Jeff Jones, Animal Health and Veterinary Laboratories Agency, UK

1. Antimicrobial Resistance- Reducing the Over-Use of Antibiotics.Institute of Food Science and Technology, Spring Conference; 18/04/2013 Jeff Jones, Animal Health and Veterinary Laboratories Agency, UK

2. Usage of antibiotics • Spread of and selection for antibiotic resistance genes and antibiotic resistant bacteria • Reducing the use of antibiotics

3. The use of antimicrobials in animals. • Treatment of animal bacterial disease. • Animal Health. • Animal Welfare. • Use of antimicrobials for growth promotion purposes was banned throughout the EU in 2006.

4. Some veterinary issues are similar to those in human medicine... • Bacterial diseases can usually be treated with antibiotics. • Viral conditions do not respond to anti-bacterials and so treatment of uncomplicated viral conditions with antibiotics is inappropriate.

5. Other similar Issues in human and veterinary medicine... • Prophylaxis. • Animals or humans are treated before a situation in which disease or infection is highly likely to occur e.g. administration of antimicrobials before intestinal surgery. • Metaphylaxis. • Animals or humans are treated which have been in-contact with diseased animals or humans and might be expected to be incubating or have contracted the same condition e.g. meningitis

6. The problems in man and animals are not all linked... • Human medicine. • Many of the resistance problems in human medicine are entirely due to the use of antimicrobials in people and have little or nothing to do with antimicrobial use in animals. • Resistance in Mycobacterium tuberculosis. • Resistance in the human pneumonia pathogen Streptococcus pneumoniae. • Veterinary medicine. • Brachyspira hyodysenteriae (swine dysentery).

7. Zoonotic bacteria. • Salmonella. • Campylobacter. Resistant strains of zoonotic bacteria occurring in food-producing animals can be transferred along the food chain to humans.

8. Commensal bacteria. • Escherichia coli. • Enterococcus spp. Resistant strains of commensal bacteria occurring in food-producing animals can form a reservoir of resistance genes which may transfer to other bacteria.

9. Use of antimicrobials is one of the factors which encourage the spread of antimicrobial resistance… • Use of Antimicrobials. There are other factors including: • Clonal spread of resistant bacteria.

10. Usage of veterinary antibacterial agents • In 2007, usage varied from 18 to 188 mg/kg biomass of food producing animals across 10 European countries • Highest usage of antibacterials is in pigs • Differences between countries not explained by differences in animal species Grave et al, 2010

11. Any use of antibiotics will select resistant bacteria…. Resistant bacterium in a population Susceptible bacteria killed by antibiotics; resistant bacterium has advantage Resistant bacterium survives to reproduce

12. General bacterial organisation: • A resistance gene. • A plasmid carrying the resistance gene. • The bacterial chromosome • The bacterial isolate.

13. Plasmids. • Plasmids are circles of DNA able to transfer genetic material between bacteria at conjugation (bacterial mating). • They provide a mechanism by which resistance can spread between different strains of bacteria. • Therefore, if a human ingests a strain of animal E. coli, it may survive transiently and transfer its resistance to human E. coli (which are adapted to live in the human intestine for a long time).

14. Basic principle – Genetic linkage and co-selection. Cephalosporin Tetracycline Apramycin Use of any one of these antimicrobials selects for resistance to all three compounds….

15. Salmonella Heidelberg in Canada. • In 2004 all the hatcheries in Quebec were using ceftiofur to control E. coli infections. • In 2005, all the hatcheries stopped using ceftiofur • within a year there was a dramatic drop in the proportion of ceftiofur resistant E. coli and S. Heidelberg from poultry and a drop in the proportion of resistant S. Heidelberg from humans.

16. Effect of withdrawal of ceftiofur use? Dutil et al, 2010 16

17. Salmonella… • The clonal spread of bacterial strains can be very important in influencing the spread of resistance • Especially important within the pyramidal structure of parts of farming (for example poultry production). • Resistant strains can spread independently of antimicrobial usage.

