Santé : résistance antibiotiques - rapport de Jim O'Neill mai 2016

Description

Concerned about the rising levels of drug resistance whereby microbes evolve to become resistant to antimicrobials, the UK Prime Minister asked economist Jim O’Neill to analyse this global problem of antimicrobial resistance (AMR) and propose concrete actions to tackle it internationally. In July 2014, the UK Government commissioned the Review on Antimicrobial Resistance in collaboration with the Wellcome Trust. The Review is independent and engages widely with international stakeholders to understand and propose solutions to the problem of antimicrobial resistance, from an economic and social perspective. In May 2015, Jim O’Neill, who is widely known for coining the term BRICs for the emerging economies of Brazil, Russia, India and China, was appointed to the House of Lords and became Commercial Secretary to Her Majesty’s Treasury in the UK. He continues to chair the Review on Antimicrobial Resistance in a personal capacity.

Informations

• Publié par: Fil_actu
• Publié le: 22 septembre 2016
• Nombre de lectures: 10
• Langue: English
• Poids de l'ouvrage: 2 Mo

Extrait

TACKlïNG DRuG-RESïSTANT ïNFECTïONS GlObAllY: FïNA REPORT AND RECOMMENDATïONS

THE REVïEW ON ANTïMïCRObïAl RESïSTANCE CHAIRED BY JIM O’NEILL

MAY 2016

CONTENTS

1.

2.

3.

4.

5.

FOREWORD BY JIM O’NEILL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . 1

EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

THEPROBLEM:WHYTACKLINGAMRISESSENTIAL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

WEMUSTREDUCETHEDEMANDFORANTIMICROBIALSSO

THE CURRENT STOCK OF DRUGS LASTS LONGER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

INTERVENTION 1:A GLOBAL PUBLIC AWARENESS CAMPAIGN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

INTERVENTION 2:IMPROVE SANITATION AND PREVENT THE SPREAD OF INFECTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

INTERVENTION 3:REDUCE UNNECESSARY USE OF ANTIMICROBIALS IN AGRICULTURE AND THEIR DISSEMINATION INTO THE ENVIRONMENT . . . . . . . . . . . . . . . . . . . . . . . . . 24

INTERVENTION 4:IMPROVE GLOBAL SURVEILLANCE OF DRUG RESISTANCE AND ANTIMICROBIAL CONSUMPTION IN HUMANS AND ANIMALS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

INTERVENTION 5:PROMOTE NEW, RAPID DIAGNOSTICS TO REDUCE UNNECESSARY USE OF ANTIMICROBIALS . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

INTERVENTION 6:PROMOTE DEVELOPMENT AND USE OF VACCINES AND ALTERNATIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

INTERVENTION 7:IMPROVE THE NUMBER, PAY AND RECOGNITION OF PEOPLE WORKING IN INFECTIOUS DISEASE . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

WEMUSTINCREASETHESUPPLYOFNEWANTIMICROBIALS

EFFECTIVE AGAINST DRUG‑RESISTANT BUGS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

INTERVENTION 8:A GLOBAL INNOVATION FUND FOR EARLY STAGE AND NON‑COMMERCIAL R&D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

INTERVENTION 9:BETTER INCENTIVES TO PROMOTE INVESTMENT FOR NEW DRUGS AND IMPROVING EXISTING ONES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

HOW TO PAY FOR IT: TACKLING AMR IS AFFORDABLE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

IDEAS FOR IMPLEMENTATION AND NEXT STEPS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

SUMMARY OF RECOMMENDATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 73

ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . 76

Tb

WHA

Word Heath Assemby

Goba Antîbîotîc Research & Deveopment

GARD

Severe Acute Respîratory Syndrome

‘Push, Pu, Poo’ înîtîatîve or TB drug deveopment

GHSA

Goba Heath Securîty Agenda

R&D

Research and deveopment

PK

Usua drug resîstance

SARS

WHO

Advance Market Commîtment

AMC

uDR

OTC

Pharmacodynamîcs

PD

Methîcîîn-resîstantStaphylococcus aureus

MRSA

US Centers or Dîsease Contro and Preventîon

CDC

ACRONYMS AND AbbREVïATïONS

DND

FDA

US Food and Drug Admînîstratîon

ND4bb New Drugs For Bad Bugs

NGO

US Natîona ïnstîtutes o Heath

MSF

bARDAAdvanced Research and Deveopment Bîomedîca Authorîty

ïnectîon preventîon and contro

Drugs or Negected Dîseases ïnîtîatîve

uK

ïnternatîona deveopment assîstance

uN

Unîted Kîngdom

US Doar

uSD

uS

OrganîsatîonorEconomîcCooperatîonand Deveopment

OECD

Over-the-counter

Brîtîsh Pound

Actîve pharmaceutîca îngredîents

GbP

APïs

AMR

3Ps

NïH

OïE

Heathcare-assocîated înectîon

Gavî, the Vaccîne Aîance

Goba Heath Rîsk Framework or the Future

ïnnovatîve Medîcînes ïnîtîatîve

Goba Antîmîcrobîa Resîstance Surveîance System

G7

Ga

GHRF

GDP

Pharmacokînetîcs

SDGs

Pharmaceutîca and Medîca Devîces Agency (Japan)

