# Presentation: 946412

## Slide 1

## 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.**
**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. **

## 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**

## 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.**

## 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.**

## 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. **

## 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. **

## 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. **

## 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. **

## 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)

## 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

## 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.**

## 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

## 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)

- 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:

## Bacteria in the survey  

## Contribution of individual spp to the overall resistance problem

- <date/time>

## Contribution of animal sources to the overall resistance problem

- <date/time>

## 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%**

## 1999 European Union Scientific Steering Committee on Antimicrobial Resistance

## 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  **

## 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.**

## Bacteria in Animals of Concern

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

## 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**

## Antibacterial Feed Additives of Concern

## Overview of Resistant Organisms

## Infections in Humans

## Hospital Acquired Infections in Humans

## Human Community Acquired Infections

## 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.**** **

## Risks of Animal Pathogens Occurring in Human Medicine 

**                   ****Pathogen by Infection Type (%):**
** **
**_________________RTI______________________**
**Community-acquired****a****        Hospital pneumonia****b**
**             ****(75% of all prescribed antibiotics)**
**___________________________________________________ SSTI****c****_______________UTI****d****_________________**
**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. **

## 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.**

## 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. **

## 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. **

## 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. **