what are the public health issues that practitioners have to consider to enforce a sustainable use...
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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, FranceNoordwijkerhout July 8-12 2012 NL
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The priorities of a sustainable veterinary antibiotherapy is
related to public health issues, not to animal health issues
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Medical consequences of antimicrobial resistance
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The antibiotic ecosystem: one world, one health
Treatment & prophylaxis
Human medicineCommunity
Veterinary medicine Animal feed additives
Environment
Hospital Agriculture
Plant protection
Industry
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But of what resistance are we
speaking?
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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 genereservoir
Global ecologicalproblem
Possible overuse of antibiotics
Natural eradication
Risk 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 genereservoir
Global ecologicalproblem
Possible overuse of antibiotics
Natural eradication
Risk 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 genereservoir
Global ecologicalproblem
Possible overuse of antibiotics
Natural eradication
Risk for permanent
colonisation
Individual issue Population issueAnimal issueAnimal issue
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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
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Q1-For AR, what are the critical veterinary
ecosystems in terms of public health (commensals)
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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
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Bacterial load exposed to antibiotics during a treatment
Infected Lungs
Digestive tract
1 mg 2-3Kg
ManureSludgewaste
Food chain
Several tons
Soil, plant….
1µg
Test tube
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Biophases & antimicrobial resistance
G.I.TProximal Distal
Résistance = lack of efficacy
Blood
Gut flora•Zoonotic (salmonella, campylobacter •commensal ( enterococcus)
1-F%
F%
Target biophaseBug of vet interest
AB: oral route
Résistance = public health concern
Food chain Environmental exposure
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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
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Biophases & antibiorésistance
Gastrointestinal tract
Proximal DistalIntestinal secretion
Bile
Résistance = lack of efficacyRésistance =public health issue
BiophaseTarget pathogen
Blood
Food chain
Environment
Systemic Administration
QuinolonesMacrolidesTétracyclines
Gut flora•Zoonotic (salmonella, campylobacter •commensal ( enterococcus)
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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
IVIM 3 days
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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
cop
ies/
g o
f fe
ces
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
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• 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
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• 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.
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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
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Innovation: PK selectivity of antibiotics
environment
ProximalDistal
Blood
Gut flora•Zoonotic (salmonella, campylobacter •commensal ( enterococcus)
BiophaseRésistance = public health concern
Food chain
1-F=90%
F=10%
Animal health
Efflux
Quinolones, macrolides
IM
Kidney
Oral
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Q2-What is the actual veterinary contribution to the human AR
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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)
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Trends and Sources of Zoonosis in EU EFSA/ECDC 2011
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Reported zoonoses in UE, 2010
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VTEC: E Coli verotoxinogène
Within Y. enterocolitica, the majority of isolates from food and environmental sources are non-pathogenic types.
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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.
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Treatments of salmonellosis & campylobacteriosis
• Usually no antibiotics
• Only to treat sever cases in a risky patients
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Antibiotics used to treat salmonellosis & campylobacteriosis
Salmonella –FluoroquinolonesFluoroquinolones
–Cephalosporins (third Cephalosporins (third generation)generation)
–No quinolones for childrenNo quinolones for children
Campylobacter – MacrolidesMacrolides
–FluoroquinolonesFluoroquinolones
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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.
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Treatments of zoonotic pathogens in man : is there
some AR?
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Salmonella & campylobacter :AR in human in US
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Percentage of non-typhoidal Salmonella isolates resistant to nalidixic acid, by year, 1996–2010
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Percentage of non-typhoidal Salmonella isolates resistant to ceftriaxone, by year, 1996–2010
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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.
