THE ANTIBIOTIC CRISIS

Mark WoolhouseCentre for Immunity, Infection and Evolution,

University of Edinburgh

UN RESOLUTION

M.E.J. Woolhouse, University of Edinburgh, March 2017

WORDS →ACTIONS→ CHANGE

• Raiseawareness• Improvesurveillance• Recogniselocalneeds• OneHealthapproach• UN-ledcoordinatingbody• Reportin2years’time

BACKGROUND

M.E.J. Woolhouse, University of Edinburgh, March 2017

NATURAL RESISTANCE

• 50-200tonnesbacteriaperperson

• Soil- Sourceof>80%antibiotics- Containshomologousresistancegenesforall

majorclassesofantibiotic- Forsbergetal.(2012)Science

• Antibioticsandantibioticresistancearenatural,ancientandubiquitous- D’Costa etal.(2011)Nature

• Antibioticproductionbyhumans175,000tonnesyr -1 =20tonneshr -1

• Antibioticproductionbybacteria>1moleculeper10Kbacteriumperhr?

M.E.J. Woolhouse, University of Edinburgh, March 2017 Woolhouseetal.(2015)Phil.Trans.B

USES OF ANTIBIOTICS

M.E.J. Woolhouse, University of Edinburgh, March 2017

• Communicablediseasesduetobacteria− Tuberculosis− Sexuallytransmitteddiseases− Respiratorytractinfections− (Some)diarrhoea− Healthcare-associatedinfections

• Endogenousbacterialinfections− Urinarytractinfections− Skinandsofttissueinfections− Infectiveendocarditis− Sepsis

• Prophylaxis− Burns,wounds− Caesareansections− Jointreplacements− Cancertherapy− Organtransplants

Antibioticsunderpinmuchofmodernmedicine

Antibioticshavesavedcountlesslives,andtheycontinuetodoso

AMR PRIORITIES

M.E.J. Woolhouse, University of Edinburgh, March 2017

WHAT’S THE PROBLEM?

DeathsduetonotusingantimicrobialsDeathsduetoAMR

Inthefuture Now

M.E.J. Woolhouse, University of Edinburgh, March 2017

EXCESSvsACCESS

RECOMMENDATIONS

M.E.J. Woolhouse, University of Edinburgh, March 2017

1) Globalpublicawareness campaign2) Improvesanitation andpreventthespreadofinfection3) Reduceunnecessaryuseofantimicrobialsinagriculture andtheir

disseminationintotheenvironment4) Improveglobalsurveillance ofdrugresistanceandantimicrobial

consumptioninhumansandanimals5) Promotenew,rapiddiagnostics toreduceunnecessaryuseof

antimicrobials6) Promotedevelopmentanduseofvaccinesandalternatives7) Improvethenumber,pay andrecognitionofpeopleworkingin

infectiousdisease8) Aglobalinnovation fundforearlystageandnon-commercialR&D9) Betterincentives topromoteinvestmentfornewdrugsand

improvingexistingones10) Buildanewglobalcoalition forrealaction– viaG20andUN

OUTLINE

• AMRburdenandsurveillance

• LivestockAMR

• Governanceandregulation

M.E.J. Woolhouse, University of Edinburgh, March 2017

OUTLINE

• AMRburdenandsurveillance

• LivestockAMR

• Governanceandregulation

M.E.J. Woolhouse, University of Edinburgh, March 2017

PUBLISHED ESTIMATES

CDC• USin2013• 16bacterialinfections

→ 23Kdeathsperyr→ 2Millnesses

M.E.J. Woolhouse, University of Edinburgh, March 2017

ECDC• EUin2009• 6 bacterialinfections

→ 25Kdeathsperyr→ 400Killnesses

O’NeillReview• Globalin2013• ExtrapolatedfromUS+

WHOestimatesforTB→ 700Kdeathsperyr

increasingto10Mdeaths peryr by2050

ANTIBIOTIC USAGE

M.E.J. Woolhouse, University of Edinburgh, March 2017

• Datafrom80countriescovering81%globalpopulation• Volume>70billionstandardunitsin2010• Globalconsumptionofantibioticsincreasedby36%between2000-2010• Brazil,Russia,India,ChinaandSouthAfricaaccountedfor76%ofincrease

VanBoeckel etal.(2014)LID

REDUCING USAGE

• Usagemuchhigherinprimarycare• AMRproblemmuchgreaterin

secondary/tertiarycare

• Point-of-decisiondiagnostics:– Virusorbacteria?– Beyondculture– Real-timegenomicsØ LongitudePrize