PMDA

Tubercuosîs

Word Heath Organîzatîon

UN Sustaînabe Deveopment Goas

Gross domestîc product

Unîted States

Unîted Natîons

TheGroupoSeven(Canada,France,Germany,ïtay, Japan, Unîted Kîngdom, and Unîted States)

DeIned Daîy Dose

DMS

Dîagnostîc Market Stîmuus

CFCs

DDD

Fîxed Dose Combînatîon

ChoroLuro carbons

Antîmîcrobîa resîstance

TheGroupo20(Argentîna,Austraîa,Brazî,Canada, Chîna, France, Germany, ïndîa, ïndonesîa, ïtay, Japan, South Korea, Mexîco, Russîa, Saudî Arabîa, South Arîca, Turkey, Unîted Kîngdom and Unîted States, pus the European Unîon)

ïPC

ïMï

JPïAMRJoînt Programmîng ïnîtîatîve on Antîmîcrobîa Resîstance

ïDA

GlASS

HCAï

G20

FDC

Foundatîon or ïnnovatîve New Dîagnostîcs

FïND

Word Organîsatîon or Anîma Heath

Medîcînes Patent Poo

European Medîcînes Agency

Food and Agrîcuture Organîzatîon o the Unîted Natîons

MPP

MDR

Mutî-drug resîstant

EMA

FAO

European Unîon

Non-government organîsatîon

Médecîns Sans Frontîères (Doctors wîthout Borders)

Eu

FOREWORD bY JïM O’NEïll

When ï was asked to chaîr the Revîew on Antîmîcrobîa Resîstance (AMR), ï was tod that AMR was one o the bîggest heath threats that mankînd aces now and în the comîng decades. My înîtîa response was to ask, ‘Why shoud an economîst ead thîs? Why not a heath economîst?’ The answer was that many o the urgent probems are economîc, so we need an economîst, especîay one versed în macro-economîc îssues and the word economy, to create the soutîons.

ï have very much kept thîs în mînd ever sînce that Irst conversatîon and ît has ramed my team’s approach.

ït îs now cear to me, as ît has been to scîentîIc experts or a ong tîme, that tackîng AMR îs absoutey essentîa. ït needs to be seen as the economîc and securîty threat that ît îs, and be at the oreront o the mînds o heads o state, Inance mînîsters, agrîcuture mînîsters, and o course heath mînîsters, or years to come.

As has now become wîdey cîted, our very Irst paper outîned a word în 2050 where AMR îs the devastatîng probem ît threatens to become uness we Ind soutîons. ï deîberatey chose 2050 as ît îs the same tîmerame assocîated wîth the so-caed BRïC (Brazî, Russîa, ïndîa and Chîna) înspîred word that ï became we-known or. We empoyed two consutancy teams, KPMG and Rand, to undertake detaîed scenarîo anayses, whîch provîded the basîs or our concusîons. As îs now quîte we known, we suggested that wîthout poîcîes to stop the worryîng spread o AMR, today's aready arge 700,000 deaths every year woud become an extremey dîsturbîng 10 mîîon every year, more peope than currenty dîe rom cancer. ïndeed, even at the current rates, ît îs aîr to assume that over one mîîon peope wî have dîed rom AMR sînce ï started thîs Revîew în the summer o 2014. Thîs îs truy shockîng. As we as these tragîc human costs, AMR aso has a very rea economîc cost, whîch wî contînue to grow î resîstance îs not tacked. The cost în terms o ost goba productîon between now and 2050 woud be an enormous 100 trîîon USD î we do not take actîon.

Indeed, even at the current rates, ît îs aîr to “ assume that over one mîllîon people wîll have dîed rom AMR sînce I started thîs Revîew în the summer o 2014. ”

1

As wîth a orecasts o thîs sort, ît îs o course possîbe that our estîmates may turn out to be too arge, but we beîeve ît îs even more îkey that they coud be too sma. Thîs îs because we dîd not even consîder the secondary efects o antîbîotîcs osîng theîr efectîveness, such as the rîsks în carryîng out caesarean sectîons, hîp repacements, or gut surgery. And în the short 19 months sînce we started, new orms o resîstance have emerged that we dîd not contempate occurrîng so soon, such as the hîghy dîsturbîng dîscovery o transerabe coîstîn resîstance, reported în ate 2015.

Sînce settîng out the scae o the probem î we do not act, we have been makîng recommendatîons on how we can avoîd such a terrîbe scenarîo. Whatever the exact number, whîch o course we hope wî never become a reaîty, the 100 trîîon USD cost o înactîon means that our recommended înterventîons are extremey good vaue or money on a reatîve basîs.

