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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
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