what are the public health issues that practitioners have...
TRANSCRIPT
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
The antibiotic ecosystem:
one world, one health
Treatment & prophylaxis
Human medicine
Community
Veterinary
medicine Animal feed additives
Environment
Hospital Agriculture
Plant protection
Industry
Prevent emergence of resistance:
but of what resistance?
Target pathogens Zoonotics Commensal flora
Drug efficacy in
animal:
A vet issue
Drug
efficacy in
man
Resistance gene
reservoir
Global ecological
problem
Possible
overuse of
antibiotics
Natural
eradicationRisk for
permanent colonisation
Individual issue Population issueAnimal issueAnimal issue
Target pathogens Zoonotics Commensal flora
Drug efficacy in
animal:
A vet issue
Drug
efficacy in
man
Resistance gene
reservoir
Global ecological
problem
Possible
overuse of
antibiotics
Natural
eradicationRisk for
permanent colonisation
Individual issue Population issueAnimal issueAnimal issue
Target pathogens Zoonotics Commensal flora
Drug efficacy in
animal:
A vet issue
Drug
efficacy in
man
Resistance gene
reservoir
Global ecological
problem
Possible
overuse of
antibiotics
Natural
eradicationRisk for
permanent colonisation
Individual issue Population issueAnimal issueAnimal issue
7
The 4 human risks associated to the use of
antibiotics in veterinary medicine to minimize
1. Decrease in susceptibility or full resistance of zoonotic pathogens passing from animal to man either directly or throughout the food chain
2. Development of resistance in commensal flora and passage of resistance gene throughout the food chain or the environment
3. Release of antibiotics in the environment with different consequences including emergence of resistance (gene, pathogens)
4. Antibiotic residues in food
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
Infected
Lungs
Digestive
tract
1 mg 2-3Kg
Manure
Sludge
waste
Food chain
Several tons
Soil, plant….
1µg
Test
tube
Biophases & antimicrobial resistance
G.I.T Proximal Distal
Résistance = lack of efficacy
Blood
Gut flora •Zoonotic (salmonella, campylobacter •commensal ( enterococcus)
1-F%
Target biophase
Bug of vet interest
AB: oral route
Résistance = public health concern
Food chain Environmental
exposure
12
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% .
• 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 Distal
Intestinal secretion
Bile
Résistance = lack of efficacy Résistance =public health issue
Biophase
Target pathogen
Blood
Food chain
Environment
Systemic Administration
Quinolones
Macrolides
Tétracyclines
Gut flora •Zoonotic (salmonella, campylobacter •commensal ( enterococcus)
14
Marbofloxacin impact on E. coli in pig intestinal flora (From P. sanders, Anses, Fougères)
• 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
days
IV IM 3 days
Iqpaïa 2010 15
Influence d’une administration d’amoxicilline
sur la flore digestive du porc
(excrétion du gène blaTEM)
0 1 2 3 4 5 6 7days
co
pie
s/g
of
feces
oral route fed
oral route fasted
intramuscular route
control group1 E+5
1 E+6
1 E+7
1 E+8
1 E+9
1 E+10
1 E+4
• 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
• E coli: 7.5 g per days
• Enterococcus: about 300 µg per days
=7.5x106
A 20- to 100-fold greater E. coli abundance
in medicated than nonmedicated swine
- 19
Innovation: PK selectivity of
antibiotics
environment
Proximal
Distal
Blood
Gut flora •Zoonotic (salmonella, campylobacter •commensal ( enterococcus)
Biophase Résistance = public health concern
Food chain
1-F=90%
F=10%
Animal health
Efflux
Quinolones, macrolides
IM
Kidney
Oral
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)
Reported zoonoses in UE, 2010
23
VTEC: E Coli verotoxinogène
Within Y. enterocolitica, the majority of isolates from food and environmental sources are non-pathogenic types.
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
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.
33
Travelling is the origin of
salmonellosis dues to
Salmonella enterica
sérotype Kentucky ST198
& resistance to
ciprofloxacin
38
Pathways of transmission between
animals and man
Slaughter house
meat
Dir
ect
pro
fessio
nal
risk
•Soil
•Water
•Air
3 possible pathways
Environment
39
Campylobacter: prevalence The food chain is a critical pathway for resistance
transmission of resistance from animal to man
Prevalence: 60-
100% in feces
Prevalence: 0-32% for carcass
Prevalence: 0-
<5% for meat
Prevalence of salmonella
contamination (EU 2009)
40
The high prevalence in poultry is due to some anatomical and physiological
specificcity
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
Contamination of the carcass
During evisceration, some degree of faecal contamination is inevitable
no matter how stringent the hygiene measures that are applied
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 PVL-positive 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 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
Pfizer Paris 2009 - 56
MRSA colonization is an occupational risk for veterinary professionals
To read the full article
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.
