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1、Bracing for SuperbugsStrengthening environmental action in the One Health response to antimicrobial resistance 2023 United Nations Environment Programme ISBN:978-92-807-4006-6 Job number:DTI/2504/GE This publication may be reproduced in whole or in part and in any form for educational or non-profit

2、services without special permission from the copyright holder,provided acknowledgement of the source is made.The United Nations Environment Programme would appreciate receiving a copy of any publication that uses this publication as a source.No use of this publication may be made for resale or any o

3、ther commercial purpose whatsoever without prior permission in writing from the United Nations Environment Programme.Applications for such permission,with a statement of the purpose and extent of the reproduction,should be addressed to the Director,Communication Division,United Nations Environment P

4、rogramme,unep-communication-directorun.org.Disclaimers The designations employed and the presentation of material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the United Nations concerning the legal status of any country,territory,city o

5、r area or of its authorities,or concerning the delimitation of its frontiers or boundaries.Mention of a commercial company or product in this document does not imply endorsement by the United Nations Environment Programme or the authors.The use of information from this document for publicity or adve

6、rtising is not permitted.Trademark names and symbols are used in an editorial fashion with no intention on infringement of trademark or copyright laws.The views expressed in this publication are those of the authors and do not necessarily reflect the views of the United Nations Environment Programme

7、.We regret any errors or omissions that may have been unwittingly made.Maps,photos and illustrations as specified Suggested citation:United Nations Environment Programme(2023).Bracing for Superbugs:Strengthening environmental action in the One Health response to antimicrobial resistance.Geneva Produ

8、ction:United Nations Environment Programme URL:https:/www.unep.org/resources/superbugs/environmental-actionAcknowledgementsThe United Nations Environment Programme(UNEP)would like to thank the authors and reviewers who have contributed to the report in their individual capacities.Their affiliations

9、are only mentioned for identification purposes.Authors:Teresa M.Coque,Ramn y Cajal Health Research Institute-IRYCIS.,Madrid(Spain);Centro de Investigacin Biomdica en Red de Enfermedades Infecciosas-CIBERINFEC,Instituto de Salud Carlos III,Madrid,(Spain)David W.Graham,Newcastle University,Newcastle u

10、pon Tyne(United Kingdom)Amy Pruden,Virginia Polytechnic Institute and State University,Virginia(United States)Anthony D.So,Johns Hopkins University,Baltimore,Maryland(United States)Ed Topp,Agriculture and Agri-Food Canada,University of Western Ontario,Ontario(Canada)UNEP:Susan Vaughn Grooters,Achim

11、Halpaap,Nada Hanna,Miguel Salazar.Coordinator and author:Aitziber Echeverria(UNEP)Contributors:David Bass,Johann Bengtsson-Palme,Carlos Bezuidenhout,Ariel Brunn,Pranab Chatterjee,Eddie Cytryn,Benjamin C.Davis,Monika Dolejska,Gail Hansen,Peiying Hong,Rai Kookana,Arshnee Moodley,Marcos Quintela-Baluja

12、,Prateek Sharma,Phil Taylor,David Verner-Jefferies,Jeff Waage.UNEP:Haosong Jiao,Tapiwa Nxele,Ambre Zwetyenga.In consultation with or reviewed by:Esteban Abad,Ruth Atkinson,Fernando Baquero,Stefan Berggren,Niketha Bhandekar,Amelia Breeze,Steve Brooks,Naomi Bull,Sandra Castro Scarone,William Calero Cc

13、eres,Kimberly Cook,Solveig Danielsen,Sally Davies,Steven Djordjevic,Gunilla Eklund,Sabiha Essack,Marinella Farre Urgell,Bart Fraaije,William Gaze,Lidija Globevnik,Thomas Harrison,Alwyn Hart,Rene Hendriksen,Ryo Honda,Amit Khurana,Manish Kumar,Joakim Larsson,Stephanie Lyon,Sunita Narain,Kaare Magne Ni

14、elsen,Jose Lus Martnez,Janet Midega,Jochen Mueller,Indumathi Nambi,Coilin Nunan,Jorge Olivares Pachecho,Ingvild Riisberg,Laetitia Sieffert,Rajeshwari Sinha,Hasmitta Stewart,Joan Tell,Pablo Tsukayama,Jayavignesh Viayan,Maria Wallin,Caroline Whalley,Sian Williams,Tong Zhang,Yong-Guan Zhu.FAO:Marlos De

15、Souza,Omar Elhassan,Jeffrey LeJeune,Jorge Pinto Ferreira,Ambra Gobena,Sasha Koo-Oshima,Junxia Song,KimAhn Tempelman,Jing Xu.UNEP:Dina Abdelhakim,Sheila Aggarwal-Khan,Jacqueline lvarez,Kevin Helps,Andrea Hinwood,Monika MacDevette,Susan Mutebi-Richards,Steven Stone,Kakuko Nagatani-Yoshida.WHO:Bruce Go

16、rdon,Kate Medlicott,Elizabeth Tayler,Suzanne Young.WOAH:Elisabeth Erlacher,lafur Valsson.Design and layout:Lowil Espada.Editorial support:Amanda Lawrence-Brown(UNEP),John Smith.Media and launch support:UNEP:Daniel Cooney,Nicolien De Lange,Maria Vittoria Galassi,Moses Osani,Keishamaza Rukikaire,Laila

17、 Saada and other members of the UNEP Communication Division.i ADIAcceptable daily intakeAMCAntimicrobial consumptionAMRAntimicrobial resistanceAMSAntimicrobial stewardshipAMUAntimicrobial useAOPAdvanced oxidation processesAPIActive pharmaceutical ingredientARGAntimicrobial resistance geneATLASSFAO A

18、ssessment Tool for Laboratory and Antimicrobial Resistance Surveillance SystemsBATBest Available TechnologyCABICentre for Agricultural Bioscience InternationalCARICOM Caribbean CommunityCBDConvention on Biological Diversity COPConference of the PartiesCPECarbapenamase-producing EnterobacteriaceaeDNA

19、Deoxyribonucleic acidEPPPEnvironmentally Persistent Pharmaceutical PollutantsERAEnvironmental Risk AssessmentESBLExtended Spectrum Beta-lactamasesEUCASTEuropean Committee on Antimicrobial Susceptibility TestingFAOFood and Agriculture Organization of the United NationsG7the Group of SevenG20the Group

20、 of TwentyGAPGlobal action plan on Antimicrobial ResistanceGARDPGlobal Antibiotic Research&Development PartnershipGBFKunming-Montreal Global Biodiversity FrameworkGDPGross Domestic ProductGLASSGlobal Antimicrobial Resistance Surveillance SystemGLGOne Health Global Leaders Group on AMR HGTHorizontal

21、gene transferIACGInteragency Coordination Group on Antimicrobial ResistanceIMIInnovative Medicines InitiativeJEFCAJoint FAO/WHO Expert Committee on Food AdditivesLICLow Income CountryLMICLower Middle-Income CountryMRLMaximum residue limitMDRMultidrug resistanceMGEMobile genetic elementMICMinimum inh

22、ibitory concentrationMPTFMulti Partner Trust FundMRSAMethicillin-resistant Staphylococcus aureusMSCMinimum selective concentrationMSWMunicipal solid wasteNAPNational Action Plan NBSAPNational Biodiversity Strategies and Action PlansNCBINational Centre for Biotechnology InformationOECDOrganisation fo

23、r Economic Co-operation and DevelopmentOHHLEPOne Health High-Level Expert Panel PCRPolymerase chain reactionPNECPredicted No Effect ConcentrationQMRAQuantitative Microbial Risk AssessmentR&DResearch and DevelopmentRNARibonucleic acidSCHERScientific Committee on Health and Environmental RisksTrACSSTr

24、acking AMR Country Self-assessment SurveyUNEAUnited Nations Environment AssemblyUNEPUnited Nations Environment ProgrammeUNGAUnited Nations General Assembly UVUltravioletVICHVeterinary International Conference on HarmonizationWASHWater,Sanitation and HygieneWEFWorld Economic ForumWGSWhole genome sequ

25、encingWHAWorld Health AssemblyWHOWorld Health OrganizationWOAHWorld Organisation for Animal Health WWTPWastewater treatment plantAcronyms and AbbreviationsiiBracing for Superbugs:Strengthening environmental action in the One Health response to antimicrobial resistanceContentsAcknowledgements iAcrony

26、ms and Abbreviations iiList of Figures ivList of Boxes ivForeword vExecutive Summary vi1Introduction12IncreaseofAMRhassevereconsequences22.1 Antimicrobials are essential and their effectiveness must be preserved 22.2 The health,social and economic impacts of AMR 32.3 Summary 53Environmentaldimension

27、sofAMR63.1 AMR development in the environment 63.1.1Selection pressure 83.2 AMR and the triple planetary crisis 123.2.1Climate change 123.2.2Biodiversity loss 133.2.3Pollution and waste 133.3 AMR transmission and spread in the environment 143.3.1Transient and diffuse spread of AMR in the environment

28、 153.3.2Examples of global dissemination of resistance genes 233.4 Summary 254ManagementtoPreventandRespondtoAMR264.1 Recognise the environment is key to advancing a One Health response to AMR 264.2 Address key economic-sector value chains affecting AMR in the environment 284.2.1Pharmaceutical and o

29、ther chemical value chains 294.2.2Agricultural and food value chains 334.2.3Healthcare value chains 414.3 Prevent and manage wastewater and solid waste as AMR sources 434.3.1Poor sanitation,wastewater and related waste effluent 434.4 Summary 50iii 5NextstepstotackleAMRintheenvironment515.1 Strengthe

30、n national action 515.1.1Boost governance,planning and regulatory frameworks 525.2 Strengthen global action 555.3 Improve reporting,surveillance and monitoring systems 575.4 Future data,information and knowledge needs 605.5 Prioritize financing,innovation and capacity development to support environm

31、ental action 615.6 A call to action 625.7 Summary 64References 65ListofFiguresFigure 1 Commercial deployment of antibiotics and emergence of antibiotic resistance a timeline 2Figure 2 Predicted mortality from AMR compared with common causes of current deaths 4Figure 3 Predicted global deaths from AM

32、R in 2050 4Figure 4 Environmental complexities in transmission and spread of AMR 7Figure 5 Horizontal and Vertical Gene Transfer 8Figure 6 Selection pressure and antimicrobial resistance(United States Centers for Disease Control and Prevention 9Figure 7 Estimated global environmental water contamina

33、tion and pollution from antimicrobials 11Figure 8 How antimicrobial resistance can spread 15Figure 9 AMR Spread from flooding and urban storm runoff 17Figure 10 Transmission and spread of AMR to and from wildlife 19Figure 11 Migration of wildlife transmission pathway 20Figure 12 One Health definitio

34、n developed by the One Health High-Level Expert Panel 26Figure 13 Sustainable production and consumption of antimicrobials can impact many other SDGs 27Figure 14 Key economic-sector value chains affecting AMR in the environment 28Figure 15 Wastewater discharges from pharmaceutical manufacturing 30Fi

35、gure 16 Trend in fungicide and bactericide use in agriculture 34Figure 17 Environmental AMR pollution sources and areas for prevention and management 44Figure 18 Potential AMR transmission pathways from landfills 46Figure 19 Wastewater and faecal sludge management solutions needed to address local c

36、ontexts 47Figure 20 Elements of a system approach to address AMR at the national level 54ListofBoxesBox 1 What is antimicrobial resistance(AMR)and how does it develop?3Box 2 The environment matters in zoonotic diseases and pandemic spread 21Box 3 The One Health approach 26Box 4 Household animals,pet

37、s and companion animals 48Box 5 Environmental surveillance methodologies 59ivBracing for Superbugs:Strengthening environmental action in the One Health response to antimicrobial resistanceForewordAntimicrobials are an essential part of modern life.Yet,the more we use them inappropriately,the more th

38、e microbial world adapts.There is strong evidence that bacteria,parasites,viruses and fungi are becoming resistant to antimicrobials.Infections in humans,animals and plants are becoming difficult,sometimes impossible,to treat.Antimicrobial resistance(AMR)has therefore emerged as a principal public h

39、ealth problem.AMR was,directly and indirectly,responsible for an estimated five million or so deaths in 2019.By 2050,up to 10 million deaths could occur annually on par with the 2020 rate of cancer deaths.If unchecked,AMR could shave US$3.4 trillion off GDP annually and push 24 million more people i

40、nto extreme poverty in the next decade.AMR is a global problem,and the risks are shared by all countries.However,it is closely linked to poverty,lack of sanitation,poor hygiene and pollution.Therefore,low-income and lower-middle-income countries are the worst affected by AMR.This report provides evi

41、dence that the environment matters in the development,transmission and spread of AMR.It offers solutions to address the development and spread of AMR in the environment,particularly by preventing and managing chemical and biological pollution from the pharmaceuticals,agriculture and healthcare secto

42、rs and municipal waste.Changes to reduce the risk of superbugs include solid regulation of discharges,strengthening wastewater treatment,realigning incentives to reduce the use of antimicrobials and the private sector stepping up corporate responsibility.The report shows the need for a more ambitiou

43、s and systemic approach,rather than working sector by sector.AMR represents a major global threat across human,animal,plant and environmental health.Using the One Health approach which recognizes that the health of people,animals,plants and the environment are interdependent can address AMR.Simply p

44、ut,tackling AMR will require all hands-on deck:government,civil society,international organizations and the private sector.While more research and development are pivotal to fighting AMR,sufficient information is already available for stakeholders to act on AMR as an issue of environmental,health an

45、d economic concern.Significant momentum has developed.But we must do more.We need to leverage high-level political engagement,financial resources and technical expertise,with a focus on country-level needs and demands.UNEP is committed to tackling this crisis.As part of the Quadripartite Alliance wi

46、th the Food and Agriculture Organization of the United Nations(FAO),the World Health Organization(WHO)and World Organisation for Animal Health(WOAH),UNEP works to strengthen environmental action as part of a One Health response to AMR.This report shows that solutions exist and can be implemented thr

47、ough international commitment.If we take proactive action,we can reduce the harm and risks of AMR.INGER ANDERSENv ExecutiveSummaryAntimicrobials have been essential in reducing the burden of infectious disease in humans,animals and plants for decades.However,their effectiveness is now in jeopardy be

