Why We Should Reexamine the “Golden Age” of Antibiotics in Social ...

Abstract

Economics is the primary discipline used to understand supply chain design, scale-up, and management. For example, antibiotics can be compared to other forms of “tragedy of the commons,” whereby a common good (effective treatment of infections) is jeopardized by individual consumption and lack of community oversight and stewardship. While economic analysis can explain innovation decline in terms of market failure, one pitfall of an early-stage focus on research and development is a failure to challenge the discovery narrative. Ethics also has a distinct place in helping us envision alternatives to what markets can produce. This article advances a more contextualized view of how science and technology policy has shaped antibiotic supply chains over many years, emphasizing how shifting the story we tell about past successes is central to securing a reliable antibiotic supply chain in the future.

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Effectiveness Paradox

Antimicrobials are treatments for microbial infections caused by bacteria, viruses, and fungi. Antibiotics are medicines especially used to treat bacterial infections. Penicillin was the first antibiotic and effective treatment developed for bacterial infections encompassing pneumonia, gonorrhea, and rheumatic fever.1 Penicillin’s reduction in human suffering is neither qualitatively nor quantitatively simple to capture, but the medicine has saved millions of lives and improved human life expectancy for many. However, antibiotics present an “effectiveness paradox”: the more they are used, the less effective they become. Repeat exposure of bacteria to an antibiotic can generate the conditions that select for resistance, or the capacity of colonies to survive despite treatment. One recent study estimated that over 1.27 million deaths in were attributable to bacterial antimicrobial-resistant infections.2 As antibiotic resistance is increasing globally, so, too, is demand for last-resort medicines that can effectively treat resistant infections.3 The effectiveness paradox can be compared to other forms of “tragedy of the commons,” whereby a common good (eg, effective treatment of infections) can be jeopardized by individual consumption.4 However, as Hardin recognized, ethics has a distinct place in helping us envision alternatives to the tragedy of the commons.5 This article advances a more contextualized view of how value-driven science and technology policy has shaped antibiotic supply chains over the years,6 emphasizing how the story we tell about past success is central to securing access to antibiotics in the future.

A Story of Antimicrobial Innovation

The sheer magnitude of lives saved by antibiotics is a staggering public health, medical, and humanitarian achievement. It is unsurprising, then, that the advent of antibiotics is among the historical developments that have the hallmarks of heroic stories. The discovery narrative is linear, simple, and marked by regular innovations of distinctive scientific personalities. Commonly depicted along a timeline, the s to s period of antibiotic development is often referred to as the “golden age” of antibiotics (see Figure).7,8

Figure. Dominant Narrative of Antibiotic Discovery

Data sources: Iskandar K, Murugaiyan J, Hammoudi Halat D, et al7; Silver LL8; Ventola CL9; National Research Council10; Davies J, Davies D11; Rahman MM, Alam Tumpa MA, Zehravi M, et al.12

The discovery narrative is in keeping with Paul De Kruif’s depiction of big scientific personalities as primary enactors of scientific achievement, which he chronicled in his influential book, Microbe Hunters.13 De Kruif focused on microbiologists of the 19th century, and his account is one of steady progress: “it is sure as the sun following the dawn of tomorrow, that the high deeds of microbe hunters have not come to an end; there will be others to fashion magic bullets.”13 Independently of who merits credit for the achievement of identifying penicillin’s medical utility and refining its production, Alexander Fleming’s ability to fit within the discovery narrative might partly explain the messy media storm that characterized him as the sole scientific genius who revolutionized medicine with penicillin.14,15 In contrast, Howard Florey’s more reserved personality and his team’s collective efforts to purify and test the effectiveness of penicillin at the University of Oxford garnered much less public attention and received delayed recognition.15

Diverging from De Kruif’s vision of steady progress, contemporary drug development is frequently depicted as an era of a “discovery void” following an “innovation gap” in which new antibiotic drug development petered out in the s and s (see Figure). The same timeline of bygone halcyon days followed by a fallow period has been presented across popular media, pharmacology, microbiology, and policy.7,8,9,10,11,16 The failure of the 21st century to live up to the promise of progress clashes with a protagonist-driven account of how scientific success occurs. For antibiotics, the oft-unexamined link between discovery and scientific heroism is so tight that, for the last decade, the phase following the “lean years” on timelines has been depicted as one of “disenchantment,”—a future that is oddly anachronistic, given that it is often explicitly depicted as a post-antibiotic return to the s and the time of Semmelweis, a physician from 200 years ago with no antibiotic armamentarium except his (widely ignored) advocacy of hand hygiene.11,12 It is notable that within the discovery narrative, there is little examination of how scientific heroism accords with a profit motive. (See Supplementary Appendix on economic concepts related to antibiotic resistance.) This lacuna in the dominant narrative of penicillin is especially striking, as patent debates marked disagreements within the scientific community from the very beginning.17 Timelines like those in the Figure demonstrate how discovery narratives continue to shape popular understanding of how science progresses. Gaps in our understanding of what drives functional antibiotic supply chains are partly due to this tendency to decouple the history of science from its social and political context.

Some turn to economics to account for the contrast between antibiotics’ profound contributions to human well-being and the current period of innovation stagnation, seeking a solution to the tragedy of the commons in a market-driven pricing model.18 It has long been widely recognized that markets confront serious limitations in their ability to supply medical services efficiently.19 Antibiotic market failures that lead to the detriment of social well-being are depicted as “deviations” from ideal economic market dynamics that concern only 2 parties (producers and consumers) and a range of stipulated conditions that enable markets to efficiently meet consumer needs. More specifically, economic analyses emphasize how, since the s, the lack of landmark antibiotic discoveries is due to sudden or newly emerging market failures such as lack of large profit margins (when compared to treatment for chronic diseases), price deviations from social value, and stewardship practices that undermine sales by volume.20 A perception that market incentives for antibiotics are misaligned has led to developments such as CARB-X (Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator), a nonprofit organization that funds preclinical and early phase novel antimicrobial research.21

Economics does provide one way to understand the market failures that contribute to a paucity of innovation and can be consonant with ethical perspectives.22 Antibiotic resistance is a prime example of an externality that contributes to market failure: a cost borne by society as a whole as infections become more difficult to treat. Industrialized agriculture pollution of waterways that results in antibiotic resistance is another form of externality.23 However, lumping together many structural failures under the label of “externalities” can conflate the value of antibiotics as prevention and treatment, obfuscate the responsibilities of states to protect public health, and evade identification of social structures that supply goods in ways that go beyond consumer satisfaction and efficiency (eg, equitably and sustainably). Other examples of market failure in antibiotic supply include monopoly (oligopoly) power of biopharmaceutical companies, which is sustained by high up-front innovation costs and control over manufacturing processes that leads to noncompetitive drug pricing and inadequate geographic dispersion of production capacity and supply chains.

In the next section, I explore how redirecting attention to science and technology policy provides a more comprehensive account of our past than economic explanations of market failure consonant with the discovery narrative’s focus on early-stage antibiotic research and development. I also discuss obstacles to policy change and recommended policies for moving forward.

Early Antimicrobial Production and Distribution

It was not only novel discoveries but also innovative approaches to science, technology, and health policy that rendered penicillin effective, available, and accessible both during and after the Second World War. For a short but incredibly intense period in the s, the US government scaled penicillin production by modifying policies on trade secrets, property rights, antitrust regulations, and drug licensure.5,13,14 The US War Production Board (WPD) broke down the barriers of trade secrets by creating consortia of private companies, academic partners, and government agencies whose members were incentivized to share and develop industry-wide best practices for antibiotic quality and scalable production. Moreover, in contrast to the narrative of scientific heroism, it was highly collaborative cross-industry and multinational structures that led to rapid innovation and scaling up of manufacturing.5 This section provides an overview of how functional antibiotic supply for some populations was previously achieved through strategic national objectives combined with shifts in domestic and global policy encompassing science, trade, and humanitarianism.

