Transfer of resistant bacteria from animals to humans

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Niels Frimodt-Møller, MD, DMSc.; Dept. for Microbiological Surveillance and Research, Statens Serum Institut, Copenhagen

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Transfer of resistant bacteria from animals to humans

  1. 1. Transfer of resistant bacteria from animals to humans – relation to antibiotic use as growth promoters and therapeutics Niels Frimodt-Møller Professor, MD, DMSc. Dept. for Microbiological Surveillance and Research Statens Serum Institut Copenhagen Denmark
  2. 2. Antibiotic resistance: Clinical consequence * P < 0.05 1,29 (1,04 – 1,59)* S.pneumoniae : PenR vs PenS Tleyjeh et al. CID 2006;42:778-97 2,52 (1,9 - 3,4)* Enterococcus : VR vs VS DiazGranados et al. CID 2005;41:327-33 4,41 (1,03 – 18,81)* E. coli : FQ-R vs FQ-S Lautenbach et al. CID 2005;41:923-9 1,93 (1,54 – 2,42)* S.aureus : MR vs MS Cosgrove et al. CID 2003;36:53-59 Odds Ratio (95% CI) for mortality
  3. 3. <ul><li>Vancomycin resistant E. faecium </li></ul><ul><li> - the growth promoter case </li></ul>
  4. 4. Enterococcus faecium : Vancomycin resistant (VRE) ~ vanA gene, located on transposon, transferable via plasmid <ul><li>1988: Clinical isolates of VRE found in human infections in France and UK Jordens JZ et al. J. Antimicrob. Chemother. 34: 515–528.; Uttley AHC et al. 1988. Lancet I, 57– 58; Leclercq R N Engl J Med 1988; 319 : 157–161. </li></ul><ul><li>Not related to Vancomycin consumption in humans, but to Avoparcin </li></ul><ul><li>(Vancomycin analogue) use as growth promoter Bates J et al. J. Antimicrob.Chemother. 1994, 34: 507–516 . </li></ul><ul><li>1995: Denmark proves direct connection between Avoparcin use and VRE in poultry and pigs – and bans Avoparcin </li></ul><ul><li>Aarestrup, F. M. 1995. Microb.Drug Resist. 1: 255–257. </li></ul><ul><li>2000: EU ban on all growth promoters </li></ul><ul><li>Ultimate risk: Transfer of vanA to Staphylococcus aureus ? </li></ul><ul><li> Noble, C. J. 1978. J. Clin. Pathol. 31: 1182–1186. </li></ul>
  5. 5. Enterococcus faecium : Vancomycin resistant (VRE) ~ vanA gene, located on transposon, transferable via plasmid <ul><li>1988: Clinical isolates of VRE found in human infections in France and UK Jordens JZ et al. J. Antimicrob. Chemother. 34: 515–528.; Uttley AHC et al. 1988. Lancet I, 57– 58; Leclercq R N Engl J Med 1988; 319 : 157–161. </li></ul><ul><li>Not related to Vancomycin consumption in humans </li></ul><ul><li>Suspicion on Avoparcin (Vancomycin analogue) use as growth promoter Bates J et al. J. Antimicrob.Chemother. 1994, 34: 507–516 . </li></ul><ul><li>1995: Denmark proves direct connection between Avoparcin use and VRE in poultry and pigs – and bans Avoparcin </li></ul><ul><li>Aarestrup, F. M. 1995. Microb.Drug Resist. 1: 255–257. </li></ul><ul><li>2000: EU ban on all growth promoters </li></ul><ul><li>Ultimate risk: Transfer of vanA to Staphylococcus aureus ? </li></ul><ul><li> Noble, C. J. 1978. J. Clin. Pathol. 31: 1182–1186. </li></ul>Isolation from a patient of a vancomycin resistant S. aureus containing the vanA element from E. faecalis present in same wound Flannagan et al. AAC 2003 ; 47:3954–9.
