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TREE 2653 No. of Pages 11

Opinion

Coevolutionary Governance of Antibiotic andPesticide Resistance

HighlightsHuman cultures coevolve withhuman environments throughecoevolutionary dynamics.

Increasing biocide resistance is a result ofhuman–environment coevolution (HEC).

Coevolutionary governance (CG) is in-formed by and proactively shapes HEC.

Three CG priorities are identified with theaim of limiting biocide resistance.

Peter Søgaard Jørgensen ,1,2,*,@ Carl Folke,1,2,3 Patrik J.G. Henriksson,2,3,4

Karin Malmros,5 Max Troell,2,3 and Anna Zorzet5; Living with Resistance project‡

Development of new biocides has dominated human responses to evolution ofantibiotic and pesticide resistance. Increasing and uniform biocide use, thespread of resistance genes, and the lack of new classes of compounds indicatethe importance of navigating toward more sustainable coevolutionary dynamicsbetween human culture and species that evolve resistance. To inform thischallenge, we introduce the concept of coevolutionary governance and proposethree priorities for its implementation: (i) new norms and mental models for low-ering use, (ii) diversifying practices to reduce directional selection, and (iii) invest-ment in collective action institutions to govern connectivity. We highlight theavailability of solutions that facilitate broader sustainable development, whichfor antibiotic resistance include improved sanitation and hygiene, strong healthsystems, and decreased meat consumption.

1Global Economic Dynamics and theBiosphere, Royal Swedish Academy ofSciences, Box 50005, 104 05Stockholm, Sweden2Stockholm Resilience Centre,Stockholm University, Kräftriket 2B,10691 Stockholm, Sweden3Beijer Institute of Ecological Economics,Royal Swedish Academy of Sciences,Box 50005, 104 05 Stockholm, Sweden4WorldFish, Jalan Batu Maung, BatuMaung, 11960 Bayan Lepas, Penang,Malaysia5ReAct Europe, Department of MedicalSciences, Uppsala University, Uppsala,Sweden‡Members of the Living with Resistanceproject: Peter Søgaard Jørgensen;Athena Aktipis, Arizona State University;Zachary Brown, North Carolina StateUniversity; Yves Carrière, University ofArizona; Sharon Downes, CSIRO Agri-culture and Food; Robert R. Dunn, NorthCarolina State University; Graham Ep-stein, University of Waterloo; GeorgeFrisvold, University of Arizona; YrjöGröhn, Cornell University; GovindTikaramsa Gujar, South Asia Biotech-nology Centre, Ex-Indian AgriculturalResearch Institute; David Hawthorne,University of Maryland, National Socio-Environmental Synthesis Center(SESYNC); Dusan Jasovsky, UppsalaUniversity, ReAct Europe; Eili Y. Klein,

Coevolution in the AnthropoceneHumans’ role as the strongest evolutionary force on Earth [1] results in widespreadecoevolutionary environmental change [2], a defining feature of the Anthropocene biosphere[3] with large implications for policy and governance [4,5]. Genetic evolution is now shapedby human actions, ranging from the level of the gene to that of the biosphere [1,4–6]. Atthe same time, human cultural evolution operates in a new context of a globally intercon-nected world with unprecedented capacity for communication and speed of change [7–9].Cultural change not only is a driver of, but is itself shaped by ongoing environmental change[10,11].

The combination of human cultural and environmental ecoevolutionary dynamics manifestsin human–environment coevolution between human social systems and the environment[10,11] (Figure 1). The term ‘coevolution’ was originally applied to studies of interdependentDarwinian evolution of pairs, groups, or communities of species [4,12,13], but with the ad-vent of theory for cultural evolution, the use of the term has been expanded to studies ofhow culture and genes coevolve within a species [8,14,15] (Figure 1). More recent advancesin the study of ecoevolutionary dynamics [2] and theories of nongenetic evolutionary change[15] emphasise the utility of recasting human–environment coevolution in terms of two sets ofinteracting multilevel ecoevolutionary dynamics (Figure 1, Text S1 in the supplemental infor-mation online).

