FEMS Microbiology Ecology, 94, 2018, fix185

doi: 10.1093/femsec/fix185
Advance Access Publication Date: 22 December 2017
Perspective

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PERSPECTIVE

Antimicrobial resistance and the environment:

assessment of advances, gaps and recommendations
for agriculture, aquaculture and pharmaceutical
manufacturing
Edward Topp1,∗ , D. G. Joakim Larsson2 , Daniel N. Miller3 , Chris Van den
Eede4 and Marko P. J. Virta5
1
Agriculture and Agri-Food Canada, London, ON, Canada N5V 4T3, 2 Department of Infectious Diseases,
Institute of Biomedicine, Sahlgrenska Academy, and Centre for Antibiotic Resistance Research (CARe),
University of Gothenburg, SE-413 46, Gothenburg, Sweden, 3 USDA-Agriculture Research Service, Lincoln, NE
68583, USA, 4 Zoetis, 1930 Zaventem, Belgium and 5 University of Helsinki, Department of Microbiology, 00014
Helsinki, Finland
∗
Corresponding author: Agriculture and Agri-Food Canada, London, ON, Canada N5V 4T3. Tel: +1 519 457-1470; E-mail: [email protected]
One sentence summary: Key issues are reviewed concerning the impact on the environment of antibiotic use in agriculture and aquaculture, and
emissions from antibiotic manufacturing.
Editor: Marcus Horn

ABSTRACT
A roundtable discussion held at the fourth International Symposium on the Environmental Dimension of Antibiotic
Resistance (EDAR4) considered key issues concerning the impact on the environment of antibiotic use in agriculture and
aquaculture, and emissions from antibiotic manufacturing. The critical control points for reducing emissions of antibiotics
from agriculture are antibiotic stewardship and the pre-treatment of manure and sludge to abate antibiotic-resistant
bacteria. Antibiotics are sometimes added to fish and shellfish production sites via the feed, representing a direct route of
contamination of the aquatic environment. Vaccination reduces the need for antibiotic use in high value (e.g. salmon)
production systems. Consumer and regulatory pressure will over time contribute to reducing the emission of very high
concentrations of antibiotics from manufacturing. Research priorities include the development of technologies, practices
and incentives that will allow effective reduction in antibiotic use, together with evidence-based standards for antibiotic
residues in effluents. All relevant stakeholders need to be aware of the threat of antimicrobial resistance and apply best
practice in agriculture, aquaculture and pharmaceutical manufacturing in order to mitigate antibiotic resistance
development. Research and policy development on antimicrobial resistance mitigation must be cognizant of the varied
challenges facing high and low income countries.

Keywords: antibiotic resistance; environmental dimension of antibiotic resistance; agriculture; aquaculture; antibiotic
manufacturing

Received: 28 November 2017; Accepted: 21 December 2017


C Crown copyright 2017. This article contains public sector information licensed under the Open Government Licence v3.0 (http://www.nationalarchi

ves.gov.uk/doc/open-government-licence/version/3/).

1
 2 FEMS Microbiology Ecology, 2018, Vol. 94, No. 3

The fourth International Symposium on the Environmental Di- stakeholder platforms such as RUMA (UK) and EPRUMA (EU)
mension of Antibiotic Resistance (EDAR4) held at Michigan State have been promoting responsible use of medicines, including
University in August 2017 followed the EDAR3 symposium held antibiotics in animals. These platforms have a broad member-
in Germany in 2015 (Smalla et al. 2016). Key issues concerning ship of farmers, veterinarians, pharmaceutical companies and
agriculture, aquaculture and antibiotic manufacturing were de- feed producer associations and also include regulators such as
liberated in a roundtable discussion. The authors of this paper the European Commission. Starting in 2007, the EU has built
were the roundtable participants, but the approximately 100 in- antibiotic use surveillance capacity with its ESVAC programme
dividuals in attendance also contributed greatly to the delibera- (http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulati

