Antibiotics

Peter Davies BVSc, PhDCollege of Veterinary Medicine

University of Minnesota

BeliefsOpinionsEvidence

ActionsOutcomesExpectations

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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

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!

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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……..

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FDA approves antibiotic labels for four purposes in animals

Disease treatment Disease control Disease prevention Growth promotion

Therapeutic UseCODEX, AVMA, FDA

FDA guidance 213 to remove AGPapprovals 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

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.

8http://www.medscape.com/viewarticle/844241

Food animal populations and infectious agents – pathways

Food animal Populations

Host specificorganisms

Foodborne exposures

Multihostorganisms

Wildlife

DomesticAnimals

ANIMAL RESERVOIRS

HUMAN RISK

Occupational(direct)

exposures

Environmentalexposures

Humans

Antibiotic resistance threats in the USA

(CDC, Am Fam Physician. 2014 Jun 15;89(12):938-941.)

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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

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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. 2014 Jun 15;89(12):938-941.)

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 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’

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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

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

Percent Positive Salmonella Tests in the PR/HACCP Verification Testing

Program 1994 Baseline vs. 2011 USDA-FSIS

1994

2011

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?

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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/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

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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. ~ 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

Diversity of MRSA in pigs globally

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ST398t011, t108

t034, t567… >30 spa

typesST5t002

ST9t899t337

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)

Ban of AGP In finishers

Ban of AGP in nurseries

MRSA ST398 Detected in NL

DANMAP 2010

MRSA ST398 Detected in DK

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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)

Summary of MRSA/MSSA in pigs in USA

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Type Year Pig Source (age) State # of farms

Pig level prevalence, % (n)

Spa types (or sequence

type)

MLST

Commercial 2009 FTF IA, IL 2 (1*) MRSA 49% (147/299)

N/A ST398

2011 Various CT 35 (5) MRSA 3% (8/259)

t008, t007, t011 ST8, ST398

MSSA 30% (85/259) t337, t034, t334, t4529 t8760, t1166

2012 Market age IA 10 (3) MRSA 18% (34/194) t002, t034, t548 ST398, ST5

2012 Market age OH 10 (3) MRSA 3% (7/240) t034, t337 ST398, ST9

2013 6 and 18 weeks IL(+) IA(+) MN, NC,

OH

45(4*) MRSA 5% (50/1085) t034, t002, t337, t571 t3446, t002

ST398, ST5 ST9

2015 FTF MN 2 (0) MSSA 91.1% (175/192) t034, t337, t7331, t2462, t3446, t001, t571, t1255, t526

ST398, ST5, ST9

2015 Nursery, finishing 11 states 36 (0) MRSA

MSSA

0/739

558/739

-

17 spa types

-

ST398, ST9, ST5

Total 140 (16) MRSA 8.7% (246/2816)

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

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 banF N

AMR in Salmonella in pigs DANMAP 2004/2012

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Timeline of EU/Dutch events(Speksnijder et al, 2015)

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Goals to reduce AMU are arbitrary and notlinked to measurable public health outcomes

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)

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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?

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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

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

BelgiumAMCRA 2020 Vision Statement

AMCRA 2020 Vision Statement1. 50% lower antibiotic use by 20202. 75% lower use of critical antibiotics by 20203. 50% lower use of medicated feed by 20174. A global data collection system by 20165. 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….

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Dr. Jim McKean

…and it is wrong!”

Questions?

Peter Davies BVSc, PhDCollege of Veterinary Medicine

University of Minnesota

BeliefsOpinionsEvidence

ActionsOutcomesExpectations