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u s food and drug administration
U.S. Food and Drug Administration

Notice: Archived Document

The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

scott a brown dvm phd dipl acvcp senior director metabolism safety pfizer animal health

Tulathromycin Solution for Parenteral Injection for Treatment of Swine and Bovine Respiratory DiseaseMicrobiological Effects on Bacteria of Human Health Concern: A Qualitative Risk Estimation

Scott A. Brown, DVM, PhD, Dipl ACVCP

Senior Director, Metabolism & Safety

Pfizer Animal Health

overview
Overview
  • Guidance #152 risk analysis terminology
  • Hazard Characterization
  • Tulathromycin risk estimation summary
  • Qualitative Risk Estimation
    • Release assessment
    • Exposure assessment
    • Consequence assessment
    • Overall risk estimation
  • Conclusions
indications and regimen
Indications and Regimen
  • For the treatment of bovine respiratory disease (BRD) associated with label pathogens, and for the control of BRD in cattle at high risk of BRD
  • For the treatment of swine respiratory disease (SRD) associated with label pathogens
  • Single parenteral injection (cattle and swine)
  • Not for use in lactating dairy cows or preruminant calves
guidance 152

Guidance #152

Risk Analysis Terminology

fda cvm guidance 152

FDA/CVM Guidance #152

Evaluating the Safety of Antimicrobial New Animal Drugs With Regard to their Microbiological Effects on Bacteria of Human Health Concern

“Microbial Safety File” Guidance

Released October 23, 2003

guidance 152 risk analysis terminology

Release

Assessment

Risk Estimation

Exposure

Assessment

Consequence

Assessment

Guidance #152 Risk Analysis Terminology

Hazard Characterization

tulathromycin hazard characterization fda cvm guidance 152
Tulathromycin Hazard Characterization (FDA/CVM Guidance #152)
  • Focus on Campylobacter
    • Macrolides are used to treat campylobacteriosis when antimicrobial therapy is indicated
    • Macrolides are not used to treat Salmonella, E. coli
    • Macrolides are not used to treat Enterococcus infections
      • High macrolide resistance rates for clinical isolates since 70s
      • Other therapeutic options available
    • Macrolide resistance determinants are transferable in Enterococcus, but tulathromycin activity is attenuated in colonic contents, feces due to binding, pH
tulathromycin hazard characterization fda cvm guidance 1521
Tulathromycin Hazard Characterization (FDA/CVM Guidance #152)
  • The “Hazard” is
    • human illness (campylobacteriosis),
    • caused by an antimicrobial-resistant bacteria (macrolide-resistant Campylobacter),
    • attributable to an animal-derived food commodity (beef or pork), and
    • treated with the human antimicrobial drug of interest (a macrolide)
tulathromycin hazard characterization fda cvm guidance 1522
Tulathromycin Hazard Characterization (FDA/CVM Guidance #152)
  • The “Hazardous Agent” is
    • antimicrobial-resistant food-borne bacteria (macrolide-resistant Campylobacter) of human health concern
    • that are in or on a food-producing animal (beef cattle or swine)
    • as a consequence of the proposed use of the antimicrobial new animal drug (tulathromycin)
tulathromycin hazard characterization fda cvm guidance 1523
Tulathromycin Hazard Characterization (FDA/CVM Guidance #152)
  • The “Specific Risk” is
    • the probability that human food-borne illness (campylobacteriosis) is
      • caused by an antimicrobial- resistant bacteria (macrolide-resistant Campylobacter),
      • attributable to an animal-derived food commodity (beef or pork), and
      • treated with the human antimicrobial drug of interest (a macrolide)
release assessment summary
Release Assessment Summary
  • “Low” probability that macrolide-resistant (MacR) Campylobacter will be selected as a result of proposed tulathromycin use
    • Attenuated microbiological activity of tulathromycin in colonic contents:
      • Low pH
      • Binding to fecal substrates
    • MacR occurs by mutation in Campylobacter
      • Frequency of spontaneous mutation is low (<10-9)
      • No evidence of transferable macrolide resistance
    • No unique resistance mechanisms detected
release assessment summary1
Release Assessment Summary
  • Proposed use of tulathromycin supports “Low” Release:
    • Parenteral use under veterinary prescription only
    • Individual animal treatment (not pre-ruminants)
    • Single dose = full course of therapy
    • Treatment of BRD and SRD usually occurs at a time substantially before slaughter
release assessment summary2
Release Assessment Summary
  • Expect selection pressure by tulathromycin will be no greater than that for macrolides currently used in livestock:
    • Tulathromycin activity attenuated in colonic content, feces
    • Tulathromycin mechanism of action, cross-resistance profile same as current-use macrolides
    • Macrolides are currently used for SRD, BRD
    • Macrolide resistance in Campylobacter acquired by mutation, not gene acquisition
    • Despite >30 years of macrolide use in livestock (parenteral, in-feed, water medications), MacR C.jejuni from humans is low (1-3%); no trends over time
campylobacter in beef exposure recommendation
Campylobacter in Beef Exposure Recommendation*

