Antibiotics Peter Davies BVSc, PhD College of Veterinary Medicine University of Minnesota Beliefs Opinions Evidence Actions Outcomes Expectations

2 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

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! 3

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…….. 4

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

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

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

CDC Head Answers Your Questions on Antibiotic Resistance Interview 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. 8

Food animal populations and infectious agents – pathways Food animal Populations Host specific organisms Foodborne exposures Multihost organisms Wildlife Domestic Animals ANIMAL RESERVOIRS HUMAN RISK Occupational (direct) exposures Environmental exposures Humans

Antibiotic resistance threats in the USA (CDC, Am Fam Physician Jun 15;89(12): ) 10 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 ESBL–producing Enterobacteriaceae Vancomycin-resistant Enterococcus MDR Pseudomonas aeruginosa Non-typhoidal Salmonella Salmonella serotype Typhi Drug-resistant Shigella MRSA MDR Streptococcus pneumoniae Drug-resistant tuberculosis

11 Urgent Clostridium difficile Carbapenem-resistant Enterobacteriaceae Concerning Vancomycin-resistant S. aureus Serious Multidrug-resistant Acinetobacter Drug-resistant Campylobacter ESBL–producing Enterobacteriaceae Vancomycin-resistant Enterococcus Non-typhoidal Salmonella MRSA Antibiotic resistance threats in the USA (CDC, Am Fam Physician Jun 15;89(12): )

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) 12

Driving the discussion – hypothetical concerns (Price et al., 2015, PNAS 112:5554) ‘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’ 13

Pan-Sensitive Salmonella Isolates in the USA NARMS, (courtesy of Craig Hedberg) Increase in pansusceptible isolates in humans No marked change in pigs or other animals

Multidrug Resistance Among Salmonella Isolates NARMS, (courtesy of Craig Hedberg) Decrease in MDR Salmonella isolates in humans No marked change in pigs or other animals

Percent Positive Salmonella Tests in the PR/HACCP Verification Testing Program 1994 Baseline vs USDA-FSIS

Relative rates by year (compared with 1996—1998) of lab-confirmed infections with Campylobacter, STEC O157, Listeria, Salmonella, and Vibrio by year ( Foodborne Diseases Active Surveillance Network, United States, 1996—2011) ~20-30% reduction in Listeria, Campylobacter ~ 50% reduction in Yersinia ~ 0% change in Salmonella

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? 18

19 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

20 Holland – an issue emerges! Very low MRSA prevalence Intensive screening and typing with sma1 PFGE ‘Search and destroy’ policy – isolation/decolonization 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

21 ST398 (livestock associated) MRSA Generally 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. ~ % in population) Mainly LA-MRSA Long term persistence can occur in some people Secondary transmission to family members Clinical infections can occur – some severe

Diversity of MRSA in pigs globally 22 ST398 t011, t108 t034, t567… >30 spa types ST5 t002 ST9 t899 t337 Not all ‘livestock associated’ MRSA are ST398

23 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

24 Growth promotants as the culprit? MRSA cases in Denmark (all types) Ban of AGP In finishers Ban of AGP in nurseries MRSA ST398 Detected in NL DANMAP 2010 MRSA ST398 Detected in DK

25 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)

Summary of MRSA/MSSA in pigs in USA 26

Changes and expectations Outcomes of EU changes FDA guidances 209/213 What might we expect How do we measure it? 27

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

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

Aggregate antimicrobial use in Danish swine industry Lowest use was in 1999 before weaned pig ban Replacement of AGP with therapeutic use Avoparcin ban and ban on vet sales AGP ban F N

AMR in Salmonella in pigs DANMAP 2004/2012

32

Timeline of EU/Dutch events (Speksnijder et al, 2015) 33 Goals to reduce AMU are arbitrary and not linked to measurable public health outcomes

AMU per kg biomass of pig meat, poultry meat and cattle meat produced in 10 EU countries (2005 data) 34

Gross sales of veterinary antimicrobials in the Netherlands (Speksnijder et al, 2015) 35 Reduced AMU is the goal!

Expectations for ‘success’ post 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? 36

Residue violations in market hogs Unheralded success! 1978: violative residues (USDA) 5.6% for antibiotics 9.7% for sulfonamides 2011: Sulfonamides No violative sulfonamide residues in 204 tests : Antibiotics No violative antibiotic residues in 1,199 market hogs 2011: 1 in 11,509 ‘inspector generated’ tests (FAST)

38 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

39 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

40 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

Belgium AMCRA 2020 Vision Statement AMCRA 2020 Vision Statement 1. 50% lower antibiotic use by % lower use of critical antibiotics by % lower use of medicated feed by A global data collection system by A plan for each farm

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

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.”

“All complex problems have a simple and straightforward explanation…. 44 Dr. Jim McKean …and it is wrong!”

Questions? Peter Davies BVSc, PhD College of Veterinary Medicine University of Minnesota Beliefs Opinions Evidence Actions Outcomes Expectations