1. Risks of Antibiotics in Animal Waste Christopher Ohl MD, FACP Associate Professor of Medicine Section on Infectious Diseases Wake Forest University School of Medicine Winston-Salem, NC cohl@wfubmc.edu

2. Objectives Overview of antimicrobial resistance Discuss the 3 origins of antibiotic resistant infections in humans Discuss antimicrobial use in humans and animals Present risk to humans from antimicrobial use and resistance in food animals and their environment Briefly present governmental and regulatory response to the problem

3. Antibiotics Have Transformed Human Medicine

4. Antimicrobial Targets Only 1 New Antibiotic With a Novel Target in Last 20 Years

5. Antimicrobial resistant Nosocomial Infections In ICU Patients 1999 compared with 1994-1998, NNIS OrganismIncrease in resistance VRE43% MRSA37% MRSE2% 3 rd Ceph E. coli8% 3 rd Ceph K. pneumoniae-3% Imipenem P. aeruginosa56% Quinolone P. aeruginosa50% 3 rd Ceph P. aeruginosa10% 3 rd Ceph Enterobacter sp.-4%

6. Campylobacter jejuni & C. coli Quinolone Resistance Engberg et al. 2001. Emerg Infect Dis 7:24

7. Doern GV. Am J Med. 1995;99: 3S-7S. Jacobs MR, et al. AAC. 1999:43:1901. Jacobs MR, et al. ICAAC. 1999; Abstract C-61. Penicillin-Resistant S. pneumoniae United States (1979-1997) 0 10 20 30 40 50 Year Penicillin Resistant, % Intermediate (0.12 to 1.0 µg/ml) Resistant (>2.0 µg/ml) 19791980198119821983 1984 1985 19861987 1988-89 1990-91 1992-93 1994-95 1997 1998 29% 16% 18% 33%

8. Morbidity and mortality of infections greater for resistant compared with susceptible organisms New drugs designed to combat bacterial resistance are becoming scarce and more costly Cost of antibiotic resistance in the U.S. estimated in 1996 at $30 billion IMPACT

10. Cycle of Antibiotic Resistance Acquisition Under Increasing Antibiotic Selection Pressure

11. The Farm The Hospital The Clinic Origins of Human Antimicrobial Resistance

13. The Farm The Hospital The Clinic Origins of Human Antimicrobial Resistance

14. Adult Antibiotic Prescriptions by Diagnosis 20.9 17.6 16.7 5.8 5.2 4.9 1.9 27 0 5 10 15 20 25 30 Diagnosis Bronchitis Sinusitis Other respiratory Otitis media Skin Pneumonia Wounds All others % Rxs Physician Drug and Diagnosis Audit (PDDA) 1997, Scott-Levin.

15. The Farm The Hospital The Clinic Origins of Human Antimicrobial Resistance

16. Percent of Cattle that Received the Following Antimicrobials in Feed or Water Feedlot 1999 – Part III, USDA/NAHMS survey, December 2000

17. Percent of Sites that Gave Antibiotics to Weaned Pigs as a Preventative Practice USDA/APHIS Veterinary Services Info Sheet, March 2002

18. Most Common Antibiotics (by route) Grower/Finisher Pigs USDA/APHIS Veterinary Services Info Sheet, March 2002 Percent of Farm Sites

19. Antimicrobials in Feed to Grower/Finisher for any Reason Swine 2000 – Part II, USDA/NAHMS survey, August 2001

20. Antimicrobials in Feed to Poultry Nontherapeutic, 1998 Mellon, et al. Union of Concerned Scientists, 2001

21. Antibiotic Use in US: Animals vs Humans Current estimated use/year –Animals: 26.6 million lbs –Humans: 3 million lbs Mellon, et al. Union of Concerned Scientists, 2001 Reasonable estimate ~50% of all antimicrobials in North America are given to animals Gorbach. 2001. NEJM. 345:1202 Classes shared: penicillin, cephalosporin (all generations), macrolides, sulfas, macrolide/lincosamide/streptogramin, aminoglycoside, quinolone

22. Antibiotic Use in US: Animals vs Humans Compare and Contrast AnimalsHumans Individual TreatmentYes, by vet or caretaker Yes, by MD Mass TreatmentYes, oftenVery rare Preventive TreatmentOftenSeldom “Growth Promotion”YesNo Duration / doseLong / lowShort / high

23. Is Antibiotic Use on the Farm Related to Antibiotic Resistance? On the Farm: Yes –Controlled challenge studies –Farm animal microbiologic surveys –Farm environmental microbiologic surveys –Abattoir investigations –Retail meat Pathogens of human interest –Campylobacter sp. (Resis. to FQ’s, macrolides) –Salmonella typhimurium, S. newport; (multidrug resistant common, FQ Resis. rare in US) –Enterococcus sp. (R Streptogramins, tetracyclines, vancomycin, macrolides) –E. coli (tetracyclines, cephalosporins, aminoglycosides, trimethoprim-sulfamethoxazole, FQs) APUA/FAAIR: 2002. Clin Inf Dis. 34: supplement 3 GAO. RCED 99-74 FDA. www.fda.gov/cvm WHO. www.who.ch