48、cause several antibiotic,antiviral,antiparasitic and antifungal treatments no longer work because of antimicrobial resistance or AMR.The World Health Organization considers AMR in humans and animals to be one of the top ten threats to global health.Estimates suggest that by 2050 up to 10 million dea

49、ths could occur annually affecting economies and shifting more people into poverty.If not dealt with,AMR could also significantly affect agricultural production,again affecting economies and food security,and low-income and lower middle-income countries will bear most of the burden.Global attention

50、to AMR has mainly focused on human health and agriculture sectors,but there is growing evidence that the environment plays a key role in the development,transmission and spread of AMR.The environmental dimensions of AMR are complex and characterized by dynamic interactions,cyclic interrelationships,

51、complexities and multiple causalities and dynamics in multi-dimensional media that impact global planetary health.AMR can occur naturally or can be acquired.Increased use and misuse of antimicrobials and other microbial stressors,such as pollution,create favourable conditions for microorganisms to d

52、evelop resistance both in humans and the environment from sources such as sewage.Bacteria in water,soil and air for example can acquire resistance following contact with resistant microorganisms.The environmental dimensions of AMR include pollution from hospital and community wastewater,effluent fro

53、m pharmaceutical production,run-off originating from plant and animal agriculture and other forms of waste and releases.These matrices may contain not only resistant microorganisms,but also antimicrobials,various pharmaceuticals,microplastics,metals and other chemicals,which all increase the risk of

54、 AMR in the environment.Polluted waterways,particularly those that have been polluted for some time,are likely to harbour microorganisms that increase AMR development and distribution in the environment.With increasing pollution and lack of management of sources of pollution,combined with AMR in cli

55、nical and hospital settings and agriculture,risks are increasing.The key economic-sectors contributing to the environmental dimensions of AMR can be broadly classified as:pharmaceutical and other chemical manufacturing and uses including a range of different chemicals,such as antibiotics,antivirals

56、and fungicides as well as disinfectants;agriculture including animal production,aquaculture,food crops or those providing inputs such as feed,textiles,ornamental plants,biofuels and other agricultural commodities;healthcare delivery in hospitals,medical facilities,community healthcare facilities and

57、 in pharmacies where a broad range of chemicals and disinfectants may be used.While the relationship between environmental pollution and AMR and the reservoir of resistance genes in the environment has been established,the significance and its contribution to AMR globally is still unclear.Even so,th

58、ere is enough knowledge to implement measures to reduce the factors that influence AMR from an environmental perspective;this will also address the triple planetary crisis by addressing sources,sinks and waste.viBracing for Superbugs:Strengthening environmental action in the One Health response to a

59、ntimicrobial resistanceUsing the One Health approach,which recognises that the health of people,animals,plants and the environment are closely linked and interdependent,can successfully address AMR.Some countries have already adopted this approach and have included environmental-related aspects into

60、 their National Action Plans on AMR.Agriculture,health and environmental agencies have in place many policy and regulatory frameworks and controls addressing some of the drivers and factors with an impact on environmental dimensions of AMR.Voluntary industry initiatives have established a common fra

61、mework for managing discharge of antimicrobial compounds and apply it across manufacturing and supply chains among their members.International organizations and bodies are taking decisions and have initiatives such as the joint efforts of the Quadripartite Alliance(FAO,UNEP,WHO and WOAH)for strong a

62、nd coordinated action.Yet still more needs to be done.This report calls for priority action to address key pollution sources from poor sanitation,sewage;community and municipal wastes;healthcare delivery;pharmaceutical manufacturing;intensive crop,and terrestrial and aquatic animal production sector

63、s.There are many co-benefits of preventing and managing pollution in these sources to address biological wastes that contain resistant microorganisms that spread AMR,and chemical wastes that select for AMR.To prevent and reduce such pollutants it is crucial to:create robust and coherent national lev

64、el governance,planning,regulatory and legal frameworks,as well as establish coordination and collaboration mechanisms increase global efforts to improve integrated water management and promote water,sanitation and hygiene to limit the development and spread of AMR in the environment as well as to re

65、duce infections and need for antimicrobials increase integration of environmental considerations into National Action Plans on AMR,and AMR into environmental-related plans such as national chemical pollution and waste management programmes,national biodiversity and climate change planning establish

66、international standards for what are good microbiological indicators of AMR from environmental samples,which can be used to guide risk reduction decisions and create effective incentives to follow such guidance explore options to redirect investments,to establish new and innovative financial incenti

67、ves and schemes,and to make the investment case to guarantee sustainable funding,including the allocation of sufficient domestic resources for tackling AMR.Prevention is at the core of the action and environment is a key part of the solution.Implementing comprehensive and coordinated strengthening o

68、f environmental action in the One Health response to AMR will not only help reduce the risk and burden of AMR on societies but will also help address the triple planetary crisis.vii Introduction1Globalattentiontoantimicrobialresistance(AMR)hasbeendominatedbyafocusonthehumanhealthandagriculturesector

69、s.However,evidenceismountingthatenvironmentaldriversplayasignificantroleinthedevelopment,transmissionandspreadofAMR,includingbacktohumansandanimals.ManyhumanactivitiescreatepollutionthatpromotestheemergenceofAMRintheenvironment.AMRintheenvironmentcancausehuman,animalorplantdiseasesorsoilbiodiversity

70、lossthatcanleadtofurtheruseofantimicrobials(anegativefeedbackfrominitialuse)thatonlyexacerbatesAMR.TheissueofAMRandtheenvironmentwasrecognizedbythethirdsessionoftheUnitedNationsEnvironmentAssembly(UNEA-3)in2017,whichrequestedthisreportontheenvironmentalimpactsofAMRandthecausesofthedevelopmentandspre

71、adofresistanceintheenvironment,includinggapsinunderstandingofthoseimpactsandcauses(UnitedNationsEnvironmentProgrammeUNEP2018).EnvironmentalimpactsofAMRincludepollution,bothbiologicalandchemical,thataffecthuman,animalandplanthealth,aswellasecosystemservices.Whilecausalpathwaysarestillbeingestablished

72、andresearchedtodemonstratehowenvironmentalfactorscontributetoresistanceinhumanandanimalpathogens,thereisalreadysufficientknowledgetoimplementmeasurestoreducethefactorsthatinfluenceAMRfromanenvironmentalperspective.ThisreportreviewstheavailableevidenceonenvironmentaldimensionsofAMR.Itwaspreparedthrou

73、ghaconsultativeandextensivereviewprocessthatengagedmorethan50expertsandstakeholdersfromcountriesaroundtheworld,includingfromtheQuadripartiteorganizations:theFoodandAgricultureOrganizationoftheUnitedNations(FAO),theUnitedNationsEnvironmentProgramme(UNEP),theWorldHealthOrganization(WHO)andtheWorldOrga

74、nisationforAnimalHealth(WOAH).Giventhepotentialcostandhigh-impactrisksofinaction(ONeill2016;WorldEconomicForumWEF2021),thisreportcallsforurgent,comprehensiveandcoordinatedstrengtheningofenvironmentalactionintheOneHealthresponsetoAMR.1IncreaseofAMRhassevereconsequences2Antimicrobialsplayanessentialro

75、leinprotectingthehealthofpeople,animalsandplants(Hernando-Amadoetal.2019;JointProgrammingInitiativeonAntimicrobialResistance2019).Formanydecades,antimicrobialshavebeeneffectiveintreatingorpreventingawiderangeofinfectiousdiseases.However,theireffectivenessisnowinjeopardy(LevyandMarshall2004).Anumbero

76、fantibiotic,antiviral,antiparasiticandantifungaltreatmentsthatonceworkednolongerdosobecausemicroorganismshavebecomeresistanttothem(Allenetal.2010;Toppetal.2018;Grahametal.2019;Murrayetal.2022).Thereisstrongevidencethatantimicrobialsareincreasinglyfailingtocureinfectionsandtheresearchanddevelopmentpi

77、pelineofnovelantimicrobialsislacking(Figure1).Therefore,AMRposesasignificantthreattohuman,animalandplanthealth,foodsecurityandeconomicdevelopmentbyreducingtheabilitytorespondtocommoninfectiousagents.FailingtoaddresstheglobalburdenofAMR,includingitsenvironmentaldimensions,couldtakehumanitybacktoanera

78、whenevenmildinfectionscouldbecomedeadly.2.1 AntimicrobialsareessentialandtheireffectivenessmustbepreservedAs antibiotics have been discovered and commercialised,resistance mechanisms soon develop.201020152020191020251935192019301955197519951945196519852005197019501990194019801960200019151925Sulfonam

79、idesSalvarsanLinezolidDaptomycinCeftolozane/tazobactamPenicillin GStreptomycinChloramphenicolErythromycinTetracyclineVancomycinCephalosporinsLinezolidSulfonamidesSalvarsanDaptomycinCeftolozane/tazobactamStreptomycinPenicillin GChloramphenicolErythromycinTetracyclineVancomycinCephalosporins Antibioti

80、c deployment Antibiotic resistanceCommercial deployment of antibiotics and emergence of antibiotic resistance a timelineFigure 12TheseWorldBankestimatesdonotcoverallthedirectandindirectcostsofAMR,whichcouldincreasetheseamounts(Moreletal.2020).ArecentWorldEconomicForumreport(2021)pointsoutthatdisease

81、causesworktimeandproductivitylosses,anditestimatesthatifcurrenttrendscontinueunchecked,AMRcouldincreaseanimalmortalityratesbyonepercent,anequivalentlossofUS$13billioninlivestockvalue(US$3billionofwhichisattributedtowaterborneAMR)andUS$3billioninaquaculturevalue.AlthoughtherisksofAMRtohuman,animaland

82、planthealthandtheenvironmentaresharedbyallcountries,Low-IncomeCountries(LICs)andLower-Middle-IncomeCountries(LMICs)bearasignificantburdenofinfectiousdiseaseandwillbeIncreasingAMRinhumanandanimalpathogensisamongthetoptenthreatscompromisingglobalhealth(WHO2021a).Accordingtorecentestimates,in2019,1.27m

83、illiondeathsweredirectlyattributedtodrug-resistantinfectionsglobally,and4.95milliondeathswereassociatedwithbacterialAMR(includingthosedirectlyattributabletoAMR)(Murrayetal.2022).Someestimatesindicatethatby2050itcouldcauseupto10milliondeathsgloballyperyear-onparwiththe2020deathtollfromcancer(ONeill20

84、16).Leftunchecked,theeconomicimpactofAMRisalsolikelytobesignificant.Inthenextdecade,itcouldresultinagrossdomesticproduct(GDP)shortfallofUS$3.4trillionannuallyandpush24millionmorepeopleintoextremepoverty(WorldBank2017).2.2 Thehealth,socialandeconomicimpactsofAMRWhat is antimicrobial resistance(AMR)an

85、d how does it develop?Antimicrobialsareagentsintendedtokillorinhibitthegrowthofmicroorganisms.Theyincludeantibiotics,fungicides,antiviralagentsandparasiticides.Someheavymetals,disinfectants,antiseptics,manyotherpharmaceuticalsandsomenaturalproductsmayalsohaveantimicrobialproperties(Karpanenet al.201

86、2;Palet al.2017;Almoudiet al.2018;JonesandJoshi2021;Mendeset al.2022).Antimicrobialsarewidelyusedinhealthcareforhumansandanimals,andinagricultureforcropandanimalproduction.AMRoccurswhenmicroorganismssuchasbacteria,viruses,parasitesorfungibecomeresistanttoantimicrobialtreatmentstowhichtheywerepreviou

87、slysusceptible.AMRcanbeintrinsicoracquired;thelattercanoccurthroughmutations,orinthecaseofbacteriabytheacquisitionofdeoxyribonucleicacid(DNA)fromdifferentmicroorganisms,viahorizontalgenetransfer(HGT)ofmobilegeneticelements(MGEs)(LevyandMarshall2004;Martnez,CoqueandBaquero2015).Acquiredresistanceisan

88、evolutionaryresponsebymicroorganisms,viamutationorHGT,suchthattheyarenolongerinhibitedorkilledbyantimicrobials.Increasinguseandmisuseofantimicrobialsandothermicrobialstressors(e.g.thepresenceofheavymetalsandotherpollutants)createsfavourableconditionsformicroorganismstodevelopresistance(LevyandMarsha

89、ll2004;WalesandDavies2015).Thiscanhappeninthedigestivetractsofhumansandanimalsorinenvironmentalmedia(e.g.waterandsoil)andfromsourcessuchassewage(WalesandDavies2015;Baqueroet al.2019;Zhuet al.2019;Figure1inLarssonandFlach2022).Consequently,thelikelihoodofAMRdevelopinginmicroorganismsinfectinghumans,a

90、nimalsandplantsisincreasing.Box 132 Increase of AMR has severe consequences moreadverselyaffectedbyAMR.Examiningprojectedglobaldeathsbycontinent(Figure3),alsoindicateswhereweareseeingproblematiclevelsofAMRparticularlyinAsiaandAfrica(ONeill2014;Murrayet al.2022).Tetanus60,000Road traffic accident1,20

91、0,000Measles130,000Diarrhoeal disease1,400,000Diabetes1,500,000Cholera100,000120,000AMR now1,270,000AMR in 205010,000,000Cancer10,000,000Predicted mortality from AMR compared with common causes of current deaths(adapted from ONeill 2016;Murray et al.2022)Figure 2North America317,000Asia4,730,000Afri

92、ca4,150,000Oceania22,000Latin America392,000Europe390,000 Number of deaths5678910 Mortality per 10,000 populationPredicted global deaths from AMR in 2050(ONeill 2014)Figure 34Bracing for Superbugs:Strengthening environmental action in the One Health response to antimicrobial resistanceAMRalsoexacerb

93、atesinequitieswithinsocieties.Groupsincludingwomen,children,migrants,refugees,peopleemployedincertainsectors(e.g.agricultureorhealthcare)andthoselivinginpovertymaybeparticularlyvulnerableand/ormoreexposedtodrug-resistantinfections(WHO2007;BhopalandBhopal2020;WHOetal.2021).Moreover,inseveralcountries

