# Presentation: 681319

## Tulathromycin Solution for Parenteral Injection for Treatment of Swine and Bovine Respiratory DiseaseMicrobiological 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

- 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

- 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

- Risk Analysis Terminology

## 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

**Hazard Characterization**

## 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

- 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 #152)

## 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 #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 #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)

## Summary of Risk Estimation

## 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 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 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*

| Probability of human exposure to Campylobacter |  |  |  |
| --- | --- | --- | --- |
| Amount of beef contamination | Beef Consumption |  |  |
|  | High | Medium | Low |
| High | High | High | Medium |
| Medium | High | Medium | Low |
| Low (<5%) | Medium | Low | Low |

- *Sponsor accepts the default recommendation

## Campylobacter in Pork Exposure Default (G#152)

| Probability of human exposure to Campylobacter |  |  |  |
| --- | --- | --- | --- |
| Amount of pork contamination | Pork Consumption |  |  |
|  | High | Medium | Low |
| High (Carcass) | High | High | Medium |
| Medium | High | Medium | Low |
| Low | Medium | Low | Low |

## Campylobacter in Pork Exposure Recommendation*

| Probability of human exposure to Campylobacter |  |  |  |
| --- | --- | --- | --- |
| Amount of pork contamination | Pork Consumption |  |  |
|  | High | Medium | Low |
| High | High | High | Medium |
| Medium | High | Medium | Low |
| Low (retail) | Medium* | Low | Low |

- *Sponsor recommendation

## 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

- 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

## Qualitative Risk Estimation Release 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

- molecular weight: 806.23

- C41H79N3O12

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

## 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

## Effects of pH on Tulathromycin Activity 

## 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

- 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

- 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

- 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

## Mechanisms of Macrolide Resistance

- Target site modification
- Sequence change in ribosome due to mutation
- rRNA methylation (e.g., *erm*A, *erm*B)
- Inducible (erythromycin does;  tilmicosin and tulathromycin do not)
- Constitutive
- Drug inactivation
- Phosphorylation (e.g., *mph*A or *mph*B)
- Hydroxylation (e.g., *ere*A and *ere*B)
- Drug efflux pumps (e.g., *msr*A and *mef*A)

## 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

- 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

- 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)

## Cross- and Co-Resistance in Gram-Positive Cocci

- The relative impact of current use patterns on resistance propagation is difficult to discern
*Erm* genes have been broadly disseminated since the 1980’s in isolates from humans
- MLSB resistance in streptococci/enterococci in livestock are broadly disseminated
- Organisms carrying the *erm* gene also often carry resistance determinants to other classes of antibiotics, so resistance co-selection can occur

## 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)

## Macrolide Resistance in Campylobacter

|  | Mutation | Gene transfer (Plasmids) | Comments |
| --- | --- | --- | --- |
| Target site modification | Yes | No | -- |
| Drug inactivation | No | No | -- |
| Drug efflux pumps | Yes | No | Rare in Campy |

## 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

- BRD & SRD in the USCurrent Macrolide Use
- Antibiotics Use

## Bovine Respiratory Disease

- Normal

- Depressed

- Labored Breathing

## Percent of Cattle that Developed Diseases after Arrival

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

## 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

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

## 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

|  | Cattle | Swine |
| --- | --- | --- |
| Erythromycin | Injectable | Injectable |
| Tylosin | Injectable
Oral | Injectable
Oral |
| Tilmicosin | Injectable | Oral |

## 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

- 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

- USDA/APHIS Veterinary Services Info Sheet, March 2002

## 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

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

## 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

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

## Approximately 10% of Cattle Are Treated on Arrival

- 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

- 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

- 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

- 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

- 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

- One dose provides full course therapy, so assurance of compliance with treatment regime
- Reduced stress for animals

## Resistance Selection Pressures in the FieldConclusions

- 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

- 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

## 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)

|  | C. jejuni | C. coli |
| --- | --- | --- |
| Poultry (NARMS)* | 0.2-5.1% | 11-23% |
| Humans (NARMS)‡ | 1-3% | Too few |
| Cattle (USDA/NAHMS)† | 2.2%
(2/92 isolates) | 7.7%
(2/26 isolates) |

- * _[www.arru.saa.ars.usda.gov//campy.htm](http://www.arru.saa.ars.usda.gov//campy.htm)_
**‡****Gupta et al., 2004**
**†**** **_[www.arru.saa.ars.usda.gov/posters.htm](http://www.arru.saa.ars.usda.gov/posters.htm)_

## 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 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

## Exposure Assessment Recommendation (template)

| Probability of human exposure to pathogen |  |  |  |
| --- | --- | --- | --- |
| Amount of commodity contamination | Amount of commodity being consumed |  |  |
|  | High | Medium | Low |
| High | High | High | Medium |
| Medium | High | Medium | Low |
| Low | Medium | Low | Low |

