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Aquaculture as yet another environmental gateway to the

development and globalisation of antimicrobial resistance
Felipe C Cabello, Henry P Godfrey, Alejandro H Buschmann, Humberto J Dölz

Aquaculture uses hundreds of tonnes of antimicrobials annually to prevent and treat bacterial infection. The passage Lancet Infect Dis 2016
of these antimicrobials into the aquatic environment selects for resistant bacteria and resistance genes and stimulates Published Online
bacterial mutation, recombination, and horizontal gene transfer. The potential bridging of aquatic and human April 12, 2016
http://dx.doi.org/10.1016/
pathogen resistomes leads to emergence of new antimicrobial-resistant bacteria and global dissemination of them
S1473-3099(16)00100-6
and their antimicrobial resistance genes into animal and human populations. Efforts to prevent antimicrobial overuse
Department of Microbiology
in aquaculture must include education of all stakeholders about its detrimental effects on the health of fish, human and Immunology and
beings, and the aquatic ecosystem (the notion of One Health), and encouragement of environmentally friendly Department of Pathology,
measures of disease prevention, including vaccines, probiotics, and bacteriophages. Adoption of these measures is a New York Medical College,
Valhalla, New York, NY, USA
crucial supplement to efforts dealing with antimicrobial resistance by developing new therapeutic agents, if headway
(Prof F C Cabello MD,
is to be made against the increasing problem of antimicrobial resistance in human and veterinary medicine. Prof H P Godfrey MD); Centro
i-mar and CeBiB, Universidad
Introduction total of 90 000 tonnes in 1985 to 436 401 tonnes of fish and de Los Lagos, Puerto Montt,
Chile (Prof A H Buschmann PhD);
There has always been a close temporal and spatial 174 000 tonnes of shellfish in 2008.13 In Chile, exported
and Instituto de Farmacia,
relation between the use of antimicrobials (often aquacultured salmonids increased from approximately Facultad de Ciencias,
generically referred to as antibiotics regardless of their 200 000 tonnes in 2000 to close to 400 000 tonnes in 2007.14 Universidad Austral de Chile,
mode of production) and the selection and emergence of In Vietnam, the production of pangasius catfish rose from Valdivia, Chile
(Prof H J Dölz PhD)
antimicrobial-resistant pathogens.1 At the very beginning a few tonnes in 1990 to more than 400 000 tonnes in 2010.15
Correspondence to:
of the antimicrobial era, antimicrobial-resistant bacteria China now generates a third of the world’s aquatic food
Prof Felipe C Cabello,
were identified in patients and the hospital environment products, with two thirds of this production being ascribed Department of Microbiology and
where most antimicrobials were used.2 With the to aquaculture.16 This low awareness of the growth in Immunology, New York Medical
application of antimicrobials to veterinary medicine and aquaculture is unfortunate because freshwater and marine College, Valhalla, New York,
NY 10595-1524, USA
husbandry came the appearance of antimicrobial-resistant environments can serve both as reservoirs of ARGs and
cabello@nymc.edu
zoonotic pathogens in agricultural environments.3,4 antimicrobial-resistant bacteria and as facilitators for their
Passage of antimicrobial resistance genes (ARGs) and transfer to the human resistome, including human
antimicrobial-resistant bacteria harbouring these genes pathogens.14,17–19 These environments can also become a
from industrially grown animals to human beings source of ARGs and antimicrobial-resistant bacteria if they
rapidly followed.3,4 Although initially detected by are contaminated with terrestrial effluents such as
serotyping and plasmid genetic analysis, conclusive agricultural wastes; discharges from human dwellings,
proof of the role of antimicrobial use in this passage only hospitals, and industry; releases from sewage and water
became available with the introduction of molecular treatment plants; and activities such as tourism.14,18
analysis and DNA sequencing.5–7 Passage of ARGs and Fish and shellfish reared under crowded and stressful
antimicrobial-resistant bacteria from terrestrial animal conditions are prone to bacterial infections. Increases in
husbandry to human environments and vice versa, with industrialisation of aquaculture has been paralleled by
detrimental effects on both human and animal health, is increased prophylactic and therapeutic use of anti-
now largely recognised. microbials and chemical disinfectants to prevent and
treat these infections (figure).14 In many countries,
The aquatic environment as a gateway for antimicrobial use in terrestrial animal husbandry
antimicrobial resistance surpasses their use in human medicine,20,21 and this
The effects of globalisation (eg, widespread human travel finding might also be the case with aquaculture in
and migration, increases in import and export of animals some countries. In Chile, for example, the use of
and animal products, unfettered circulation of foodstuffs, fluoroquinolones in aquaculture was more than ten times
and outsourcing of food production to countries with their use in human medicine in some years; additionally,
cheap labour and unexploited natural resources) on the annual consumption of florfenicol, an antimicrobial
the distribution of ARGs and antimicrobial-resistant used mainly by this industry, rose from approximately
bacteria have not been well acknowledged.1,8–11 The role of 400 kg in 2000 to 233 000 kg in 2007.22 In Vietnam, a report
aquaculture in this process has not always been found that all 32 fish farms surveyed used antimicrobials.15
appreciated. This issue is perhaps because aquaculture’s High antimicrobial use in aquaculture can have several
growth as a commercial activity has been rapid since 1970 deleterious consequences. For example, modification of
(8·5% annually).12 By 2009, more than 48% of consumed the normal flora of farmed fish and shellfish and
seafood was produced by aquaculture.12 In the increases in their susceptibility to infection by anti-
Mediterranean Sea, aquacultural production went from a microbial-resistant fish pathogens.23,24 This occurrence

www.thelancet.com/infection Published online April 12, 2016 http://dx.doi.org/10.1016/S1473-3099(16)00100-6 1

