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

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 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

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

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

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

–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

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

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

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

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 an international 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

Veterinary

antibiotics

Animal

Black box

Resistance

human

Prevention principle

Antibiotics

Animal

Grey box

Zoonotics

AR homme

Commensals

AR homme

Pathogens

AR animal

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. Generics

2. Low price

3. 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

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

Conclusion: What is the most dangerous situation?

Eating pork

Travelling

Licking