Tout ce qu un praticien devrait savoir pour mettre en œuvre une antibiothérapie raisonnée chez le porc: I:Les questionnements

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questionnements Pierre-Louis Toutain Ecole Nationale

1 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. Liszt F. Schubert W.A. Mozart J. Hallyday 2 G. Mahler

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 3

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

5 Ce que l on ne pourra plus traiter en routine dans 30 ans Cancer treatment Organ Transplant Hip Replacement Without effective antibiotics, 30 40% of patients having total hip replacements would have a postoperative infection, with a case-fatality rate of roughly 30%. Gonorrhea Preterm Babies Complicated deliveries Wound Infection Urinary tract Infection Pneumonia Blood infection

6 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 evidencebased 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.

7 One world, one health & one resistome Treatment & prophylaxis Human medicine Community Veterinary medicine Animal feed additives Hospital Environment Agriculture Plant protection Industrial and household biocids

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

surgeons and farmers in the pig industry in the UK.

9 One health? Yes for vets focus groups to explore the drivers and motivators behind antimicrobial use and 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.

10 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..

11 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.

12 One world, one health & one resistome Treatment & prophylaxis Human medicine Community Veterinary medicine Hospital Agriculture Environment

13 Q1: What types of antimicrobial drug resistance does veterinary medicine face and which raise public health issues?

14 Résistance? Epidémiologie (microbiologique) Perte de sensibilité ECOFF Epidemiological cutoff Clinique Perte d efficacité thérapeutique Breakpoint clinique AST/Antibiogramme Paramètre Variables

15 The three types of AMR faced by vet medicine Target pathogen Zoonotic Commensal Efficacy in animal Efficacy in man Global ecological problem Farm Food chain Environment Animal health Issue Human health issue Public health Issue

Quid de la résistance des pathogènes vétérinaires VetPath programme by the European Animal Health Study Centre (CEESA) in EU (2009-2012).

16 Quid de la résistance des pathogènes vétérinaires VetPath programme by the European Animal Health Study Centre (CEESA) in EU ( ). 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

17 Prevalence of antibiotic resistance (%) in bacteria isolated from the respiratory tract versus CLSI BP when available

18 Brachyspira (US): August isolates; broth microdilution, MIC 50, MIC 90 Valnemuline (µg/ml) Ecoff Burch SVARM n& Szancer >0.25 >0.5 >2 >4

19 Brachyspira & Tiamulin results 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.

susceptibility to Lincomycin and tylosin.

20 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.

21 The three types of AMR faced by vet medicine Target pathogen Zoonotic Commensal Efficacy in animal Efficacy in man Global ecological problem Farm Food chain Environment Animal health Issue Human health issue Public health Issue

22 Quelles sont les pricipales infections humaines imputables à la chaîne alimentaire Salmonella spp 95% des cas humains (USA) soit 1.4x10 6 cas par an sont d'origine alimentaire Campylobacter jejuni 80% des cas humains (USA) soit 2x10 6 cas par an sont d'origine alimentaire E. Coli Verotoxinogènes (ex: O157:H7): 85% Enterotoxiques: 70% Autres: 30% Uropathogènes:? 25

23 Mortalité liée aux zoonoses (EU, 2012 ) (le nombre total de morts dans l UE est d environ 4,84 millions par an )

24 Zoonoses in EU 2012

25 Prevalence of Salmonella in retail meat samples

26 3-Traitements des zoonoses : Les germes zoonotiques retrouvés chez l homme sont-ils résistants? 30

27 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

28 Salmonella: resistance to ciprofloxacine

29 Salmonella: resistance to ceftriaxone (C3G)

30 Campylobacter coli: resistance to macrolides

31 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

32 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 The three types of AMR faced by vet medicine Target pathogen Zoonotic Commensal Efficacy in animal Efficacy in man Global ecological problem Farm Food chain Environment Animal health Issue Human health issue Public health Issue

34 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 42

35 Prevalence of Indicator bacteria in meat 2013: E Coli Enterococcus

36 E Coli (n=520) healthy animals Antibiotics %R BP (µg/ml) CLSI Ampicillin Cefipime (C4G) 0 32 Cefotaxime (C3G) 0 4 Ciprofloxacin Colistine Tetracycline TMP/sulfa /76 Gentamicin

37 Resistance (%) among Enterococcus faecium from retail meat 2013

38 Q2: What are the animal s ecosystems potentially able to raise public health concerns in terms of resistance to antibiotics

39 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

40 Bacterial load & duration of exposition to antibiotics during treatment Test tube Infected Lungs Digestive tract Manure Sludge Waste µg Hours mg Days Kg Weeks Tons Months Food chain Environment

41 Q3: what is the pathways for transmission between animal and human resistomes

42 Commensal flora is the turnstile betweeen and within the two medicines 52

43 Classical natural history of bacterial infections (at hospital) Specific pathogen Disease Andremont et al, The lancet infection

«New» natural history of bacterial infections

CTX-M To have a clean commensal flora is an

resistance Specific pathogen Dissemination of

44 «New» natural history of bacterial infections (in the community) Commensal bacteria of a future patient (100g) Disease Colonization/carriage Gene of resistance ESBL: CTX-M To have a clean commensal flora is an individual issue Disselmination of gene of resistance Specific pathogen Dissemination of genes of resistance Adapted from Andremont et al, The lancet infection

