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1、Citi is one of the worlds largest financial institutions,operating in all major established and emerging markets.Across these world markets,our employees conduct an ongoing multi-disciplinary conversation accessing information,analyzing data,developing insights,and formulating advice.As our premier

2、thought leadership product,Citi GPS is designed to help our readers navigate the global economys most demanding challenges and to anticipate future themes and trends in a fast-changing and interconnected world.Citi GPS accesses the best elements of our global conversation and harvests the thought le

3、adership of a wide range of senior professionals across our firm.This is not a research report and does not constitute advice on investments or a solicitations to buy or sell any financial instruments.For more information on Citi GPS,please visit our website at GPS:Global Perspectives&Solutions Dece

4、mber 2022ANTIMICROBIAL RESISTANCEThe Silent Pandemic Citi GPS:Citi GPS:Global Perspectives&Solutions December 2022 Authors Anita McBain Head of ESG Research,EMEA Citi Research +44-20-7508-4361| Amy Thompson Senior Research Associate Citi Global Insights +44-20-7986-3542| Andrew Baum,MD Global Head o

5、f Healthcare Research Citi Research +44-20-7986-4498| Veronika Dubajova Head of MedTech&Healthcare Services,EMEA Citi Research +44-20-7986-4585| Georgina Smartt ESG Analyst,EMEA Citi Research +44-20-7500-0708| Makanjuola Senbanjo ESG Research Associate,EMEA Citi Research +44-20-7508-4593| Prof.Timot

6、hy R.Walsh OBE Director of Biology Ineos Oxford Institute for Antimicrobial Research Lord Jim ONeill of Gatley Crossbench Peer House of Lords Prof.Dame Sally C.Davies U.K.Special Envoy on Antimicrobial Resistance Dr.Damiano de Felice Director of Development&External Engagement,CARB-X Abigail Herron

7、Global Head of ESG Strategic Partnership,Sustainable Finance Centre of Excellence,Aviva Investors Maria Larsson Ortino Global ESG Manager,Investment Stewardship,Legal&General Investment Management(LGIM)Alexander Burr ESG Policy Lead Legal&General Investment Management(LGIM)Emma Cameron ESG Analyst L

8、egal&General Investment Management(LGIM)Emma Walmsley CEO GSK Contributors Sofia Conds Senior Investor Outreach Manager FAIRR Initiative Melissa Gong Mitchell AMR Industry Alliance Secretariat Lead AMR Industry Alliance Dr.Fatema Rafiqi Research Program Manager Access to Medicine Foundation Isobel R

9、osen Outreach Intern FAIRR Initiative Bram Wagner Investor Engagement Officer Access to Medicine Foundation With thanks to:Isabelle Hamment,Ineos Oxford Institute for Antimicrobial Research;Genevieve Holmes,CARB-X;Mara Lilley,Investor Engagement Officer,Access to Medicine Foundation;Claire Oxlade,Pr

10、ivate Secretary to Professor Dame Sally C.Davies;and Monica Thomas,Investor Engagement Officer,Access to Medicine Foundation.December 2022 Citi GPS:Citi GPS:Global Perspectives&Solutions 2022 Citigroup 3 ANTIMICROBIAL RESISTANCE The Silent Pandemic In the Citi GPS Disruptive Innovation series,we hav

11、e highlighted amazing new advancements in healthcare over the years from immunotherapy,and CRISPR-based gene editing to virtual care and blood tests for cancer.One healthcare area notably absent from the innovation series is antibiotics.In the U.S.,251.1 million antibiotic prescriptions were written

12、 in 2019,making it the second most prescribed drug category behind cholesterol reducers.But half of the antibiotics commonly used today were discovered in the 1950s,and the last antibiotic class successfully introduced as treatment was discovered in 1987.Why is this an issue?Because bacteria are inc

13、reasingly becoming resistant to todays antibiotics.In 2019,4.95 million deaths were associated with bacterial drug resistance,with 1.27 million deaths directly attributed to it.If the issue of antimicrobial resistance(AMR)is not addressed,it could lead to 10 million deaths by 2050.The drivers of AMR

14、 include overuse and misuse of antibiotics in humans and animals,poor hygiene and sanitation,and a lack of research and innovation to develop novel antimicrobials.At the same time,climate change is exacerbating many health challenges.Rising temperatures have increased the frequency and intensity of

15、outbreaks of some diseases,as well as their geographical scope.Extreme weather can also increase the burden of infectious disease.Flooding leads to increased agricultural run-off as well as sewage contamination,which both increase the risk of disease spread.And as extreme weather increases,populatio

16、ns become displaced as homes become uninhabitable and access to potable water is threatened.The report that follows looks at interventions that could avert the worst outcomes,and although AMR is a significant problem,many solutions are within reach.However,these solutions require the collaboration o

17、f a broad range of stakeholders,including the public and private sectors as well as civil society.The first step in addressing AMR is reducing the burden of infectious disease.This can be done through improving sanitation and developing vaccines to prevent infections in both humans and animals.The s

18、econd is reducing the use of antimicrobials in humans and animals by raising awareness on AMR,reducing unnecessary antimicrobials in food production,and developing rapid diagnostics.Facilitating innovation with investment in early-stage research and drug discovery will help in the quest for new nove

19、l antimicrobials.Finally,implementing steps to curtail the spread of resistance,such as strengthening global surveillance of drug resistance and improving treatment of wastewater with attention to antimicrobials.Most importantly,the report calls for tackling AMR with the same effort as climate chang

20、e.We view AMR,climate change,and biodiversity loss as closely related;this aligns with a“One Health”approach,which recognizes that animal,human,and environmental health should be considered holistically.Based on discussions with experts throughout the report,policymaking appears to be the single mos

21、t effective starting point in tackling AMR.The report summarizes their views and provides key recommendations for policymakers.Kathleen Boyle,CFA Managing Editor,Citi GPS The Tragedy of the CommonsWHY IS ANTIMICROBIAL RESISTANCE(AMR)IMPORTANT?If we fail to protect the current suite of antibiotics an

22、d invest in research and development into new antibiotics,we could find ourselves in a scenario where most,if not all,antibiotics no longer work.This would limit our ability to treat common infections.In 2019,an estimated 1.27 million deaths globally were directly attributed to AMR and by 2050 up to

23、 10 million may die from AMR-related illnesses.Annual AMR-Related Deaths Compared to Other Major Causes of Death8.9 MILLION2.6 MILLIONLower respiratory infections2 MILLIONNeonatal conditions1.8 MILLIONTrachea,bronchus,lung cancers1.6 MILLIONAlzheimer and other dementias1.5 MILLIONDiarrheal diseasesP

24、redicted AMR in 2050Coronary heart disease 2022 CitigroupDRIVERS OF ANTIMICROBIAL RESISTANCEOveruse and misuse in humansOveruse and misuse in animalsPoor hygiene and sanitationLack of research and innovation to develop antimicrobialsAlmost 50%of the global population lacked access to adequate sanita

25、tion in 2020Better sanitation in low-income countries could reduce antibiotic use to treat diarrhea by 60%Stroke6.2 MILLION3.3 MILLIONCOVID-19Source:WHO10 MILLION66%of antibiotics used in U.S.are likely non-prescribed30%of antibiotics prescribed in U.S.are likely unnecessary70%-80%of global antimicr

26、obial consumption is by animals75%-90%of antibiotics are excreted by animals unmetabolized and leak into the environment.Only 5%of venture capital invested in pharmaceutical R&D went to antimicrobials research between 2003 and 20141.2%of grant funding by the U.S.National Institutes of Health went to

27、 AMR-related research between 2009 and 2013CONSEQUENCES OF ANTIMICROBIAL RESISTANCEUsing two scenarios corresponding to low and high AMR impacts,World Bank simulations have quantified the potential economic losses from AMR globally between 2017 and 2050.Real World GDPBy 2050,the high-AMR scenario wo

28、uld cause:10195100999897962019203420262043Base=100Source:The World BankACTIONS TO PREVENT ANTIMICROBIAL RESISTANCEHalt and reduce the over prescription of antimicrobial medicinesGlobal real exports to fall 3.8%28 million more people to fall into extreme povertyGlobal healthcare costs to inflate by$1

29、 trillion a yearAnnual livestock production to fall by 7.5%globallyControl the spread of infection through proper handwashing with soap and waterImprove education and societal awareness campaignsDevelop rapid,robust,and affordable diagnosticsIntroduce surveillance monitoring in developed and develop

30、ing nationsBASELOW-AMRHIGH-AMR2050Annual global GDP to fall by 3.8%Support innovationthat develops new antimicrobials and non-traditional approaches to target infectionsReduce the use of antibiotics in livestock for disease prevention and growth promotion Citi GPS:Citi GPS:Global Perspectives&Soluti

31、ons December 2022 2022 Citigroup 6 Foreword 8 AMR Is a Collective Responsibility 8 Executive Summary 10 Expert Contribution:Lord Jim ONeill 13 Are We Serious About AMR?13 Chapter 1:Why Antimicrobial Resistance Is a Problem 17 What Is Antimicrobial Resistance?17 Why Is Antimicrobial Resistance Import

32、ant?18 What Causes Antimicrobial Resistance?20 What Is Driving Increased Antimicrobial Resistance?22 Chapter 2:Climate Change and AMR 27 Climate Change and Increasing Infectious Disease Burden 28 Climate Change and Increasing Resistance 30 Extreme Weather Events and Pathogen Exchange 30 Resistant Ba

33、cteria in the Environment 31 A One Health Approach to AMR 32 Expert Contribution:Professor Dame Sally Davies 34 What Next for AMR?34 Chapter 3:Interventions to Tackle Antimicrobial Resistance 36 1.Reducing the Burden of Infectious Disease 37 2.Reducing the Use of Antimicrobials 39 3.Innovating for N

34、ovel Antimicrobials 41 4.Curtailing the Spread of Resistance 45 Expert Contribution:Dr.Damiano de Felice 48 Replenishing the Clinical Pipeline 48 Chapter 4:Human Antimicrobials and Food Production 50 Antibiotic Use in Food Systems Expected to Increase 50 Medically Important Antimicrobials Used for G

35、rowth Promotion 51 The Need for Infrastructure and International Interdisciplinary Implementation 52 Population Growth Will Drive Global Meat Consumption 52 Farming in Low-Middle Income Countries 53 Chapter 5:The Role of Investors in Addressing the AMR Threat 55 Sustainable Investing on the Rise 55

36、Why Investors Care About Responsible Investment 57 The Role of Responsible Investment in Tackling AMR 58 Investors Lack Necessary Tools to Evaluate Impact of AMR 60 Subset of Investors Reveal AMR Focus 61 Why AMR Is an Investment Consideration 61 UN SDGS:Making the Case for AMR 62 Expert Contributio

37、n:Aviva Investors and LGIM The Financial Materiality of AMR for Investors 65 Chapter 6:Investor Tools&Best Practice 71 Access to Medicine Foundations 2021 Antimicrobial Resistance Benchmark 71 FAIRR Initiative:Research,Tools,and Engagement to Tackle AMR 72 Business Benchmark on Farm Animal Welfare(B

38、BFAW)Report 74 AMR Industry Alliance 75 Expert Contribution:AMR Industry Alliance Industry Steps 77 Steps Industry Should Take to Prevent the Spread of AMR in the Environment 77 Contents December 2022 Citi GPS:Citi GPS:Global Perspectives&Solutions 2022 Citigroup 7 Chapter 7:The Role of Big Pharma a