24. Is Antibiotic Use on the Farm Related to Antibiotic Resistance in Humans? Colonized Animal Susceptible Human Slaughter Retail Meat Occupational Soil Ground water Surface water Air 3 Possible Routes Food borneEnvironmental Van den Bogaard. 2000. Int J. Antimicrob Agents. 14:327

25. Quinolone Resistant C. jejuni Minnesota 1992-1998 4953 isolates from ill humans 1997: 14% of retail chicken meat with quinolone resistant C. jejuni Human and chicken isolates related molecularly Only 15% of cases could be explained by prior human quinolone use or foreign travel FQ Use in Poultry Smith, et al. 1999. NEJM 340:1525

26. Glynn, M. K. et al. N Engl J Med 1998;338:1333-1339 Prevalence of Resistance to Ampicillin, Chloramphenicol, Streptomycin, Sulfonamides, and Tetracycline among Typhimurium Isolates Identified by Surveys of Antimicrobial-Drug Resistance in Sentinel Counties

27. Enterococcus faecium Streptogramin Resistance Common in chicken retail meat, but rare in humans: microbiologic survey of stools submitted to clinical laboratories show 1% colonized. –McDonald. 2001. NEJM 345:1155 Challenge study in 6 humans with streptogramin resistant E. faecium spiked chicken or pork – Sorensen. 2001. NEJM. 345:1161 Recent risk assessment by FDA-CVM –“ assuming a food pathway attribution of 10%, the average risk to a random member of the US population of having SREF attributable to animal uses of virginiamycin and that may result in impaired Synercid therapy ranges from 7 chances in 1 billion to 14 chances in 100 million in one year” –FDA-CVM. 2004. www.fda.gov/cvm

28. Possible Animal Origin of Human- Associated, MDR uropathogenic E. coli Multistate outbreak of TMP-SXT resistant E. coli urinary tract infections PFGE and PCR fingerprinting 1 isolate from a cow was found in a cluster of human isolates Conclusion: origin of this drug resistant strain potentially has an animal origin

29. Occupational and Farm Resident Risk Tetracycline resistant E. coli transferred to farmers and farm families (31.3% compared with 6.8% of neighbors) –Levy. 1976. NEJM 295:583 Macrolide resistant S. aureus and Streptococci as well as Enterobacteriaceae resistant to quinolone, TMP-SXT, tetracycline and aminoglycoside more common in pig farmers than controls – Aubry-Damon et al. 2004. Emerg Infect Dis. 10:873 Enterococci resistant to streptogramins or vancomyin transferred from chicken and turkey flocks to farm workers –Willems et al. 2000. J. Infect Dis. 182:816 –Van den Boggard et al. 1997. NEJM. 337:1558 Ceftriaxone resistant S. typhimurium transferred from cattle to 12 y.o. farm resident causing severe intestinal illness. –Fey et al. 2000. NEJM. 342:1242

30. 1 or more antibiotics found in 48% of streams sampled. 14 of 22 antibiotics detected at least once. Concentrations generally low (<0.5 ppb). Most frequently detected antibiotics: trimethoprim (27.4%), erythromycin-H2O (21.5%), lincomycin (19.2%), sulfamethoxazole (19.0%), tylison (13.5%). Antibiotics found in streams downstream of both intensive urban (68%) and livestock (39%) activity. Antibiotics in Surface Water Kolpin et al. Environ Sci Technol 2002. 36:1202

31. US Governmental Response

32. Release Assessment Exposure Assessment Qualitative Risk Assessment Consequence Assessment Risk Estimation Risk estimation integrates results from release, exposure and consequence assessments to produce overall measure of risk associated with hazards _____________________________________________________________________________________________________ Text only version Press Release: Antimicrobial Animal Drugs FDA Home Page FDA Home Page | Search FDA Site | FDA A-Z Index | Contact FDA | Privacy | AccessibilitySearch FDA Site FDA A-Z Index Contact FDA PrivacyAccessibility Slide 11 of 21 Back to Slide 1Back to Slide 1

33. Can Risk Be Reversed? Danish Growth Promoter Withdrawal Experience Complete withdrawal of antimicrobials for growth promotion or disease prevention but not therapeutics by end of 1999 Antimicrobial use decreased 54% from 1994 to 2001 Some increase in therapeutic use in pigs but not poultry Dramatically reduced food animal reservoir AR enterococci Possible increase in tetracycline resistance in food animal salmonella No measurable change in food-borne pathogen AR in humans (illness or commensal) Minimal impact on animal welfare Economic impact: Modest decreased feed efficiency in weaners and poultry. GDP 0.03% decrease. (~1 euro/pig) WHO/CDS/CPE/2FK/2003.1

34. “I say we do it … and trichinosis be damned!”