1. The Role of NARMS in Risk Analysis Dr. Heather Tate Coordinator, NARMS FDA Center for Veterinary Medicine Office of Research Laurel, MD 1 Food Advisory Committee Meeting September 29, 2014

2. 2 Uses of Antimicrobials in Food Animal Production Therapy - to treat diseased animals Metaphylaxis - to control outbreaks of disease Prophylaxis - to prevent infections Feed efficiency - to increase feed efficiency (sub- therapeutics, growth promotants, health maintenance) –New guidance (#213) details process to phase out these uses

3. How does the use of antimicrobials in food animal production affect resistance among foodborne pathogens and commensals? Antimicrobial Use in Agriculture: Assessing the Risk What is the impact on public health? 3

4. Center for Veterinary Medicine (CVM) Strategy  Aimed at assessing relationships between antimicrobial use in agriculture and potential human health consequences  Multi-pronged approach that includes:  Expanded research activities  Revised safety assessment process (GFI #152) 2003  Revised judicious use guidance (GFI #209) 2012  Industry guidance on phasing out production uses (GFI #213) 2013  Update on veterinary feed directive  Enhanced surveillance activities (NARMS) 1996  Education/outreach activities  Participation in international activities (WHO, PAHO, OIE, Codex) 4

5. NARMS Goals 1.Monitor trends in antimicrobial resistance among foodborne bacteria from humans, retail meats and animals 2.Disseminate timely information on antimicrobial resistance to promote interventions that reduce resistance among foodborne bacteria 3.Conduct research to better understand the emergence, persistence, and spread of antimicrobial resistance 4.Assist the FDA in making decisions related to the approval of safe and effective antimicrobial drugs for animals 5

6. NARMS data collection design What is sampled? –food animals, retail meats, humans Where are the samples collected? –at slaughter, at retail, public health laboratories What geographic areas? –nationwide (food animals and humans); select states (retail and humans) How many samples collected? –varies per source (food animals and humans- statistically robust sampling design) What are samples analyzed for? –resistant enteric bacteria Considerations –cost, representativeness of sample, new technologies 6

7. Elements of an integrated antimicrobial resistance surveillance system 1. Study population – Humans, food producing animals, retail meats 2. Target Microorganisms a. Major foodborne pathogens b. Sentinel organisms c. Other bacteria 3. Sampling Design a. Sample source b. Sample information c.Sampling representativeness d.Collection frequency e.Sample size 4.Laboratory testing methodology a. Bacterial culture methods b. Storage f isolates c. Isolate identification d.Standardized antimicrobial susceptibility testing and quality control e.Recommended antimicrobials for surveillance Source: 2013 WHO-AGISAR report

8. 8 NARMS Study Population and Target Organisms Food-producing animals Human Isolates Retail Food Isolates 1997 2002 1996 **also piloted MRSA, C. diff and VRE in foods Campylobacter Non-typhoidal Salmonella Generic E. coli Enterococcus Campylobacter Non-typhoidal Salmonella E. coli O157:H7 Typhoidal Salmonella Shigella Vibrio (2009) Campylobacter Non-typhoidal Salmonella Generic E. coli Enterococcus **

9. 9 Farm to Fork Food-producing animals Human Isolates Retail Food Isolates Resistant bacteria in animals Resistant bacteria that consumers may potentially be exposed to Resistant bacteria, potentially acquired through consumption of foods

10. Animals on - farm Does not always reflect pathogens that will be recovered post-slaughter Most direct indication of resistance arising from on-farm antimicrobial use o May not address resistance from historical use or from exogenous sources Holding Reflects what is expected to contaminate retail meats o Bacteria on-farm plus bacteria from cross- contamination during transport and lairage Less indicative of current antimicrobial use on-farm o Cross-contamination by strains persisting in environment can confound analysis Post-slaughter Cecal samples immediately post- holding may overlap with farm sampling Carcass samples reflect cross- contamination in plant and/or poor carcass preparation Addresses what has contaminated meat May overlap with retail meat sampling Same limitations as holding Transport In-plant Pre/post harvest sampling considerations Source: WHO-AGISAR report

11. NARMS Animal Component – as of 2013 In-plant testing Led by USDA-Food Safety Inspection Service (FSIS) Cecal samples better reflect animal status and less confounded by plant events A randomized, nationally representative testing of slaughterhouses Complete microbiology of all production classes Old System (HACCP) SwineCattleChickenTurkeys Campylobacterx Salmonellaxxxx E. colix Enterococcusx New System (Cecal) SwineCattleChickenTurkeys Campylobacterxxxx Salmonellaxxxx E. colixxxx Enterococcusxxxx FSIS PR/HACCP samples Western Lab Eastern Lab Midwestern Lab ARS Eastern Lab received Salmonella isolates Chicken carcasses Campylobacter, E coli, Enterococcus

12. Retail Meat Surveillance Partnership with State Labs States selected based on existing public health infrastructure (FoodNet) Each state lab purchases 10 packages each of chicken breasts, pork chops, ground turkey, and ground beef per month All 14 states culture for Salmonella and Campylobacter Four states (GA, OR, TN, MD) culture for E. coli and Enterococcus Total samples now tested = 6,720 meats/year Isolates sent to FDA-CVM for susceptibility testing and other testing (Pulsed Field Gel Electrophoresis, Whole Genome Sequencing) More isolates are needed for statistically strong trend analysis, particularly by serotype. Desire to sample in major metropolitan areas. 2013: 14 States