39、nd R&D Into Novel Anti-Infectives 78 Big Pharma and Novel Antibiotics 78 A Dichotomy for the Pharmaceutical Industry 79 Lack of Appropriate Incentives for Continued Development 79 A“Netflix Subscription Model”79 Transferable Exclusivity Extension 80 The Development of Small Molecule Antibiotics 80 A

40、ntimicrobial Innovation and ESG rankings 80 Expert Contribution:Emma Walmsley 82 Ambitious Innovation Needs Ambitious Policymakers 82 Chapter 8:The Paradox Precious Medicines and International Trade in Colistin 84 Resistance in Last-Resort Antibiotics:The Last Frontier of Human Pharmacopeia 85 The W

41、orld is a Small Place for Viruses and Antibiotic Resistance 85 MCR:A Global Phenomenon 86 Halting the Use of Colistin in Farming 86 The Emergence of Intensive Livestock Farming in LMICs 87 Developing Animal Feed Additives 87 Chapter 9:How Governments Are Rising to the AMR Challenge 88 The Global Act

42、ion Plan 89 European Regulation 90 U.K.Action Plan 91 U.S.National Action Plan 91 Chapter 10:Recommendations for Policymakers 93 Conclusion 95 Appendix A:Initiatives 97 Appendix B:Investor Action on Antimicrobial Resistance 99 Citi GPS:Citi GPS:Global Perspectives&Solutions December 2022 2022 Citigr

43、oup 8 AMR Is a Collective Responsibility The COVID-19 pandemic has taught us,as a global community,that the planet is deeply interconnected economically,culturally,and socially with the ultimate consequence that what happens in one country soon appears in another.Antimicrobial resistance(AMR),like C

44、OVID-19,knows no boundaries it can spread via humans,animals(both domestic and wild),water,and air.Every time a country is flooded,such as the recent tragic events in Pakistan,not only is cholera and shigellosis an issue,but the unimaginable spread of AMR bacteria from animal and human feces is vast

45、,contaminating potable water throughout numerous communities.AMR is a critical public health crisis and an example of a“One Health”priority.COVID-19 could be described as an earthquake,but AMR is a silent pandemic and,unlike COVID-19,cannot be negated by vaccination programs.Bacteria are complex cre

46、atures and have a highly impressive system for responding to their immediate environment either by creating mutants or,more impressively,by sharing large chunks of DNA that can encode for a variety of different functions,not least,AMR.A 2022 article in The Lancet claims that drug-resistant infection

47、s directly caused by AMR killed 1.27 million people in 2019 more than HIV/AIDS(864,000 deaths)or malaria(643,000 deaths).As data is lacking from many low-middle income countries(LMICs),these numbers are likely to be an underestimation and there is no doubt that the bulk of the clinical burden will b

48、e borne by LMICs.Out of the 17 UN Sustainable Development Goals(SDGs),AMR is directly related to 16 and indeed should be considered to have its own SDG platform.The negative impact of AMR extends beyond the hospital environment,with severe negative implications for poverty and inequality,animal welf

49、are,the environment,as well as food security.While more than 150 countries have developed AMR national action plans(NAPs),only around 20%are costed or budgeted and therefore the implementation of these NAPs is an ongoing challenge.As a result,the response at the country level is sometimes fragmented

50、 without rational prioritization.The commitment to public health expenditure from gross domestic product(GDP)varies significantly by country and region.An ongoing challenge is to provide AMR diagnostics across all health centers involving tractable,reliable,and cost-effective diagnostic tools ensuri

51、ng sustainability.Cost-benefit analysis models have rarely been applied to AMR in LMICs and therefore development programs to tackle AMR have seldom been sustainable.Each country has different capacities in terms of economy,knowledge,diagnostics,and investment in facing these challenges.AMR is a col

52、lective responsibility,and we are all ultimately responsible for the AMR challenge across all countries and all sectors.While AMR should be our focus,ensuring appropriate antibiotics are given to critical patient populations(neonates with sepsis in LMICs)without the burden of cost deferment to extre

53、mely poor families must be a key priority.Foreword Professor Timothy R.Walsh OBE Director of Biology,Ineos Oxford Institute for Antimicrobial Research Prof.Tim Walsh has been studying AMR mechanisms for over 25 years and publishes regularly in Nature and The Lancet journals.Notably,in his career he

54、has discovered and named two of the most notorious antibiotic resistant genes NDM-1 and MCR-1.His work also helped discover the mobile tigecycline genes.He is director of BARNARDS,a Gates Foundation project on AMR,prospectively examining the burden of neonatal sepsis in Pakistan,India,Bangladesh,Rwa

55、nda,South Africa,Nigeria(Abuja and Kano),and Ethiopia.Prof.Walsh co-established the Ineos Oxford Institute of Antimicrobial Research(with a 100 million gift from INEOS)where he is IOI Director of Biology.Walsh has been appointed to the Fleming Fund expert advisory panel a rolling U.K.government AMR

56、capacity building program in LMICs.In 2020,he was awarded an O.B.E for“Microbiology and International Development”and in 2022 was awarded his DSc.In addition to the above,he holds an honorary chair at the China Agricultural University in veterinary microbiology.He is advisor to the Fleming Fund,WHO,

57、Mdecins Sans Frontires and several publicly funded drug discovery initiative programs.December 2022 Citi GPS:Citi GPS:Global Perspectives&Solutions 2022 Citigroup 9 A stronger health system is important to address AMR and ensure that antimicrobials remain effective for future generations.In 2022,we

58、still use more than 100,000 metric tons of antibiotics in meat production(and crops),and it seems counterintuitive that governments and pharma will spend billions in creating the next“wondermycin”without the global community addressing antibiotic use across the planet.Surely,the solution is to look

59、for disease-protective molecules/therapies that are not“antibiotic-like”and will not enhance AMR in the human sector?It is now established that the use of ampicillin in animals maintains carbapenem a World Health Organization(WHO)reserve antibiotic for humans resistance.The same is also known for te

60、tracycline(an antibiotic widely used in animals)and tigecycline(a WHO critical antibiotic used for humans).In 2022,with the immense knowledge we have gained since the 1950s and 1960s when these farming practices began,one would hope for better.But apparently not.AMR has many similarities to climate

61、change and indeed they are inextricably linked.Yet,while the public has engaged with the debate around climate change and global warming,few know about AMR.The language we use to describe AMR is often laced with jargon and the subject is,by its nature,highly complex.Yet,its impact across the globe w

62、ill mirror that of climate change.Perhaps,AMR requires a dedicated Conference of Parties(COP)summit?There is little doubt that for the last three years COVID-19 has occluded AMR,but there is now hope AMR can return to center stage as a public health priority and be afforded the attention it richly m

63、erits.Citi GPS:Citi GPS:Global Perspectives&Solutions December 2022 2022 Citigroup 10 Antimicrobial resistance(AMR)is regarded as one of the biggest threats to human health,animal health,sustainable development,and food security.It has been compared to other large-scale problems such as the global p

64、andemic,climate change,and biodiversity loss.The reliance on antimicrobials such as antibiotics is a major issue for modern medicine and global food production,particularly given slow development and investment into new medicines by the pharmaceutical industry.What can we learn from the economics of

65、 climate change and biodiversity loss?In 2006,Lord Nicholas Stern published his seminal work on The Economics of Climate Change.1 The Review concluded that strong and early action will outweigh future costs and that scientific evidence points to increasing risk of serious,irreversible impacts.Estima

66、tes at the time of publication suggested that 1%of global GDP would be required to stabilize greenhouse gas levels at between 500 and 550 parts per million(ppm)CO2,if supported by policies to encourage the development of low-carbon technologies.2 Lord Stern warned that there was still time to act to

67、 avoid the worst impacts of climate change,but it would require strong and collective action.In February 2021,Professor Sir Partha Dasgupta published The Economics of Biodiversity.3 The Dasgupta Review,as it is commonly called,outlined the collective failure to engage with nature to limit excess dem

68、and of natural resources,which has resulted in reduced resilience to future shocks.The collective failure to manage the global portfolio of natural assets has impaired the quality and quantity of those assets,thereby reducing the ability of ecosystems to regenerate.The unprecedented decline in biodi

69、versity has undermined productivity,resilience,and adaptability and is pushing ecosystems towards imminent tipping points,underpinning both the human ecosystem and financial health of the global economy.Dasgupta describes the loss of biodiversity as the“tragedy of the commons”where people,thinking o

70、nly of their own self-interest,deplete a shared resource.4 In Dasguptas case,this referenced biodiversity loss and in the case of this report we use the same language to describe the overuse of antibiotics critical to human health.In 2016,the final report from the Review on Antimicrobial Resistance,

71、chaired by Lord Jim ONeill,was published.The Review estimated that 10 million people could die each year by 2050 as a result of AMR-related illnesses.5 1 Nicholas Stern,The Economics of Climate Change;The Stern Review,Cambridge University Press,2007.Originally published by Her Majestys Treasury of t

72、he U.K.Government in October 2006.2 Ibid.3 Partha Dasgupta,The Economics of Biodiversity:The Dasgupta Review,UK Government HM Treasury,February 2021.4 Ibid.In referencing the“tragedy of the commons”Dasgupta cites the 1968 work of Garret Hardin.5 The Review on Antimicrobial Resistance,Chaired by Jim

73、ONeill,Tackling Drug-Resistant Infections Globally:Final Report and Recommendations,May 2016.Estimates were first released in The Review on Antimicrobial Resistance,Chaired by Jim ONeill,Executive Summary December 2022 Citi GPS:Citi GPS:Global Perspectives&Solutions 2022 Citigroup 11 According to th

74、e Review,the projected economic loss related to AMR by 2050 could be a staggering$100 trillion and to avert the worst outcomes it identified ten different intervention areas.6 Among the most important were the need for robust,rapid,and affordable diagnostics,support of modern technology,and a drasti

75、c reduction in the injudicious use of antibiotics in livestock bred for human consumption.In 2022,a study published in The Lancet indicated that the burden on human health is likely to be much higher than previously thought and in 2019,the deaths of 4.95 million people were associated with drug-resi

76、stant bacterial infections.7 To keep ahead of antimicrobial resistance,the world needs highly innovative products to prevent,diagnose,and treat the most dangerous drug-resistant infections.Much has been written about the lack of progress of affordable,state-of-the art diagnostics.This Citi GPS repor

77、t shines a spotlight on the work of CARB-X(Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator),which is focused on the most significant bacterial threats to human health,primarily those identified as“Urgent/Serious”in the Centers for Disease Control and Prevention(CDC)Threat Asses

78、sments or“Critical/High”in the WHO Global Priority Pathogens List.This report engages with a core group of highly focused medical practitioners,scientists,and microbiologists working on infectious diseases.Based on these conversations,we find that while innovation is not lacking from the early stage

79、s of AMR research and development,these initiatives require an increase in the number of highly skilled practitioners and investment to achieve scale.Examples of areas seeing new investment include bacteriophage,peptide,and anti-virulence therapeutic strategies.By applying learning from the intersec

80、tion of climate change and biodiversity loss,we adopt similar language to tackle the global economic problem of AMR.Like climate change and biodiversity loss,the incentives for individual decision makers do not consider the economic costs to society at large.AMR represents an impending“tragedy of th

81、e commons”and there is a need for collective action to prevent negative societal impacts.New products and investment into robust,rigorous,and affordable diagnostics will provide hope and can save millions of lives.This in turn can drive a public return on investment while also potentially being prof

82、itable for private investors.This will contribute to their further development towards the patients who desperately need them,as well as the UN Sustainable Development Goals and human and planetary health over the longer term.Antimicrobial Resistance:Tackling a Crisis for the Health and Wealth of Na

83、tions,December 2014.6 Ibid.7 Christopher J.L.Murray et al.,“Global Burden of Bacterial Antimicrobial Resistance in 2019:A Systematic Analysis,”The Lancet,Vol.399,Issue 10325,February 2022.7 Editorial,“Antimicrobial Resistance:Time to Repurpose the Global Fund,”The Lancet,Vol.399,No.10322,January 22,

84、2022.Citi GPS:Citi GPS:Global Perspectives&Solutions December 2022 2022 Citigroup 12 Figure 1.The Emergence of Antimicrobial Resistance Timeline Source:Adapted from Healthcare in Europe,Citi GPS December 2022 Citi GPS:Citi GPS:Global Perspectives&Solutions 2022 Citigroup 13 Are We Serious About AMR?