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tions. Informed by this discussion, this paper is intended to pro- on/document listing/document listing 000302.jsp) while some
vide a perspective on where we have been, and where we need of its member states have had use monitoring in place since
to go on these matters. These discussions were timely in light the 1990s. Since 2009, there has been a clear decrease in
of the recent (December 2017) draft resolution by the United Na- antibiotic use in animals in the EU, which is predicted to
tions Environment Assembly on Environment and Health that steadily continue in the years ahead. In the USA, annual sales of
clearly articulates the concern for the environmental dimension antibiotics are monitored and published by the Food and Drug
of antimicrobial resistance (resolution UNEP/EA.3/L.8/REV.1; Administration, but a decrease in use has not been observed
https://papersmart.unon.org/resolution/index). thus far. Surveillance of antimicrobial use in animals, where
available, generally follows official antibiotic sales, not actual
AGRICULTURE use. It is therefore often not possible to know the antibiotic
consumption by individual commodity groups. Most countries
The use of antibiotics in food-animal production selects for and do not implement surveillance for antimicrobial resistance in
enriches antibiotic resistance (Hoelzer et al. 2017). In the past animal pathogens; where resistance surveillance is in place,
several years we have obtained a clearer understanding of the this mostly concerns commensal and zoonotic bacteria. How-
microbial composition of animal waste using molecular tools. ever, diagnostic laboratories in, for example, Sweden, Germany
But, in general, we do not have a clear understanding of the re- and France are required to publish information on antibiotic
lationship between antibiotic use and the burden of enteric an- resistance in animal pathogens, and it would greatly help global
timicrobial resistance in manures. This is further complicated by data coordination if this practice were to be adopted by other
co-selection in which the development of resistance to in-feed countries using a harmonised approach (Schrijver et al. 2018).
metals (Zn, Cu) may be accompanied by the development of re- While there clearly is a serious situation with antimicrobial
sistance to antibiotics. Inventories of antibiotic-resistance genes resistance in human medicine, multidrug resistance in animal
from shotgun metagenomics do not provide a genetic context, pathogens is far less well documented.
and therefore the potential for horizontal gene transfer, and do In lower income countries, challenges are often greater. An-
not provide insights into functional expression. Two further con- tibiotic use in low income settings is very poorly regulated, and
textual challenges involve i) coming to terms with the abun- there are few or no surveillance data. Consumer demand in
dance and diversity of ‘natural’ resistance in soil communities, China and India for meat protein and the adoption of commer-
and ii) the development of realistic target ranges for reducing cial production practices in which antibiotics are widely em-
resistance in agricultural environments impacted by antibiotic ployed have the potential to massively increase the global use
residues of crop and animal origin. of antibiotics in agriculture (Van Boeckel et al. 2015).
Recent insights into particular agroecological niches are en- For antibiotic use in animals to decline, innovations are
abling scientists to better understand environmental factors af- needed in technology and practice that keep farmers profitable
fecting horizontal gene transfer in agroecosystems. Of particu- while maintaining animal welfare and ensuring food safety (Van
lar interest is the plant rhizosphere where nutrient resources Boeckel et al. 2017). Vaccines, feed additives, improved biosecu-
and active microbial groups are in close proximity to crops used rity and barn design appropriate for each commodity may each
for livestock or human consumption (Kopmann et al. 2013). Tar- have a role. Recent research in antimicrobial alternatives con-
geting management efforts to the particular niches where hor- tinues, but it must be paired with a thorough analysis of their
izontal gene transfer is most promiscuous and where there is effects on antimicrobial resistance. Including copper or zinc in
the potential for microbes to easily leap into the animal or hu- livestock diets is often considered as an alternative to an an-
man microbiome makes good sense compared with large-scale tibiotic. Soils in Denmark showed greater concentrations of cop-
potentially expensive whole-farm soil and manure treatment. per and zinc as antibiotic use was curtailed (Jensen, Larsen and
Numerous investigations (Jia et al. 2017; Tien et al. 2017; Yoon Bak 2016), and both elements can enrich tetracycline resistance
et al. 2017) concerning the impact of manure treatment options in soil (Song et al. 2017). As changes in food-animal production
typically used on commercial farms indicate that these do not practices are implemented, potential changes in the broader
always effectively reduce, and in some instances (e.g. anaero- agroecosystems need to be assessed. Unfortunately, to date no
bic digestion) may increase, the abundance of some antibiotic- effective alternative to antibiotics for the treatment of diseased
resistance genes. Further research into effective and economi- animals has been discovered. Since it is unlikely that any new
cally viable treatment of agricultural waste streams is required. antibiotics will be introduced for veterinary use in the future, it
Over the past decades, initiatives to streamline antibiotic is essential for animal health and livestock production to main-
use in animals have evolved in higher income countries. Swe- tain the efficacy of existing veterinary antibiotics through stew-
den banned the use of antibiotic growth promoters as early ardship, and further research is needed into efficient and viable
as 1986, a move that was followed gradually by the whole EU techniques to limit the potential spread of resistant bacteria and
implementing a total ban on antibiotic growth promoter use genes.
by 2006. In North America the use of antibiotics for growth On the other hand, farmers and veterinarians in low income
promotion is being constrained. In some sectors (e.g. poultry) countries that face food insecurity often experience difficulties
producers are reducing antimicrobial use due to consumer de- in accessing effective antibiotics to treat their livestock. The sup-
mand for antibiotic-free products. For more than 10 years now, ply may not be assured and the quality of the drugs can be
 Topp et al. 3

