antimicrobial use and resistance insights from a veterinary perspective

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  • Op een melkveebedrijf worden de meeste diergeneesmiddelen ingezet in kader van de uiergezondheid, vandaar dat dit project specifiek op de uiergezondheid gericht is. Ook niet overroepen: uit gegevens van Nederland (in Nederland is sinds 2009 een programma gestart (reductie AB van 20% in 2011, 50% in 2013)) is gebleken dat het gebruik van diergeneesmiddelen in de melkveehouderij meevalt relatief ten opzichte van de kalver-, varkens-, en pluimveehouderij. Doch, er is ruimte voor verbetering en zolang er geen gegevens beschikbaar zijn over het werkelijke gebruik van antibiotica in de melkveehouderij, kunnen we ons ook niet verdedigen tegenover dergelijke beschuldigingen ivm resistentie. In dit project willen we de uiergezondheid verbeteren wat logischerwijs zou moeten resulteren in een verminderd, of alleszins meer verantwoord gebruik van diergeneesmiddelen. Elke schakel in de zuivelsector heeft dus baat bij het project.
  • Op een melkveebedrijf worden de meeste diergeneesmiddelen ingezet in kader van de uiergezondheid, vandaar dat dit project specifiek op de uiergezondheid gericht is. Ook niet overroepen: uit gegevens van Nederland (in Nederland is sinds 2009 een programma gestart (reductie AB van 20% in 2011, 50% in 2013)) is gebleken dat het gebruik van diergeneesmiddelen in de melkveehouderij meevalt relatief ten opzichte van de kalver-, varkens-, en pluimveehouderij. Doch, er is ruimte voor verbetering en zolang er geen gegevens beschikbaar zijn over het werkelijke gebruik van antibiotica in de melkveehouderij, kunnen we ons ook niet verdedigen tegenover dergelijke beschuldigingen ivm resistentie. In dit project willen we de uiergezondheid verbeteren wat logischerwijs zou moeten resulteren in een verminderd, of alleszins meer verantwoord gebruik van diergeneesmiddelen. Elke schakel in de zuivelsector heeft dus baat bij het project.
  • antimicrobial use and resistance insights from a veterinary perspective

    1. 1. Antimicrobial use and resistance: Background from a veterinary perspective Prof. Dr. Jeroen Dewulf Jeroen.Dewulf@UGent.be Unit for Veterinary Epidemiology, Faculty of Veterinary Medicine Ghent University Centre of excellence AMCRA
    2. 2. Content  The epidemiology of antimicrobial resistance in animals  Antimicrobial consumption  Transmission of resistance from animals too humans and vice versa
    3. 3. Epidemiology of antimicrobial resistance Fase I: Development of AR
    4. 4. Antimicrobial resistance genes are naturally present in the environment • Development of antimicrobial resistance is independant of antimicrobial use • Function of the genes is often unknown
    5. 5. Antibioticumresistentiegenen zijn natuurlijk aanwezig in de omgeving • Ontstaan antibioticumresistentiegenen onafhankelijk van blootstelling aan antibiotica • Functie van genen in de omgeving ongekend
    6. 6. Bacteria have sex….. 6
    7. 7. Resistance can easily be transmitted
    8. 8. Epidemiology of antimicrobial resistance Fase I: Development of AR Fase II: Selection of AR resistance
    9. 9. Selection of resistance • Selection of antimicrobial resitance is the result of :  Antimicrobial use!  Non-use risk factors (persistance and spread):  Stress  Feed  Hygiene  Housing  …
