Frank Møller Aarestrup

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1 Danish Veterinary Laboratory Bacterial populations and resistance development: Intestinal tract of meat animals Frank Møller Aarestrup

2 12 Antibiotic production 10 Mill. Kg Animal feed Therapy Total

3 Use of antimicrobials in agriculture Therapy treatement of disorders or disease in sick animals Metaphylaxis Treatment of groups of healthy animals after clinical signs in pen mates Prophylaxis Use of antibiotics in advance of symptomatic disease e.g. medicated early weaning Growth promotion antibiotics used as feed additives increases growth rate, but mechanism not entirely known

4 Classes of antimicrobials used in agriculture All classes also used in humans, including the substances considered the most potent for human therapy today (Fluoroquinolones, 3rd gen. Cephalosporins, Glycopeptides, streptogramins, etc.)

5 200,00 180,00 160,00 Usage of Antimicrobials for Food-animals in the EU Milligram of antibiotics for growth promotion per kg meat produced Milligram of antibiotics for therapy per kg meat produced 140,00 120,00 100,00 80,00 60,00 40,00 20,00 0,00 Austria Belgium & Lux Denmark Finland France Germany Greece Ireland Italy Netherlands Portugal Spain Sweden United Kingdom Average EU

6 Distribution of Animal Health products in United Kingdom Producer Veterinary whole sale Non-veterinarian whole sale Products sold freely Veterinarian Pharmacy Retail sale >40% of income!! Food animal producer

7 Distribution of Animal Health products in Denmark Producer Medicines Vaccines Products sold freely Whole sale Veterinary Services Retail sale Pharmacy Veterinarian < 5% profit! Food animal producer

8 Selection of antimicrobial resistance and bacterial transfer in the farm-to-fork chain Wild fauna Environment (Natural antimicrobials) (Detergents) Environment Sewage, etc. (Antibiotic waste) Oral use Prophylaxis Mass medication Long duration Low doses Long term carriage Therapeutic use in rare cases Clinical disease and short term carriage Selective pressure favoring antibiotic resistance development

9 % resistance Fluoroquinolone resistance in Campylobacter Endtz et al Use of enrofloxacin for animals Human Poultry

10 Transfer of resistance genes Streptothricin Used in Eastern Germany for growth promotion Resistant E. coli in pigs - Transferable plasmid Resistant E. coli in pig farmers Resistant E. coli in community acquired UTI Plasmid in Shigella Tschäpe et al. (1984), Hummel et al. (1986), Witte (1998)

11 Special concerns Fluoroquinolone-resistant Salmonella 3rd gen. Cephalosporin-resistant Salmonella Fluoroquinolone-resistant Campylobacter Macrolide-resistant Campylobacter Vancomycin-resistant E. faecium Synercid-resistant E. faecium

12 Potential problems with AGP Growth promoter Avilamycin Avoparcin Tylosin/spiramycin Virginiamycin Bacitracin Therapeutic Ziracin* Vancomycin Erythromycin Synercid *: No longer developed for human use Carbadox, olaquindox Flavomycin, monensin, salinomycin

13 Occurrence of glycopeptide resistant enterococci (GRE) 1986: Humans (Leclercq et al. 1988, Uttley et al. 1988) 1993: Environment and pigs (Klare et al. 1993, Bates et al. 1994) 1994: Poultry, pigs and humans (Klare et al. 1995)

14 Steps in a causal link Selection of resistance by the use of AGP Transfer of resistance from animals to humans Directly, Food, Environment Infections caused by resistant bacteria of animal origin Clone, Gene

15 Epidemiological studies Broilers GRE Pigs GRE Avoparcin use Fishers exact: Fishers exact: 0.04 Bager et al. 1997

16 Map of glycopeptide resistance transposon Tn1546 ORF1 ORF2 vanr vans vanh vana vanx vany vanz

17 Spread of GRE to humans GRE in food of animal origin (Klare et al. 1995, Wegener et al. 1997, Klein et al. 1998) GRE in humans outside hospitals in Europe, not USA, not in vegetarians (Gordts et al. 1995, van der Auwera et al. 1996, Coque et al. 1996, van den Braak et al. 1997, Endtz et al. 1997)