13. 13 Sampling Locations Randomly select 10 grocery stores to sample from each month Identify areas to sample Identify grocery store locations within sample areas

14. Retail Meat Sampling Scheme 14 Generate randomized sampling lists for each site Visit 5 Primary Stores Purchase 2 Samples of Chicken (bone in skin on), Ground Turkey, Ground Beef, Pork Chop Assign 5 primary + 5 secondary grocery stores per month Select 2 Different Brands OR If Same Brand, Select 2 Different Establishment Numbers/Sell by Dates/Lot Numbers If Meat Product Not Found, Visit a Secondary Store Total Samples: 40* meat samples/month 14 retail meat sites 12 months of sampling 6,720 meats/year *2001 Iowa Retail Meat Pilot; Sample Size Under Revision FDA/CDC Retail Site

15. 15 Human NARMS Isolate/Data Collection Samples cultured at state public health laboratories Isolates sent to CDC for confirmatory ID, AST, and additional testing

16. 1996: 14 sites1999: 17 sites 2002: 28 sites 2003: 53 sites Human Salmonella Surveillance Sites* *In 1996, surveillance began in 14 sites. In 2003, participation increased to nationwide: 50 state and three local health departments, Los Angeles County (joined in 1996), New York City (1996), and Houston, Texas (2003). 16

17. Human Campylobacter Surveillance Sites In 1997, surveillance was initiated in five states. Additional sites joined after 1997. By 2003, participation included 10 sites: CA, CO, CT, GA, MD, MN, NM, NY, OR, and TN. 17

18. 18 NARMS Laboratory Methods Animal, human, retail lab testing comparable Same antimicrobial susceptibility testing methods Broth microdilution methods Sensititre® System – Salmonella, E. coli, Enterococcus 2005, Campylobacter Same antimicrobial panel formats Same isolate handling procedures Quality Assurance Internal and external programs CLSI standards

19. Recommended antimicrobials for surveillance 19 OrganismsAntimicrobialsCritically ImportantHighly Important Azithromycin Amikacin Gentamicin Kanamycin Streptomycin Ampicillin Amoxy-Clav Cefoxitin Ceftiofur Ceftriaxone Sulfa Trim-Sulfa Chloramphenicol Ciprofloxacin Nalidixic acid Tetracycline Telithromycin Clindamycin Erythromycin Florfenicol Campylobacter Salmonella/E.coli Source: FDA GFI #152 Appendix A

20. FDA/CVM Regulatory Approach Microbial Food Safety Risk Assessment Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to Their Microbiological Effects on Bacteria of Human Health Concern GFI #152 http://www.fda.gov/cvm/Documents/fguide152.pdf 20

21. Qualitative Risk Assessment: Components and Procedures 21

22. 22 Release Assessment Release parameters (examples) Release assessment Mechanism of activity Spectrum of activityNARMS susceptibility data used Pharmacokinetics Pharmacodynamics Resistance mechanismsNARMS research could be used Resistance transferNARMS research could be used Selection pressureNARMS research could be used

23. 23 Exposure Assessment Amount of food commodity being consumed M Low Medium High LowMediumHighAmount of food commodity contamination (NARMS Data) H HH M L L L M GFI #152, Table 5, pp. 19

24. 24 Consequence Assessment Critically Important 3 rd Generation cephalosporins, macrolides, fluoroquinolones Highly Important 4 th Generation cephalosporins, aminoglycosides, clindamycin Important 1 st & 2 nd Generation cephalosporins, monobactams, quinolones Drug Rankings and Examples

25. Criteria used to rank drugs 1.Antimicrobial drugs used to treat enteric pathogens that cause foodborne disease 2.Sole therapy or one of few alternatives to treat serious human disease or drug is essential component among many antimicrobials in treatment of human disease 3.Antimicrobials used to treat enteric pathogens in non-foodborne disease 4.No cross-resistance within drug class and absence of linked resistance with other drug classes 5.Difficulty in transmitting resistance elements within or across genera and species of organisms 25 Critically Important- Drug meets BOTH criteria 1 and 2 Highly Important- Drug meets EITHER criteria 1 or 2 Important- Drug meets EITHER criterion 3 and/or 4 and/or 5 GFI #152, Appendix A

26. Some possible risk estimation outcomes ReleaseExposureConsequenceRisk Estimation Low ImportantLow MediumImportantLow MediumLowImportantLow Highly ImportantLow HighImportantMedium HighLowImportantMedium ImportantMedium Low Critically ImportantHigh LowCritically ImportantHigh Highly ImportantHigh Medium Critically ImportantHigh GFI #152, Table 6, pp. 21

27. GFI #152, Table 8, pp. 25 Approval conditions Risk Category Category 1 (H)Category 2 (M)Category 3 (L) Marketing status RxRx/VFDRx/VFD/OTC Extra-label useELU restrictionRestricted in some cases ELU permitted Extent of useLowLow, mediumLow, medium, high Post-approval monitoring NARMS Advisory committee review YESIn certain casesNO Examples of Possible Risk Management Strategies Based on the Level of Risk (H, M, or L).

28. http://www.fda.gov/NARMS THANK YOU 28