There has aready been some excîtîng progress sînce we began to set out our proposed soutîons. ïn February 2015, we recommended that a dramatîc boost în surveîance was needed to track resîstance, especîay în the emergîng word. We are very peased în thîs regard, that the UK government has înîtîated theFlemîng Fundto împrove dîsease surveîance ocused on drug-resîstant înectîons în ow and mîdde-încome countrîes, and has contrîbuted 375 mîîon USD to ît. Thîs work îs încredîby împortant or tackîng AMR and ît must go hand în hand wîth the recent împetus to achîeve truy efectîve goba dîsease surveîance and to make sure that heath systems are better prepared or epîdemîcs.

We aso recommended that more research undîng îs needed or AMR to kîck-start eary research înto new antîmîcrobîas and dîagnostîcs. We are deîghted that the UK and Chînese governments have each aready agreed to contrîbute 50 mîîon GBP (72 mîîon USD) to a newGlobal Innovatîon Fund. Thîs Fund wî need to grow înternatîonay and partner wîth other exîstîng sources o undîng or AMR, to I the gaps et by tradîtîona undîng streams and make sure exîstîng and new undîng streams are we coordînated or the beneIt o researchers everywhere în the word.

ït îs greaty rewardîng that many o our recommendatîons are aready beîng taken orward, even beore we pubîshed thîs, our Ina report. But so much more remaîns to be done over the rest o thîs year and the oowîng years. We need to ensure that the approprîate goba bodîes are învoved în reachîng poîcy agreements, and ï have spent consîderabe

2

tîme ocusîng on thîs over the ast two years. Gîven my own background and the nature o the AMR chaenge, ît was obvîous that the G20 eaders as we as theîr Fînance Mînîsters woud need to pay a centra roe, and we are peased that the pîeces are în pace or successu progress. ït îs a hîstorîc opportunîty or goba governance that Chîna îs hostîng the G20 în 2016 or the Irst tîme; ît îs în Chîna’s power to ead the word în tackîng the AMR probem meanînguy and gobay rom theîr presîdency onwards.

Four înterventîons are goîng to be partîcuary împortant, out o the 10-poînt pan or tackîng AMR set out în our Ina report.

Fîrst, we need aglobal publîc awareness campaîgnto educate a o us about the probem o drug resîstance, and în partîcuar chîdren and teenagers. ï see thîs as an urgent prîorîty and urge înternatîona campaîgn deveopers, îndustry experts, and non-governmenta organîsatîons to consîder how they coud hep to support an urgent goba campaîgn on AMR. ï thînk thîs îs somethîng that coud, and shoud, begîn thîs summer î we are to reay make progress on AMR, and ît coud be supported at the UN Genera Assemby în September.

Secondy, we need to tacke the suppy probem: we need new drugs to repace the ones that are not workîng anymore because o resîstance. We have not seen a truy new cass o antîbîotîcs or decades. ït îs în poîcymakers' hands to change thîs. We have recommended that countrîes must revîew careuy how they buy and prîce antîbîotîcs, to reward înnovatîve new drugs wîthout encouragîng unnecessary use o new antîbîotîcs. ïn addîtîon to thîs work at the natîona eve, we need a group o countrîes such as the G20 to get together and provîde or a reward to deveopers o new antîbîotîcs ater they are approved or use by patîents. Thesemarket entry rewards, o around one bîîon USD each woud be gîven to the deveopers o successu new drugs, subject to certaîn condîtîons to ensure that the new drugs are not ‘over-marketed’ and yet are avaîabe to patîents who need them wherever they îve. ït îs great to see thîs îdea aready beîng dîscussed by senîor G20 oicîas. ï hope thîs dîscussîon wî transate înto tangîbe actîon durîng theîr Heads o States’ meetîng în September.

Thîrdy, we need to use antîbîotîcs more sparîngy în humans and anîmas, to reduce the unnecessary use that speeds up drug resîstance. To do thîs, we need a step change în the dîagnostîc technoogy avaîabe. ï Ind ît încredîbe that doctors must stî prescrîbe antîbîotîcs based ony on theîr îmmedîate assessment o a patîent’s symptoms, just îke they used to when antîbîotîcs

Irst entered common use în the 1950s. When a test îs used to conIrm the dîagnosîs ît îs oten based on a sow technoogy that hasn’t changed sîgnîIcanty sînce the 1860s. ï can understand why thîs îs the sîtuatîon: there aren’t enough good and rapîd tests to conIrm the proessîona judgment o the doctor, and the tests that are avaîabe are oten more expensîve than prescrîbîng the drugs ‘just în case’. Yet thîs îs not acceptabe: we need to encourage more înnovatîon and, împortanty, must ensure that useu products are used. ï ca on the governments o the rîchest countrîes to mandate now that by 2020, a antîbîotîc prescrîptîons wî need to be înormed by up-to-date surveîance înormatîon and a rapîd dîagnostîc test wherever one exîsts. Thîs wî open the door to învestment and înnovatîon, by showîng cever deveopers that î they buîd rapîd tests they wî Ind a market or them. Once the technoogy has împroved, markets în deveopîng countrîes can be supported wîth a system we have caed adîagnostîc market stîmulus, not dîssîmîar to the great work that Gavî, the Vaccîne Aîance, has done to împrove goba chîd vaccînatîon.