compromised by counterfeiting. The latter constitutes a high mously. For example, the production of 1 tonne of salmon in
risk for selection and dissemination of resistant bacteria, while Norway requires 0.0008 kg of antibiotics whereas 1.4 kg of antibi-
compromising the health of the animals, and hence increases otics are used per tonne of salmon produced in Chile (Cabello et
food insecurity. Recycling wastewater for crop irrigation is com- al. 2013). The reasons behind this vast difference are not entirely
monly practiced in low income countries, and is becoming in- clear but in the Chilean context include lack of vaccination, high
creasingly so in arid regions of middle and high income coun- animal density and sub-optimal farming practices. The latter in-
tries. The risks of soil, water and crop contamination, and clude underdeveloped hygiene and use of feeds with unknown
how these vary with production practice, remain to be ade- components that may contain unknown antibiotics at unknown

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quately characterised (Christou et al. 2017). Wastewater reuse dosage. Likewise, aquaculture systems that integrate the wastes
and fertilization with sewage sludge have the potential to en- from livestock production are efficient with respect to nutrient
train antibiotic-resistant bacteria selected for in humans into cycling, but have additional potential problems with antibiotic
agroecosystems (Lau et al. 2017), underscoring the complexity resistance (Cabello et al. 2016).
of the issue. Aquaculture products are an important source of export in-
come for many low- and middle-income countries. Products
destined for export are strictly monitored for antibiotic residues,
and concentrations within the product must fall below interna-
AQUACULTURE
tionally accepted minimum residue limits. In contrast products
The significance of aquaculture as a source of fish and shell- containing an antibiotic above the minimum residue limit can
fish has increased tremendously in the past 50 years (Watts be consumed domestically. The application of antibiotics to the
et al. 2017). Approximately 90% of global aquaculture production aquatic environment may select for antibiotic-resistance genes
is now undertaken in Norway, Chile, Egypt, and several Asian not only in fish pathogens, but also in environmental bacteria
countries with China accounting for two-thirds of global pro- (Muziasari et al. 2016). Some antibiotic-resistance genes confer-
duction (FAO 2015; Liu et al. 2017). The steep increase in produc- ring resistance to certain antibiotics such as quinolones, tetra-
tion has happened in the same period of time when antibiotic cyclines and β-lactams can be found in fish pathogens, human
consumption has multiplied, but there is no clear relationship pathogens and aquatic bacteria, which are suspected of being
between those events. The term aquaculture refers to very dif- the original hosts for these genes (Cabello et al. 2013). Rico et al.
ferent activities ranging from extensive aquaculture where the (2018) assessed the risks for development of resistance for 12
predators and competitive species are removed, to the most in- antibiotics in an intensive aquaculture production scenario us-
tensive aquaculture where all food needs are supplied. More- ing a probabilistic approach. Risks were high for all antibiotics in
over, the term covers everything from farming salmon offshore pond sediment and high for the majority of antibiotics in pond
in cold Atlantic waters to tropical integrated aquaculture where water. Risks were low in the effluent mixing area for most an-
livestock manure and excess animal feed are the nutrients for tibiotics, with the exception of rifampicin and levofloxacin. Fish
aquaculture ponds. Moreover, the economic conditions in the farms using tetracyclines have been found to increase the di-
countries with substantial aquaculture vary from extremely versity of tetracycline antibiotic-resistance genes in river water,
wealthy to very poor. There is therefore tremendous diversity in while no significant differences in the abundance of antibiotic-
