What are the public health issues
that practitioners have to consider
to enforce a sustainable use of
antibiotics
P.L. Toutain
National Veterinary School ;
Toulouse, France
Noordwijkerhout July 8-12 2012 NL
The priorities of a sustainable
veterinary antibiotherapy is
related to public health issues,
not to animal health issues
Medical consequences of
antimicrobial resistance
The antibiotic ecosystem:
one world, one health
Treatment & prophylaxis
Human medicine
Community
Hospital
Veterinary
medicine
Animal feed additives
Agriculture
Plant protection
Environment
Industry
But of what
resistance are we
speaking?
Prevent emergence of resistance:
but of what resistance?
Target pathogens
Drug efficacy in
animal:
A vet issue
Possible
overuse of
antibiotics
Animal issue
Zoonotics
Drug
efficacy in
man
Natural
eradication
Individual issue
Commensal flora
Resistance gene
reservoir
Global ecological
problem
Risk for
permanent
colonisation
Population issue
The 4 human risks associated to the use of
antibiotics in veterinary medicine to minimize
1.
2.
3.
4.
Decrease in susceptibility or full resistance of zoonotic
pathogens passing from animal to man either directly or
throughout the food chain
Development of resistance in commensal flora and
passage of resistance gene throughout the food chain
or the environment
Release of antibiotics in the environment with
different consequences including emergence of
resistance (gene, pathogens)
Antibiotic residues in food
7
Q1-For AR, what are the
critical veterinary
ecosystems in terms of
public health (commensals)
The critical animal ecosystems in terms of
emergence and spreading of resistance
• Open and large ecosystems
– Digestive tract
– Skin
• Open but small ecosystem
– Respiratory tract
• Closed and small ecosystem
– Mammary gland
Bacterial load exposed to
antibiotics during a treatment
Test
tube
1µg
Infected
Lungs
Digestive
tract
1 mg
2-3Kg
Food chain
Manure
Sludge
waste
Several tons
Soil, plant….
Biophases & antimicrobial resistance
AB: oral route
Proximal
G.I.T
1-F%
Distal
Gut flora
•Zoonotic (salmonella, campylobacter
•commensal ( enterococcus)
Food chain
Environmental
exposure
Blood
Target biophase
Bug of vet interest
Résistance = lack of efficacy
Résistance = public health concern
Biodisponibilité orale des
tétracyclines chez le porc
• Chlortétracycline:
– Pigs Fasted or fed: 18 to 19%
• Doxycycline:
– Pigs :23%
• Oxytétracycline:
– Pigs:4.8%
– Piglets, weaned, 10 weeks of age: by drench: 9%;in medicated feed
for 3 days: 3.7% .
• Tétracycline:
– Pigs fasted:23% .
12
• La majeure partie des doses administrées de
tétracyclines n’est pas utile pour l’animal mais
expose inutilement ses flores digestives et
l’environnement
Biophases & antibiorésistance
Gastrointestinal tract
Proximal
Gut flora
•Zoonotic (salmonella, campylobacter
•commensal ( enterococcus)
Intestinal secretion
Bile
Systemic Administration
Distal
Quinolones
Macrolides
Tétracyclines
Food chain
Environment
Blood
Biophase
Target pathogen
Résistance =public health issue
Résistance = lack of efficacy
Marbofloxacin impact on E. coli in pig intestinal flora
(From P. sanders, Anses, Fougères)
IV
•
•
•
•
IM 3 days
Before treatment : E. coli R (0.01 to 0.1%)
After IV. :Decrease of total E coli , slight increase of E. coli R (4 to 8 %)
Back to initial level
After repeated IM (3d) : Decrease below LoD E. coli (2 days), fast growth (~ 3
106 ufc/g 1 d). E. coli R followed to a slow decrease back to initial level after 12
14
days
Influence d’une administration d’amoxicilline
sur la flore digestive du porc
(excrétion du gène blaTEM)
1 E+10
oral route fed
copies/g of feces
1 E+9
1 E+8
oral route fasted
1 E+7
intramuscular route
1 E+6
control group
1 E+5
1 E+4
0
1
2
3
days
4
5
6
7
Iqpaïa 2010 15
• Performance-enhancing antibiotics (old
antibiotics)
– chlortetracycline, sulfamethazine, and penicillin
(known as ASP250)]
• phylogenetic, metagenomic, and quantitative
PCR-based approaches to address the
impact of antibiotics on the swine gut
microbiota
• It was shown that antibiotic resistance
genes increased in abundance and diversity
in the medicated swine microbiome despite a
high background of resistance genes in
nonmedicated swine.
