J Public Health Pol

https://doi.org/10.1057/s41271-018-0144-x

ORIGINAL ARTICLE

Policy options for reducing antibiotics

and antibiotic‑resistant genes in the environment

Ellen Bloomer1 · Martin McKee1

© Springer Nature Limited 2018

Abstract  Responses to the threat posed by antimicrobial resistance have been

inadequate. Most attention has focused on the emergence of resistant organisms in
human medicine and in agriculture. Much less attention has been given to antibiotic
contamination of the environment. To assist health advocates to engage with this
issue, we review the evidence on the role of agriculture, aquaculture, domestic waste
and pharmaceutical manufacturing in the spread of antibiotic resistance, concluding
that all of these activities pose a potentially serious threat. We then examine ways
that this threat might be mitigated by specific measures, such as improved waste-
water treatment processes, reduction of manufacturing emissions, consideration
of environmental impacts in procurement and drug approval decisions, and better
manure management. We conclude by placing this problem within the growing lit-
erature on commercial determinants of health, stressing the need for effective legis-
lation and regulation developed independent of vested interests.

Keywords  Environment · Antimicrobial resistance · Agriculture · Aquaculture ·

Pharmaceuticals · Corporate determinants

* Martin McKee
Martin.McKee@lshtm.ac.uk
Ellen Bloomer
ellen.bloomer@nhs.net
1
London School of Hygiene and Tropical Medicine, 15‑17 Tavistock Place, London WC1H 9SH,
UK
 E. Bloomer, M. McKee

Introduction

“We have more than enough scientific evidence to justify curbing the rampant use of
antibiotics for livestock, yet the food and drug industries are not only fighting pro-
posed legislation to reduce these practices, they also oppose collecting the data” [1].
Antimicrobial resistance (AMR) might seem uncontroversial. Already an esti-
mated 700,000 deaths from antibiotic-resistant infections occur annually worldwide,
with this figure predicted to rise to ten million a year and an estimated loss to global
production of US$ 100 trillion by 2050 [2]. Understandably, the world’s govern-
ments have placed it very high on the global policy agenda [3], and some measures
have attracted widespread consensus. Thus, few question the importance of meas-
ures to reduce inappropriate antibiotic prescribing in humans, especially given the
39% increase in per capita human consumption between 2000 and 2015 reported in
a study of 76 countries [4].
More controversial have been calls for a reduction in antibiotics in animal pro-
duction, both as growth promoters and therapeutically, with concerns that they are
often used to compensate for unsanitary living conditions that encourage infections.
Global consumption of antimicrobials in animals raised for food will increase by
67% between 2010 and 2030 [5] and, already, it is estimated that the global mar-
ket for antibiotics for animals is worth US$5 billion [6]. A 2001 study found that
90% of antibiotics sold in the United States (US) were for non-therapeutic uses in
animals [7]. Since 2006, their use as growth promoters has been banned in the Euro-
pean Union (EU), although sales data suggest that, in some countries, this was ini-
tially circumvented by increased use for ‘therapeutic’ purposes. A similar ban was
implemented in the US, but only in 2017, after years of opposition. Although some
have argued that the risks arising from such restrictions may exceed the benefits [8],
one former Director of the US Food and Drug Administration (FDA) has stated that
“There’s no question that routinely administering non-therapeutic doses of antibiot-
ics to food animals contributes to antibiotic resistance” [9]. Another former FDA
Director has pointed to the intensive lobbying by the powerful agri-food industry
as a reason for inaction, saying that “We have more than enough scientific evidence
to justify curbing the rampant use of antibiotics for livestock, yet the food and drug
industries are not only fighting proposed legislation to reduce these practices, they
also oppose collecting the data” [1]. Indeed, the administration of President Trump,
whose election campaign received an estimated $4.6 million from agribusiness, is
currently striving to limit international action to reduce the use of medically impor-
tant antibiotics in agriculture [8], seeking to shift decisions away from the World
Health Organization (WHO), where industrial interests have little influence, to the
Codex Alimentarius mechanisms, where they are much more powerful [10]. In the
United Kingdom, some supporters of the country’s exit from the European Union
are seeing an opportunity to roll back the existing regulations [11]. Yet, even if
implementation is inadequate, there is at least a broad scientific consensus favour-
ing “banning antibiotic use as growth promoters and limiting its use for other non-
therapeutic applications” [12].
Policy options for reducing antibiotics and…

While undoubtedly important, measures to tackle overuse in humans and animals

are only part of a comprehensive solution. Rather less attention has been devoted
to another source of exposure to antibiotics: domestic, industrial, and agricul-
tural waste. Yet while the 2015 World Health Organization’s Global Action Plan
on Antimicrobial Resistance [13], subsequently adopted by the Food and Agricul-
ture Organization (FAO) and by the World Organization for Animal Health (OIE),
includes measures that will mitigate environmental exposures by minimising antibi-
otic use, it does not explicitly prioritise environmental contamination. Similarly, the
2017 Antimicrobial Resistance Action Plan from the European Union, while noting
the growing importance of environmental contamination, did not propose any spe-
cific measures to combat it [14].
Environmental contamination by antibiotics is, from an economic perspec-
tive, a classic ‘externality’. The costs involved do not fall on those producing the
problem. Consequently, at least in the short term, producers have little interest in
addressing it. Even if some do accept responsibility, there is a risk of ‘free riders’,
with some unwilling to bear the costs accepted by the more responsible producers.
These considerations point to the need for a regulatory or legislative approach. Yet
this has generated considerable opposition, exemplified by a report from a coali-
tion of American producers who argue that antibiotics are already used responsibly
and existing provisions are adequate [15]. A report from Johns Hopkins University
has catalogued numerous efforts by industry to exempt agricultural producers from
regulations and to conceal their activities in the United States, for example by sup-
pression of whistle blowers (in this case referred to as “ag-gag”) [16]. A newspa-
per report of documents leaked in 2018 suggested that European Union proposals to
monitor contamination from pharmaceutical manufacturing may have been watered
down following pressure from the manufacturers [17]. In 2016, an umbrella group
representing manufacturers, entitled the “Responsible Use of Medicines in Agricul-
ture Alliance” [18] rejected a demand by presidents of the United Kingdom’s Medi-
cal Royal Colleges to ban all routine mass use of antibiotics in British agriculture
[19]. A subsequent report by investigative journalists described how one major man-
ufacturer was targeting mothers in the US with messages seeking to divert attention
from the risk posed by antibiotics in food [20]. Such tactics reflect experience with
other powerful vested interests [21], characterised by the use of lobbying groups to
deny that there is a problem or, if it is conceded that there is, claims that little can
be done, at least without prohibitive costs, while attention is diverted to other issues,
such as over-prescribing by physicians.
If effective policies on antibiotics in the environment are to be adopted, the pub-
lic health community must understand the scale and nature of the problem. Con-
sequently, we here present a scoping review examining what is known in four key
areas: agriculture, aquaculture, domestic waste, and pharmaceutical manufacturing.
 E. Bloomer, M. McKee

