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AnimalHealthandAntibiotics–LookingAheadwithScience

TheOvertonWindow

• Unthinkable• Radical• Acceptable• Sensible• Popular• Policy

Prohibitionofgrowthpromotion usesofmedicallyimportantantimicrobials

Prohibitionofpreventionandcontrolusesofmedicallyimportantantimicrobials

Prohibitionoftherapeuticusesofmedicallyimportantantimicrobials

AMDUCA?

• ThesameregulationsaspublishedintheFederalRegisterin1996stillapplytoday.• TheAMDUCAregs wereutilizedtolimittheabilitytousecephalosporins inanextralabelmannerinfoodanimals.

GuidanceDocuments

• GuidanceforIndustry(GFI)209– April,2012• Imaginingadelineationbetweengrowthpromotion,prevention/control, andtherapy• “judicious”vs.“hazard”

• Principle1:Theuseofmedicallyimportantantimicrobialdrugsinfood-producinganimalsshouldbelimitedtothoseusesthatareconsiderednecessaryforassuringanimalhealth.

U.S.CTC,TCandOTCCattleApprovalExamples(FeedandWater)

CTC:0.1mg/hd perdayincalves upto250lbs

CTC:25- 70mg/hd perday incalves250– 400lbs

CTC:70mg/hd perdayingrowingcattle over400lbs

CTC:350mg/hd perdayinbeefcattleunder700lbs

CTC:0.5mg/lbperdayinbeefcattle over700lbs

CTC:350mg/hd perdayinbeefcattle

CTC:400g/tontoprovide10mg/lbperdayincalvesupto250lbs

CTC:10mg/lbBWforupto5days

OTC:0.5to2.0g/hd perday

Feedefficiency/Rate ofgain Prevention/Control Treatment

TC:22mg/kgfor3-5daysincalves

ThesearenotalloftheCTC,TC,andOTCindications, butareselected toillustrate theregimen range.

GoneasofJanuary1,2017

?????

“However,theAgencybelievesthatitisnotlimitedtomakingriskdeterminationsbasedsolelyondocumentedscientificinformation,butmayuseothersuitableinformationasappropriate.’’

Whodefinesmedicallyimportant?• AppendixA,GFI#152• ListisdeterminedbyanexpertFDApanelmanagedbytheCenterforDrugEvaluationandResearch(CDER)WithintheFDA• TheWorldHealthAssociationalsohasalistofmedicallyimportantantibiotoics• Humanhealth• Animalhealth

WHOPrioritization…

• withinthecriticallyimportantdesignation• Glycopeptides• Fluoroquinolones• Cephalosporins• Macrolides

AntimicrobialsNot Classifiedas“MedicallyImportant”• Ionophores:monensin,lasalocid• Flavophospholipol:bambermycins(e.g.,Flavomycin®,Gainpro®)• Bacitracin• Pleuromutilins:Tiamulin

• Notmedically importantintheU.S.,butclassifiedashighlyimportantbyWHO

MedicallyImportantAntimicrobialswith FeedorWaterLabels• Aminoglycosides: gentamicin,neomycin• Lincosamides: lincomycin• Macrolides: tylosin,tilmicosin (Pulmotil®currentlyrequiresaVFDinswineandcattle)• Penicillins(natural):penicillinGincludedincombinationproducts• Florfenicol:CHPCincludedashighlyimportantdruginGFI#152appendixA,Florfenicolisconsideredmedicallyimportant.ExistingVFDstatusforfeedinaquaculture.

MedicallyImportantAntimicrobialswith FeedorWaterLabels

• Streptogramins:virginiamycin• Sulfonamides: Includesbothpotentiated(e.g.,trimethoprim/sulfa)andnon-potentiatedsulfonamides.• Tetracyclines: chlortetracycline,oxytetracycline,tetracycline

GuidanceforIndustry213

• December,2013• ThisguidancedocumentputsforthnonbindingrecommendationsforcompaniestocomplywithGuidance209.• Therewasa3monthperiodforcompaniestocommunicatewiththeFDA/CVMregardingtheirintenttocomplywiththevoluntaryrecommendationsinGuidance209.• A3yearperiodforcompaniestocomplyendsinDecemberof2016.

