Where are we with resistance in veterinary medicine?

Are we having an effect on human medicine?

Mike ApleyKansas State University

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 - oxazolidinones2003 - 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?

First, what are we using in food animals?

Oral and FEED neomycin

INJ and IMM ceftiofur, IMM cephapirin

FEED monensin, lasaslocid

IMM pirlimycin

ORAL (administered individually), IMM (intramammary), INJ (injected individually), FEED (administered through feed to groups), WATER (administered in water to groups

INJ tilmicosin, tildipirosin,tulathromycin, gamithromycin, tylosin, FEED tylosin and tilmicosin

INJ and IMM penicillin G, ampicillin

INJ , WATER, and FEED labels

INJ , WATER, and FEED labels

INJ florfenicol, fluoroquinolones, FEED virginiamycin

Cattle Approvals

2 Includes antimicrobial drug products which are approved and labeled for use in multiple species, including both food- and nonfood-producing animals, such as dogs and horses.

42%

29%

These antimicrobials are not on the list of “medically important” as defined by the FDA/CVM in Guidance 152

Apley M, Bush E, Morrison B, Singer R, Snelson H. Use estimates of in-feed antimicrobials inswine production in the U.S. Journal of Foodborne Pathogens and Disease, 9, 2012.

533,973

165,803

154,956

15% 39% 46%

64% of medically important use

66% of medically important P and T

Are we having an effect on human medicine?

• For me, I accept that antimicrobial use in food animals can change bacterial population susceptibility profiles, and that this can lead to resistant pathogens and other microbiota which may then be transferred through the food chain or directly transferred to people, and…

• I also accept that there a multiple safe uses of antimicrobials in food animals, which have benefits that outweigh any risks.

The responsible conversation which will move us forward involves discussion of specific antimicrobial uses in relation

to specific pathogens and epidemiological links

Organisms of specific interest to me

• Salmonella• Campylobacter• Staphylococcus aureus• Bacteria of animal origin found on food

products

My Concern

• I don’t want us enact policy in the name of human health which results in harm to food animal health but with no benefit, or possibly a detrimental result, to human health.

The Thought ProcessBacterial populations exposed to antimicrobials on farm

Selection for resistant organisms on farm

Increased incidence of resistant organisms on farm

Transfer through the food chain or direct transfer

Presence of food animal derived resistant bacteria in a human

Contribution of food animal derived resistant bacteria to human disease

Treatment failure or prolonged disease course due to pathogen resistance

Release

Exposure

Consequence

Risk

MarketBirth

Risk for foodborne effects?

Timing of Antimicrobial Use

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.

What about food animals?

• Bovine respiratory disease– Mannheimia haemolytica and Pasteurella

multocida

Where do these come from?

We can’t conclude anything

from D-lab trends!

My Definition of Judicious Use

• There is not an effective alternative to the antimicrobial for treatment or prevention of disease.– Use of an antimicrobial for therapy or control

should not be the permanent solution for an infectious disease challenge

My Definition of Judicious Use

• There is evidence that the antimicrobial will be safe and effective for this use– What is the expected outcome for an

antimicrobial?– Is a 30 year old infectious disease therapy or

prevention claim still valid today?

0 1 2 3 4 5 6 70

5

10

15

20

25

30

35

40

45

Masti-tis

Footrot

Pinkeye RespiratorySuccess

RespiratoryMortality

RespiratoryMorbidity

7

Number Needed to Treat by Disease

5

30(9) 1-8

21(7) 2-40

10(7) 2-30

9(5) 2-8

11(5) 1-3

4(2)3-6

# studies (# drugs)NNT Range

5

23

2

My Definition of Judicious Use

• There is a commitment to administering the antimicrobial according to the regimen demonstrated to be safe and effective for this use.– We are severely lacking in information needed to

optimize…• duration of therapy, and…• optimal pharmacodynamics for suppression of

resistance development for many of our antimicrobial classes

My Definition of Judicious Use

• There is a constant search for alternative management practices which would alleviate the need for the antimicrobial– This requires a partnership between a veterinarian

and a producer

Control of Veterinary Antimicrobials…

• should be in the hands of veterinarians, and…• training and information availability must be

improved for veterinarians across all food animal practice types– Knowledge of antimicrobial clinical pharmacology

varies greatly across the profession– Knowledge of regulations and commitment to

following them varies across the profession

Training

• Veterinary school is a good for training to start• Post-graduate training is imperative• What is most essential is an intolerance of

inappropriate activities by veterinary and producer organizations

Antimicrobial Use Statistics

• The Danish model?• Reporting burden?• What are we worried about?

Getting “policied”

• Cephalosporin ELDU prohibition in food animals– Retains the ability to use cephalosporins for

extralabel indications in food animals but prohibits regimen adjustment for the ELDU

– Also prohibits regimens which decrease overall exposure of food animals to cephalosporins

• e.g., regional intravenous limb perfusion

Direct quote

• Cephalosporin order of ELDU prohibition• “However, the Agency believes that it is not

limited to making risk determinations based solely on documented scientific information, but may use other suitable information as appropriate.’’

• We talk about benefit vs. risk, but we are regulated only on risk.

Immediate Gains

• Win/Win strategies– Are we getting benefits from all of our current

uses?– Are dosing regimens optimized for our current

uses?– How do we get optimal use information to

veterinarians in the field?– What decision making tools can we put in the

hands of veterinarians?

The Bottom Line for Veterinarians

• Will we retain our relevancy to antimicrobial use decisions in food animals, or…

• will we just sign authorizations based on a regulatory formulary developed out of political pressure exerted on regulatory agencies?

Definitions

• Complacent: marked by self-satisfaction especially when accompanied by unawareness of actual dangers or deficiencies

• Complicit: An individual is complicit in an illegal activity if he/she is aware of its occurrence and has the ability to report the activity, but fails to do so.

How Things Work

Consumer

Retail and Restaurant

Packer

Producer

Animal Agriculture Evolution

• Cost and availability of– Land– Animals– Feed– Fuel– Labor– Water– Prevention and therapeutic options

• Regulation• Consumers

Things that are broken

• Our understanding of the relationship of magnitude and duration of exposure with relation to resistance development, and…

• our understanding of the balance between duration of therapy and treatment success/relapse rates.

So where to from here

• Veterinarians should have control of all uses of antimicrobials in animals.

• Emphasize veterinary education on optimal use of these resources.

• Duration of therapy research is an absolute requirement

• Continue the emphasis on prevention of infectious disease

So where to from here• Revisit efficacy research for many of the

preventive applications (especially administered to a group through feed and water) to see if we actually still make a difference.

• Enforce our current regulations!!• Include data and the correct analysis in the

decision process• It is reasonable to monitor both antibiotic

resistance and antibiotic use (also reasonable to have a plan for analysis)