Methods

Unlike a systematic review, where the aim is to answer a specific question, usually by
combining data from studies that have asked it, we set out to provide an interpretive
and discursive synthesis of the literature. Hence, a narrative review is more appropriate
[22]. We began by identifying key issues, then establishing a structure for the review,
using the literature to understand the issues involved and the policy context. We used
the databases EMBASE, PubMed, and Google Scholar to identify relevant literature.
We took an iterative approach, with our initial search restricted to reviews, using a
range of search terms. Our early findings were then explored in more detail using the
references cited in these reviews and related papers. Where relevant, we used Google
to search for grey literature that added meaning to our findings. In synthesising our
findings, we adopted a realist approach where appropriate, taking account, where pos-
sible, of the influence of context on generalisability [23]. We now look at the routes of
environmental contamination in turn, beginning with the scale of the problem, then the
pathways to contamination, and finally evidence on what can be done.

Routes of Environmental Contamination

Agriculture and aquaculture

Remarkably, given its importance, existing surveillance systems are largely unable to
provide reliable data on total annual antibiotic consumption in agriculture in many coun-
tries [24]. Nor is it possible to differentiate what is used for treatment of diseased ani-
mals, for prevention in healthy animals considered at risk of infection, and for growth
promotion (although as noted above, the last is banned in some countries [25]). What
evidence that is available shows a striking international variation. The ‘population cor-
rection unit’ (PCU) is a measure of the animal population that takes account of numbers
and weight [26]. Use of antibiotics ranges from 8 mg/PCU in Norway to 318 mg/PCU
in China in 2013 [27]. Emerging economies (Brazil, Russia, India, China and South
Africa) are projected to increase their use of antimicrobials in livestock by 99% from
2010 to 2030, contributing to a global increase of 67% [5]. Antibiotics are also used to
treat infected plants, but the amount used is very small in comparison to other uses [28].
Antibiotics are also used extensively in aquaculture, both for treatment and proph-
ylaxis [29]. Once again, there is considerable variation among countries [30]. Use is
strictly controlled in Europe, and limited to therapeutic applications, with only a small
number of antibiotics permitted [31]. More than 90% of aquaculture production occurs
in low and middle income countries, where there is less effective regulation [31].
Antibiotics used in agriculture and aquaculture inevitably leak into the wider environ-
ment. Between 70% and 80% of antibiotics administered to fish are excreted directly into
the water, while between 30% and 90% of antibiotics administered to livestock escape,
either through direct spread of effluent or animal manure being spread on land as ferti-
liser that further contaminates soil and thus plants and crops grown on it, as well as
groundwater [32, 33]. This increases levels of antibiotics and antibiotic-resistant bacteria
Policy options for reducing antibiotics and…

(ARB) in agricultural land and farm effluent flowing into rivers and coastal waters. Fur-
ther, reclaimed wastewater for irrigation of crops may result in continued exposure of the
agricultural environment to antibiotics and ARB, which may then enter the food chain via
crops [34].

Wastewater

Most antibiotics consumed by humans are excreted and enter wastewater treatment
plants in a biologically active form [33]. Additionally, antibiotics can select for micro-
organisms in the human body with ‘antibiotic-resistance genes’ (ARGs), disproportion-
ately increasing the number of ARGs entering wastewater treatment plants. Incorrect
disposal of unused antibiotics, for example by flushing them down the toilet or sink,
adds to contamination of wastewater. The evidence that health facilities act as ‘hot-
spots’ discharging antibiotics into the environment is contested. One study found par-
ticularly high levels of antibiotics in the influent and effluent of wastewater treatment
plants serving hospitals [35], but another questioned whether this is greater than with
other similarly sized wastewater treatment plants [33].
While, ideally, wastewater treatment would remove all antibiotics and ARB from
effluents, this does not happen: even a three-step (mechanical, biological, and chemi-
cal) treatment is not sufficient to remove all antibiotics [36]. As a result, antibiotics may
undergo biodegradation, be absorbed by sewage sludge (resulting in a risk of contami-
nation if spread on land for agricultural use), or exit in the effluent unchanged (risking
contamination of rivers, estuaries or coastal water) [33]. In some countries, wastewater
is not treated at all, which leads to greater environmental contamination.

Industrial manufacturing

Direct emissions from drug manufacturing facilities, specifically those manufacturing

active pharmaceutical ingredients (APIs) that are antibiotics, has been linked to very
high concentrations of antibiotics in the environment, in some cases greatly exceed-
ing thresholds for toxicity [37]. An analysis of pharmaceuticals in the effluent from a
wastewater treatment plant serving about 90 bulk drug manufacturers in Patancheru,
near Hyderabad in India (a major production site of generic drugs for the world mar-
ket) found high levels of several broad-spectrum antibiotics [38]. The concentration of
the most abundant drug, ciprofloxacin, exceeded levels toxic to some bacteria by over
1000-fold [38]. Other studies in Asia, including China, Korea, Taiwan and Pakistan,
have also demonstrated high concentrations of APIs linked to manufacturing discharges
[37]. These discharges have led to pollution of river sediment, surface, ground, and
drinking water, and irrigated soils [37].
The main centres for API manufacturing are India and China. Though regulatory
requirements for manufacturing sites and emission control exist, they vary between
countries and there are also considerable differences in enforcement of environmental
regulations. Further, it is rare for API emissions from manufacturing to be specifically
regulated. Accordingly, publicly available data from industry or monitoring data from
 E. Bloomer, M. McKee

authorities on API emissions are scarce [37]. It is thus difficult to know the extent of
pollution with antibiotics from manufacturing.
To summarise, there is considerable evidence that, under conditions prevailing in
many countries, all four of the activities considered in this review are sources of envi-
ronmental contamination with antibiotics. The next section examines whether this mat-
ters for the development of resistance.

