sulfonamides
• No violative sulfonamide residues in 204 tests
• 2008-2011 Antibiotics
• No violative antibiotic residues in 1,199 market
  hogs
• 2011 1 in 11,509 inspector generated tests
  (FAST)

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What can industry do?

• Communicate documented improvements
• Residues
• Reduced Salmonella prevalence in meat
• Reduced resistance in human Salmonella isolates
• Manage expectations of FDA guidances
• Impact on producers (small vs. large)
• Impact on veterinary workforce (with AASV)
• Public expectations of AMU/AMR

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What can industry do?

• Evaluate impact on animal health and production
• Need to address now
• Anticipate Future Pressures
• Measurement of AMU
• Pressures on prevention and control
• Science and Communication
• Reliable data on AMU
• Value of preventive AMU

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Can research help?

• Are we getting closer to an answer?
• Is the argument over, regardless of the truth?
• Precautionary regulations
• Food service enterprises
• Consumer opinion
• When is enough (reduction) enough?
• No restriction on use?
• Ban all antimicrobial use in food animals?
• Measure the costs of restriction in the
  short/long term

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BelgiumAMCRA 2020 Vision Statement

• AMCRA 2020 Vision Statement
• 1. 50 lower antibiotic use by 2020
• 2. 75 lower use of critical antibiotics by 2020
• 3. 50 lower use of medicated feed by 2017
• 4. A global data collection system by 2016
• 5. A plan for each farm

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AMCRA 2020 Vision Statement

• 6. Benchmarking of farmers and veterinarians
• 7. No antibiotics for prophylaxis, promotion of
  alternatives
• 8. Awareness-raising, repeatedly
• 9. Transparency and monitoring of suppliers and
  users
• 10. Surveillance of resistance to antibiotics

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Belgium goal 7

• It should no longer be possible for any
  antibiotic to include a prophylactic indication
  with the exception of pre- and peri-operational
  uses and preparation for the lactation dry
  period
• It is advisable to launch a pan-European
  initiative since the adaptations should become
  effective in all European countries and because
  numerous registrations are already managed at the
  European level
• The pharmaceutical industry will also suspend
  all forms of marketing relating to the
  prophylactic use of antibiotics.

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All complex problems have a simple and
straightforward explanation.
Dr. Jim McKean
and it is wrong!
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Questions?
Beliefs Opinions Evidence
Actions Outcomes Expectations

• Peter Davies BVSc, PhD
• College of Veterinary Medicine
• University of Minnesota