Antibiotics Resistance and Antibiotic Use in Beef Cattle ...saskbeefconference.com/2015...

46
Antibiotics Resistance and Antibiotic Use in Beef Cattle Production Tim McAllister Principal Research Scientist Lethbridge Research Centre Agriculture and Agri-Food Canada Agriculture et Agroalimentaire Canada SBIC Beef and Forage Symposium January 21 st , 2015

Transcript of Antibiotics Resistance and Antibiotic Use in Beef Cattle ...saskbeefconference.com/2015...

Antibiotics Resistance and Antibiotic Use in Beef Cattle Production Tim McAllister Principal Research Scientist Lethbridge Research Centre

Agriculture and Agri-Food Canada

Agriculture et Agroalimentaire Canada

SBIC Beef and Forage Symposium January 21st, 2015

Source: WHO, 2014

Nature doi:10.1038/nature.2014.15135

Microbes are part of the natural world

Deep sea vents

In our food

On our skin and in our digestive tract

In the digestive tract of cattle

Resistance genes are ubiquitous and ancient

Bhuller et al., 2012 D’Costa et al., 2011

Lechuguilla Cave, New Mexico

Region isolated for 4M years

Permafrost sediment

Resistance genes are ubiquitous and ancient

Schmieder and Edwards, 2012 Chait et al., 2012

Void in antibiotic development pipeline

Antibiotic use in Canada

Linton, A.H. (1977) and Irwin, R. (2007).

Number of superbug infections in 2012 from 57 Canadian hospitals

3479 1788

482

81 Clostridium difficile

Methicillin resistant

Staphylococcus aureus

(MRSA)

Vancomycin resistant

Enterococci

Carbapenem-resistant

Enterobacteriaceae

Source: AMMI, 2013

Elanco Animal Health

ANTIMICROBIAL RESISTANCE AND USE IN CANADA A Federal Framework for Action

Public Health Agency of Canada, Health Canada, Candian Food Inspection Agency, Canadian Institutes of Health Research and Agriculture and Agri-Food Canada • Surveillance • Stewardship • Innovation

Health Canada, 2014

Canadian Animal Health Institute April 11, 2014 - Agreed to phase out the usage of medically important antibiotics for growth promotion and supports increased veterinary oversight in antimicrobial use

• Announced on April 11 2014 by Canadian Animal Health Institute

(CAHI) companies

• Restricts medically important antibiotic usage in food animals to specific disease challenges under veterinarian direction

• Expected to be implemented over the next three years possibly

through the Regulatory Cooperation Council

Elanco Animal Health

Importance in treating serious human infections

CATEGORY

I I V I I I I I

Preferred option for serious

infections and limited or no

treatment alternatives

available

Preferred option for serious infections,

alternatives available

Not a preferred option for

serious infections,

Not a preferred option, not used

in human medicine

SWINE FEED Antibiotic Rank

Virginiamycin II

Lincomycin II

Tilmicosin II

Tylosin phosphate II

Chlortetracycline ,

sulfamethazine and procaine

penicillin

II/III

Lincomycin and Spectinomycin II/III

Tylosin phosphate and

Sulfamethazine

II/III

Zinc bacitracin and procaine

penicillin

II/III

Bacitracin methylene

disalicylate

III

Bacitracins III

Chlortetracycline III

Oxytetracycline III

Ionophores IV

POULTRY FEED Antibiotic Rank

Virginiamycin II

Erythromycin thiocyanate II

Hygromycin B II

Penicillin from Procaine

penicillin

II

Zinc bacitracin and Procaine

Penicillin

II

Bacitracins III

Chlortetracycline III

Oxytetracycline III

Bambermycins IV

Ionophores IV

CATTLE FEED Antibiotic Rank

Tylosin phosphate II

Oxytetracycline hydrochloride

and Neomycin sulphate

II/III

Bacitracins III

Chlortetracycline III

Chlortetracycline and

Sulfamethazine

III

Oxytetracycline III

Ionophores IV

Antibiotics approved for animal feed, ranked by importance to humans

Rankings according to Health Canada criteria

I 0.03%

II 15.35%

II/III 13.05%

III 42.33%

IV 29.24%

Source: CIPARS report, 2008

Ranked by importance to human medicine (I-IV)