94、,womenarelargelyresponsibleforthecollectionofwater,andthelackofaccesstowaterandsanitationonpremisesnotonlylimitsthetimewomencaninvestineducation,incomegenerationactivitiesorleisurebutalsoexposesthemtoahigherriskofsufferinggender-basedviolence(Travers,KhoslaandDhar2011;Houseetal.2014;UNEPandInternati

95、onalUnionforConservationofNatureIUCN2018,p.25)Moreresearchonthegender-andage-differentiatedimpactsandoutcomeofresistantinfectionsisrequiredtounderstandhowtotargetpoliciesandassistthemostvulnerablepopulationswhoremainatriskofbeingleftfurthestbehind(WHO2018a).2.3 Summary Theeffectivenessofantimicrobia

96、lsisnowinjeopardyascertainmicroorganisms,suchasbacteria,viruses,parasitesorfungi,becomeresistanttoantimicrobialtreatmentstowhichtheywerepreviouslysusceptible.AMRisasignificantthreattohumanandanimalhealth,foodsecurity,economicdevelopmentandequitywithinsocieties.Unlesstheworldactsurgentlyinaddressingt

97、heglobalburdenofAMR,includingitsenvironmentaldimensions,AMRwillhavedisproportionateanddevastatingimpacts,especiallytoLICsandLMICs.Policysettingthatisinformedbythecollectionofdisaggregateddata(e.g.ongender,ageandsocioeconomicstatus)canhelptoaddressinequalitiesfromAMR.52 Increase of AMR has severe con

98、sequences Microorganisms(particularlybacteria)inwater,soilandaircanacquireresistancefollowingcontactwithresistantmicroorganismsthatmayhaveoriginatedintheenvironmentoverevolutionarytimeorhavebeenintroducedthroughhumanand/oranimalwastestreams(Cantn,Gonzlez-AlbaandGaln2012;Perry,WaglechnerandWright2016

99、).Resistancecandevelopduetoselectivepressuresfromantibiotics,fungicides,antiviralcompounds,parasiticides,certaindisinfectantchemicals(e.g.quaternaryammoniumcompounds,triclosanandchlorine)andotherco-selectingcompounds(e.g.biocidesandmetalssuchaszincandcopper),whicharereleasedintotheenvironmentbyhuman

100、activity,poorsanitationorfromcontaminatedlandandwater.Resistantmicroorganismscanspreadandbetransmittedtohumans,animals,foodanimals,plantsandwildlifebecauseofcomplexinterconnectionsacrossnature(Grahametal.2019;LarssonandFlach2022).EnvironmentaldimensionsofAMR3EnvironmentaldimensionsofAMRarecomplex.To

101、viewtheenvironmentasasingleentityperhapsasareservoir,orintermsofruralorurbansectors,ordescribingallwaters,soilsandairasiftheirgroupingsarestaticdoesnotproperlycapturethebroader,sharedenvironmentandhoweverythingislinked(Figure4).Tounderstandthedevelopment,transmissionandspreadofAMRintheenvironment,it

102、isimperativetoviewitthroughamulti-dimensionallens.3.1 AMRdevelopmentintheenvironmentAMRisanevolutionaryphenomenonexacerbatedsincethebeginningoftheindustrialagebyhumanactivities,biologicalandchemicalpollutionsources(Rodgersetal.2019).Whenantimicrobialsarereleasedintotheenvironment,theycanselectforres

103、istantmicroorganismsand/ornewAMRcandevelop.Thismayhappenbyspontaneousmutation,acquisitionandtransmissionbymobilegeneticelements(MGE),orthroughhorizontalgenetransfer(HGT)events(Figure5)betweenenvironmentalandplant,animalorhumanassociatedbacteria(KumarandPal2018;LarssonandFlach2022).Antimicrobialresis

104、tancegenes(ARGs)areportionsofDNAthatencoderesistancetooneormoreantimicrobialcompounds(Martnez,CoqueandBaquero2015).ARGsareeitherintrinsic,developedthroughmutationsthatoccurinevolutionaryprocesses,orcanbeacquiredfromadjacentmicroorganismsinaprocessofHGT(e.g.conjugation,transductionortransformation).T

105、hegroupofallintrinsicandacquiredARGscollectivelycarriedbymicroorganismsinhabitingagivenenvironmentalniche,isreferredtoasthatenvironmentsresistome(Perry,WaglechnerandWright2016).Locationssuchasrivers,lakesandoceans,whichovertimereceivepollution,aremorelikelytoharbourmicroorganismswithARGsandMGEsthatc

106、anfuelAMRdevelopmentandprovideasourceofAMRspreadwithintheenvironment(Kristianssonetal.2011;Chen,H.etal.2019).ThemicroorganismscomprisingtheseaquaticandsedimentmicrobiomesmaybeofindigenousenvironmentaloriginthathaveevolvedAMRoverevolutionarytime(Waglechner,CulpandWright2021),ortheymayrepresentinvasiv

107、especiesofresistantmicroorganismsintroducedintotheenvironment,suchasinanimalandhumanwastestreams.6Livestock farmDomestic animalAntimicrobial productionClinical environmentAquacultureDredgingLandfillSewage or wastewater treatment plantLivestock farmContaminated feedingLivestock farmCrop productionSew

108、age or wastewater treatment plant Human airways Ingestion or direct contactDrinking and recreational waterLiquid effluents and solid wasteLiquid effluents and solid wasteManure application and storageManure application and storageDischargesDischargesDredging sedimentsLeachedDischargesRun-offDischarg

109、esConsumption productsAir emissionAir emissionDirect contactExcretionExcretionSludge/dischargeManure application and storageWaterHumansWildlifeSoilAirWildlifeWildlifeWildlifeEnvironmentWaterLivestock farmClinical environmentReferences Resistant microorganisms Antimicrobial residue Activities Environ

110、mental aspectsEnvironmental complexities in transmission and spread of AMRFigure 473 Environmental dimensions of AMR Intheenvironment,notalltransmissionnetworksandconnectionsspreadAMRequally,butinlandwatersourcesareconsideredacriticalvehicle(Fondietal.2016).Riversedimentsinthevicinityofwastewatersou

111、rces,mayincreasethepotentialforselection,co-selectionandHGT.LongercontacttimesbetweenchemicalsandwastewaterwithindigenousmicroorganismsincreasethelikelihoodofAMRselectionandtransmissionevents(Kristianssonetal.2011),althoughotherfactorssuchasthespecificenvironmentalsourcesandmicroorganisms,thatarecar

112、ryingtheARGs,alsoareimportanttoAMRfateinsuchlocations(Quintela-Balujaetal.2019;Wuetal.2022).3.1.1SelectionpressureSelection,co-selectionandcross-selectionofresistancePollutionfromhospitalandcommunitywastewater,effluentfrompharmaceuticalproduction,run-offoriginatingfromplantandanimalagricultureandoth

113、erformsofwastearefrequentlycomposedof,oraredepositedinto,nutrientrichenvironmentscontainingcomplexmixturesofchemicalsandbiologicalsubstances.Thesematricesmaycontainnotonlyresistantmicroorganisms,butalsoantimicrobials,variouspharmaceuticals,microplastics,metalsandotherchemicals.Physiochemicalproperti

114、essuchasoxygencontent,pH,nutrientavailabilityandtemperaturearealsoknowntoinfluenceAMR(Jiangetal.2022).Pollutantsintheenvironmenthaveseveralimportantramifications.Inthepresenceofselectiveagents,theevolutionaryprocessesofselection,co-selectionandcross-selectionfavourproliferationofresistantbacteria.Co

115、-selectionreferstowhenresistancetoagivenantimicrobialisselectedforbyanother,differentantimicrobialorchemical.ThishappenswhengenesconferringresistancetodifferentantimicrobialsareinthesamemicroorganismorVertical Gene TransferGenetic elementresistanceZincDisinfectantresistanceresistancePenicillinresist

116、anceCiprofl oxacinresistanceTetracyclineHorizontal Gene TransferHorizontal and Vertical Gene TransferFigure 58Bracing for Superbugs:Strengthening environmental action in the One Health response to antimicrobial resistanceDNAsegment.Cross-selectioncanoccurwhenasingleresistancemechanismconfersresistan

117、cetomultipleantimicrobialsorotherchemicals(e.g.effluxpumpsinbacteria).Also,co-regulatorymechanismscanresultinco-selectionofAMR.Manypollutantsalsoincreasetheratethatresistancegenesareexchanged(e.g.HGTfromconjugativeplasmids,transformation,andtransductionbybacteriophages)amongbacteria.Resistancetransm

118、issioncantakeplacewhentheconcentrationoftheantimicrobial(orotherchemicalagents)are10to1,000timeslowerthantheconcentrationsusedinhumanandanimalmedicineasduringclinicaltreatment(Bengtsson-PalmeandLarsson2016).Wastewatertreatmentinfrastructurecansignificantlyreduceantimicrobialsandotherco-selectingchem

119、icalsineffluent(Murrayetal.2020),andiskeytoenvironmentalpollutionmanagement.However,theconcentrationofantimicrobialsandotherselectiveagentspresentinsewage,evenwhendiluted,mayexceedpredictednoeffectconcentrations(PNECs)forresistancedevelopmentinaquaticenvironments(Haennietal.2022;Bengtsson-PalmeandLa

120、rsson2016).Environmentalriskassessments,thattakeintoconsiderationthelikelihoodforresistancedevelopmentandseekconsolidationofterminology,havebeensuggested(Murrayetal.2021).Althoughfurtherfieldvalidationisneededtodetermineminimalselectiveconcentrations(MSCs)andtoevaluatehowwellPNECvaluesreflectthepote

121、ntialforAMRdevelopmentandtransmissioninenvironmentalmedia(e.g.waterandsoil).Inconsideringantimicrobialresiduesandfood,theJointFAO/WHOExpertCommitteeonFoodAdditives(JECFA)hasrecommendedmaximumresiduelimits(MRLs)ofantimicrobialsinfoodsofanimalorigintoprovideanacceptabledailyintake(ADI)thatconsidersnot

122、onlytoxicity,butforsomeagentsamicrobiologicalADIforthelikelihoodofdevelopmentofAMRinthehumangutmicrobiome,usingamodelthatisbasedonconcentrationsofantimicrobialsthatareknownasminimallyinhibitoryconcentrations(MIC)(CodexAlimentarius2021).Currently,someMRLsforantibiotic Quaternary disinfectant1Certain

123、microorganisms have resistance genes.2When antimicrobials are present,they create a competitive advantage and“select”for resistant microorganisms.3The antimicrobial-resistant microorganisms multiply.Selection pressure and antimicrobial resistance(United States Centers for Disease Control and Prevent

124、ion US CDC n.d.)Figure 693 Environmental dimensions of AMR residuesinfood,recommendedbyJECFAandadoptedbyCodex,canselectforresistantbacteria.Therehasbeenacademicdiscussionontheneedtore-evaluatetheselimitssothattheyinsteadconsiderMSCsofantimicrobials(Subirats,DominquesandTopp2019),whichisamoreconserva

125、tivemeasurement.ThisisbecausewhenconcentrationsofantimicrobialresiduesexceedtheMSCs,thenselectionforresistancemayoccur.TheseconcentrationsmaybebelowtheestablishedMRLsthathavebeenmostlyestablishedtopreventanallergicresponseortoxicity(AnderssonandHughes2017).Likewise,iftheingestionofcontaminatedfoodre

126、sultsinaconcentrationofantimicrobialwhichexceedstheMSCs,selectionforresistancemayoccurinthehumangutmicrobiome.Whenquaternaryammoniumcompounds,otherbiocidesandsomeheavymetals(e.g.zincandcopper)arefoundinwastestreams,theycanhaveadverseeffectsonaquaticandterrestrialspecies.Thesechemicalscancreateaco-se

127、lectivepressurewhenbacterialspecieshavemultiplegenesthatconferresistancetotheseagentsandotherantimicrobials(WalesandDavies2015).Whentheresistancegenesco-occurinthesamemicroorganisms,thepresenceofoneagentmayco-selectforresistanceoftheother,eveninitsabsence(Paletal.2015).Thus,oneantimicrobialcanco-sel

128、ectforresistancetootherantimicrobials,whichiscommonlyseeninenvironmentalsystems.Forexample,zincandcopperareusedextensivelyassupplementsinanimalfeedfornutritionalpurposesanddiseasecontrolandthismayselectforimprovedenvironmentalsurvivalofdrug-resistantbacteriainenvironmentscontainingmetalssuchasintheg

129、astrointestinaltractofanimalsfedtheseelements(Bearsonetal.2020).Theuseofdisinfectantsinhealthcarefacilitiesandfoodanimalproductioniswidespread.Sublethalconcentrationsofdisinfectants(e.g.chlorine,chloramineandhydrogenperoxide)canpromotetheexchangeofARGsbetweenbacteria(Zhangetal.2017).Furtherresearchi

130、sneededtobetterunderstandthesignificanceofdisinfectantsandbacterialresponsegoverningthisphenomenon.Inanagriculturalcontext,herbicideusetocontrolweedsinagriculturemayenrichARGsandMGEsbyalteringsoilmicrobiomesandmaycontributetofurtherAMRdevelopmentinagriculturalenvironments(Li etal.2022;Liaoetal.2021)

131、.Microplasticsalsoposeaproblem,astheyharbourresistantmicroorganisms(Liuetal.2021;Bartkovaetal.2021;Kauretal.2022).Useofplasticsinagriculturesettingscreatesmicroplasticpollutionofsoils(Heetal.2018)andisconcerningbecausecurrentusesareunsustainable(FAO2021a).Whenmicroplasticsarefoundinwaterthereisaninc

132、reaseingenetransferfrequencyinbacteriaattachedtotheplasticsurface(Arias-Andresetal.2018).MicroplasticspollutingriversshowthaturbansettingsarecorrelatedwithincreasedabundanceanddisseminationofARGs,andthatpolypropyleneismoreassociatedwithAMRacquisitionandspread(Lietal.2021).Resistantmicroorganismsonmi

133、croplastics,foundinwastewatertreatmentplants(WWTPs),water,soilandairhavebeenstudiedtounderstandthemechanismsanddynamicsoftransportandtransferofresistantmicroorganismsharbouredinbiofilms(Piergiacomo,BrusettiandPagani2022).However,mostliteratureinvestigatingenvironmentaltransportandtransferofAMRwithmi