GFI213

• Acompanymayremovethelabelindicationsforgrowthpromotionandinsertlabelrequirementsforveterinaryauthorizationwithoutbeingsubjectedtootherrequirementssuchasupdatingthelabelinotherareas(e.g.,microbialsafety).

TheVFDinoneslide

• Writtenonly,non-verbal• Feed,freechoicefeed,handfedfeed,milk,milkreplacerarefeeds• Absolutelynoextralabeluse• StartingJanuary1,2017,musthaveaVFDtofeedthefeedcontainingaVFDdrugtofoodanimals• AnanimalonlyappearsonaVFDonce,multipleVFDsrequiredforpulsing• TypeAmedicatedarticlesarenotfeeds,TypeBandTypeCmedicatedfeedsarefeeds.G

SomeOtherHotTopics

CaliforniaSB27

• GoesbeyondGFI#209• Routineprevention• Allantibioticsunderveterinarycontrol

Penicillin/TetracyclinesinAnimalFeed

• 1977NOOHontheuseofpenicillinsandtetracyclinesinanimalfeed• 2011– NRDC,CSPI,UCS,FACTfiledalawsuitinU.S.DistrictCourttoforcetheCVMtohavethehearings• 2012– JudgesaysCVMmusthavethehearings• 2012– AppealbyHHS/FDA/CVM• 2014– RulinginfavorofFDA• Appeal?

ExecutiveOrder9-18-2014

• TheExecutiveOrderdirectsestablishmentoftheTaskForceforCombatingAntibiotic-ResistantBacteria,co-chairedbytheSecretariesofDefense,Agriculture,andHealthandHumanServices(HHS).

ExecutiveOrder9-18-2014

• TheExecutiveOrderdirectstheSecretaryofHHS,inconsultationwiththeSecretaryofAgriculture,toestablishaPresidentialAdvisoryCouncilonCombatingAntibiotic-ResistantBacteria,tobecomposedofleadingnon-governmentalexperts

ExecutiveOrder9-18-2014

• ThePresidentialAdvisoryCouncilwillprovideadvice,information,andrecommendationsregardingprogramsandpoliciesintendedto:• preserveantibioticeffectiveness;• strengthensurveillanceofantibiotic-resistantinfections;• advancethedevelopmentofrapid,point-of-carediagnosticsforuseinhumanhealthcareandagriculture;• advanceresearchonnewtreatmentsforbacterialinfections;• developalternativestotheuseofantibioticsforsomeagriculturalpurposes;• andimproveinternationalcoordinationofeffortstocombatantibioticresistance.

ExecutiveOrder9-18-2014• TheNationalStrategyprovidesdetailedactionsforfiveinterrelatednationalgoalstobeachievedby2020incollaborationwithpartnersinhealthcare,publichealth,veterinarymedicine,agriculture,andfoodsafety,aswellasinacademic,Federal,andindustrialresearchanddevelopment.Thegoalsare:• 1.Slowtheemergenceandpreventthespreadofresistantbacteria.• 2.StrengthenNationaleffortstoidentifyandreportcasesofantibioticresistance.

ExecutiveOrder9-18-2014• TheNationalStrategy• 3.Advancethedevelopmentanduseofrapiddiagnostictestsfortheidentificationandcharacterizationofantibiotic-resistantbacteria.• 4.Acceleratebasicandappliedresearchanddevelopmentfornewantibioticsaswellasothertherapeuticsandvaccines.• 5.Improveinternationalcollaboration,capacitiesforantibiotic-resistanceprevention,surveillance,control,andantibioticresearchanddevelopment.

Theveterinaryprofessionisnotonlygoingtoberesponsible forallmedically-importantantimicrobialusesinfoodanimals…

wearegoingtobeaccountable

AntibioticUseMonitoring

AntimicrobialUseMonitoring

• Inmyopinion,shouldbeactualuse,tiedtoreasonforuse• Totalkgasametriconlyservesasasticktodrive“cuttheuse”asagoal• AnimalDailyDoses(ADD)andAnimalRegimens(AR)providealookintodrugexposureaswellasnumberofanimalsreceivingtheregimen.• Theremaybedifferentregimensforthesamedruginaspecies.