Strategic national objectives. During the Second World War, the US government’s compelling interest was to prevent and treat infections of Armed Services personnel on the front line. The WPD consortium increased penicillin supply in part by creatively utilizing American farmers’ know-how and existing resources. For example, an agricultural research laboratory in Peoria, Illinois, helped adapt deep fermentation processes using corn-steep liquor to increase the penicillin content in each production batch.24 Meanwhile, in the United Kingdom, penicillin was such a precious resource that its use was restricted to objectives integral to the war effort. In , Florey himself provided some doses to veterinarians addressing mastitis infections in cows; dairy farms were crucial to a populace whose diets were severely limited by international shortages.25

Domestic trade policy. Notably, intellectual property policies were also rearranged to support domestic penicillin development and manufacturing scale-up. Scientists in the Oxford group disagreed about the wisdom and ethics of obtaining a patent, including about whether products as opposed to processes could be considered intellectual property. Such disagreements are especially pertinent to bioethics, as it was an ethical obligation to serve humanity that shaped Florey’s decision not to patent the Oxford team’s process for producing penicillin.13,14 Meanwhile, most US process patents were held by the US Department of Agriculture and widely licensed without royalties. Quinn contends that it was the absence of product patents that enabled commercial pharmaceutical companies to create novel reciprocal licensing arrangements, engage collaboratively in ways that were far superior to competitive research and development, and share information more effectively.5 With scientific cooperation surreptitiously hidden from Nazi occupying forces, a distinct Netherlands research group refined its own process. After the war, the group’s separate patent led to both more supply and lower prices.13

Global trade policy. During the postwar era, antibiotic availability was driven by other global policy shifts that sought to recognize the distinctive global value of antibiotics. US intellectual property arrangements may have supported scalability to meet needs within the Global North, but access in the Global South still lagged. The Indian Patents Act reshaped drug manufacturing globally, in part by abolishing product-based drug patents, enabling generic versions of drugs to be produced through reverse engineering of pharmaceuticals in India.26 Antibiotics have also been at the center of determining international implications of the rule of law. For example, India, Iran, and the Philippines filed suit against Pfizer for violation of the Sherman Act by establishing monopoly practices. In , in Pfizer, Inc v Government of India, the US Supreme Court recognized the status of sovereign nations to sue under US domestic law.27 India’s subsequent rapid development of pharmaceutical manufacturing, combined with a US regulatory abbreviated new drug application process in the s, allowed Indian manufacturers to avoid repeating clinical trials or marketing comparable generics in the United States, resulting in India becoming a current leader in world antibiotic manufacturing and the United States becoming the largest importer of their antibiotic exports.26

Global health policy. Because antibiotics are lifesaving, ensuring access to them has been a high priority in global health policy. However, global access to antibiotics is highly variable and fragile,27,28,29 both with and without a prescription.30 The World Health Organization (WHO) included antibiotics on its essential medicines list (EML) for the first time in .31 Although the WHO definition of essential medicines and its processes for listing medicines has changed over time, by the EML prioritized infectious disease health needs and articulated adequate antibiotic supply as a criterion of functional national health systems.32 More recently, the WHO has proposed categorizing antibiotics on the essential medicines list as Access, Watch, or Reserve, depending on their lifesaving potential and likelihood of generating resistance.33

Many of the economic strategies suggested by a discovery void narrative rely on leveraging policy to serve economic goals. Conversely, economics can be a tool by which we ascertain how well we are achieving antibiotic clinical and stewardship goals (eg, monitoring WHO Access-Watch-Reserve antibiotics). For example, Orubu and colleagues identified 16 indicators across the antibiotic supply chain that can be used to assess national capacity to ensure population access to antibiotics and mitigate inappropriate use, in part due to dispensaries outside the control of pharmacists.34 They found that over half of the licenses for antibiotic products in Bangladesh belonged to the WHO Watch group rather than the Access group; the authors contend that the proportion of licensed WHO Watch antibiotics on the market provides one way to measure misuse of antibiotics that might be replaced by treatment options with fewer risks of producing resistance.34

Moving Forward

Current policy interventions for mitigating the rise of antibiotic resistance are wide-ranging, including price controls, taxation, improved surveillance, legal reform, health services infrastructure investment, public and expert educational initiatives, pharmacy guidance, and regulatory oversight of agricultural or human use.35,36,37 Bioethics and social science have also offered a variety of contributions that draw on economic, anthropological, sociological, historical, and normative approaches.25,38,39,40,41,42,43,44 These discourses share the insight that the drivers of resistance are sufficiently complex that coordinated policy solutions that cross national and geographic boundaries are needed.45,46 As the Bangladeshi study demonstrates, attending to policy and socio-behavioral dynamics of antibiotic resistance also redirects attention to the evidence base for stewarding antibiotics, including both facilitators and barriers.47,48,49 Collaborative effort could leverage multidisciplinary insights, with cultural analysis50 and ethical analysis helping to identify values reflected in policy alternatives, values-based attitudes of stakeholders, and justificatory grounds of policy change. The resources listed in the Table focus specifically on policies that can improve antibiotic supply and distribution. These resources provide initial insight into formulating multidisciplinary research questions that can advance more contextualized approaches to antibiotic supply chain policy.

Conclusion

In sum, the “golden age” of antibiotics is arguably a sociopolitical story, one that recapitulates the tendency to nostalgically view the s through s as a bygone heyday of the United States’ rise to global dominance, including through strategic advancement of science and technology. The discovery narrative, however, fails to explicate how the benefits of antibiotics were and continue to be accrued by some groups while excluding others. Governments have always intervened in antibiotic production, and therefore the “innovation gap” does not reflect a novel state of market failure in antibiotic supply chains. Rather, the benefits and harms of antibiotic usage extend well beyond the innovation stage. Relinquishing the dominant, ahistorical discovery narrative is the first step to redirecting our analyses appropriately: toward questioning how the rise of antibiotics resistance has failed to generate the political will necessary to propel science and technology policies that prioritize access, equity, and sustainability.

In , Britain’s Chief Medical Officer Dame Sally Davies triggered what has amounted to half a decade of increasingly dire warnings about antibiotic overuse and antimicrobial resistance (AMR). Davies publicly likened AMR to a “ticking time bomb” (Walsh, ) and lobbied to include AMR in the UK’s National Risk Register of Civil Emergencies as a threat comparable to major coastal flooding or a catastrophic terrorist attack (Sample, ). Davies’ warnings were followed by a flood of expert reports, national action plans, and pledges to reduce antibiotic use by members of the World Health Organisation (WHO), the Farm and Agricultural Organisation (FAO), and the G20 (WHO, ; FAO, ; G20, ). In addition to subsidising antibiotic research and tackling human overuse, most actors have also committed to reducing antibiotic consumption in food production.

Achieving these reductions will not be easy. Globally, agricultural antibiotic use likely exceeds human consumption (Van Boeckel et al., ). Meanwhile, routine antibiotic use to treat and prevent disease, increase feed efficacy, and substitute labour previously devoted to the care of individual animals has acquired an infrastructural importance for many food supply chains. This antibiotic infrastructure is destined to undermine itself. Although agriculture’s overall contribution to AMR remains contested, new metagenomics research and cases like the recent global spread of colistin resistance from Chinese pigs are clarifying the true threat posed by agricultural AMR selection (Liu et al., ; Tran-Dien et al., ).

However, so far, knowledge of the threat posed by AMR has failed to translate into effective international plans for antibiotic reductions. Recent projections predict that growing meat consumption in middle- and low-income countries will lead to a 69% increase of global agricultural antibiotic use between and (Van Boeckel et al., ). The situation is hardly better in high-income countries. Although decades of increasing use have recently plateaued or declined in the US and some European countries, overall consumption remains high, many producers remain dependent on routine antibiotic use, and antibiotic-intensive productions systems are still being exported to other parts of the world (FDA, ; VARSS, ). While everybody agrees that something has to be done, a robust way of tackling global non-human antibiotic use has yet to emerge.

Looking back at the past eight decades of agricultural antibiotic use, this paper argues that the lack of effective international reform should not surprise us. What emerges from the archives is not a story of simple political or economic choices but a story of antibiotic proliferation that is intimately connected to the industrialisation and integration of global agricultural production as well as to Cold War promises of development and prosperity. On both sides of the Iron Curtain, the twentieth century saw more people eat more meat than ever before. Whereas average per capita global meat consumption totalled 24 kg in , it totalled 43 kg in . Although significant disparities remain between high- and low-income countries, meat consumption rose faster than global population growth. Unsurprisingly, rising demand has entailed substantial changes of global animal production, which grew 4–5-fold since (Ritchie and Roser, ). Although the beginnings of agricultural intensification, large confinement operations, and integrated supply chains predate the s (Fitzgerald, ; Saraiva, ), rising meat consumption and the farm as factory became powerful symbols of Cold War competition. By the s, industrialised animal production had emerged as an important export of both capitalist and non-capitalist systems to allies and non-aligned countries alike. Antibiotics’ role in this story of systems proliferation was initially that of a universal lubricant to control disease pressure, increase yields, reduce labour costs, and contain economic risks for producers. However, with farm sizes and productivity rising rapidly, their lubricant function was soon seen as essential for the smooth running of food production. Facilitated by rising meat consumption, ideological rivalry, and genuine market demand, the system of intensive and antibiotic-dependent high volume livestock production took on global dimensions.