  6. 6. Growth promoters select for resistance in animals and transfer of resistance (or resistant bacteria) from food production animal to humans ? e.g. vancomycin resistant E. faecium (VRE) <ul><li>Proof of : </li></ul><ul><li>Resistant bacteria (VRE) in animals in farm </li></ul><ul><li>VRE in animals at slaughter </li></ul><ul><li>VRE in meat (products) from animals </li></ul><ul><li>VRE in gut (feces) of humans eating meat </li></ul><ul><li>and not found in gut (feces) of vegetarians </li></ul><ul><li>VRE in gut (feces) of patients </li></ul><ul><li>VRE in infections (as in gut) </li></ul><ul><li>Experimental uptake and colonization in gut (feces) of VRE </li></ul><ul><li>Experimental transfer of resistance genes in gut (feces) of VRE </li></ul><ul><li>Disappearance of VRE with reduction of antibiotic selection </li></ul>
  7. 7. Correlation between use of Avoparcin as growth promoter and prevalence of Vancomycin-Resistant E. faecium (VRE) Aarestrup, F. M. 1995. Occurrence of glycopeptide resistance among E.faecium isolates from conventional and ecological poultry farms. Microb.Drug Resist. 1: 255–257. 2 32 <ul><li>avoparcin in </li></ul><ul><li>feed </li></ul>32 40 + avoparcin in feed No. of flocks with VRE No. of flocks investigated Poultry farms
  8. 8. Transfer of VRE from animal to humans: Scientific evidence Same type VRE in poultry and farmer Simonsen et al. Microb Drug Resist. 1998; 4: 313-8. Same VRE in poultry before and after slaughter Aarestrup et al. APMIS 1998; 106:606–22 VRE in food . Wegener et al. Int J Food Microbiol 1997; 35:57–66. Robredo Int J Food Microbiol. 2000; 54: 197-204. VRE carriers in countries, where avoparcin used, but not else Ieven [abstract LB-8, 41st ICAAC, 2001. Klare et al. Microb Drug Resist. 1999; 5: 45-52. Klare et al. Microb Drug Resist. 1995;1: 265-72. Same type VRE in pigs and patients Jensen et al. AAC 1999; 43:724–5; Hammerum et al. JAC 2004; 53:547–9.
  9. 9. Results of ban of growth promoters Avoparcin and Virginiamycin in Denmark
  10. 10. Fecal carrier rates of Vancomycin Resistant E. faecium (VRE) in non-hospitalised humans 12/100 11/40 6/100 13/400 1/670 3/169 2/6023 % pos with VRE Ban of Avoparcin Van den Bogard et al., JAC 2000, 46: 146 Van den Auwera et al. JID 1996, 173: Klare et al. Microb Drug Resist. 1999;5:45-52. Gambarotto et al. J Clin Microbiol. 2000; 38: 620–624. Torell et al. J Clin Microbiol . 1999; 37: 3509–3513 Kolar et al.J Med Microbiol. 2005; 54: 965-7. . S F D NL D Cz D
  11. 11. Significant decrease of VRE infections and colonization rates in patients at hospital admission after AGP ban Colonization at admission Infections in hospitals W. Witte, personal comm. M. Leven et.al. ICAAC 2001 Germany Belgium N=335 N=353 % vanA % vanA
  12. 12. Growth promoters select for resistance in animals and transfer of resistance (or resistant bacteria) from food production animal to humans ? e.g. vancomycin resistant E. faecium (VRE) <ul><li>Proof of : </li></ul><ul><li>Resistant bacteria (VRE) in animals in farm </li></ul><ul><li>VRE in animals at slaughter </li></ul><ul><li>VRE in meat (products) from animals </li></ul><ul><li>VRE in gut (feces) of humans eating meat </li></ul><ul><li>and not found in gut (feces) of vegetarians </li></ul><ul><li>VRE in gut (feces) of patients </li></ul><ul><li>VRE in infections (as in gut) </li></ul><ul><li>Experimental uptake and colonization in gut (feces) of VRE </li></ul><ul><li>Experimental transfer of resistance genes in gut (feces) of VRE </li></ul><ul><li>Disappearance of VRE with reduction of antibiotic selection </li></ul>
  13. 13. Use of Streptogramin Growth Promoters in Poultry and Isolation of Streptogramin-Resistant Enterococcus faecium from Humans Kieke et al. The Journal of Infectious Diseases 2006; 194:1200–8 Minnesota, Wiscosin, USA
  14. 14. <ul><li>Campylobacter </li></ul>
  15. 15. Campylobacter infection: Clinical consequences <ul><li>121 cases with extra-digestive manifestations admitted to French hospitals were reviewed: 88% had bacteraemia; 15% died (Tchamgoue et.al., ICAAC 2001, abstract no. L-770) </li></ul>
  16. 16. Campylobacter, erythromycin-resistance and relative mortality <ul><li>4,7 times higher risk of death when infected with erythromycin-resistant Campylobacter </li></ul><ul><li>There is a trend of decreasing erythromycin resistance in Danish Campylobacter spp. after ban of growth promoters </li></ul><ul><li>In 2001, there were 104 fewer Campylobacter cases in Denmark, with 3,5 fewer deaths </li></ul>Helms et al. JID 2005; Molbak et al. 2002