## Exposure Assessment Recommendation (template)

| Probability of human exposure to pathogen |  |  |  |
| --- | --- | --- | --- |
| Amount of commodity contamination | Amount of commodity being consumed |  |  |
|  | High | Medium | Low |
| High | High | High | Medium |
| Medium | High | Medium | Low |
| Low | Medium | Low | Low |

## Exposure Assessment Recommendation (template)

| Probability of human exposure to pathogen |  |  |  |
| --- | --- | --- | --- |
| Amount of commodity contamination | Amount of commodity being consumed |  |  |
|  | High | Medium | Low |
| High | High | High | Medium |
| Medium | High | Medium | Low |
| Low | Medium | Low | Low |

## Campylobacter in Beef Exposure Recommendation

| Probability of human exposure to Campylobacter |  |  |  |
| --- | --- | --- | --- |
| Amount of beef contamination | Beef Consumption |  |  |
|  | High | Medium | Low |
| High | High | High | Medium |
| Medium | High | Medium | Low |
| Low (carcass) | Medium | Low | Low |

## Campylobacter in Pork Exposure Default (Guidance #152)

| Probability of human exposure to Campylobacter |  |  |  |
| --- | --- | --- | --- |
| Amount of pork contamination | Pork Consumption  |  |  |
|  | High | Medium | Low |
| High (Carcass) | High | High | Medium |
| Medium | High | Medium | Low |
| Low | Medium | Low | Low |

## 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

- 60-100% prevalence
- In swine feces

- 0-32% prevalence
- In carcasses & processing

- 0-<5% prevalence
- At retail

- Hedberg, 2002;
- Nesbakken et al., 2002;
- Manser & Dalziel, 1985

- Oosterom et al., 1985;
- Nesbakken et al., 2002;
- Pierce et al., 2003

- Duffy et al., 2001;
- Duffy et al., 2002;
- White, 2004
- Zhao et al., 2001;

## Campylobacter in Pork Exposure Recommendation

| Probability of human exposure to Campylobacter |  |  |  |
| --- | --- | --- | --- |
| Amount of pork contamination | Pork Consumption |  |  |
|  | High | Medium | Low |
| High | High | High | Medium |
| Medium | High | Medium | Low |
| Low (retail) | Medium | Low | Low |

## Qualitative Risk Estimation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

## Qualitative Risk Assessment (Guidance #152)

**Release **
**Assessment**

**Exposure**
**Assessment**

**Consequence**
**Assessment**

**Risk Estimation**

**Hazard Characterization**

## Qualitative Risk Assessment - Beef

**Release **
**Assessment**

**Exposure**
**Assessment**

**Consequence**
**Assessment**

**Risk Estimation**

**Hazard Characterization**

- Low

- Medium

- Critically Important

- High

## Qualitative Risk Assessment - Swine

**Release **
**Assessment**

**Exposure**
**Assessment**

**Consequence**
**Assessment**

**Risk Estimation**

**Hazard Characterization**

- Low

- Medium

- Critically Important

- High

## Modulations on “High”

| Release | Exposure | Consequence | Overall Risk Estim. |
| --- | --- | --- | --- |
| Low | Low | Critically Imp. | High |
| Low | Medium | Critically Imp. | High |
| Medium | Low | Critically Imp. | High |
| Medium | Medium | Critically Imp. | High |
| Low | High | Critically Imp. | High |
| High | Low | Critically Imp. | High |
| Medium  | High | Critically Imp. | High |
| High | Medium | Critically Imp. | High |
| High | High | Critically Imp. | High |

**Notes:**
Factors inherent in the proposed tulathromycin label indications that mitigate against selection of macrolide-resistant Campylobacter:
No unique mechanism of resistance cross-resistance compared to macrolides used in animals
Limited activity of tulathromycin in colon/feces due to pH 
Macrolide resistance occurs by mutation, not acquisition
Prevalence of Campylobacter in retail pork and beef is <5%
Target species (pork and beef) are not significant risk factors for Campylobacter disease in humans
Macrolide resistance in Campylobacter isolates from humans has remained  3%; no trends over time

## 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)

| Potential Approval Conditions         | Overall Risk Categorization |  |  |
| --- | --- | --- | --- |
|  | 1 (High) | 2 (Medium) | 3 (Low) |
| Marketing Status | Rx | Rx/VFD | Rx/VFD/OTC |
| Extralabel drug use restrictions | Restrictions | Restricted in some cases* | ELDU permitted |
| Extent of use | Low | Low or medium | Low, medium, or high |
| Post-approval monitoring | Yes | Yes | In certain cases |
| VMAC review | Yes | In certain cases* | No |

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

## Recommended Risk Management Steps

| Considerations | Proposal | Comments |
| --- | --- | --- |
| Categorization | 1 | Guidance #152 default |
| Marketing Status | Rx | Sponsor recommendation |
| Extralabel Drug Use Restrictions | No Restrictions | Broad macrolide use ongoing in livestock |
| Extent of use | Low | Individual animal injection; not used in lactating cows/preruminant calves |
| Post-approval monitoring | Yes | NARMS Campylobacter in humans |
| VMAC review | Yes | Current |

## 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.

## Thank you