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

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 medicineCommunity

Veterinary medicine Animal feed additives

Environment

Hospital Agriculture

Plant protection

Industry

But of what resistance are we

speaking?

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

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

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

Infected Lungs

Digestive tract

1 mg 2-3Kg

ManureSludgewaste

Food chain

Several tons

Soil, plant….

1µg

Test tube

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

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 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)

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

IVIM 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

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

• 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

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

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

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 –FluoroquinolonesFluoroquinolones

–Cephalosporins (third Cephalosporins (third generation)generation)

–No quinolones for childrenNo quinolones for children

Campylobacter – MacrolidesMacrolides

–FluoroquinolonesFluoroquinolones

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

28

Treatments of zoonotic pathogens in man : is there

some AR?

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.

33

Travelling is the origin of salmonellosis dues to Salmonella enterica

sérotype Kentucky ST198 & resistance to ciprofloxacin

What could be the human health consequence of exposure to resistant zoonotic bacteria

34

35

Impact of AR on the human mortality due to salmonellosis

Macrolide resistance in Campylobacter jejuni and Campylobacter coli

37

Q3: What are the transmission pathways between animals and

man

38

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

39

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

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

Feather removal in a contaminated environment by feces (scald tank)

Contamination of the carcass

During evisceration, some degree of faecal contamination is inevitableno matter how stringent the hygiene measures that are applied

45

Direct transfer from animal to man(professional risk )

Also direct contact with antibiotic

The case of Methicillin-Resistant 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 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 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

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.

57

Indirect transfer from animal to man via the butcher’hands : a consumer risk

The case of MRSA

Hazard associated to the release of antibiotic in environment

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

Environ. Sci. Technol. 2010, 44, 580–587

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.)

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

Prevention principle

Reduction of antibiotic consumption

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. Generics2. Low price3. Turnover for the veterinarians

Consequences of generic marketing on antibiotic

consumption and the spread of resistance

75

Generics and antibiotic consumption

- 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

How to reduce the antibiotic consumption: reconsider some

dosage regimens

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

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) Bact

eria

cou

nts

per l

ung

(CFU

/lun

g)

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) Bact

eria

cou

nts

per l

ung

(CFU

/lun

g)

100

102

104

106

108

1010no 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

urce

ntag

es o

f mic

e al

ive

control

1-Clinical outcome (survival) A low early dose better than a late high dose

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

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

• 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

Conclusion: What is the most dangerous situation?

Eating pork

Travelling

Licking