• Some enriched genes, demonstrated the
potential for indirect selection of resistance
to classes of antibiotics not fed.
Daily bacterial shedding for a grower
pigs
6
=7.5x10
• E coli: 7.5 g per days
• Enterococcus: about 300 µg per days
A 20- to 100-fold greater E. coli abundance
in medicated than nonmedicated swine
Innovation: PK selectivity of
antibiotics
Proximal
Distal
1-F=90%
Oral
Efflux
F=10%
IM
Gut flora
•Zoonotic (salmonella, campylobacter
•commensal ( enterococcus)
Food chain
Quinolones, macrolides
environment
Blood
Kidney
Biophase
Résistance = public health concern
Animal health
- 19
Q2-What is the actual veterinary
contribution to the human AR
What is the actual veterinary
contribution to the human AR
1.
A direct contribution to resistance for zoonotic
pathogens (Salmonella, Campylobacter…)
2.
A possible transmission of commensal bacteria that
may transmit resistance determinants to human
pathogens
3.
An indirect contribution for MRSA (pets as carriers and
reservoirs)
Trends and Sources of Zoonosis in EU
EFSA/ECDC 2011
22
Reported zoonoses in UE, 2010
VTEC: E Coli verotoxinogène
Within Y. enterocolitica, the majority of isolates from food and environmental
sources are non-pathogenic types.
23
Deaths due to salmonellosis,
campylobacteriosis & E coli (report2010)
• Based on the reported fatality rates and the
total numbers of reported confirmed cases, it
is estimated that there were approximately
130 deaths due to salmonellosis, 212 due to
campylobacteriosis and 16 due to E coli in EU.
24
Treatments of salmonellosis &
campylobacteriosis
• Usually no antibiotics
• Only to treat sever cases in a risky
patients
25
Antibiotics used to treat
salmonellosis & campylobacteriosis
Salmonella
–Fluoroquinolones
–Cephalosporins (third generation)
–No quinolones for children
Campylobacter
– Macrolides
–Fluoroquinolones
Antibiotics used to treat
Verotoxigenic E coli
• The use of antimicrobials for the treatment
of human infections with VTEC is
controversial.
• In general, antimicrobials are not
recommended as their usage may
exacerbate symptoms, particularly
haemolytic uraemic syndrome.
27
Treatments of zoonotic
pathogens in man : is there
some AR?
28
Salmonella & campylobacter :
AR in human in US
Percentage of non-typhoidal Salmonella isolates
resistant to nalidixic acid, by year, 1996–2010
Percentage of non-typhoidal Salmonella isolates
resistant to ceftriaxone, by year, 1996–2010
Whilst there has been much debate about the
contribution of antibiotic use in veterinary medicine to
the overall resistance development in human
pathogens, these data suggest that clinical resistance
to fluoroquinolones in E. coli and nontyphoidal
Salmonella is uncommon, except for a few countries.
Travelling is the origin of
salmonellosis dues to
Salmonella enterica
sérotype Kentucky ST198
& resistance to
ciprofloxacin
33
What could be the human health
consequence of exposure to
resistant zoonotic bacteria
34
Impact of AR on the human mortality due
to salmonellosis
35
Macrolide resistance in Campylobacter
jejuni and Campylobacter coli
Q3: What are the transmission
pathways between animals and
man
37
Slaughter house
meat
Direct professional risk
Pathways of transmission between
animals and man
•Soil
•Water
•Air
Environment
3 possible
38 pathways
Campylobacter: prevalence
The food chain is a critical pathway for resistance
transmission of resistance from animal to man
Prevalence: 60100% in feces
Prevalence: 0<5% for meat
Prevalence: 0-32% for carcass
39
Prevalence of salmonella
contamination (EU 2009)
The high prevalence in poultry is due to some anatomical and physiological
specificcity
40
Several critical steps when
processing chickens
• Feed withdrawal
– Not too long, not too short
• Collecting and transportation of the chickens
– Stacked several raw high and top to bottom
contamination during transportation
• Feather removal
– Scalding tanks to remove the feather
• Removal of the internal organs
– Carcass contamination
Transportation of poultry
– Campylobacter : Top to bottom
contamination by feces during transportation
Feather removal in a contaminated
environment by feces (scald tank)
Contamination of the carcass
During evisceration, some degree of faecal contamination is inevitable
no matter how stringent the hygiene measures that are applied
Direct transfer from animal to man
(professional risk )
Also direct contact with antibiotic
45
The case of MethicillinResistant Staphylococcus
Aureus (MRSA)
46
MRSA
MRSA prevalence in animals
• There are differences in the occurrence of
MRSA between companion animals (pets and
horses) and livestock (mostly pigs, poultry, cattle
and sheep).