The trajectory of human–environment coevolution is not predetermined but is path-dependentand can proceed along several trajectories, depending on how and whether it is governedby humans. However, coevolution is poorly integrated into current governance theories forstudying how societies, at all levels, steer themselves toward desirable ends. To provide avenue for such integration, we introduce the concept of ‘coevolutionary governance,’ which is

Trends in Ecology & Evolution, Month 2020, Vol. xx, No. xx https://doi.org/10.1016/j.tree.2020.01.011 1© 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Center for Disease Dynamics, Econom-ics and Policy and Johns HopkinsSchool of Medicine, Department ofEmergency Medicine; Franziska Klein,Global Economic Dynamics and theBiosphere; Guillaume Lhermie, CornellUniversity; David Mota-Sanchez, Michi-gan State University; Celso Omoto,Universidade de São Paulo; H. MorganScott, Texas A&M University; DidierWernli, University of Geneva; Scott P.Carroll, University of California, Davis,Department of Entomology and Nema-tology.@Twitter: @PSJorgensen (P.S. Jørgensen).

*Correspondence:psjorgensen@kva.se(P. Søgaard Jørgensen).@Twitter: @PSJorgensen (P.S. Jørgensen).

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the explicit governance of human–environment coevolution [4]. Coevolutionary governanceis related to but distinct from adaptive [16] and other forms of anticipatory governance [17]in that it recognises to a larger extent, anticipates, and explicitly analyses these interdepen-dent ecoevolutionary dynamics in its attempt to guide human societies toward identifiedgoals [4].

We highlight the value and insights of coevolutionary governance through two classical examplesof human–environment coevolution: that of human antibiotic and pesticide use and the evolutionof resistance to these compounds. In this paper, we refer to these compounds collectively as‘biocides.’ Modern health systems and production of food, fuel, and fibre are reliant on biocidesfor controlling unwanted microorganisms, arthropods, and plants with which human societieshave coevolved [5,10]. However, biocide resistance is an increasing risk, with multiple resistanceto antibiotics, insecticides, and herbicides on the rise [5,18]. Antibiotic resistance is associatedwith hundreds of thousands of deaths per year [19], and insecticide and herbicide resistance isa potential threat to food, fuel, and fibre security that also entails economic losses for farmersand health risks from exposure to increasing pesticide use [5,20,21]. Not only are levels ofresistance to a much wider array of compounds now much higher, but for both antibiotics andpesticides, there are declining prospects for developing more conventional compounds in thenext decades [22]. Simultaneously, the next decade will be critical for meeting a set of intercon-nected global environmental and societal challenges captured in part by the 17 SustainableDevelopment Goals (SDGs; https://sustainabledevelopment.un.org/sdgs) put forth by theUnited Nations [5].

Rising resistance levels are evolutionary consequences of widespread practices employed tocontrol pests and pathogens [1,5,8,22] (Figure 1), and resistance is therefore unlikely to be solvedthrough quick fixes. Rather, it represents the dual challenge of governing coevolution betweenhuman culture and species targeted for control with strategies that cofacilitate broader goals ofsustainable development [5,8,10,23]. After reviewing the emerging global dynamics of biocideuse and resistance, we identify priorities for coevolutionary governance of biocide resistanceand then focus on the challenges of promoting them in the context of the SDGs. We believethat coevolutionary governance has the potential to help promote successful transformationsto sustainability in the Anthropocene biosphere by, for example, stimulating the evolution ofnorms and technology for sustainability.

The Global Dynamics of ResistanceThe global dynamics of resistance evolution can be characterised by the scale, intensity, andcomposition of biocide use, as well as the spatial extent of resistance gene exchange. Overthe past 30 years, antibiotics, insecticides, and herbicides have undergone major changes inthese four aspects and present both unique and shared governance challenges (Figure 2).For all three biocides, scale of use – indicating global selection for resistance – has increasedmarkedly since monitoring began (Figure 2A,D,G). Only conventional insecticide use hasstarted to decline as transgenic crops producing the insecticidal Bacillus thuringiensis proteins(Bt crops) replace conventional insecticides and as integrated pest management (IPM) isimplemented [20,24].