How Environmental Contamination Impacts Human Health

When soil and water environments receive antibiotics and ARGs, they can act as
reservoirs for AMR. Antibiotics and ARGs interact with existing microorganisms
in the environment leading to development and spread of AMR among existing
bacteria, some pathogenic to humans. There are two main mechanisms by which
this occurs: by exerting selection pressure on existing bacteria in that environment
(resistant bacteria are more likely to survive and multiply in the presence of an anti-
biotic), and horizontal gene transfer, whereby bacteria can acquire resistance from
another via mobile genetic elements such as plasmids (Fig. 1). The role of different
mechanisms varies in different ecosystems [39].
Recent systematic reviews on the impact of point sources (such as agricultural
facilities or wastewater treatment plants) on ARB and ARGs in the natural environ-
ment found that most studies reported higher ARB/ARG prevalence or concentra-
tion downstream or near the source [40, 41]. However, this evidence was primarily
descriptive and the authors were unable to draw robust conclusions about any causal
relationship, calling for further studies to provide estimates of effect size [40, 41].
The fundamental concern is that antibiotics and ARB in the environment can be
transmitted to humans, thereby adding to the AMR threat to human populations.

Fig. 1  How environmental contamination impacts human health

Policy options for reducing antibiotics and…

There are potential risks of ARB being transmitted to humans via contaminated
drinking water, direct contact with contaminated land or water (e.g. living in close
proximity to highly contaminated water, agricultural workers, bathing in contami-
nated coastal waters), or eating crops grown on contaminated land.
Some of these questions are beginning to be answered by advances in genetic
epidemiology, which can provide new insights into how human pathogens acquire
resistance genes from bacteria in the environment [42]. Consumption of infected
drinking water can allow colonisation of the gastrointestinal tract with bacteria con-
taining resistance genes. One study found that the risk of carriage of resistant E.
coli was 1.26 times higher in consumers of water contaminated with these resistant
bacteria [43]. However, even with these new tools, demonstrating a direct impact of
anthropogenic increases in AMR in the environment on humans is challenging, for
several reasons.

• First, antibiotics and ARGs exist in the environment even without anthropo-
genic environmental contamination. They are naturally occurring and pre-date
human use of antibiotics. Thus, it is difficult to ascertain whether transmission to
humans is actually due to earlier contamination of the environment.
• Second, there is a lack of consensus on the impact of low concentrations of anti-
biotics in the environment, which is likely to vary in different ecosystems. There
have been concerns that antibiotics at far lower than the minimal inhibitory con-
centration (MIC) (i.e. the lowest that will prevent visible growth of bacteria) may
select for resistant bacteria and promote mutation and horizontal gene transfer
[44]. Until recently, there has been uncertainty about the extent to which low
concentrations increase resistance: if they do, how, and whether laboratory stud-
ies can be generalised to the real world [45]. Thus, while one study found that
low level of exposure to tetracycline was associated with increased resistance,
how this occurred was less clear, as there was no measurement of initial gene
prevalence [46]. A recent study has, however, addressed this question [47]. Addi-
tion of Cefotaxime to samples of raw untreated wastewater was associated with
selection for resistance genes even at extremely low concentrations, well below
the MIC, at levels observed in hospital effluent and wastewater influent, with no
dose–response relationship.

In summary, while the evidence is still limited, there are sufficient grounds for
concern that, even in low levels, environmental contamination poses a real threat.

Proposals for Tackling Environmental Causes of AMR

We now move to actions that can tackle AMR in the environment, noting where fur-
ther evidence is needed.
 E. Bloomer, M. McKee

Prevention: reducing the need for and use of antimicrobials

A first set of measures seeks to reduce use of antibiotics in humans and animals.
There are two broad approaches. One involves reducing infections—preventing their
introduction and spread through improved infection control; increased use of vac-
cines; improved sanitation; and improved farming methods that include enhanced
biosecurity measures and alternatives to intensive rearing.
Another seeks to ensure that antimicrobials are used appropriately, in both human
and animal populations. This includes AMR awareness campaigns [48, 49], rapid
diagnostic tests to ensure that they are only given when indicated [50], alternatives
to antibiotics [51], and prudent use guidelines [52]. The ban on use of antibiotics for
growth promotion in the EU in 2006, and WHO guidance restricting use of clini-
cally important antibiotics for animal use in 2017 exemplify such policies.
Within these broad approaches, there are many specific practical measures that
can be applied in particular circumstances, but it is beyond the scope of this review
to examine them all in detail. The extent and quality of evidence for different options
varies, but there is considerable evidence to suggest that success in reducing use is
possible [50, 51, 53].
It is, however, necessary to look at some of the broader drivers of antibiotic use.
Their increased use in human and animal medicine is not only a consequence of
inappropriate use, but because of human population growth and rising demand for
animal proteins in developing countries, among other factors. Again, it is beyond the
scope of this review to address these complex factors but it is important that they not
be overlooked in any comprehensive response.

Measures to prevent or reduce antimicrobials contaminating the environment

A second set of measures seeks to reduce the efflux of antibiotics into the environ-
ment. These relate to contamination of wastewater, emissions from pharmaceutical
manufacturing, and by-products of agriculture. We now look at each of these in turn.