45 The link animal/man Environment Globalisation The commensal genetic pool is large and encompasses the potential for many different mechanisms conferring AMR

46 Greening our AB One world, one health Commensal flora Genes of resistance (zoonotic pathogens) Environment Food chain Commensal microbiota Most of the prudent use recommendations do not address this question

47 Intestinal microbiota is the turnstile between the two medicine

48 Main digestive or environmental reservoirs of EBSL A global ecological issue 58

49 Q10: what are epidemiological evidence of the veterinary contribution to the human antimicrobial resistance 60

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

50 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. 61

51 Transfer from pigs to farmer: Enterococcus faciens 64

52 Corrélation entre le niveau d antibiorésistance chez le porc et chez l homme pour E coli dans 11 pays de l UE 65 Viera et al

53 Evidence provided by metagenomic of a potential contribution of veterinary antimicrobials to the human resistome 67

54 Resistance gene penetration is higher for antibiotics approved for use in animals or with analogs that have such approval. 69 The colors of the bars represent whether or not animal use has been approved by the U.S. FDA Genome research:

55 Antibiotics approved for animal use and that have a longer use have significantly higher resistance potential Genome research:

56 Q5: Why veterinary antibiotic treatments are able to alter the resistome of the animal gut microbiota.

campylobacter commensal ( enterococcus) Food chain Blood Environment

57 Oral route of administration AMD: oral route Proximal Gastro-intestinal tract Distal 1-F% Microbiota Zoonotics (salmonella, campylobacter commensal ( enterococcus) Food chain Blood Environment Biophase Target pathogen Resistance :animal health issue Resistance: public health issue

58 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 75

Non-oral route of adminsitration Gastro-intestinal tract

Quinolones Macrolides Tetracyclines Distal Microbiota

enterococcus) Food chain Blood Environment Biophase

59 Non-oral route of adminsitration Gastro-intestinal tract Intestinal efflux Bile Non oral route Proximal Quinolones Macrolides Tetracyclines Distal Microbiota Zoonotics (salmonella, campylobacter ) commensal ( enterococcus) Food chain Blood Environment Biophase Target pathogen Resistance: animal health issue Resistance: public health issue

60 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 bla TEM gene

61 Genotypic evaluation of ampicillin resistance: copy of bla TEM genes per gram of feces 1 E+10 1 E+9 oral route fed copies/g of feces 1 E+8 1 E+7 1 E+6 1 E+5 oral route fasted intramuscular route control group 1 E days A significant effect of route of administration on bla TEM fecal elimination (p<0.001).

62 Marbofloxacin impact on E. coli in pig intestinal flora (From P. sanders, Anses, Fougères) IV IM 3 days 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 (~ ufc/g 1 d). E. coli R followed to a slow decrease back to initial level after 12 days 79

63 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

64 Une excellente revue by Agriculture and Agri-food Canada on 09/28/15

65 Q6-How antibiotics increase the prevalence of resistance in Commensal microbiota 82

66 Horizontal genes exchanges (BLSE)

presence or absence of antibiotics Gnotobiotic mice harboring a

67 How antibiotics promote colonization by resistant bacteria Fate of a multiantibiotic-resistant strain of Serratia liquefaciens in presence or absence of antibiotics Gnotobiotic mice harboring a susceptible strain of E. coli From Duval-Yflah Y. et al. IAI 1980; 28 :981

68 Q9-What are the hazard associated to the release of antibiotic and genes of resistance in environment 86

69 Sewage production in a pigs setting Annual sewage production is about tons per sow unit i.e. about 1500 to 2000 tons of sewage per year for a setting of 100 sows 87

70 Feces production About 5 tons of feces per american per year The fecal peril

71 Fate of antibiotics, zoonotic pathogens and resistance genes: residence time in the different biotopes Digestive tract: 48h Lagoon: few weeks Ex:T1/2 tiamuline=180 days Bio-aérosol Air, water & ground pollution Air pollution 89

72 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

73 Rate of antibiotic degradation in manure, soil, waste Antibiotics matrix Degradation % Days Chlortétracycline Fumier bovin Tétracyclines Porc fumier Oxytetracycline Sol+contam fumier Oxytetracycline Sédiment, aérobiose TMP lisier Sulfamides Fumier/lisier 0 28 Aminoglycosides fumier 0 30 Tiamuline Tylosine Lisier porc aérobie 50 2 Bacitracine Sable fèces bovin Enrofloxacine Fumier bovin <

the tetracyclines, with some individual ARG being >15 times

74 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. PL Toutain Ecole vétérinaire Toulouse 93

75 Urban wastwater are hot spots for horizontal exchanges between the two medicine Waste-water treatment facilities can be hotspots for horizontal transfer of resistance (The Lancet 2013) 94

76 95

77 Many of the resistance factors we see in clinics today have been recruited from nonpathogenic bacteria around us (Bonomo and Szabo 2006). 96

78 L antibiorésistance doit être comprise comme un problème écologique global et non comme une simple impasse médicale

2 nd UK-Russia Round Table on AMR. Christopher Teale, Animal and Plant Health Agency. Moscow, st February 2017.

2 nd UK-Russia Round Table on AMR. Christopher Teale, Animal and Plant Health Agency. Moscow, 20-21 st February 2017. Veterinary Approaches and Priorities. Indicator organisms (commensals) E. coli enterococci