AntimicrobialUseMonitoring• Theonlywaytodrivetheneededgranularityinthedataisto…• Giveagriculturethesteeringwheelfordatacollection• Governmentauditofthesampling strategyanddatahandling• Absoluteguaranteeofanonymityforparticipants• Samplingstructuremustbalance

• Abilitytoengagethesameparticipantsyearafteryear• Newparticipantsandrandomsamplingofrepeatparticipantseachyearforappropriatesamplingoftheindustry.

• Granularityofpublicdataanddatausedtodriveantibioticstewardshipmayvary

Fundamentals

• Denominatorsreally,reallymatter• Numeratorsarerelativelyeasy

• Andthishasdrivenaninteractiveenvironmentforthisissueinwhichsomeengagebasedonlyonnumerators

MyView

• Stewardshipisgood,but…• “noantibiotics”– notanoption

• “Never-ever”systemswheretreatedanimalsorgroupsareremovedfromthesystemaredisingenuous• Itisaboutthesystemandtheoveralleffectofthesystemonantibioticuse• Whenthereisanincentivetonottreatananimalwithaninfectiousdisease,whatdoyouthinkhappenstospeedoftreatmentandtimetoalleviationofaninfectiousdisease?

Whatis“Stewardship”?

2. Isthereanon-antibioticalternativewhichwillappropriatelyprevent,control,ortreatthisdiseasechallenge?

3. Selectionofanantibioticwhichhasbeendemonstratedtobesafeandeffectiveforthispurpose

4.Assuringuseoftheantibioticasshowntobesafeandeffective

Yes…

1.Responsibilityforappropriatediagnosticsandestablishmentofanaccurateandfunctionalcasedefinition

5.Isthisantibioticinterventionstillnecessary?

While…

Whoisdrivingchangeinfoodanimalantimicrobialuse?

Legislation

Regulation

Retailation

DriversofChangeinFoodAnimalAntimicrobialUse

DART– HR2459

PAMTA– HR1552

PARA– S621

VFD

GFI213GFI209

FluoroquinolonesCephalosporins

AMDUCA

ADUFA

ChipotleMcDonald’s

Tyson

Walmart Chic–Fil- A

Panera

ABigDifference…

• Indurationofdiseaserisk• Chicken

• 4#38-42days• 10#58-60days

• Swine• 6months

• Beefcattle• 14-22months

Whatpricetosay“antibioticfree”withnoasterisk?• Ionophores

Antimicrobialstewardshipcannotbeusedasa

competitiveadvantagebetweenorwithinfood

animalindustries.

isgoingto

…fromhere

• Thedaysofverbaltreatmentprotocolsaregone• Thedaysofunacceptabletreatmentrecordsaregone• Thedaysofnontransparentuseofantimicrobialsinfoodanimalsarecomingtoanend• Neitherveterinariansorproducerscanbepassiveintheseefforts.

http://bullfightingmaza.blogspot.com/2013/02/bulls-fighting.html

AntibioticResistanceIssues

AlexanderFleming- 1945“ButIwouldliketosoundonenoteofwarning.Penicillinistoallintentsandpurposesnon-poisonoussothereisnoneedtoworryaboutgivinganoverdoseandpoisoningthepatient.Theremaybeadanger,though,inunderdosage.Itisnotdifficulttomakemicrobesresistanttopenicillininthelaboratorybyexposingthemtoconcentrationsnotsufficienttokillthem,andthesamethinghasoccasionallyhappenedinthebody.”

RiceLB.Mechanismsofresistanceandclinicalrelevanceofresistancetobeta-lactams,glycopeptides,andfluoroquinolones.MayoClinicProceedings,97:198-208,2012.

FoodAnimalAntibioticUseintheUnitedStates

Yearlysalesdataareavailable…

• Butthelastpublicallyavailablehumandataarefrom2011.

