Antibiotic Stewardship in Veterinary Medicine and

Production Animal Agriculture

Mike ApleyKansas State University

Defining Resistance

• Susceptibility or resistance testing?

• Clinical resistance?

• Epidemiological cutoffs?

– “Wildtype vs. Non-wildtype”

Antimicrobial Timeline

1910 – Arsphenamine (Salvarsan) – 1912 Neosalvarsan

1949 - Chloramphenicol

1949 – Neomycin - aminoglycosides1948 - Chlortetracycline

1955– Vancomycin - glycopeptides

1959 – Virginiamycin - streptogramins

Commercial availability for first member of major antimicrobial groups

1952 – Erythromycin - macrolides

1960 – Metronidazole

1968 - Clindamycin -lincosamides

1970 – Cefalexin - cephalosporins

1978 - Norfloxacin - fluoroquinolones

2000 - Linezolid - oxazolidinones

2003 - Daptomycin – cyclic lipopeptides

1935 – Prontosil(sulfanilamide)

1942 - Benzylpenicillin

The Basics of Clinical Pharmacology (in one slide)

• Can I do some good?

• Can I do any harm?

• Can I get it in the animal(s)?

• What is the cost?

Rice LB. Mechanisms of resistance and clinical relevance of resistance to beta-lactams, glycopeptides, and fluoroquinolones. Mayo Clinic Proceedings, 97:198-208, 2012.

Yearly sales data are available…

• These are the most recent data for veterinary sales with a food animal indication.

Resistance Challenges in Human and Veterinary Medicine

Resistance Challenges in Vet Medicine

• Weese has published an excellent review of antimicrobial resistance issues in companion animals (2008). The primary organisms addressed in this review are as follows.

– Staphylococcus aureus and Staphylococcus pseudintermedius: both methicillin susceptible and resistant.

– Enterococci: Enterocococcus faecium and Entercoccus faecalis.– Streptococci: Strep. zooepidemicus and Strep. Equi in horses,

Strep. canis– Escherichia coli– Salmonella– Pseudomonas

Animal Health Research Reviews. 9(2):169-176, 2008.

Mannheimia haemolytica

Mannheimia haemolytica

2008

2010

2012

2014

2016

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

≤0.25 0.5 1 2 4 8 >8

Ceftiofur

Mannheimia haemolytica

20082009

20102011

20122013

20142015

2016

0%

10%

20%

30%

40%

50%

60%

70%

80%

≤0.12 0.25 0.5 1 2 >2

Enrofloxacin

Mannheimia haemolytica

2008

2010

2012

2014

2016

0%

10%

20%

30%

40%

50%

60%

70%

≤0.25 0.5 1 2 4 8 >8

Florfenicol

Mannheimia haemolytica

20082009

20102011

20122013

20142015

2016

0%

10%

20%

30%

40%

50%

60%

70%

80%

≤0.5 1 2 4 8 >8

Oxytetracycline

2008

2010

2012

2014

2016

0%

10%

20%

30%

40%

50%

60%

≤0.12 0.25 0.5 1 2 4 8 >8

Penicillin

Mannheimia haemolytica

Mannheimia haemolytica

20082009

20102011

20122013

20142015

2016

0%

10%

20%

30%

40%

50%

60%

70%

≤8 16 32 64 >64

Spectinomycin

Mannheimia haemolytica

20082009

20102011

20122013

20142015

2016

0%

10%

20%

30%

40%

50%

60%

70%

≤4 8 16 32 64 >64

Tilmicosin

Mannheimia haemolytica

2008

2010

2012

2014

2016

0%

10%

20%

30%

40%

50%

60%

70%

≤1 2 4 8 16 32 64 >64

Tulathromycin

tilm

ico

sin

>64 1 27 94 15 693

64 5 8 3 6 99

32 8 4 1 3 4 53

16 46 44 5 1 1 16

8 2 62 34 1 1 2

≤4 8 71 204 26 2

≤1 2 4 8 16 32 64 >64

tulathromycin

Mannheimia haemolytica (n=1550 isolates)

83% - S/S or I/I or R/R3.6% - S/R mismatch

Macrolide agreement

• Reasons for discrepancies:

– Macrolide resistance in veterinary medicine

• erm(42) – tilmicosin, tildipirosin

• msr(E)-mph(E) – gamithromycin, tulathromycin

– Michael GB et al. 2012. Increased MICs of gamithromycin and tildipirosin in the

presence of the genes erm(42) and msr(E)-mph(E) for bovine Pasteurella

multocida and Mannheimia haemolytica. J Antimicrob Chemother.