The ensuing global spread of ‘antibiotic infrastructures’ (Chandler et al., ) in agriculture does not mean that they developed identically. Although the same substances were employed in the Midwest, Yugoslavia, and Japan, national and regional patterns of use could vary substantially. A similar variation also characterised perceptions of risk. Experts had been warning about antibiotic hazards since the s. While initial warnings were often ignored with reference to antibiotics’ immediate benefits in the quest to improve agricultural productivity, the following decades saw rising international concern over residues and AMR proliferation. Significantly, different publics prioritised different risks. This variation of risk perceptions both between nations and between different social groups has been studied intensively by historians and sociologists and strongly impacted antibiotic use and policymaking (Smith-Howard, ; Morris et al., ; Etienne et al., ; Hockenhull et al., ; Begemann et al., ): some countries decided to target antibiotic residues in food and milk, others decided to tackle agricultural AMR selection, and others decided to do nothing at all. Although it is beyond the scope of this paper to reconstruct national case studies in detail, varying risk perceptions, economic imperatives, and local patterns of use had given rise to a global patchwork of antibiotic regulations by the early s. This regulatory patchwork fragmented further over the next three decades and proved unable to curb either antibiotic use or AMR. In the vast majority of countries, antibiotic regulation ultimately remained subject to a risk benefit matrix, which prioritised the fiat of cheap and reliable protein over more abstract considerations of antibiotic stewardship.

In many ways, current policymakers remain subject to the path dependencies and blind spots of the past 80 years of antibiotic use and regulation. Acknowledging our rootedness in these structures is a necessary first step to reforming them. While recent reports present AMR as a monolithic challenge to be solved via narrow reforms and national antibiotic reductions, this essay argues for more adaptable, multi-faceted, and long-term global reforms. For interventions to be successful beyond the nation state, they will have to take into account the complex cultural, political, and economic systems driving global antibiotic use on factory farms and backyard operations alike. Effective policies will also have to adapt quickly to constantly evolving AMR research and production systems. Finally, the story of regulatory failure featured in this essay also serves as a warning not to displace blame for drug overuse on middle- and low-income countries. Having pioneered and exported antibiotic-dependent production and consumption since the s, high-income countries have a moral responsibility to contain the fallout of these systems in other parts of the world.

The history of agricultural antibiotics begins with the synthetic sulphonamides. In , German pharmaceutical manufacturer Bayer marketed Prontosil (sulfochrysoidine). Prontosil was the first effective drug against Gram-positive infections and a commercial success (Lesch, ). By the end of the decade, Prontosil and other often closely related sulphonamides had ushered in a new era of chemotherapy. The drugs were also introduced to agriculture. In Britain, Prontosil and other sulphonamides like sulphapyridine were marketed for use in animals from onwards.Footnote 1 What would eventually come to be termed biological antibiotics were also adopted rapidly. In , gramicidin was used to treat a mass outbreak of mastitis (udder infection in cows) at New York’s World Exhibition (Bud, ). The wartime importance of milk production also meant that precious penicillin supplies were tested against mastitis in both Britain and Denmark as early as (Woods, ; Cozzoli, ).

While the Second World War constrained European drug manufacturing, US companies like Merck, Pfizer, and American Cyanamid emerged as leading producers of synthetic and biological antibiotics. With strong interwar links connecting US pharmaceutical and feedstuff companies (Landecker, ), researchers also trialled the mass-medication of entire herds and flocks. Medicated feeds and water not only promised to curb disease in concentrated animal populations but also to raise productivity by reducing the expensive labour spent caring for individual animals. In , Merck’s sulfaquinoxaline was the first antibiotic to be officially licensed for routine inclusion in poultry feeds against coccidiosis. Antibiotic use also increased in other areas of US food production: sulphonamides were used against foulbrood in commercial bee hives; biological antibiotics curbed infections in farmed fish; and antibiotic tubes against mastitis proved popular in the dairy sector (Jones, ; Lesch, ; Campbell, ; Smith-Howard, ; Kirchhelle, ).

Nontherapeutic antibiotic use soon proved equally lucrative. Investigating antibiotic fermentation wastes as an alternative source of expensive vitamin B12 feed supplements, researchers at American Cyanamid’s Lederle Laboratories found that unextracted antibiotic residues were capable of increasing animals’ weight gains. Feeding low-dosed antibiotic growth promoters (AGPs) was also believed to prophylactically protect against bacterial disease (Finlay, ; Bud, ; Finlay and Marcus, ). Following the announcement of the antibiotic growth effect in late , Lederle sales boomed. Across the US, the new feeds were rapidly adopted by farmers eager to supply booming post-war demand for meat. According to AGP co-discoverer, Thomas Jukes, Lederle was soon selling “tankcars of brine containing residues from the fermentation” (Jukes, ). The new B12/AGP feeds proved particularly popular in the corn-rich Midwest and were officially licensed in . On farms, the boundaries between growth promotion, therapy, and prophylaxis soon blurred. Meanwhile, industry scientists devised further non-human antibiotic applications as a lucrative source of revenue beyond the seemingly saturated human antibiotic market. By the mid-s, streptomycin sprays and solutions were used to treat and prevent bacterial plant infections while tetracycline preservatives delayed spoilage in US fish, shellfish, and poultry (Kirchhelle, ).

Promoted by manufactures and authorities like the US High Commission in West Germany, it did not take long for new antibiotic applications to cross the Atlantic (Cozzoli, ; Kirchhelle, ). Although European veterinarians were already using antibiotics to treat individual animals, the end of rationing, falling drug prices, and new AGPs led to a rapid expansion of overall antibiotic consumption. AGPs were licensed for use without veterinary prescription in West Germany in , in Britain in , in the Netherlands in ,Footnote 2 and in France in (Thoms, , Kirchhelle, ).Footnote 3 Most countries initially licensed penicillin, oxytetracycline, and chlortetracycline growth promoters. Probably due to its strong penicillin industry (Burns, ; Burns, ), the Netherlands only licensed tetracycline AGPs in (Witte, ; Manten et al., ).Footnote 4 In Britain, a legal loophole also enabled the use of tylosin (Kirchhelle, ). In France, the three standard AGPs were soon joined by erythromycin and—on a smaller scale—by oleandomycin, spiramycin, neomycin, and framycetin. In West Germany, bacitracin, oleandomycin, taomycin, and flavomycin AGPs were also licensed (Manten, ; Tiews, ). In contrast to the US, farmers could usually only purchase premixed antibiotic solutions and feeds. West European veterinarians thus retained far greater control over antibiotics than their US colleagues, whose post-war loss of influence was exacerbated by farmers’ easy antibiotic access (Jones, ; Smith-Howard, ).

Europeans’ rapid licensing of AGPs was in part due to genuine agricultural demand and in part due to post-war policies designed to reduce feedstuff imports, free agricultural labour for industry, and increase livestock production and consumption. Uptake also varied between different livestock sectors. Medicated feeds were adopted rapidly in the poultry sector. Importing US breeds and confined housing systems, producers like Geoffrey Sykes in the UK, Heinz Lohmann (Wiesenhof) in West Germany, and CipZoo in Italy developed large-scale integrated production facilities. Similar to the US, rising animal concentrations were facilitated by routine antibiotic use (Thoms, ; Godley and Williams, ; Tessari and Godley, ). Pig and cattle producers were more selective. While areas with cheap grain access along the North Sea coast gradually adopted confined and more antibiotic-dependent forms of pig production during the s, the smaller and varied structure of pig operations in other areas reduced antibiotic uptake. In Britain, mixed feed trials, popular outdoor systems, and the fishing industry’s production of cheap alternative vitamin B12 disappointed initial projections of rapid AGP uptake (Woods, ; Kirchhelle, ).Footnote 5 In the cattle sector, producers’ frequent focus on dairy rather than meat production also made antibiotic additives less popular than in the US (Kirchhelle, ). Although there is thus not always a clear correlation between European intensification and antibiotic use, sinking drug prices and pressure for feed efficiency gradually overcame initial agricultural hesitancy. In , it was estimated that up to 50% of British pigs were fed antibiotics and that nearly all unweaned piglets had access to food containing tetracyclines (Williams Smith, ). Eight years later, West Germany’s Minister of Agriculture estimated that 80% of mixed feeds for young pigs, veal calves, and poultry contained antibiotic additives (Kirchhelle, ).

Similar to the US, antibiotics also entered other areas of European food production. Mostly streptomycin-based plant sprays and solutions were licensed from the mid-s onwards to combat American fire blight, a destructive bacterial disease of fruit trees and related plants, which had spread to Europe in . After extensive trials, the British government also licensed antibiotic preservatives for fish in (Bundestag, ; Kirchhelle, ). Although antibiotic preservatives did not prove popular in continental Europe, Norway and Iceland trialled the use of antibiotics to preserve whale meat. In the whaling industry, bacterial spoilage and long processing times posed significant problems. Before a harpooned animal could be processed, it had to be pulled in and inflated with oxygen to stop it from sinking—which increased autolysis. Even after processing commenced, carcases cooled slowly. In order to increase whale meat and offal yields, whalers began to experiment with tetracyclines around . Antibiotics were incorporated into explosive harpoons and injected into carcasses via inflation devices or aboard ships. The results were excellent: bacterial contamination and carcass swelling decreased while offal, meat, and oil quality increased. By , the Icelandic whaling station at Hvalurfjördur started routinely using Pfizer’s biostat (oxytetracycline). Norwegian and Soviet whalers soon followed suit (Tonnessen and Johnsen, ).

