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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
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