Challenges of Integrating Policy into Antibiotic ...

Challenges of Integrating Policy into Antibiotic Resistance

Mitigation Efforts

Randall Singer, DVM, MPVM, PhDProfessor of Epidemiology

Department of Veterinary and Biomedical Sciences

Concept of One Health

Berkner et al., EMBO Reports, 2014

• Are policies aimed at reducing antibiotic use effective at reducing antimicrobial resistance?

• How do we incentivize strategies that combat AMR?

• Is raising animals without antibiotics (RWA) the solution?

Overview

Classification of Antibiotics• Non-Medically Important Antibiotics

– Those antibiotic classes NOT used in human medicine

• Medically Important Antibiotics

– Those antibiotic classes used in human medicine

• Critically Important Antibiotics (WHO)

– Those antibiotic classes used in human medicine and meet the two criteria:

• The antimicrobial class is the sole, or one of limited available therapies, to treat serious bacterial infections in people

• The antimicrobial class is used to treat infections in people caused by either (1) bacteria that may be transmitted to humans from non-human sources or (2) bacteria that may acquire resistance genes from non-human sources

WHO Antibiotic Classification

https://www.who.int/foodsafety/publications/antimicrobials-sixth/en/


WHO Antibiotic Classification



https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cvm-gfi-152-evaluating-

safety-antimicrobial-new-animal-drugs-regard-their-microbiological-effects

FDA Antibiotic Classification

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cvm-gfi-152-evaluating-safety-antimicrobial-new-animal-drugs-regard-their-microbiological-effects

Summary of Antibiotic Classification

• Globally, there are lists from WHO and some at the national/regional level

• It is difficult to have consistency among these lists because the national/regional lists are based on antibiotics actually used within those areas

• National/regional lists can influence commerce (import and export) of animals and animal products if there are conflicts among the lists

Antibiotic Approvals in U.S.• Growth promotion / feed efficiency

– Use of antimicrobial substances to increase the rate of weight gain and/or the efficiency of feed utilization

• Disease prevention

– Use of an antimicrobial(s) in healthy animals considered to be at risk of infection

• Disease control

– Use of an antimicrobial(s) in animals exposed to an infectious disease or illness

• Disease treatment

– Use of an antimicrobial(s) for the specific purpose of treating an animal(s) with a clinically diagnosed infectious disease or illness

http://who.int/foodsafety/publications/cia_guidelines/en/

• Very difficult to evaluate the analysis conducted by WHO and collaborators

• WHO says that low quality evidence is due to lack of studies evaluating antibiotic use in controlled trials

– Completely untrue. There are many studies available

• 36 total studies, at least 4 are conference posters or PhD dissertations

• Only 1 study evaluated the effect of an antibiotic on animals; the rest compared organic to conventional

– Most of the studies took samples in the supermarket with no evidence that antibiotics were even used in the animals

Antibiotic Regulation

• In 2013, FDA published Guidance for Industry (GFI) #213

– Defines “medically important”

– Voluntarily removes claims relating to production uses (growth promotion / feed efficiency)

– Brings remaining therapeutic uses under veterinary oversight by changing marketing status from over-the-counter (OTC) to veterinary feed directive (VFD) or prescription (Rx)

• Fully enacted by January 2017

Antibiotic Regulation

• Veterinary Feed Directive (VFD) Regulation

– Requirements relating to distribution and use of VFD drugs (feed-use drugs that require supervision of licensed veterinarian)

– Updated regulations went into effect October 2015

– Critical step for facilitating transition to veterinary oversight

• Illegal to use feed-grade antibiotics off-label

– Manufacturers voluntarily removed the growth promotion / feed efficiency label for the medically important antibiotics

• European Parliament voted 583 to 16 on October 25, 2018 to outlaw routine use of antibiotics in animal agriculture by 2022

– Statement made that this legislation would ban the use of medicines to improve animal performance or to make up for poor farming practices

• Blanket dry cow therapy would be banned

– Already banned in some EU countries

European Union Legislation

• Acquired

– Mutation

• Fluoroquinolone resistance

– Gene acquisition

• Plasmids with gene for third-generation cephalosporin resistance

• Multi-drug resistance

The Nature of Resistance

PLoS ONE, 2012; Nature, 2011, PLoS ONE, 2015

Is Resistance New?

Antimicrobial Use and Resistance

http://deansalamone.com

Multidrug Resistance Plasmids

Call et al., Antimicrob. Agents Chemother., 2010

Effect of Dose and Density of Treatment

0

1

2

3

4

5

6

-6 -4 -2 0 2 4 6 8 10

Day

Lo

g c

fu/g

Treat

No Treat

1/5 7%

2/5 100%

1/5 100%

Singer et al., Appl Environ Microbiol, 2008

Collignon et al., Lancet Planet Health, 2018

Global AMR

Collignon et al., Lancet Planet Health, 2018

Global AMR

“Reduction of antibiotic consumption will not be sufficient to control antimicrobial resistance because contagion-the spread of resistant strains and resistance genes-seems to be the dominant contributing factor. Improving sanitation, increasing access to clean water, and ensuring good governance, as well as increasing public health-care expenditure and better regulating the private health sector are all necessary to reduce global antimicrobial resistance.”