    10. 10. Introduction of antimicrobials and development of resistance in Staphylococcus aureus Year of introduction of the antimicrobial Year of first detection of resistance
    11. 11. Selection of resistance Callens et al., 201211
    12. 12. Linking antimicrobial use to antimicrobial resistance in 7 EU countries based on surveillance data (a) Aminopenicillins (ampicillin) (b) Third generation Cephalosporins (cefotaxime) 0.12 0.5 0.4 y = -0,0002x2 + 0,0255x - 0,0707 R² = 0,93 0.2 0.1 0 0.1 0.08 0.06 0.04 0.02 10 20 30 40 Antimicrobial use (mg/PCU) 50 0 0.1 Arcsin % AM resistance Arcsin % AM resistance 0.15 0.1 0.05 0.2 0.3 0.4 Antimicrobial use (mg/PCU) 0.5 0 0.6 0.2 0.4 0.6 Antimicrobial use (mg/PCU) 0.8 0.6 0.05 0.04 0.03 y = -0,0021x2 + 0,0241x - 0,0188 R² = 0,80 0.02 0.01 0.8 1 0.5 0.4 y = -0,0149x2 + 0,1752x + 0,0057 R² = 0,81 0.3 0.2 0.1 0 0 0 0.4 0.6 Antimicrobial use (mg/PCU) 0.1 (e) Aminoglycosids (gentamicin) 0.06 y = 0,1313x2 + 0,1234x - 0,0112 R² = 0,99 0.2 0.2 0.15 (f) Aminoglycosids (streptomycin) (d) Amphenicols (chloramphenicol) 0 0.3 0.25 0 60 0.25 0.2 0.35 0.05 0 0 y = 1,1278x2 - 0,2875x + 0,0221 R² = 0,99 0.4 y = 0,6887x2 - 0,1812x + 0,0135 R² = 0,94 Arcsin % AM resistance 0.3 0.45 Arcsin % AM resistance 0.6 (c) Fluoroquinolons (ciprofloxacin) 0.14 Arcsin % AM resistance Arcsin % AM resistance 0.7 0 2 4 6 Antimicrobial use (mg/PCU) 8 0 1 2 3 4 5 Antimicrobial use (mg/PCU) 6 Chantziaras et al., 2013 7
    13. 13. Linking antimicrobial use to antimicrobial resistance in 7 EU countries based on surveillance data Average antimicrobial resistance ranking 7 Belgium 6 Netherlands 5 Switzerland 4 Austria 3 Denmark Norway 2 Sweden 1 1 2 3 4 5 6 7 Average antimicrobial use ranking Chantziaras et al., 2013
    14. 14. Belgian broilers: 35 – 40% E. coli resistant for ceftiofur 60% of broilers carrier of ESBL Persoons et al., 2010
    15. 15. resistentie percentage Fattening Pigs: ANTIMICROBIAL RESISTANCE Escherichia coli end fattening period 100 80 63 60 40 20 60 58 51 20092010 39 28 26 15 9 7 7 4 4 3 2 0 Callens et al., 2011
    16. 16. Belgian surveillance data 2011 100 Broiler chickens Pigs 80 Bovines 70 Antimicrobial resistance (%) 90 Veal Calves 60 50 40 30 20 10 0 AMP SMX TET TMP NAL STR CIP CHL Antimicrobial agent FOT TAZ KAN GEN FFN COL AMP: ampicillin, CHL: chloramphenicol, CIP: ciprofloxacin, COL: colistin, FFN: florfenicol, FOT: cefotaxime, GEN: gentamicin, KAN: kanamycin, NAL: nalidixic acid, SMX: sulfomethoxazole, STR: streptomycin, TAZ: ceftazidime, TET: tetracycline, TMP: trimethoprim Chantziaris et al., 2013
    17. 17. Epidemiology of antimicrobial resistance Fase I: Development of AR Fase II: Selection of AR resistance Fase III: Persistance of AR resistance
    18. 18. resistentie percentage Fattening pigs: ANTIMICROBIELE RESISTENTIE Escherichia coli end of fattening period 100 80 63 60 40 20 60 58 51 20092010 39 28 26 15 9 7 7 4 4 3 2 0 Callens et al., 2011
    19. 19. Belgian broilers Persoons et al., 2010
    20. 20. Prevalence of LA-MRSA in pigs
    21. 21. Epidemiology of antimicrobial resistance Fase I: Development of AR Fase II: Selection of AR resistance Fase III: Persistance of AR resistance Fase IV: Reduction of AR resistance
    22. 22. Reversion to susceptebility by reduced antimicrobial consumption
    23. 23. Epidemiology of antimicrobial resistance Where do we find resistance? • Production animals? • Companion animals? • Wildlife? • Environment?
