Tout ce qu’un praticien devrait savoir pour mettre en œuvre une antibiothérapie raisonnée

chez le porc:

I:Les questionnements

Pierre-Louis Toutain

Ecole Nationale Vétérinaire de Toulouse

France

AVIA, Québec 21 octobre 2016

2

Qui est l’intrus?

F. Schubert

W.A. Mozart

G. Mahler

F. Liszt

J. Hallyday

3

Qui est l’intrus?

• Schubert, Mozart, Liszt et Mahler sont morts prématurément d’infections bactériennes qui aujourd’hui seraient traitables avec succès par un antibiotique.

Pour lui, les antibiotiques ont fait le job et ce doit être le cas pour tous dans l’avenir

Expected Annual deaths attributable to AMR compared to other major causes of death in 2050.

Source: Antimicrobial resistance: tackling a crisis for the health and wealth of nations. Review on Antimicrobial Resistance

10 millions de morts / an en 2050 en lien avec l’antibiorésistance

Ce que l’on ne pourra plus traiter en routine dans 30 ans

PneumoniaUrinary tractInfection

WoundInfection

Cancer treatment

OrganTransplant

HipReplacement

Complicateddeliveries

PretermBabies

Gonorrhea

Without effective antibiotics, 30–40% of patients having total hip replacements would have a postoperative infection, with a case-fatality rate of roughly 30%.

Blood infection

46: Antimicrobial resistance (AMR) poses a serious threat to public health, growth and global economic stability. We affirm the need to explore in an inclusive manner to fight antimicrobial resistance by developing evidence-based ways to prevent and mitigate resistance, and unlock research and development into new and existing antimicrobials from a G20 value-added perspective, and call on the WHO, FAO, OIE and OECD to collectively report back in 2017 on options to address this including the economic aspects. In this context, we will promote prudent use of antibiotics and take into consideration huge challenges of affordability and access of antimicrobials and their impact on public health. We strongly support the work of the WHO, FAO and the OIE and look forward to a successful high-level meeting on AMR during the UN General Assembly. We look forward to the discussion under the upcoming presidency for dealing with these issues.

One world, one health & one resistome

Treatment & prophylaxis

Human medicineCommunity

Veterinary medicine

Animal feed additives

Environment

Hospital Agriculture

Plant protection

Industrial and household biocids

The priorities of a sustainable veterinary antimicrobial therapy is related to public health issues, not to animal health issues

focus groups to explore the drivers and motivators behind antimicrobial useand prescribing by veterinary surgeons and farmers in the pig industry in the UK.

Veterinary opinion was such that ‘external pressures’, such as

pressure from clients, legislation and public perception, were considered

to strongly influence prescribing behaviour,

whereas, farmers considered issues surrounding farming systems and

management to be greater drivers towards antimicrobial use.

One health?Yes for vets

One health?No for farmer

Pig farmers were significantly more worried about

financial/legal issues than about antimicrobial resistance.

They perceived many benefits and moderate to low levels of

public health risk from using antimicrobials..

One health?No for farmer

• They believed that a reduction in revenues for slaughter pigs treated with a large amount of antimicrobials would have the most impact on reduced antimicrobial usage in their country.

Treatment & prophylaxis

Human medicineCommunity

Veterinary medicine

Environment

Hospital Agriculture

One world, one health & one resistome

Q1: What types of antimicrobial

drug resistance does veterinary medicine face and which raise

public health issues?

Résistance?

Epidémiologie

(microbiologique)

Perte de sensibilité

ECOFF

Epidemiological cutoff

Paramètre

Clinique

Perte d’efficacité thérapeutique

Breakpoint clinique

AST/Antibiogramme

Variables

Target pathogen Zoonotic Commensal

Efficacy in animal Efficacy in man Global ecological problem

Animal health Issue Human health issue Public health Issue

Food chain EnvironmentFarm

The three types of AMR faced by vet medicine

• VetPath programme by the European Animal Health Study Centre (CEESA) in EU (2009-2012).