• Both genes present on Mh1 and Pmu1 ICE

Mannheimia haemolytica MDR

2008

2010

2012

2014

2016

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

0 1 2 3 4 5 6 7

Why MDR Mannheimia haemolytica?

Tetracycline resistance

Tetracycline resistance

Aminoglycoside / spectinomycin

resistance

Tilmicosin / gamithromycin /

tulathromycinresistance

Ampicillin resistance

Aminoglycoside resistance

Streptomycin resistance

Sulfonamide resistance

Phenicolresistance

Tilmicosin / tildipirosin resistance

From: Michael, 2012 & Michael, 2012b

Individual Susceptibility Data

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

2009 2010 2011 2012 2013

Pe

rce

nt

of

Iso

late

s -

Susc

ep

tib

le

Oxytetracycline

Tilmicosin

Enrofloxacin

Spectinomycin

Ceftiofur

Florfenicol

0%

10%

20%

30%

40%

50%

60%

0 1 2 3 4 5 6

Pe

rce

nt

of

Iso

late

s fo

r G

ive

n Y

ear

Number of Resistant Interpretations per Individual Isolate

2009 (55)

2010 (155)

2011 (179)

2012 (160)

2013 (240)

Pan-Susceptible

Multidrug Resistant

Threat level of URGENT

Clostridum difficile

Carbapenem-resistant Enterobacteriaceae

Drug-resistant Neisseria gonorrhoeae

Threat level of Serious Multidrug-resistant Acinetobacter

Drug-resistant Campylobacter

Fluconazole-resistant Candida

Extended spectrum -lactamase Enterobacteriaceae (ESBLs)

Vancomycin-resistant Enterococcus (VRE)

Multidrug-resistant Pseudomonas aeruginosa

Drug-resistant non-typhoidal Salmonella

Drug-resistant Salmonella typhi

Drug-resistant Shigella

Methicillin-resistant Staphylococcus aureus (MRSA)

Drug-resistant Streptococcus pneumoniae

Drug-resistant tuberculosis

Threat level of Concerning

Vancomycin-resistant Staphylococcus aureus (VRSA)

Erythromycin-resistant Group A Streptococcus

Clindamycin-resistant Group B Streptococcus

Antimicrobial stewardship refers to coordinated interventions designed to improve and measure the appropriate use of antimicrobials by promoting the selection of the optimal antimicrobial drug regimen, dose, duration of therapy, and route of administration.

Antimicrobial stewards seek to achieve optimal clinical outcomes related to antimicrobial use, minimize toxicity and other adverse events, reduce the costs of health care for infections, and limit the selection for antimicrobial resistant strains.

Infectious Disease Society of America

What is “Stewardship”?

2. Is there a non-antibiotic alternative which will appropriately prevent, control, or treat this disease challenge?

3. Selection of an antibiotic which has been demonstrated to be safe and effective for this purpose

4. Assuring use of the antibiotic as shown to be safe and effective

Yes…

1. Responsibility for appropriate diagnostics and establishment of an accurate and functional case definition

5. Is this antibiotic intervention still necessary?

While…

Current Guideline Examples

•AVMA Committee on Antimicrobials• Antimicrobial Stewardship for Veterinarians Defined

(policy adopted by the AVMA, 2018)• Includes core principles of antimicrobial stewardship in veterinary

medicine

• https://www.avma.org/KB/Policies/Pages/Antimicrobial-Stewardship-for-Veterinarians-Defined.aspx

• This is the start of the committee’s work.

AVMA Antimicrobial Stewardship Definition

Antimicrobial stewardship refers to the actions veterinarians take individually and as a profession to preserve the effectiveness and availability of antimicrobial drugs through conscientious oversight and responsible medical decision-making while safeguarding animal, public, and environmental health.

AVMA Antimicrobial Stewardship Definition

• Antimicrobial stewardship involves maintaining animal health and welfare by…

• implementing a variety of preventive and management strategies to prevent common diseases;

• using an evidence-based approach in making decisions to use antimicrobial drugs;

• and then using antimicrobials judiciously, sparingly, and with continual evaluation of the outcomes of therapy, respecting the client’s available resources.