85、It has been six years since we published the final report on combating AMR including 29 specific recommendations.If these recommendations were not followed,it was likely that by 2050,10 million people a year would die from AMR-related illnesses,and over the 34-year period,an accumulated loss of$100

86、trillion of economic potential would be squandered.The AMR Review received considerable attention for these dramatic estimates and our proposed remedies.In the six years since,two things are worth pointing out strongly.Firstly,the world has gone through a COVID-19 pandemic in which millions of lives

87、 have been lost and the decline in global GDP was close to$8 trillion.Arguably,some of the subsequent global economic challenges are a consequence of the pandemic,especially as it is far from over and supply and labor shortages persist in many nations.Fewer people now would think our Review projecti

88、ons are quite so wild.Secondly,detailed research published in The Lancet in 2022 suggests that at least two times as many people died in 2019 from AMR than the 700,000 we had initially assumed,possibly more.This is not necessarily because of the passage of three years but more detailed research unde

89、rtaken over many years.So,if anything,the estimates we undertook,if based on these current numbers,could be even higher.If it were reflecting the passage of time,obviously a linear progression would mean troubling consequences.Either way,it makes us believe that AMR is a serious problem.So,what abou

90、t progress on our ideas?I often try to describe the broad thrust of our specific recommendations as the“Ten Commandments”of how to stop this terrifying problem.As an economics and finance person,I led the team to explore potential solutions in terms of supply and demand interventions.It appears what

91、 needs to happen is:(1)a reduction in the demand for antibiotics,especially their inappropriate use;and(2)a boost in the supply of useful antibiotics and alternative treatments.Of our recommendations,five and a half might be seen as demand reducing interventions,three and a half as supply boosting o

92、nes,with the other global policy focused on coordination and implementation.Lets briefly discuss where we stand today,as well as other ideas we might have proposed if I knew then what I know now,and what investors can do to help.On the supply side,one recommendation was more researchers needed to be

93、 attracted into the field,as well as for them to be remunerated better compared to other health researchers.I am not sure about the latter nor statistically the former,but my impression is that the number of academic research organizations focused on AMR has risen in the U.K.purely based on many ask

94、ing me to speak there or help them in some way.The Ineos Oxford Institute is admirable and ambitious in this respect.Expert Contribution:Lord Jim ONeill Lord ONeill of Gatley Lord ONeill is a crossbench peer in the House of Lords.He is a member of the panel of Senior Advisors to Chatham House and re

95、cently became Chair of Northern Gritstone.His previous roles include:joint head of research at Goldman Sachs(19952000),its chief economist(200110),and chairman of its asset management division(201013);creator of the acronym BRIC;chair of the City Growth Commission(2014);chair of the Review on Antimi

96、crobial Resistance AMR(2014-16);and commercial secretary to the U.K.Treasury(2015-16).He is a board member,and one of the founding trustees of educational charity SHINE.Lord ONeill was created a life peer in 2015 and serves as a crossbench member of the House of Lords.He is an honorary professor of

97、economics,University of Manchester,and holds honorary degrees from the University of Sheffield,University of Manchester,University of London and from City University London.He received his PhD from the University of Surrey and is now a Visiting Professor there.Citi GPS:Citi GPS:Global Perspectives&S

98、olutions December 2022 2022 Citigroup 14 The second area relates to so-called push incentives with more money available to stimulate early stage research and development.In the immediate aftermath of our Review,there was a notable increase in such funding especially from the Biomedical Advanced Rese

99、arch and Development Authority(BARDA)in the U.S.,the EU,and a small number of foundations including the Wellcome Trust in the U.K.8 The$1 billion industry-wide AMR Action Fund should probably be regarded as a push-type fund,although it is aimed at helping take early stage research along the S-curve

100、of progress.In finance jargon,some might think of it in terms of“valley of death”type money akin to beyond seed funding.Funding may become very important as evidence is accumulating that without a huge development in the third area,so-called pull funding,early stage companies disappear as there is n

101、o one to support their growth or indeed,survival.This is a particularly worrying development.It also means the continued slow disappearance of so many pharmaceutical companies from the antibiotics business it is all the more troubling as their business model simply isnt flexible enough to eagerly pr

102、oduce low-priced antibiotics at scale,especially when the costs entailed are high and some policies are aimed at reducing demand.This is clearly where investors can help if they are serious about Responsible Investment by not investing in firms that fail to participate in antibiotics,so the leadersh

103、ip understands there is a price to their absence.An alternative is for philanthropic investors as well as governments to give sizable rewards such as our recommended Market Entry Rewards to participate.The most depressing thing for me personally has been the endless talk about pull-market incentives

104、 relative to the actual development.This obviously needs to change.The U.K.has shown some leadership with its own initiative to pay pharmaceutical companies upfront for two antibiotics,but without the U.S.or EU and probably leading Asian nations doing the same,pharmaceutical companies are unlikely t

105、o change their reluctant ways.Ultimately,perhaps my Reviews controversial idea of Pay or Play may need to be imposed by governments to help shift the risk/reward thinking in the leadership of big pharmaceutical companies.Vaccines(and alternatives)are a very interesting area as they straddle both the

106、 supply-boosting and demand-reducing side.We eagerly proposed ideas for greater use of vaccines for this reason,especially in animals.Indeed,if animal vaccine illness prevention were strongly adopted,the need to use antibiotics would fall dramatically.Needless to say,very little has happened here.In

107、 some ways this is even more amazing given the COVID-19 pandemic and the evidence that vaccines can be usefully developed quickly.8 Medical Countermeasures,“We Are BARDA,”accessed November 16,2022;Wellcome,“Science to Solve the Urgent Health Challenges Facing Everyone,”accessed November 16,2022.Dece

108、mber 2022 Citi GPS:Citi GPS:Global Perspectives&Solutions 2022 Citigroup 15 I was a member of the U.K.G7 Carbis Bay task force that was asked to find ways of even faster vaccine development to allow even quicker response rates to pandemics that might appear in the future.9 What would be an obvious w

109、ay to keep pharmaceutical firms permanently interested in the vaccine business would be to advance vaccine usage in other areas,in particular AMR.Of our 10 million estimated deaths,one-third are because drug resistant tuberculosis(TB)is rising sharply in the emerging world.10 More vaccine developmen

110、t here is urgently needed.On the demand side,progress is less encouraging,with the possible exception of agricultural reduction.To our surprise,evidence is mounting of a decline in usage in at least the developed world,especially the U.S.This is a reflection of both policy development and consumers

111、choosing to be tougher about what they will eat.We used to call this the Shake Shack factor as evidence the younger generation were attracted to antibiotic-free meat and seemed to be attracting business away from more established players,resulting in most of them claiming,at least with chicken,a sim

112、ilar approach.It is also the case that some big emerging countries,such as China,have banned the use of Colistin,a crucial“last in line”antibiotic for human use,in animals.I cant understand why all such vital antibiotics are not banned in the developed world.Obviously,the goal of the Ineos Oxford In

113、stitute to support animal-only antibiotics is a very welcome development.But a speedier decline in usage would be fantastic.Let me discuss the others.We called for additional public awareness campaigns,as knowledge about the AMR problem was scant.It still is.Indeed,because of COVID-19 it might even

114、have receded as how much can our citizens take,especially when they have seen the staggering disruption we all have suffered,and are still being warned about fresh COVID-19 outbreaks?But if we dont increase public awareness,how can policymakers find the determination to act?It is unfortunately neede

115、d.Hopefully,this Citi GPS report will help.On hygiene,you would hope the pandemic should help the most basic needs at least at the margin,especially basics like washing hands.Ex U.K.Chief Medical Officer Professor Dame Sally Davies used to say,washing hands in warm soapy water while singing along to

116、 Happy Birthday twice,would help reduce infection spread.Surely,what we all have learned from COVID-19 will partially help?A fourth demand intervention we called for was vastly superior surveillance.We were shocked as to how poor knowledge of incidence and infection rates were across the world and o

117、bviously if we dont really know what kind of AMR problems there are,and the scale of them,how can we solve the problem?9 U.K.Government,“Carbis Bay G7 Summit Communique,”PDF,July 12,2021.10 Tuberculosis(TB)is caused by bacteria(Mycobacterium tuberculosis)that most often affect the lungs.Tuberculosis

118、 is curable and preventable.TB is spread from person to person through the air.S.pneumoniaeCiti GPS:Citi GPS:Global Perspectives&Solutions December 2022 2022 Citigroup 16 One of our early successes is that the U.K.government announced the launch of the Fleming Fund,a bold initiative to improve surve

119、illance in parts of the emerging world.11 We were very pleased.But years later,while it has progressed and there are some countries benefiting,AMR needs a truly global preventive health infection warning system.Yet again,the pandemic showed the obvious need,and our Carbis Bay team recommended this t

120、o be a focus for G7 agreement and development,but nothing has happened.I shall discuss the international cooperation aspects,or lack of,below A big disappointment,as much as the behavior of pharmaceutical companies,is the lack of progress of affordable state-of-the-art diagnostics the fifth demand i

121、ntervention and definitely one of our biggest recommendations.Seen as an economist,we need to permanently reduce the demand for antibiotics,especially unnecessary usage.If we use mobile phones and similar technology every day in our lives,why cant we use these things for our doctors to legitimately

122、tell us whether we need an antibiotic or not?It is extremely silly that we pressurize doctors and allow them to have an educated guess.Our most aggressive recommendation was to force all developed countries to ban antibiotic prescriptions unless they have been deemed necessary through approved diagn

123、ostic tests.The problem centers on the obsession with cheap antibiotics and our faith in the judgment of medical professionals,which makes it hard to find affordable antibiotics and also,therefore,fund diagnostic research.Financial participants might be able to help by encouraging the growth of vent

124、ure capital(VC)diagnostic businesses.Indeed,due to the importance I attach to this factor,I am trying to support some early stage businesses.We need huge progress here.Let me finish with a few words on AMR and global policy cooperation.One of our most gratifying aspects of the Review was that it hel