Total Mortality in Broilers

Source: AgriStats

Courtesy of Dr. Matthew Salois

0%

5%

10%

15%

20% Historical Mortality

RWA Uptick

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

Jan

-09

Nov-0

9

Sep

-10

Ju

l-11

May-1

2

Mar-

13

Jan

-14

Nov-1

4

Sep

-15

Ju

l-16

May-1

7

Perc

en

t (%

)

Ten-Year Mortality Trend

RWA Uptick

Mortality in Broilers Raised without Antibiotics

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

Percent of Broilers RWA

2.0%

2.5%

3.0%

3.5%

4.0%

4.5%

5.0%

5.5%

6.0%

2013 2014 2015 2016 2017

Average Monthly Mortality

RWA CNV NMI

Raised Without Antibiotics (RWA); Non-Medically

Important (NMI); Conventional (CNV)Source: AgriStats


Impact of 100% RWA production

Source: Salois et al., 2016


More Birds Needed

to Meet Demand

680 and 880 million

more birds

RWA

Mortality

~24-52%

Grow-out Time

~3-4%

Bird Density

~5-12%

Cycle Downtime

~21-29%




5.4 to 7.2 million more tons of feed per year(Roughly equal to rail cars filled with grain that span 655 to 873 miles)




3.9 to 5.2 thousand more square miles of land to

grow the feed(About 10x the size of Los Angeles)




1.9 to 3.0 billion more gallons of water consumed

by the birds per year(About the water consumed annually by 3,400-5,400 families of four in the U.S.)




4.6 to 6.1 million more tons of manure per year(Approximately equal to the amount of sewage produced by the people in

Texas annually)

• Ensuring the safety, health, and overall well-being of animals raised for food is an ethical obligation

• Changes have been made to antibiotic use in animal agriculture

– Many producers, especially in poultry, have eliminated much of their antibiotic use

– Shift to raising animals without antibiotics (RWA)

• Demand for RWA products is growing in the U.S. but there are concerns that RWA claims and associated practices are negatively affecting animal health and welfare

Animal Health and Welfare

• Survey veterinarians and producers in animal agriculture about their experiences and opinions of raising animals without antibiotics (RWA)

• The survey was designed in Qualtrics and was announced and disseminated through professional organizations and commodity groups

• The survey was open from February 15 through March 23, 2018

• Data were analyzed in Qualtrics, Stata and Excel

Survey of Impacts of RWA Production

Total Broiler Turkey Swine Beef Dairy

Role 565 69 23 148 244 81

Practicing Veterinarian 43.9% 31.9% 52.2% 37.6% 43.4% 64.2%

Producer/Grower/Owner 37.9% 26.1% 26.1% 47.3% 44.3% 14.8%

Country of Experience

United States 95.2% 86.8% 95.8% 96.0% 97.5% 92.6%

International 4.8% 13.2% 4.2% 4.1% 2.5% 7.4%

Experience with RWA

Current Experience 42.7% 63.8% 95.7% 33.8% 36.1% 45.7%

Previous Experience 13.5% 2.9% - 20.3% 13.5% 13.6%

No Experience 43.9% 33.3% 4.4% 46.0% 50.4% 40.7%

Characteristics of Participants

Factors Contributing to Decision to Raise Animals RWA or Conventionally

Broiler Turkey Swine Beef Dairy

RWA Respondents 19 17 59 97 36

To decrease antibiotic resistance 26.3% 5.9% 8.5% 21.6% 2.8%To improve animal health and welfare 26.3% 5.9% 10.2% 17.5% 8.3%To increase sale price of animals/product 42.1% 41.2% 62.7% 41.2% 11.1%To gain market entry into a retail program 36.8% 58.8% 37.3% 27.8% 8.3%To fulfill a client/customer request 84.2% 82.4% 69.5% 62.9% 77.8%To eliminate the use of medically

important antibiotics10.5% 0.0% 5.1% 11.3% 5.6%

Conventional Respondents 15 1 63 110 25

Not profitable 33.3% - 27.0% 22.7% 8.0%Concerned about negative impacts to

animal health and welfare 93.3% - 76.2% 68.2% 68.0%

No market pressure 20.0% - 31.7% 26.4% 24.0%Not a sustainable consumer trend 40.0% - 25.4% 13.6% 8.0%Food safety concerns 13.3% - 30.2% 8.2% 24.0%Already raising animals in a responsible

use program 60.0% - 71.4% 57.3% 68.0%

Health & Welfare – What Respondent Believes

How do you think raised without antibiotics production impacts animal health and welfare?