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Travelling is the origin of salmonellosis dues to Salmonella enterica
sérotype Kentucky ST198 & resistance to ciprofloxacin
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What could be the human health consequence of exposure to resistant zoonotic bacteria
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Impact of AR on the human mortality due to salmonellosis
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Macrolide resistance in Campylobacter jejuni and Campylobacter coli
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Q3: What are the transmission pathways between animals and
man
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Pathways of transmission between animals and man
Slaughter house
meat
Dir
ect
pro
fess
ion
al r
isk
•Soil•Water•Air
3 possible pathways
Environment
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Campylobacter: prevalenceThe 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
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Prevalence of salmonella contamination (EU 2009)
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The high prevalence in poultry is due to some anatomical and physiological specificcity
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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
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Transportation of poultry
– Campylobacter : Top to bottom contamination by feces during transportation
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Feather removal in a contaminated environment by feces (scald tank)
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Contamination of the carcass
During evisceration, some degree of faecal contamination is inevitableno matter how stringent the hygiene measures that are applied
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Direct transfer from animal to man(professional risk )
Also direct contact with antibiotic
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The case of Methicillin-Resistant Staphylococcus
Aureus (MRSA)
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MRSA
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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).
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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
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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).
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MRSA in pigs
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MRSA: Risk factor analysis
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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.
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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
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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 aninternational veterinary conference: 23/345 (7.0%) veterinarians,4/34 (12.0%) technicians, and 0/38 others.
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Indirect transfer from animal to man via the butcher’hands : a consumer risk
The case of MRSA
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Hazard associated to the release of antibiotic in environment
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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
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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
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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
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Hazard associated to the release of antibiotic in environment
• Resistance selection conditions are also present in the environment.
• Contributes to antimicrobial resistance Spread
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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
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Environ. Sci. Technol. 2010, 44, 580–587
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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
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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.)
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Antimicrobial resistance:risk management options
Ispaia 2010-67
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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)
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Precaution principles
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Prevention principle
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Reduction of antibiotic consumption
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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
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How to reduce antibiotic consumption
1. Suppress incentives to antibiotic consumption
1. Generics2. Low price3. Turnover for the veterinarians
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Consequences of generic marketing on antibiotic
consumption and the spread of resistance
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75
Generics and antibiotic consumption
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- 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
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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
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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
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Use of fluoroquinolones in veterinary medicine: Germany, DK, UK
From Hellmann: Assoc Vet Consult. SAGAM 2005
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Use of fluoroquinolones in veterinary medicine: Eastern EU, Spain, Portugal
From Hellmann: Assoc Vet Consult. SAGAM 2005
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How to reduce the antibiotic consumption: reconsider some
dosage regimens
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Disease health
TherapyMetaphylaxis
(Control)Prophylaxis(prévention)
Growth promotion
The different modalities of antibiotic uses in food producing animals
HighHighPathogen loadPathogen load
SmallSmall NoNoNANA
Antibiotic consumptionAntibiotic consumption
Only a risk factor
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MICs estimated with different inoculmum densities, relative to that MIC at 2x105
Ciprofloxacin
Gentamicin
Linezolid
Daptomycin
Oxacillin
Vancomycin
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Materials and methods
Progression of infection
Inoculation of Pasteurella multocida
1500 CFU/lung
0 10 20 30 40 50
Time (h) Bact
eria
cou
nts
per l
ung
(CFU
/lun
g)
100
102
104
106
108
1010
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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) Bact
eria
cou
nts
per l
ung
(CFU
/lun
g)
100
102
104
106
108
1010no clinical
signs of infection
anorexia lethargy
dehydration
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0
20
40
60
80
100 %
1 mg/kg
Marbofloxacin doses
40 mg/kg
early late
Marbofloxacin administrations Po
urce
ntag
es o
f mic
e al
ive
control
1-Clinical outcome (survival) A low early dose better than a late high dose
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2-Bacterial eradicationEarly low dose= late high dose
0
20
40
60
80
100 %
% o
f mic
e w
ith b
acte
rial
erad
icati
on
1 mg/kg
Marbofloxacin doses
40 mg/kg
Early Late
Marbofloxacin administrations
control
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3-Selection of resistant target bacteriaA 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 mic
e w
ith re
sist
ant
bact
eria
control
Early late
Marbofloxacin administrations
+38h1 mg/kg 40 mg/kg
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• 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
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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
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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
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Conclusion: What is the most dangerous situation?
Eating pork
Travelling
Licking