Improved/alternative wastewater treatment processes

Even the most advanced wastewater treatment plants are designed to remove con-
ventional pollutants rather than antibiotics and, as noted above, ARB may remain in
effluent and sewage released into the environment. A recent review [54] identified
the following methods as being able to achieve efficient removal:

• Low-energy anaerobic–aerobic treatment reactors (biological treatment meth-

ods) particularly if used in combination with membrane-based technologies,
• Constructed wetlands (small semi-aquatic ecosystems in which different micro-
bial communities multiply and various physical–chemical reactions happen),
• Some disinfection processes (in particular chlorination, but also ozone and UV
radiation) [54].
Policy options for reducing antibiotics and…

The review concluded that novel developments such as nanomaterials, coagula-

tion, and biochar may hold promise but more research is needed [54]. It also identi-
fied some gaps in the evidence, including the need for more large-scale testing on
real samples obtained from the environment, as most studies have been in laboratory
settings and based on short timescales. It also highlighted the effect of plant operat-
ing conditions and other environmental factors and mechanisms as under-explored
factors impacting the levels of ARB in wastewater environments [54].
Widespread use of efficient treatment processes would reduce the amount of antibi-
otics and ARB in the environment. However, it is necessary to select the process that
is most appropriate for particular circumstances, including different antimicrobials in
different environments. This is an area that would benefit from further research and
resulting guidance. It is also necessary to take account of cost-effectiveness, the risk of
unintended consequences for AMR and other environmental contaminants (for exam-
ple, biological treatment may increase ARGs in wastewater) [55], and compatibility
with existing wastewater treatment infrastructure.
Other considerations include what should be done with the resulting output. Anti-
biotics and ARGs are present in sludge/biosolids from wastewater treatment plants
that are spread on land. Incineration is suggested as an alternative, although this would
have negative impacts on air quality and costs of alternative fertilisers [51]. This is not
an ideal solution and better alternatives will be needed. In addition, while wastewater
reuse may be important for water sustainability, it may have consequences for spread of
AMR [51].

Reduced API emissions by manufacturers

The APIs of most antibiotics used in the EU are produced in China and India, and while
the threat posed by AMR does not respect national borders, many regulatory regimes
are constrained by them. Sweden has proposed that the EU amend the Good Manufac-
turing Practices (GMP) framework, a quality assurance mechanism for pharmaceuti-
cals, to add environmental considerations—a measure described in further detail in an
EU-commissioned report by Deloitte [37, 51, 56]. Another suggestion is that individual
countries use their purchasing power to include environmental considerations as part of
their purchasing decisions, rather than basing it on cost alone [51], but without inter-
national agreement, this might be subject to challenge as a non-tariff barrier to trade.
It may also be possible to consider manufacturing emissions as part of the risk assess-
ment for registration of a medicinal product [37].
These measures will, however, only work with greater transparency in the pharma-
ceutical supply chain, and that is problematic. There is no requirement for the pharma-
ceutical company producing a drug to declare the original source as this is considered
to be commercially sensitive information. It can be difficult for the end producer and
consumer of antibiotic products to know who originally produced the API, let alone
their API emissions history.
 E. Bloomer, M. McKee

Management of manure

Pruden et al. present evidence to suggest that composting and, in some cases, lagoon
treatment and anaerobic treatment, can reduce antibiotics and ARGs in the environ-
ment. Similarly, containment of animal wastes is recommended—including prevention
of lagoon spills and seepage, control of surface runoff, and limiting sediment erosion
and transport from animal farms [51].

Making It Happen

Having summarised the main areas where action might be effective, the final sec-
tion of this review discusses ways that change might be brought about. Each of
these is discussed briefly– where they have or might be used, and the evidence for
effectiveness.

Improving surveillance systems

The WHO and EU Action Plans both highlight the importance of national surveil-
lance to provide crucial data on antimicrobial use and AMR [13, 14]. At present,
low quality and missing data on antibiotic consumption and AMR in many countries
prohibit a full understanding of the scale of the problem, where action is needed,
and what action has been effective in reducing use.
It is important that these data extend across human, agriculture, and aquaculture
use. Further, regular monitoring and surveillance of antimicrobials and AMR in the
environment is needed to build an understanding of the severity of the issue and on
which to build a more robust evidence base of what works to reduce it. The lack
of good data undermines policy and legislation around use of antimicrobials, as it
makes it difficult to set targets and to hold different actors to account.

Building the evidence base through research

There is an urgent need for further research to tackle knowledge gaps and improve
the quality of evidence. In particular, robust research, building on the recent find-
ings noted earlier, can generate a better understanding of the links between envi-
ronmental contamination and AMR, which in turn will influence policy-makers to
take action. Crucially, much more evidence is needed around what works to reduce
environmental contamination with antimicrobials: across manufacturing, wastewater
treatment, agriculture, and aquaculture, as there is already sufficient evidence to take
action.
An example of where more research—and the translation of that research into
policy/action—would be valuable (though efforts have been made), is to determine
minimum levels above which antibiotic resistance selection might occur, or ‘mini-
mum selective concentrations’ (MSCs), in complex, real-life scenarios [36, 57].
Despite difficulties in setting these standards, this is needed to inform policy and
Policy options for reducing antibiotics and…

standards for acceptable levels of antibiotic concentrations in the environment [31],

especially as it now seems that the relevant levels may be very low.

Raising public and professional awareness of AMR

There have been many campaigns to increase public awareness of AMR. Primarily,
the goal is to reduce demand for and use of antibiotics in the human patient popu-
lation. Antibiotic awareness campaigns in England, using posters or leaflets have
had little or no impact on knowledge, behaviour, or prescription rates [48]. Perhaps
this is unsurprising given the limited effectiveness of educational interventions on
behaviour change. In contrast, coordinated and comprehensive interdisciplinary
and multi-faceted approaches targeted at specific groups—both public and profes-
sional—have shown some success, such as the Antibiotic Guardian Campaign in
England [49].
Consumer demand for antibiotic-free food has put pressure on companies to
reduce their use of antibiotics [24]. Harnessing public opinion may in future influ-
ence policy-makers and the pharmaceutical industry to take action on antibiotic pol-
lution of the environment.

Advocacy

Civil society, NGOs, and community organisations can play a role in pushing for
action on the environmental causes of AMR, raising public and professional aware-
ness, informing key decision-makers, and acting as a counter-balance to lobbying
by the pharmaceutical and agricultural industries. In the previous sections, we have
cited the works of several US organisations, such as the Union of Concerned Scien-
tists. In Europe, Changing Markets, a UK-based NGO, have collaborated with the
European Public Health Alliance (EPHA), a Brussels-based NGO alliance. The for-
mer has published a number of in-depth reports exposing high levels of pollution at
factories in India and China and their links with global pharmaceutical companies
[58]. The two organisations have worked closely with partners to lobby the Euro-
pean Commission to take action on pharmaceutical pollution in third countries [59,
60]. EPHA has campaigned to strengthen the EU AMR Action Plan more generally,
including the environmental dimension [61].