Health & Welfare – Perception of Customer Beliefs

In your opinion, how do retailers/restaurants/food services think raised without antibiotics production

impacts animal health and welfare?

RWA Impacts on Cost

RWA Impacts on Demand

“There are times that maintaining an RWA label has priority over flock/herd health and welfare”

Antimicrobial Stewardship (CDFA)

Used with permission of Dr. Karen Hoelzer, Pew Charitable Trusts

1. Commitment to Partnership

• Collaboration between veterinarians and livestock owners / animal caretakers

2. Animal Health and Disease Prevention

• Comprehensive program that promotes health, reduces need for antibiotics & economic losses

3. Judicious Use of Antimicrobials

• Careful assessment of the need for antibiotics & the availability of non-antibiotic alternatives

4. Record, Reevaluate, and Report

• Record-keeping system that provides complete picture of on-farm animal health management

5. Expertise in Antimicrobial Stewardship

• Maintaining necessary experience & training to ensure judicious antimicrobial use

Source: https://www.cdfa.ca.gov/ahfss/AUS/Stewardship.html

Antibiotic Excretion Model

Cow

Body weight

Antibiotic

Feces Urine Milk

CalvesMilk WH

Feces Urine

• Ceftiofur Crystalline Free Acid (CCFA)

– No milk withholding

• Amoxicillin

– Milk 60 hr withholding

• Oxytetracycline

– Milk 5 day withholding

• Penicillin plus Streptomycin

– Milk 60 hr withholding

Exposure Assessment

Antibiotic ExcretionCCFA Oxytetracycline

Ingestion and Subsequent Excretion

Oxytetracycline

Antibiotic Excretion

Antibiotic DoseCowFeces

Cow Urine

Calf Feces

Calf Urine

% of Original

Dose

CCFA 4950 47.5 1936.6 N/A N/A 40.1 %

Oxytetracycline 37500 8023.8 29293.4 176.2 7.7 100.0 %

Amoxicillin 26250 7601.9 17718.9 348.1 512.4 99.7 %

Penicillin –Streptomycin

18000 1173.3 12881.2 2.9 4.3 78.1 %

Penicillin –Streptomycin

22500 278.2 17916.4 15.8 3.9 81.0 %

• Few data available concerning concentration of compound in each compartment

• Older compounds have very sparse data

• Dairy example highlights dilemma of discarding waste milk or feeding it to the calves

Excretion Data Gaps and Concerns

• Environmental concerns and waste management will continue to be key issues

• Residues will decrease with time in the environment, but the rate of decay will vary with many factors

• Biological activity in environment remains highly uncertain

• Excretion data from animals is lacking

Take Home Messages

• Antimicrobial resistance has been around for eons

• Our use of antibiotics (and other compounds) has increased the frequency, diversity, and global distribution of these resistance mechanisms

Take Home Messages

• Reducing antibiotic use may slow the development and spread of some resistances in some bacteria but will not stop the constant “emergence” of resistances important to human health

• Responsible use of antibiotics includes an understanding of the resistances that will be exposed to the antibiotic

• Policies being developed at local, national and international levels to reduce AMR are often based on assumptions of what will work rather than actual scientific evidence of effectiveness

Take Home Messages

• Across all surveyed commodities, the main reason for going RWA was market-driven: “to fulfill a client/customer request”

• Huge discrepancy between what the Respondent believes and the perception of what the Customer / Retailer believes

• Many respondents felt that there are times when the RWA label takes priority over animal health and welfare

Take Home Messages

• Antibiotics available for use in animal agriculture are diminishing rapidly

– Stewardship and responsible use

– Customer demand and pressure

– Legislation and regulation

• Disease prevention with non-antibiotic approaches is critical

– Husbandry and herd/flock management

– Vaccination, prebiotic/probiotic, other novel directions

• Need to think about entire production system and stop focusing on one aspect of health management

– Sustainability is more than just antibiotic use

Take Home Messages

• Reduced use should not be the primary goal

– Reduction can be a part of a stewardship

– May be years when antimicrobial use increases due to increases in disease incidence that necessitates increased therapy

• Reducing the need for antimicrobials should be considered a more important goal

– Some of the most important diseases have imperfect interventions

Take Home Messages

Acknowledgments• Dr. Kathe Bjork

• Dr. Shabbir Simjee

• Dr. Dan Thomson

• Dr. Mike Apley

• Leah Porter

• Dr. Matt Salois

• Dr. Jennifer Wishnie

http://www.pork.org/Environment/default.asp

Challenges of Integrating Policy into Antibiotic ...

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