• Moreintelligentuse- Overkillstrategies- Combinationtherapies- Re-useandre-cycling

Imamovic &Sommer (2013)Sci TransMed

M.E.J. Woolhouse, University of Edinburgh, March 2017

? Settargets? Switchtonarrow-spectrumdrugs? Developalternatives

ALTERNATIVES TO ANTIBIOTICS

• PrebioticsandprobioticsCommerciallyavailablebutefficacyunclearandlikelyvariable

• Phagetherapy,e.g.lyticphagevsS.aureus

• Vaccination

M.E.J. Woolhouse, University of Edinburgh, March 2017

INCREASING RESISTANCE

M.E.J. Woolhouse, University of Edinburgh, March 2017

Sanchezetal.(2013)EID

Klebsiella pneumoniae intheUSA,1998-2010

M.E.J. Woolhouse, University of Edinburgh, March 2017 WHOreport(2014)

• Globalsurveyofnationalresistancedata

• Collatedestimatesofresistanceratestoselectedantimicrobialsforcommonbacteriainc.150countries

Ø Frequentreportsof>50%resistancefor:

− E.colivs3rd gencephalosporins− E.colivsfluoroquinolones− Klebsiella vs3rd gencephalosporins− Klebsiella vscarbapenems− S.aureusvsmethicillin

GLOBAL SURVEILLANCE

M.E.J. Woolhouse, University of Edinburgh, March 2017 WHOreport(2014)

• Lackofstandardmethodology

• Lackofdatasharing

• Significantgapsinresistancesurveillance

• Lessthan50%ofglobalpopulationunderanykindofsurveillanceatall

GLOBAL SURVEILLANCE

CAN WE DO BETTER?

• ICD-11

• Sentinelhospitals

• Sentinelclinicians

• Notifiable,e.g.XDR-TB,CREs

M.E.J. Woolhouse, University of Edinburgh, March 2017 Woolhouseetal.(2016)J.Glob.Hlth

Metagenomics+ResFinder

bioinformaticspipeline

GLOBALSEWAGESURVEILLANCE

M.E.J. Woolhouse, University of Edinburgh, March 2017

BUSIAFIELDLABORATORY,W.KENYA

M.E.J. Woolhouse, University of Edinburgh, March 2017

SURVEILLANCEINREMOTESETTINGS

OUTLINE

• AMRburdenandsurveillance

• LivestockAMR

• Governanceandregulation

M.E.J. Woolhouse, University of Edinburgh, March 2017

AMR IS A ONE HEALTH ISSUE

Multiplemodesofmovement:• bacteria• mobilegeneticelements

Multipledrug-bugcombinations

Woolhouse&Ward(2013)Science

M.E.J. Woolhouse, University of Edinburgh, March 2017

ANTIBIOTICS ON THE FARM

• Industrialagricultureworkswithverysmallmargins

• Antibioticsusedas:- metaphylaxis- “targeted”prophylaxis- and...

• Growthpromoters- Usedsince1950s- Achieveupto15-20%higherweightgain- Worksforantibacterials,butnotantifungalsorantivirals- Mechanismuncertain- Worksinchildrentoo

M.E.J. Woolhouse, University of Edinburgh, March 2017

CONSUMPTION ON THE FARM

EUgrowthpromoterban2006

Increasedmetaphylactic, prophylacticuse

→ Antibioticusage→ livestock:humans ≈ 1:1

M.E.J. Woolhouse, University of Edinburgh, March 2017

Elliot(2015)CDDEP

RESISTANCE ON THE FARM

M.E.J. Woolhouse, University of Edinburgh, March 2017

COLISTIN RESISTANCE

• Polymyxin classantibioticdiscoveredin1949• Widelyusedinagriculture(esp.China)but

littleusedinhumansduetonephro- andneuro-toxicity

• Newplasmid-mediatedcolistin resistancegene(mcr-1)identifiedinChinain2015[Liuetal.2016LID]

• Highprevalenceofmcr-1 in Ecoli isolatesfromfoodanimalsandretailmeat

• Sincereported in35othercountries,inmultiplegram–ve organismsandfrommanydifferentsources

• Oldestpositiveisolatesdatebackto1980’s(chickensinChina)[Shenetal.2016LID]

M.E.J. Woolhouse, University of Edinburgh, March 2017

Failureofglobalsurveillance?