Iind ît încredîble that doctors must stîll “ prescrîbe antîbîotîcs based only on theîr îmmedîate assessment o a patîent’s symptoms, just lîke they used to when antîbîotîcs irst entered common use în the 1950s. ” Fourthy, we must reduce the extensîve and unnecessary use o antîbîotîcs în agrîculture. We Irst need to împrove surveîance în many parts o the word, so we know the extent o antîbîotîc use în the agrîcutura sector. We have then proposed that targets shoud be set by îndîvîdua countrîes or antîbîotîc use în agrîcuture, enabîng governments to have the Lexîbîîty to decîde how they wî reach ower eves o use. Aongsîde thîs we need to make much aster progress on bannîng or restrîctîng the use în anîmas o antîbîotîcs that are vîta or human heath. ï hope the Unîted Natîons meetîng în September wî take actîon on each o these poînts and make progress wîth the Word Heath Organîzatîon (WHO), Food and Agrîcutura Organîzatîon o the Unîted Natîons (FAO), and the Word Organîsatîon or Anîma Heath (OïE).

There are a number o ways to raîse the undîng requîred or actîon rom the pubîc or the prîvate sector: the amounts are

very sma în the context o both spendîng on heathcare and the costs o rîsîng AMR î we do not act. Gîven that antîbîotîcs are a shared resource that socîety and the pharmaceutîca îndustry depend on, there îs a strong case or pharmaceutîca companîes învestîng în AMR to sustaîn theîr own revenue rom other sectors such as oncoogy or surgîca operatîons. That îs why ï have proposed that governments shoud consîder a sma evy on the pharmaceutîca sector, as one o the optîons to raîse undîng or the market entry rewards or new antîbîotîcs. ï woud Ind such a undîng mechanîsm partîcuary attractîve î ît coud be appîed on a ‘pay or pay’ basîs, where those Irms who învest în R&D that îs useu or AMR can deduct theîr învestment rom the charge owed by a payers wîthîn the îndustry.

Athough AMR îs a massîve chaenge, ît îs one that ï beîeve îs we wîthîn our abîîty to tacke efectîvey. The human and economîc costs compe us to act: î we aî to do so, the brunt o these wî be borne by our chîdren and grandchîdren, and et most keeny în the poorest parts o the word.

Chaîrîng thîs Revîew has been one o the most stîmulatîng thîngs I have been lucky enough to do în my proessîonal career, and în addîtîon to many people to thank, I want to both thank and congratulate the UK Prîme Mînîster, Davîd Cameron, or havîng the oresîght to establîsh thîs Revîew, as well as the UK Chancellor, George Osborne. I would also lîke to thank the helpul guîdance o the Revîew’s steerîng group – Dame Sally Davîes, Dr Jeremy Farrar, John Kîngman, Karen Pîerce and Ed Whîtîng, as well as the enthusîasm o Dave Ramsden. And o course my Revîew team: Hala Audî, Jeremy Knox, Wîllîam Hall, Anthony McDonnell, Anjana Seshadrî, James Mudd, Nehanda Truscott-Reîd, Olîvîa Macdonald, Dr Flavîo Toxvaerd and Proessor Neîl Woodord.

May, 2016

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EXECuTïVE SuMMARY

Foowîng 19 months o consutatîon and eîght înterîm papers, each ocusîng on a specîIc aspect o antîmîcrobîa resîstance (AMR), thîs report sets out the Revîew on Antîmîcrobîa Resîstance’s Ina recommendatîons to tacke AMR în a goba way, as commîssîoned by our sponsors, the UK Government and the Wecome Trust.

The magnîtude o the probem îs now accepted. We estîmate that by 2050, 10 mîîon îves a year and a cumuatîve 100 trîîon USD o economîc output are at rîsk due to the rîse o drug- resîstant înectîons î we do not Ind proactîve soutîons now to sow down the rîse o drug resîstance. Even today, 700,000 peope dîe o resîstant înectîons every year. Antîbîotîcs are a specîa category o antîmîcrobîa drugs that underpîn modern medîcîne as we know ît: î they ose theîr efectîveness, key medîca procedures (such as gut surgery, caesarean sectîons, joînt repacements, and treatments that depress the îmmune system, such as chemotherapy or cancer) coud become too dangerous to perorm. Most o the dîrect and much o the îndîrect împact o AMR wî a on ow and mîdde-încome countrîes.