  17. 17. Macrolide use and - resistance in Campylobacter coli from pigs
  18. 18. <ul><li>Salmonella </li></ul>
  19. 19. Antibiotic resistant Salmonella: Clinical importance <ul><li>Ciprofloxacin-R Salm. had a significantly longer fever defervescence time (7.7 vs 4.7 days, p<0.001) and hospital stay (12.1 vs 8.2 days, p<0.001), and higher rates of complications (55.5% vs 24.0%, p=0.014) and mortality than cipro-S Salmonella Walia et al. Ann Trop Paediatr. 2005; 25:161-74 </li></ul><ul><li>Antibiotic resistant Salmonella Typhimurium was associated with a 3.15-fold (95% confidence interval, 1.39-7.10-fold) higher risk of invasive illness or death within 90 days of infection, compared with that observed for infection with pansusceptible strains. Helms et al. J Infect Dis. 2004; 190: 1652-4 </li></ul>
  20. 20. Salmonella: Antibiotic resistance associated with antibiotic use ? <ul><li>Salmonella as a primary human pathogen is seldom carried by humans (e.g. chronic carriers occur) and therefore not subjected to selection by antibiotic use in humans </li></ul><ul><li>In contrast, Salmonella is carried by production-animals (i.e. not causing infection) and therefore present in reservoirs where antibiotic selection during treatment with antibiotics takes place </li></ul><ul><li>Therefore, most antibiotic resistance in Salmonella is due to selection by antibiotics used in animals </li></ul>
  21. 21. No. of human Salmonella, Campylobacter and Yersinia cases in Denmark 1980-2009
  22. 22. <ul><li>E. coli </li></ul>
  23. 23. E. coli: Intestinal commensal, causing diarrhoea or extraintestinal infections such as urinary tract infection (UTI) Lautenbach et al. CID 2005;41:923-9 Manges et al, NEJM 2001, 345: 1007; Burman et al., Am J Med 2003, 115: 358; Johnson et al. Lancet 2002; 359:2249; Phillips et al. Lancet 1988, 331: 1038; Olesen et al. SJID 1994, 26: 406; Pitout et al. JCM 2005; 43: 2844 <ul><li>UTI: Annually 6-8 mill. cases in USA, 130-175 mill. cases globally; >80% associated with E.coli; most common source of bloodstream infections ~ 40.000 deaths/y in USA </li></ul><ul><li>Antibiotic resistance in E.coli increases mortality with a factor 2 - 4 </li></ul><ul><li>Since 1980´ies several reports of state- or countrywide outbreaks with clones of antibiotic-resistant E. coli causing UTI including pyelonephritis </li></ul>
  24. 24. E. coli: UTI <ul><li>Increasing evidence of production-animals/food as source : </li></ul><ul><li>Resistance and virulence genes in human E. coli (both found in feces and in UTI) and E. coli in production animals and related food products are highly correlated (exact same DNA-types) </li></ul><ul><li> Vincent et al. Emerg Infect Dis 2010; Jakobsen et al., submitted </li></ul><ul><li>Resistance genes, e.g. for sulphonamides, in E. coli from humans and production animals carry the exact same mutations – and different between e.g. poultry and pigs Trobos et.al. Microbiology 2009 </li></ul><ul><li>Experimental intake of resistant E. coli in food leads to high level colonization without antibiotic selection . </li></ul>Trobos et al. JAC, 2009
  25. 25. Conclusion: Transfer of resistance animal > human: Enterococci, Salmonella, Campylobacter and E. coli : <ul><li>Antibiotic resistance in these pathogens when causing infection in humans is associated with a worse outcome, even increased risk of death </li></ul><ul><li>Scientific evidence is amounting that enterococci and E. coli – as is well known for Campylobacter and Salmonella - are spread via the food chain </li></ul><ul><li>The evidence further shows, that the risk for humans includes antibiotic resistance, which is highly correlated to antibiotic use in production-animals </li></ul><ul><li>Ban of growth promoters prevented spread of VRE in humans, reduced resistance in pathogens like Campylobacter, and reduced serious human infections (e.g. macrolide-resistant Campylobacter) </li></ul>
  26. 26. <ul><li>Acknowledgements: </li></ul><ul><li>Anette Hammerum </li></ul><ul><li>Camilla Lester </li></ul><ul><li>Lotte Jakobsen </li></ul><ul><li>Margareta Trobos </li></ul><ul><li>Frank Aarestrup </li></ul><ul><li>DANMAP editorial group </li></ul>
  27. 27. Why was VRE more prevalent in US hospitals than in Europe ? Vancomycin usage in USA vs. Europe Klare et al. IJFM 2003
  28. 28. EARSS 2008
  29. 29. Staphylococcus aureus (Sa) : MRSA epidemiology Spa types in 2008 1 % of SA bacteraemias ~

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