• Bacteria from diseased non-treated food-producing animals across EU employing a protocol with

harmonized methods of sampling and bacterial isolation

• Regarding pigs, five major respiratory tract pathogens (first cause of mortality in swine nursery

and grower operations),

• P. multocida, Actinobacillus pleuropneumoniae, Hamophilus parasuis, Bordetella

bronchiseptica and Streptococcus suis

Quid de la résistance des pathogènes

vétérinaires

Prevalence of antibiotic resistance (%) in bacteria isolated from the respiratory tract 2002–2006 versus 2009–2012.

CLSI BP when available

Brachyspira (US): August 2016

124 isolates; broth microdilution, MIC50, MIC90

Valnemuline (µg/mL)

Ecoff Burch SVARM n& Szancer

>0.25 >0.5 >2 >4

Brachyspira & Tiamulinresults according to the interpretative criteria

Conclusion:

Brachyspira species showed high susceptibility to tiamulin, valnemulin, and carbadox, heterogeneous susceptibility to doxycycline, and low susceptibility to Lincomycin and tylosin.

In general, Brachyspira isolates from the United States were more susceptible to these antimicrobials than were isolates from other countries.

Brachyspira (US): August 2016

Brachyspira species showed high susceptibility to tiamulin, valnemulin,

and carbadox, heterogeneous susceptibility to doxycycline, and low

susceptibility to Lincomycin and tylosin.

In general, Brachyspira isolates from the United States were more

susceptible to these antimicrobials than were isolates from other

countries.

Target pathogen Zoonotic Commensal

Efficacy in animal Efficacy in man Global ecological problem

Animal health Issue Human health issue Public health Issue

Food chain EnvironmentFarm

The three types of AMR faced by vet medicine

25

Quelles sont les pricipales infections humaines imputables à la chaîne alimentaire

• Salmonella spp– 95% des cas humains (USA) soit 1.4x106 cas par an sont

d'origine alimentaire

• Campylobacter jejuni– 80% des cas humains (USA) soit 2x106 cas par an sont

d'origine alimentaire

• E. Coli– Verotoxinogènes (ex: O157:H7): 85%

– Enterotoxiques: 70%

– Autres: 30%

– Uropathogènes: ?

Mortalité liée aux zoonoses (EU, 2012 )

(le nombre total de morts dans l’UE est d’environ 4,84 millions par an )

Zoonoses in EU 2012

Prevalence of Salmonella in retail meat samples

30

3-Traitements des zoonoses : Les germes zoonotiques retrouvés chez l’homme

sont-ils résistants ?

Problème potentiel de santé publique lié à l’antibiothérapie des germes zoonotiques

Emergence de résistance vis-à-vis des traitements de première

intention pour les infections intestinales.

Salmonella

– Fluoroquinolones

– Céphalosporines de 3eme génération

– Impossibilité de traiter des enfants avec des quinolones

Campylobacter

– Macrolides

– Fluoroquinolones

Salmonella: resistance to ciprofloxacine

Salmonella: resistance to ceftriaxone (C3G)

Campylobacter coli: resistance to macrolides

Campylobacter coli: resistance to ciprofloxacin

For Campylobacter,

fluoroquinolones and

macrolides are important

treatment options for severe

infections.

Epidemiologic cutoff values

(ECVs) are used for

interpreting antimicrobial

susceptibility data. Because

ECVs differ between

Campylobacter species,

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.

Target pathogen Zoonotic Commensal

Efficacy in animal Efficacy in man Global ecological problem

Animal health Issue Human health issue Public health Issue

Food chain EnvironmentFarm

The three types of AMR faced by vet medicine

42

Les germes commensaux du tube digestifs à

considérer

1. Les Entérobactéries• Gram negatif

2. Les Entérocoques• Gram positif• Les deux espèces les plus fréquemment rencontrées en

pathologie humaine sont : Enterococcus faecalis (80%) et Enterococcus faecium (10-20%) qui peuvent être à l'origine d'infections nosocomiales chez les patients fragilisés

Prevalence of Indicator bacteria in meat 2013:

E Coli Enterococcus

E Coli (n=520)healthy animals

Antibiotics %R BP (µg/mL) CLSI

Ampicillin 34.6 32

Cefipime (C4G) 0 32

Cefotaxime (C3G) 0 4

Ciprofloxacin 0.2 4

Colistine 0.2 4

Tetracycline 70.6 16

TMP/sulfa 41.3 4/76

Gentamicin 1.4 16

Resistance (%) among Enterococcus faecium from retail meat 2013

Q2: What are the animal’s ecosystems potentially able to raise public health concerns in

terms of resistance to antibiotics

The critical animal’ecosytems in terms of

emergence and spreading of resistance

• Open and large ecosystems

– Digestive tract

– Skin

• Open but small ecosystem

– Respiratory tract (infection)

• Closed and small ecosystem

– Mammary gland

Bacterial load & duration of exposition to antibiotics during treatment

Infected

LungsDigestive

tract

mg

Days

Kg

Weeks

Manure

Sludge

Waste

Food chain

Tons

Monthsµg

Hours

Test

tube

Environment

Q3: what is the pathways for transmission between

animal and human resistomes

Commensal flora is the turnstile betweeen and within the two

medicines

52

“Classical” natural history of bacterial infections (at hospital)

DiseaseSpecific pathogen

Andremont et al, The lancet infection 2011 11 6-8 53

« New » natural history of bacterial infections(in the community)

Commensal bacteria

of a future patient

(100g)

Colonization/carriage

Gene of resistance

ESBL: CTX-M…

Dissemination of

genes of resistance

Disease

Specific pathogen

Adapted from Andremont et al, The lancet infection 2011 11 6-8

Disselmination of gene of resistance

To have a clean commensal flora is an individual issue

The link animal/man

The commensal genetic pool is large and encompasses the potential for many different mechanisms conferring AMR

EnvironmentGlobalisation…

One world, one health

Commensal flora

Genes of resistance

(zoonotic pathogens)

Commensal microbiota

Environment

Food chain

Greening our AB

Most of the prudent use recommendations do not address this question

Intestinal microbiota is the turnstile between the two medicine

Main digestive or environmental reservoirs of EBSL

• A global ecological issue58

60

Q10: what are epidemiological

evidence of the veterinary

contribution to the human

antimicrobial resistance

61

The historical and emblematic case:

Nourseothricin in animal husbandry for growth

promotion,

• After using of the streptothricin antibiotic for growth promotion, plasmid-borne resistance to streptothricin could be observed in E. coli from nourseothricin fed pigs, from employees in pig farms and from their family members. Moreover, streptothricin resistance plasmids also occurred in E. coli of man without any contact to pig farms (gut flora and even urinary tract infections). However, these individuals live in villages and towns of the territory where nourseothricin was applied to pigs.

64

Transfer from pigs to farmer: Enterococcus faciens

65

Corrélation entre le niveau d’antibiorésistance chez le

porc et chez l’homme pour E coli dans 11 pays de l’UE

Viera et al

Evidence provided by metagenomic of a potential

contribution of veterinary antimicrobials to the

human resistome

67

Resistance gene penetration is higher for antibiotics approved

for use in animals or with analogs that have such approval.

69The colors of the bars represent whether or not animal use has been approved by the U.S. FDA

Genome research: 2013 23 1163-1169

Antibiotics approved for animal use and that have a longer use have

significantly higher resistance potential

70

Genome research: 2013 23 1163-1169

Q5: Why veterinary antibiotic treatments are able to alter the

resistome of the animal gut microbiota.

Gastro-intestinal tract

Proximal Distal

1-F%

Resistance :animal health issue Resistance: public health issue

Biophase

Target pathogen

Blood

Microbiota•Zoonotics (salmonella, campylobacter •commensal ( enterococcus)

AMD: oral route

Food chain

Environment

Oral route of administration

75

Bioavailability of tetracyclins by oral route

• Chlortetracycline:– about 20%

• Doxycycline:– About 20%

• Oxytetracycline:– Pigs:4.8%– Piglets, weaned, 10 weeks of age: by drench: 9%;– in medicated feed for 3 days: 3.7% .