125、ped us play a role in driving for the September 2016 UN High Level Agreement a rare time the UN has had any such health policy focus.We also,with the help of the U.K.Treasury,forced AMR onto the G20 agenda,which persisted from 2016 until the COVID-19 pandemic,and in 2017 and 2018,many features of ou

126、r recommendations were included.But,as I now discover yet again,words can be cheap and action more challenging,especially when money and international politics are involved.Since the near collapse in any policy coordination between the U.S.and China,even before COVID-19,many crucial issues for genui

127、ne global cooperation have fallen by the wayside.Sadly,this includes global health and any efforts to truly progress AMR global cooperation.There is,to be fair,continued focus on AMR of sorts,from the U.K.and among G7 Health Ministers and to their credit,Finance Ministers.But AMR is a truly global c

128、hallenge.Bugs become resistant wherever they are,and AMR is truly a global challenge and needs true focus and determined solutions.Personally,AMR has become one of the most interesting things I have ever been asked to focus on.I am captured by its challenge.But we need others.AMR needs much more gal

129、vanizing.I am proud of the role our Review played and the initiatives that followed.But we need more.Hopefully,this Citi GPS report on AMR can help.11 The Fleming Fund,“Aims&Values,”accessed November 16,2022 December 2022 Citi GPS:Citi GPS:Global Perspectives&Solutions 2022 Citigroup 17 What Is Anti

130、microbial Resistance?Antimicrobials are medicines mainly prescribed to tackle infections(e.g.,antibiotics,antivirals,antifungals,and anti-parasitic medicines).These medicines are used in humans,animals,and plants;in some cases,the exact same medicines are used in both humans and animals.Antimicrobia

131、l resistance(AMR)describes the process by which these medicines become ineffective as pathogens build up resistance to them.This makes infections initially more difficult and eventually impossible to treat,resulting in an increased risk of severe illness and,potentially,death.In this chapter,we disc

132、uss why AMR is important,what causes it,and what is driving its growth.In the next chapter,we discuss how rising temperatures and increased incidences of extreme weather events,such as hurricanes and floods,make infection and bacteria spread more likely and increase the chances of AMR.Chapter 1:Why

133、Antimicrobial Resistance Is a Problem Citi GPS:Citi GPS:Global Perspectives&Solutions December 2022 2022 Citigroup 18 Figure 2.Antimicrobial Resistance:The Global Health and Economic Threat Source:Citi GPS Why Is Antimicrobial Resistance Important?AMR has vast implications for modern medicine.It rep

134、resents one of the worlds greatest public health threats,as treatment of infections both common and complex with antibiotics becomes increasingly ineffective due to bacteria evolving and becoming resistant to available medicines.A proliferation of AMR would raise the risk of infection for routine me

135、dical procedures,such as hip replacements and cesarean sections.If we fail to protect the current suite of antibiotics and to invest in research and development(R&D)for new antibiotics,we could find ourselves in a scenario where most,if not all,antibiotics“no longer work and we are cast back into th

136、e dark ages of medicine,”as then U.K.prime minister David Cameron warned in 2014.12 By 2050,drug resistance could lead to 10 million deaths per year and cost the world$100 trillion in global economic losses,according to the final 2016 report by the Review on Antimicrobial Resistance,chaired by the e

137、conomist Lord Jim ONeill.The Review also estimated that 700,000 people die each year from bacteria,viruses,fungi,and parasites resisting treatment.13 12 Alona Ferber,“Sally Davies:Anti-Microbial Resistance Could Kill Us Before the Climate Crisis Does,”New Statesman,October 17,2022.13 The Review on A

138、ntimicrobial Resistance,Chaired by Jim ONeill,Tackling Drug-Resistant Infections Globally:Final Report and Recommendations,May 2016.Estimates Drug resistance is the result of microbes changing in ways that reduce or eliminate the effectiveness of drugs,chemicals,or other agents to cure or prevent in

139、fections.December 2022 Citi GPS:Citi GPS:Global Perspectives&Solutions 2022 Citigroup 19 Figure 3.Deaths Attributed to AMR Source:World Health Organization,Citi GPS More recently,a 2022 study published in The Lancet estimated that in 2019“there were 4.95 million deaths associated with bacterial AMR,

140、including 1.27 million deaths directly attributable”to it.This makes AMR the third leading cause of death after heart disease and stroke based on the higher estimate.Based only on deaths directly attributable to it,AMR is the 12th leading cause of death,surpassing HIV/AIDS,breast cancer,and malaria(

141、see Figure 4).14 Figure 4.Global Deaths in 2019 from AMR Source:The Lancet(2022),Citi GPS were first released in The Review on Antimicrobial Resistance,Chaired by Jim ONeill,Antimicrobial Resistance:Tackling a Crisis for the Health and Wealth of Nations,December 2014.14 Christopher J.L.Murray et al.

142、,“Global Burden of Bacterial Antimicrobial Resistance in 2019:A Systematic Analysis,”The Lancet,Vol.399,Issue 10325,February 2022.Citi GPS:Citi GPS:Global Perspectives&Solutions December 2022 2022 Citigroup 20 What Causes Antimicrobial Resistance?At the level of microbiology,resistance builds up thr

143、ough two mechanisms:first,bacteria mutate as they reproduce and some of these mutations provide an advantage in resisting antibiotics.15 Through natural selection,the resistant bacteria multiply and pass on this resistance to their descendants.This is vertical gene transfer:Advantageous genetic muta

144、tions are transferred from parent to offspring cells.Second,bacteria share DNA with one another through horizontal gene transfer,including between diverse species of bacteria.As a result,bacteria which were previously susceptible to a given antibiotic,or tranche of antibiotics,become resistant.16 Th

145、is is considered more consequential because it allows the determinants of resistance to spread between different species of bacteria and the mobile DNA(called plasmids)can mediate multi-drug resistance.17 Figure 5.Development of Antimicrobial Resistance Source:Adapted from American Society of Microb

146、iology,Citi GPS The potential for pathogens to become resistant was recognized as a threat even before penicillin entered common use.In his Nobel lecture,Alexander Fleming noted that“It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not

147、 sufficient to kill them,and the same thing has occasionally happened in the body.”18 Previously,there was always another antibiotic on the shelf,but now many factors are accelerating the emergence of resistance,which outpaces the development of novel drugs.15 Research has focused on antibiotic resi

148、stance,but there is growing concern around antivirals(e.g.,HIV drugs),antifungals,and antiparasitics(e.g.,malaria treatments).See World Bank Group,Pulling Together to Beat Superbugs:Knowledge and Implementation Gaps in Addressing Antimicrobial Resistance,October 2019.16 Dongchang Sun et al.,“Editori

149、al:Horizontal Gene Transfer Mediated Bacterial Antibiotic Resistance,”Frontiers in Microbiology,August 27,2019.17 Mario Gajdacs et al.,“Antimicrobial Resistance in the Context of the Sustainable Development Goals,”European Journal of Investigation in Health,Psychology and Education,Vol.11,No.1,2021.

150、18 Sir Alexander Fleming,“Penicillin,”PDF,Nobel Lecture,December 11,1945.Antibiotics are a type of antimicrobial agent,either made from mold of bacterium,or synthetically produced that kills or slows the growth of other bacteria.Examples include penicillin and streptomycin.Vertical gene transfer is

151、the transfer of genetic information from parent to offspring cells.Horizontal gene transfer is when bacteria share mobile DNA with one another,including between diverse genera of bacteria.Multi-drug resistance is a property of a bacterial pathogen that is resistant to two or more different classes o

152、f antimicrobial agents.December 2022 Citi GPS:Citi GPS:Global Perspectives&Solutions 2022 Citigroup 21 Figure 6.Emergence of Resistance Timeline Source:CDC(2013),CDC(2019),Adapted from FERN:Imagining the Post-Antibiotics Future,Citi GPS Citi GPS:Citi GPS:Global Perspectives&Solutions December 2022 2

153、022 Citigroup 22 What Is Driving Increased Antimicrobial Resistance?The drivers of AMR can be categorized into four groups:(1)overuse and misuse in humans,(2)overuse and misuse in animals,(3)poor hygiene and sanitation,and(4)a lack of research and innovation to develop novel antimicrobials.Figure 7.

154、Causes of Antimicrobial Resistance Source:Citi GPS 1.Overuse and Misuse in Humans First,non-prescription use of antimicrobials is a significant challenge.A 2019 study in the U.S.found that the prevalence of non-prescription use of antibiotics was as high as 66%for some parts of the population.19 The

155、 situation is expected to be even worse in low-and middle-income countries,where one study suggests that self-medication is“highly prevalent.”20 Healthcare costs and inaccessibility are key drivers here.Another is the lack of public awareness about when antimicrobials are an effective treatment:For

156、example,a 2018 survey of the EU found that almost 50%of people thought antibiotics could kill viruses,when of course they are only effective against bacterial infections.21 Yet another is illicit sales of antimicrobials outside medical contexts,including Internet sales and purchases from veterinary

157、health sources.22 19 Larissa Grigoryan et al.,“Use of Antibiotics Without a Prescription in the U.S.Population:A Scoping Review,”Annals of Internal Medicine,Vol.171,No.4,2019.20 Adeel Aslam et al.,“Evidence of Practice of Self-Medication With Antibiotics Among the Lay Public in Low-and Middle-Income

158、 Countries:A Scoping Review,”Antibiotics,Vol.9,No.9,2020.21 European Commission,Special Eurobarometer 478 Report:Antimicrobial Resistance,November 2018.22 Mario Gajdacs et al.,“Antimicrobial Resistance in the Context of the Sustainable Development Goals,”European Journal of Investigation in Health,P

159、sychology and Education,Vol.11,No.1,2021.E.coli December 2022 Citi GPS:Citi GPS:Global Perspectives&Solutions 2022 Citigroup 23 Over-prescription is a related issue.A World Bank study simulated a young female presenting to a pharmacy with symptoms of a lower urinary-tract infection in six low-and mi

160、ddle-income countries.More than 60%of visits resulted in dispensing antimicrobials without clinical diagnosis.23 This is not only a challenge for primary care:One study found that 30%of the antibiotics prescribed in U.S.emergency departments were unnecessary.24 Moreover,antimicrobials are often give

161、n prophylactically(i.e.,to prevent infections)in hospitals,including before surgery and for patients receiving chemotherapy.A survey in Australia found that up to 40%of these prescriptions were inappropriate.25 The COVID-19 pandemic is expected to have exacerbated this problem:A U.S.report notes tha

162、t between March and October 2020,80%of patients hospitalized with COVID-19 received an antibiotic.26 2.Overuse and Misuse in Animals Animals constitute 70%-80%of total antimicrobial consumption.27 Moreover,a 2015 study expects this consumption to increase by 67%by 2030,including almost doubling in B

163、razil,Russia,India,China,and South Africa,driven by intensification of farming.Much of this consumption is not to treat infection but to maximize the productivity of the agricultural industry by increasing the growth of animals and allowing them to be kept in smaller,less sanitary conditions without

164、 illness.This accounts for a high share of antimicrobial consumption in animals:One study of the Mekong Delta region of Vietnam found that 84%of total antibiotic use in animal agriculture is used for prophylaxis.In a 2018 study of China,growth promotion accounted for 53%of antimicrobial consumption