*Sponsor accepts the default recommendation

consequence assessment summary
Consequence Assessment Summary
  • Guidance #152 defines macrolides as “Critically Important” in human medicine
    • For the treatment of Legionnaire’s disease; and atypical Mycobacterium (Mycobacterium avium complexus/M. avium intracellulaire) prophylaxis and therapy
    • For the treatment of foodborne diseases (i.e., Campylobacter)
sponsor conclusions microbial safety of tulathromycin
Sponsor Conclusions:Microbial Safety of Tulathromycin
  • The proposed label use of tulathromycin includes management considerations of:
    • prescription status
    • inherent low extent of use due to parenteral single dose administration
    • Advisory Committee Review
  • MacR is currently monitored by NARMS
  • With these management considerations, approval of the proposed indications for injectable tulathromycin in cattle and swine poses no appreciable risk to public health with respect to microbial food safety.
qualitative risk estimation

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Qualitative Risk Estimation

qualitative risk estimation release assessment

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Qualitative Risk Estimation Release Assessment

qualitative risk estimation release assessment chemistry and disposition

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Qualitative Risk Estimation Release Assessment Chemistry and Disposition

tulathromycin chemistry
3 basic amino groups = highly charged form in solution

pKa 8.6, 9.6, 9.9

aids penetration of the outer membrane of Gram-negative bacteria.

Lipophilic when unionized

Metabolically stable

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Tulathromycin Chemistry

C41H79N3O12

molecular weight: 806.23

Letavic et al., 2002; Norcia et al., 2004

tulathromycin mechanism of action spectrum of activity

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Tulathromycin Mechanism of Action/Spectrum of Activity
  • Mechanism: Inhibits protein synthesis
    • Similar to other macrolides (e.g., erythromycin, tilmicosin)
    • Binds to the 23s rRNA of bacterial ribosomes
      • Competes for erythromycin-binding
      • Binds to erythromycin-sensitive ribosomes
      • No binding to erythromycin-resistant ribosomes
  • Spectrum: Broad-spectrum activity against bacterial respiratory disease pathogens in cattle and swine
mics of tulathromycin tested against foodborne microorganisms

Release

Assessment

Risk

Estimation

Exposure

Assessment

Microorganism

No. strains

MIC (g/ml)

Consequence

Assessment

Range

MIC50

MIC90

Campylobacter spp1

30

0.25 – 128

0.5

64

Enterococcus faecalis

9

4.0 - >128

8.0

NA

E. faecium

21

4.0 - > 128

8.0

>128

Enterococcus spp2

8

4.0 - >128

4.0

NA

Escherichia coli

16

4.0 – 8.0

8.0

8.0

Salmonella spp3

15

4.0->128

4.0

8.0

1Includes: 2 C. fetus, 13 C. jejuni, 15 Campylobacter spp.