Therapeutic and nontherapeutic antibiotic use also spread to other US allies. Japan had launched its own antibiotic production trials during World War II. After , US developmental aid and new factories led to antibiotic self-sufficiency within 3 years (Bud, ). Licensing antimicrobial feed additives from onwards (Morita, ), Japan soon experienced its own agricultural antibiotic boom. Although it established residue limits and banned antibiotic preservatives, expensive fodder imports, limited land availability, and productivity-oriented policies fostered increasingly antibiotic intensive forms of livestock and fish production from the s onwards (Wesley, ; Morita, ). Antibiotics also acquired an important role in rice production. In , Japanese researchers isolated the streptogramin antibiotic blasticidin S. Licensed for use against rice blast disease in , blasticidin S. dusts and solutions were heralded as a safe substitute for mercury and arsenic-based products in the wake of contemporary organic mercury poisonings in the Minamata area. Further antibiotics like kasugamycin (licensed ), polyoxin (licensed ), and validamycin (licensed ) were also deployed against plant infections (Misato, ). Caught in a vicious cycle of AMR selection and higher-dosed treatment, Japan’s annual use of blasticidin S., kasugamycin, polyoxin, validamycin, streptomycin, and chloramphenicol-based plant products totalled over 14,000 tonnes by (Misato et al., ).

Non-human antibiotic use was not confined to capitalist countries. During the s, the Soviet Union (USSR) and China had also developed limited penicillin capabilities. However, production increased dramatically after when the US, Britain, and the United Nations Relief and Rehabilitation Agency (UNRRA) disseminated more advanced penicillin know-how. Expertise and non-commercial pilot plants were provided to Italy, Belarus, Ukraine, Poland, China, Czechoslovakia, and Yugoslavia (Bud, ). However, as a result of growing Cold War tensions, UNRRA was largely shut down in and Western exports curtailed. Antibiotic production and research subsequently emerged as a field of superpower rivalry and espionage (Krementsov, ; Cozzoli, ; Capocci, ). From the s onwards, communist publications regularly celebrated the construction of new antibiotic plants, antibiotic aid to communist or non-aligned states, and new ‘Soviet’ antibiotics like albomycin (), furacillin (), and grisemin (/57) (Gause, ; Suskind, ).Footnote 6 Communist antibiotic experts were also sent to Western countries as part of high-profile delegations.Footnote 7

However, behind the scenes, the Soviet bloc struggled to maintain reliable drug supplies. Throughout the s, Western diplomats and dissidents claimed that communist antibiotics were scarce and of poor quality. Those who could afford it preferred expensive Western imports.Footnote 8 In , the British legation to Budapest reported rumours about ‘positively lethal’Footnote 9 Hungarian penicillin exports to China. Although quality problems persisted, the overall supply situation gradually improved. In addition to penicillin and streptomycin, the USSR and Eastern European countries began to produce generic versions of illegally sourced proprietary Western tetracyclines from the mid-s onwards—albeit with names like tetran or biomycine.Footnote 10

Agricultural antibiotic use also became more common. In , experts at Moscow’s Soviet Agricultural Exhibition proudly demonstrated antibiotic mastitis treatments to rather unimpressed British delegates.Footnote 11 Attempting to ameliorate the effects of unpredictable harvests, Soviet planners were also interested in antibiotic preservatives and feed additives.Footnote 12 From the late s onwards, countries throughout the Soviet bloc began constructing factories for antibiotic/B12 supplements. Planners’ shift towards AGPs coincided with a new emphasis on increasing living standards and meat consumption as well as freeing agricultural labour via industrialised food production. In , Pravda announced that bottlenecks in livestock production would be overcome by integrating the fodder industry and feeding ‘bone and fish meal, fodder dregs, antibiotics, biostimulators, acidophilous preparations, and vitamins’.Footnote 13 In Bulgaria, construction of a new antibiotic plant began in Peshtera in . The plant was supposed to annually produce 200 tons of ‘Biovit-60’ (containing ‘biomycin’—probably chlor- or oxytetracycline—and vitamin B12), which would be sold in special fodder shops. Another chlortetracycline-B12 factory was constructed with the help of Soviet engineers in Iasi in Rumania in and further factories were planned in Czechoslovakia.Footnote 14 In the East German Democratic Republic (GDR), the early s had been marked by a crisis of drugs availability— in part caused by Soviet antibiotic requisitions for North Korea.Footnote 15 However, by , the GDR was producing its own penicillin, streptomycin, and chloramphenicol. Regular tetracycline production started with the help of modified Yugoslav cultures in the s (Schramm, ). Although complete GDR self-sufficiency was only achieved around (Thoms, ), available drugs were used to treat conditions like mastitis from the mid-s onwards (Müller, ). AGPs were made available around . Initially, penicillin and streptomycin were added to bone meal and other B12-rations. Tetracycline AGPs became available from ca. onwards (Nehring, ; Jeroch et al., ; Stock, ).

Agricultural antibiotic use not only spread in the northern hemisphere. Concerned about overpopulation and hunger-fuelled communism, American policymakers and researchers came to see the global export of yield-increasing technologies like antibiotics as a way of defending Western values (Cullather, ). US researchers also trialled antibiotic feeds to alleviate malnutrition in humans. In addition to s trials in the US, low-dosed “aureomycin candy” was fed to malnourished children in Guatemala (Podolsky, ).

The systematic export of surpluses and yield-increasing technologies suited both US farmers as well as larger pharmaceutical and integrated feed manufacturers. Fostered by US developmental politics, US antibiotics and feeds were soon being fed to livestock in Africa, South America, and Southeast Asia where governments were keen to modernise agriculture in order to trigger a ‘take-off’ of national economies. In , Antonio Santos Ocampo Jr from Arenata University expressed concern about the rapid increase of Philippine antibiotic use. Promoted by ‘Pfizer people’, ‘terramycin egg formula and the anti-germ 77 sells like hot cake’.Footnote 16 In South Africa, a dearth of veterinarians had led to the waiving of prescription requirements for many drugs in (Henton et al., ). Widely-advertised Anglo-American antibiotics soon proved popular on farms. A survey of large South African pig farms (producing ca. 10% of pigs slaughtered in ) found that ca. 80% of producers routinely fed antibiotic creep feeds—dietary supplements for young animals—to piglets for 2 to 3 weeks (Bakker and Davies, ). Other Western companies followed the example of US producers by building antibiotic plants abroad or by signing franchise agreements with local producers.Footnote 17

By the s, antibiotics were thus spreading rapidly throughout global food production. While reliable data from the Soviet bloc is difficult to obtain, the period between and saw total US antibiotic use increase over 11-fold from 690 to tonnes and non-medicinal antibiotic use (i.e., AGPs, sprays, etc.) increase over 30-fold from 110 to tonnes (43.3% of total use) (NAS, ).Footnote 18 In France, ca. 30 tonnes were added to animal feed in (François, ). In Britain, experts estimated that ca. 41% (168 tonnes) of all antibiotics were consumed by animals in —of which ca. 84 tonnes were feed additives (Swann, ). Commentators also noted that drug dosages in feed were steadily increasing (Weber, ). With farmers on both sides of the Iron Curtain under political and economic pressure to produce more animals more efficiently, easy access to antibiotics seemed necessary for further agricultural and societal development.

Spreading antibiotic infrastructures initially elicited few concerns. During the s and s, the vast majority of US and Soviet commentators celebrated agricultural antibiotics as a sound way to enhance animal productivity and preserve food. When Soviet leader Nikita Khrushchev visited US farms in , US commentators stressed the superior productivity of American farms and praised the widespread application of post-war technologies like antibiotics.Footnote 19 According to Britain’s Times, antibiotic preservatives were ‘the greatest advance in the field of processing perishable foods since the advent of refrigeration’.Footnote 20 Prevailing complacency changed only slowly in the face of growing concerns about antibiotic residues, antibiotics’ alleged facilitation of animal welfare abuse, and agricultural AMR selection. Significantly, concerns evolved in a fragmented fashion. Heavily influenced by different cultural risk perceptions (risk epistemes) and economic priorities, regulatory frameworks diverged (Kirchhelle, ).