Guidelines

Prescribing guidelines are an important method of quality improvement in both

human and animal medicine, to ensure that professionals are aware of current best
practice around antibiotic prescribing. EU guidelines for the prudent use of antimi-
crobials in veterinary medicine were published in 2015 and their use is widespread
across the continent as part of measures to reduce AMR [52].
 E. Bloomer, M. McKee

Incentives

There are many ways in which direct financial incentives might help to reduce anti-
biotic contamination of the environment. This includes incentivising wastewater
treatment plants to implement more effective processes and incentivising agricul-
ture/aquaculture workers to use fewer and alternatives to antibiotics. Larsson sug-
gests that incentives to invest in and operate efficient wastewater technology are
vital: “The strongest incentives are economic, including legal obligations which can
lead to fines or the removal of operation permits” [37].
Other examples where this might be a helpful approach is including environmen-
tal criteria in procurement of drugs as discussed earlier. Sweden is leading in this
area. Swedish county councils have started to request monitoring of emissions dur-
ing manufacturing when procuring medicines [37]. This is an area that would ben-
efit from a clearer consensus on environmental risk assessment and MSCs.

Regulation

Measuring the impact of regulation is difficult because it is rarely possible to control

for all of the many confounding factors that might influence the outcome. Obser-
vational studies have shown that some countries/regions implementing stringent
regulations restricting antibiotic use in agriculture and aquaculture have been able
to reduce use.
One example is banning the use of antibiotics for growth promotion in agricul-
ture. The evidence base for their use for this purpose is actually very limited and,
at least in chickens, seems to be associated with a net cost [62]. A ban was imple-
mented in Denmark in the late 1990s, and a dramatic decline in the total use of
veterinary antibiotics was achieved there, from more than 200 metric tons in 1994
to around 70 metric tons in 1999. There is also evidence to suggest that this ban led
to marked reductions of antibiotic resistance among faecal enterococci in the animal
populations [51].
Monitoring and enforcement of regulations is important. Taking the example of
Denmark’s ban on antibiotic use for growth promotion, although overall antibiotic
use fell substantially, ‘therapeutic’ use in Danish pigs slowly doubled over ten years,
but was curtailed by about 25% after stricter monitoring and enforcement of sanc-
tions for illegal use in 2010/2011 [51].
Another example of successful regulation and enforcement is Norway’s reduc-
tion in antibiotic use in aquaculture. Between 1987 and 2013, the country reduced
its antibiotic use by 99% despite a 20-fold increase in production. The main factors
contributing to this were reported to be the implementation of strict hygiene require-
ments and the use of vaccines [31]. The use of antibiotics requires a prescription,
they are only sold in authorised pharmacies or feed plants and it is mandatory to
report the amount of antibiotics used [63].
Policy options for reducing antibiotics and…

Self‑regulation by industry

One option that is commonly proposed to address environmental contamination

is self-regulation by industry. In January 2016, a Davos Declaration on combating
AMR was signed by a number of pharmaceutical, biotechnology, and diagnostics
industries [64]. This resulted in the Industry Roadmap for Progress on Combatting
AMR in September of that year [65], and the formation of the AMR Industry Alli-
ance to drive and measure industry progress to curb AMR. In addition, industry
has developed a holistic environmental risk management programme, ECO-PHAR-
MACO-STEWARDSHIP, to better manage environmental pollution of pharmaceuti-
cals [66]. A commitment from food suppliers to restrict antibiotic use in food is also
discussed in one article, naming a number of large corporate food suppliers who
have made commitments [31]. However, research on the effectiveness of industry
self-regulation in other public health issues such as food and alcohol shows that it
has not generally been effective and is often used as a strategy to delay or deflect
effective statutory regulation [67–70].
The AMR Industry Alliance publishes a progress report every two years, based
primarily on survey responses from its members as to their progress, with the latest
published in 2018 [71]. They report some positive developments, including many
Roadmap signatories reporting that they had assessed the potential impact of their
internal manufacturing and supply chains on AMR in 2017, and that signatories
have developed a common framework for managing antibiotic discharge and have
committed to start applying it across their internal manufacturing and supply chain
by the end of 2018. However, not only does this progress report rely on self-reported
data, but the response rate from Alliance members was only 36% (out of 101 signa-
tories) suggesting that the report does not reflect action across all signatories. Fur-
ther, a crucial problem with industry self-regulation is the concern around what is
happening in companies who do not sign up to participate. Those who self-select out
of self-regulation might be more likely to be those with the practices least aligned to
the Roadmap, as they will have the most to lose out of making the required changes.

Conclusion

AMR is one of the greatest threats to humanity. Yet, although there is compelling
evidence of environmental contamination by antibiotics and ARGs, this important
contributor to the problem has received far too little attention. The reason is clear.
Effective action will threaten powerful commercial interests that prioritise short-
term profits over long-term sustainability.
Strategies to tackle AMR have so far focussed on policies such as rational pre-
scribing, including advances in diagnostics to assess sensitivities, but this review
has highlighted the necessity of tackling environmental contamination too.
First, the use of antibiotics in agriculture and aquaculture must urgently be
reduced. This can be achieved by preventing the occurrence and spread of infec-
tious disease, with improved sanitary conditions and vaccines, and by limiting non-
essential use of antibiotics (as set out in prudent use guidelines). This will require
 E. Bloomer, M. McKee

an explicit recognition that, in many cases, antibiotics are seen as a cheap means of
avoiding investment in appropriate facilities for the animals concerned. Given the
failure of voluntary agreements with producers, this will have to be supported by
legislation, backed up by effective enforcement. Crucially, this may require an inter-
national dimension given how resistant organisms do not respect borders.
Turning to the other sources, these measures must be coupled with other practi-
cal measures to reduce emissions into the environment, including improvements in
treatment of wastewater, again a subject requiring further research. The pharmaceu-
tical industry also has a role to play, beyond its efforts to develop new antibiotics.
The evidence reviewed shows that some drug manufacturing is contributing to the
problem.
Such measures are likely to face powerful opposition from those whose interests
are threatened, and it will be necessary for the public health community to antici-
pate and respond appropriately, supported by investment in research on the scale
and nature of the threat and, in particular, its upstream corporate determinants. One
argument that can be anticipated is that the evidence is incomplete, even if this is
in part because those vested interests have, at best, failed to produce it. As noted,
the quality of data on antibiotic use in many countries is woeful. This should not be
allowed to block action, which should be underpinned by the precautionary princi-
ple. Action is needed now.