2Includes: 1 E. avium, 7 E. gallinarium

3Includes: 7 S. choleraesuis, 6 S. dublin, 2 S. enteritidis

MICs of Tulathromycin Tested Against Foodborne Microorganisms
effects of ph on tulathromycin activity

Release

Assessment

Risk

Estimation

Exposure

Assessment

Microorganism

Mean MIC (g/mL) atpH:

Consequence

Assessment

6.5

7.0

7.2

7.4

7.6

8.0

E. coli ATCC 25922

>128

18.4

4.59

2.0

2.0

2.0

E. faecalis ATCC 29212

>128

36.8

12.1

3.48

2.0

2.30

S. aureus ATCC 29213

>128

24.3

8.00

3.03

1.74

2.0

Effects of pH on Tulathromycin Activity
tulathromycin pharmacokinetics bovine plasma profile

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Parenteral dosing Plasma

Tmax(hours)1

Cmax(µg/mL) 0.5

t1/2(hours)90

AUC0-¥ h(ng·h/mL) 16,700

VSS(L/kg) 11

F(%) 87.70

Tmax = time to maximum concentration; Cmax = maximum concentration; t1/2 = half life; AUC = area under conc.-time curve;Vss = volume of distribution at steady state; F = bioavailability

Tulathromycin Pharmacokinetics Bovine Plasma Profile
  • Fast-acting due to rapid release from injection site
  • Extensively distributed; high volume of distribution
  • Extended half-life; prolonged duration
  • High bioavailability
tulathromycin pharmacokinetics swine plasma profile

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Parenteral Dosing Plasma

Tmax(hours)0.92

Cmax(µg/mL) 0.581

t1/2(hours)91

AUC0-¥ h(ng·h/mL) 12,200

VSS(L/kg) 13.2

F(%) 88

Tmax = time to maximum concentration; Cmax = maximum concentration; t1/2 = half life; AUC = area under conc.-time curve;Vss = volume of distribution at steady state; F = bioavailability

Tulathromycin Pharmacokinetics Swine Plasma Profile
  • Fast-acting due to rapid release from injection site
  • Extensively distributed; high volume of distribution
  • Extended half-life; prolonged duration
  • High bioavailability
metabolism excretion in feces

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Metabolism/Excretion in Feces
  • 30-60% of total dose excreted in feces, depending on the species
    • Peak concentrations 30-100 g total drug residues/g
      • 90% as unchanged drug
  • Tulathromycin activity in colon contents and feces is substantially attenuated
    • Significant percentage (>70%) binds to fecal solids
    • In vitro activity of tulathromycin is reduced when sterilized feces added to growth media
      • E. coli
      • Enterococcus
      • Bifidobacterium
      • Fusobacterium
tulathromycin chemistry and disposition conclusions

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Tulathromycin Chemistry and Disposition Conclusions
  • Low in vitro activity against enteric foodborne pathogens
  • Attenuated activity at pH found in colonic contents
  • High fecal binding of drug
  • Transient concentrations in colon
resistance mechanisms genetics and location

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Resistance Mechanisms, Genetics, and Location

mechanisms of macrolide resistance

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Mechanisms of Macrolide Resistance
  • Target site modification
    • Sequence change in ribosome due to mutation
    • rRNA methylation (e.g., ermA, ermB)
      • Inducible (erythromycin does; tilmicosin and tulathromycin do not)
      • Constitutive
  • Drug inactivation
    • Phosphorylation (e.g., mphA or mphB)
    • Hydroxylation (e.g., ereA and ereB)
  • Drug efflux pumps (e.g., msrA and mefA)
transferable resistance

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Transferable Resistance
  • Macrolide resistance genes are transferable
    • Study showed no difference in transfer frequency of plasmid-mediated macrolide resistance when tulathromycin was added to E. faecalis mating pair
    • Tulathromycin activity is attenuated due to pH and binding, thus limiting tulathromycin’s ability to select for enterococci containing these genetic elements
transferable resistance determinants

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Transferable Resistance Determinants
  • Transferable genes for MACR have not been reported in Campylobacter*
    • Unlike other bacteria, erm gene resistance has not been reported in Campylobacter
    • Macrolide resistance due to mutation only