antibiotic use in aquaculture with, for example, 13 different an- resistant bacteria and antibiotic-resistance genes were seen be-
tibiotics authorised for use in aquaculture in China, compared tween upstream, post-treatment or downstream water samples
with only five in the UK (Liu et al. 2017). Antibiotic residues can (Harnisz, Korzeniewska and Golaś 2015). These studies suggest
be detected in aquaculture products, and among these oxytetra- that the effective means of treating effluent from fish ponds is a
cycline and its epimers were the ones most commonly detected matter for further research.
in a recent American study investigating aquaculture-derived The practical reality is that fish or other aquaculture species
products imported from a variety of countries (Done and Halden in ponds or sea cages attract pathogens that require either pre-
2015). However, by analysing the data available from different vention or treatment, and very few alternatives to antibiotics
aquaculture settings, some conclusions can be drawn regarding are currently available (Defoirdt, Sorgeloos and Bossier 2011).
best aquaculture practice with respect to managing antibiotic Because of the ever increasing importance of aquaculture for
resistance. the global food supply, research into vaccines has stepped up
Antibiotic use in aquaculture in Europe, Northern America in the past decades and this is encouraging. Fish DNA vaccines
and Japan is strictly controlled and limited to therapeutic ap- are very effective as demonstrated by the Norwegian experi-
plications, with only a limited number of approved antibiotics. ence. But they are difficult and expensive to deploy. Currently
A prime example of the effect of rigorous control on antibiotic every fish must be injected so the skill level for management is
use is the Norwegian experience, where antibiotic use was re- very high. Further research into more practical means of vac-
duced by 99% between 1987 and 2013, despite a more than cine administration is warranted to increase overall vaccine use
20-fold increase in production over this time (Norwegian Min- in aquaculture as a valuable alternative to prevention of disease
istry of Health and Care Services 2015). The main factors be- by antibiotics.
hind that development were implementation of strict hygienic
requirements and use of vaccines, which were at least partly
the result of active scientific research in the field. Vaccina-
MANUFACTURING
tion is an economically viable practice with high value species
such as salmon, which, however, represent only a small fraction The highest concentrations of antibiotics and the highest abun-
of global aquaculture production. In contrast, over 90% of the dances of antibiotic-resistance genes detected in the environ-
world aquaculture production is carried out in low- or middle- ment are found in environments polluted by direct discharges
income countries where the regulation, practices and resources from the manufacturing of antibiotics (Larsson 2014; Pal et al.
are much more limited (Watts et al. 2017). Even with the same 2016). Major discharges, in the mg/L range, clearly selective for
fish species the use of antibiotics in aquaculture can vary enor- resistance, have been documented from several countries and
 4 FEMS Microbiology Ecology, 2018, Vol. 94, No. 3

regions (Larsson 2014; Bielen et al. 2017). Accordingly, there is involved in these initiatives. Industries producing mainly for na-
a growing consensus from major pharmaceutical companies, tional markets, particularly in low and middle income countries,
academia and other actors that managing and reducing such may be considerably more difficult to incentivise from abroad,
discharges is important and urgent. Compared with agricul- and would be more dependent on national regulations and
tural and human sources, industrial point sources for antibiotics enforcement.
and antibiotic-resistant bacteria are considerably fewer, making
them a more graspable target, both economically and practically. GENERAL CONCLUSIONS
Still, there are major knowledge gaps in how widespread infe-