ANIMALS

I 26.26%

II 57.58%

III 16.16%

Ranked by importance to human medicine (I-IV)

Source: CIPARS report, 2008

HUMANS

ribosomes

DHF

THF

PABA

cell wall

synthesis &

integrity

bacitracin

carbapenems

cephalosporins

D-cycloserine

monobactams

penicillins

vancomycin

translation (protein synthesis)

50s inhibitors: 30s

inhibitors:

erythromycin tetracycline

chloramphenicol streptomycin

clindamycin spectinomycin

lincomycin kanamycin

gentamycin

folic acid

metabolism

trimethoprim

sulfonamide

DNA replication

nalidixic acid

quinolones DNA synthesis

metronidizole

transcription

rifampicin

cytoplasmic

membrane

polymyxins

chromosomal

DNA

mRNA

Antibiotic classes (cellular target)

antibiotic altering enzyme

antibiotic degrading enzyme

antibiotic

antibiotic

antibiotic antibiotic resistance

genes

chromosomal DNA

plasmid DNA

antibiotic efflux pump

Adapted from Levy & Marshall, 2004

EU withdrawal of nontherapeutic antibiotics in food animal production

1970 1980 1990 2000 2010

EU ban on all AGPs

Sweden bans AGPs

Denmark bans routine prophylactics

Specific antibiotic bans in Norway,

Germany, Netherlands,

Denmark, Sweden & EU

European ban on tet, pen & strep for growth promotion

Sweden stops use of prophylactic

drugs

POSITIVE outcomes of removing subtherapeutic antibiotics

Johnsen et al., 2009. Lancet Infect Dis 9: 357-364

Experimental timeline

DAY 1

ARRIVAL AT FEEDLOT

DAY 315

SLAUGHTER

BACKGROUNDING FINISHING

= Feeding of subtherapeutic levels of antimicrobial agents

= Sampling date

15 57 36 71 92 113 134 183 225 204 246 1

DAY

315

Design

• 150 feedlot steers fed finishing diet

• 4 antimicrobial treatments (3 pens per treatment) – Control (no antimicrobials)

– A44 (chlortetracycline, 44 ppm)

– AS700 (chlortetracycline + sulfamethazine, 44 ppm each)

– T11 (tylosin, 11 ppm)

• Within each treatment, feces from each pen were pooled and formed into duplicate artificial fecal pats

Prevalence of shedding: tetracycline resistant E. coli

0

20

40

60

80

100

0 50 100 150 200 250

Control Aureo S-700 Aureomycin

Virginiamycin Monensin Tylosin

Pro

po

rtio

n o

f st

ee

rs s

he

dd

ing

(%)

Prevalence of steers shedding ampicillin resistant E. coli

0

20

40

60

80

100

0 50 100 150 200 250 300

Day

Pre

vale

nce

Control Aureo S-700 Aureomycin

Virginiamycin Monensin Tylosin

Pro

po

rtio

n o

f st

ee

rs s

he

dd

ing

(%)

Tylosin (Tylan™)

in-feed 11ppm

n = 1 0

Tulathromycin (Draxxin™)

2.5 mg/kg BW

n = 1 0

Tilmicosin (Micotil™)

10 mg/kg BW

n = 1 0

Control

n = 1 0

Day 0 7 14 21 28

Systemic treatment

Barley (70% silage; 25% grain) + 5% supplement

1 JANUARY

TREATMENT

DURATION

ANALYSIS

In-feed treatment

housed in individual pens in

separate wings

* Faecal & Nasal sample collection * * * *

Enterococci Isolation on BEA & BEA+Ery

EryR genes PCR

Species identification by pyrosequencing

PFGE

Co-isolated species

M. haemolytica isolation on BAC & BAC+Ery

EryR genes PCR

16S rRNA PCR for species identification

PFGE

Disc diffusion

Experimental Design

Enterococci

Erythromycin resistance

n: Number of isolates pyro-sequenced

Bovine isolates n = 130

Human clinical isolates n = 51

The species profiles of bovine isolates differ from clinical isolates of human origin