Current Guideline Examples

• AVMA Task Force on Antimicrobial Use in Companion Animal Practice • https://www.avma.org/KB/Resources/Reference/Pages/Guidance-

for-Antimicrobial-Use-in-Companion-Animal-Practice.aspx

• American Association of Equine Practitioners guidelines

• American Association of Feline Practitioners/American Animal Hospital Association guidelines

• AVMA Judicious Therapeutic Use of Antimicrobials• With links to species-specific documents

• https://www.avma.org/KB/Policies/Pages/Judicious-Therapeutic-Use-of-Antimicrobials.aspx

Current Guideline Examples

• American Association of Bovine Practitioners

• Implementing Antibiotic Stewardship Plans

• Drug Use Guidelines for Bovine Practice

• Prudent Antimicrobial Use Guidelines

• http://www.aabp.org/about/AABP_Guidelines.asp

• American Association of Swine Veterinarians

• AASV Judicious Use Guidelines• https://www.aasv.org/aasv%20website/Resources/Antimicrobial%20Use/Antimicrobi

alUse.php

• Take Care - Use Antibiotics Responsibly brochure for producers (from Pork Checkoff Services Center.• http://porkcdn.s3.amazonaws.com/sites/all/files/documents/Anitbiotics/TAKECAREa

ntibioticFAQ.pdf

• American Association of Avian Pathologists

• AAAP-AVMA Guidelines for Judicious Therapeutic Use of Antimicrobials in Poultry

• https://aaap.memberclicks.net/assets/Positions/aaap.pdf

Food Animal Producer Organizations

•Policies, educational programs

•National Cattlemen’s Beef Association• Antibiotics Resource Center• http://www.beefusa.org/antibioticsresourcecenter.aspx

•National Dairy FARM Program• http://www.nationaldairyfarm.com/

•Pork Quality Assurance Plus• https://www.pork.org/certifications/pork-quality-

assurance-plus/

Challenges

•Moving from guidelines to implementation•Education•Research•Incentives•Resource availability and conservation•Monitoring with feedback loops

Total Use = Effective Use + Ineffective Use

The Ultimate Antibiotic Failure

= Bacterial Population Exposure Without Achieving the Desired Effect

Antibiotic

Resistance

Selection

= Antibiotic

Exposure +Exposed

Bacterial

Population

Equations

Water

Land

Fuel

Labor

$$$$

Technology

Feed

Base Livestock Production

Efficiency

Welfare

Food

Environment

Human Health?

Antibiotics

AnimalDisease

Outcome

DiseasePathogen

Location

Antimicrobials

Anti-inflammatory?

diffusionpHions

proteinsbiofilms

susceptibility

virulence

inoculum

age

other

disease

genetics

Therapy

total vs.

free?

pharmacokineticsregimen

pharmacodynamics

Physiological state

Husbandry

Immunity

diagnostics

case definition

Progression

nutrition

environment

stress

biosecurity

body

temperature

hydration

acid/base

production

level

Water

Land

Fuel

Labor

$$$$

Technology

Feed

Base Livestock Production

Efficiency

Welfare

Food

Environment

Human Health?

Antibiotics

Capturing Use Data

Granular

Coupled to cause

Accurate

Current Significant lag

Not coupled to cause

Approximate

Aggregate

What we would like… We would really rather not…

Easy Resource intensive

Enables benchmarking Unable to benchmark

Capturing Use Data

Granular

Coupled to cause

Accurate

Current Historical

Not coupled to cause

Approximate

Aggregate

Reality…

Easy Resource intensive

Enables benchmarking Unable to benchmark

Utility for individual production unit benchmarking

Ease of collection

Use by cause

Production unit

Tradeoffs

Sales Data

Population Estimates

DDD

DCD

Numerators

Drug Amount Exposures Duration

Denominators

Population Production

Disease Incidence?

No Records

Sophisticated Electronic Systems

Grams of drug Individual animal treatment records

Sales to production unit being measured Entire unit

Specific animal groups moving through the unit

Group level Feed consumption and inclusion rate

Target inclusion rate

Supplement used and inclusion rate of supplement

Micromachine records

Water consumption and inclusion rate or amount administered through water

Animals exposed (regimens)• Individual animal or group records

• Grams of drug used extrapolated by using Defined

Course Dose (DCD)

Protocol defined regimens for extrapolating average

course administration (grams)

If all animals receive a drug, then simple, it is the number

of animals in the system during the observed time period.

DCD accuracy declines as spread over more varying

administrations in different systems. (e.g., multiple

regimens and varying weights of animals at times of

administration)

Duration of exposure• Relatively straight forward for In-feed or in-water drugs where duration of exposure

equals regimen duration

Drugs administered daily (e.g., injection, intramammary tubes, oral medications

Individual animal records or group records may be used, or

Extrapolation from grams of drug based on DDD

• Breaks down for… Single administration antibiotics

2. Is there a non-antibiotic

alternative which will appropriately

prevent, control, or treat this

disease challenge?

3. Selection of an antibiotic

which has been demonstrated

to be safe and effective for

this purpose

4. Assuring use of the

antibiotic as shown to

be safe and effective

Yes…

1. Responsibility for appropriate

diagnostics and establishment of an

accurate and functional case definition

5. Is this antibiotic

intervention still

necessary?

While…

Antibiotic Stewardship