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rior pollution control is, but perhaps most importantly, there are Education on best practices of all parties involved in the distribu-
knowledge gaps with regards to how improvements are best in- tion and use of antibiotics in terrestrial or aquatic food produc-
centivised and implemented. tion systems is key to implementing antibiotic stewardship. Dig-
Regulatory requirements for manufacturing sites and emis- ital communication tools (e.g. mobile phones) could have an im-
sion control worldwide vary from being non-existent to the portant role in providing stakeholders (e.g. veterinarians, farm-
application of high standards. Where they exist, environmen- ers) with useful information and guidance and this needs to
tal permits are provided and controlled by individual countries be developed. Consumer demand is having variable impact on
or states, again with vast differences in requirements and en- the global demand for antibiotics. On the one hand the demand
forcement. The production and supply chain for antibiotics of- for antibiotic-free meats is increasing in high income countries.
ten involves several steps and actors in different parts of the In some instances (e.g. Sweden) hospital organizations are in-
world, providing challenges for the end producer, and to an even creasingly including environmental contamination control dur-
larger extent the consumer, to gain insight into and influence ing manufacturing in their procurement of antibiotics. On the
over the degree of environmental pollution control in the early, other hand, rising income in lower income countries is increas-
most critical steps of production of active ingredient and for- ing the market for animal proteins, driving the increasing imple-
mulated product. Antibiotic discharges are rarely regulated di- mentation of production practices that rely heavily on antibiotic
rectly, although discharge limits have recently been proposed use. It is very important to note that good animal production
(Bengtsson-Palme and Larsson 2016). India is the first country practice varies tremendously across different commodities, dif-
to explicitly have declared an intent to regulate antibiotic emis- ferent levels of economic development and different climates.
sions nationally (Government of India 2017). Increased trans- No one set of policies or practices or any one technology will
parency has been stressed as a critical measure (Larsson and have a substantial impact on reducing antimicrobial use in ev-
Fick 2009) to create pressure on manufacturers, a measure that, ery region or on every farm or aquaculture facility. Thus it is im-
at least for the EU market, would be helped by making parts of portant to engage policy-makers, researchers and food-animal
the existing registration dossiers public. The strong price pres- producers in every region to grapple with this global problem.
sure on the generics market, together with substitution systems China unveiled an antimicrobial resistance action plan in 2016,
for generic exchange in human medicine, has not favoured in- and India intends to drastically curtail antibiotic emissions from
vestments in pollution control and has played a role in the re- the manufacturing sector by 2020. These are very positive de-
location of production facilities to countries with lower produc- velopments. Finally, science-based standards for acceptable an-
tion costs and also less strict environmental regulation. One pos- tibiotic concentrations (and antibiotic-resistance genes) in ter-
sible way to incentivise ‘green’ investments would be to value restrial and aquatic food-animal production environments and
documented pollution control, in addition to low price, when manufacturing effluents are required to inform policy and stan-
exchangeable products eligible for tax subsidy are identified dards. This is clearly an important research priority.
(Bengtsson-Palme, Gunnarsson and Larsson 2018). Other means
involve the inclusion of pollution control in procurement pro- ACKNOWLEDGEMENTS
cesses, and in public ranking/benchmarking schemes for drug
We thank all of the participants in the roundtable session for
companies (Access to Medicines Foundation 2017; Bengtsson-
their contributions. We are indebted to Dele Ogunseitan and
Palme, Gunnarsson and Larsson 2018).
Shannon Manning for their diligent work as rapporteurs.
Initiatives from industry are also critical. In 2006, the Phar-
maceutical Supply Chain Initiative (PSCI; https://pscinitiative Conflict of interest. None declared.
.org/home) was formed, with the broader aim of establishing
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