MERIAL PRESENTATION OCTOBER XX, 1999

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(No Transcript)
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Ranking of Antimicrobial Drugs Relative to Their
Use in Animals

• Richard Carnevale VMD
• Vice President, Scientific, Regulatory and
  International Affairs
• Animal Health Institute

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Why are we here?

• AHI represents the major animal health companies
  in the US.
• CDER/CVM has asked this committee to consider the
  relationship of human and animal antimicrobials.
• The advice of this committee is critical as it
  will affect the practice of veterinary medicine
  and animal production.

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Why are we here?

• FDA regulatory approach will affect new and
  existing antimicrobial drugs for food animals
• Infectious bacterial, fungal,and viral diseases
  are common problems in food animal production.
• Antimicrobials are a vital product line with many
  of our members

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Why are we here?

• AHI members as part of larger human health
  companies are greatly concerned with resistance
  development.
• Selection of resistant bacteria can affect
  efficacy of products for animal diseases as well
  as potential human health affects.

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Availability of a wide variety of products is
critical

• Range of products reduces resistance pressure on
  any one or a few compounds.
• Timely and effective treatment of animal diseases
  improves animal health and food safety.

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Animal medicines are highly regulated

• FD C Act applies same standards to animal
  antimicrobials as with human products.
• Additional burden is to prove that residues that
  may be left in animal are safe.
• Resistance concerns must now be addressed as
  well.

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Industry supports science based requirements

• Industry believes in a strong FDA and rigorous
  standards.
• Standards must be grounded in science and not
  based on supposition or emotion.
• Industry relies on a predictable process and
  reasonable set of standards in order to invest in
  new product development.

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CVM Guidance to Industry 152

• Qualitative risk assessment process to determine
  risk to human health of approving an animal
  antimicrobial.
• Categorization of importance to human medicine is
  a key component.
• Foodborne zoonotic infections considered most
  likely route of transmission.
• Commensal to non-commensal resistance transfer is
  cited as a major concern.

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What is AHIs Concern?

• Most drugs in appendix A are ranked of high
  importance based on meeting one or more of ten
  different criteria.
• Most of the criteria have little to do with how
  the drugs are used in animals or the infections
  veterinarians are treating.
• Macrolides are rated High because of Legionella
  pneumophila which is not zoonotic.
• High risk category likely means no or very
  limited animal approvals.

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What is AHIs Concern?

• Underlying assumption by the agency appears to be
  that there is resistance gene transfer between
  animal commensal and human non-enteric bacteria.
• We know of no documented in vivo evidence for
  such a transfer.
• Experimental efforts to colonise humans with
  animal E. faecium strains-transient presence only
  (Sorensen et al, 2001)
• Similarly, human-animal inoculation unsuccessful
  (Qaiyumi et al 2000)

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What is AHIs Concern?

• AHI believes that majority of the infections that
  are critical for antimicrobial treatment in
  humans will not be jeopardized by allowing
  certain uses in animals.
• Ranking of importance should factor in whether or
  not there is real evidence of an animal
  connection.
• Appendix A ranking is double jeopardy.
• Sole criterion for the Consequence Assessment
  portion
• Drives re-evaluation of currently approved
  antibiotics

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Experts Survey

• Bywater, Casewell, Journal of Antimicrobial
  Chemotherapy 2000 46 643-645
• Assessment of the impact of antibiotic
  resistance in different bacterial species and of
  the contribution of animal sources to resistance
  in human infections
• Surveyed practicing physicians and medical
  microbiologists in UK and elsewhere on major
  human antibiotic resistance problems.

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Contribution to human resistance of a)
individual spp and b) animal sources?

• Designed simple questionnaire.
• Based on list of organisms causing resistance
  problems.
• Sent to experts in the field (n26)
• Senior academics/medical microbiologists with
  clinical knowledge and experience
• No pre-selection for known attitudes
• 16 replies

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Questions for Each Bacterial spp

• Q1-What is the burden of ill health resulting
  from this bacterial spp?
• Scored 1 (negligible) -5 (major burden)
• Q2-What is the impact of antibiotic resistance on
  treatment choices for this spp.?
• Scored 1 (resistance rare) - 5 (resistance common
  and few treatment options available)
• Q3-What is the contribution of animal sources to
  human resistance for this spp?
• Scored 0 (none) - 5 (main source)