So, where does the "80% used in food animals" come from? Well, if you add the 4,122,397 kg of ionophores sales reported for 2011, then you come up with the following values. It doesn't move the value that much to take the ionophores out because they go into both the numerator and denominator.

All Antimicrobial Sales Totals 13,569,039 3,289,175

Expressed as percent of total human and food animal sales 80.5% 19.5%

Food Animal Sales 2011 (kg)

Human Sales 2011 (kg)

Medically Important Antimicrobial Totals (kg) 9,446,641 3,289,175

Expressed as percent of total human and food animal sales of medically important antimicrobials

74.2% 25.8%

Antibiotic-ResistantMicroorganism

InfectionsIncludedInfections

notIncluded

EstimatedAnnualNumber

ofCases

EstimatedAnnual

NumberofDeaths

CarbapenemResistantEnterobacteriaceae(CRE)

HAIscausedbyKlebsiellaandE.coli withonsetinhospitalizedpatients

1,2,3 9,300 610

Drug-resistantNeisseriagonorrhoeae (anydrug)

Allinfections 246,000 <5

Multidrug-resistantAcinetobacter(threeormoredrugclasses)

HAIswithonsetinhospitalizedpatients

1,2 7,300 500

Drug-resistantCampylobacter(azithromycinorciprofloxacin)

Allinfections 310,000 28

Drug-resistantCandida(fluconazole)

HAIswithonsetinhospitalizedpatients

1,2 3,400 220

Extended-spectrumβ-LactamaseproducingEnterobacteriaceae(ESBLs)

HAIscausedbyKlebsiellaandE.coli withonsetinhospitalizedpatients

1,2,3 26,000 1700

Vancomycin-resistantEnterococcus (VRE)

HAIswithonsetinhospitalizedpatients

1,2 20,000 1300

Multidrug-resistantPseudomonasaeruginosa (threeormoredrugclasses)

HAIswithonsetinhospitalizedpatients

1,2 6,700 440

Drug-resistantnon-typhoidalSalmonella (ceftriaxone,ciprofloxacin7,or5ormoredrugclasses)

Allinfections 100,000 40

Antibiotic-ResistantMicroorganism

InfectionsIncludedInfections

notIncluded

EstimatedAnnualNumber

ofCases

EstimatedAnnual

NumberofDeaths

Drug-resistantSalmonella Typhi(Ciprofloxacin7)

Allinfections 3,800 <5

Drug-resistantShigella(Azithromycinorciprofloxacin)

Allinfections 27,000 <5

Methicillin-resistantStaphylococcusaureus (MRSA)

Invasiveinfections 4 80,000 11000

Streptococcuspneumoniae (fullresistancetoclinicallyrelevantdrugs)

Allinfections 1,200,000 7000

Drug-resistanttuberculosis(anyclinicallyrelevantdrug)

Allinfections 1,042 50

Vancomycin-resistantStaphylococcusaureus (VRSA)

Allinfections <5 <5

Erythromycin-resistantGroupAStreptococcus

Invasiveinfections 5 1,300 160

Erythromycin-resistantGroupBStreptococcus

Invasiveinfections 6 7,600 440

1,473,442 22,130

Clostridiumdifficile Infections

Healthcare-associatedinfectionsinacutecarehospitalsorinpatientsrequiringhospitalization

250,000 14,000

SummaryTotalsforAntibiotic-ResistantInfections 2,049,442 23,488

6.Non-invasiveinfectionsandasymptomaticintrapartumcolonizationrequiringprophylaxis7Resistanceorpartialresistance

1.Infectionsoccuringoutsideofacute-carehospitals(e.g.,nursinghomes)

2.Infectionsacquiredinacutecarehospitalsbutnotdiagnoseduntilafterdischarge

3.InfectionscausedbyEnterobacteriaceaeotherthanKlebsiella andE.coli (e.g.,Enterobacter spp.)

4.Bothhealthcareandcommunity-associatednon-invasiveinfectionssuchaswoundandskinandsofttissueinfections5.Non-invasiveinfectionsincludingcommonupper-respiratoryinfectionslikestrepthroat