134、croplasticsdescribesstudiesinacontrolledlaboratorysettingandthereisaneedtobetterunderstandtheprocessesinmorecomplexenvironmentalmediaandmatrices(Liuetal.2021).Asnaturalenvironmentsnormallycontaincomplexchemicalmixturesresultingindifferentselectivepressures,afuturechallengewillbetodeterminethefrequen

135、cyandtheeffectsofsuchinteractionstoassessanenvironmentsselectivepotentialmorecomprehensively(ONeill2016).Animportant,butdifficulttask,mightincludethere-evaluationandharmonisationofdataandterminologyforseveralsafetymeasures.TheseincludemicrobialsafetylimitsfortheenvironmenttoconsiderAMR,MRLssetforant

136、ibioticsinfoodandestablishedPNECsforresistancedevelopmentinaquaticenvironment,andtoalsoincludemeasuresforassessingriskofAMRdevelopmentinsoilandotherenvironmentalmedia(LePageetal.2017).Furthermore,bothenvironmentalrisksofresistancedevelopmentandecotoxicityneedtobeassessed.Theroleofindividualbioactive

137、andmixturesofchemicalsindiffuseandpointsourcedischargesshouldbeevaluatedinthecontextofenvironmentalriskassessments.Thepharmaceuticalmanufacturingindustryhasbegunthiskindofapproachinestablishingvoluntarydischarge10Bracing for Superbugs:Strengthening environmental action in the One Health response to

138、antimicrobial resistancestandards(Tell etal.2019).Additionally,moreresearchintothegender-andage-differentiatedimpactsoftheseindividualchemicalsandmixturesofchemicalsisrequired(StrategicApproachtoInternationalChemicalsManagementSAICM2018).AntimicrobialuseandenvironmentalpollutionAmajorpublichealthcha

139、llengeistheextremelycontext-dependenteffectofantimicrobialpollution(Danneretal.2019).Antimicrobialagentsarewidelyusedinhumanmedicine,aquaculture,livestockandcropproduction,andarealsoputintothefeedandwateroffoodanimals.Theyareexcretedinsignificantquantitiesintotheenvironmentasactivemolecules,orpartia

140、llydegraded,fromvarioussources.Theconcentrationofantimicrobialsexcretedunmetabolizedinthefaecesandurineofhumansandanimalsishighlyvariableandisdependentupontheantimicrobialdrugclass,formulation,therouteofadministration,animalspeciesandhealthstatus(KmmererandHenninger2003;Gigure,PrescottandDowling2013

141、).Whereprovisionofwastewatertreatmentisnotadequate,closecontactwithpollutedwaterscanresultinaconsumption-excretioncycle(WEF2021).Theconsumption-excretioncycleoccurswhencontainment,controlsorbarriersforthesepollutantsarelacking,suchaspitlatrineswithoutconfiningbarriers,orwheninadequatelytreatedoruntr

142、eatedwastewaterisusedtoirrigatefarmland,oranimalmanureorhumanwasteisusedtofertilizecrops.ThisresultsinfunctionalantimicrobialsenteringtheenvironmentunlesswastemanagementmeasurestoaddressAMRdevelopmentandspreadareapplied.SuchreleasestransmitantimicrobialresistantmicroorganismsandARGs,whichcanconditio

143、nallypromoteAMR,intotheenvironment(Bengtsson-Palme,KristianssonandLarsson2018;Brgmannetal.2018;Karkman,PrnnenandLarsson,2019;Berendesetal.2020).Environmentalreleasescanalsooccurwhenunusedorexpiredantimicrobialsarenotproperlydisposed(e.g.take-backprogrammes)(Bashaaretal.2017;Nepaletal.2020).Atechnica

144、lreportwaspreparedfortheWorldEconomicForum(VividEconomics2020)assessingthecostsandrisksofwaterpollutionglobally.Itgatheredavailabledataonemissionsfromclinicaluseofantimicrobials,agriculturaluses,aswellasantimicrobialmanufacturing.Thesemeasurescombinedmakeuppartofameasuredscoreforpollutionemittedinto

145、water.Ashavingwastewatertreatmentinfrastructuresinplacecanreduceenvironmentalpollution,thisalsofactorsintoacountrysoverallpollutionscore.Therefore,apollutionscorecanbedeterminedbycombiningwaterdischargesourcesagainstconnectionstoPollution score(0 100)Missing 02 213 1320 2026 2653Estimated global env

146、ironmental water contamination and pollution from antimicrobials(Vivid Economics 2020)Figure 7113 Environmental dimensions of AMR availablewastewatertreatmentinfrastructure(Figure7).Regionswithhigherscoresindicatethereareopportunitiesforfurtherpollutionmanagement.Wastewaterfromdifferentgeographicreg

147、ionshascomparativelydifferentAMRburdenandgeneprofiles;withAfricaandSouthAmericahavingthehighestpercapitalevelsintheirwastewater,andEuropeandOceaniahavingtheleast(Hendriksenetal.2019;Munketal.2022).SuchregionalvariationsinAMRarebestexplainedbyantimicrobialusage,microbialdiversityandanthropologicfacto

148、rs,suchastheextentofsanitationinfrastructureandavailabilityofqualityhealthcare(Collignonetal.2018).Collectively,chemicalpollutantscaninfluencetheselectionofARGsintheenvironmentandaltertherelativeabundanceofresistantpathogensofhuman,plantsandanimals(KumarandPal2018).Pollutionbychemicalswithantimicrob

149、ialactivity(e.g.pharmaceuticals,certainmetals,biocidesandothercompounds)mayinfluencethegeneticmobilisationofARGsincertainmicroorganismsorenhanceAMRinmicroorganismsintheenvironment(Murrayetal.2021),althoughtherelativeimportanceofsuchdriverstoactualAMRselectionisuncertain.Factorsthatinfluencethemagnit

150、udeofeffectsofantimicrobialpollutiononenvironmentalAMRincludethephysicalandchemicalpropertiesofanantimicrobial(i.e.antimicrobialdrugclass)andtheamount(i.e.concentration),thepresenceofotherantimicrobialsand/orcontaminants,thedurationofexposureandthephysio-chemicalpropertiesofenvironmentalmedia(e.g.wa

151、terorsoil)(Almakkietal.2019).Inaddition,thepotentialforantimicrobialstoselectforAMRatenvironmentallyrelevantconcentrationsvariesdramatically(Bengtsson-PalmeandLarsson2016;Stantonetal.2020).Antimicrobialshavebeendetectedinwaterbodiesandotherlandscapesatconcentrationsthatcanprovideselectionpressurefor

152、AMRdevelopment(Haennietal.2022).Insomerarecasesthedetectedconcentrationsaregreaterthanthetherapeuticbloodconcentrationsusedtotreatdiseases(Kristianssonetal.2011;Bracketal.2022;Wilkinsonetal.2022).3.2 AMRandthetripleplanetarycrisisAMRchallengescannotbeunderstoodoraddressedseparatelyfromthetripleplane

153、tarycrisisofclimatechange,biodiversitylossandpollutionandwastebecausetheyarealldrivenbyunsustainableconsumptionandproductionpatterns(Cavicchiolietal.2019;UN2022).Fuelledbypopulationgrowth,urbanizationandgrowingdemandforfoodandhealthcare,wecanexpectanincreaseintheuseofantimicrobialsandinpollutantrele

154、asesintotheenvironment.Unsustainableconsumptionandproductionpatternsareofparticularconcerntoagri-foodsystems,butalsoothersectorssuchaschemicals,includingantimicrobials,whichasnotedabovearenowinjeopardyoflosingtheireffectiveness.3.2.1ClimatechangeTheclimatecrisishasnumerousimpactsonecosystems,humanhe

155、alth,animalhealthandfoodproduction,whichalsoaffectAMR(GlobalLeadersGroupGLGonAMR2021a).Highertemperaturescanbeassociatedwithincreasedfrequencyofhorizontalgenetransfer,especiallythoseassociatedwithconjugation(LermanandTolmach1957;Kim,KimandKathariou2008;Veggeetal.2012),aswellasanincreaseinantimicrobi

156、alresistantinfections(MacFaddenetal.2018;McGoughetal.2020;PepiandFocardi2021).TheclimatecrisisalsocontributestotheemergenceandspreadofAMRintheenvironmentduetothecontinuingdisruptionoftheenvironmentduetoextremeweatherpatterns(Burnham2021).Additionally,thefrequency,compositionandamountsofpollutioncont

157、ainingbioticandabioticagentsmaybeincreasingduetotheclimatecrisis.Temperature,oxygenandcarbondioxideconcentrationsintheenvironmentcanalsoinfluencethesurvivalandproliferationofbacteria,andtherateatwhichtheyacquireresistance(Liao,ChenandHuang2019;Gupta,LaskarandKadouri2016;Jongetal.2020).12Bracing for

158、Superbugs:Strengthening environmental action in the One Health response to antimicrobial resistanceAntimicrobialimpactsonmicrobialbiodiversitymayinturnaffectbiogeochemicalcyclessuchasthecarbonandmethanecycles,whicharedirectlyinvolvedinregulatingearthsclimate(Bollingeret al.2021).3.2.2Biodiversitylos

159、sHumanactivityandclimatechangehavealteredsoilmicrobialdiversityinrecentdecades,whichmayalsopromotethecirculationofantibioticresistancegenesintheenvironment(ZhuandPenuelas2020).Naturalmicrobialcommunitiesprovideimportantecosystemfunctions,andtheecotoxicologicaleffectsofantimicrobialsonenvironmentalmi

160、crobiomesmayalsoimpactbroaderecosystemservicessuchasthoserelatedtobiogeochemicalcyclesandplanthealth(Brandtetal.2015).Eventreatingcattlewithcertainantibioticschangesdungbeetlemicroflora,whichcaninterrupttheessentialecosystemservicethatdungbeetlesprovide(Hammeretal.2016).Biodiversityandfullyfunctiona

161、lecosystemsarecriticalforplanetaryhealth,andantimicrobialspotentiallythreatenthehealthofecosystems(Grenni,AnconaandBarraCaracciolo2018;Banerjietal.2019).HighmicrobialdiversitycanactasabiologicalbarriertoresistthespreadofAMR(Chen,Q.etal.2019);conversely,antimicrobialusecanthreatentodiminishmicrobiald

162、iversity(Chen,J.etal.2019),andmicrobiologicalbiodiversitypreservationisessentialtomaintainadiversemolecularreservoirforfuturepharmaceuticaldiscovery.Microbesinhabitingnaturalenvironmentshavelongbeen,andwillcontinuetobe,sourcesofpharmaceuticaldiscoveryforwellness,diseasepreventionandhealthcareuse(Nee

163、rgheen-Bhujunetal.2017).Sincesoilbiotaisanessentialcomponentofplanetaryhealth(Zhuetal.2019;ZhuandPenuelas2020),maintainingsoilmicrobialdiversityandidentifyingtheforcesthatshapesoilmicrobialdiversityiscrucialinpreservingthissoil-bornelegacy(Neergheen-Bhujunetal.2017;ZhuandPenuelas2020).Shiftsinmicrob

164、ialdiversityinnaturalhabitatsareabioindicatorofchangeinecosystemfunctions(Grenni,AnconaandBarraCaracciolo2018;Jrgensenetal.2018;Banerjietal.2019).Humanactivities,suchasthegenerationofwastewater,elevateARGsinaffectedenvironments,butfewstudieshaveexaminedhowthemicrobescarryingtheseARGspersistandintera

165、ctwithothermicrobialspeciesintheirsurroundings(Rodriguez-Mozazetal.2015;Bengtsson-Palme,KristianssonandLarsson2018;Smallaetal.2018;Banerjietal.2019).Whiletheimpactstoecosystemservicesandbiodiversitylossfromantimicrobialuseandpollutionarebeingbetterelucidated,thereremainsverylimitedevidenceforacausal

166、linkbetweenAMRandimpactstobiodiversityloss.3.2.3PollutionandwasteAntimicrobial resistance genes are increasingly recognizedasemergingcontaminants,withthemagnitudeoftheiroccurrencecorrelatingwithanthropogenicinputs(Prudenetal.2006;Sandersonetal.2016;UNEP2017),andcontaminatedFlooding contributes to th

167、e spread of AMR in the environment Kafeel Ahmed133 Environmental dimensions of AMR environmentscanbecomesourcesofAMR.OfparticularconcernisthereleaseofbiologicalAMRpollutantsoriginatingfromdischargesofbothtreatedanduntreatedhumanandanimalexcretaintotheenvironment.Dischargesofchemicalwastes,includingf

168、rompharmaceuticalmanufacturinganddisposalofunusedandexpiredantimicrobials,addtopollutionconcerns.3.3 AMRtransmissionandspreadintheenvironmentResistantmicroorganismsarefoundinhumans,animals,plantsandtheenvironment(inwater,sewage,soilandair),andspreadcanoccurfromallthesemedia(Fergusonetal.2016;Priceet

169、al.2017;Hernando-Amadoetal.2019).Environmentalmediatransmitandspreadantimicrobialresistantmicroorganismswithinandbetweenhumans,animalsandenvironment(Baqueroetal.2019;Hernando-Amadoetal.2019).Thepresenceandrelativeabundanceofspecificresistantandsusceptiblemicroorganisms,particularlyindomesticwastewat

170、er,canindicatewhatiscirculatinginsociety,includinginhealthcarefacilities(Prudenetal.2021).Identifiedsourcesofresistantmicroorganisms,genesandantimicrobialsinitiatetheirspreadfromspecificorrelativelylocalpointsofrelease.However,theactualpathofAMRspreadincludesplaceswithintheenvironmentthattemporarily

171、harbourAMR,whichcanthenbetransmittedonwardstohumansoranimals(Figure8).SuchlocationsaretransientorconditionalsourcesofAMRandareofteninfluencedbyhydrologicalandanthropogeniceventsintheenvironment.HumanexposuretoAMRcanalsotakeplacefollowingconsumptionoffoodthathasbecomecontaminatedwithresistantmicroorg

172、anismsfromtheproductionenvironment,foodanimalmicrobiomesortheprocessingenvironments,orwhenwatercontaminatedwithfaecalmatterisingested(Hlzel,TetensandSchwaiger2018;Leonardetal.2018;FAOandWHO2019;Koutsoumanisetal.2021).Whenwastewatertreatmentandwastemanagementisinsufficient,therearehigherexposuresandg