ït does not have to be thîs way. ït îs în poîcy makers and governments’ hands to take steps to change thîs sîtuatîon. Because mîcrobes trave reey, some o the steps that are requîred wî need to be taken în a coordînated way înternatîonay. What îs certaîn îs that no sînge country can sove the AMR probem on îts own and severa o our proposed soutîons wî requîre at east a crîtîca mass o countrîes behînd them î they are to make a dîference. Tackîng AMR îs core to the ong-term economîc deveopment o countrîes and our we-beîng. Soutîons to address ît must have goba access to heathcare at theîr heart and they must hep us to stop wastîng medîcînes that we rey on and yet are exhaustîbe.

To stop the goba rîse o drug-resîstant înectîons, there îs a suppy and demand probem that needs to be Ixed. The suppy o new medîcînes îs însuicîent to keep up wîth the încrease în drug resîstance as oder medîcînes are used more wîdey and mîcrobes evove to resîst them. At the same tîme, the demand or these medîcînes îs very bady managed: huge quantîtîes o antîmîcrobîas, în partîcuar antîbîotîcs, are wasted gobay on patîents and anîmas who do not need them, whîe others who need them do not have access.

Fundamenta change îs requîred în the way that antîbîotîcs are consumed and prescrîbed, to preserve the useuness o exîstîng products or onger and to reduce the urgency o dîscoverîng new ones. Governments shoud be hed accountabe on thîs

goa to reduce the demand or antîmîcrobîas and în partîcuar antîbîotîcs, as shoud the maîn sectors that drîve antîbîotîc consumptîon: heathcare systems, the pharmaceutîca îndustry and the armîng and ood productîon îndustry.

Frsty, thé spécîc stéps to rédûcé démand aré:

1. A massé goa pûc awarénéss campagn

We need to împrove goba awareness o AMR across the board, so that patîents and armers do not demand, and cînîcîans and veterînarîans do not prescrîbe, antîbîotîcs when they are not needed, and so that poîcy makers ensure that poîcîes to tacke AMR are taken orward now. The cost o runnîng a sustaîned pubîc awareness campaîgn across the word woud depend on îts nature and scope. Based on estîmates we have consîdered, ît coud cost between 40 and 100 mîîon USD a year. ït coud be met by a mîx o exîstîng pubîc heath programmes în hîgh- încome countrîes, support or programmes în ow and mîdde- încome countrîes and corporate sponsorshîp or major events.

2. ïmproé hygéné and préént thé spréad o nécton

ïmprovîng hygîene and sanîtatîon was essentîa în the 19th century to counter înectîous dîseases. Two centurîes ater, thîs îs stî true and îs aso crucîa to reducîng the rîse în drug resîstance: the ess peope get înected, the ess they need to use medîcînes such as antîbîotîcs, and the ess drug resîstance arîses. A countrîes need to act. Some în the deveopîng word wî need to ocus on împrovîng the basîcs Irst, by expandîng access to cean water and sanîtatîon. For other countrîes the ocus wî be to reduce înectîons în heath and care settîngs, such as îmîtîng superbugs în hospîtas. The sîmpest way that a o us can hep counter the spread o înectîons îs by proper hand washîng.

3. Rédûcé ûnnécéssary ûsé o antmcroas n agrcûtûré and thér dssémnaton nto thé énronmént

There are cîrcumstances where antîbîotîcs are requîred în agrîcuture and aquacuture – to maîntaîn anîma weare and ood securîty. However, much o theîr goba use îs not or treatîng sîck anîmas, but rather to prevent înectîons or sîmpy to promote growth. The quantîty o antîbîotîcs used în îvestock îs vast. ïn the US, or exampe, o the antîbîotîcs deIned as medîcay împortant or humans by the US Food and Drug Admînîstratîon (FDA), over 70 percent (by weîght) are sod or use în anîmas. Many countrîes are aso îkey to

use more antîbîotîcs în agrîcuture than în humans but they do not even hod or pubîsh the înormatîon. The majorîty o scîentîsts see thîs as a threat to human heath, gîven that wîde-scae use o antîbîotîcs encourages the deveopment o resîstance, whîch can spread to afect humans and anîmas aîke. We propose three steps to împrove thîs sîtuatîon. Frst, 10-year targets to reduce unnecessary antîbîotîc use în agrîcuture, întroduced în 2018 wîth mîestones to support progress consîstent wîth countrîes’ economîc deveopment. For thîs to succeed, governments must support and speed up current eforts, încudîng those o the Word Organîsatîon or Anîma Heath (OïE) and others, to measure antîbîotîc use and armîng practîces.Sécond, restrîctîons on certaîn types o hîghy crîtîca antîbîotîcs. Too many antîbîotîcs that are now ast-îne drugs or humans are beîng used în agrîcuture; actîon shoud be taken on thîs urgenty by an înternatîona pane. Thrd, we must împrove transparency rom ood producers on the antîbîotîcs used to raîse the meat that we eat, to enabe consumers to make more înormed purchase decîsîons.