165、among animals.28 23 World Bank Group,Drug Resistant Infections:A Threat to our Economic Future,March 2017.24 Katherine E.Fleming-Dutra MD et al.,“Prevalence of Inappropriate Antibiotic Prescriptions Among US Ambulatory Care Visits,2010-2011,”JAMA,Vol.315,No.17,2016.25 National Centre for Antimicrobi

166、al Stewardship and Australian Commission on Safety and Quality in Health Care,Antimicrobial Prescribing Practice in Australian Hospitals:Results of the 2015 National Antimicrobial Prescribing Survey,2016.26 Centers for Disease Control and Prevention(CDC),2022 Special Report:COVID-19 U.S.Impact on An

167、timicrobial Resistance,2022.27 Mario Gajdacs et al.,“Antimicrobial Resistance in the Context of the Sustainable Development Goals,”European Journal of Investigation in Health,Psychology and Education,Vol.11,No.1,2021.28 FAIRR Initiative,Feeding Resistance:Antimicrobial Stewardship in the Animal Heal

168、th Industry,July 2021.Prophylaxis(prophylactic)is the use ofantimicrobials to prevent an infection,for example in animals housed in unsanitary conditions or in high-risk human patients.Citi GPS:Citi GPS:Global Perspectives&Solutions December 2022 2022 Citigroup 24 3.Poor Hygiene and Sanitation Poor

169、hygiene and sanitation exacerbate demand for antimicrobials.According to a UN progress report,almost half the global population lacked access to adequate sanitation in 2020.29 Increasing access to appropriate sanitation in households and care settings would reduce the spread of AMR bacteria,and subs

170、equent infections,therefore lessening both the demand for antimicrobials and the growth of resistance.Sanitation also concerns waste.Studies suggest that 75%-90%of antibiotics are still active when they are excreted by animals.30 As a result,the active ingredients enter sewage systems and waterways

171、resulting in low-dose exposure to pathogens.This accelerates the emergence of resistance by providing the perfect“training ground”for pathogens to develop resistance.Furthermore,bodies of water act as reservoirs and transmission mechanisms for resistant pathogens.As such,poor sanitation systems dire

172、ctly contribute to the growth of resistance.4.Lack of Novel Antimicrobials Few novel antimicrobials have come to market in recent decades and the pharmaceutical industrys pipeline remains relatively small.For example,in 2019 only six of the 32 antibiotics in clinical development that address the WHO

173、 list of priority pathogens could be considered innovative.31 Despite gains in recent years,an analysis of 17 of the worlds largest pharmaceutical companies in 2021 recorded only 92 active projects targeting infections caused by priority pathogens.32 This includes both novel antimicrobials and AMR-r

174、elevant vaccines.Other actors in the antimicrobial space have not filled this investment gap:Of the$38 billion venture capital invested into pharmaceutical R&D between 2003 and 2013,only$1.8 billion was invested into antimicrobials research,with total investments falling by more than a quarter over

175、the period.33 Similarly,antimicrobial research has not been a priority of the public sector:According to data from the U.S.National Institute of Health(NIH),just 1.2%of its grant funding went to AMR-related research between 2009 and 2014 versus over 18%to cancer-related research.The causes of this u

176、nderinvestment are multifaceted.First,there is a lack of economic incentives to create novel antimicrobials.The Office for Health Economics estimated that the net present value of a new antibiotic is$50 million compared to approximately$1 billion for a drug used to treat neuromuscular disease.34 Mor

177、eover,any new drugs that do come to market may be held back by public health authorities to preserve their efficacy,cutting off their potential revenue stream.29 WHO and United Nations Childrens Fund(UNICEF),Progress on Household Drinking Water,Sanitation,and Hygiene 2000-2020:Five Years into the SD

178、Gs,2021.30 The Review on Antimicrobial Resistance,Chaired by Jim ONeill,Tackling Drug-Resistant Infections Globally:Final Report and Recommendations,May 2016.31 World Health Organization(WHO),“Antimicrobial Resistance,”November 2021.32 Access to Medicine Foundation,Antimicrobial Resistance Benchmark

179、 2021,November 18,2021.33 David Thomas and Chad Wessel,“Venture Funding of Therapeutic Innovation,Biotechnology Industry Organization,February 2015.34 Abigail Rhea Herron,Superbugs and Super Risks:A Critical Assessment of Antibiotic Resistance as a Frontier Topic in Responsible and Sustainable Inves

180、tment,University of Cambridge Institute for Sustainability Leadership,December 2019.P.aeruginosa December 2022 Citi GPS:Citi GPS:Global Perspectives&Solutions 2022 Citigroup 25 Second,running clinical trials is often prohibitively expensive:More than 80%of the costs of bringing an antibiotic to mark

181、et center around clinical trials.35 Antimicrobial resistance is clearly a complex issue with multiple drivers but,as many expert contributors note in this Citi GPS report on AMR,the solutions are also well known.Figure 8.Causes and Effects of AMR Source:Citi GPS 35 The Review on Antimicrobial Resist

182、ance,Chaired by Jim ONeill,Tackling Drug-Resistant Infections Globally:Final Report and Recommendations,May 2016.Citi GPS:Citi GPS:Global Perspectives&Solutions December 2022 2022 Citigroup 26 The Discovery of Penicillin:Alexander Fleming The discovery of penicillin ushered in a new era in medicine

183、but it was a chance discovery from a discarded Petri dish that brought about the antibiotic age.In 1928,the British bacteriologist Sir Alexander Fleming returned from holiday to St.Marys Hospital in London,where a number of discarded Petri dishes remained piled up on his workbench.As he rummaged thr

184、ough the pile,he came across one dish,on which a mold had grown and killed the Staphylococcus aureus that had previously been growing.Seeing the potential of this mold to be the wonder drug that he had spent much of his career looking for,Fleming grew more of it in an attempt to determine what was k

185、illing the bacteria.With the help of his colleagues,he observed it was a Penicillium mold,likely originating from the lab downstairs.Hence,Fleming called the antibacterial agent penicillin.Running further experiments,Fleming found first,that the mold killed many other harmful bacteria and second,tha

186、t it was non-toxic and could therefore be used as a medicine.Fleming did not turn this discovery into a medicine that could be used in humans.That would have to wait until 1940,when the scientists Howard Florey of Australia and Ernst Chain of Germany turned the mold into a medicinal form that could

187、be used in humans to treat bacterial infections.Mass production started very quickly owing to the urgency of treating those wounded in World War II.Fleming,Florey and Chain were jointly awarded the Nobel Prize in Physiology in 1945 for their discovery of penicillin.December 2022 Citi GPS:Citi GPS:Gl

188、obal Perspectives&Solutions 2022 Citigroup 27 AMR sits firmly within a nexus of broader sustainable development issues,including climate change,biodiversity loss,and food security.In this chapter,we focus on UN Sustainable Development Goal(SDG)13 Climate Action,SDG 14 Life Below Water,and SDG 15 Lif

189、e on Land.By examining both the scientific and social consequences of climate change,we illustrate that the consequences of a lack of climate action risks intensifying the threat of AMR.We conclude that addressing AMR requires adopting a“One Health”approach to public health,recognizing the close lin

190、ks among animal,human,and environmental health.In the Citi GPS report Systemic Risk:Systemic Solutions for an Increasingly Interconnected World,we noted that while antimicrobial resistance(AMR)is itself a significant risk,it is also deeply interconnected with many other global risks,including climat

191、e change and biodiversity loss.Climate change is one of the most significant challenges of the 21st century.Its impacts are already being felt across the globe:2022 alone has seen unprecedented heat stress in Northern Europe and significant flooding in Pakistan.On its own terms,climate change requir

192、es urgent action to avert a“Hothouse Earth”scenario,in which the global temperature settles between four and five degrees higher than pre-industrial averages.36 But a lack of climate action is believed to also increase the threat of AMR.We argue that tackling AMR requires equal effort to tackling cl

193、imate change.We first illustrate that increasing temperatures are linked with the spread of infectious disease,the(re-)emergence of novel and ancient pathogens,and the accelerated emergence of antimicrobial resistance.We then show that other elements of climate change,like extreme weather events and

194、 the population displacement that often follows them,also increase the threat of AMR.Hence,tackling AMR is predicated on urgent climate action.36 Stockholm Resilience Centre,Stockholm University,“Planet At Risk of Heading Towards Hothouse Earth State,”accessed November 14,2022.Chapter 2:Climate Chan

195、ge and AMR Citi GPS:Citi GPS:Global Perspectives&Solutions December 2022 2022 Citigroup 28 Figure 9.AMR and the UN Sustainable Development Goals Source:United Nations Climate Change and Increasing Infectious Disease Burden Climate change exacerbates many health challenges.37 For example,the World He

196、alth Organization has estimated that the heat stress seen in Europe in 2022 caused the deaths of around 15,000 people.38 The evidence supporting a link between infectious diseases and climate change continues to mount.Long-run historical data compiled in 2020 suggest that climate change continues to

197、 create conditions that support the transmission of various infectious diseases,including some that are significant for global development,including dengue fever and malaria.39 Four paths mediate the relationship between climate change and an increased infectious disease burden:1.Rising temperatures

198、 increase the frequency and intensity of outbreaks of some diseases.One paper examining the spread of helminths,a parasite harmful to both humans and animals,found that even modest increases in temperature could have a significant impact on the severity of an outbreak.40 37 Jason P.Burnham,“Climate

199、Change and Antibiotic Resistance:A Deadly Combination,”Therapeutic Advances in Infectious Disease,February 15,2021.38 World Health Organization.“Statement Climate Change Is Already Killing Us,but Strong Action Now Can Prevent More Deaths,”November 7,2022.39 Nick Watts et al.,“The 2020 report of The

200、Lancet Countdown on Health and Climate Change:Responding to Converging Crises,The Lancet,December 2,2020.40 Naomi J.Fox et al.,“Climate-Driven Tipping Points Could Lead to Sudden,High-Intensity Parasite Outbreaks,”Royal Society Open Science,May 20,2015.December 2022 Citi GPS:Citi GPS:Global Perspect

201、ives&Solutions 2022 Citigroup 29 2.Rising temperatures increase the geographical scope of specific diseases and the vectors that transmit them as more of the globe becomes an amenable temperature for transmission.For example,while sand flies are usually found only in Mediterranean Europe,one study c

202、oncluded that climate change would see them spread as far as Northern Europe.41 3.Climate change facilitates the(re-)emergence of both novel and ancient pathogens.In 2016,the thawing of the permafrost in Siberia exposed the carcass of a reindeer that had died of anthrax.A subsequent outbreak of anth

203、rax in the region is attributed to this event.Some have also suggested that climate change accounts for the pathogenicity of the fungus Candida Auris,which may not always have been harmful to humans.42 4.As temperatures rise and levels of precipitation and flooding increase,the intensity of pathogen

204、 transfer and disease outbreak is expected to increase.The World Economic Forum in its 2022 Global Risk Report highlighted the massive spread of bacteria that could result in an epidemic or pandemic placing further burdens on the global economy.43 There is a feedback loop here:As outbreaks of infect

205、ious diseases become more severe and larger in scale due to climate change,more antimicrobials will be required for treatment and the emergence of resistance will accelerate.Curtailing the number of infections is critical to addressing AMR.41 Lisa K.Koch,Judith Kochmann,Sven Klimpel,and Sarah Cunze,