Global trends in biocide use intensity imply changes in local selection for resistance and are highlydivergent between the three types of biocides. Human antibiotic use (monitored mainly viapharmaceutical sales) has increased by 36% since 2000 [25] (Figure 2B). Although similar globalscale monitoring is lacking in important high-use environments such as communities andhospitals as well as animal farming, available regional data show that antibiotic use for animals

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Figure 1. Governing Coevolution. (A) Conceptual illustration of some of the major types of coevolution and the direct and indirect effects of coevolutionary governanceof human–environment coevolution. Eco-evolutionary dynamics take place both within and between the cultural and environmental sub-systems with some of their major levelsindicated in the figure. (B) Priorities for coevolutionary governance of biocide resistance include (i) reducing use by shiftingmental models and social norms for what might be likelyand desirable solutions (blue); (ii) systematically diversifying practices, including by integrating selected past practices with new technologies (green); and (iii) governing local toglobal connectivity through collective action institutions (yellow). Implementation of these priorities will help decrease biocide use and manage resistance in a highly connectedworld (see Spatial dynamics).

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Figure 2. Global Dynamics of Resistance Selection and Spread. Global dynamics of antibiotic (A–C), herbicide (D–F), and insecticide resistance (G–I) ascharacterised by changes in the scale (A, D, G), intensity (B, E, H), and simplification of use (F, I), as well as global connectivity of resistance gene exchange(C) [22,25,27,28,57]. Insecticide and herbicide intensity is calculated by dividing mean sales with agricultural area over 5-year periods for countries with data availablethroughout the period at http://www.fao.org/faostat/ (E, H). Countries with endemic Klebsiella pneumonia carbapenemase (KPC)-producing [58] and autochthonousNew Delhi metallo-β-lactamase 1 (NDM1) infections [59] are mapped as endemic, and areas with the earliest record of these infections, as well as the plasmidmobilised colistin resistance (MCR1) gene, are possible origins [22] (C). Abbreviations: GR crops, transgenic glyphosate-resistant crops; Bt crops, transgenic cropsproducing the insecticidal Bacillus thuringiensis proteins.

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varies widely among countries [26]. Conventional insecticide sales per agricultural area havedropped more than 10% over the past 5 years and are now below levels from the 1990s(Figure 2H). In contrast, herbicide sales per area have increased by 70% (Figure 2E). These

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diverging trends are in part explained by adoption of transgenic crops: Insecticidal Bt crops helpedreduce use of conventional insecticides [20], whereas glyphosate-resistant crops encouraged a15-fold increase in the use of glyphosate, driving the herbicide trend [27] (Figure 2D,F,I).

Biocide use can become uniform through widespread adoption of successful compounds, butthe large area across which selection occurs also makes such biocides vulnerable to resistance.The adoption of transgenic crops has homogenised selection pressures through increasinguniformity of pesticide use and of pest management in general. Today transgenic crops makeup more than 30% (glyphosate-resistant crops) and 15% (Bt crops) of the planted area of certaincrops, such as corn, cotton, and soybean, worldwide (Figure 2F,I) and more than 90% in some ofthe largest-producing countries [28]. Similarly, as low- andmiddle-income countries (LMICs) haveseen economic growth, their use of antibiotics has increased dramatically, leading to a globalconvergence in antibiotic use [25].

Resistance can spread rapidly in highly connected systems. Historical efforts to govern antibioticresistance have, for good reasons, largely focused on managing local and regional use and lesson governing international spread. However, intercontinental spread of antibiotic resistance is in-creasingly well documented for some of the most worrying resistance genes in gram-negativepathogens, which are reported as endemic in a growing set of countries (Figure 2C) [22].Although there are still few reports of intercontinental spread of insecticide and herbicide resis-tance, common exchange of plant and insect pests among continents similarly imperils pesticidesusceptibility (see [22] for examples).

Priorities for Coevolutionary GovernancePriorities for governing coevolution can be derived from analysing the structure of selection andconnectivity in human–environment systems. Here we focus on the overarching challenge ofshifting away from the escalating coevolutionary dynamics of alternating increases in biocideuse and biocide resistance. We propose three priorities for shifting cultural evolution towardachieving that goal (Figure 1B). The first is to promote cultural evolution of mental models and so-cial norms that reduce unnecessary biocide use. The second is to diversify practices to reducedirectional selection on the basis of systematic evaluation of new technology as well as principlesunderlying past practices. The third priority is promoting collective action to govern connectivityfrom the local to the global scale, which will help reduce the spread of resistance. A range ofcase studies illustrate the implementation of these priorities for biocide resistance in the contextof production systems and health systems (Figure S1 in the supplemental information online).