173、reaterchancesRivers,lakes and sediment can be transient sources of AMR Matthew Montrone14Bracing for Superbugs:Strengthening environmental action in the One Health response to antimicrobial resistanceforspread(Brgmannetal.2018).Inlow-resourcesettings,clinicallyimportantmultidrugresistantbacteriaareo

174、ftenwidespreadintheenvironment,increasingtheprobabilityofAMRtransmissionbetweenhumansandanimals(Iskandaretal.2020).ExactlyhowbacteriaandothermicroorganismsacquireARGsandthespecifictransmissionroutesaredifficulttotrace,butspreadinwatersystemsseemstoplayanimportantroleinbothprocesses(Baquero,Martnezan

175、dCantn2008;Lupo,CoyneandBerendonk2012;Fondi2016).3.3.1TransientanddiffusespreadofAMRintheenvironmentThetransmissionandspreadofAMRarenotconfinedtopoint-sources,suchaswastewateremittedfromapipeoragri-foodsystemdrainageoutlets.Diffuseornon-pointsourcepollutioncanalsobeimportantbecauseitisoftenanunbound

176、edphenomenonthatcanoverlapacrossecologicalscales.Transientanddiffusesourcesincluderivers,lakesandsediments,overflows,agriculturalrunoff,soil,airbornetransmissionandwildlifemigration.Globalization,internationaltradeandmigrationofbothpeopleand Resistant microbes spread to other people through poor san

177、itation and hygiene,and close proximityResistant microbes spread to humans and other animals through contaminated food,close proximity and poor hygieneResistant microbes spread from the environment to plants,humans,other animals and wildlife.Global transmission can occur through travelPollution from

178、 pharmaceutical manufacturing,food production,community and healthcare settings spreads resistant microbes to our shared environmentThe more we use antimicrobials,the more chance microbes have to become resistant to themAntimicrobial resistance is the inherited or acquired ability of microorganisms

179、to survive or proliferate at concentrations of an antimicrobial that would otherwise kill or inhibit themAntimicrobials used in food productionAntimicrobials used in hospital and community settingsHow antimicrobial resistance can spread(adapted from Australia,Department of Health and Aged Care 2017)

180、Figure 8153 Environmental dimensions of AMR wildlifemakesitimportanttoconsidernon-pointspreadofAMRbecauseitoccursirrespectiveofborders.Waterrivers,lakesandsedimentsRiverandlakesedimentscanbeatransientsourceofAMR(Prudenetal.2006)thatreadilyaccumulatesresistantmicroorganismsandgenes,MGEsandchemicalpol

181、lutantsthathavebeendepositedintransit(LuandLu2020).SuchdepositionmakessuchlocationsnewsourcesforAMRspread,whichcanhavedifferentresistantmicrobialhoststhanoriginalsources,havingtransformedduringtransit.SedimentisalsoalocationwhereinsituAMRevolutionandtransmissioncanoccur.Sedimentscanbepseudo-staticfo

182、rlongperiods,slowlyaccumulatingAMRfromwastewaterandotherreleases.However,theybecomesourcesduringextremeweatherevents,andremobiliseAMRenmasseintothewiderenvironment.AstudyoftheCache-LaPoudreRiver,whichemanatesfromapristineoriginintheRockyMountains,wasthefirsttodemonstrateagradientinmagnitudesofARGsin

183、waterandsedimentasthereweremoreWWTPsandagriculturalrunoffinputstotheriver(Prudenetal.2006).StudiesontheAlmendaresRiverinCubashowedthatalthoughuntreatedwastewaterreleasesoccuryear-roundandaccumulatenearwasteoutfallsinthedryseason(Grahametal.2011),over98percentofassociatedARGsaretransporteddownstreamd

184、uringthewetseason(Knappetal.2012).Similarphenomenahavebeenseeninotherlocations,includingtheGanges,wherethesummermonsoonwashesaccumulatedsedimentwithresistant microorganisms and genes downstream(Ahammadetal.2014).Similareffectswereseeninariver-lakecontinuuminChinawhereARGsindownstreamlakesedimentsres

185、embledupstreamriversediments,suggestingAMRspreadwithsedimenttransport(Chenetal.2020).Thegeneticsignature(ARGs)inriversedimentsresembledupstreamwastewatersources,implyingharbouredAMRoriginatedfromhumanwastesourcestotheriverandthenthelake,probablyinaseriesofsteps.Notably,ARGconcentrationsdidnotincreas

186、eduringsedimenttransport,althoughAMRdiversitydidincrease,implyingminimalinsitumicrobialgrowth,butincreasedAMRpotentiationofARGsbetweenhumanandenvironmentalmicroorganisms.AcatchmentscalestudyintheRiverThamesshowedstrong associations between wastewater treatment plantsandtheprevalenceofAMRinsediments,

187、withtheproximityto,sizeandtypeoftreatmentplantbeingthemostsignificantpredictorofAMRlevelsinsediments(Amos etal.2015).Combinedseweroverflowsspreadtreatedanduntreatedwasteintotheenvironment.Untreatedwastewatercontainsdiverseandelevatedconcentrationsofresistantmicroorganismsandgenes.Inplaceswithwastewa

188、tercollectionnetworks(i.e.sewersordrains),thewastewaterflowsinpipesorchannelstoWWTPsorreceivingenvironmentsincombinedorsanitarysewers.Sanitarysewersonlytransportwastewater,whereascombinedsewerdrainsreceivebothwastewaterandsurfacerunoff,whichmeansflowratescanvarywidelydependingonprecipitationevents(N

189、appieretal.2020).CombinedflowscansometimesexceedthedesigncapacityofsewersandimpairWWTPoperations.Asaresult,combinedsewershaveoutfallsthatreleaseblendedbutuntreatedwastewaterduringmajorweatherevents(UnitedStatesEnvironmentalProtectionAgency2019;Dittmer,Bachmann-MachnikandLaunay2020).Combinedsewerover

190、flowsexistaroundtheworldandmaybeasignificantsourceforenvironmentalAMRincountriesofallincomelevelsbecausetheyessentiallyaresourcesofrawsewageenteringtheenvironment(i.e.bypassingwastewatertreatmentsystems)(Hondaetal.2020).Unplannedoverflowsofsewers,oropendrainsduringprecipitationevents,canresultinwast

191、ewaterflooding,whichcanbemostdramaticinplaceswithlimitedinfrastructure(Figure9).Suchreleasescanalsoresultinuntreatedwastewaterleachingintogroundwater,wellsandwatersources,especiallyifthesewersordrainsarepoorlymaintained(Pauletal.2004).Inmanycases,combinedseweroverflowsaredesignedtobypassWWTPsresulti

192、nginflowscontainingabundantresistantmicroorganismsandresistance genes entering downstream receiving waters.TheeffectsofcombinedseweroverflowsaresometimesmisconstruedasbeingfromtheWWTP16Bracing for Superbugs:Strengthening environmental action in the One Health response to antimicrobial resistanceitse

193、lf(Quintela-Balujaetal.2019),whereaselevatedresistantmicroorganismsandARGlevelsmaybelegaciesfrompreviouscombinedseweroverflowevents.Asanexample,resistantE.coliabundancescanbe5,000timesgreaterincombinedseweroverflowthaninWWTPreleases(Hondaetal.2020).Combinedseweroverflowsareespeciallydifficulttomonit

194、orasAMRsourcesbecausetheyaredrivenbylocalweathereventsandlandscapes.Arecentstudyonurbanstormwater,whichlookedspecificallyatARGsandMGEs,andmetagenomicstocharacteriseresistomes,foundAMRwithinstormwaterwashighlyvariablebetweenstormsandlocations,andelevatedduringstormevents(Garneretal.2017).Sedimentalso

195、fuelsAMRspreadduringmajorweatherevents,suchasflooding,whichisexemplifiedbytheconsequencesofHurricaneMariainPuertoRico(Davisetal.2020).HumanfaecalandgeneticanthropogenicAMRmarkerswerequantifiedinthreewatershedssixmonthsafterthehurricane,andrelativeARGabundancesanddiversityincreaseddownstreamofallimpa

196、ctedsites,probablyduetoflooding.AlthoughcombinedseweroverflowscannotbedirectlylinkedtosomeenvironmentAMRexposureCombined sewer overflow(during storm events)To waste water treatment plantOverwhelmed sewers emit raw sewage into urban streetsPlastic pollution harbours resistant microbesLarge fluxes of

197、resistant microbes and selective agents during storm eventsLandfillLandfill leachates are a part of urban water cycleRecreational water use instigates direct ingestion and transmission of resistant microbesSurface water used as drinking water and food source in informal settlementsInformal settlemen

198、tsDrinking water plantAMR Spread from flooding and urban storm runoff Figure 9173 Environmental dimensions of AMR scenarios,theymightpartiallyexplainobservations,suchaselevatedlevelsofcephalosporin-resistantE.coli inEnglishandWelshcoastalsurfacewaters(Leonard etal.2015).Therewasevidenceofincreasedco

199、lonisationbyresistantstrainsinfrequentrecreationalwaterusersthatsuggestswastewaterreleasescantranslateintocarriageofAMRstrainsinexposedpeople(Leonardetal.2018),whichagainmaybeinpartduetocombinedsewageoverflowswithincatchments,whicharecommonintheUnitedKingdom.Thisexampleshowsthatwastewaterreleasesinf

200、luenceAMRinexposedindividuals,butdelineatingtherootcause,i.e.routinewastewatertreatmentplantreleasesversuscombinedseweroverflows,isacriticalknowledgegap.SoilsAnothertransientsourceofAMRissoil,yetnotasphysicallymobileasourceaswater.Nevertheless,soilisanalogoustoasediment,asitharboursARGsandcanactasat

201、ransientsourceofAMRspread.SoilsretaintheirpreviousexposurehistorytopollutantsandAMR.Certainpollutantsareretainedandothersnot,dependinguponthesoilitself,water(e.g.leaching)andair(e.g.wind)circulation.Soilsassourcesareespeciallyimportantrelativetoagriculturalpracticesandlocationswheresolidorindustrial

202、wasteshavebeenplaced(Manyi-Lohetal.2018),orwhereantimicrobialsorotherbioactivecompoundshavebeenemployedareimportanttoconsider.Thisincludeslegacyindustrialanddisposallocations,whereARGshavebeennotedinestuarinesediments(Rodgersetal.2019).AirbornetransmissionThepotentialforairborneexposureisalsogaining

203、attentionandisincreasinglyrecognizedasanenvironmentaltransmissionpathway(Chen,KumariandAchal2020).AirisaparticularlydynamicmediumthatcanallowthetransmissionandspreadofAMR(Jinetal.2021;Kormosetal.2022).TransientairbornespreadofAMRcanoccuratdifferentscales,rangingfromseasonalandinternationaltoincident

204、alandlocal,andincludebacterial,fungalandviralpathogens.ARGsandresistantbacteriaarepresentinbiologicalaerosolsfromwindbornedust,watervapourfromwastewatertreatmentplantsandlandfills(Miakiewicz-PskaandSzyak-Szydowski2015;Breza-Boruta2016;Behzad,MinetaandGojobori2018;Kraemer,Ramachandran,andPerron2019;L

205、i,L.etal.2020).Thesemovementscanbeexacerbatedbyairpollutionandclimatechangeimpacts,particularlysevereweathereventsandwildfires(Kobziaretal.2018).Atmosphericparticulatematter,whichcomesfrommanysources,hasbeenshowntocarryAMRKlebsiellaandAeromonasstrains,especiallyatwarmertemperatures(Zhangetal.2021).I

206、naHongKongstudy,themajorityofARGsassociatedwithairborneparticulatesintheinhalablerange(PM2.5)wereassociatedwithWWTPsources(Xieetal.2022).SimilarobservationshavebeenmadeforvariousARGsandresistantpathogensondustparticlesandaerosols,usingmetagenomic,high-throughputqPCRandothermethods.Scenariosincludein

207、doordustinbuildings(BenMaamaretal.2020),regionalduststorms(Gat etal.2017),globalurbanairquality(Li,J.etal.2018)andfoodanimalproductionoperations(DaviesandWales2019).Dust-associatedmethicillin-resistantStaphylococcus aureus(MRSA)hasbeendetecteddownwindofswineproductionfacilities(Fergusonetal.2016).Pr

208、oximitytoswineproductionandMRSAinfectionhasalsobeenshowntobeassociated(Beresinetal.2017).Anotherexampleisthetransportofantifungal-resistantstrainsofPhakopsora pachyrhizi,thecausativeagentofsoybeanrust,oneofthemosteconomicallydevastatingfungaldiseasesofsoybeans(Furlan,CarvalhoandAntuniassi2018).Theex

209、tentofmicrobialspreaddependsupondilution,dispersionandmixing,andprimarymodesoftransmission,bacterialsurvivalindifferentenvironments,probabilityofcolonisationandinfectivedoses,whichdiffersamongbacterialpathogensandhosts(Zhaietal.2018).ThereisaneedtoaddressknowledgegapssurroundingairborneAMRtransmissi

210、onandspreadespeciallygivenitstransientnatureandassociationwithrelativelevelsofventilationandweatherandclimaticconditions.TherelativeimpactofairbornetransmissionandspreadofAMRtohuman,animalsandplantsisaOneHealthissuethatdeservesmoreresearchfocus(Jinetal.2021).Airqualitystandardscouldbefurtherdevelope

211、dtoconsiderARGs,whichmaybetterprotectpublichealth(Li etal.2018).18Bracing for Superbugs:Strengthening environmental action in the One Health response to antimicrobial resistanceWildlifeInparalleltothelossofnaturallandscapes,increasinglivestockandhumanpopulationdensitieshavebeensuggestedasimportantdr

212、iversforAMRtransmissionandcarriageinexposedwildlife.Birds,smallmammalsandinsectsarefrequentcarriersofresistantmicroorganisms(ZurekandGhosh2014;Hoetal.2015;Furnessetal.2017;Rogersetal.2018;Onwugambaetal.2020;Ahlstrometal.2021).SomeofthemainsourcesofAMRtransmissiontowildlifeincludelandfills,insufficie