206、“Modeling the Climatic Suitability of Leishmaniasis Vector Species in Europe.Nature Scientific Reports,2017.42 Arturo Casadevall,Dimitrios P.Kontoyiannis,and Vincent Robert,“Environmental Candida Auris and the Global Warming Emergence Hypothesis”mBio,March 16,2021.43 World Economic Forum,“The Global

207、 Risks Report 2022,”January 2022.Citi GPS:Citi GPS:Global Perspectives&Solutions December 2022 2022 Citigroup 30 Figure 10.AMR Sits in a Close Nexus with Other Global Challenges Source:Citi GPS Climate Change and Increasing Resistance Climate change can also be connected directly with resistance.Mac

208、Fadden et al.(2018)explore the impact of climate change on the distribution of antibiotic resistance across the U.S.44 Their data suggest that for multiple common pathogens,including E.Coli,K.Pneumoniae,and Staphylococcus Aureus,an increase in temperature is associated with an increase in resistance

209、.This finding is of global significance in understanding the threat that AMR presents.Estimates of the human and economic impact of AMR,including the calculations that AMR could be responsible for up to 10 million deaths per year by 2050 and a$100 trillion impact on GDP by 2050,do not account for th

210、e link with climate change and the impact it could have on accelerating resistance.45 The true figures may be much higher unless significant action is taken to limit climate change.Extreme Weather Events and Pathogen Exchange So far,we have considered only the scientific effects of an increasing tem

211、perature on AMR.Broader issues of climate change,such as the increasing frequency of extreme weather events like flooding and water scarcity,together with their social consequences,also pose a threat of increasing AMR.44 Derek R.MacFadden et al.,“Antibiotic Resistance Increases with Local Temperatur

212、e,Nature Climate Change,May 21,2018.45 The Review on Antimicrobial Resistance,Chaired by Jim ONeill,Tackling Drug-Resistant Infections Globally:Final Report and Recommendations,May 2016.;45 World Bank Group,Drug-Resistant Infections:A Threat to Our Economic Future,March 2017.December 2022 Citi GPS:C

213、iti GPS:Global Perspectives&Solutions 2022 Citigroup 31 Flooding facilitates the increased transmission of both water-and vector-borne diseases:One review calls attention to the significant outbreaks of cholera and E.Coli that were seen in Bangladesh following periods of flooding.46 The risk of spre

214、ading disease is particularly high where agricultural run-off or sewage contaminate floodwaters.Where resistant pathogens are found in a body of water,flooding enables their wider dissemination and can lead to greater incidences of urinary tract infections in female populations.Both flooding and wat

215、er scarcity can lead to an increased infectious disease burden:Flooding and water scarcity disrupt the infrastructure of sanitation systems,especially in low-and middle-income countries where those systems may already be weak.47 Droughts bring a second challenge to sanitation as a larger population

216、is forced to use the same water source,increasing the potential scale of any outbreak of waterborne diseases.All kinds of extreme weather events contribute to population displacement:Extreme weather makes homes become uninhabitable and threatens access to potable water.The sanitary conditions of dis

217、placed persons are often more challenging than for the broader population,especially where there is significant crowding resulting in increased pathogen exchange.Furthermore,in some cases,displaced people may move closer to animal habitats,leading to an increased risk of novel zoonotic diseases(i.e.

218、,diseases that spread between humans and animals)emerging.On each of these counts,an increase in the prevalence and severity of extreme weather events contributes to an increased infectious disease burden and,therefore,accelerates the emergence of resistant pathogens.Resistant Bacteria in the Enviro

219、nment Antimicrobial waste is a pollutant that,on the one hand,contributes to the emergence of resistance,and on the other,can have a deleterious impact on local biodiversity and ecosystem integrity.Waste is produced in the manufacture of antimicrobials,from the run-off of intensive livestock product

220、ion,and some is also due to the biological fact that when animals and humans consume antibiotics,some of the ingredients are still active upon excretion.48 As a result,active pharmaceutical ingredients find their way into our waterways.Yet,waste sanitation systems do not adequately remove these acti

221、ve ingredients.Above a critical threshold,the presence of these antimicrobials in bodies of water presents a training ground for bacteria to develop resistance.By needlessly exposing bacteria to antimicrobial waste,we present bacteria with an opportunity to evolve and become resistant,“learning”from

222、 their interaction with waste antimicrobial ingredients in wastewater.46 David L.Paterson,Hugh Wright,and Patrick N A Harris,“Health Risks of Flood Disasters,”Clinical Infectious Diseases,October 15,2018.47 Jason P.Burnham,“Climate Change and Antibiotic Resistance:A Deadly Combination,”Therapeutic A

223、dvances in Infectious Disease,February 15,2021.48 University of Exeter,“Stemming the Tide of AMR in the Natural Environment,”December 5,2020.Zoonotic diseases(also known as zoonoses)are caused by germs that spread between animals and people.Animals sometimes carry harmful germs that can spread to pe

224、ople and cause illness.Scientists estimate that more than 6 out of every 10 known infectious diseases in people can be spread from animals,and 3 out of every 4 new or emerging infectious diseases in people come from animals.S.aureus Citi GPS:Citi GPS:Global Perspectives&Solutions December 2022 2022

225、Citigroup 32 Moreover,the contamination of water and solid waste by these antimicrobials can affect water and soil quality and have further negative consequences for marine and terrestrial ecosystem integrity,impacting freshwater fish and the animals that eat them,marine wildlife near the mouths of

226、rivers,and the essential fungi and bacteria that make the soil productive,including the soils carbon sequestration potential.We noted in the 2021 Citi GPS report,Biodiversity:The Ecosystem at the Heart of Business,that biodiversity loss is inextricably linked to climate change,calling specific atten

227、tion to the fact that building and maintaining the resilience of ecosystems plays a central role in mitigating emissions.This illustrates the final leg of the tight-knit nexus among AMR,climate change,and biodiversity:Just as preventing climate change decreases the threat of AMR,climate change is it

228、self worsened by biodiversity loss,which in turn becomes more challenging by contributing factors to AMR like the presence of active pharmaceutical ingredients in the environment.Figure 11.The Climate,AMR,Biodiversity Nexus Source:Citi GPS A One Health Approach to AMR The nexus among AMR,climate cha

229、nge,and biodiversity loss is closely aligned to the“One Health”approach.The One Health approach is not entirely new:It has been recognized since the 19th century that many diseases have similar impacts on both humans and animals.The term first emerged in discussions of severe acute respiratory syndr

230、ome(SARS)when the spilling over of viruses from animals into humans,known as zoonotic disease,came sharply into focus.49 One Health approaches to public health start from the recognition that animal,human,and environmental health are all closely linked and are best considered holistically.In practic

231、e,the guiding principle of the One Health approach is that professionals from human,animal,and environmental health must communicate,coordinate,and collaborate on their shared priorities.49 John S.Mackenzie and Martyn Jeggo,“The One Health Approach Why Is It So Important?”Tropical Medicine and Infec

232、tious Disease,June 2019.December 2022 Citi GPS:Citi GPS:Global Perspectives&Solutions 2022 Citigroup 33 AMR is not just a medical problem.Its also a threat to crops,to food security,and to animals.This interconnection between people,animals,plants,and their shared environment demands a collaborative

233、,trans-disciplinary One Health approach to finding solutions.PROFESSOR NEIL GOS,PROFESSOR OF MICROBIOLOGY,UNIVERSITY OF EXETER Figure 12.A One Health Approach Source:Barcaccia et al.(2020)Citi GPS:Citi GPS:Global Perspectives&Solutions December 2022 2022 Citigroup 34 Expert Contribution:Professor Da

234、me Sally Davies What Next for AMR?The COVID-19 pandemic was a wake-up call on the impact of an initially untreatable infection on lives and livelihoods.Antimicrobial resistance(AMR)is also a pandemic,which currently kills almost 1.3 million people annually globally.As the world continues to emerge f

235、rom the darkest days of the COVID-19 pandemic,we must seize this wake-up call and learn the lessons of the pandemic,bringing the same energy and focus to addressing the silent pandemic of AMR.The past two years have shown us what is possible when scientists,policymakers,the public,and investors quic

236、kly mobilize to focus on prevention,diagnosis,and effective treatments.Antibiotics are critical infrastructure for modern health systems,food systems,and the planet.This is why the threat of AMR is both global and complex,with drivers,impacts,and risks from across different sectors.As such,everyone

237、has a role to play in addressing it.The bottom line is simple:we must prevent,control,and treat infections.We,the world,can choose to produce and consume differently to preserve our antibiotics.Investors,in particular,have an important role to play as antibiotic stewards,advocating for sustainable i

238、nnovation,production,and use of antibiotics.Global demand for antibiotics is high and increasing,having almost doubled globally between 2000 and 2018.But our valuation and payments for these drugs is at an all-time low,with the proliferation of generics driving a race to the bottom in pricing.As a r

239、esult,the financial and societal as well as the environmental value of antibiotics has plummeted.Less than half of the new chemical entities developed between 1999 and 2014 were even available in more than ten countries including in some instances,G7 economies.As it stands,the weak market and lack o

240、f access leaves the public paying through premature death,expensive treatments,or higher taxes for our collective inability to anticipate or act on risks.But the benefits of coordinated action are high.Staying one step ahead of superbugs requires global leadership from the G7,G20,and G77 with Health

241、 and,importantly,Finance Ministers leveraging the investments and approaches that we needed for COVID-19.Under the UK G7 Presidency in 2021,Finance Ministers made commitments to strengthen antibiotic development through exploring“pull”incentive mechanisms.The leadership from Finance Ministers of the

242、 AMR agenda marks a monumental step forward as it underlines the fact that,as they learned during the COVID-19 pandemic,infectious disease presents an economic threat alongside risks to health.Finance Ministers have already committed to taking steps to create the right economic conditions to catalyz

243、e innovation and bring novel antimicrobials to market,to push for better stewardship of existing medicines,and to ensure the antimicrobial supply chain is safe and transparent.With thanks to Germanys leadership of the G7 this year,Finance Ministers reiterated their commitments,and we now look to Jap

244、an to ensure that they are delivered.Professor Dame Sally Davies UK Special Envoy on Antimicrobial Resistance Dame Sally Davies was appointed as the UK Governments Special Envoy on AMR in 2019.She is also the 40th Master of Trinity College,Cambridge University.Dame Sally was the Chief Medical Office

245、r for England and Senior Medical Advisor to the UK Government from 2011-2019.She is a leading figure in global health,having served as a member of the World Health Organization(WHO)Executive Board 2014-2016,and as co-convener of the United Nations Inter-Agency Co-ordination Group(IACG)on Antimicrobi

246、al Resistance(AMR),reporting in 2019.In November 2020,Dame Sally was announced as a member of the new UN Global Leaders Group on AMR,serving alongside Heads of State,Ministers and prominent figures from around the world to advocate for action on AMR.In the 2020 New Year Honours,Dame Sally became the

247、 second woman to be appointed Dame Grand Cross of the Order of the Bath(GCB)for services to public health and research,having received her DBE in 2009.December 2022 Citi GPS:Citi GPS:Global Perspectives&Solutions 2022 Citigroup 35 The first steps towards positive action are being taken by some count

248、ries across the world that are exploring ways to pay for antimicrobials in a way that reflects their value to healthcare systems.For example,in the U.K.,the worlds first subscription-based model is paying for the availability of antibiotics to National Health Service(NHS)patients,including cefideroc