Fate of antibiotics, zoonotic pathogens and resistance genes: residence time in the
different biotopes Digestive tract: 48h
Lagoon: few weeks
Air pollution
Bio-aérosol
Air, water & ground pollution
Ex:T1/2 tiamuline=180 days
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
Tiamuline 50 26
Tylosine Pig manure,
anaerobic
50 2
Bacitracin Sandy loam & manure 77 30
Enrofloxacin Cattle mannure <1 56
61
Sewage production in a pigs setting
• Annual sewage production is about 15- 20 tons per sow unit i.e. about 1500 to
2000 tons of sewage per year for a setting of 100 sows
62
Hazard associated to the release of antibiotic in environment
• Resistance selection conditions are also present in the environment.
• Contributes to antimicrobial resistance Spread
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 (methicillin-resistant 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
65
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
66
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.)
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)
Prevention principle
Antibiotics
Animal
Grey box
Zoonotics
AR homme
Commensals
AR homme
Pathogens
AR animal
72
Sales of veterinary antibacterial agents for different species
43.9%
16.1%
7.8%
1.83%
0.51%
22.5% 7.18
France 2009 Tonnage total en 2009= 1067 Tonnes
How to reduce antibiotic consumption
1. Suppress incentives to antibiotic consumption
1. Generics
2. Low price
3. Turnover for the veterinarians
- 76
Number of ciprofloxacin trade names (black line)
and the median price per DDD (red line) and the
influence of the introduction of generics
Number of
trade names
Generics
PriceNumber of
trade names
Generics
Price
Generics
Price
Generics
Price
PL Toutain Ecole vétérinaire Toulouse
The influence of the introduction of generics on the total use of ciprofloxacin (black line) and median price
per DDD (red line)
GenericsConsumption priceGenericsConsumption price
PL Toutain Ecole vétérinaire Toulouse
Trends in the frequency of ciprofloxacin resistance among E. coli urine (brown line) and the consumption of ciprofloxacin (black
line) from 1995 to 2005
Generics
ResistanceConsumption
Generics
ResistanceConsumption
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
Disease health
Therapy Metaphylaxis
(Control) Prophylaxis (prévention)
Growth promotion
The different modalities of antibiotic uses in food producing animals
High
Pathogen load
Small No
NA
Antibiotic consumption
Only a risk factor
MICs estimated with different inoculmum densities, relative to that MIC at 2x105
Ciprofloxacin
Gentamicin
Linezolid
Daptomycin
Oxacillin
Vancomycin
Materials and methods
Progression of infection
Inoculation of Pasteurella multocida
1500 CFU/lung
0 10 20 30 40 50
Time (h) Bac
teri
a co
un
ts p
er lu
ng
(CFU
/lu
ng)
100
102
104
106
108
1010
Materials and methods
Progression of infection
early (10h)
Administration
Late (32h) Administration
Inoculation of Pasteurella multocida
1500 CFU/lung
0 10 20 30 40 50
Time (h) Bac
teri
a co
un
ts p
er lu
ng
(CFU
/lu
ng)
100
102
104
106
108
1010 no clinical
signs of infection
anorexia lethargy
dehydration
0
20
40
60
80
100 %
1 mg/kg
Marbofloxacin doses
40 mg/kg
early late
Marbofloxacin administrations Po
urc
enta
ges
of
mic
e al
ive
control
1-Clinical outcome (survival) A low early dose better than a late high dose
2-Bacterial eradication Early low dose= late high dose
0
20
40
60
80
100 %
% o
f m
ice
wit
h b
acte
rial
er
adic
atio
n
1 mg/kg
Marbofloxacin doses
40 mg/kg
Early Late
Marbofloxacin administrations
control
3-Selection of resistant target bacteria
A late 1 mg/kg marbofloxacin dose select resistance (observation at 16 or 38h after the marbofloxacin administration)
0
10
20
30
40
50 %
+38h
observation 16 hours after marbofloxacin administration = 48 hours after the infection = like early administration
1 mg/kg
Marbofloxacin doses
40 mg/kg
% o
f m
ice
wit
h r
esis
tan
t b
acte
ria
control
Early late
Marbofloxacin administrations
+38h 1 mg/kg 40 mg/kg
• 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)
Conclusion
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