DAVID WOLFGANG, VMD, MPH DABVP-DAIRYDIRECTOR, BUREAU OF ANIMAL HEALTH AND DIAGNOSTIC SERVICESPENNSYLVANIA DEPARTMENT OF AGRICULTURE

ImpactofAntibioticUseinAnimalAgricultureandInfluenceonResistanceControversy

www.nourishlife.org

GetSmartPSUNov.15,2016

Presentation Outline• AnimalCareandTherapeutics• Preventativecarevs.diseasetreatment• Quality concerns• Regulatory issues & food safety concerns–What does that mean for producers–What does that mean for consumers–Whatdoesitmeanforanimalwell-being– Impact for markets and environment

TimeMagazine,March19,2014p.20

TheWorriedWell

ReviewAntibioticResistance,2014

AllAnimalAgSpecies- CareandWell-beingInitiatives

• Addressinjuredorillanimals– Treatmentprotocols

• Painfulconditions• Chronicconditionsandeuthanasia• Relativeeconomicvalueanimals• Routinecareproceduresofcaretakers(+training)• Careandwelfareofanimalsduringtransportation• Prevention&keepwell>treatwhenill

Animaluseandcontributiontoresistance?• Animalsconsumeandexcreteantibiotics(~2trillionlbsofmanuregeneratedinUSAannually)

• Animalscantransmitresistantbacteriainfood– Foodofanimaloriginascauseoffood-borneinfections:• Salmonella• Campylobacter• Yersinia• EColi0157-H7

• Transfertohumanspecificorganisms(esp.seeninexamplesfrompigsandchickenswhensick).

AntibioticbyRouteofUse• ANTIMICROBIALDRUGSAPPROVEDFORUSEINFOOD-PRODUCINGANIMALS1• ACTIVELYMARKETEDIN2014• DOMESTICSALESANDDISTRIBUTIONDATA• REPORTEDBYMEDICALIMPORTANCEANDROUTEOFADMINISTRATION

AnnualTotals(kg)%Subtotal%GrandTotal• MedicallyImportant Feed1 6,977,747 74% 45%• MedicallyImportant Injection1 341,790 4% 2%• MedicallyImportant3 Intramammary 11,450 <1% <1%• MedicallyImportant Oral5orTopical1 104,082 1% <1%• MedicallyImportant Water6 2,040,920 22% 13%• MedicallyImportant Subtotal 9,475,989 100% 62%• NotMedicallyImportant4AllRoutes7 5,882,221 38%

• GrandTotal 15,358,210 100%

NARMS2014,p44

Whyuseantibioticsinfeed?• Useatperiodsofhigherstress:feedchanges,transportation,weatherchanges

• Reducessheddingoffoodsafetypathogens– Trade1/53,000,000illnessduetoresistance– Vs.1/32,900illnessduetogreaterfoodsafetyillness(additional6,000severecases/yr)

• Lowercarbonfootprint– Average13%greatergain/kgoffeed– Saves4-6%ofinputcost CoxandRicci,Envir Sci,2007

Matthew,etal.,FoodPathDis 2007

• Acutelyillanimals• Manyfeweranimals• Higherdoses(gmvs.mg)• Morehandling• Tissueresidue• Newproducts&costR&D• Treatpainandsuffering• Stuntedgrowth• Highercost/animal

• Keephealthyvs.sick• Entireherdorflock• Lowdose,noresidue• Fewerfoodpathogens• Olderproducts,notnormallyforhumans

• Avoidpreventpain/suffering

• Lowerscostofproduction• Improvesefficiency(lessmanure,lessacres)

AntibioticsTherapeutic vs.DiseasePrevention/control

http://www.nppc.org/issues/animal-health-safety/antimicrobials-antibiotics/

ReductionofResiduesandResistance• Judicioususeprograms• Restrictextralabeluse– Diagnosticstoinformsciencebasedprotocols– Createwrittenprotocolsforcommonconditions– UptodateandwrittenVCPRandVFD

• Superviseuseasmuchaspossibleonfarms• Extendedwithdrawaltimes– Physiologicalstateofanimal– Dose,depotandtissuelocation

• FARAD(www.farad.org)