Antîbîotîcs can reach the envîronment în many ways such as through sewage systems (încudîng rom hospîtas) and run-of rom ood-producîng unîts such as arms, and can then pose potentîa probems or AMR. One area that has not receîved enough ocus so ar îs the way that the actîve îngredîents or antîbîotîcs are manuactured, and partîcuary the împact o eluent rom actorîes on AMR în nearby water systems. To tacke thîs we need reguators to set mînîmum standards or the treatment and reease o manuacturîng waste; and manuacturers to drîve hîgher standards through theîr suppy chaîns. Both must take responsîbîîty and correct thîs unnecessary envîronmenta poutîon îmmedîatey.

4.ïmproé goa sûréancé o drûg résstancé and antmcroa consûmpton n hûmans and anmas

Surveîance îs one o the cornerstones o înectîous dîsease management, yet has untî recenty been oten îgnored and remaîns under-resourced în the Ight agaînst AMR. earnîng the essons rom Eboa, countrîes have started to încrease undîng în thîs area recenty, în partîcuar the US government vîa the Goba Heath Securîty Agenda (GHSA), the UK government wîth îts announcement ast year o the 375 mîîon USD Femîng Fund în response to eary recommendatîons made by thîs Revîew, and the Word Heath Organîzatîon (WHO) wîth îts deveopîng Goba AMR Surveîance System (GASS). Wîth oversîght rom the WHO, governments must buîd on these eforts to coect data about the consumptîon o antîmîcrobîas, the eves o resîstance, and the underyîng bîoogîca reasons

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or resîstance, supportîng countrîes that need ît most în doîng so. They must aso put systems în pace now that wî make the most out o the ‘bîg data’ on drug resîstance that wî be generated on an unprecedented scae as dîagnostîc toos are modernîsed and coud computîng îs embraced. These new toos are just round the corner, and ower încome countrîes may be abe to ‘eaprog’ înto usîng them to support surveîance în some cîrcumstances.

5. Promoté néw, rapd dagnostcs to cût ûnnécéssary ûsé o antotcs

Rapîd dîagnostîcs coud transorm the way we use antîmîcrobîas în humans and anîmas: reducîng unnecessary use, sowîng AMR and so makîng exîstîng drugs ast onger. ït îs not acceptabe that much o the technoogy used to înorm the prescrîptîon o împortant medîcînes îke antîbîotîcs has not evoved substantîay în more than 140 years. Rîch countrîes must ead the way to change thîs: they shoud make ît mandatory that by 2020 the prescrîptîon o antîbîotîcs wî need to be înormed by data and testîng technoogy wherever avaîabe and efectîve în înormîng the doctor’s judgement to prescrîbe. Thîs wî spur învestment by gîvîng dîagnostîcs deveopers the assurance that efectîve tests wî be used. Our proposed Goba ïnnovatîon Fund or AMR woud support eary-stage research în thîs area. ïn ow and mîdde-încome countrîes where access and afordabîîty are the maîn barrîers, a dîagnostîc market stîmuus woud provîde top-up payments when dîagnostîcs are purchased, în a sîmîar way that settîng up Gavî, the Vaccîne Aîance, în the eary 2000’s revoutîonîsed goba vaccîne coverage în what was one o the best returns on învestment to support economîc deveopment and webeîng.

6.Promoté dééopmént and ûsé o accnés and atérnatés

Vaccînes can prevent înectîons and thereore ower the demand or therapeutîc treatments, reducîng use o antîmîcrobîas and so sowîng the rîse o drug resîstance. Other aternatîve approaches to both preventîng and treatîng bacterîa înectîons are aso beîng researched, and coud provîde aternatîves to antîbîotîcs în some cases în the uture. We beîeve these approaches shoud be eîgîbe or the same încentîves that we recommend or antîbîotîc deveopment. We thereore need to: 1) Use exîstîng vaccînes and aternatîves more wîdey în humans and anîmas; 2) Renew împetus or eary-stage research; and 3) Sustaîn a vîabe market or vaccînes and aternatîves.

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7. ïmproé thé nûmérs, pay and récognton o péopé workng n néctoûs dséasé

ïnectîous dîsease doctors are the owest paîd o 25 medîca Ieds we anaysed în the Unîted States. ït îs no surprîse that there are not currenty enough candîdates to I hospîta traînîng vacancîes. A sîmîar story appîes to other proessîons reevant to tackîng AMR, rom nurses and pharmacîsts în hospîtas traîned to împrove stewardshîp, to mîcrobîoogîsts and other aboratory scîentîsts doîng surveîance, dîagnostîc testîng and R&D în academîa, governments, pubîc sector organîsatîons or companîes: ocusîng on AMR-reated specîatîes îs oten ess rewardîng Inancîay and în terms o prestîge than other areas o scîence and medîcîne. To change thîs we need an urgent rethînk and împroved undîng to împrove career paths and rewards în these Ieds.

Sécondy, wé mûst ncréasé thé nûmér o éfécté antmcroa drûgs to dééat néctons that haé écomé résstant to éxstng médcnés.

