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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
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
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
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
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
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.
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