The epidemiology of antimicrobial resistance and the link between human and veterinary medicine

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1 The epidemiology of antimicrobial resistance and the link between human and veterinary medicine Prof. Dr. Jeroen Dewulf Unit for Veterinary Epidemiology, Faculty of Veterinary Medicine Ghent University Centre of excellence AMCRA 1

2 Content The epidemiology of antimicrobial resistance in animals Antimicrobial consumption Transmission of resistance from animals too humans and vice versa Epidemiology of antimicrobial resistance Fase I: Development of AR 2

3 Antibioticumresistentiegenen zijn natuurlijk aanwezig in de omgeving Ontstaan antibioticumresistentiegenen onafhankelijk van blootstelling aan antibiotica Functie van genen in de omgeving ongekend Bacteria have sex.. 6 3

4 Epidemiology of antimicrobial resistance Fase I: Development of AR Fase II: Selection of AR resistance Selection of resistance Selection of antimicrobial resitance is the result of : Antimicrobial use! Non-use risk factors (persistance and spread): Stress Feed Hygiene Housing 4

5 Introductionof antimicrobialsanddevelopmentof resistance in Staphylococcus aureus Year of introduction of the antimicrobial Year of first detection of resistance Selection of resistance Callens et al.,

6 Linking antimicrobial use to antimicrobial resistance in 7 EU countries based on surveillance data Arcsin % AM resistance (a) Aminopenicillins (ampicillin),7,6,5,4,3 y = -,2x 2 +,255x -,77,2 R² =,93, Antimicrobial use (mg/pcu) Arcsin % AM resistance (b) Third generation Cephalosporins (cefotaxime),14,12 y =,6887x 2 -,1812x +,135 R² =,94,1,8,6,4,2,1,2,3,4,5,6 Antimicrobial use (mg/pcu) Arcsin % AM resistance (c) Fluoroquinolons (ciprofloxacin),45,4 y = 1,1278x 2 -,2875x +,221,35 R² =,99,3,25,2,15,1,5,2,4,6,8 Antimicrobial use (mg/pcu) Arcsin % AM resistance,25,2,15,1,5 (d) Amphenicols (chloramphenicol) y =,1313x 2 +,1234x -,112 R² =,99 Arcsin % AM resistance,6,5,4,3,2,1 (e) Aminoglycosids (gentamicin) y = -,21x 2 +,241x -,188 R² =,8 Arcsin % AM resistance,6,5,4,3,2,1 (f) Aminoglycosids (streptomycin) y = -,149x 2 +,1752x +,57 R² =,81,2,4,6,8 1 Antimicrobial use (mg/pcu) Antimicrobial use (mg/pcu) 2Antimicrobial 4use (mg/pcu) 6 8 Chantziaras et al., 213 Linking antimicrobial use to antimicrobial resistance in 7 EU countries based on surveillance data 7 Belgium Average antimicrobial resistance ranking Norway Sweden Denmark Netherlands Austria Switzerland Average antimicrobial use ranking Chantziaras et al., 213 6

7 Belgian broilers (E. coli): 35 4% E. coli resistant for ceftiofur 6% of broilers carrier of ESBL Persoons et al., 21 Use or correct use? Dosing Antimicrobial class Correctness of dosing ARclass OR p-value Under 42,8% Ref. β-lactams Correct 42,2%.98 =.92 Over 4,9%.93 =.69 Under 62,1% Ref. Tetracyclines Correct 31,6%.28 <.5 Over 79,2% 2.32 <.1 Callens et al., 213 7

8 Defining a DDDA and DCDA list spectinomycin per oral non feed/water Belgium (n=1), recommended dose = 4 mg/kg, Germany (n=1), recommended dose = 15 mg/kg * 3,75 sulphaguanidine + sulphadimidin (France, n=2) min=38.4 mg/kg, * 4,16 max=16 mg/kg tylosin (Belgium, n=7) min=4.5 mg/kg, max= 45 mg/kg * 1 JAC, Postma et al., 214 Belgian surveillance data 211 (E. coli) Antimicrobial resistance (%) Broiler chickens Pigs Bovines Veal Calves 2 1 AMP SMX TET TMP NAL STR CIP CHL FOT TAZ KAN GEN FFN COL Antimicrobial agent 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., 213 8

