Mary J. Bartholomew, Ph.D. Center for Veterinary Medicine January 9, 2003

1. Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to Their Microbiological Effects on Bacteria of Human Health Concern Qualitative Antimicrobial Resistance Risk Assessment – Example of Miracin™ Mary J. Bartholomew, Ph.D. Center for Veterinary Medicine January 9, 2003

2. Risk Analysis Process • The analysis process is intended to organize and integrate an array of relevant information and to provide guidance as to how this information may be used to manage risk • The process is composed of: • Hazard identification • Qualitative antimicrobial resistance risk assessment • Release assessment • Exposure assessment • Consequence assessment • Risk estimation • Risk management

3. Example • Hazard Identification • Drug/Product Information • Drug: • Miraclemycin, Miracin™ • Class: • 2nd generation Curalloside; CAS 2002 • Use information: • A. Dosage regimen • Miracin is intended to be administered as an oral solution in drinking water for 5 days • B. Product indication • Treatment of swine respiratory disease • C. Target species • Swine

4. Release Assessment • Probability that resistant bacteria or resistance determinants are present in the target animal as a consequence of the antimicrobial new animal drug use • Probability is ranked as Low, Medium, or High

5. Factors to Consider in Release Assessment • Product and drug substance description • Mechanism and type of action • Spectrum of activity • Pharmacokinetics/pharmacodynamics • Resistance selection pressures • Prevalence of resistance • Resistance mechanisms • Resistance transfer • Other relevant information

6. Relevant parameters Extent to which relevant factors favor resistance emergence Comments and conclusions regarding factors Mechanism of activity Inhibition of protein synthesis; Bactericidal Spectrum of activity Gram-positive and some Gram-negative activity; Appropriate zoonotic pathogens display low MICs Rapid absorption, high distribution to tissues Pharmacokinetics Serum concentration > MIC for 6 hours; in vivo PAE = 3.5 hours Pharmacodynamics Resistance mechanism(s) Multiple mechanisms (DNA point mutations most relevant) Resistance transfer Infrequent (no evidence of transfer) Selection pressure Moderate Other factors1 Low mutation rate Related to other curallosides used in human medicine ExampleRelease Assessment of Miracin What is the likelihood (high, medium, low) that these factors favor resistance emergence or of release of the hazardous agent? Miracin: Bactericidal drug, some activity against gram-positives; Campylobacter exhibit low MICs; PK/PD parameters favorable for minimizing resistance release; Transfer of resistance is infrequent; Low baseline resistance; Low mutation rate. The release assessment conclusion for Miracin would be a low probability of release.

7. Exposure Assessment • Probability for humans to ingest the resistant bacteria/resistance determinants in question from the particular relevant food commodity • Probability is ranked as Low, Medium, or High

8. Exposure Assessment Factors to Consider: • The probability for humans to be exposed to given bacteria via a particular food commodity • Probability that bacteria of interest (to which humans are exposed) are resistant to a particular antimicrobial drug or possess associated resistance determinants

9. ExampleExposure Assessment of Miracin • The probability for humans to be exposed to given bacteria via a particular food commodity • Estimated by considerations of: • Per capita consumption of the food commodity(pork) • e.g., USDA Economic Research Service reports • Probability of contamination ofpork by bacteria of interest(Campylobacter) • e.g., USDA Food Safety and Inspection Service data

10. ExampleExposure Assessment of Miracin • Consumption ranking and contamination ranking are merged to derive qualitative ranking for probability that a human is exposed to Campylobacter on pork

11. Example Summarizing Exposure Assessment of Miracin for Use in Swine • Exposure assessment ranking • Derived by integrating the ranking for probability of human exposure (through food) to the bacteria in question • High from previous slide • With the probability that the bacteria will be resistant to the antimicrobial drug in question • Low from release assessment

12. Example Summarizing Exposure Assessment of Miracin for Use in Swine

13. Consequence Assessment • Probability that human exposure to resistant bacteria/determinants results in an adverse human health consequence • Based on the medical importance of the antimicrobial drug under review • Ranked as Low, Medium, or High

14. Example Consequence Assessment of Miracin • Appendix A provides ranking of antimicrobial drugs developed by FDA CDER • Miracin is determined to be high from the table of antimicrobial drug rankings

15. Risk Estimation • Integration of the results from the release assessment, exposure assessment, and consequence assessment • Result is low, medium, or high risk for human health to be adversely impacted by emergence of antimicrobial resistance associated with the use of the drug in animals

16. Risk Estimation • Low - Low rankings on all three assessments or two low and one medium • High- High rankings on all three assessments or two high and one medium • Medium-All intermediate combinations of the three assessments

17. Example Miracin™ Oral Solution for swine • Release assessment - low • Exposure assessment - medium • Consequence assessment – high • Overall Risk Estimate – medium(Category 2)

18. SummaryPossible Risk Management Steps

19. Example Miracin™ Oral Solution for swine Conditions/limitations proposed by sponsor: • Limited to prescription use only (use by or under the order of a licensed veterinarian) • Limited to therapy of select pens/groups of animals • Limited to 5 days of administration

20. Example Miracin™ Oral Solution for swine • Based on the risk assessment and the drug application as a whole, FDA concludes that the antimicrobial new animal drug, Miracin™,is safe • That is, there is a reasonable certainty of no harm when the drug is approved under the defined use conditions.

21. Questions ?