References
1. Kessler DA. Antibiotics and the meat we eat. New York Times. 2013. https​://www.nytim​
es.com/2013/03/28/opini​on/antib​iotic​s-and-the-meat-we-eat.html. Updated 27 Mar 2013. Cited 28
June 2018.
2. O’Neill J. Tackling drug-resistant infections globally: final report and recommendations. London:
Review on Antimicrobial Resistance; 2016.
3. United Nations General Assembly. High-level meeting on antimicrobial resistance. New York:
UN. 2016. https​://www.un.org/pga/71/event​-lates​t/high-level​-meeti​ng-on-antim​icrob​ial-resis​tance​/.
Cited 4 June 2018.
4. Klein EY, Van Boeckel TP, Martinez EM, Pant S, Gandra S, Levin SA, et al. Global increase and
geographic convergence in antibiotic consumption between 2000 and 2015. Proc Natl Acad Sci
USA. 2018;115(15):E3463–70.
5. Van Boeckel TP, Brower C, Gilbert M, Grenfell BT, Levin SA, Robinson TP, et al. Global trends in
antimicrobial use in food animals. Proc Natl Acad Sci USA. 2015;112(18):5649–54.
6. Watt H. How much does big pharma make from animal antibiotics? The Guardian. 2018. http://
www.thegu​ardia​n.com/envir​onmen​t/2018/jun/19/how-much-does-big-pharm​a-make-from-anima​
l-antib​iotic​s. Updated 19 June 2018. Cited 20 June 2018.
7. Mellon M, Benbrook C, Benbrook KL. Hogging it: estimates of antimicrobial abuse in livestock.
Washington DC: Union of Concerned Scientists; 2001.
8. Martin A, Hopkins JS. Trump’s USDA fights global guidelines on livestock antibiotics. Bloomberg.
2018. https​://www.bloom​berg.com/amp/news/artic​les/2018-07-23/trump​-s-usda-fight​s-globa​l-guide​
lines​-on-lives​tock-antib​iotic​s?_twitt​er_impre​ssion​=true. Cited 28 July 2018.
9. McVeigh K. Scientists: overuse of antibiotics in animal agriculture endangers humans. The Guard-
ian. 2012. http://www.thegu​ardia​n.com/scien​ce/2012/sep/19/scien​tists​-antib​iotic​s-anima​l-agric​ultur​
e. Updated 19 Sep 2012. Cited 28 July 2018.
Policy options for reducing antibiotics and…

10. Halabi SF. The Codex Alimentarius commission, corporate influence, and international trade: a per-
spective on FDA’s global role. Am J Law Med. 2015;41(2–3):406–21.
11. Farming UK. Brexit threatens ‘bold but essential’ EU rules on reducing farm antibiotics, warns
MEP. Farming: Farming UK News; 2018. https​://www.farmi​nguk.com/News/Brexi​t-threa​tens-bold-
but-essen​tial-EU-rules​-on-reduc​ing-farm-antib​iotic​s-warns​-MEP_49616​.html. Cited 28 July 2018.
12. Roca I, Akova M, Baquero F, Carlet J, Cavaleri M, Coenen S, et al. The global threat of antimicro-
bial resistance: science for intervention. New Microbes New Infect. 2015;6:22–9.
13. World Health Organization. Global Action Plan on antimicrobial resistance. Geneva: World Health
Organization; 2015. http://www.who.int/antim​icrob​ial-resis​tance​/publi​catio​ns/globa​l-actio​n-plan/
en/. Accessed 3 Sept 2018.
14. European Commission. A European One Health Action Plan against Antimicrobial Resistance
(AMR). 2017. https​://ec.europ​a.eu/healt​h/amr/sites​/amr/files​/amr_actio​n_plan_2017_en.pdf.
Accessed 3 Sept 2018.
15. Animal Agriculture Alliance. What the centre for a livable future, pew commission & others aren’t
telling you about food production. Washington DC: Animal Agriculture Alliance; 2013.
16. Kim BE, Laestadius LI, Lawrence RS, Martin RP, McKenzie SE, Nachman KE, et  al. Industrial
food animal production in America: examining the impact of the Pew Commission’s Priority Rec-
ommendations. Baltimore, MD: Johns Hopkins Center for a Livable Future.
17. Neslen A. Antibiotic apocalypse: EU scraps plans to tackle drug pollution, despite fears of rising
resistance. Guardian. 2018. http://www.thegu​ardia​n.com/envir​onmen​t/2018/jun/01/antib​iotic​-apoca​
lypse​-eu-scrap​s-plans​-to-tackl​e-drug-pollu​tion-despi​te-fears​-of-risin​g-resis​tance​. Updated 01 June
2018. Cited 2 June 2018.
18. Responsible Use of Medicines in Agriculture A. RUMA Members. 2018. https​://www.ruma.org.uk/
about​/ruma-membe​rs/. Cited 20 June 2018.
19. Bodkin H. Brexit Britain should lead the way by banning mass antibiotic use in agriculture, says top
doctors. Daily Telegraph; 2018. https​://www.teleg​raph.co.uk/news/2016/11/14/brexi​t-brita​in-shoul​
d-lead-the-way-by-banni​ng-mass-antib​iotic​-us/. Cited 20 June 2018.
20. The Bureau of Investigative Journalism. The story behind the mom, the chicken and the superbug
threat. The Bureau of Investigative Journalism. 2018. https​://www.thebu​reaui​nvest​igate​s.com/stori​
es/2018-06-19/how-adver ​tisin​g-campa​igns-downp​lay-consu​mer-conce​r ns-over-givin​g-antib​iotic​
s-to-anima​ls. Cited 20 June 2018.
21. Madureira Lima J, Galea S. Corporate practices and health: a framework and mechanisms. Glob
Health. 2018;14(1):21.
22. Greenhalgh T, Thorne S, Malterud K. Time to challenge the spurious hierarchy of systematic over
narrative reviews? Eur J Clin Investig. 2018;48(6):e12931.
23. Wong G, Greenhalgh T, Westhorp G, Buckingham J, Pawson R. RAMESES publication standards:
realist syntheses. BMC Med. 2013;11:21.
24. O’Neill J. Antimicrobials in agriculture and the environment: reducing unnecessary use and waste.
The review on antimicrobial resistance.
25. Maron DF, Smith TJ, Nachman KE. Restrictions on antimicrobial use in food animal production: an
international regulatory and economic survey. Glob Health. 2013;9(1):48.
26. Veterinary Medicines Directorate. Understanding the Population Correction Unit used to calculate
antibiotic use in food-producing animals. 2016. https​://asset​s.publi​shing​.servi​ce.gov.uk/gover​nment​/
uploa​ds/syste​m/uploa​ds/attac​hment​_data/file/58071​0/11010​60-v1-Under​stand​ing_the_PCU_-_gov_
uk_guida​nce.pdf. Cited 4 June 2018.
27. Van Boeckel TP, Glennon EE, Chen D, Gilbert M, Robinson TP, Grenfell BT, et al. Reducing anti-
microbial use in food animals. Science. 2017;357(6358):1350–2.
28. Martinez JL. Environmental pollution by antibiotics and by antibiotic resistance determinants. Envi-
ron Pollut. 2009;157(11):2893–902.
29. Watts JE, Schreier HJ, Lanska L, Hale MS. The rising tide of antimicrobial resistance in aquacul-
ture: sources, sinks and solutions. Marine Drugs. 2017;15(6):158.
30. Burridge L, Weis JS, Cabello F, Pizarro J, Bostick K. Chemical use in salmon aquaculture: a review
of current practices and possible environmental effects. Aquaculture. 2010;306(1–4):7–23.
31. Topp E, Larsson DGJ, Miller DN, Van den Eede C, Virta MPJ. Antimicrobial resistance and the
environment: assessment of advances, gaps and recommendations for agriculture, aquaculture and
pharmaceutical manufacturing. FEMS Microbiol Ecol. 2018. https​://doi.org/10.1093/femse​c/fix18​5.
32. Watts JEM, Schreier HJ, Lanska L, Hale MS. The rising tide of antimicrobial resistance in aquacul-
ture: sources, sinks and solutions. Mar Drugs. 2017;15(6):158.
 E. Bloomer, M. McKee

