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