213、ntlytreatedwastewatersdrainingintoriversandlakesthatthenaffectaquaticspecies,aswellaswastefromintensivelymanagedlivestockfarms(DolejskaandPapagiannitsis2018;seeFigure10).Landfillsalsoprovideaccessible,consistentandnearlylimitlessfoodsourcesforscavenginganimals.Gulls,storksandsmallmammalsfeedingonWil

214、dlifeSewage CitiesCompanion animals Livestock animals ManureLandfillsWastewaterPlants Transmission and spread of AMR to and from wildlife(adapted from Dolejska and Papagiannitsis 2018;reprinted with permission from Elsevier)Figure 10193 Environmental dimensions of AMR landfillshavebeenidentifiedtoca

215、rryantimicrobialresistantbacteriaincludingthosewithsignificantclinicalimportance(Allenetal.2011;Ahlstrometal.2018;Martn-Maldonadoetal.2020).However,AMRspreadviawildlifeisnotexclusivetospecificanthropogenicsettings.Atlocalandregionalscales,wildanimalsfrequentlyresidenearanimaloperations,pastures,urba

216、nenvironmentsandreservoirsofdrinkingorrecreationalwaters,andinthiswaytransmitAMRbacktohumans,plantsandanimals(Arnold,WilliamsandBennet2016).Globally,seasonalmigrationofwildlife,especiallywildbirdsthatarecapableoflong-rangetravel,representanimportantpathwayforthetransmissionofinfectiousdiseasesinclud

217、ingfromresistantpathogens(Reedetal.2003).BirdmigrationhascontributedtotheglobalspreadofAMRinwayssimilartointernationaltourism.MassmigratorypatternsofwildlifeallowthespreadofresistantorganismsfromtheregionswithhighlevelsofenvironmentalAMRcontaminationtoregionswithevenprudentAMRstewardship.Forexample,

218、thefirstreportedoccurrenceofcarbapenemase-producingbacteria(NDM-1enzymeinSalmonella enterica)inawildanimalwereisolatedfromblackkites(Milvusmigrans)inGermanyin2013(Fischeretal.2013).Migratingbirds,becauseoflong-rangemovements,canspreadresistanceglobally(DolejskaandLiterak2019).Forexample,blackkitesse

219、asonallymigratebetweenEuropeandAfricabywayoftheBalkanStateswhereNDM-1producingbacteriaarecommon(Nordmannetal.2011).Clinicallyrelevantresistance,suchasproductionofextendedspectrumbeta-lactamases(ESBL),AmpCcephalosporinases,carbapenemasesandcolistin-associatedresistance,havenowbeenisolatedfrommigrator

220、ybirdsfromaroundtheworld(Guentheretal.2012;Guentheretal.2017;Wang,J.etal.2017).TherehasshowntobeanincreasedriskofAMRcarriageinwater-associatedspecies,suchasmallards,thatcommonlyforagedownstreamofWWTPsordirectlyonpartiallytreatedwastewaterlagoons(Coleetal.2005;Hessmanetal.2018).AntibioticresistantE.c

221、oliwithhighlysimilargenomicprofileshavebeendetectedinwildbirdsandwastewater,suggestingtheirpotentialroleinthespreadofAMR(Varelaetal.2015).UrbanrodentsindomesticwastewatersystemsalsofrequentlycarryAMR(Swiftetal.2019).Black Sea/Mediterranean flywayEast Asian-Australasian flywayPacific Americas flywayC

222、entral Asian flywayWest Pacific flywayEast Atlantic flywayMississippi Americas flywayWest Asian-East African flywayAtlantic Americas flywayMigration of wildlife transmission pathway(East Asian-Australasian Flyway Partnership Secretariat n.d.)Figure 1120Bracing for Superbugs:Strengthening environment

223、al action in the One Health response to antimicrobial resistanceFarmsites(water,soil,feeds,wastewater,sewage,lagoon,manureandtreatedsludge)serveaskeypointsforpotentialAMRpollution.Wildanimalscaneasilypickupbacterialpathogensandantimicrobialresistantbacteriawhenmovingandfeedinginthefarmenvironmentors

224、urroundingcontaminatedareasincludingfertilizedfields.Antimicrobialresistantbacteriahavebeenreportedindifferentgroupsoffarm-associatedanimals,includinginsects(Literaketal.2009;Poudeletal.2019),poultry(Wang,Y.etal.2017)andmammals(Nhungetal.2015).Forexample,smallwildmammalslivingonfarmsorintheirvicinit

225、ywerefoundseveraltimesmorelikelytocarryE.coli isolateswithtetracyclineresistancedeterminantsandmultidrugresistancestrainsthananimalslivinginnaturalareas(Kozaketal.2009).ManagementoflivestockwasteisthereforecrucialtolimittransmissionofAMRtowildlifepopulations.Togainadeeperandmorecomprehensiveinsighti

226、ntotheresistomescarriedbywildlifemicrobiota,laboratoryapproaches,suchasqPCRormetagenomicsexistbutneedtobeappliedinastandardizedmannertoimprovecomparabilityofdata(Martinyetal.2011;Marcelinoetal.2019;Milleretal.2020;Skaryskaetal.2020;Huetal.2021).Futureresearchshouldfocusmoreonthehuman-animal-environm

227、entinterfacetoclearlyidentifysourcesofAMRtransmissionpathwaysinvolvingwildlife.Manyofthestrategiestoprevent,prepareandrespondtopandemicshaveco-benefitstotheactionstoaddressAMR.CombiningeffortsforpandemicandAMRprevention,preparednessandresponsewillimprovesynergiesthusincreasingimpact,effectivenessand

228、harmonizationinthehuman,The environment matters in zoonotic diseases and pandemic spreadTheCOVID-19pandemichighlightstheimportanceoftheenvironmentaldimensionsofzoonoticinfectiousdiseases,especiallythepotentialforantimicrobialresistantmicroorganismstobetransmittedfromtheenvironmenttohumans(UNEPandInt

229、ernationalLivestockResearchInstituteILRI2020).Around400emergentdiseaseeventshaveoccurredsince1940,and14globaloutbreakscausedbymicroorganismshavebeenreportedsince2000,includingCOVID-19(SARS-CoV-2)(Jonesetal.2008;Morse2012;Smithetal.2014;LePan2020;Stephensetal.2021;Destoumieux-Garznetal.2022;Larssonan

230、dFlach2022).Mostoftheseeventswererelatedtotheemergenceofpathogensfromtheenvironment.Whiletheywerelow-probabilityevents,sucheventscanhavehighlysignificantadverseimpacts.Theoriginofthegreatmajorityofantimicrobialresistantgenes(ARGs)isnotwellknown.However,itisthoughtmanynovelformsofresistanceobservedin

231、theclinictodayoriginatedfromalow-probabilitytransferofanovelARGfromabacteriumofenvironmentalorigin(Humeniuketal.2002;Yuetal.2022).ThetaxonomyofspeciesthatcontainARGs,manyofwhicharenowmobile,needtobefurtheridentifiedandsequencedtodeterminetheirenvironmentaloriginpotential.Furtherinclusionofnewlyseque

232、ncedoriginspeciesinreferencedatabaseswouldbeimportant,asmanydatabasescurrentlyattributeARGstopathogens,andthismayrepresentonlyrecentHGTeventsandselectionpressures(Ebmeyer,KristianssonandLarsson2021).Theworldhasnottakenthethreatofzoonoticdiseasesandpandemicsandtheirenvironmentaldimensionsseriouslyeno

233、ugh.Preventionandcontrolmeasuressuchastimelynotification,acloserscience-policyinterface,adequateco-operationwithinandamongcountries,systematicdatacollectionandsustainableandpredictablefundingandlogisticsinLICsandLMICsmustbetaken(Sachsetal.2022).Further,anunderstandingofthegender-andage-differentiate

234、dsusceptibilitiestozoonosesiscrucial(BhopalandBhopal2020).Box 2213 Environmental dimensions of AMR animal,plantandenvironmentinterface,foodsafetyandsecurityandwater,sanitationandhygiene(GLGonAMR2022).Thislackofpandemicpreparednesscannotbeallowedtohappenagain.TheCOVID-19pandemicisawake-upcalltobetter

235、understandandimproveallareasofpreventionofandpreparednessforinfectiousdiseases,includingtheirenvironmentaldimensions(Pachaurietal.2021).Itcanalsoprovidelessonslearned.Oneoftheseistheneedtobenefitfromsynergiesthroughpreventingandtacklingvariousdiseasethreatsconcurrently,especiallymitigatingenvironmen

236、talpathwaysofspread.MobilityofpeopleandgoodsTransnationalandintercontinentaltransportandmovementsofgoodsandpeoplehavebeengrowingsteadilyinthepast100years(Zhuetal.2017),andtherapidglobalizationofAMRandARGsfollowstheinterconnectednessoftradeandmovementacrossborders.Throughthesemovements,resistantmicro

237、organismsspreadfromonesideoftheworldtotheother,particularlythroughhumantravelandshipmentsofcropsandanimals(Sakeretal.2004).Toplacethescaleofhumantravelintocontext,in2019thetotalnumberofpassengerscarriedonscheduledairlineservicesroseto4.5billion(ICAO2019),andtherewere29.7millionoceancruisepassengers,

238、withmostshipsstoppinginseveralcountries(Statista2021).Itisreportedthatresistantstrainsandgenescarriedbyhumanindividualscanberetainedforupto12monthsaftertravel(Arcillaetal.2017)furthercontributingtopotentialspread.AMRspreadcanoccurduetowastereleasesduringtraveltoo,suchasfromshipsorairplanes.TheIntern

239、ationalConventionforthePreventionofPollutionfromShipsstipulatesthatsewagefromashipcanonlybedischargedafteritistreatedbythetreatmentplantonboardanddischargedfournauticalmilesfromthenearestland(Wankhede2019).However,shipsareallowedtodischargeuntreatedwastewater12nauticalmilesawayfromtheland.Similarint

240、ernationalconventionsdonotexistforcross-borderairflightsandmanagementofwaste.Mass gatherings of people include sporting events such as the FIFA World Cup Pixabay22Bracing for Superbugs:Strengthening environmental action in the One Health response to antimicrobial resistanceCommercialshippingmovesdiv

241、ersemicroorganismsinballastwaterfromaroundtheglobe.Morethan80percentofcommercialtradeistransportedinternationallybytheworldsoceans(UnitedNationsConferenceonTradeandDevelopmentUNCTD2017;Hess-Ergaetal.2019).Since1970,marinetraffichasincreasedatanaveragerateof2.1percentperyear,reaching11billiontonsofca

242、rgoin2021(UNCTD2022).Anestimated100millionmetrictonsofballastwaterisdischargedeachyearintoUSportsalone(Lv etal.2018).Foodproductsareyetanothersourceofcross-bordertransportationofAMR.Foodborneoutbreaksofdrug-resistantpathogenslinkedtoimportedfoodproductshavebeenreportedfrommultiplecountries.Globalmea

243、tproductionin2020wasforecastedtobe333milliontons,onlyabout6milliontonslowerthan2019(FAO,UNDPandUNEP2021).Givensuchtrends,itisunsurprisingtoseethatseveralnotableexamplesofdrugresistancehaveproliferatedinternationally(Sarnoetal.2021).Massgatheringsresultinthecongregationofmillionsofpeopleatasingleloca

244、tion.Suchcongregationsofindividualsrequiremasstravelfromdifferentgeographicplacesandsocioeconomicbackgrounds,whichcanspreadregionalAMRinthehostlocation,andtoandfromtravellerdestinations(Bokharyetal.2021).Withoutprecautions,suchplacescanbecomepotentialsuper-spreaderlocationsofAMRandinfectiousdisease.

245、Attendeescanalsoacquireresistantpathogensaftergatheringsandcarrythembacktotheirpointsoforigin(Leangapichartetal.2016).Displacementsduetopoliticalunrest,warandchangesinresourcesoropportunitiescanalldrivethemassmovementofpeopleandimpactAMR(Baltay2020).Displacementandmigrationalmostcertainlyincreasethe

246、riskofoverloadedwater,wastewaterandhygienecapacitiesenrouteandatdestinations,andequitableaccesstoandappropriateuseofantibioticsbyrefugeesandmigrantsisimportanttoaddressAMR(WHO2022a).Oftendisplacedindividualslackaccesstobasicrightsincludingproperhousing,healthcare,waterandsanitation,whichareallfactor

247、swithdemonstratedinversecorrelationswithAMR(Collignon etal.2018)andincreaseitspossiblespread.Delineatinghowsuchtransport,movementsandeventsimpactAMRspreadisamajorknowledgegap.3.3.2ExamplesofglobaldisseminationofresistancegenesInexaminingcasesofAMRdissemination,itcanbedifficulttodeterminehowresistanc

248、espreadsglobally,butgenomicandepidemiologicevidenceillustratehowthiscanbepossible.Ofthemanyexamples,mcr-1,blaCTX-M,andblaNDM-1representglobalspreadofARGsintheOneHealthsectors.Firstdetectedin2015,mcr-1producesanenzymethatconfersresistancetocolistin,apolymyxin,consideredacriticallyimportantantibiotic(

249、Liuetal.2016;WHO2019).Colistinisoneofthelastremainingclinicallyeffectiveoptionsagainstcarbapenem-resistantEnterobacteriaceae,andisusedasalast-resort,life-savingtreatmentinhumanmedicineformultidrug-resistantbacterialinfections.Withinafewyearsofthegenesdiscovery,rapidglobaldisseminationwasdocumentedas

250、 mcr-1spreadacrossfivecontinents(Liuetal.2016;Wangetal.2018;Ling etal.2020).Indeed,mcr-1isnowdetectedaroundtheworldindifferentenvironments.Ananalysisofgloballyavailablesequencedisolatescontaining mcr-1suggestthatfoodanimalsandcolonizedorinfectedhumansweretheprimarymechanismofglobaldissemination,with

251、aquaticorganismsnowrecognizedasprimaryreservoirsofmcr-1ARGs(Gramietal.2016;Wang,Y.etal.2017;CabelloandGodfrey2018;Zhangetal.2019;Anyanwu,JajaandNwobi2020).Healthyindividuals,withoutpriorexposuretocolistin,butcolonizedbybacteriacarrying mcr-1afterinternationaltravelbolstertheevidencethatsuchcross-bor