*Jensen & Aarestrup, 2001; Yan & Taylor, 1991

cross resistance

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Cross-Resistance
  • Constitutively expressed erm genes confer cross-resistance to macrolides, lincosamides, streptogramin B (MLSB)
    • Tulathromycin and tilmicosin have similar cross-resistance profiles for human pathogens, both are weak inducers of erm genes
  • Efflux pumps
  • Campylobacter having high erythromycin MIC’s have high tulathromycin MIC’s (I.e., are cross-resistant)
point mutations

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Point Mutations
  • E. coli, Salmonella, Enterococcus, and Campylobacter studies:
    • No tulathromycin- or macrolide-resistant mutants found at the frequency expected for spontaneous mutation (10-9)
resistance genetics conclusions

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Resistance/Genetics Conclusions
  • Three types of macrolide resistance mechanisms documented
    • Many of the genes are transferable
    • Erm genes are broadly disseminated and confer cross-resistance to MLSB
  • Transferable macrolide resistance genes have not been documented in macrolide-resistant Campylobacter
  • Macrolide-resistance in Campylobacter occurs via chromosomal mutation
    • Mutation frequency to macrolideR is very low (< 10-9 )
resistance selection pressures in the field

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Resistance Selection Pressures in the Field

BRD & SRD in the USCurrent Macrolide Use

Antibiotics Use

bovine respiratory disease

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Bovine Respiratory Disease

Labored Breathing

Normal

Depressed

percent of cattle that developed diseases after arrival

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Percent of Cattle that Developed Diseases after Arrival

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

brd impact

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

BRD: Impact
  • Animal welfare
    • 31.1% of all bovine deaths
    • 57-79% of feedlot mortality
  • Cost to the industry
    • Over 23 million cattle in feedlots annually (residence time in feedlots is about 6 months)
    • 15% (BRD) of 23M cattle = 3.45M feedlot cattle affected by BRD
    • Hundreds of millions of dollars lost due to BRD

Vogel 1994; Lonergan et al, 2001

swine grower finisher deaths by producer identified causes

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Swine Grower/Finisher Deaths by Producer-Identified Causes

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

brd and srd in the us summary

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

BRD and SRD in the US Summary
  • BRD affects approximately 15% of feedlot cattle (over 3.4M feedlot cattle affected) - morbidity
  • SRD causes approximately 40% of deaths in swine - mortality
macrolide approvals in cattle and swine

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Macrolide Approvals in Cattle and Swine
uses of currently approved macrolides

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Uses of Currently Approved Macrolides
  • Treatment of respiratory disease
  • Treatment of cattle at high risk of respiratory disease
  • Control of diseases (swine dysentery caused by Brachyspira hyodysenteriae, bacterial respiratory disease)
  • Growth promotion
percent of cattle that received the following antimicrobials in feed or water

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Percent of Cattle that Received the Following Antimicrobials in Feed or Water

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

percent of sites that gave antibiotics to weaned pigs as a preventative practice

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

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

USDA/APHIS Veterinary Services Info Sheet, March 2002

five most common antibiotics by route of administration given to grower finisher pigs

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Five Most Common Antibiotics (by route of administration) Given to Grower/Finisher Pigs

USDA/APHIS Veterinary Services Info Sheet, March 2002

percent of sites that used antimicrobials in feed to grower finisher for any reason

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Percent of Sites that Used Antimicrobials in Feed to Grower/Finisher for any Reason

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

less than 20 of feedlot cattle received an injectable antimicrobial

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Less than 20% of Feedlot Cattle Received an Injectable Antimicrobial

Feedlot 1999 – Part II, USDA/NAHMS survey, December 2000)

major antimicrobials used as primary initial brd treatment

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Major Antimicrobials Used as Primary Initial BRD Treatment

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

approximately 10 of cattle are treated on arrival

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Approximately 10% of Cattle Are Treated on Arrival

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

criteria for treatment on arrival in feedlot cattle

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Criteria for Treatment on Arrival in Feedlot Cattle
  • Appearance of cattle upon arrival
  • Source of arriving cattle
  • BRD in some of the arriving cattle
  • Prior BRD problems from sourced cattle
  • Known history of no vaccination for BRD
  • Less important criteria
    • shipping distance
    • season of year