BACTERIA IN HUMANS AND LIVESTOCK

Lowder etal.(2009)PNAS

ST5INHUMANS+POULTRY

CC97INHUMANS +CATTLE

Spooretal.(2013)mBio

Matheretal.(2013)Science

DT104INHUMANS +CATTLE

←Betweenspecies↓Withinspecies

M.E.J. Woolhouse, University of Edinburgh, March 2017

TWO-WAY TRAFFIC

M.E.J. Woolhouse, University of Edinburgh, March 2017

MANAGING AMR IN LIVESTOCK

M.E.J. Woolhouse, University of Edinburgh, March 2017

Voluntaryguidance

Legalpartialban

Blanketban→↓antibioticconsumption↓animalhealth↓welfare↓production↑prices? publichealthbenefit

TWO-WAY TRAFFIC

M.E.J. Woolhouse, University of Edinburgh, March 2017

LowtransmissionH→A HightransmissionH→A

vanBunnik&Woolhouse(inpress)RSOpenSci

- In many circumstances, curbing antibiotic consumption by food animals, as a stand-alone measure, will often havevery limited benefits for human health.- A better strategy is an integrated approach that tackles resistance in humans and food animals at the same time.

Impact

WHAT’S THE PROBLEM?

M.E.J. Woolhouse, University of Edinburgh, March 2017

DeathsduetonotusingantimicrobialsDeathsduetoAMR

Includesfoodsafetyandfoodsecurity

Withdrawinganimalantibioticscancausefarmorehumanillness-daysthanitwouldprevent:theestimatehumanbenefit:risk ratio…exceeds1000:1inmanycases.

ACTION PLANS

M.E.J. Woolhouse, University of Edinburgh, March 2017

• Improveawareness

• Developcapacityforsurveillanceandmonitoring

• Promotegoodpractice

• Strengthengovernance

− Provideinformation− Developregulatory

frameworks− ImplementOneHealth

approaches

CHINA: Reduceveterinaryprescriptionby50%UK: Reducefoodanimalconsumptionto50mg/kg“average”

OUTLINE

• AMRburdenandsurveillance

• LivestockAMR

• Governanceandregulation

M.E.J. Woolhouse, University of Edinburgh, March 2017

GOVERNANCE OF AMR

• IPAMRwillneedtobe:- Global internationalhealthregulations- Cross-sectormedicine,agriculture,environment- Interdisciplinary clinicalandveterinarymedicine,

epidemiology,microbiology,pharmacology,healtheconomics,internationallaw,socialscience

- Multi-agencyWHO,OIE,UN,WTO,OECD- Buyinmedics,patients,vets,farmers,industry,

governments- Agenda→roadmaptoimprovedantimicrobial

stewardshipandsustainablealternatives

Woolhouse&Farrar(2014)NatureM.E.J. Woolhouse, University of Edinburgh, March 2017

SETEVIDENCE-BASED,QUANTITATIVEGOALSANDTARGETS

GOVERNANCE OF AMR

• Targetsforusage- phaseoutgrowthpromotersinanimals- limitto≤medianDDDinhumans

• Targetsforresistance- noincreaseintertiarycaresetting

• Governanceandfinancing- HighLevelCoordinatingMechanism

[UN,WHO,OIE,WorldBank,non-stateactors]

- Globalfund

Laxminarayan etal.(2016)ScienceM.E.J. Woolhouse, University of Edinburgh, March 2017

UK

ACKNOWLEDGEMENTS

- BramvanBunnik- MargoChase-Topping- GilesEdwards(SMRSARL)- JeremyFarrar(WellcomeTrust)- RossFitzgerald(Roslin Institute)- CherylGibbons- DeborahHoyle- RamananLaxminarayan(CDDEP)

- DishonMuloi- HarishNair- MeghanPerry- StefanRooke- DeviSridhar- NickSparks(SRUC)- MingguiWang(Fudan)- MelissaWard- CatrionaWaugh

KEY POINTS

• Theproblemisurgentandweneedtotakeaction

• Evidencebaseispatchyandthisimpedespolicydevelopment

• Nomagicbullet;needconcertedR&Dandconcertedactionsacrossmultiplesectors

• Helpfultosettargets- butwhatshouldtheybe?

• EdinburghInfectiousDiseases communityisexceptionallywellplacedtomakeameaningfulcontributiontothiseffort

M.E.J. Woolhouse, University of Edinburgh, March 2017