18 Spread of GRE to humans Identical strains of GRE from humans and food animals (van den Bogaard et al. 1997, Simonsen et al. 1998, Descheemaeker et al. 1999, Willems et al. 2000) Identical types of Tn1546 among food animals and humans (Werner et al. 1997, Jensen et al. 1998, Woodford et al. 1998, Simonsen et al. 1998, Descheemaeker et al. 1999, Willems et al. 2000)

19 AFLP typing of glycopeptide resistant E. faecium Geno-group Origin and No. of isolates Calf Volunteer Patient Chickens Pigs Willems et al & pers. comm.

20 Interventions in Denmark concerning antimicrobial growth promoters (AGP) Avoparcin ban in Denmark, May 1995 (EU 1997) Virginiamycin ban in Denmark, January 1998 Voluntary stop of AGP for finishing pigs and poultry 1998 EU ban on the use of 4 AGP s from July 1999 (Tylosin, Spiramycin, Virginiamycin, Bacitracin) Agreement of total stop with all use of AGP s in Denmark for pigs before 2000

21 Consumption of antimicrobial growth promoters 120 Consumption in Tonnes Avilamycin Avoparcin Carb/ola Tylosin Virginiamycin Andre

22 Occurrence of VRE 80 6 Percent resistance Decreased use of tylosin Consumption in Tonnes E. faecium from broilers E. faecium from pigs Avoparcin use Aarestrup et al., 2001

23 GRE from pigs and transconjugants

24 Effect of prohibiting avoparcin in Germany and The Netherlands % human samples Humans Pigs Broilers Klare et al., 1997; van den Bogaard et al. 2000

25 Occurrence of macrolide resistance Percent resistance E. faecium E. faecalis Tylosin use Consumption Aarestrup et al., 2000

26 Percent resistance Avilamycin resistance ,5 2 1,5 1 0,5 0 Consumption Aarestrup et al., 2000 E. faecium from broilers Avilamycin use

27 Salmonella Typhimurium DT104 Resistant to: Ampicillin, chloramphenicol, streptomycin, sulphonamides, tetracycline Emerged worldwide within the 1990 ties

28 Quinolone-resistant Salmonella Typhimurium DT104 (UK) Percent of isolates November 93 Enrofloxacin licensed for animal use Chickens Cattle Pigs Humans

29 10 8 Slaughterhouse contamination Number of cases 6 4 Outbreak recoqnised Swine herd identified Mølbak et al., 1999 Week of 1998

30 Outbreak of QR, MR S. Typhimurium DT104, Denmark Clinical features 27 patients identified (2 occupational, 1 nosocomial) 7 (26%) history of antibiotic use prior to onset 11 (44%) hospitalized 6 treated with fluoroquinolones Lack of treatment effect reported in at least 4 patients 2 patients died; one previously healthy patient died from complications of intestinal perforation Mølbak, NEJM, 1999

31 60 Quinolone resistance among E. coli 450 Percent resistance Consumption Broiler Cattle Pigs Enrofloxacin 0

32 Conclusions Use of antimicrobials selects for resistance The same clones and resistance genes can be found in bacteria from animal and human origin A more limited use of antimicrobial agents for food animals are followed by a decrease in the occurrence of resistance

FACT SHEETS. On the Danish restrictions of non-therapeutical use of antibiotics for growth promotion and its consequences

FACT SHEETS. On the Danish restrictions of non-therapeutical use of antibiotics for growth promotion and its consequences 12 July 2010 FACT SHEETS On the Danish restrictions of non-therapeutical use of antibiotics for growth promotion and its consequences Denmark is a major livestock producer in Europe, and the worlds largest