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

swine injectable antimicrobials

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Swine Injectable Antimicrobials
  • Injectable antimicrobials are a distant second to in-feed use of antimicrobials in swine
  • Injectable penicillins command nearly 2/3 of the market (number of doses)*
  • Other injectable antimicrobials used in swine include oxytetracycline, tylosin, lincomycin, and ceftiofur*

*Doane’s Animal Health Marketing Survey

injectable antibiotic use summary

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Injectable Antibiotic Use Summary
  • Use of therapeutic antibiotics is an investment for the producer
  • Less than 20% of all feedlot cattle receive an injectable antibiotic
  • Slightly more than 10% of arriving cattle receive injectable antibiotic therapy when one or more “at risk” factors are present
  • Macrolides, tetracyclines, phenicols, fluoroquinolones, and cephalosporins are used as injectables in cattle
  • Penicillins, tetracyclines, macrolides, and cephalosporins are used as injectables in swine
indications and dosage regimen for tulathromycin

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Indications and Dosage Regimen for Tulathromycin
  • For the treatment of bovine respiratory disease (BRD) associated with label pathogens, and for the control of BRD in cattle at high risk of BRD
  • For the treatment of swine respiratory disease (SRD) associated with label pathogens
  • Single parenteral injection (cattle and swine)
  • Not for use in lactating dairy cows or preruminant calves
clinical use of tulathromycin

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Clinical Use of Tulathromycin
  • One dose provides full course therapy, so assurance of compliance with treatment regime
  • Reduced stress for animals
resistance selection pressures in the field conclusions
Resistance Selection Pressures in the FieldConclusions
  • BRD and SRD are important bacterial infections, with animal welfare and production costs
  • Antibiotics are administered to cattle and swine by various routes and for a variety of indications
    • Injectable antibiotics are a small subset of the antibiotics used in livestock, and for therapeutic purposes
      • Tulathromycin is one of several injectable antibiotic choices for the veterinarian for BRD and SRD treatment
resistance selection pressure conclusions

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Resistance Selection Pressure Conclusions
  • Selection pressure exerted by tulathromycin will be no greater than that for macrolide products currently used in livestock
    • Macrolide selection pressure has existed for >30 years (multiple indications and routes of administration)
    • Use of tulathromycin will be by prescription parenteral injection only to individual animals
baseline prevalence of resistance

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Baseline Prevalence of Resistance

campylobacter resistance surveillance

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Campylobacter Resistance Surveillance
  • Programs have different sampling strategies and isolation procedures
  • NCCLS performance standards for susceptibility testing recently issued (2003)
  • NCCLS has not established macrolide breakpoints predictive of efficacy against Campylobacter
  • CDC NARMS* isolates from humans has consistently used the E-test
  • US NARMS veterinary isolate program monitors resistant Campylobacter isolates from poultry, but not cattle and swine
  • US NARMS has recently conducted monitoring in retail beef and pork

*National Antimicrobial Resistance Monitoring System

us campylobacter macrolide resistance surveys 1998 2003

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

US Campylobacter Macrolide Resistance Surveys (1998-2003)

*www.arru.saa.ars.usda.gov//campy.htm

‡Gupta et al., 2004

†www.arru.saa.ars.usda.gov/posters.htm

baseline campylobacter mic conclusions

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Baseline Campylobacter MIC Conclusions
  • Prevalence of macrolide resistance 1-3% in NARMS human isolates in C. jejuni
  • Prevalence of macrolide resistance in Campylobacter jejuni in pigs cannot be assessed due to limited isolates
release assessment summary3
Release Assessment Summary
  • Probability is “Low” that macrolide-resistant Campylobacter will emerge or be selected as a consequence of the proposed use of tulathromycin
    • Tulathromycin mechanism of action, cross-resistance profile same as macrolides used in livestock
    • Tulathromycin activity attenuated in colonic content, feces
    • Macrolide resistance in Campylobacter acquired by mutation, not gene acquisition
      • Mutation rate is at frequency of spontaneous mutation
    • Macrolides are currently used for SRD, BRD
    • Despite >30 years of macrolide use in livestock (parenteral, in-feed, water medications), baseline prevalence shows MacR C.jejuni from humans is low (1-3%) with no trends over time
qualitative risk estimation exposure assessment