252、dertrafficcontributestoitsrapidglobalspread.TargetedmetagenomicanalysesofthefaecesofhealthyDutchtravellerstoSouthernAfrica,andSouthandSoutheastAsiafoundthatalmostfivepercentofthemacquiredthemcr-1genewhileontravels(vonWintersdorffetal.2016;Wang etal.2018).Asystematicreviewthatpooleddatafromover632,00

253、0travellersdocumented30,060isolatesofresistantmicroorganisms,withmostbeingacquiredbytravellerstolow-andlower-middle-incomecountries(Bokharyetal.2021).233 Environmental dimensions of AMR Bacteriathatproduceextendedspectrumbeta-lactamases(ESBL)areresistanttosomeofthemostimportantandcommonantibioticsus

254、edinhumanmedicine,suchaspenicillinandcephalosporin,butnotcarbapenemallantibioticssharingacommonbeta-lactamringchemicalstructure.TheglobalepidemiologyoftheplasmidassociatedCTX-M-typeESBLiscomplexgiventhatthereareover50allelicvariants;however,theyhavebeennotedtohavebecomeincreasinglycommoninallregions

255、oftheworldinthelasttwodecades(Bevan,JonesandHawkey2017).GiventhatCTX-Menzymesarelinkedtomicrobialspeciesoriginatingfrommicrobiomesoftherhizosphere,aroundtherootsofplants,theassociatedgeneticbackgrounds(clonalandmobilegeneticplatforms)alsospeaktotheimportanceofenvironmentaloriginsoftheirdissemination

256、andspread.Inaddition,theroleofpoorsanitation,carriageinthehumangutmicrobiotaandthroughfoodanimalshavealsobeenconsideredtohavecontributedtotherapidglobalspreadofblaCTX-Mgenes.Carbapenemsareusedtotreatlife-threateninginfectionscausedbyESBL-producingbacteria.NewDelhimetallo-beta-lactamase-1(NDM-1codedb

257、yblaNDM-1gene)causesmultidrug-resistanceinbacteriaandconfersresistancenotonlytocarbapenems,butalsotootherbeta-lactamantibiotics,whichcomplicatesthetreatmentofcommoninfections.Travel,eitherhumanorwildlife,isevidentinthespreadofblaNDM-1.Firstdocumentedfromatraveller,blaNDM-1 wasfoundin2008inSwedeninap

258、atientpreviouslyhospitalizedinIndia(Yongetal.2009),inaGermanhospitalpatientin2009(Pfeiferetal.2011)andinsurfacewatersinDelhiin2010(Walshetal.2011).TheblaNDM-1geneapparentlywasmovingbothwithpeopleandduetoenvironmentalpollution(Walshetal.2011).Asanexample,thegenewasdetectedintheGangesin2012whererelati

259、veblaNDM-1prevalencewashighestduringthepilgrimageseasonwhenvisitorsincreasedatspecificsitesthathadinadequatesanitationARGs have been found in many remote areas of the world,including in Arctic regions Pixabay24Bracing for Superbugs:Strengthening environmental action in the One Health response to ant

260、imicrobial resistance Environmentaldimensionsofantimicrobialresistancearenumerousandinterconnected,andtounderstandthedevelopment,transmissionandspreadofAMRintheenvironment,itisimperativetoviewitthroughamulti-dimensionallens.AMRchallengesarecloselylinkedtothetripleplanetarycrisisofclimatechange,biodi

261、versitylossandpollutionandwaste,allofwhicharedrivenbyhumanactivity,includingunsustainableconsumptionandproductionpatterns.Whenantimicrobialsarereleasedintotheenvironment,theycanselectforresistantmicroorganismsandresistanceemergence.Biologicalandchemicalpollutionsourcescontainingantimicrobialscontrib

262、utetoresistancedevelopment.Resistantmicroorganismscanspreadandbetransmittedtohumans,companionanimals,foodanimals,plantsandwildlifebecauseofcomplexinterconnectionsacrossnature.HumanexposuretoAMRfromtheenvironmentcantakeplacefollowingconsumptionoffoodand/orwaterthathavebecomecontaminatedbyresistantmic

263、roorganisms.ThetransmissionandspreadofAMRarenotconfinedtopoint-sources.Transientanddiffusesources,whichincludewater(rivers,lakesandsediments),overflows,agriculturalrunoff,soil,airbornetransmissionandwildlifemigrationcanalsobeimportant.Othercriticalfactorsareglobalization,climatechangeandthemobilityo

264、fpeopleandgoods,andwildlife.ImprovedunderstandingoftheassociationsbetweenAMRanddifferentpopulationgroups(e.g.gender,ageandoccupation)iscrucial.3.4 Summary(Ahammadetal.2014).SuchtransientexposuresareespeciallyproblematicbecauseinitialAMRexposuremightoccuralongtheriver,butthenexposedindividualsreturnt

265、otheirprimaryresidencespreadingAMRfromthegatheringpoints(Kanteleetal.2015).ThisenvironmentalassociationofblaNDM-1hasbeenrecognized,alongwithconcernsonhowtomanageit(Shahid2011;Walshetal.2011).By2011,blaNDM-1 wasnotedtohavespreadtoallcontinents,exceptAntarctica(Nordmannetal.2011),andwasevenfoundinHigh

266、ArcticsoilsofNorwaysnorthernmostislandsin2013nearremotehumanandwildlifecongregationpoints(McCannetal.2019).TheblaNDM-1spreadisbestexplainedbyhumantravel,disseminationinmigratorywildlifeorboth.TherapidandglobalspreadofcertainARGs,suchasmcr-1,blaCTX-M and blaNDM-1,makeacompellingcaseforcoordinatedloca

267、landglobalaction.253 Environmental dimensions of AMR ActionableevidenceoftheimportanceoftheenvironmentaldimensionsofAMRhasbeenmounting.Assuch,AMRrequiresaresponsebasedonaconcertedsystemsapproach,suchasOneHealth,atglobal,regionalandcountrylevelsfromallsectors,stakeholdersandinstitutions.4Managementto

268、PreventandRespondtoAMR4.1 RecognisetheenvironmentiskeytoadvancingaOneHealthresponsetoAMRThe One Health approach“OneHealthisanintegrated,unifyingapproachthataimstosustainablybalanceandoptimizethehealthofpeople,animalsandecosystems.Itrecognizesthehealthofhumans,domesticandwildanimals,plants,andthewide

269、renvironment(includingecosystems)arecloselylinkedandinter-dependent.Theapproachmobilizesmultiplesectors,disciplinesandcommunitiesatvaryinglevelsofsocietytoworktogethertofosterwell-beingandtacklethreatstohealthandecosystems,whileaddressingthecollectiveneedforcleanwater,energyandair,safeandnutritiousf

270、ood,takingactiononclimatechange,andcontributingtosustainabledevelopment.”SECTORS and DISCIPLINESENVIRONMENTHealthy ecosystemsHealthy animalsHealthy humansRural,urban,mobile communitiesInclusivity,equity and accessANIMALHUMANONE HEALTHSOCIETYCommunicationCapacity buildingCollaborationCoordinationOne

271、Health definition developed by the One Health High-Level Expert Panel(WHO 2021b)Box 3Figure 1226 Responsible,monitored use.production and consumption patterns of antimicrobials change.AMR could create annually up to$3.4 trillion(US)in shortfall by 2030 unless.Multi-drug resistant bacteria are preval

272、ent in marine waters and sediments in close proximity to aquaculture,industrial and municipal discharge sites.Life on land is impacted when food animal and food crop production use antimicrobials injudiciously.AMR could push an additional 24 million people into extreme poverty by 2030.Reduced econom

273、ic growth would be primarily faced in low-income countries,widening gaps of inequalityCrop productionLivestock and aquacultureHealthcare facilitiesPatientsAntimicrobial productionUnchecked consumption of antimicrobials is unsustainableTriple planetary crisesPollutionBiodiversity lossClimate changeSu

274、stainable production and consumption of antimicrobials can impact many other SDGsFigure 13274 Management to Prevent and Respond to AMR AOneHealthapproach,whichconsidersthehealthofpeople,animals,plantsandecosystemsinunison,isurgentlyneededtoreducetheburdenofAMRandpreventdeaths.Reducingtheneedforantim

275、icrobials,leadstolessuseandthereforelessAMRdevelopment,thuscreatingapositiveneteffectacrosssectors.TheOneHealthapproachhasmanybenefits,includingcostsavingsduetoaddressingmultiplethreatsatthesametime(Hernando-Amadoetal.2019;Bracketal.2022).Therefore,solutionsneedtofurtherbeaddressedinthecontextofachi

276、evingseveralSustainableDevelopmentGoals(SDGs)suchasSDG2,SDG3,SDG6,SDG11,SDG12andSDG13.Forhumans,vulnerabilitytoAMRisfurtherheightenedbasedononessex,ageandsocio-economicstatus(Yoshikawa2002;Collignonetal.2018;WHO2018a).Therefore,approachesandplansthatalignwiththeSDGsarehighlyrecommendedastheseareunde

277、rlinedbytheprincipleofleavenoonebehind,whichembedstheindivisibledimensionsofsustainabledevelopment:social,economicandenvironmental(UN2021a).4.2 Addresskeyeconomic-sectorvaluechainsaffectingAMRintheenvironmentTake-back programmesUse(3 key economic sectors)Healthcare deliveryAgriculture and foodPharma

278、ceuticals and other chemicalsWaste streamDistributionExpired productsPharmaceutical and chemical productionResearch and developmentKey economic-sector value chains affecting AMR in the environmentFigure 1428Bracing for Superbugs:Strengthening environmental action in the One Health response to antimi

279、crobial resistanceAvaluechaindescribestheinputsandoutputsneededtobringaproductorservicetomarket.Fromasustainabilityperspective,avaluechainapproachcanserveto“identifykeypointsofinterventionwithineconomicsystemstoreducenatural-resourceuseandenvironmentalimpactscausedbyproductionandconsumption,andtodef

280、ineacommonagendaforaction”(UNEP2021a).ThreeeconomicsectorsandtheirvaluechainsarekeydriversofAMRdevelopmentandspreadintheenvironment:pharmaceuticalsandotherchemicals,agricultureandfood,andhealthcare.Effectivemonitoring,disclosureandtransparencyareneededineachvaluechaintounderstandwhenandwhereantimicr

281、obialsareusedandwhereAMRislikelytooccur.Itisequallyimportanttobetterunderstandthegovernancestructuresandkeyactorsinthesevaluechainstotargetinterventions,realignincentivestominimizeAMRandforgepartnerships.Togetherwithpollutantsfrompoorsanitation,sewageandwasteeffluentinmunicipalsystems,theinputsandou

282、tputsfromthesethreekeyeconomic-sectorvaluechainsprofoundlyinfluencethedevelopmentandspreadofAMR,andconsequentlytheoveralllong-termvalueofantimicrobialsforpromotinghuman,animal,cropandenvironmentalhealth.4.2.1PharmaceuticalandotherchemicalvaluechainsProductionfromthissectorincludesarangeofdifferentch

283、emicals,includingantibiotics,antiviralsandfungicides,aswellasdisinfectants.Theiruse,applicationandenvironmentalfatemayvarysignificantly.Pharmaceuticalproductionstartswiththeprocessingofrawmaterials,themanufactureofactivepharmaceuticalingredients,drugformulation,packaginganddistributionandtheconsumpt

284、ionandmanagementofexpiredend-of-lifeproducts.Oftenthedifferentpartsofthisvaluechainareinseparatecountries.Curbingantimicrobialpollutionfrommanufacturingandkeepingproductioncostslowtoensureaffordableaccesstoantimicrobialscreatespolicytensionsthatrequirecarefulglobalandnationalcoordination,policyandre

285、gulationtoresolve(Nijsingh,MuntheandLarsson2019).Inadequatemanagementofpharmaceuticalmanufacturingdischargescanleadtonegativeimpactsontheenvironment(AMRIndustryAlliance2022).Recentevidencesuggestssub-minimalinhibitoryconcentrationofantimicrobialsfrompharmaceuticalmanufacturing,municipalandlivestockw

286、astewaterdischargesmayinfluenceAMRtransmission(Bengtsson-PalmeandLarsson2016;Murrayetal.2021).However,therelativeimportanceoflowconcentrationsofantimicrobialsindrivingAMRemergenceversusmoreacutefactors,suchasfaecalwastereleases,isstilldebated.Environmentalfielddata are lacking and selection is also

287、known to be drivenbyotherecologicalfactors(Knappetal.2008).Inaddition,increasingthetransparencyofrelevantchemicalandpharmaceuticalproduction,sales,useanddisposal,aswellasdataonenvironmentalreleases,isneededtohelpaddresstheseknowledgegaps(LarssonandFick2009;rdaletal.2021).Effluentandwastefrompharmace

288、uticalmanufacturingPharmaceuticalproductioncanperiodicallyreleaseresistantmicroorganismsandgenes,whichincombinationwithchemicalreleases,canimpactthetransmissionandspreadofAMRintheenvironmentasnotedabove(Larsson,dePedro,andPaxeus2007;Ficketal.2009).Thiscanoccurthroughmanufacturingoperationsandeffluen

289、tgeneration.ImplementingmeasurestopreventandcontrolpharmaceuticalssuchasantimicrobialsineffluentiscrucialtominimizetheselectionandspreadofAMRintheenvironmentbutalsotominimisetheecotoxicityeffectsonaquaticorganisms(e.g.bacteriaandalga)(Isidorietal.2005;Larsson,dePedroandPaxeus2007;Bengtsson-PalmeandL

290、arsson2016).Lessthanatenthofantimicrobialshavebeentestedforinwastewaterandenvironmentalsamples,withnoenvironmentaltoxicitydatabeingavailableformostmedicines(OECD2019).Theuntreateddischargeofpharmaceuticalwastesisakeyexampleofwhereantimicrobialandotherselectiveagentsintheenvironmentaresufficientlyhig

291、htoselectforresistantmicroorganismsandARGsinsituandincreaseabundanceofresistantmicroorganisms(Kookanaetal.2014;Bielenetal.2017;Binhetal.2018;Maratheetal.2018;Bengtsson-Palmeetal.2019;Gonzlez-Plazaetal.2019).294 Management to Prevent and Respond to AMR Thepharmaceuticalindustryisconsideredlargelyanun