In the US and West Germany, public concerns and regulatory action tended to centre on antibiotic residues, rather than AMR. Following long-standing complaints by dairies about antibiotics’ disruption of cheese production, consumers were shocked to learn that up to 10% of US milk samples were contaminated with penicillin during the mid-s. Residues occurred as a result of over-dosed mastitis treatments, farmers’ noncompliance with withdrawal times, and illegal antibiotic sprinkling into milk to delay spoilage. The bulked collection of milk from multiple farms also meant that drug residues from one cow could now contaminate thousands of litres of milk. When problems persisted despite stricter rules by the US Food and Drugs Administration (FDA), antibiotics became culturally associated with other dangerous chemicals suspected of ‘poisoning’ Americans or causing cancer. Under intense pressure, the FDA introduced the first national monitoring programme for penicillin residues in milk in (Smith-Howard, ). Six years later, similar public concerns and new residue detections resulted in the first national monitoring programme for antibiotics in meat and license withdrawals for antibiotic preservatives (Kirchhelle, ).

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In West Germany, antibiotic residues acquired a similar cultural status as dangerous chemistry (‘Chemie’). Rooted in interwar concerns about adulteration, degenerative disease, and cancer, s protest against chemical contaminants was fostered by prominent scientists like Nobel laureate Adolf Butenandt and pharmacologist Hermann Druckrey. Although the antibiotics involved were not carcinogenic, the prospect of US-style antibiotic food preservation evoked particularly strong public concerns about alleged invisible poisoning. In , West Germany’s new Food Law (Lebensmittelgesetz) explicitly banned antibiotic preservatives. Although officials managed to circumvent expensive residue monitoring by dubiously claiming that they were unaware of problems,Footnote 21 public concerns persisted. After spot tests revealed considerable residues in German meat, the government eventually introduced a mass-monitoring programme in the mid-s (Kirchhelle, ; Thoms, ).

Although they also established penicillin monitoring for milk in , British regulators were far more concerned about agricultural AMR selection. This concern was in part due to the bacteriological surveillance capabilities of Britain’s Public Health Laboratory Service (PHLS). In , PHLS data on AMR proliferation in agricultural settings led to the creation of the so-called Netherthorpe Committee. Strongly influenced by power struggles between British veterinarians and farmers, the Netherthorpe Report endorsed existing antibiotic use but recommended restrictions of future antibiotics. This initial compromise came under fire in when Ruth Harrison’s bestseller Animal Machines attacked alleged welfare abuses, drug overuse, and AMR selection on ‘factory farms’. High-profile warnings about ‘infectious AMR’ by PHLS researcher Ephraim Saul (“Andy”) Anderson enhanced public concerns about agricultural antibiotics. Building on s Japanese research, Anderson highlighted that bacteria could ‘communicate’ AMR by exchanging small fragments of extrachromosomal DNA called plasmids. This ‘infectious’ mode of AMR proliferation also occurred between different bacteria species (horizontal resistance transfer) and was capable of conferring resistance against multiple antibiotics simultaneously.

Anderson’s reports subverted existing risk models. Researchers had previously believed that certain bacteria were either inherently resistant to specific antibiotics or evolved new defence mechanisms via spontaneous mutations. Inherent or mutational resistance could then be passed on ‘vertically’ to subsequent generations. Vertical proliferation models made most experts think of AMR as a common phenomenon that could, however, be contained by: (1) curbing the spread of resistant bacteria via infection control; (2) reducing antibiotic selection pressure; (3) competitively inhibiting resistant strains with sensitive strains; (4) combining different antibiotics to reduce the chance of successful resistance mutations. Horizontal resistance proliferation undermined these control models by necessitating not only the organismal containment of bacteria but also the containment of mobile genetic elements. According to this ecological view of AMR, any form of routine antibiotic use greatly exacerbated the risk of AMR selection and genetic proliferation. Crucially, Anderson’s data showed that the selection and transfer of multiple resistance had taken place on British farms. A multi-resistant S. typhimurium had subsequently caused severe food poisoning outbreaks. According to Anderson, medically relevant antibiotics had to be restricted before uncontrolled agricultural use allowed more dangerous pathogens like Salmonella enterica serovar Typhi (typhoid) to acquire multiple resistance (Kirchhelle, ).

Under intense public pressure, British officials commissioned a major antibiotic review in . In November , the so-called Swann Committee recommended a series of reforms of which the restriction of medically relevant antibiotics to veterinary prescription was the most significant (Bud, ; Swann, ). Although critics argued that agricultural antibiotic use had not been shown to harm health, precautionary restrictions of medically relevant AGPs like penicillin and the tetracyclines were subsequently adopted by Britain (), member states of the European Economic Community (–), and Switzerland () (Lebek and Gubelmann, ; Castanon, ).

Outside of Western Europe, the adoption of AMR-oriented AGP bans was far from universal. Preoccupied with ensuring the purity of US food, FDA regulators tried to equate AMR and residue hazards in but failed to enact AGP restrictions (Finlay and Marcus, ; Kirchhelle, ). In the Soviet sphere, acknowledgements of antibiotic hazards did not lead to residue or AMR-oriented restrictions. The same was true in South Africa where veterinary warnings about drug overuse and the detection of antibiotic residues in ca. 5% of Johannesburg’s milk did not lead to substantial reform (Anon., ; Meara, ; Van Den Heewer and Giesecke ). In Japan, resistant plant pathogens led to rotating antibiotic use on fields but no wider revaluation of antibiotic use in livestock production (Misato et al., ).

While consumer concerns and moral panics had led to residue controls and precautionary antibiotic restrictions in individual countries, they were not widespread enough and of sufficient duration to trigger wider international reforms of agricultural antibiotic use or of antibiotic-dependent production systems. Once high-profile problems were perceived to have been fixed at the national level, public pressure usually evaporated. With no broader consensus on reform emerging, the increasingly kaleidoscopic nature of international regulations further diminished the prospect of sustained collective action against the growing global threat posed by AMR.

In the absence of meaningful international agreement on AMR risks or on measures to reduce drug dependencies, global antibiotic consumption surged. Between and , the amount of US antibiotics used for non-medicinal purposes (excluding sulphonamides) rose from to tonnes (NAS, ). Even countries with AGP restrictions in place experienced a further rise of antibiotic consumption. In Britain, a brief post-Swann dip was followed by an increase in the use of nontherapeutic antibiotics and of prescribed higher-dosed penicillin and tetracyclines (Braude, ). In Spain, a study found that roughly half of antibiotics were being consumed by livestock despite similar AGP restrictions (Santesmases, ). Meanwhile, antibiotic infrastructures spread to new countries and food production sectors.

In the US, feedlot systems drove a significant increase of drug consumption. Midwest feedlots had fattened cattle ahead of slaughter since the nineteenth century. However, as a result of the fencing off of grazing lands and cheap grain and corn feeds, the systems spread to other states from the late s onwards. By , nearly two-thirds of the US calf crop were placed in feedlots prior to slaughter. Feedlot conditions were conducive to antibiotic use. Since the s, owners had used antibiotics to treat infections like footrot. By the mid-s, experts also recommended prophylactic antibiotic feeds to counteract production-related conditions like liver abscesses caused by high-grain diets or depressions of carcase quality caused by hormonal growth promoters. A decade later, cattle producers began to use new ionophore antibiotics like monensin (Coban/Rumensin—licensed in ) to prevent bloat and coccidiosis and to enhance animals’ processing of high-roughage and grain diets. Within 10 years of monensin’s licensing, ionophores were being fed to over 90% of US feedlot cattle (Dyer and O’Mary, ; Perry, ; Owens et al., ; Kirchhelle, ).

FDA regulators were powerless to stop proliferating antibiotic use. Reacting to EEC AGP restrictions, the agency launched three abortive attempts to restrict penicillin and tetracycline AGPs between and . Calling for concrete proof of harm and employing counter science, pharmaceutical lobbyists successfully played on growing regulation wariness and concerns about ‘stagflation’ to defeat restrictions. With scientists appearing divided, Congress effectively imposed a moratorium on statutory AGP restrictions by calling for more research in . Six years later, a National Resources Defence Council petition to ban AGPs suffered a similar fate (Finlay and Marcus, ; Kirchhelle, ).

Despite having restricted some AGPs, the situation was only marginally better in West Europe. While rising antibiotic use on farms was driven by economic pressure and easy drug access, it was also enabled by lacking political transparency and self-assessment. Once an antibiotic policy package had been enacted, officials were often missionary in their zeal to foster reforms’ adoption abroad but lacklustre when it came to evaluating their own policies. In Britain, internal studies showed that partial AGP bans had failed to reduce AMR by the mid-s. However, the studies were embargoed and officials continued to preach the ‘Swann gospel’ of partial AGP bans abroad (Kirchhelle, ). A similar non-adjustment of AGP bans occurred in Switzerland (Lebek and Gubelmann, ). After being forced to establish national antibiotic residue monitoring, West German officials pressed for EEC-wide monitoring from onwards. However, officials reacted slowly to criticism of imprecise assay methods. Similar to rhetoric in other countries, criticism of patchy domestic legislation was deflected with reference to alleged German leadership when it came to policing antibiotics and worse conditions abroad (Kirchhelle, ).