9 Epidemiology of antimicrobial resistance Fase I: Development of AR Fase II: Selection of AR resistance Fase III: Persistance of AR resistance Vleesvarkens: E. coli 9 * * * 8 Commensal strains (VAR) Antmicrobial resistance (%) * Pathogenic strains (VAR) 2 1 AMP SMX TET TMP NAL STR ENR¹ CHL GEN FFN Antimicrobial agents AMP: ampicillin, SMX: sulfomethoxazole, TET: tetracycline, NAL: nalidixic acid, STR: streptomycin, ENR¹: enrofloxacin (national monitoring report used ciprofloxacin), CHL: chloramphenicol, GEN: gentamycin, FFN: florfenicol 18 Chantziaras et al., 214 9

10 Prevalence of LA-MRSA in pigs 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 1

11 MARAN rapport Content The epidemiology of antimicrobial resistance in animals Antimicrobial consumption Transmission of resistance from animals too humans and vice versa 11

12 Use of antimicrobials in broiler production 6 5 production cycle 1 production cycle 2 4 Treatment Incidence farm Average treatment incidence (udd) (ddd) Persoons et al., 21 Use of antimicrobials in broiler production Classification of antimicrobials according to importance in human medicine III II I flumequin tilmicosin penicillin enrofloxacin tylosin amoxicillin doxycycline linco-spec trim-sulfa lincomycin chickens per 1 TIddd TIudd Persoons et al., 21 12

13 Use of antimicrobials in pig production 1 TI for 5 herds TIudd TIadd average TIadd average TIudd herd Callens et al., 211 Group treatments p e r c e n t a g e b e d r i j v e n kraamperiode batterijperiode 1ste helft opfok de helft opfok Callens et al.,

14 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., Treatment incidence on UDD (animals/1 daily treaed) Antimicrobial use in livestock in Belgium poultry pigs dairy cattle beef cattle veal calves veal calves (164 Persoons et al., 212 Callens et al., 212 Catry et al., under revision kg) Bron: Bart Pardon, Ugent 14

15 Which antimicrobials are critical? REFLECTION PAPER / SCIENTIFIC OPINIONS WHO AMCRA FORMULARIA OIE HG Center of Expertise on Antimicrobial Consumption and Resistance in Animals 15

16 16

17 antimicrobial use in companion animals 18, 16, BelVet-Sac Antimicrobial use in animals in Belgium 14,56 18,18 25,2 29,14 28,16 27,22 25,29 14, mg Active Substance/ kg Biomass 12, 1, 8, 6, 154,1 129,45 124,3 116,85 118,54 19,39 12,74 4, 2,, Antimicrobial Pharmaceuticals medicated premixes : - 12,7% 17

18 45 Antimicrobial use in Europe: EMA / ESVAC Content The epidemiology of antimicrobial resistance in animals Antimicrobial consumption Transmission of resistance from animals too humans and vice versa 18

19 Antimicrobials in animals Animal commensals Animal pathogenes Zoonotic bacteria Residues in meat Human commensals Human pathogenes Antimicrobials in human Antimicrobial resistant Salmonella Typhimuriumtransmission too human through food = AMRP pig 74,5% 94,1% 92,1% = ABRP broiler 53,6% 9,7% 79% Amp pig/broiler 48,5%/56,1% 35,3%/76,7% 5,3% AMRP=antimicrobial resistance profile; Amp=ampicilline resistence; Research scientific comity FASFC 29 19

20 Clinical Microbiology and Infection 211 Transfer of antimicrobial resistance in the gut In vitro simulation of the human gut 1,E+8 1,E+7 1,E+6 CFU/ml 1,E+5 1,E+4 1,E+3 1,E+2 1,E+1 1,E time after inoculation (days) Inoculatie ESBLsource strain Cefotaxime treatment E. coli (human) B1-54 transconjugants acceptor ESBL-donor pluimvee Smet et al.,

21 Ecosystem 41 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 21

22 Thank you for your attention Prof. Dr. Jeroen Dewulf Unit for Veterinary Epidemiology, Faculty of Veterinary Medicine Ghent University Centre of expertise AMCRA 22