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Qualitative Risk Estimation Exposure Assessment

exposure assessment recommendation template

Release

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Exposure Assessment Recommendation (template)
exposure assessment recommendation template1

Release

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Assessment

Exposure Assessment Recommendation (template)
exposure assessment recommendation template2

Release

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Exposure Assessment Recommendation (template)
campylobacter in beef exposure recommendation1

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Campylobacter in Beef Exposure Recommendation
campylobacter in pork exposure default guidance 152

Release

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Risk

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Exposure

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Consequence

Assessment

Campylobacter in Pork Exposure Default (Guidance #152)
exposure of humans to campylobacter

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Exposure of Humans to Campylobacter
  • Primary isolate in swine is C. coli (C. jejuni <5% of isolates from swine/carcasses)
  • Swine contamination rates decrease substantially as swine move through the food chain (slaughter to retail)
  • Primary risk factors
    • Consumption of raw/unpasteurized milk
    • Untreated surface water
    • Consumption/handling of raw/undercooked poultry
    • Pork, beef considered a low risk factor by all assessors
  • C. jejuni the causative agent (90% of CDC isolates in NARMS)
campylobacter prevalence

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Campylobacter prevalence

0-<5% prevalence

At retail

60-100% prevalence

In swine feces

Hedberg, 2002;

Nesbakken et al., 2002;

Manser & Dalziel, 1985

Duffy et al., 2001;

Duffy et al., 2002;

White, 2004

Zhao et al., 2001;

0-32% prevalence

In carcasses & processing

Oosterom et al., 1985;

Nesbakken et al., 2002;

Pierce et al., 2003

campylobacter in pork exposure recommendation1

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Campylobacter in Pork Exposure Recommendation
qualitative risk estimation consequence assessment

Release

Assessment

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Estimation

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Assessment

Consequence

Assessment

Qualitative Risk EstimationConsequence Assessment

consequence assessment summary1

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Consequence Assessment Summary
  • Guidance #152 defines macrolides as “Critically Important” in human medicine, namely for:
    • Treatment of Legionnaire’s disease: MAC/MAI prophylaxis and therapy
    • Treatment of campylobacteriosis in humans
qualitative risk estimation overall risk estimation

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Qualitative Risk EstimationOverall Risk Estimation

qualitative risk assessment guidance 152

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Qualitative Risk Assessment (Guidance #152)

Hazard Characterization

Release

Assessment

Risk Estimation

Exposure

Assessment

Consequence

Assessment

qualitative risk assessment beef

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Qualitative Risk Assessment - Beef

Hazard Characterization

Release

Assessment

Low

Risk Estimation

Exposure

Assessment

Medium

High

Consequence

Assessment

Critically Important

qualitative risk assessment swine

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Qualitative Risk Assessment - Swine

Hazard Characterization

Release

Assessment

Low

Risk Estimation

Exposure

Assessment

Medium

High

Consequence

Assessment

Critically Important

extent of use

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Extent of Use
  • Guidance #152 declares the extent of use is considered “Low” if:
    • Individual animals are injected
    • Duration of use is either short or medium (less than 21 days)
  • Tulathromycin qualifies as having a “Low” extent of use
potential risk management steps guidance 152

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Potential Risk Management Steps (Guidance #152)

*Category 2 drugs ranked ”critically” important and “High” for either release or exposure

recommended risk management steps

Release

Assessment

Risk

Estimation

Exposure

Assessment

Consequence

Assessment

Recommended Risk Management Steps
sponsor conclusions microbial safety of tulathromycin1
Sponsor Conclusions Microbial Safety of Tulathromycin
  • Proposed label use of tulathromycin include management considerations of:
    • prescription status
    • inherent low extent of use due to parenteral single dose administration
    • Advisory Committee Review
  • MacR is currently monitored by NARMS
  • With these management considerations, approval of the proposed indications for injectable tulathromycin in cattle and swine poses no appreciable risk to public health with respect to microbial food safety.