    24. 24. E.Coli in different ecological niches Occurrence of multiresistance percentage of strains 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 resistant against ... antimicrobials fattening pig broilers dairy cows hare human sewage surface water Casteleyn et al., 2007
    25. 25. E.Coli in different ecological niches Occurrence of multiresistance percentage of strains 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 resistant against ... antimicrobials dairy cows hare Casteleyn et al., 2007
    26. 26. E.Coli in different ecological niches Occurrence of multiresistance percentage of strains 25 20 15 10 5 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 resistant against ... antimicrobials human sewage surface water Casteleyn et al., 2007
    27. 27. E.Coli in different ecological niches percentage of strains Occurrence of multiresistance 18 16 14 12 10 8 6 4 2 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 resistant against ... antimicrobials fattening pig Broilers Casteleyn et al., 2007
    28. 28. Content  The epidemiology of antimicrobial resistance in animals  Antimicrobial consumption  Transmission of resistance from animals too humans and vice versa
    29. 29. Antimicrobials in veterinary medicine • Use:  Curative (all animals)  Metaphylactic (predominantly production animals)  Prophylactic (only production animals) • Administration:  Vets (all animals)  Owner / farmer (predominantly production animals)  Feed industry (only production animals)
    30. 30. Use of antimicrobials in broiler production 600 500 production cycle 1 production cycle 2 Treatment Incidence 400 300 200 100 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 farm Average treatment incidence 121.4 131.8 (udd) (ddd) Persoons et al., 2010
    31. 31. Classification of antimicrobials according to importance in human medicine II III I Use of antimicrobials in broiler production flumequin TIddd tilmicosin penicillin TIudd enrofloxacin tylosin amoxicillin doxycycline linco-spec trim-sulfa lincomycin 0 10 20 30 40 50 60 70 chickens per 1000 Persoons et al., 2010
    32. 32. Use of antimicrobials in pig production 600 Total TIDDDpig/herd Total TIUDDpig/herd DDDpig or UDDpig/1000 pigs at risk/day 500 400 300 200 100 0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 Farm num ber Timmerman et al., 2005
    33. 33. Use of antimicrobials in pig production TIudd 1000 TI for 50 herds TIadd average TIadd average TIudd 900 800 700 600 500 400 300 200 100 0 0 10 20 herd 30 40 Callens et al., 2011 50
    34. 34. Use of antimicrobials in pig production Prophylactic vs metaphylactic use Percentage 100 80 60 2003 2010 40 20 0 preventief metafylactisch Callens et al., 2011
    35. 35. Group treatments p e r c e n t a g e b 100 e 80 d r 60 i j 40 v e 20 n 0 84 80 72 70 2003 2010 31 24 14 4 kraamperiode batterijperiode 1ste helft opfok 2de helft opfok Callens et al., 2011
    36. 36. Doseringen Doseringen P e 100.00 r 80.00 c 60.00 e 40.00 n t 20.00 a 0.00 g e 93 80 What is a correct dosis? 47 40 Correct dosis for what? 31 29 29 2003 2010 23 12 8 Callens et al., 2011
    37. 37. Dairy production 25 Treatment days per cowyear ADUR/koejaar 20 15 10 5 0 1 5 9 13 17 21 25 29 33 37 41 45 49 53 Herd Stevens et al., 2013
    38. 38. Dairy production 40 +/- 60% 35 30 Percentage 25 20 15 10 5 0 Stevens et al., 2013
    39. 39. Antimicrobial use in veal calves • 15 herds • TI DDD = 416,8 • 96% oral group treatments • 12% profylactisch • 88% metafylactisch • 44% of the grouptreatments underdosed Pardon et al., 2012 39
    40. 40. Antimicrobial use in veal calves 100.0 90.0 Percentage of veal cohorts 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Weeks on feed respiratory disease arrival prophylaxis diarrhea dysbacteriosis enterotoxaemia idiopathic peritonitis Figure 1: Percentage of veal cohorts (n=15) receiving antimicrobial group treatment at least four days of the week by indication and by week of production (20072009, Belgium) Pardon et al., 2012 40
    41. 41. Treatment incidence on UDD (animals/1000 daily treaed) Antimicrobial use in livestock in Belgium 600 500 400 300 200 100 0 poultry Persoons et al., 2012 pigs Callens et al., 2012 dairy cattle beef cattle Catry et al., under revision veal calves veal calves (164 kg) Bron: Bart Pardon, Ugent
    42. 42. Which antimicrobials are critical? WHO: Critically Important Antimicrobials for Human Medicine: Categorization for the Development of Risk Management Strategies to contain Antimicrobial Resistance due to Non-Human Antimicrobial Use CONCLUSIONS The prioritization of classes of antimicrobials to be addressed most urgently in terms of risk management strategies for non-human use of antimicrobials resulted in the selection of three groups of drugs: quinolones, 3rd /4th generation cephalosporins, and macrolides.