MRSA: animal reservoir
• The most common MRSA isolates from animals
are ST398, the main reservoirs being pigs and
veal calves.
– This type, which is also isolated from chickens and
horses, can be transferred to humans.
– There is a limited overlap with humans, and
transmission to humans is rare.
– Most isolates are multidrug resistant, and some PVLpositive isolates are found.
• MRSA is rarely found in meat and then only in
low quantities; the source is thought to be the
butcher/meat handler rather than animals
MRSA in pigs
• The prevalence of MRSA-positive herds
was 67% in breeding herds and 71% in
finishing herds.
• The most likely explanation for the
observed increase in MRSA-positive herds
is that MRSA is easily transmitted between
herds (e.g. when purchasing animals).
MRSA in pigs
MRSA: Risk factor analysis
MRSA carriage in veal calves
• Prevalence in veal calf far higher than in adult
cow.
• A study carried out on 102 farms in the
Netherlands found that 28% of calves carried
MRSA and 88% of the farms sampled had
calves with MRSA.
• The farmers and their family members were
also sampled, and 33% of the farmers carried
MRSA but only 8% of family members.
– The isolates from both animals and humans
belonged to the clonal complex ST398.
MRSA in calf
• Studies in humans show an association
between antimicrobial use and the
occurrence of MRSA, and batch-treated
calves were more often MRSA positive
than untreated calves
MRSA colonization is an occupational risk for
veterinary professionals
MRSA was isolated from nares of 27/417 (6.5%) attendees at an
international veterinary conference: 23/345 (7.0%) veterinarians,
4/34 (12.0%) technicians, and 0/38 others.
To read the full article
Pfizer Paris 2009 - 56
Indirect transfer from animal to man via the
butcher’hands : a consumer risk
The case
of MRSA
57
Hazard associated to the release of
antibiotic in environment
Fate of antibiotics, zoonotic pathogens and
resistance genes: residence time in the
different biotopes
Lagoon: few weeks
Digestive tract: 48h
Ex:T1/2 tiamuline=180 days
Bio-aérosol
Air, water & ground pollution
Air pollution
Rate of antibiotic degradation in manure, soil, waste…
Antibiotics
matrix
Dégradation %
Days
Chlortétracycline
Cattle manure
24
84
Tétracycline
Pig manure
50
48
Oxytetracycline
Soil+contam manure
0
180
Oxytetracycline
Sediment slurry ,
aeobiose
50
43
TMP
Sewage sludge
50
22-41
Sulfamides
Manure/sludge
0
28
Aminoglycosides
manure
0
30
50
26
Tiamuline
Tylosine
Pig manure,
anaerobic
50
2
Bacitracin
Sandy loam & manure
77
30
Enrofloxacin
Cattle mannure
<1
56
Sewage production in a pigs setting
• Annual sewage production is about 1520 tons per sow unit i.e. about 1500 to
2000 tons of sewage per year for a
setting of 100 sows
61
Hazard associated to the release of
antibiotic in environment
• Resistance selection conditions are also
present in the environment.
• Contributes to antimicrobial resistance Spread
62
Risk associated to bioaerosols
• Studies of bioaerosols inside intensive pig
farms have shown more than 90% had
multi-drug resistance.*,**
• Antibiotic resistance bacteria have been
recovered 150 meters downwind from
intensive pig farms.**
• Swine workers and veterinarians have
elevated carriage of MRSA (methicillinresistant Staphyloccoccus aureus).*, ***
*A.Chapin, et.al, Airborne Multidrug-Resistance Bacteria Isolated from Swine CAFO, 2005.
**S.G. Gibbs, et.al. Isolation of Antibiotic-Resistant Bacteria Downwind of Swine CAFO, 2006
*** Wulf, M, et.al. MRSA in Veterinary Doctors and Students in Netherlands, 2006
Environ. Sci. Technol. 2010, 44, 580–587
Sewage management is in order
•Anaerobic digestion destroyed only 59% of
oxytetracycline in manures in 64 days.
•However, composting destroyed 95% of
oxytetracyline in manures within first week.
Also, levels of oxytetracycline resistant
bacteria were 10-fold lower
65
Hazard due to the presence of
antibiotic residues in food
• No public health issue
– No observance of the withdrawal time
– Inappropriate withdrawal time (generics)
– Surveillance from the french ministery
• Positive sample: 0.3% for antibiotics and 0.4% for
sulfamides
• Many control for milk (technological risk for chees
production etc.)
66
Antimicrobial resistance:
risk management options
Ispaia 2010-67
Risk management for the
veterinary contribution to the
human resistance: precaution
principle or prevention principle?