249、ol and avibactam,rather than paying for the number of antibiotics consumed working with Shionogi and Pfizer.Other countries have taken up a similar model.For example,Germany aims to transition to value-based pricing through innovation in reimbursement structures.These schemes will collectively give

250、a meaningful incentive for investing in antibiotics.The PASTEUR Act(2021)in the U.S.,which aims to tackle the shortcomings of market-led antimicrobial development and ensure the availability of novel,effective antimicrobials for patients,would be a global step forward in addressing the challenge of

251、AMR.The Act would establish a subscription-based payment mechanism to encourage innovation and protect the health systems ability to treat resistant infections.The sheer scale of the U.S.market would both make this a watershed moment in addressing the challenge of AMR and send a signal to other econ

252、omies on the importance of changing our approach to antimicrobial consumption.It gives us a glimpse of how the future might look,with a level playing field,so that it makes as much sense for companies to develop a new antimicrobial treatment as it would to pursue a new cancer therapy.What comes next

253、 in addressing the AMR challenge?The PASTEUR Act sets the stage for future multilateral action.AMR cannot be solved once and moved on from it requires ongoing action over many years.It is only by sustained,global action that the world can address the threat of AMR.As a member of the UN Global Leader

254、s Group on Antimicrobial Resistance,I have noted the importance of a coordinated response to this threat and the need for action at a global scale.This global governance mechanism will catalyze political action,including through the High-Level Meeting that will take place at the United Nations in 20

255、24,where the world will look to countries for their leadership and ambition on AMR.It will also be vital that the private sector has a voice in the run-up to this meeting.Investors can lead the way in mitigating AMR risks and create long-term value.AMR should be integrated into investment decision-m

256、aking,with investors stewarding antibiotics.Alongside FAIRR,the UN Principles for Responsible Investment,and the Access to Medicine Foundation,the U.K.s Department of Health and Social Care launched the Investor Action on AMR initiative.Together,we have galvanized some of the worlds leading asset ma

257、nagers and development finance institutions to demonstrate that AMR does represent a material risk.Over 16 investors with a collective asset portfolio exceeding$11 trillion are aligning with global best practices on AMR by incorporating AMR into their ESG standards.We welcome additional investors to

258、 join us in this effort.The World Bank,European Bank for Reconstruction and Development,and the CDC Group are all supporting AMR interventions through technical partnership,financing,and training.A one-size-fits-all approach will not sufficiently address the challenge of AMR,but global collaboration

259、 and collective learning are both vital in protecting this precious resource for global health.Citi GPS:Citi GPS:Global Perspectives&Solutions December 2022 2022 Citigroup 36 The projected economic losses related to AMR between 2015 and 2050 could reach a staggering$100 trillion currently eightfold

260、the global cost of COVID.50 The solutions are just as well understood as the costs,and they are achievable.This chapter summarizes the possible interventions to avert the worst outcomes,among the most important of which are rapid,robust,and affordable diagnostics;the support of modern technology;and

261、 a drastic reduction of antibiotics consumption in the production of animal protein(meat and dairy)bred for human consumption.AMR is a significant global problem,but many of the solutions are within reach.As Professor Dame Sally Davies puts it,“this is not insurmountable,this is doable.”In this chap

262、ter,we explore some of the interventions and solutions that can help address the global challenge of AMR and catalogue them under four headings:(1)reducing the burden of infectious disease,(2)reducing the use of antimicrobials,(3)innovating for novel antimicrobials,and(4)curtailing the spread of res

263、istance where it has already emerged.These solutions require the collaboration of a broad range of stakeholders,including the public and private sectors together with civil society.50 Reuters,“IMF Sees Cost of COVID Pandemic Rising Beyond$12.5 Trillion Estimate,”January 20,2022;The Review on Antimic

264、robial Resistance,Chaired by Jim ONeill,Tackling Drug-Resistant Infections Globally:Final Report and Recommendations,May 2016.Chapter 3:Interventions to Tackle Antimicrobial Resistance December 2022 Citi GPS:Citi GPS:Global Perspectives&Solutions 2022 Citigroup 37 Figure 13.Preventing Antimicrobial

265、Resistance Source:Citi GPS 1.Reducing the Burden of Infectious DiseaseOne of the first steps in addressing AMR is reducing the burden of infectious disease.This would feed through to reductions in the antimicrobials required to treat infections and hence slow the emergence of resistance.Multiple int

266、erventions are required to achieve any reduction in the transmission of infectious diseases.These include improved sanitation systems,especially in low-and middle-income countries(LMICs),developing vaccines for both human and animal populations,and implementing biosecurity strategies in the livestoc

267、k sector to maintain animal health.Improving Sanitation to Prevent Spread of Infection Improving sanitation,hygiene,and access to safe water is a key sustainable development goal;according to Macintyre et al.(2017),the link with antimicrobial resistance is“multifaceted and complex.”51 Populations th

268、at do not have access to infrastructure supporting good hygiene practices and sanitation are at higher risk of contracting infectious diseases.The COVID-19 pandemic issued a reminder that good hygiene and regular hand washing are a vital and cost-effective intervention to reduce the burden of infect

269、ious diseases.52 51 Alison McIntyre,Megan Wilson-Jones,and Yael Velleman,“Prevention First:Tackling AMR Through Water,Sanitation AND Hygiene,”AMR Control,July 31,2017.52 UN Water,“Summary Progress Update 2021:SDG 6 Water and Sanitation for All,”July 2021.Infrastructure to support good hygiene includ

270、es access to handwashing stations and facilities utilizing soap and clean water for communities and households,safe disposal of human waste(feces and urine),the collection and management of industrial and household waste,and the treatment of wastewater and solid waste.Citi GPS:Citi GPS:Global Perspe

271、ctives&Solutions December 2022 2022 Citigroup 38 Illustrating the point with reference to diarrheal disease,a March 2016 report concluded that access to sanitation could reduce the burden of these diseases by between 69%and 72%.53 The same report estimates this could feed through to a reduction in a

272、ntimicrobial consumption due to diarrheal disease of between 47%and 72%.Complementary measures such as educating clinicians and increasing vaccination coverage,which are discussed elsewhere in this chapter,could further add to this reduction in antibiotic consumption.Development and Use of Vaccines

273、and Alternatives Vaccines also play a significant role in reducing the burden of infectious diseases by preventing infections in immunized populations.This applies equally to both human and animal populations,where vaccines can reduce reliance on antimicrobial medicines.However,just as novel antimic

274、robials are difficult and expensive to develop,many of the same challenges plague vaccine development.The Review on Antimicrobial Resistance,commissioned by the U.K.government,notes that developing vaccines can take over a decade and very few of the products that enter early stage research ever come

275、 to market.This has resulted in a situation in which multiple priority pathogens,including those that the CDC has designated in need of“urgent”innovation to produce novel antimicrobials,have no corresponding vaccine that could reduce the number of infections.54 As a result,in its final 2016 report,t

276、he Review on AMR concludes that increased vaccine coverage in both human and animal populations should be pursued and greater investment is required to support the development of vaccines with a particular focus on priority pathogens.55 Biosecurity Improving sanitation and increasing vaccine coverag

277、e could feed into a biosecurity strategy.In the context of AMR,the term biosecurity refers to the steps taken either to avoid the introduction of pathogens,like bacteria and viruses,to animal and plant populations,or to reduce their spread.56 As this section suggests,reducing the disease burden feed

278、s through to a reduction in the number of antimicrobials required for treatment should infection occur.Indeed,multiple studies have shown that farms with high biosecurity compliance require fewer antimicrobials.Moreover,better farm management both strengthens productivity and improves measures to pr

279、event disease.As a result,adopting a biosecurity strategy and investing in compliance with it constitutes a cost-effective intervention in tackling the overuse of antimicrobials.53 Pablo Araya et al.,“The Impact of Water and Sanitation on Diarrhoeal Disease Burden and Over-Prescription of Antibiotic

280、s,”Review on Antimicrobial Resistance,March 2016.54 U.K.Government,“Vaccines and Alternative Approaches:Reducing Our Dependence on Antimicrobials,”February 15,2016.54 Teja Sirec and Tomasz Benedyk,“One Health:10 Ways to Tackle Antimicrobial Resistance,”Federation of European Microbiological Societie

281、s,September 19,2017.55 The Review on Antimicrobial Resistance,Chaired by Jim ONeill,Tackling Drug-Resistant Infections Globally:Final Report and Recommendations,May 2016.56 A survey article on the definition and evolution of this term shows that it has also been applied to humans and used in the spe

282、cific context of biological weapons.See Vronique Renault,Marie-France Humblet,and Claude Saegerman,“Biosecurity Concept:Origins,Evolution and Perspectives,”Animals,December 28,2021.H.influenzaeBiosecurity:Biosecurity refers to measures aimed at preventing the introduction and/or spread of harmful or

283、ganisms(e.g.,viruses,bacteria,etc.)to animals and plants in order to minimize the risk of transmission of infectious disease.December 2022 Citi GPS:Citi GPS:Global Perspectives&Solutions 2022 Citigroup 39 2.Reducing the Use of AntimicrobialsA second cluster of interventions aims at reducing the use

284、of antimicrobials in both humans and animals.There is a significant opportunity here because many antibiotic prescriptions,even in humans,are unnecessarily administered.One U.S.statistic suggests that as many as 30%of antibiotic prescriptions may be unnecessary.57 Appropriate deployment of antimicro

285、bials may be even worse in LMICs where a World Bank study of six countries found that in 60%of cases,a young woman reporting to a pharmacist with symptoms of a lower urinary tract infection was administered with antibiotics without a prescription.58 Government regulation has already started to addre

286、ss this pillar significantly:In 2015,the White House released a National Action Plan for Combating Antibiotic-Resistant Bacteria(CARB),which set a goal of reducing inappropriate outpatient antibiotic use in the U.S.by at least half by 2020.Raising Awareness:Education on Antimicrobial Resistance Beha

287、vioral change is critical to improving the stewardship of antimicrobials.This can only be achieved by education to improve awareness and understanding of antimicrobial resistance,particularly among two key audiences:1.Patients and consumers of antimicrobial products,where public awarenesscampaigns h

288、ave previously reduced the number of antimicrobials prescribed byup to 36%.592.Professionals across the fields of human and animal health,where AMRcould be included in certifications and continuing professional development.60One element of this public awareness campaign will involve public education

289、 on the role of antimicrobials and what they are effective in treating.There is a significant lack of knowledge here with one report on the EU finding that almost half of the population thought antibiotics would be effective against a virus,when of course they only target bacterial infections.61 Red

290、uce Unnecessary Antimicrobials in Agriculture and the Environment We highlight in Chapter 4 the imprudent use of antimicrobials in food production and call for better governance of antimicrobials across the industry by both farmers and veterinarians.Antimicrobials are routinely used in food producti

291、on both to prevent infection and,which has proven somewhat more contentious,to promote the faster growth of animals in intensive farms.Figure 14 reminds us of some key statistics on the use of antimicrobials in food production.57 CDC,“CDC:1 in 3 Antibiotic Prescriptions Unnecessary,”updated January

292、1,2016.58 World Bank Group,“Drug Resistant Infections:A Threat to our Economic Future,”March 2017.59 The Review on Antimicrobial Resistance,Chaired by Jim ONeill,Tackling Drug-Resistant Infections Globally:Final Report and Recommendations,May 2016.60 WHO,“Raising Awareness and Educating on Antimicro