8. Estash a Goa ïnnoaton Fûnd or éary-stagé and non-commérca réséarch

There îs însuicîent prîvate and pubîc învestment în R&D ocused on tackîng AMR. To support eary-stage research, whether ‘bue sky’ or ocused on negected areas îke pharmacoogy or dîagnostîcs, we have proposed a Goba ïnnovatîon Fund endowed wîth up to 2 bîîon USD over Ive years. Excîtîng progress has aready happened durîng the îetîme o thîs Revîew, încudîng the UK and Chîna’s nascent ïnnovatîon Fund ocused on AMR, stepped up eforts în the US vîa the Bîomedîca Advanced Research and Deveopment Authorîty (BARDA), and în Europe vîa the ïnnovatîve Medîcînes ïnîtîatîve (ïMï) and Joînt Programmîng ïnîtîatîve or AMR (JPï-AMR) programmes. The spîrît o the Goba ïnnovatîon Fund we envîsage coud be achîeved by înkîng up and încreasîng the sîze o these înîtîatîves. ït îs crucîa however that ît becomes more than the sum o îts parts: undîng both eary-stage ‘bue sky’ scîence, and R&D that may not be regarded scîentîIcay as ‘cuttîng-edge’, and whîch acks a commercîa împeratîve, în a way that breaks down barrîers to entry and makes undîng avaîabe în countrîes and or organîsatîons that woud not have had access to undîng prevîousy.

9. béttér ncéntés to promoté néstmént or néw drûgs and mprong éxstng onés

For antîbîotîcs, the commercîa return on R&D învestment ooks unattractîve untî wîdespread resîstance has emerged agaînst prevîous generatîons o drugs, by whîch tîme the new antîbîotîc may no onger have patent protectîon or may soon ose ît. The tota market or antîbîotîcs îs reatîvey arge: about 40 bîîon USD o saes a year, but wîth ony about 4.7 bîîon USD o thîs tota rom saes o patented antîbîotîcs (that îs about the same as yeary saes oronetop-seîng cancer drug). So ît îs no wonder that Irms are not învestîng în antîbîotîcs despîte the very hîgh medîca needs. Thîs wî not change untî we aîgn better the pubîc heath needs wîth the commercîa încentîves. Governments must change thîs at the natîona eve by consîderîng possîbe changes to theîr purchase and dîstrîbutîon systems or antîbîotîcs, to Ind ways to support better rewards or înnovatîon whîe hepîng to avoîd over-use o a new product. Thîs can be party achîeved through adjustments to natîona purchasîng and dîstrîbutîon systems, to reLect the dîversîty o heath systems around the word. At the same tîme, or the drugs that are most needed gobay and or whîch goba stewardshîp and goba access are împortant, we need new ways to reward înnovatîon whîe reducîng the înk between proIt and voume o saes and ensurîng that deveopers gîve access and promote stewardshîp gobay. We have proposed a system o market entry rewards o around one bîîon USD per drug or efectîve treatments, whether they are based on new or od drugs that work agaînst resîstant pathogens în areas o most urgent need. As an exampe, tubercuosîs, gonorrhoea, so-caed ‘Gram-negatîve’ pathogens as we as some unga îndîcatîons are a recognîsed to represent a hîgh area o need that are currenty î-served by antîmîcrobîa deveopment. Fînay, harmonîsed reguatîons and cînîca trîa networks can pay an împortant roe în thîs area to ower drug deveopment costs.

Noné o ths w sûccééd wthoût ûdng a goa coaton or acton on AMR and wé consdér that to é oûr ténth récomméndéd ntérénton.

10.bûd a goa coaton or réa acton – a thé G20 and thé uN

AMR îs not a probem that can be soved by any one country, or even any one regîon. We îve în a connected word where peope, anîmas and ood trave, and mîcrobes trave wîth

them. Goba actîon îs thereore essentîa to make meanîngu progress over the ong-term. We ca on the G20 and the UN to ocus on thîs îssue în 2016 and to take actîon on both the suppy and demand o antîmîcrobîas, sparkîng a step-change în the Ight agaînst AMR.

What goa acton on AMR woûd cost

Our broad estîmate or the cost o takîng goba actîon on AMR îs up to 40 bîîon USD over a 10-year perîod.

Wîthîn thîs, we have estîmated that ît woud cost about 16 bîîon USD to overhau the antîbîotîcs and TB R&D pîpeîne usîng new market încentîves such as market entry rewards. Our costs are modeed on achîevîng 15 new antîbîotîcs a decade, o whîch at east our woud be breakthrough products targetîng the bacterîa specîes o greatest concern. We have aso recommended settîng up an AMR Goba ïnnovatîon Fund endowed wîth two bîîon USD over Ive years.

ït îs more dîicut to estîmate the cost o supportîng înnovatîve new dîagnostîcs and vaccînes and then roîng them out, as the cost woud depend very much on the type o products and the sîze o popuatîon who need them. At thîs stage o our work and based on ro out costs or other arge pubîc heath programmes, we estîmate that one to two bîîon USD a year to support take- up gobay woud make a very materîa dîference în these areas.

