Antibiotic Resistance

1. Antibiotic Resistance Background information, current issues and policy, and the veterinarian’s role

2. Outline • Recent news and importance of issue • Antibiotics: information, mode of action • Factors that contribute to resistance • In the free environment • In animals • Resistance: a working definition • The Veterinarians role and current policy • Discussion

4. Meropenem, an example of a carbapenem

6. www.usatoday.com

8. Level of Importance • One of the most important issues for current treatment for human and animal patients • Will probably become the most challenging treatment complication while we are practicing • 68% of acute respiratory tract visits were prescribed antibiotics. • Of these, 80% of the prescriptions were unnecessary according to CDC guidelines1. 1) Scott JG, Cohen D, DiCicco-Bloom B, Orzano AJ, et al: Antibiotic use in acute respiratory infections and the ways patients pressure physicians for a prescription. J FamPract: 50(10): 853-8, 2001.

9. Antibiotics • Take advantage of a difference between bacterial cells and host cells to be selectively bactericidal or bacteriostatic • FDA has four approved uses of antibiotics: treatment, prevention, control, and growth promotion/feed efficiency Gram-positive cell wall Gram-negative cell wall Eukaryotic cell membrane Pictures from Doug Johnson

10. http://en.wikipedia.org/wiki/File:Antibiotics_action.png

11. Transpeptidation inhibition • Transpeptidation is the cross-linking of peptides within cell wall. Necessary for cell wall integrity • Penicillin-binding proteins (pbp) catalyze this process • Penicillin and related antibiotics (β-lactams) inhibit this process + Transpeptidation by pbp Penicillin Cell lysis and death

12. MRSA • Multiple Resistant Staphylococcus aureus? • Skin infections are common and relatively easy to treat • Infections acquired in healthcare settings, both human and animal, are often more severe • Immunocompromised or vulnerable to infection • Post-operative risk • Presence of many ill individuals • Large reservoir for infection • Most human hospitals have protocols in place for Multiple Drug Resistant Organisms • Animal hospitals are lacking in robust protocols • Methicillin Resistant Staphylococcus aureus cdc.gov

13. Tracking Resistance

14. Tracking Resistance HealthMap.org

15. Resistance – A Working Definition • Antibiotic resistance is the ability of bacteria to resist the effects of an antibiotic. In a clinical setting this means the persistence of disease. • Antibiotic resistance occurs when bacteria change in some way that reduces or eliminates the effectiveness of drugs, chemicals, or other agents designed to cure or prevent infections. • Huge selective pressure is placed on bacteria when antibiotics are present cdc.gov

16. Resistance – possible causes • Mutation – change of drug target • Inevitable mutations that occur normally are enhanced by increased rates of DNA damage • Conjugation – direct transfer of genes • Transformation – eDNA is incorporated into cell • Transduction – transfer of genes via viruses • Destruction or inactivation of drug • Ability to pump drug out http://kentsimmons.uwinnipeg.ca/16cm05/1116/16monera.htm

17. Determining Resistance Disk Diffusion Assay Aminoglycoside Quinolone Tetracycline Ciprofloxacin NARMS Retail Meat Annual Report, 2007 Cephamycin

18. Contributing factors to resistance- Biofilms • The extreme majority of microbes do not live as isolated, pure cultures in the planktonic state • Rather they exist in complex communities surrounded by the extracellular polymeric substance (EPS) • The EPS consists of • Protein • eDNA • Sugars • Water Confocal Scanning Laser Microscopy Flemming and Wingender. Nature reviews 2010

19. Contributing factors to resistance- Biofilms • Biofilms offer many advantages over planktonic cells: • Protective barrier from direct harm and predation • Complex array of enzymes that otherwise may not be available to a particular species • Retention and storage of water and nutrients • Maintenance of chemical gradients • A diverse set of nuclear material for exchange (horizontal transfer) Flemming and Wingender. Nature reviews 2010

20. Contributing factors to resistance- Biofilms • Implications for human and animal health • Also consider achieving and maintaining the minimum inhibitory concentration in tissues (different tissue types having the same effect as a biofilm) Photo from Doug Johnson

21. Contributing factors to resistance- Exposure Kaufmann et al. 2010

22. Contributing factors to resistance- Exposure • Causes for continued low level exposure: • Non-therapeutic dose • Missed dose/early discontinuation • Did not achieve MIC at site of infection • Not the appropriate antibiotic LexA inhibition Kaufmann et al. 2010 Cirz et al. (2005)

23. Briefing on Current Issue • July 3, 2008. FDA issued an order that prohibited the extralabel use of cephalosporin drugs in food-producing animals • The AVMA recommended the FDA postponed the ruling until a risk assessment was preformed • Felt there was a lack of scientific evidence • No promise that it would benefit human health • Unintended consequences of animal health, food safety • In November of 2008 the FDA withdrew the order

24. Briefing on Current Issue • The Preservation of Antibiotics for Medical Treatment Act of 2009 - PAMTA (S.619/H.R.1549) • Eliminate the use of non-therapeutic use of antibiotics that are important in human health, meant to decrease the development of antibiotic resistant bacteria • Non-therapeutic use = use of a drug as a feed or water additive for an animal in the absence of any clinical sign of disease • Drugs listed: penicillin, tetracycline, macrolide, sulfonamide, or any drug that is used in humans to treat and prevent disease

25. The AVMA Position on PAMTA • The AVMA opposes this legislation • Increase in animal disease and death • Compromise disease prevention and control • PAMTA is not risk-based (backed up by a solid risk assessment) • Contrary to the practice of veterinary medicine • Current layers of protection • Conflicting scientific data on risk to humans

26. What YOU can do • Need for more information on to what extent antibiotics in animals play a role in human health • Novel drugs are desperately needed • Properly set up protocols should be established and followed

27. What do you think? • Now everyone has plenty of basic information and a general knowledge of the importance of the issue. • What do you think about …? • PAMTA and the current AVMA position • Current veterinary practices (draw from your own experiences) • Current human medicine practices (draw from your own experiences) • How things will change in the next 10 years (from now to time when some of you may be practicing) • Any general thoughts?