18. A current example…..Salmonella Kentucky. • International spread of S. Kentucky ST198 – increasing human cases from 2002-2008 in four EU MSs and the US. Clonal spread occurred, mainly related to travel of people to Middle East and Africa.[Le Hello et al, 2011) • In 2011 unexpectedly appeared in turkeys – Poland. No clinical signs in turkeys. • Also recovered from: • Turkey meat • Municipal sewage sludge (considered to indicate spread to humans).

19. Salmonella Kentucky (2). • Shows multiple drug resistance to 7 antibiotics including ciprofloxacin. • Isolates unusual in that they show high level resistance to ciprofloxacin. • Ciprofloxacin resistance is linked to three mutations. • Turkey isolates and those from human cases are indistinguishable. • Primary infection of turkeys may have been outside Poland as most fattening flocks are imported as day old birds or hatching eggs.

20. Salmonella Kentucky (3). • Also occurs in poultry in some North African countries. • Little or no poultry movement from Africa to Europe. • ? Transferred to European poultry via humans? • Confirmed in the recent case of a turkey farmer in France who contracted the infection on holiday in North Africa and transferred it to his livestock...

21. Critically-Important Antimicrobials – WHO, 2007 Quinolones / fluoroquinolones 3rd / 4th generation cephalosporins

22. Cascade (Off label) use of third and fourth generation cephaloporins has now been banned in poultry (including eggs) due to the risk of spread of antimicrobial resistance to humans.

23. How do we reduce the use of antibiotics? • Adopt alternative strategies for the control and prevention of bacterial diseases of animals… • Vaccination. This has (for example) dramatically reduced the usage of antimicrobials in farmed fish. • Animal Health Planning including disease eradication. • Adopt alternative strategies eg teat sealant rather than dry cow antibiotic in dairy cows. • Improve hygiene and husbandry to reduce the occurrence of certain diseases, for example bovine and porcine respiratory disease can be influenced by ventilation and building design.

24. How do we reduce the use of antibiotics? • Ensure adequate farm and national biosecurity measures are in place to prevent the importation of resistant bacteria from • Neighbouring farms. • Other countries. Free trade, widespread global movement of animals, people, products can allow rapid dissemination of organisms….

25. How do we reduce the use of Antibiotics? • Ensure adequate terminal hygiene and disinfection procedures are put in place, with all-in; all-out management so that any resistant organisms do not persist on farms.

26. How do we reduce the use of antibiotics? • Adopt the prudent and responsible use guidelines published by the Responsible Use of Medicines in Agriculture (RUMA) Alliance in the UK (other associations have similar guidelines in other countries). • OIE Guidelines have been published which provide guidance for all OIE Member Countries and list responsibilities of all those involved.

27. Key points. • Antibiotics are important for animal health. • Large variation in usage between countries. • Use of antimicrobials is one of the factors which encourages the spread of antimicrobial resistance • Methods for reducing need for antibiotic use include good biosecurity, adoption of prudent use guidelines, effective disinfection and hygiene, improvements in management and husbandry, and vaccination.

28. References Dutil L, Irwin R, Finley R,et al. Ceftiofur resistance in Salmonella enterica serovar Heidelberg in chicken meat and humans, Canada. Emerg Infect Dis 2010 Jan [accessed 15.04.13]. Available from http://www.cdc.gov/EID/content/16/1/48.htm Grave K, Torren-Edo J, Mackay D Comparison of the sales of veterinary antibacterial agents between 10 European countries J. Antimicrob. Chemother. (2010) 65(9): 2037-2040 Le Hello S,Weill FX Guibert V,et al. Early strains of multidrug-resistant Salmonella enterica serovar Kentucky sequence type 198 from Southeast Asia harbor Salmonella genomic island 1-J variants with a novel insertion sequence. Antimicrob Agents Chemother 2012;56:5096-102 Thank you for listening…..