33. Singer AC, Shaw H, Rhodes V, Hart A. Review of antimicrobial resistance in the environment and
its relevance to environmental regulators. Front Microbiol. 2016;7:1728.
34. Christou A, Aguera A, Bayona JM, Cytryn E, Fotopoulos V, Lambropoulou D, et  al. The poten-
tial implications of reclaimed wastewater reuse for irrigation on the agricultural environment: the
knowns and unknowns of the fate of antibiotics and antibiotic resistant bacteria and resistance
genes—a review. Water Res. 2017;123:448–67.
35. Verlicchi P, Al Aukidy M, Galletti A, Petrovic M, Barcelo D. Hospital effluent: investigation of
the concentrations and distribution of pharmaceuticals and environmental risk assessment. Sci Tot
Environ. 2012;430:109–18.
36. Berkner S, Konradi S, Schonfeld J. Antibiotic resistance and the environment–there and back again:
Science & Society series on Science and Drugs. EMBO Rep. 2014;15(7):740–4.
37. Larsson DG. Pollution from drug manufacturing: review and perspectives. Philos Trans R Soc Lond
B Biol Sci. 2014;369(1656):20130571.
38. Larsson DG, de Pedro C, Paxeus N. Effluent from drug manufactures contains extremely high levels
of pharmaceuticals. J Hazard Mater. 2007;148(3):751–5.
39. Grenni P, Anacona V, Caracciolo AB. Ecological effects of antibiotics on natural ecosystems.
Microchem J. 2017;136:25–39.
40. Bueno I, Williams-Nguyen J, Hwang H, Sargeant JM, Nault AJ, Singer RS. Systematic review:
Impact of point sources on antibiotic-resistant bacteria in the natural environment. Zoonoses Public
Health. 2018;65(1):e162–84.
41. Bueno I, Williams-Nguyen J, Hwang H, Sargeant JM, Nault AJ, Singer RS. Impact of point sources
on antibiotic resistance genes in the natural environment: a systematic review of the evidence. Anim
Health Res Rev. 2017;12:1–16.
42. Finley RL, Collignon P, Larsson DG, McEwen SA, Li XZ, Gaze WH, et al. The scourge of antibi-
otic resistance: the important role of the environment. Clin Infect Dis. 2013;57(5):704–10.
43. Coleman BL, Salvadori MI, McGeer AJ, Sibley KA, Neumann NF, Bondy SJ, et  al. The role
of drinking water in the transmission of antimicrobial-resistant E.  coli. Epidemiol Infect.
2012;140(4):633–42.
44. Andersson DI, Hughes D. Microbiological effects of sublethal levels of antibiotics. Nat Rev Micro-
biol. 2014;12(7):465–78.
45. Karkman A, Do TT, Walsh F, Virta MP. Antibiotic-resistance genes in waste water. Trends Micro-
biol. 2017;26(3):220–8.
46. Lundström SV, Östman M, Bengtsson-Palme J, Rutgersson C, Thoudal M, Sircar T, et  al. Mini-
mal selective concentrations of tetracycline in complex aquatic bacterial biofilms. Sci Tot Environ.
2016;553:587–95.
47. Murray AK, Zhang L, Yin X, Zhang T, Buckling A, Snape J, et al. Novel Insights into Selection for
Antibiotic Resistance in Complex Microbial Communities. mBio. 2018;9(4).
48. Ashiru-Oredope D, Hopkins S. Antimicrobial resistance: moving from professional engagement to
public action. J Antimicrob Chemother. 2015;70(11):2927–30.
49. Chaintarli K, Ingle S, Bhattacharya A, Ashiru-Oredope D, Oliver I, Gobin M. Impact of a United
Kingdom-wide campaign to tackle antimicrobial resistance on self-reported knowledge and behav-
iour change. BMC Public Health. 2016;16:393.
50. O’Neill J. Tackling drug-resistant infections globally: final report and recommendations. Lon-
don. 2016. https​://amr-revie​w.org/sites​/defau​lt/files​/16051​8_Final​%20pap​er_with%20cov​er.pdf.
Accessed 3 Sept 2018.
51. Pruden A, Larsson DG, Amezquita A, Collignon P, Brandt KK, Graham DW, et  al. Management
options for reducing the release of antibiotics and antibiotic resistance genes to the environment.
Environ Health Perspect. 2013;121(8):878–85.
52. European Commission. Guidelines for the prudent use of antimicrobials in veterinary medicine
(2015/C 299/04). Official Journal of the European Union. 2015. https​://ec.europ​a.eu/healt​h/sites​/
healt​h/files​/antim​icrob​ial_resis​tance​/docs/2015_prude​nt_use_guide​lines​_en.pdf. Accessed 3 Sept
2018.
53. EMA (European Medicines Agency), EFSA (European Food Safety Authority). EMA and EFSA
Joint Scientific Opinion on measures to reduce the need to use antimicrobial agents in animal hus-
bandry in the European Union, and the resulting impacts on food safety. EFSA J. 2017;15(1):4666.
54. Barancheshme F, Munir M. Strategies to combat antibiotic resistance in the wastewater treatment
plants. Front Microbiol. 2017;8:2603.
Policy options for reducing antibiotics and…