• Tetracycline:– Pigs fasted:23% .

• Most of the administered dose is lost for the animal and is only spill in the environment

Gastro-intestinal tract

Proximal DistalIntestinal efflux

Bile

Resistance: animal health issue Resistance: public health issue

Biophase

Target pathogen

Blood

Non oral route

Quinolones

Macrolides

Tetracyclines

Microbiota•Zoonotics (salmonella, campylobacter )•commensal ( enterococcus)

Food chain

Environment

Non-oral route of adminsitration

The aim was to assess the impact of 3 ampicillin dosage regimens on ampicillin resistance among Entrobacteriaceae recovered from swine feces and on the excretion in feces of the blaTEM gene

Genotypic evaluation of ampicillin resistance:copy of blaTEM genes per gram of feces

A significant effect of route of administration on blaTEMfecal elimination (p<0.001).

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

79

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

Colistine• Piglets were given either underdoses of colistin by oral gavage for five days or overdoses by in-feed

medication for 14 days.

The composition of fecal microbiota was studied by quantitative PCR, 16S rRNA sequencing, culture of

Enterobacteriaceae, and quantification of short-chain fatty acids (SCFAs).

• The main perturbation was the significant but transitory decrease in the E. coli population during

treatment, yet all the E. coli isolates were susceptible to colistin.

Under- or overdoses of colistin do not result in any major disturbance of piglet fecal microbiota and

rarely select for chromosomal resistance in the dominant E. coli population

Une excellente revue

www.nrcresearchpress.com by Agriculture and Agri-food Canada on 09/28/15

82

Q6-How antibiotics increase the prevalence of resistance in Commensal

microbiota

Horizontal genes exchanges(BLSE)

How antibiotics promote colonization by resistant bacteriaFate of a multiantibiotic-resistant strain of Serratia liquefaciens in presence or

absence of antibiotics

From Duval-Yflah Y. et al. IAI 1980; 28 :981

Gnotobiotic mice harboring a susceptible strain of E. coli

86

Q9-What are the hazard associated

to the release of antibiotic and

genes of resistance in environment

87

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

Feces production

• About 5 tons of feces per

american per year

The fecal peril

89

Fate of antibiotics, zoonotic pathogens and resistance

genes: residence time in the different biotopes

Digestive tract: 48hLagoon: few weeks

Air pollution

Bio-aérosol

Air, water & ground pollution

Ex:T1/2 tiamuline=180 days

Elimination of antibiotics into the

environment

• As much as 75% of the antibiotics

administered to food producing animals are

directly excreted into the environment

without any benefit for the animal

• The case of aquaculture

91

Rate of antibiotic degradation in manure, soil, waste…

Antibiotics matrix Degradation % Days

Chlortétracycline Fumier bovin 24 84

Tétracyclines Porc fumier 50 48

Oxytetracycline Sol+contam fumier 0 180

Oxytetracycline Sédiment,

aérobiose

50 43

TMP lisier 50 22-41

Sulfamides Fumier/lisier 0 28

Aminoglycosides fumier 0 30

Tiamuline 50 26

Tylosine Lisier porc aérobie 50 2

Bacitracine Sable fèces bovin 77 30

Enrofloxacine Fumier bovin <1 56

PL Toutain Ecole vétérinaire Toulouse 93

ARG from all classes of antibiotics tested have

significantly increased since 1940, but especially within

the tetracyclines, with some individual ARG being >15

times more abundant now than in the 1970s.

Urban wastwater are hot spots for

horizontal exchanges between the two

medicine

94

Waste-water treatment facilities can be hotspots for horizontal transfer of resistance (The Lancet 2013)

95

• Many of the resistance factors we see in clinics

today have been recruited from nonpathogenic

bacteria around us (Bonomo and Szabo 2006).

96

L’antibiorésistance doit être comprise comme un problème

écologique global et non comme une simple impasse médicale