Further economîc anaysîs îs needed urgenty to understand the împact o reducîng the unnecessary use o antîbîotîcs în agrîcuture, whether that transîtîon woud împose a cost on the armîng sector, how bîg, how dîstrîbuted and or how ong. So ar most anaysîs has ocused on hîgh-încome countrîes and thereore more anaysîs îs needed o the împact în ow and mîdde-încome settîngs.

Fînay, we recommend înterventîons that are not specîIc to AMR but happen to hep address drug resîstance, such as good genera dîsease surveîance and better water and sanîtatîon. These costs are part o norma învestment to achîeve good heathcare and so are not part o the package o goba costs we descrîbe here.

So în tota, we estîmate that the word can avert the worst o AMR by învestîng three to our bîîon USD a year to take goba actîon. Thîs îs tîny în comparîson to the cost o înactîon. ït îs aso a very sma ractîon o what the G20 countrîes spend on heathcare today: about 0.05 percent.

Théré aré sééra ways to coér thé cost o oûr ntéréntons

Governments can aford to cover the cost o addressîng AMR by aocatîng resources rom exîstîng heath and economîc deveopment budgets: commîttîng unds to AMR now wî reduce the amount ît costs ater when ît deveops înto an even bîgger crîsîs, whîch wî înevîtaby a to governments. Most o the încentîves we recommend are structured as ‘payments or success’ so they do not requîre upront pubîc învestment înto projects that may not deîver împrovements.

Countrîes can aso decîde to create new streams o undîng to contrîbute to AMR and these woud not need to be the same everywhere, such as transerabe vouchers to reward new antîmîcrobîas, or taxes on antîbîotîcs. These optîons a have theîr pros and cons and în the end wî be reLected în the prîce socîety pays or heathcare.

7

What matters most now îs that actîon starts quîcky to reduce unnecessary use o antîmîcrobîas and to revîve învestment în theîr deveopment. ïn thîs respect, one undîng optîon that coud be partîcuary efectîve to shît suppy-sîde resources towards AMR research îs an antîbîotîc învestment charge, whîch woud be împosed wîdey on the pharmaceutîca sector and appîed on a ‘pay or pay’ basîs, meanîng companîes coud eîther pay the charge or învest în R&D that îs deemed useu or AMR. The money rom companîes who pay the charge woud be used to împrove the commercîa market or the successu products such as news drugs, vaccînes or dîagnostîcs. Thîs woud push many more companîes to învest în AMR, matchîng theîr short-term Inancîa încentîves better wîth the act that the îndustry as a whoe depends on efectîve antîbîotîcs to sustaîn a range o areas rom oncoogy to joînt surgery.

Fînay, we hîghîght prîncîpes or how these înterventîons shoud be deîvered în practîce, to îmît new bureaucracy, and co-exîst wîth current înternatîona înstîtutîons and natîona heath systems. Untî the new încentîves are în pace at a goba eve, ît woud be very useu or governments, charîtîes and îndustry to try and test new îdeas and modes at a oca eve.

ït îs tîme to turn îdeas înto efectîve actîon and to sove the probem o drug resîstance. Thanks to the courage and determînatîon o a ew eaders în thîs area, the probem o AMR wî be dîscussed at the UN Genera Assemby ater thîs year and contînues to rîse up the agenda or the G7 and G20 groups o countrîes. eaders în these goba orums must now rîse to the occasîon and agree on practîca soutîons.

8

Rééw on Antmcroa Résstancé

ïn 2014, the UK Prîme Mînîster Davîd Cameron commîssîoned the îndependent Revîew on Antîmîcrobîa Resîstance, Chaîred by macroeconomîst Jîm O’Neî, to examîne the growîng threat o AMR rom an economîc perspectîve and to recommend soutîons. The Revîew has been co-sponsored by the Wecome Trust and the Department o Heath. Over the ast 19 months the Revîew has pubîshed eîght thematîc papers that address dîferent aspects o the probem o AMR. These are as oows:

• Antîmîcrobîal Resîstance: Tacklîng a crîsîs or the health and wealth o natîons, December 2014

• Tacklîng a global health crîsîs: ïnîtîal steps, February 2015

• Securîng new drugs: The pîpelîne o antîbîotîcs,May 2015

• Rapîd Dîagnostîcs: Stoppîng unnecessary use o antîbîotîcs, October 2015

• Sae, secure and controlled: Managîng the supply chaîn o antîmîcrobîals, November 2015

• Antîmîcrobîals în agrîculture and the envîronment: Reducîng unnecessary use and waste, December 2015

• Vaccînes and alternatîve approaches: Reducîng our dependence on antîmîcrobîals, February 2016

• ïnectîon preventîon, control and surveîllance: Lîmîtîng the development and spread o drug resîstance, March 2016

Thîs îs the Ina report that pus together a our prevîous recommendatîons as a package o actîons that we beîeve wî be needed to tacke thîs rîsîng threat.