55. Michael-Kordatou I, Karaolia P, Fatta-Kassinos D. The role of operating parameters and oxidative
damage mechanisms of advanced chemical oxidation processes in the combat against antibiotic-
resistant bacteria and resistance genes present in urban wastewater. Water Res. 2018;129:208–30.
56. Deloitte Sustainabiliy. Background document for public consultation on pharmaceuticals in the
environment. 2017. https​://ec.europ​a.eu/info/sites​/info/files​/backg​round​_docum​ent_publi​c_consu​
ltati​on_pharm​aceut​icals​_envir​onmen​t.pdf. Accessed 3 Sept 2018.
57. Bengtsson-Palme J, Larsson DG. Concentrations of antibiotics predicted to select for resistant bac-
teria: proposed limits for environmental regulation. Environ Int. 2016;86:140–9.
58. Changing Markets. Bad Medicine. Addressing pharmaceutical pollution: a key cause of AMR.
2018. https​://chang​ingma​rkets​.org/portf​olio/bad-medic​ine/. Accessed 12 July 2018.
59. European Public Health Alliance. Joint Statement: Europe must align policies to tackle Pharma-
ceuticals in the Environment and Antimicrobial Resistance. 2018. https​://epha.org/joint​-state​ment-
europ​e-must-align​-polic​ies-to-tackl​e-pharm​aceut​icals​-in-the-envir​onmen​t-and-antim​icrob​ial-resis​
tance​/. Accessed 3 Sept 2018.
60. European Public Health Alliance. Investors, NGOs and water industry urge European Commission
to take action on pharmaceuticals in the environment and halt Antimicrobial Resistance (AMR).
2018. https​://epha.org/inves​tors-ngos-and-water​-indus​try-urge-europ​ean-commi​ssion​-to-take-actio​
n-on-pharm​aceut​icals​-in-the-envir​onmen​t-and-halt-antim​icrob​ial-resis​tance​-amr/.
61. European Public Health Alliance. EU Health Policy Platform. Joint Statement on Antimicrobial
Resistance (AMR). 2018. https​://epha.org/wp-conte​nt/uploa​ds/2018/02/antim​icrob​ial-resis​tance​
-joint​-state​ment_final​.pdf. Accessed 3 Sept 2018.
62. Graham JP, Boland JJ, Silbergeld E. Growth promoting antibiotics in food animal production: an
economic analysis. Public Health Rep. 2007;122(1):79–87.
63. Romero J, Feijoo C, Navarrtet P. Antibiotics in aquaculture—use, abuse and alternatives. In: Car-
valho E, David G, Silva R, editors. Health and environment in aquaculture. London: IntechOpen;
2012.
64. Declaration by the Pharmaceutical, Biotechnology and Diagnostics Industries on Combating Anti-
microbial Resistance. January 2016. https​://amr-revie​w.org/sites​/defau​lt/files​/Decla​ratio​n_of_Suppo​
rt_for_Comba​ting_AMR_Jan_2016.pdf. Accessed 3 Sept 2018.
65. Industry Roadmap for Progress on Combating Antimicrobial Resistance. September 2016. https​
://www.ifpma​ . org/wp-conte ​ n t/uploa ​ d s/2018/06/Roadm ​ a p-for-Progr ​ e ss-on-AMR-FINAL ​ . pdf.
Accessed 3 Sept 2018.
66. ECO-PHARMACO-STEWARDSHIP (EPS). A holistic environmental risk management program.
https​://www.efpia​.eu/media​/25628​/eps-a-holis​tic-envir​onmen​tal-risk-manag​ement​-progr​am.pdf.
Accessed 3 Sept 2018.
67. Cécile K, Mark P, Alison DM, Courtney S, Lesley J, Anushka M, et al. The Public Health Respon-
sibility deal: has a public–private partnership brought about action on alcohol reduction? Addiction.
2015;110(8):1217–25.
68. Knai C, James L, Petticrew M, Eastmure E, Durand M, Mays N. An evaluation of a public–pri-
vate partnership to reduce artificial trans fatty acids in England, 2011–2016. Eur J Public Health.
2017;27(4):605–8.
69. Knai C, Petticrew M, Durand M, Eastmure E, James L, Mehrotra A, et al. Has a public–private part-
nership resulted in action on healthier diets in England? An analysis of the Public Health Responsi-
bility Deal food pledges. Food Policy. 2015;54:1–10.
70. Caraher M, Perry I. Sugar, salt, and the limits of self regulation in the food industry. BMJ.

2017;357:1709.
71. SustainAbility. Tracking progress to address AMR. 2018. https​://www.amrin​dustr​yalli​ance.org/wp-
conte​nt/uploa​ds/2018/01/AMR_Indus​try_Allia​nce_Progr​ess_Repor​t_Janua​ry201​8.pdf. Accessed 3
Sept 2018.

Ellen Bloomer  is a Public Health Specialty Registrar in the UK, currently on placement at the London
School of Hygiene & Tropical Medicine and the European Public Health Alliance. She has a background
in social policy, advocacy and research. Prior to becoming a Public Health Registrar, she worked at the
UCL Institute for Health Equity and Public Health England. She holds a M.Sc. in International Public
Policy and a M.Sc. in Public Health. Her main interests are health inequalities, social policy, health sys-
tems leadership and antimicrobial resistance.
 E. Bloomer, M. McKee

Martin McKee  is a Professor of European Public Health and Medical Director at the London School
of Hygiene & Tropical Medicine and Research Director at the European Observatory on Health Systems
and Policies. He has published extensively on the health consequences of social, political, and economic
changes.