Priority 1: Shifting Mental Models and Social NormsMental models and social norms play an important role in determining which solutions are appliedto a problem [29,30] and can become engrained as part of emergent world views or ideologies[31]. Norms are embedded in cultural and historical contexts, underpin legal systems of action,can evolve with changing conditions, and may arise around novel opportunities such as thoseafforded by new technologies. The multigenerational state shifts in practice brought about byindustrially produced biocides and transgenic crops can make agricultural communities andbroader society more likely to assume that new pesticide technologies will continue to replacecurrent ones, should widespread resistance become a problem [32]. The importance of thischange in perception is supported bymodelling showing that the time horizon of farmers is impor-tant for how likely they are to implement resistance management strategies [33,34]. To shift theseevolving perspectives, initiatives to lower excess antibiotic prescribing illustrate that social normfeedback, including from authorities and peers, can substantially reduce antibiotic prescribingat low cost and on a national scale [35,36].

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Priority 2: Systematically Diversifying PracticesEvaluating opportunities for integration of new as well as old technologies and practices is apriority for meeting the challenge of systematic diversification. Although focus is often onnew technological opportunities, the advances of modern medicine and agriculture can some-times lead us to forget the practices of the past that, in combination with new technologicalcapabilities and scientific insights, can help build critical resilience [10]. Signs of systematicprioritisation of diversity are emerging. The diversity provided by some experienced-basedpractices in agriculture was adopted under the name of IPM in the middle of the 20th century(Figure S1A in the supplemental information online). IPM can help reduce pesticide use(Figure S1A1 in the supplemental information online) and is often mandated in industrialisedagriculture to reduce resistance as well as pesticide health risks [24] (Figure S1A5 in the sup-plemental information online). Especially for transgenic Bt crops but also for other insecticides,the old tradition of planting refuges where insecticides are not used has been key to slowingresistance evolution [21].

Likewise, in human health, recent events associated with antibiotic use have necessitatedre-evaluating established practices. For example, the origin of the important antimalarialdrug artemisinin in Chinese traditional medicine demonstrates the value of historical usesfor expanding the repertoire of current medicines [37]. More broadly, our rapidly developingknowledge and technological expertise give reason for reconsidering opportunities for mas-tering practices beyond pharmacotherapy, practices that once were considered unsafe andundesirable. A rapidly shifting perspective in Western medicine is in the understanding of themultiple and complex roles of microorganisms in human–microbe interactions and the riskthat antibiotics disrupt these symbioses [38]. Microorganisms are increasingly recognisedas a contribution rather than principally as a threat to human health. Resistant coinfectionsof virulent new strains of Clostridioides difficile (formerly Clostridium difficile) in patientspreviously treated with antibiotics infect 450,000 and are involved in 30,000 deaths in theUSA annually [39]. These infections can be treated with faecal transplants that restore thegut microbiome to a healthy state (Figure S2 in the supplemental information online).

Priority 3: Collective Action for Governing ConnectivityDecisions about whether to use a pesticide or administer an antibiotic tend to be taken in consul-tation with crop consultants and fellow farmers or with doctors and family, respectively. There isincreasing evidence that trust, participation, coordination, and regulation are important for effectiveresistance management. For instance, high levels of competition can undermine trust betweendoctors and patients and lead to antibiotic overprescribing in areas of the USA with high densitiesof health care providers [40] (Figure S1B1 in the supplemental information online). Building trustthrough engagement and local monitoring may help overcome perceived barriers of collectiveaction in the adoption of IPM (Figure S1A1–A4 in the supplemental information online). At theregional or national level, taxing particularly harmful pesticides can help lower their use and encour-age IPM (Figure S1A5 in the supplemental information online). Similarly, the regulation andmonitor-ing of non-Bt refuge requirements in the USA and Australia have been important for thesecountries’ relative success compared with countries such as Brazil and India, where resistancehas evolved rapidly [21]. The potential international significance of such decisions is illustrated bythe recently documented intercontinental transfer of insect pests that could be carrying insecticideresistance genes [22].

