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Ranking of Antimicrobial Drugs Relative to Their Use in Animals

Ranking of Antimicrobial Drugs Relative to Their Use in Animals. Richard Carnevale VMD Vice President, Scientific, Regulatory and International Affairs Animal Health Institute. Why are we here?. AHI represents the major animal health companies in the US.

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Ranking of Antimicrobial Drugs Relative to Their Use in Animals

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  1. Ranking of Antimicrobial Drugs Relative to Their Use in Animals Richard Carnevale VMD Vice President, Scientific, Regulatory and International Affairs Animal Health Institute

  2. 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.

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. What is AHI’s 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.

  10. What is AHI’s 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)

  11. What is AHI’s 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

  12. 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.

  13. 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 (n=26) • Senior academics/medical microbiologists with clinical knowledge and experience • No pre-selection for known attitudes • 16 replies

  14. 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) Questions for Each Bacterial spp:

  15. Bacteria in the survey

  16. Contribution of individual spp to the overall resistance problem

  17. Contribution of animal sources to the overall resistance problem

  18. 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 <5% of total resistance problem • Enterococci (growth promoter link?) contribute <1%

  19. 1999 European Union Scientific Steering Committee on Antimicrobial Resistance

  20. 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

  21. 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.

  22. Bacteria in Animals of Concern • Enteric, potentially foodborne bacteria. • enterococci, E. coli • zoonotic bacteria: non-typhoid Salmonella, campylobacters • Other bacteria?

  23. 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

  24. Antibacterial Feed Additives of Concern

  25. Overview of Resistant Organisms

  26. Infections in Humans

  27. Hospital Acquired Infections in Humans

  28. Human Community Acquired Infections

  29. 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.

  30. 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 • ________________________________________________________________________________________ • None None Possible* Possible* • Source : Dr. Ron Jones and SENTRY Program publications 2001, 2002.

  31. Publications • SENTRY Program, Hoban et al., Clinical Inf. Dis. 32 (Suppl 2): S81-93, 2001. • SENTRY Program, Mathai, et al., Diagn. Microbiol. Inf. Dis. 39:105-116, 2001. • SENTRY Program, Kirby et al., Diagn. Microbiol. Inf. Dis. 43:303-309, 2002. • SENTRY Program, Mathai et al., Diagn. Microbiol. Inf. Dis. 40:129-136, 2001.

  32. 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.

  33. 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.

  34. 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.

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