293、bial Resistance,”accessed November 14,2022.61 European Commission,“Antimicrobial Resistance,”November 2018.S.baumanniiCiti GPS:Citi GPS:Global Perspectives&Solutions December 2022 2022 Citigroup 40 Figure 14.Overuse and Misuse of Antimicrobials in Animals Bred for Human Consumption Source:FAIRR(2016

294、),Citi GPS Regulation has already started to move here:The use of antimicrobials for growth promotion was banned in the EU as early as 2006 as part of a strategy aimed at slowing the emergence of antimicrobial resistance.62 However,in LMICs,the politics of such a ban are challenging.As the populatio

295、n in these countries gets larger and richer,increased demand for animal protein(meat and dairy)is expected to follow.In the short term,over-reliance on antimicrobials supports attempts to address food insecurity,which is likely to remain a significant issue in growing lower-income countries.In Chapt

296、er 4 we explore in more detail what is needed to facilitate reducing the use of antimicrobials in food production.Modern Tools for Rapid Diagnostics In a paper on modern tools for rapid diagnostics by Vasala et al.(2020),the authors call for“fast,robust,and affordable antimicrobial susceptibility te

297、sting.”63 Where pathogens have been inaccurately identified,patients can be prescribed antibiotics to treat a believed bacterial infection when the infection is actually a viral infection and,as a result,unresponsive to antibiotics.Inaccurate prescriptions could be minimized by using rapid diagnosti

298、c tools.62 European Commission,“Ban on Antibiotics as Growth Promoters in Animal Feed Enters Into Effect,”December 2005.63 Antti Vasala,Vesa P.Hytonen,and Olli H.Laitinen,“Modern Tools for Rapid Diagnostics of Antimicrobial Resistance,”Frontiers in Microbiology,Vol.10,Article 308,2020.December 2022

299、Citi GPS:Citi GPS:Global Perspectives&Solutions 2022 Citigroup 41 We have witnessed the powerful impact of rapid COVID-19 tests which admittedly test for fewer infection markers but have been instrumental in helping patients understand if their symptoms are viral or bacterial.Similar investment into

300、 rapid diagnostics for pathogen identification to better treat the presentation of infection in human and animal patients(companion pet and livestock)could result in more effective deployment of the correct antibacterial treatment.Similar rapid diagnostics also offer visibility into the susceptibili

301、ty of pathogens to antibiotic treatment.From a clinical perspective this is referred to as“antibiotic susceptibility testing”rather than“antibiotic resistance testing.”3.Innovating for Novel AntimicrobialsImprovements to tackle an over-reliance on antimicrobials are a vital first step in addressing

302、AMR and without better stewardship,novel antimicrobials would be only a temporary solution to the challenge.However,innovation is also critical to replenish the clinical pipeline of new medicines.Facilitating innovation requires investment into early stage research and drug discovery,where emerging

303、technologies may also have a role to play.Another element of this involves building the pipeline of talent to ensure that scientists continue to be attracted into AMR-relevant fields.Incentivizing Drug Discovery in the Pharmaceutical Industry We discuss holistically the role of the pharmaceutical in

304、dustry in addressing the challenge of AMR in Chapter 7.For now,it is sufficient to note that the development of novel antibiotics has presented difficulties for the pharmaceutical sector and more must be done at the level of policy to alter the economics of research and development in AMR-relevant f

305、ields.Opening up the research capacity of the pharmaceutical industry to this space would constitute a significant step in tackling AMR.Many of the recommendations presented in the 2016 AMR Review still apply at this stage:The regulatory hurdle for bringing novel antimicrobials to market is still ve

306、ry high and there are limited economic incentives to enter the anti-infectives market at all.In his commentary,Lord Jim ONeill notes that more progress is needed here and suggests again a“Pay or Play”funding scheme,which would require pharmaceutical companies either to invest in the research and dev

307、elopment of novel antimicrobials or to pay a charge.Public Sector and Philanthropic Funding for Early Stage Research There is likely to remain an investment gap in early stage drug discovery,even if the pharmaceutical industry can be incentivized to take more action on AMR.This is because of the ris

308、ks involved in earlier stage research.As a result,funding from alternative sources,including the public sector and philanthropists,plays a significant role in supporting drug development.Citi GPS:Citi GPS:Global Perspectives&Solutions December 2022 2022 Citigroup 42 Case Study:Combating Antibiotic-R

309、esistant Bacteria Biopharmaceutical Accelerator(CARB-X)CARB-X is a non-profit organization with global support from a range of institutions,including the U.K.government and the Bill&Melinda Gates Foundation.The organization exists to accelerate and support scientific research to create novel antimic

310、robials,vaccines,and diagnostic tools that tackle AMR-relevant pathogens.Figure 15.How CARB-X Works Source:CARB-X In its Annual Report 2020-2021,CARB-X reported on the diverse portfolio of innovative antibacterial products moving toward clinical development and regulatory approval with funding,exper

311、t support,and cross-project initiatives.64 CARB-X focuses on the dangerous bacteria identified by the WHO and CDC priority lists,see Figure 16 below.Figure 16.CARB-X Targeting Infections Identified by the WHO and CDC Priority Lists Source:CARB-X Annual Report 2020-2021 In its annual report,CARB-X cl

312、aims it is pursuing“radically innovative classes,targets,and non-traditional approaches”compared to existing research methods that build on the“the extension”of well-known classes”of antibiotics.64 CARB-X,Annual Report 2020-2021:Preparing the World Against Antibiotic-Resistant Bacteria,October 2021.

313、December 2022 Citi GPS:Citi GPS:Global Perspectives&Solutions 2022 Citigroup 43 Figure 17.CARB-X Targeting Worlds Deadliest Infections Source:CARB-X Annual Report 2020-2021 Highlights from the 2020-2021 CARB-X annual report include the development of:65 A differentiated oral combination of a novel b

314、road-spectrum inhibitor of Class A and C beta-lactamases withcefpodoxime to treat complicated urinary tract infections(UTIs)including carbapenem resistant Enterobacteriaceae(CRE).An oral,rationally designed microbiome consortium for the prevention of breakthrough antibiotic-resistant bacterialinfect

315、ions and graft-versus-host disease in patients following solid organ and allogeneic stem cell transplantation.A novel class,broad-spectrum antibiotic to target multi-drug resistant Gram-negative bacteria.An orally bioavailable small-molecule drug that targets an adhesion protein found on the surface

316、 of Escherichia colibacteria called FimH.E.coli is a key causative pathogen resulting in UTIs.An innovative“soft drug”polymyxin antibiotic that targets clinically important therapy of multidrug-resistant infectionsincluding E.coli,Pseudomonas aeruginosa,Klebsiella pneumoniae,and Acinetobacter bauman

317、nii.An orally active small molecule with activity against N.gonorrhoeae,including multidrug-resistant forms.An oral cyclic-boronate as a penicillin-binding protein(PBP)inhibitor for third-generation cephalosporin-resistantgonorrhea.Emerging Technologies Support Drug Discovery Advances in technology

318、might support the discovery of novel antimicrobials.Some companies working on emerging technologies have explained that technology can be deployed not only to search out those that might have antimicrobial properties from known molecules more efficiently than human researchers,but these technologies

319、 can even learn the underlying structures of antimicrobial medicines and generate new molecules that have not yet been synthesized.66 65 Ibid.66 World Economic Forum,“Tackling Antibiotic Resistance with AI and Quantum Computing,”August 2,2022.Citi GPS:Citi GPS:Global Perspectives&Solutions December

320、2022 2022 Citigroup 44 Combining powerful emerging AI techniques could be the most promising route to successfully tackling antibiotic resistance.ALESSANDRO CURIONI,VP EUROPE AND AFRICA DIRECTOR,IBM RESEARCH EUROPE67Two examples illustrate the potential of these technologies:In 2020,a group of acade

321、mics from North America trained a deep neuralnetwork to predict which molecules might have antibacterial properties andpublished their findings.Their investigations predict that Halicin,a moleculefound in the Drug Repurposing Hub,would have antimicrobial properties.Trials in mice then provided confi

322、rmation that Halicin does show antimicrobialproperties.68 A 2021 paper proposes a fully offline mobile application capable of analyzingantibiotic susceptibility testing.69 While the system will still require basicmicrobiology,the proposed AI-based model is designed to partially alleviateneed of expe

323、rt human resources,highly relevant in LMICs,to make,forexample,disk-reading more reliable and potentially enable faster interpretedresults.Deploying these technologies to support drug discovery does stand to significantly reduce the costs of replenishing the clinical pipeline and the time it would t

324、ake to do so compared with traditional research,which is significantly more labor intensive.However,this is not a panacea:Computational techniques do not always predict the toxicity of novel molecules,and this is a key factor in the suitability of antimicrobials as medication that can limit their pr

325、ogression to clinical trials.Number and Recognition of People Working With Infectious Disease We know the challenge of AMR will require continuous monitoring for as long as we have the need of antimicrobials and keeping the pipeline of novel antimicrobials replenished will be an ongoing task.Hence,p

326、art of the solution requires ensuring there is a qualified workforce to support surveillance systems and innovation efforts going forward.The broader problem of an under-resourced global health workforce persists:The WHO expects that there will be a shortage of 10 million workers by 2030,with the ma

327、jority of this shortfall experienced by LMICs.70 Moreover,attracting workers into the infectious diseases specialty remains challenging:The 2016 AMR Review suggested that the specialty had among lowest earnings of all medical specialties in 2012 and,according to Medscape data,infectious disease rema

328、ins in the five lowest-paid specialties in the U.S.71 67 Ibid.68 Jonathan M.Stokes et al.,“A Deep Learning Approach to Antibiotic Discovery,”Cell,Vol.180,No.4,February 20,2020.69 Marco Pascucci et al.,“AI-Based Mobile Application to Fight Antibiotic Resistance,”Nature Communications,Vol.12,No.1173,F

329、ebruary 19,2021.70 WHO“Health Workforce,”accessed November 16,2022.71 Leslie Kane,Medscape Physician Compensation Report 2022:Incomes Gain,Pay Gaps Remain,Medscape,April 15,2022.Surveillance systems involve the ongoing systematic collection,collation,and analysis of information related to public hea

330、lth(animal and human)and the timely dissemination of information so that action can be taken.The information is used,for example,for actions that prevent and control infectious disease.December 2022 Citi GPS:Citi GPS:Global Perspectives&Solutions 2022 Citigroup 45 4.Curtailing the Spread of Resistan

331、ceThe final set of solutions aims at curtailing the spread of resistance that has already emerged.The first stage must be to improve surveillance systems,especially in LMICs,and to understand the current state of resistance and target actions appropriately.Second,treating wastewater will be critical

332、 to halting the spread of resistant pathogens as well as preventing the emergence of further resistance.Global Surveillance of Drug Resistance Surveillance involves tracking both the emergence of AMR in humans,animals,and the environment,as well as the use of antimicrobial medicines.Without this inf

333、ormation,it is impossible to develop a targeted and informed strategy to curtail resistance.This must also be complemented by an understanding of the microbiological mechanisms by which resistance emerges.Figure 18.Global Surveillance of Drug Resistance Source:Citi GPS Many surveillance systems are attempting to build a global picture of the current state of AMR.One example is the WHOs Global Anti