Factorsthatcanaffecteliminationoftherapeuticproduct

• Doseandsizeofdepo– Rateofabsorption– IV<IM<SQ(productmovesdepotoplasma)– Pharmokenetics

• Overallhealthandstatusofanimal• Targetpluseliminationorgans• Specialcharacteristicsofproduct

–Multipledosesordifferentdoses– Doseindifferentsitethandesigned

ExtendedWDT• WDTisthetimerequiredafterdosingfortissueconcentrationstobedepletedtoorbelowspecificsafeconcentration

• Morecloselyassociatedtotissuedepotsvs.plasmadepots

• TissuewiththeslowestdepletiondeterminestheWDTforthespecies– 10t½=99.9%depletion,daysusuallyroundedup(nofractionsofdays),physiologicalstate,differenttissue

– InUSsafeconcentrationcanbedefinedasthetolerancelimit-lawiszerofornotapprovedcompounds

• InEuropeusuallytermedMaximumresiduelevel

NormalDoseNormalKidney/Liver~Predictable

Withdrawal

Safewithdraw

al

MIC

Re-treat~1daysSingledose~10wdMultipledoses- safe~+fewd

• Samedosebutrepeated• Withdrawal(slightlyextended)• (e.g.,fewdplusnewdose)

• Milkwithholding• Prettypredictableevenif1ppb

ExtendedTreatmentorCompromisedKidney/Liver

VeryLongWithdrawal

Safewithdraw

al

MIC

Re-treat~3daysSafe~30dSafe~50+d

• Samedosebutrepeated• Withdrawal(canbegreatly

extended)• (e.g.,notjust3dplusnew

dose)• Milkwithholding

• Verylongiftargetis1ppb

MalariaResistanceandLessonsLearned• ReadandHuijben,Evol.App.,2009Fallacies• Drugswithlonghalflivesarepreferable• Denovoresistancemutationsaremainenemy– (vs.transportationaroundglobe)

• Genetictradeoffsalonedeterminecostsofresistancetopathogen– (vs.inhostecology)

• Fixationofresistanceisinevitableifdrugpressureismaintained

Staphylococcusaureus• SamplessubmittedtoADLformastitisorbulktankmilk

culture(2008,2013,2014,2015)examinedforS.aureus

• S.aureusisolates

– 163isolates(n=115QMS;n=48BTM)from77farms• Smallcellvariantphenotypeanalysis• Antibioticresistance

– Amoxicillin+Clavulanicacid,Cefoxitin,Ciprofloxacin,Clindamycin,Erythromycin,Gentamicin,Oxacillin,Tetracycline,Vancomycin,Penicillin.

• Enterotoxingenes:A,B,C,D,E,F,G,H,I,J,K,L,M,O,P,Q,R,TSST-1• Leukocidingenes:LukAB,LukED,LukMF• DNAFingerprinting:MultiLocusSequenceTyping

Jayarao,unpublished2015

AntimicrobialResistance

AntibioticResistanceProfile No ofIsolates No. ofFarms

None 130 74

Clindamycin 1 1(QMS)

Cefoxitin 32(BTM)1(QMS)

Penicillin 71(BTM)6(QMS)

Tetracycline 5 5(QMS)

Vancomycin 11

2(BTM)3(QMS)2(BTM)

3Amoxicillin, Penicillin 1 1(BTM)Clindamycin,Erythromycin 2 1(QMS)Oxacillin, Penicillin 1 1(QMS)

Clindamycin,Erythromycin,Tetracycline,Penicillin 2 2(BTM,QMS)

• Sensitivity– 130/163=80%ofisolatessensitivetoalltenantimicrobialsexamined.– BTM:37/48=77%– QMS:93/115=81%NOMRSAstrainisolatedfromPennsylvaniadairyherds