0%

10%

20%

30%

40%

50%

60%

70%

0 7 14 21 28

Ave

rage

pro

po

rtio

n E

ry r

esi

stan

ce

Day

Control Tilmicosin Tulathromycin Tylosin

Proportion of Ery-resistant bovine enterococci over the study period, with d 0 samples collected prior to treatment. Compared to the control group, treated groups were 76 times more likely (P < 0.05) to have erythromycin resistant enterococci.

Enumeration data

34

-20.0

0.0

20.0

40.0

60.0

80.0

100.0

120.0

140.0

160.0

-10 40 90 140 190 240

Ave

rage

pro

po

rtio

n o

f ty

l res

ista

nce

(%

)

Day

Control

Tylosin

-25.0

-5.0

15.0

35.0

55.0

75.0

95.0

115.0

-50 0 50 100 150 200 250

Ave

rage

pro

po

rtio

n o

f er

y re

sist

ance

(%

)

Day

Control

Tylosin

Distribution of enterococcus species over sampling days and between treatments

35

0

10

20

30

40

50

60

70

80

90

100

Control Tylosin Control Tylosin Control Tylosin Control Tylosin Control Tylosin

0 14 84 112 224

Spe

cie

s p

reva

len

ce (

%)

E. hirae E.faecium E. durans E. casseliflavus E. faecalis

75

100

2.7 0.5

95.1

100

32.6

0.5 0

10

20

30

40

50

60

70

80

90

100

Fecal Samples at Processing

Hides at Processing Pre-evisceration Carcasses

Final Carcasses

Pre

vale

nce

of

Res

ista

nce

(%

)

3rd Generation Cephalosporin

Trimethoprim-Sulfamethoxazole

Adapted from: Schmidt et al., 2014 AEM 81:713-725

Resistance in E. coli from beef processing continuum

Resistance is encoded by diverse soil phyla.

KJ Forsberg et al. Nature 000, 1-5 (2014) doi:10.1038/nature13377

Functional selections of 18 soil libraries yield diverse ARGs.

KJ Forsberg et al. Nature 000, 1-5 (2014) doi:10.1038/nature13377

Udikovic-Kolic N et al. PNAS 2014;111:15202-15207

Effects of manure on the abundances of culturable soil bacteria.

I Chip Culturing the Unculturable.

The structure of teixobactin and the predicted biosynthetic gene cluster.

LL Ling et al. Nature 000, 1-5 (2015) doi:10.1038/nature14098

Time-dependent killing of S. aureus by teixobactin.

LL Ling et al. Nature 000, 1-5 (2015) doi:10.1038/nature14098

Teixobactin is efficacious against MRSA and S. pneumoniae

LL Ling et al. Nature 000, 1-5 (2015) doi:10.1038/nature14098

MRSA - speticemia

MRSA – muscle

infection

Streptococcus

pneumoniae – lung

challenge

RESEARCH

Study the kinds & flow of resistance (genes) and zoonotic potential of

microbes

MANAGEMENT

Consider livestock production practices to reduce use and potential impact on human

medicine

SURVEILLANCE

Monitor the emergence of resistance (genes) and potential for transfer

between livestock – the environment – and consumer

products

DEVELOPMENT OF ALTERNATIVES

Design/test therapeutic approaches against

veterinary or zoonotic diseases

Take Home Point

• Microbes are masters of adaptation

Oct. 15, 2012 -Health Canada Recalls Antibacterial hand soap

– Pseudomonas aeruginosa

Beef AMR / AMU funding

Questions?