Meanwhile, EEC restrictions of US broadspectrum AGPS also suited European pharmaceutical manufacturers. Since the s, companies like Bayer had used the spectre of AMR to promote allegedly safe nontherapeutic AGPs like virginiamycin.Footnote 22 During the s, officials were happy to aid pharmaceutical producers license new products and applications. West Germany’s Ministry of Agriculture actively encouraged temporal exemptions from EEC feed directives to trial new additives like Hoffmann LaRoche’s avoparcin or Hoechst’s bambermycin (flavomycin) in cow fodder. Licensing decisions were made despite internal concerns about compromised hygiene in the case of flavomycin and flawed AMR testing protocols in the case of avoparcin AGPs (Castanon, ; Kirchhelle, ).Footnote 23

European antibiotic use not only increased in livestock production but also in aquaculture and plant protection. Growing by over 8% p.a. from onwards (Culver and Castle, ), rearing systems for salmon and other species boomed along the North Sea coast with Scandinavia—particularly Norway—and Scotland emerging as hotspots.Footnote 24 Problems with bacterial and fungal infections fostered routine use of antibiotics like oxytetracycline, amoxicillin, and sulfadimethoxine-ormetoprim (Romet 30). In addition to selecting for resistance in farmed fish, almost 80% of these antibiotics entered maritime environments where they selected for AMR in sediments and wild fish and shellfish populations (Munro, ; Samuelsen et al., ; Black, ; Capone et al., ). Meanwhile, spreading fire blight led to an expansion of antibiotic spraying and dusting in Belgian, Dutch, French, German, and Greek orchards (Backhaus and Klingauf, ).Footnote 25

On both sides of the Atlantic, legal sales increases were paralleled by flourishing black and grey markets. From the s onwards, officials warned about the unlicensed use of antibiotics like penicillin, erythromycin, and chloramphenicol. Often selling their wares at agricultural fairs or directly on farms, dubious merchants profited from divergent national regulations, some veterinarians’ willingness to prescribe drugs for animals they had never seen, and farmers’ interest in testing alleged performance boosters. In Germany, the word Autobahntierarzt (motorway veterinarian) emerged to characterise a person selling drugs out of the back of a car at service areas. The illegal merchandise was frequently of substandard quality and could lead to dangerous residues in animal tissues. Although exact numbers do not exist, the substantial scale of the European black market is attested by investigative journalism, prosecutions against black market retailers, and complaints logged by farmers about drugs’ quality or by local veterinarians about illegal competition (Thoms, ; Kirchhelle, ; Thoms, ; Kirchhelle, ). In the US, a Congressional investigation found that “as many as 90 percent or more of the 20,000 to 30,000 new animal drugs estimated to be on the market” (Anon., ) had not been approved as safe and efficacious by the FDA.

Unsurprisingly, the public was not reassured by reports on AMR, residues, and illegal drug sales. During the s and s, a growing number of consumers turned to ‘safe’ organic food. Initially, consumers were served by an eclectic mix of young dropouts, old ‘cranks’, and artisanal producers—one of whose common denominators was that they reared animals without routine recourse to antibiotics or hormones. However, growing demand soon led to a professionalisation and upscaling of organic production. By the s, supermarkets began stocking organic produce and producer associations established binding definitions of natural and organic farming (Belasco, ; Conford and Holden, ; Thoms, ; O’Sullivan, ). The organic movement was not exclusive to Europe or the US. Although sales were small by comparison, other high-income countries like Japan produced international bestsellers like Masanobu Fukuoka’s Natural Farming, which explicitly rejected antibiotics and hormones in animal production (Fukuoka, ). Consumer concerns about chemical contaminants also pressured conventional producers to ‘green’ their rhetoric and reform rearing systems as well as chemical and pharmaceutical use. However, it would be wrong to speak of a wider agricultural paradigm shift: responsible for only a small fraction of overall food sales, organic farming offered a way for often wealthier consumers to opt out of conventional agriculture and a mode of antibiotic-intensive production that was still gathering steam (Mart, ; Kirchhelle, ).

In the Soviet sphere, purchasing organic was not an option. Instead, routine antibiotic use for growth promotion, therapy, and prophylaxis remained common. Fearful of fomenting political unrest by raising food prices and keen to maximise exports, officials were unwilling to rethink animal production. As a consequence, critical discussions of AMR and residue problems remained academic (Jeroch et al., ; Anon., ; Krüger, ). In East Germany, the s saw antibiotic consumption skyrocket. Proud of the intensification of broiler production and increases of domestic meat consumption (Thoms, ), GDR officials decided to industrialise other livestock sectors. From onwards, GDR poultry, pigs, and cattle were moved into massive indoor facilities like the so-called pig high-rise (Schweinehochhaus) near Halle (Poutrus, ). Built as a symbol of communist efficiency with Soviet support between and , the high-rise housed 500 sows and their offspring on three different floors. Piglets were transported offsite on elevators. Other facilities were similarly immense. In Neustadt an der Orla, GDR engineers constructed a 70-hectare facility for up to 185,000 pigs whose proximity to West Germany would generate lucrative exports. By , the GDR had ten further similar-sized pig facilities, five 18,000–20,000 cattle production units, 112 milk facilities with over dairy cows each, and 35 laying units producing 200–295 million eggs p.a. (Laue, ).

Conditions in these facilities were often atrocious. In Neustadt, high ammoniac concentrations and feedstuff dust harmed farm workers while air- and waterborne emissions caused environmental damage throughout the region (Schönfelder, ). Inadequate animal welfare was compensated with liberal drug use. In addition to the mandatory inclusion of antibiotics into feeds,Footnote 26 psychotherapeutic drugs like chlorpromazine, azaperon, and diazepam were used to reduce animal stress. Haphazard drug use increased residue and AMR problems—the latter problem was exacerbated by the GDR’s status as a transit country for animal exports from other communist countries.Footnote 27 Concerned about rejections of vital meat exports, the GDR introduced residue controls in and tightened controls for export animals in (Krüger, ; Stock, ; Laue, ).Footnote 28

Supplying the pharmaceutical needs of the new livestock facilities proved difficult (Poutrus, ). With GDR drug production remaining unreliable, there were national shortages. In , Hans-Joachim Hausmann remembered being called to a s meeting with the medical director of the district Sternberg. Attendees were informed that limited supplies of Depovernil (sulfamethoxypyridazine), a popular treatment for urinary tract infections, had been redirected to poultry production—one doctor proposed prescribing broilers instead (Hausmann, ). Trying to alleviate the shortages, GDR researchers trialled new alternative feed antibiotics like kormogrisin (grisin), paromycin, and lambdamycin. (Jeroch et al., ; Jeroch et al.; , Jeroch et al., ). In , nourseothricin feed antibiotics were developed at the GDR’s Institute for Microbiology and Experimental Therapy to substitute the ca. 170 tonnes of oxytetracycline annually needed for AGPs. A close relative of kormogrisin, the streptogramin nourseothricin was subsequently mass-produced by the VEB Jenapharm and fed to GDR pigs and poultry from onwards (Schramm, ).

Nourseothricin’s rollout provided a natural experiment for agricultural AMR selection. Between and , GDR microbiologists traced previously non-existent transposon-encoded streptogramin resistance: first in E.coli from pigs, then in farm workers’ gut flora, then in the gut flora of workers’ family members, then in the gut flora of citizens in municipal communities, then in isolates from urinary tract infections, and finally in Salmonella and Shigella spp isolated from human diarrhoea cases (Hummel et al., ; Witte, ; Witte, ). Although their findings received international attention, they did not change GDR antibiotic policies or nourseothricin use. Following reunification in , Germany successfully applied for a one year EEC exemption to exhaust remaining nourseothricin AGPs (Bundestag, ) and also trialled nourseothricin sprays against fire blight (Backhaus and Klingauf, ).

While nourseothricin AGPs were a response to growing economic problems within the communist bloc, rising affluence was simultaneously spreading and expanding antibiotic-dependent production systems in middle- and low-income countries. In Thailand, antibiotic-dependent intensification was driven by the Charoen Pokphand Group’s (CPG) acquisition of US animal and pharmaceutical technologies around and subsequent integration of feed and animal production (Silbergeld, ). In South Africa, the introduction of limited restrictions and labelling changes for scheduled veterinary antibiotic products in failed to control consumption. Instead, overall use increased as a result of the parallel intensification of poultry, beef, and dairy production. Between and , tonnes of antibiotics were sold as in-feed medications, 190.4 tonnes as water medications, and 269.8 tonnes as parenteral medications. Chloramphenicol and the nitrofurans were the only drugs banned for food animals (Eagar et al., ; Eagar and Naidoo, ). In Brazil, import substitution policies and booming grain and soy production fostered a similar increase of antibiotic intensive livestock rearing. Authorities actively welcomed foreign companies like Tyson Foods to turn crop surpluses into meat. Between and , chicken production increased 20-fold and also became more intensive. By , 90% of Brazilian poultry were produced in confined settings and the country is now the world’s largest poultry producer (Silbergeld, ). Pig production also intensified. The effects on antibiotic consumption were predictable. By , Brazil accounted for 9% of global agricultural antibiotic use (Van Boeckel et al., ).