    43. 43. percentage bedrijven Use of antimicrobials in pig production 100 80 60 40 20 0 Callens et al., 2011
    44. 44. Dairy production 7 ADUR/ koejaar 6 5 4 3 Excenel Naxcel Cobactan Eficur Cefenil Ceftiocyl cevoxel Advocin Baytril Floxadil Marbocyl Vlaanderen Canada 2 1 0 Stevens et al., 2013
    45. 45. antimicrobial use in companion animals
    46. 46. BelVet-Sac Antimicrobial use in animals in Belgium 400.00 2011-2012 Total: - 7,2% 350.00 30.12 300.00 Tons Active Substance 36.81 51.37 57.40 59.74 250.00 55.37 200.00 150.00 318.66 262.09 252.81 239.56 241.66 2010 2011 100.00 222.48 50.00 0.00 2007 2008 2009 Antimicrobial pharmaceuticals 2012 Medicated premixes www.belvetsac.ugent.be
    47. 47. BelVet-Sac Antimicrobial use in animals in Belgium 2011-2012 Total: - 6,9% 180.00 160.00 14.56 mg Active Substance/ kg Biomass 140.00 17.94 25.20 29.14 28.16 27.22 120.00 100.00 80.00 154.10 127.75 60.00 124.03 116.85 118.54 2010 2011 109.39 40.00 20.00 0.00 2007 2008 2009 Antimicrobial pharmaceuticals 2012 Medicated premixes www.belvetsac.ugent.be
    48. 48. Antimicrobial use in Europe: EMA / ESVAC
    49. 49. EMA-ESVAC mg/PCU 300 250 200 150 mg/PCU 100 50 0 Data 2010 www.belvetsac.ugent.be
    50. 50. ESVAC 2011
    51. 51. EMA-ESVAC Antimicrobial use in mg/PCU (ESVAC) 450 400 350 300 250 200 150 100 50 0 MG/PCU 2010 MG/PCU 2011 Data 2011 www.belvetsac.ugent.be
    52. 52. Content  The epidemiology of antimicrobial resistance in animals  Antimicrobial consumption  Transmission of resistance from animals too humans and vice versa
    53. 53. Transmission of antimicrobial resistance from animal-human: Literature data
    54. 54. Antimicrobials in animals Animal commensals Animal pathogenes Zoonotic bacteria Residues in meat Human commensals Antimicrobials in human Human pathogenes
    55. 55. Antimicrobial resistant Salmonella Typhimuriumtransmission too human through food = AMRP pig 74,5% 94,1% 92,1% = ABRP broiler 53,6% 90,7% 79% Amp pig/broiler 48,5%/56,1% 35,3%/76,7% 50,3% AMRP=antimicrobial resistance profile; Amp=ampicilline resistence; Research scientific comity FASFC 2009
    56. 56. Clinical Microbiology and Infection 2011
    57. 57. Assessment of human exposure to cephalosporin resistant E.coli (CREC) from chicken through consumption of broiler meat Probability of the exposure to CREC through consumption of a meal containing chicken meat and in function of 4 arbitrarily chosen infection doses. Infection doses (arbitrarily chosen) 10000 cfu 1000 cfu 100 cfu 10 cfu Exposure through insufficient heating of chicken meat preparations 0% 0% 0% 0,03 bought cooked / prepared) 0,39% 1,53% 3,26% 6,97% Total exposure 0,39% 1,53% 3,26% 7% Exposure through cross contamination (all types of chicken excl. chicken meat De Poorter et al., 2012
    58. 58. Transfer of antimicrobial resistance in the gut In vitro simulation of the human gut 1,00E+08 1,00E+07 CFU/ml 1,00E+06 1,00E+05 E. coli (human) 1,00E+04 B1-54 1,00E+03 acceptor transconjugants ESBL-donor pluimvee 1,00E+02 1,00E+01 1,00E+00 0 1 2 3 4 6 7 8 9 10 11 12 13 14 16 17 time after inoculation (days) Inoculatie ESBLsource strain Cefotaxime treatment Smet et al., 2011 58
    59. 59. Ecosystem
    60. 60. Conclusions  AMR is selected for by use of     antimicrobials Once AMR is present it is difficult to get rid of again AM are often used unnecessary AMR may spread from animals to humans through food, direct contact and environment Lots of unknowns
    61. 61. Thank you for your attention Prof. Dr. Jeroen Dewulf Jeroen.Dewulf@UGent.be Unit for Veterinary Epidemiology, Faculty of Veterinary Medicine Ghent University Centre of expertise AMCRA

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