Jayarao,unpublished2015

PrevalenceofAntibioticResistance%Antibiotic Salmonella E coli‘07 Salmonella Ecoli‘08 Salmonella Ecoli‘09

n=202 n=525 n=232 n=500 n=117 n=510

Amikacin 0 0 0 0 0 0

Amoxi/clav. 1.0 1.5 0 1.1 0 0.6

Ampicillin 1.5 2.1 0 2.2 0 1.6

Cefoxitin 1.0 1.5 0 1.3 0 0.4

Ceftiofur 1.0 0.8 0 1.1 0 0Chloramphenicol 1.0 0.2 0 0.9 0 0.4

Kanamycin 0 3.8 0 4.8 1.7 3.3Streptomycin 1.0 5.1 0.4 6.5 1.7 2.8Sulfizoxazole 1.0 3.8 0 4.8 1.7 2.8

Tetracycline 1.0 13.1 0 9.8 1.7 7.8Trim./sulfa 0 1.0 0 1.5 0 1.2

Schukken,etal,USDA/RDQMAPilotProject

ResistantE.coli isolatesfromVariousCattleGroupsinPA

AntimicrobialAgents

FarmPrevalence(%)Pre-weanedcalves(n=77)

Post-weanedcalves(n=75)

Drycows(n=72)

Lact.cow(n=80)

AUG 40.3(31) 14.7(11) 0.0(0) 5.0(4)AMP 57.1(44) 33.3(25) 1.4(1) 12.5(10)AZI 2.6(2) 1.3(1) 0.0(0) 0.0(0)FOX 37.7(29) 13.3(10) 0.0(0) 5.0(4)TIO 31.2(24) 12.0(9) 0.0(0) 5.0(4)AXO 36.4(28) 13.3(10) 0.0(0) 6.3(5)CHL 29.9(23) 18.7(14) 1.4(1) 1.3(1)CIP 1.3(1) 1.3(1) 0.0(0) 0.0(0)GEN 13.0(10) 5.3(4) 0.0(0) 0.0(0)NAL 7.8(6) 4.0(3) 0.0(0) 0.0(0)STR 70.1(54) 38.7(29) 6.9(5) 21.3(17)FIS 67.5(52) 44.0(33) 11.1(8) 22.5(18)TET 81.8(63) 69.3(52) 26.4(19) 40.0(32)SXT 26.0(20) 8.0(6) 0.0(0) 2.5(2)

Liu,inpress2016

Noresistancedetected

0

10

20

30

40

50

60

70

80

90

100

2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

Sal.HeidlebergSal.NewportSal.TyphimuriumSal.NonTyphiSal.Typhi

NARMS‘14

MalariaResistanceandLessonsLearned• White,et.al.,MalariaJournal,2009Resistance• Greater:fastparasitegrowthandhighburdens• Recrudescenceandmultiplerecrudescencearerequiredfordenovoselectionofresistance

• Inadvertenttreatmentofasymptomaticparasitemiaisunlikelysourceofresistance

• Strivefortherapeuticlevelsinallpatients• Illpatientswithhyperparasetemiaveryrisky

AntibioticusetheonlycauseorsolutionforAMR?

• Genesinenvironment– Coselectionagainstmetals– Allowsforplasmidsandintegrons+cassettestoDNA

– Co-resistancetoheavymetalsallowsformaintenanceofresistance(pollutedcountries)

– Increaseduseoftracemineralstoimproveperformance

• Heavyindustrialimpact=greaterresistanceBerendonk,et.al,NatRevMicro,2015McAurther,et.al,MicroEcol,2015

TheWorriedWell

ReviewAntibioticResistance,2014

Example:ImportedShrimp• ~OnehundredpercentofVietnamese

shrimpfarmsuseciprofloxacin.• Fluoroquinoloneconcentrationsin

sedimentsandsurfacewatersmayreach>4,000μg/kg.

• Allkindsofbacteriainhabittheseponds,includingthosepresentinthemanureofterrestrialanimals(suchaschickens)thatisfedtotheshrimp

• “Wheredoesthislead?”

25

http://cdn.intechopen.com/pdfs-wm/35141.pdf

SystemsApproachAdvantagesofUSFoodSupplyvs.ProductionForcedOutofCountry26

INTEGRATORDRIVEN

BMP/HACCP PROGRAMS

Food Safety and Security

Market Incentives

Rearing Practices &Housing

Environmental Stewardship

Diet Options

Antimicrobial Usage

Well being-Welfare

PennStateiscommittedtoaffirmativeaction,equalopportunityanddiversityofitsworkforce.