The expansion of antibiotic intensive animal production was even more dramatic in China. Since the s, the Chinese had possessed Soviet-designed antibiotic plants and fed accruing mycelia wastes to animals (Shaohong, ). However, routine antibiotic use was not common on many farms until the s. Following the death of Mao and the introduction of liberal economic policies, the government’s strategy of inviting large US and Thai corporations rapidly increased the number of confined and integrated poultry operations. Although backyard production remained common, the Chinese pig sector also intensified. In , a policy shift led to the Chinese acquisition of many foreign-owned facilities. Four years later, China was already producing almost eight times as many pigs as the US. In , the Chinese Shunghui Group became the world’s largest pig producer after acquiring the American Smithfield Foods Group (Silbergeld, ). Post-s production increases were facilitated by legal and illegal antibiotic use. Although China’s Ministry of Agriculture introduced withdrawal times and banned medically relevant feed additives in , regulations were ignored. According to a report, 750– tonnes of chlortetracycline and – tonnes of oxytetracycline were annually fed ca. 500 million pigs, 36 million cattle, and 70 billion poultry. In , ca. 43,000 tonnes of mycelia wastes were also fed to animals (Shaohong, ; Milanov et al., ). By , China had become the world’s largest consumer of agricultural antibiotics (ca. 23% of global use) (Van Boeckel et al., ).

With s AGP restrictions barely making a difference in West Europe or elsewhere, global antibiotic use continued to increase. A significant part of this increase was caused by the adoption of antibiotic intensive production in new countries and livestock sectors. However, the increase was also caused by a growing cycle of antibiotic dependency within already intensified areas of production. On both sides of the Iron Curtain, policymakers were not only unwilling to challenge developmentalist narratives of cheap meat but also found themselves powerless to reign in the antibiotic ghosts they had summoned: in the capitalist ‘West’, FDA officials failed to ban AGPs against sustained agro-industrial opposition while European regulators proved unable to control black markets and rethink their own policies. In the non-capitalist ‘East’, officials were caught in a dilemma of having to provide sufficient antibiotics to maintain inefficient livestock facilities and the need to combat drug residues and AMR. While widening access to cheap meat may be interpreted as a public benefit, the main financial beneficiaries of rising antibiotic use were the companies producing and selling animals, veterinary products, and medicated feeds on an increasingly global scale. The early dominance of US and European corporations is now, however, being challenged by companies from the middle-income countries Western corporations were once invited to.

The effects of rising antibiotic use on global AMR were predictable. With antibiotic research stalling, s experts renewed warnings of an imminent post-antibiotic era. In Western countries, bestsellers like Orville Shell’s Modern Meat (Schell, ), Jeremy Rifkin’s Beyond Beef (Rifkin, ), or Stuart Levy’s Antibiotic Paradox (Levy, ) led to fierce finger-pointing between medical, veterinary, and agricultural practitioners. Although public debates initially had little impact on policymaking among major antibiotic consumers, they led to significant reforms in Scandinavia.

Historically, the efficacy requirements of the ‘Nordic Welfare State’ had made Scandinavian countries very conservative when it came to antibiotic use in medicine (Lie, ). However, medical conservatism had not prevented rising antibiotic use in agri- and aquaculture. This changed during the s. In Sweden, Swann-style AGP restrictions had been introduced in . However, in , newspaper articles and the influential children’s book author Astrid Lindgren began calling for further bans. In contrast to other countries, Swedish farmers reacted proactively and tried to improve their image by petitioning for a total AGP ban. Parliament reacted by banning all AGPs from onwards. Struggling to adapt production systems, some farmers, however, replaced AGPs with higher-dosed prophylactics. In , public criticism of Swedish animal husbandry’s ongoing antibiotic-dependency was one of the factors leading to the passage of a comprehensive new animal welfare law designed to reform industry. Prime Minister Ingvar Carlson personally drove to Lindgren’s house to inform her of the so-called Lex Lindgren, which among other things mandated greater space requirements, increased weaning ages, and new straw and litter requirements for pigs (Wierup, ; Andersen, ; Kahn, ).

Other Scandinavian countries also reformed antibiotic use and rearing systems. In Norway, AMR concerns led to a review of antibiotics in aquaculture. While nearly 50 tonnes of antibacterial substances were used in Norwegian aquaculture in , preventive measures like vaccines helped reduce consumption to below five tonnes in (Anon., ). Denmark also underwent a radical restructuring of non-human antibiotic use. Since the nineteenth century, Danish farmers had supplied global markets with pork and bacon. Organised in large integrated cooperatives, farmers had also adopted confined production systems and routine antibiotic use. Following similar detections in Germany and Britain, Danish microbiologists reported the isolation of vancomycin resistant enterococci (VRE) from healthy pigs and poultry in . VRE detections were likely due to the extensive use of avoparcin. While ca. 22 kg of the reserve antibiotic vancomycin had been used to treat humans in Denmark in , 19,472 kg of closely related avoparcin had been used as AGPs (Aarestrup, ). Following heated debates, farmers stopped using avoparcin voluntarily and Denmark banned avoparcin in . Although it resulted in a temporary rise of therapeutic antibiotic use, Danish AGP consumption plummeted from 115,786 kg in to 12,283 kg in when producers voluntarily phased out AGPs altogether (Aarestrup et al., ; Kahn, ).

Scandinavian countries also lobbied for wider EU restrictions. In , Denmark, the Netherlands, and Germany opposed a British request to license avoparcin for dairy cows.Footnote 29 A German avoparcin ban was followed by an EU-wide ban in . Scandinavian pressure soon led to further restrictions. Concerned about having to abandon its stricter laws to comply with more permissive EU feed regulations after its accession, Sweden campaigned for wider AGP bans. The Swedish campaign profited from Britain’s mad cow disease (BSE) crisis and won the support of EU consumer organisations and medical experts. Ignoring industry protest and the EU’s Scientific Committee on Animal Nutrition (SCAN), member states banned four popular AGPs and established the European Antibiotic Resistance Surveillance System (EARSS) in . Although a planned phase-out of coccidiostats was abandoned in , the EU restricted remaining AGPs by (Kirchhelle, ; Kahn, ). Two years earlier, residue detections in honey had also led to a ban of routine streptomycin spraying against fire blight (Bundestag, ; Mayerhofer et al., ). Although European farmers retained access to higher-dosed therapeutic and prophylactic antibiotics via veterinary prescriptions and emergency spraying permits, the EU’s precautionary bans marked a significant victory for antibiotic critics. The EU’s perceived leadership and large protected market also placed significant pressure on other countries to reform—or at least to appear to reform—agricultural antibiotic use.

In the US, antibiotic reforms proved difficult. After failing to overcome industrial resistance to bans, FDA officials had stopped pushing for AGP restrictions and were battling allegations of inadequate enforcement following sulfamethazine detections in milk and reports of widespread noncompliance with existing antibiotic regulations on farms. The mood in Washington also dampened hopes for AMR-oriented reform. During the s, Congress shortened FDA licensing periods and facilitated extra-label drug use in animal feeds. Under conflicting pressure to respond to rising AMR and reduce alleged market barriers, the FDA’s dilemma was particularly pronounced in the case of agricultural fluoroquinolone use. In , FDA officials licensed two fluoroquinolone antibiotics for use in poultry feeds and water despite warnings about the drugs’ close relation to human reserve antibiotics. Officials reassured critics that AMR detections would lead to quick withdrawals. This promise proved difficult to keep. In , the FDA reacted hesitantly to AMR reports by banning extra-label applications. After this measure proved toothless, officials launched formal withdrawal procedures in . However, Bayer, the manufacturer of one of the fluoroquinolones (Baytril/enrofloxacin), resisted in court. Although Baytril’s similarity to Bayer’s reserve antibiotic ciprofloxacin became a national security matter in the wake of the anthrax letters, it took the FDA until to formally withdraw the drug (Kahn, ; Kirchhelle, ).