As the global spread of resistance increasingly undermines national efforts, the need is growingfor new types of international institutions (i.e., accepted formal or informal practices) [23]. In atime of consolidated seed production, there remain opportunities for such institutions to govern

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global dynamics by eliminating perverse incentives. For example, use of single-toxin andmultitoxin Bt crops that share common toxins facilitates the evolution of resistance to multitoxins.Incentives for rapidly withdrawing single-toxin crops when multitoxin crops become available willhelp limit resistance [41]. In the absence of international legally binding instruments that regulatebiocide use and harmonised surveillance, targeted interventions are of high importance.Following the international spread of plasmid-borne colistin resistance, likely fromChina, a diversearray of organisations engaged with the Chinese government to lobby for restricting use of colistinas a growth promoter [42]. However, for successful reduction of antibiotic use and resistance,governments need to implement their national action plans following the guidance of the WorldHealth Organization global action plan on antimicrobial resistance (AMR) [23,43].

Coevolutionary Governance and Sustainable DevelopmentGovernance of resistance evolution occurs in a complex societal context with multiple and some-times conflicting political agendas. Understanding these agendas can help guide the applicationof coevolutionary governance by identifying suitable solutions and leverage points. Sustainabledevelopment, concretised by the SDGs, illustrates these many competing ambitions. In thissection, we discuss how coevolutionary governance of biocide resistance can be guided byand integrated with actions striving to achieve sustainable development. We identify two keySDGs for leveraging coevolutionary governance of biocide resistance, namely sustainableproduction and consumption and good health for all (Figures S3 and S4, Boxes 1 and 2).

Priority 1: Shifting Mental Models and Social NormsA general challenge in promoting new perspectives in production and consumption is thelimited knowledge we have about the implications of typical sustainable development strat-egies, such as agricultural intensification, on antibiotic and pesticide use [44]. These knowl-edge gaps mean that new perspectives will have to be promoted in the context of bothincreasing risks and high uncertainty. From a production perspective, a potential approachto reducing antibiotic use and pesticide use while contributing to sustainable developmentis to use ecological intensification strategies [45] that promote regulating and provisioningecosystem services, such as biological control in crop agriculture and microbially enhancedimmunocompetency in livestock [22]. For consumers, one dominant perspective that rein-forces excessive antibiotic use is the norm of wasteful and meat-heavy diets [26,44]. Forpesticide use, prevailing norms about the aesthetic appearance of fruit and vegetables in re-tail necessitates higher amounts of pesticides or other environmentally intensive means ofproduction and storage [46].

In human health, improved basic hygiene and sanitation go a long way toward reducing theincidence of bacterial infections (Figure S3 in the supplemental information online), but newresearch funding is disproportionately directed to innovation of therapeutics [47]. From 1990 to2015, the number of countries with more than 90% of the population having access to improveddrinking water and sanitation increased by approximately 50% [48]. Yet, at the global level,946 million people still defecate in the open, and 9% of the global population lack accessto safe drinking water, emphasising the importance of a continued focus on improved water,sanitation, and hygiene [48].

Priority 2: Systematically Diversifying PracticesThe successful promotion of the above perspectives relies on the implementation of a diversity ofpractices in production and consumption, as well as in health systems. In production, beyond thepromotion of IPM in crop production, aquaculture is a tremendously diverse practice that canprovide alternative and potentially more sustainable protein sources [49]. However, aquaculture

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Box 1. Antibiotic Resistance and Sustainable Development

Antibiotics are widely used for both human health and food production, and antibiotic resistance therefore epitomises thechallenge of governing coevolution in the context of interlinked sustainable development goals [5,43] (Figure S3 in thesupplemental information online). Because we are unlikely to see new and widely available classes of antibiotics on themarket before 2030, we must preserve susceptibility to current antibiotics [22,23,38]. Succeeding with this goal is anenormous challenge because the demand for antibiotics for both animals and humans is projected to increase drasticallyunder business-as-usual conditions [25,26].