292、regulatedsectorintermsofenvironmentalpollution(LarssonandFick2009;Bengtsson-Palme,GunnarssonandLarsson2018;Nijsinghetal.2019).ThiscouldbeduetotheabsenceofcriteriaforindividualpharmaceuticalsandtheirimpactsincludingAMR(seesection3).Untreateddischargehasresultedinhighlevelsofantimicrobialmixturesinexp

293、osedsurfacewaters(Larsson,dePedroandPaxeus2007;Grahametal.2011)anddetectionofnovelformsofAMRfromsuchenvironments(Kristianssonetal.2011).Treatmentofwastewaterfromactivepharmaceuticalingredient(API)productionshouldreducetheconcentrationsofAPIstobelowlevelsthatselectforAMR(Bengtsson-PalmeandLarsson2016

294、;Tell etal.2019).Addressingpollutionfromantimicrobialmanufacturinghasconsistentlybeenidentifiedasapriorityareaofintervention.Sterilizationofeffluentfromtheproductionofactivepharmaceuticalingredientsisanoptionforminimizingpollutionwithresistantmicroorganisms,thatmayhavebeenselectedduringproduction,fr

295、omescapingthetreatmentfacility.Treatmenttechnologiesthatmightachievethiscriterionincludeadvanceoxidationprocess(AOPs),incinerationandfiltrationwithactivatedcarbon,butnewandmoresustainabletechnologiesareneeded.AOPsandincinerationarehighlyenergyconsuming,whereasactivatedcarbonwouldrequirevastamountsof

296、carbonfiltersforlargervolumewastestreams.CarbonfiltrationalsocreatesfilterwastethatneedstobeincineratedandmaynotbeadequatetoreducealltypesofAPIstosafelevels.Option 2:Wastewater is sent to a municipal wastewater treatment plant,before being discharged into the environmentPharmaceutical manufacturing

297、plantRiverContains high concentrations of API1Compliance with limits set for river waterOther wastewater3Wastewater contains APIs and resistant microorganisms 2Municipal wastewater treatment plantOn-site treatmentOption 1:Wastewater is directly discharged into the environmentPharmaceutical manufactu

298、ring plantContains high concentrations of APIOn-site treatment1Compliance with limits set for river waterWastewater contains APIs and resistant microorganisms 2River Active pharmaceutical ingredients(APIs)Microorganisms Resistant microorganismsWastewater discharges from pharmaceutical manufacturing

299、Figure 1530Bracing for Superbugs:Strengthening environmental action in the One Health response to antimicrobial resistanceAnothersolutionthathasbeenproposedtodealwithAPIsproductionwasteistouseadvancedcatalyststogenerateoxidants,whichthenneutralizestheAPIs.Thislattertechnologyhasthepotentialtobelesse

300、nergy-demandingthananAOPwhileperformingatsimilarremovallevels,butcurrentoptionsareexpensive.Therefore,greenengineeringofin-factoryproductionprocessestoreducewastereleasesshouldalsobepartofthesolution.Therearelimitedproventreatmentoptionsforpharmaceuticalwastewaterbeforereleasetotheenvironment.Forexa

301、mple,activatedsludgebiologicaltreatmenthasbeenused,suchasinChina(Lietal.2009;Lietal.2010)andIndia(Kristianssonetal.2011;Maratheetal.2016),buthighlevelsofantibioticsinsuchwasteprovideastrongselectionpressuretowardsAMRstrains(Johnningetal.2013).ThisresultsintreatmentthatproducesAMRratherthanasystemtha

302、treducesAPIsandtheexposureandpossiblerisksassociatedwiththem(Larsson2014).Ingeneral,emissionsofAPIsarealsonotregulatedglobally(Larsson2010;AMRIndustryAlliance2022;TrackingAMRCountrySelf-assessmentSurvey2022,Question6.2.8),andtheglobalregulatorylandscapeforthecontrolofpharmaceuticalreleasesvarieswide

303、ly.Acriticalknowledgegapthatneedstobeaddressedtoeffectivelyinformregulationsisidentifyingreasonableandeffectivedischargelimits(Bengtsson-Palme,GunnarssonandLarsson2018;Toppetal.2018;Nijsinghetal.2019;rdaletal.2021).Voluntaryindustryinitiativesareestablishingacommonframeworkformanagingdischargeofanti

304、microbialcompoundsandapplyingitacrossmanufacturingandsupplychainsamongtheirmembers(FAO,WOAHandWHO2020;AMRIndustryAlliance2022)andhavedevelopedanantibioticmanufacturingstandard.Concernsaboutthesupplychainresilienceanddrugpriceshavesofarpreventedthedemandforspecificdischargelimitsaspartoftheirprocurem

305、entsofmedicines,althoughthishasbeendiscussedinseveralfora(SustainableProcurementintheHealthSectorSecretariatandUNDP2015;AccesstoMedicineFoundation2018).Contributingtothisproblemisthepricepressureforinexpensivedrugs,particularlyantibiotics,whichhavemadeenvironmentalconcernsandAMRdevelopmentandspreada

306、lowerprioritytocostcuts(Laxminarayanetal.2016;Bengtsson-Palme,GunnarssonandLarsson2018;Nijsinghetal.2019).Moreactionisstillneeded,andenvironmentalregulatorsshouldstrengthentheframeworktoprotecttheenvironmentfromAMRandantimicrobialpollutants.ItisimportanttoeffectivelycontrolAPIemissionsfrommanufactur

307、ingbothinproductionoftheAPIitselfanditsformulationintodrugproductsforpatientuse(AMRIndustryAlliance2022).Environmentalregulatorsshouldalsobeempoweredandfundedtoenforceregulationsandlegislationrelatedtopharmaceuticalreleasesdistinguishingproductsthataremanufacturedundergoodemissioncontrolandprioritiz

308、etheminforexampleprocurementdecisions.Theseactivitiesshouldbeimplementedinwaysthatdonotaddadditionalcosttotheconsumers,asantimicrobialsneedtobekeptaffordable.TheGroupofSeven(G7)countriesrequestedWHOtoincludepharmaceuticalwastestreamsaspartofqualitycontrolsinstandardoperatingprocedures(G72021a).Thecu

309、rrentlackofconsistentregulatoryoversightandcoordinatedglobalactionmakesitchallengingtoresolvethissourceofAMRrisk.314 Management to Prevent and Respond to AMR Management options to address effluent and waste from pharmaceutical manufacturingDevelop and enforce standards to reduce antimicrobial discha

310、rges/emissions that prevent AMR emergence in the environment,including strengthening of regulatory frameworks and inspection systems,incentives and subsidies for implementing upgrades in the manufacturing process,and ensuring stability of fragile generic supply chains critical to maintaining afforda

311、ble,low-cost antimicrobials for healthcare.Introduce environmental and social risk management strategies,gender impact assessments,and implement cost and energy-efficient Best Available Technologies(BAT)for the management of effluent and waste and social safeguards.Set discharge targets for antimicr

312、obial manufacturing waste and wastewater such that more appropriate waste management technologies are employed,which balance PNEC aspirations and the need for local sustainability.Monitor antimicrobial residues,resistant microorganisms,ARGs and MGEs in the environment in the vicinity of pharmaceutic

313、al production plants.Incorporate waste management into standard operating procedures used in the production of antimicrobials with a lifecycle approach.Improve supply chain transparency(e.g.sharing data regarding emission levels,site of APIs production and formulation).Put in place and promote susta

314、inable procurement and reimbursement systems for manufacturers adhering to environmental standards and good emission control.Develop incentives to utilize and design degradable antibiotics.Consider research and development of new antimicrobials,as replacements and substitutes are needed as resistanc

315、e develops.Resistance mechanisms exist in all approved antimicrobial classes,whether derived from natural,semi-synthetic,or synthetic compounds.Therefore,approaching how antimicrobials are designed needs to be thought about differently.Ensure appropriate labelling(including information about the cor

316、rect use,dosage,pharmaceutical expiration dates,environmental impact of antimicrobials and special instruction on proper disposal of unused antimicrobials)and packaging suitable for intended use,such as in single capsules for oral administration in humans or other sized units for use in different sp

317、ecies of animals.Increase understanding and improve prescription patterns(e.g.stewardship programmes in healthcare and veterinary medicine).Enhance controls for marketing and sale of antimicrobials(e.g.advertising,internet sales,over-the-counter sales without a prescription and the black market).32B

318、racing for Superbugs:Strengthening environmental action in the One Health response to antimicrobial resistance4.2.2AgriculturalandfoodvaluechainsAgricultureproductionentailsraisingfoodanimals,engaginginaquaculture,producingfoodcropsorprovidinginputssuchasfeed,textiles,ornamentalplants,biofuelsandoth

319、eragriculturalcommodities.Thepathwaysalongtheagri-foodvaluechainsvary,butallbeginwiththeproductionofplantsoranimalsincludingtheprocurementandprovisionofnutrients(suchasfeedorfertilizerrichinantimicrobialsoressentialminerals),sourcewater,growingcrops/animals,administratingmedicine(e.g.antimicrobials)

320、andwastemanagement.Storage,processing,packaginganddistributionforsaleandconsumptionarealsoimportantaspectsofvaluechains,alongwiththestorage,disposalandmanagementofinputs(e.g.pesticides,fertilizersandmedicines)andwaste.Severalpointsintheagriculturevaluechainserveasentrypointsforantimicrobialsandantim

321、icrobialresistantorganismsintotheenvironmentsuchastheuseofantimicrobialstotreatinfectionandpromotegrowth,useofreclaimedwastewaterforirrigatingcrops,useofmanureasfertilizerandinadequatewastemanagement.Populationgrowthandincreaseddemandforfoodhasresultedinanincreaseindemandandconsumptionofanimalprotei

322、n(Tiseoetal.2020).Aquaticanimalscurrentlyprovide20percentofanimalproteintothehumandietforover40percentoftheworld(FAO2020;FAO,UNDPandUNEP2021).Thishasledtotheintensificationofagriculture,andlandandwateruseinlivestockproductionsystems,aswellassmall-scale,backyardandaquaculturefarmsinsomelow-andmiddle-

323、incomecountriesthataresubjecttominimalregulatoryoversight(Smil2011;Coyne etal.2019;FAO,UNDPandUNEP2021;Scharetal.2021).Ingeneralwomenfaceinequalitiesintermsofaccessingresources,services,employmentopportunities,takingpartindecision-makingandotheraspectsrelatedtofoodlossandfoodwastefromaquaticfoodprod

324、uctionsystems(Grever2021).Unlessbroaderstepsaretakentowardsmakingfoodsystemsmoresustainableandcurbingtheuseofantimicrobialsinanimalhusbandrypractices,theuseofantimicrobialsinfoodproductionwillcontinuetogrow(Tilman etal.2011).Examplesofcountriesthathavemeaningfullyreducedantimicrobialuseinfoodanimalh

325、usbandryincludeBelgium,China,Denmark,theNetherlandsandThailand(Baudoin,HogeveenandWauters2021;Hogetal.2021;GlobalHigh-levelMinisterialConferenceonAntimicrobialResistance2022;WOAH2022).Vegetables for sale at market,an end point in Agriculture and Food Value chains.Davide Provolo334 Management to Prev

326、ent and Respond to AMR UseofantimicrobialsandmanureincropproductionFungicides,antibiotics and other chemicals applied in crops may affect AMR developmentUnlikeantimicrobialsusedinhumansandanimals,pesticidesareapplieddirectlyintotheenvironmentandcouldresultinhigherlocalconcentrationsofthesepollutants

327、withsubsequenteffectsonAMR.Pesticideswithantimicrobialpropertiessuchasantibiotics,fungicides(includingmetal-basedplantprotectionproductssuchasthosecontainingcopper)areusedtomaintainplanthealth.Theseagentsshouldbeused,storedanddisposedofinwaysthatlimitenvironmentalcontamination.Countryself-reportedes

328、timatesoffungicidesandbactericidesusedinagriculturewere605,986tonsin2020(FAO2022a).Thisglobaluseinagricultureshowsanoverallincreasingtrendoverthepastthirtyyears(Figure16),andofparticularconcernistheuseoffungicidesincropproduction.Increasingresistancetofungicidesusedoncropshaswideimplications,includi

329、ngforhumanandveterinarymedicine,astriazolefungicidesarewidelyusedincropproductionbutarealsousedtotreatfungalinfectionsinhumans(Fisheretal.2018;Schoustraetal.2019;Jrgensenetal.2021).Widespreaduseoffungicidesinagricultureislinkedtoagrowingnumberofazole-resistantlunginfectionsinhumans,acquiredfrominhal

330、ationofAspergillus fumigatusfungalspores(Meisetal.2016).Increasedazole-resistantaspergillosis(Braueretal.2019)hasbeenpartiallyfuelledbytriazolefungicideuseincropproduction(Sneldersetal.2012).Moreover,disruptionofsoilandchangingweatherandclimatemayaffectvalleyfever(coccidioidomycosis),causedby Coccid

331、ioides,andtheseinfections,aswellasthosefromCandida auris,havebeendocumentedassevereandmulti-drugresistant(Todaetal.2019;USCDC2019).Underliningtheimportanceofairborneexposures,aspergillosisandcoccidiomycosisaretypicallyacquiredviainhalation.Thevolumeofantibioticsusedinhorticultureincountrieswherelegi

332、slationgoverningtheiruseisstrongrepresentsonlyasmallfractionoftotalantimicrobialuseinagriculture.However,inLICsandLMICs,theamountsofantimicrobialsusedoncropsisunknown,butlikelywidespread(TaylorandReeder2020).Unlikeantimicrobialsusedintonnes700k600k500k400k19901991199219931994199519961997199819992000

333、20012002200320042005200620072008200920102011201220132014201520162017201820192020 WorldTrend in fungicide and bactericide use in agriculture(FAO 2022a)Figure 1634Bracing for Superbugs:Strengthening environmental action in the One Health response to antimicrobial resistancehumansandanimals,pesticidesareapplieddirectlyintotheenvironmentandcouldresultinhigherlocalconcentrationsofthesepollutantswithsub