Concerned about their ability to ban substances, FDA officials also reacted hesitantly to contemporary EU AGP restrictions. Despite several Congressional initiatives for statutory restrictions of medically relevant antibiotics, the agency focused on developing voluntary guidances to phase out antibiotic growth promotion via label changes (Kirchhelle, ). Although US agricultural antibiotic use has recently declined (FDA, ), it remains to be seen whether reductions are due to voluntary FDA guidances or to shifting consumer demand and growing doubt about AGPs’ economic efficacy. Meanwhile, therapeutic and prophylactic antibiotic use in animal and plant production remain legal.Footnote 30

Regulatory change has also occurred in other high-income countries. In Japan, regulators reacted to EU reforms by banning avoparcin and orienticin feed additives in . Residue problems in domestic and imported produce also led to a reduction of antibiotic tolerances (Morita, ). Although Japan continues to allow multiple AGPs, agricultural antibiotic consumption declined from ca. to 781 tonnes between and . Japan has recently announced that it will cut overall antibiotic use by another third by ((Milanov et al., ; JVARM, ; Anon., ). In South Korea, AMR detections in 18 major food items sparked major public concern during the s. Following , over 45 antimicrobial feed additives were restricted to veterinary prescription. Although it remains high, antibiotic consumption declined from over to under tonnes between and .Footnote 31

Middle- and low-income countries have similarly endorsed antibiotic reform. The mcr-1 episode triggered colistin bans in Brazil and China (Walsh and Wu, ; Davies and Walsh, ). In , Vietnam announced that it would reduce the number of feed antibiotics to 15 and ban AGPs by (USDA, ). India has similarly developed an action plan for antibiotic reductions and has introduced drug withdrawal times for livestock production (Kahn, ). According to a report, Russian antibiotic consumption and AMR rates in farm-related organisms declined 1.5–3-fold following the collapse of the USSR. Only non-medical growth promoters like bacitracin, grisin, flavomycin, and virginiamycin remained permitted (Panin et al., ). Russia is also backing FAO-led efforts to promote food safety and prevent AMR in Central Asia and Eastern Europe (FAO, ). In reaction to new WHO initiatives, Bangladesh, Bhutan, Indonesia, Myanmar, Nepal, Sri Lanka, and Thailand have similarly announced agricultural antibiotic restrictions and national action plans (Goutard, ).

The international wave of antibiotic stewardship commitments is commendable. However, a closer look often reveals an historically familiar lack of enthusiasm when it comes to enforcing regulations or supporting further reform.

Wealthy countries like Korea, Japan, the US, and EU member states have managed to stall decades of increasing antibiotic use and establish surveillance systems with which to hold policymakers accountable to stewardship commitments. However, significant differences of antibiotic regulation and consumption remain. Even within the EU, countries like Spain and Italy consume significantly more drugs than Northern members (EMA, ). Many countries have restricted medically relevant AGPs but have not reformed prescribed access to higher-dosed antibiotics. Despite recent reductions, antibiotic use in most high-income countries remains significantly higher than during the s when agricultural AMR selection first caused international alarm (Kirchhelle, ).

In the absence of long-term funding commitments and international controls, antibiotic stewardship also remains patchy in middle- and low-income countries. A review of the WHO’s South East Asia Region (SEAR) found that many SEAR states did not enforce regulations or monitor antibiotic use in agri- and aquaculture (Goutard, ). In Russia, the past 18 years have seen a sharp rise in agricultural antibiotic use and imports. Although authorities are trying to curb residues in food, AMR-oriented regulations have not made an impact (Witte, ; Van Boeckel et al., ; Vorotnikov, ). In China, domestic colistin bans have resulted in the export of thousands of tonnes of domestically produced colistin to India, Vietnam, and South Korea. In , at least five Indian pharmaceutical companies openly advertised colistin growth promoters or metaphylactic applications (Davies and Walsh, ).

With the global regulatory landscape still resembling a patchwork, industry itself has emerged as an ambivalent force for antibiotic stewardship. Reacting to shifting consumer preferences and doubts about AGP efficacy, international corporations like McDonalds are offering ‘antibiotic free’ products. Other major fast food chains, supermarkets, and suppliers have also committed to reducing antibiotic use (Kirchhelle, ). Historically, the integration of feed, animal, and food companies was a force for intensification and antibiotic use. Established international supply chains could now, however, function as a force for quick antibiotic reductions. The question is whether incentives for meaningful change are strong enough. So far, industry’s record is mixed as recently evidenced in India where one of McDonalds’ major suppliers imported colistin growth promoters (Davies and Walsh, ). ‘Antibiotic free’ also does not mean that drugs were never used therapeutically or prophylactically during production. In the absence of statutory bans, there is moreover no guarantee that companies will not reintroduce antibiotics in the future. Historically, this has occurred in both the UK and the US (Kirchhelle, ). Perhaps most importantly, companies have little incentive to rethink antibiotic use holistically. Producing ‘antibiotic free’ products for wealthy consumers is one thing, committing to open-ended reductions of total antibiotic use is another thing. The ongoing rise of global drug consumption indicates that antibiotics remain an accepted industrial go-to for the management of microbial populations.

Although most nation states’ stewardship record is certainly not impressive, industry thus remains an unlikely leader of long-term antibiotic reform. Similar to the history of pesticide regulation (Mart, ), relying on the market-driven provision of ‘antibiotic free meat’ not only risks the creation of very unequal access to allegedly safe food. What is more, it also runs danger of reinforcing regulatory stagnation by rhetorically displacing responsibility for what can only be tackled at the societal and political level onto the shoulders of individuals. This is not to say that consumer action and industry reform are not important when it comes to creating more sustainable, safe, and antibiotic-free forms of food production. Historically, the alignment of consumer pressure for ‘pure’ milk and improved animal welfare led to successful reforms at the national and transnational level. However, for change to become permanent and burdens to be distributed in a just way, agricultural reform requires long-term institutionalisation in the form of nuanced statutory intervention at the nation state and international level.

So, what can an historical perspective bring to current debates? At first glance, the message of this paper is grim: over the last 83 years, the global story of sulpha drug, antibiotic, and AMR regulations has been one of failure or stagnation.

Probably the most important reason for this story of failure is that many countries have historically favoured reliable access to cheap meat over broader agricultural and antibiotic reform. Despite popular attacks on ‘Big Ag’ for spreading antibiotic-dependent production, the global history of agricultural antibiotics was initially one of immediate economic and political pressures as well as of ideological promises of plenty. Reacting to genuine agricultural demand and concerned about reducing imports, freeing agricultural labour, preventing communism, or sating the appetites of restive citizens, capitalist and communist planners alike licensed one antibiotic application after another. With the exception of early bans on antibiotic preservatives and residues in milk, the fiat of widening access to cheap food outweighed early warnings about antibiotic hazards. By around , antibiotic infrastructures had become firmly entrenched in ‘Western’ and ‘Eastern’ food production. Once a system had become culturally and materially reliant on routine antibiotic use, further production increases were usually accompanied by rising drug use. Over time, the shared productivist ideal of the farm as factory led to a remarkably similar development of agricultural systems on both sides of the Iron Curtain: more food was produced with less feed, labour, and space but with more external pharmaceutical inputs. Even after the fall of the USSR, this logic of industrialised intensive production is still gathering pace and transforming agriculture in low- and medium income countries.

The second reason for failure is that antibiotics’ perceived importance within global protein production repeatedly narrowed the scope of reforms. In the Soviet sphere and the US, officials mostly focussed on curbing residues in food and milk but not antibiotic consumption per se. Although European countries pioneered precautionary AGP restrictions, decision-makers ignored calls for a revaluation of overall antibiotic dependencies. With the exception of Sweden, the ongoing availability of nontherapeutic AGPs, coccidiostats, and higher-dosed prescriptions minimised early bans’ impact on European agriculture until the s. Meanwhile, the kaleidoscopic nature of international antibiotic regulations repeatedly served as a useful argument against more ambitious reforms. Why should national farmers be put at a disadvantage if their competitors retained freer access to antibiotics? Despite the recent international wave of wider AGP restrictions and voluntary antibiotic reductions by industry, higher-dosed forms of antibiotic use have not been reviewed systematically and global antibiotic consumption and AMR continue to rise.

Stories of failure are bleak but can hold important lessons for current regulators. One of the most crucial ones is that national regulations have limited impacts. Historically, the international patchwork of regulations has been a major obstacle for effective antibiotic stewardship. Since the s, the capitalist and non-capitalist supply chains driving antibiotic production and consumption have been international. Regulating these supply chains and reducing antibiotic consumption will require global solutions that are mid- to long-term, flexible, and are subject to transparent evaluation. It is one thing for a government to sign international accords but a very different thing to enact concrete and verifiable antibiotic reductions. Recent WHO plans for global AMR and antibiotic surveillance are an important step but require global enactment as well as consistent funding by wealthier nations (WHO, ). However, from an historical perspective, even these measures will only go so far. Without challenging the ideals of factory-like production and cheap protein that are still driving antibiotic use, current reforms will have limited success.

Data availability

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

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