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Bacteria in the survey
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Contribution of individual spp to the overall
resistance problem
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Contribution of animal sources to the overall
resistance problem
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Results of the Questionnaire

• Relative impact of individual organisms
  quantified for the first time
• MRSA is clearly the main problem in human
• Animal sources resulting from all uses account
  for lt5 of total resistance problem
• Enterococci (growth promoter link?) contribute lt1

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1999 European Union Scientific Steering Committee
on Antimicrobial Resistance
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SSCAR Mandate

• Scientifically evaluate the current position
  regarding the prevalence of antimicrobial
  resistance
• Examine implications for human and animal health
• Evaluate factors contributing to the present
  situation

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SSCAR Mandate (continued)

• Examine any means of influencing or controlling
  the development of resistance.
• Make recommendations based on scientific
  evidence.
• Advise on monitoring of the outcome of measures
  and consider implication of advice.

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Bacteria in Animals of Concern

• Enteric, potentially foodborne bacteria.
• enterococci, E. coli
• zoonotic bacteria non-typhoid Salmonella,
  campylobacters
• Other bacteria?

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Antibiotic Use in Animals of Concern

• 1. Performance / enhancing use growth
  promoters with an antimicrobial effect
  (antibacterial feed additives)
• 2. Prophylactic use antimicrobial applied to
  healthy animals for the prevention of crowding
  diseases (medicinal feed additives)
• 3. Therapeutic use antimicrobial for the
  treatment of diseased animals

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Antibacterial Feed Additives of Concern
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Overview of Resistant Organisms
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Infections in Humans
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Hospital Acquired Infections in Humans
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Human Community Acquired Infections
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SENTRY Antimicrobial Surveillance Program

• Established in 1997 by the Jones Group/JMI
  laboratories through funding by SmithKline Glaxo.
  
• Monitors antimicrobial resistance patterns of
  predominant pathogens.
• National and International networks of sentinel
  hospitals supply isolates from nosocomial and
  community acquired infections.

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Risks of Animal Pathogens Occurring in Human
Medicine

• Pathogen by Infection Type
  ()
•  
• _________________RTI______________________
• Community-acquireda Hospital pneumoniab
• (75 of all prescribed antibiotics)
• __________________________________________________
  _ SSTIc_______________UTId_________________
• 1. S. pneumoniae 1. S. aureus
  1. S. aureus
  1. E. coli
• 2. H. influenzae 2. P. aeruginosa
  2. P.
  aeruginosa 2. ENT (12.8)
• 3. M. catarrhalis 3. H. influenzae
  3. E. coli
• 4. S.
  pneumoniae 4. ENTEROCOCCI (8.2)
• 5.
  Klebsiella spp.
• 6.
  Enterobacter spp.
• 7. E.
  coli
• 8. S.
  maltophilia
• 9. S.
  marcescens
• 10.
  Acinetobacter
•  
• Animal related risk
• __________________________________________________
  ______________________________________

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Publications

• SENTRY Program, Hoban et al., Clinical Inf. Dis.
  32 (Suppl 2) S81-93, 2001.
• SENTRY Program, Mathai, et al., Diagn. Microbiol.
  Inf. Dis. 39105-116, 2001.
• SENTRY Program, Kirby et al., Diagn. Microbiol.
  Inf. Dis. 43303-309, 2002.
• SENTRY Program, Mathai et al., Diagn. Microbiol.
  Inf. Dis. 40129-136, 2001.

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Conclusions

• Antibiotics are important to animal health and
  food safety
• Veterinarians need a wide range of products as do
  physicians to combat bacterial disease and reduce
  selection pressures.
• The vast majority of antimicrobial uses in food
  animals appear to have little consequence to
  human health.

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Conclusions (cont.)

• Stimulating research and development into safer
  and more effective antimicrobials for animals
  requires a rationale approach to assessing risk.
• Current ranking criteria will likely result in
  conclusions that overestimate the risk to human
  health.

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Conclusions (cont.)

• Absent evidence of an actual connection between
  an antimicrobial use in animals and non-enteric
  human disease, only those antimicrobials for
  treating food-borne disease should carry a high
  ranking.
• AHI requests that this Committee take this into
  consideration in advising the agency on the
  ranking of antimicrobials.