Themain opportunities for decreasing antibiotic use for humans through sustainable development are (i) improving hygieneand sanitation to reduce infection rates, (ii) changing health systems to improve treatment and prevention, and (iii) reducingpoverty. Infectious diseases are among the largest contributors to global mortality rates, especially among children, andtherefore one of the greatest challenges to achieving the goal of universal good health [1,5,18,43]. Treatment of infectiousdiseases accounts for a large proportion of global antibiotic use; yet, insights about how global progress in preventinginfectious diseases translates to reductions in antibiotic use are hampered by lack of monitoring of the latter. With regardto sanitation, antibiotics are used to treat an estimated 494million diarrhoea cases annually just in Nigeria, India, Indonesia,and Brazil, and unless the sanitation infrastructure is improved by 2030, this number is estimated to increase to 622 million[18]. Providing universal access to improved water and sanitation in these countries could reduce the volume of prescribedantibiotics by 60% [18]. The pressing need for improved access to universal health care (UHC) is illustrated by the fact thata minimum of 50% of the world’s population lack full coverage of essential health services [53]. In this process of providingUHC, it is important to consider the economic structure of health systems to reduce poverty and facilitate sustainable useof antibiotics. Finally, the twomain opportunities to decrease antibiotic use in food production are (i) dietary change towardreduced meat consumption and redistribution of the resources used to produce animal protein, which will help improvefood security and reduce hunger; and (ii) sustainable ecological intensification of production systems, which will helpaddress climate change, biodiversity loss, and land and ocean degradation [22,26].

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also poses challenges to resistance management stock, highlighting the importance of a diversityof locally adapted practices. For example, although a vaccine used in Norwegian salmonaquaculture has reduced antibiotic use there to almost zero, it is not as efficient for salmon farmedin Chile due to a complex set of biological and operational factors [49] (Figure S1B4 in thesupplemental information online).

At the consumer level, the potential for reducing biocide use and other environmental harmsthrough purchasing of quality, local, or in-season products depends on context [50,51]. Organic

Box 2. Pesticide Resistance and Sustainable Development

Compared with antibiotic resistance, resistance to insecticidal and herbicidal pesticides exhibit more limited geneexchange between human health and production systems. Pesticide use mainly takes place in crop production and con-sumption with complementary uses in domestic and industrial pest control and human health (especially for vector con-trol). With projected increases in global population and national economies, pesticide use will likely increase in thefuture, although no formal projections have been attempted as they have for antibiotics. Many analyses often assume thatfood production must intensify to feed a growing and wealthier population but are vague on the means through which thisintensification will take place [44]. Whether such increases in yield take place through increases in agricultural inputs, suchas pesticides, or through intensification of agroecological management practices will have great impacts on pesticideresistance and ultimately on the sustainability and plausibility of these scenarios [60].

The main opportunities for reducing and improving pesticide use are through change in consumption and productionpatterns (Figure S4 in the supplemental information online). Ecologically sustainable intensification can help reducepesticide use, biodiversity loss, climate change, and land and water degradation while improving food security andreducing hunger [44,45]. The main opportunities for improving pesticide use through sustainable development is reducingpoverty, which will improve farmer capacity to reduce pesticide misuse and consumer capacity to buy products with lowand less harmful pesticide use. Evidence suggests that a significant proportion of pesticide use could be removed to thebenefit of farmers, consumers, and society in general, especially in low- and middle-income countries, but also withoutcompromising yields among producers in some large, high-income countries [61]. For example, 78% of pesticide use inThailand was described as unnecessary overuse from both a private and societal perspective [62]. Studies in thePhilippines and Ecuador estimated that reduced pesticide use could lessen acute health problems, increase labour pro-ductivity, and increase farm profits [63,64]. In Africa and Asia, wider adoption of integrated pest management resultedin a yield increase of 40% and a 30% decline in pesticide use, suggesting that at least 50% of pesticide use was notneeded in many agroecosystems [65].

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Outstanding QuestionsBiocide resistance provides a classiccase of human–environment coevolu-tion and a clear example of where co-evolutionary governance is needed.However, major questions need to beanswered to better understand thegeneral potential of coevolutionary gov-ernance in social-ecological systems:

• What are other applications ofcoevolutionary governance to societalchallenges, such as climate change,fisheries management, and biodiversityconservation?

• What are limitations of the currentframework in its application beyondbiocide resistance and associatedneeds for innovation or integration, suchas identifying common coevolutionaryregimes beyond (de-)escalation?