Rem: WHO do not consider that transmission of
such organisms or their genes must be proven,
but only the potential for such transmission to
occur (precaution principles)
Precaution principles
Veterinary
Animal
Resistance
antibiotics
Black box
human
Prevention principle
Antibiotics
Animal
Grey box
Zoonotics
AR
homme
Commensals
AR
homme
Pathogens
AR animal
Reduction of antibiotic consumption
Sales of veterinary antibacterial
agents for different species
43.9%
7.8%
7.18
22.5%
1.83%
16.1%
0.51%
France 2009 Tonnage total en 2009= 1067 Tonnes
72
How to reduce antibiotic
consumption
1. Suppress incentives to antibiotic
consumption
1. Generics
2. Low price
3. Turnover for the veterinarians
Consequences of generic
marketing on antibiotic
consumption and the spread of
resistance
Generics and antibiotic consumption
75
Number of ciprofloxacin trade names (black line)
and the median price per DDD (red line) and the
influence of the introduction of generics
Generics
Number of
trade names
Price
- 76
The influence of the introduction of generics on the
total use of ciprofloxacin (black line) and median price
per DDD (red line)
Consumption
Generics
PL Toutain Ecole vétérinaire Toulouse
price
Trends in the frequency of ciprofloxacin resistance among E. coli
urine (brown line) and the consumption of ciprofloxacin (black
line) from 1995 to 2005
Resistance
Consumption
Generics
PL Toutain Ecole vétérinaire Toulouse
Use of fluoroquinolones in veterinary medicine:
Germany, DK, UK
From Hellmann: Assoc Vet Consult. SAGAM 2005
Use of fluoroquinolones in veterinary medicine:
Eastern EU, Spain, Portugal
From Hellmann: Assoc Vet Consult. SAGAM 2005
How to reduce the antibiotic
consumption: reconsider some
dosage regimens
The different modalities of antibiotic uses in
food producing animals
Disease
health
Antibiotic consumption
Therapy
Metaphylaxis
(Control)
Pathogen load
Prophylaxis
(prévention)
Growth
promotion
Only a risk factor
High
Small
No
NA
MICs estimated with different inoculmum densities, relative to
that MIC at 2x105
Ciprofloxacin
Gentamicin
Linezolid
Oxacillin
Daptomycin
Vancomycin
Progression of
infection
Inoculation of Pasteurella
multocida
1500 CFU/lung
Bacteria counts per lung (CFU/lung)
Materials and methods
1010
108
106
104
102
100
0
10
20
30
40
50
Time (h)
Progression of
infection
Inoculation of Pasteurella
multocida
1500 CFU/lung
Bacteria counts per lung (CFU/lung)
Materials and methods
anorexia
lethargy
dehydration
no clinical
signs of
infection
1010
108
106
104
102
100
0
10
20
30
40
50
Time (h)
early (10h)
Administration
Late (32h)
Administration
1-Clinical outcome (survival)
A low early dose better than a late high dose
Marbofloxacin administrations
Pourcentages of mice alive
early
100 %
late
80
60
40
20
0
control 1 mg/kg
40 mg/kg
Marbofloxacin doses
2-Bacterial eradication
Early low dose= late high dose
Marbofloxacin administrations
% of mice with bacterial
eradication
Early
Late
100 %
80
60
40
20
0
control
1 mg/kg
40 mg/kg
Marbofloxacin doses
3-Selection of resistant target bacteria
A late 1 mg/kg marbofloxacin dose select resistance
(observation at 16 or 38h after the marbofloxacin administration)
% of mice with resistant
bacteria
Marbofloxacin administrations
50 %
late
Early
40
30
20
+38h
10
observation 16 hours after
marbofloxacin
administration
= 48 hours after the
infection = like early
administration
0
control
1 mg/kg 40 mg/kg
1 mg/kg
Marbofloxacin doses
40 mg/kg
+38h
Conclusion
• For a same dose of marbofloxacin, early treatments
(10 hours after the infection) were associated to
– more frequent clinical cure
– more frequent bacteriological cure
– less frequent selection of resistant bacteria
than late treatments (32 hours after the infection)
Early administrations were more favourable than late
administrations
Metaphylaxis and Very Early
Treatment (VET)
• I suggest to replace metaphylaxis by VET
because metaphylaxis convey negative values
– Confuse with mass treatment,
– Confuse with prophylaxis
When to finish a treatment?
• ASAP
• Should be determined in clinics
• Should be when clinical cure is actually
achieved
• Should not be a hidden prophylactic
treatment for a possible next infectious
episode
Conclusion:
What is the most dangerous situation?
Travelling
Licking
Eating pork