Risks of Antibiotics inAnimal Waste

Christopher Ohl MD, FACPAssociate Professor of MedicineSection on Infectious Diseases

Wake Forest University School of MedicineWinston-Salem, NCcohl@wfubmc.edu

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

Antibiotics Have Transformed Human Medicine

Antimicrobial TargetsOnly 1 New Antibiotic With a Novel Target in Last 20 Years

Antimicrobial resistant Nosocomial Infections In ICU Patients1999 compared with 1994-1998, NNIS

Organism Increase in resistance

VRE 43%

MRSA 37%

MRSE 2%

3rd Ceph E. coli 8%

3rd Ceph K. pneumoniae -3%

Imipenem P. aeruginosa 56%

Quinolone P. aeruginosa 50%

3rd Ceph P. aeruginosa 10%

3rd Ceph Enterobacter sp. -4%

Campylobacter jejuni & C. coliQuinolone Resistance

Engberg et al. 2001. Emerg Infect Dis 7:24

Doern GV. Doern GV. Am J Med.Am J Med. 1995;99: 3S-7S. 1995;99: 3S-7S. Jacobs MR, et al. AAC. 1999:43:1901.Jacobs MR, et al. AAC. 1999:43:1901.Jacobs MR, et al. ICAAC. 1999; Abstract C-61. Jacobs MR, et al. ICAAC. 1999; Abstract C-61.

Penicillin-Resistant Penicillin-Resistant S. pneumoniaeS. pneumoniaeUnited States (1979-1997)United States (1979-1997)

0

10

20

30

40

50

Year

Pen

icil

lin

Res

ista

nt,

%

Intermediate (0.12 to 1.0 µg/ml)Resistant (>2.0 µg/ml)

1979

1980

1981

1982

1983

1984

1985

1986

1987

1988

-89

1990

-91

1992

-93

1994

-95

1997

1998

29%29%

16%16%18%18%

33%33%

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

Cycle of Antibiotic Resistance Acquisition

UnderIncreasingAntibioticSelectionPressure

The Farm

The Hospital

The Clinic

Origins of Human Antimicrobial Resistance

The Farm

The Hospital

The Clinic

Origins of Human Antimicrobial Resistance

Adult Antibiotic Prescriptions by Diagnosis

20.920.9

17.617.616.716.7

5.85.8 5.25.2 4.94.9

1.91.9

2727

00

55

1010

1515

2020

2525

3030

DiagnosisDiagnosis

BronchitisBronchitis

SinusitisSinusitis

Other respiratoryOther respiratory

Otitis mediaOtitis media

SkinSkin

PneumoniaPneumonia

WoundsWounds

All othersAll others

% R

xs%

Rxs

Physician Drug and Diagnosis Audit (PDDA) 1997, Scott-Levin.

The Farm

The Hospital

The Clinic

Origins of Human Antimicrobial Resistance

Percent of Cattle that Receivedthe Following Antimicrobials in Feed or Water

0

10

20

30

40

50

Per

cen

t o

f al

l ca

ttle

bacitracin chlortetracyclinechlortet/sulfamethazine neomycinoxytetracycline sulfastetracycline tylosinvirginiamycin other

Feedlot 1999 – Part III, USDA/NAHMS survey, December 2000

Percent of Sites that Gave Antibiotics to Weaned Pigs as a Preventative Practice

0102030405060708090

Percent of swine

production sites

Feed

Injection

Water

Oral

USDA/APHIS Veterinary Services Info Sheet, March 2002

Most Common Antibiotics (by route) Grower/Finisher Pigs

0

10

20

30

40

50

60

tylosin

penicillin

oxytetra.

chlortetra.

bacitracin

ceftiofur

lincomycin

carbadox

neomycin

sulfa.

FeedInjection Water

USDA/APHIS Veterinary Services Info Sheet, March 2002

Pe

rce

nt o

f Fa

rm S

ites

Antimicrobials in Feed to Grower/Finisher for any Reason

0

10

20

30

40

50

60

Per

cen

t o

f si

tes

tylosin (62.3 days) chlortetracycline (31.7 days)

bacitracin (67.7 days) lincomycin (31.6 days)

carbadox (22.6 days)

Swine 2000 – Part II, USDA/NAHMS survey, August 2001

Antimicrobials in Feed to PoultryNontherapeutic, 1998

0

5

10

15

20

25

30

Per

cen

t o

f b

roil

ers

Bambermycin erythromycin chlortetra.

penicillin lincomycin virginiamycin

Mellon, et al. Union of Concerned Scientists, 2001

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

Antibiotic Use in US: Animals vs HumansCompare and Contrast

Animals Humans

Individual Treatment Yes, by vet or caretaker

Yes, by MD

Mass Treatment Yes, often Very rare

Preventive Treatment Often Seldom

“Growth Promotion” Yes No

Duration / dose Long / low Short / high

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 3GAO. RCED 99-74

FDA. www.fda.gov/cvmWHO. www.who.ch

Is Antibiotic Use on the Farm Related to Antibiotic Resistance in Humans?

Colonized Animal

Susceptible Human

Slaughter

Retail Meat

Occ

upat

iona

l

•Soil•Ground water•Surface water•Air

3 Possible Routes

Food borne EnvironmentalVan den Bogaard. 2000. Int J. Antimicrob Agents. 14:327

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

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

Enterococcus faeciumStreptogramin 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

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

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

• 1 or more antibiotics foundin 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

US Governmental Response

Release Assessment

ExposureAssessment

Qualitative Risk Assessment

ConsequenceAssessment

Risk Estimation

Risk estimation integrates results from release, exposure and consequence assessments to produce overall measure of risk associated with hazards

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Text only version

Press Release: Antimicrobial Animal DrugsFDA Home Page | Search FDA Site | FDA A-Z Index | Contact FDA | Privacy | Accessibility

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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

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