• What are practical methods formonitoring of cultural evolution?

•What is the potential for integrating thewealth of data on human behaviourgathered by digital technologies forunderstanding cultural evolution?

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products, for example, tend to have lower antibiotic use than conventional production forms aswell as lower prevalence of multiresistant bacteria (in meat) and pesticide residues (in produce),with one estimate of 30% overall risk reduction [50,51].

In human health, effective health systems use a diversity of strategies in the pursuit of limitingantibiotic misuse. Access to such systems through universal health coverage (UHC) can reducemortality, limit the incentives for self-medication, and reduce unregulated sales of antibiotics(Figure S3 in the supplemental information online). UHC can improve access to a range of keyservices, such as vaccines, with 11.4 million annual antibiotic days per year potentially avoidedin children younger than 5 years of age through universal coverage with the pneumococcalconjugate vaccine [19].

Priority 3: Collective Action for Governing ConnectivityInstitutions for collective action are needed to realise a number of synergies for decreased biocideuse and the SDGs. Promising examples of where IPM implementation on an areawide, collectivebasis has succeeded and where individual, farm-by-farm approaches have previously failedcould help overcome persistent obstacles to further IPM adoption [52]. Additionally, large-scaletraining of millions of smallholder farmers have proved successful in enhancing yields andlowering nutrient-related environmental pressures with 10–15% without increasing pesticideuse [53].

Collective action is also key to the pursuit of providing UHC while reducing antibiotic misuse asout-of-pocket health expenses push close to 100 million people into extreme poverty everyyear [54] (Figures S3 and S4). For example, the median overall cost of treating sepsis causedby resistant pathogens in India corresponds to 442 days of wages earned by a rural maleworker [55]. These out-of-pocket expenditures are strongly correlated with resistance inLMICs, likely because patients are pushed into the less well-regulated private sector topurchase medicines [56]. Finally, with slow political progress in limiting antibiotic use in animalproduction, alternative collective action strategies are needed. Here, pressure from consumergroups has pushed some fast-food restaurants to increase transparency about meat sourcingin relation to antibiotic use [23].

Concluding RemarksUnderstanding how human cultures and living environments coevolve provides key lever-age points for governance toward sustainability. Because biocide resistance is a challengecharacterised by tightly coupled coevolutionary dynamics, it can also inform the waysociety faces other problems where ungoverned environmental change risks underminingsustainable development (see Outstanding Questions). For such benefits to materialise,online learning platforms for empirically studying and synthesising evidence on thesocial-ecological dynamics of biocide resistance and other environmental challengeswill be important because they can provide distributed mechanisms for uptake of newinsights. Such platforms will also be able to inform much-needed consolidated sciencepolicy interfaces, such as the proposed independent panel on evidence on AMR, whichwould allow for an integrated coevolutionary approach to inform lasting global governancemechanisms.

Author ContributionsP.S.J. conceived of the manuscript on the basis of discussion with all coauthors. P.S.J., C.F., K.M., P.J.G.H., M.T., and A.Z.

wrote the first draft of the manuscript with subsequent contributions from all coauthors. All data are available via the references

cited in the article.

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AcknowledgmentsWe acknowledge support from theMistra Foundation, the Erling Persson Family Foundation, Kjell andMärta Beijer’s Foundation,

FORMAS (2016-00451, 2016-00227), and the Swedish International Development Cooperation Agency (SIDA; P.S.J., C.F.,

P.J.G.H., M.T). P.S.J. acknowledges funding from the Carlsberg Foundation (CF14-1050, CF15-0988). P.J.G.H. is funded by

FORMASSeaWin project (2016-00227) and undertook thework as part of theCGIARResearchProgramon FishAgri-Food Sys-

tems (FISH) led by WorldFish. A.Z. acknowledges funding from SIDA. K.M. acknowledges funding from Uppsala University. The

Living with Resistance project is supported by the National Socio-Environmental Synthesis Center (SESYNC) with funding from

National Science Foundation grant DBI-1639145 and led by P.S.J. and S.P.C.

Supplemental Information

Supplemental information associated with this article can be found online at https://doi.org/10.1016/j.tree.2020.01.011.

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