Antibiotic ResistanceBackground information, current issues and policy,

and the veterinarian’s role

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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

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Meropenem, an example of a carbapenem

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6www.usatoday.com

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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 Fam Pract: 50(10): 853-8, 2001.

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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

Pictures from Doug Johnson

Gram-positive cell wall Gram-negative cell wall Eukaryotic cell membrane

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

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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

Cell lysis and death

Penicillin

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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

cdc.gov

• Methicillin Resistant Staphylococcus aureus

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Tracking Resistance

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Tracking Resistance

HealthMap.org

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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

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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

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Determining Resistance

Aminoglycoside

Tetracycline

Quinolone

Ciprofloxacin

Cephamycin

Disk Diffusion Assay

NARMS Retail Meat Annual Report, 2007

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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

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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

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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

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Contributing factors to resistance- Exposure

Kaufmann et al. 2010

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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

Kaufmann et al. 2010

LexA inhibition

Cirz et al. (2005)

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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

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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

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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

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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

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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?