 Personal View
Feed
Medicated feed
Heavy metals, disinfectants,
or other chemicals
Ablation of normal flora
Selection of mutants
Stimulation of HGT
Increase
se iin
n bacterial
bac
bac
acter
teriial
ter al co
conce
concentrations
ncent
ncentr
t t
Selection of mutant genes and bacteria
Stimulation of mutagenesis, HGT,
integron recombination, and
Currents
bacterial persistence
Alterations in nutrient cycling
Unabsorbed antimicrobials
Ingested antimicrobials
in stools, urine, or secretions
Antimicrobial resistant normal
flora and pathogens
Microbial communities: eg, planktonic, biofilms, or bacteriophages
Figure: Antimicrobials in feed and their residues in the aquatic environment
Selective and hormetic effects are noted on aquatic microbial flora and on normal flora and pathogens of farmed
and wild fish. HGT=horizontal gene transfer.
has been noted in salmon aquaculture with Piscirickettsia
salmonis and Aeromonas salmonicida.25–27 In the presence
of ineffective vaccines and high densities of aquacultured
animals, selection of antimicrobial-resistant pathogens
with increased virulence is favoured.28 High antimicrobial
use can also select for aquatic antimicrobial-resistant
bacteria that can contaminate aquacultural products
marketed for human consumption.14,24,29–32 Additionally,
this situation can lead to inadvertent exposure of
aquacultural products and wild species to water-borne
and unexpected contamination with antimicrobials and
their metabolites from aquaculture sites in the absence
of any history of antimicrobial treatment (figure).32–34
Foodstuffs contaminated with antimicrobial-resistant
bacteria and antimicrobial residues from any source can
then reach human consumers and alter their
microbiome.9,29,35 Non-antimicrobial chemicals (eg, heavy
metals or disinfectants) used in aquaculture can also
increase antimicrobial resistance in the aquacultural
environment.36,37 Excessive antimicrobial use in aqua-
culture can even damage aquaculture itself. The collapse
of the shrimp aquaculture industry in Taiwan was
ascribed to such overuse.38
Antimicrobials used in aquaculture are largely
administered in feed, occasionally by bath (the
administration of antimicrobials by immersion of fish or
shellfish in closed containers containing antimicrobials),
and generally to groups composed of sick, healthy, and
carrier individuals.14,39 Up to 80% of the antimicrobials are
deposited in water and sediments close to sites of
application in the absence of collectors under pens to
catch uneaten medicated feed (figure).40,41 Ingested but
not absorbed antimicrobials, together with their
metabolites in stools, urine, and other secretions,
2 www.thelancet.com/infection Published online April 12, 2016 http://dx.doi.org/10.1016/S1473-3099(16)00100-6
sediment to these same areas with their antimicrobial
activity largely intact (figure).33,39,42,43 Although a few studies
have reported that antimicrobials in aquatic environments
are rapidly transported from sites of application and
diluted,44,45 most have confirmed that antimicrobials and
their metabolites remain active in aquatic sediments for
months at sufficiently high concentrations to exert
selective effects on aquatic bacterial diversity in these
environments.33,42,43,46 For example, tetracycline has been
shown to be present in sediments from aquaculture sites
at approximately 1–100 μg/g and similarly for oxolinic
acid at 10–100 μg/g.42,43 These concentrations of
antimicrobials are inhibitory or subinhibitory for many
bacteria, including edwardsiella and aeromonas.47–50
Surprisingly, these selective effects persist despite the
presence of cations and minerals in sea water that are
able to neutralise antimicrobial activity and most
probably, microorganisms capable of degrading the
antimicrobials themselves.14,42,43,51 As a result, bacterial
populations in sediments at aquaculture sites temporarily
become 50–100% resistant to tetracycline after its
aquacultural use.42,52 The diversity of the normal intestinal
flora of fish under aquaculture receiving antimicrobials is
also drastically reduced, with levels of resistance in
culturable bacteria of 60% or more and with the potential
to favour infections by pathogens.23,24 These drastic
changes in bacterial populations might also alter
environmental bacterial communities and ecosystem
services, including nutrient cycling in the sediments
needed for healthy aquaculture.50,53
Genetic variation and ARGs in the aquatic
environment
Several features of the aquatic environment foster genetic
variation and development of new ARGs and new strains
of antimicrobial-resistant bacteria in niches influenced by
antimicrobials and human activities (figure). Although
limited metagenomic analyses indicate only low levels of
ARG in the aquatic environment and in fish microbiota
(approximately 4%),54 evidence is mounting to show
that the aquatic environment is the source of new
transmissible ARG present in human pathogens.14,55,56
Many aquatic bacteria harbour a large assortment of
mobile genetic elements (eg, plasmids, integrons,
transposons, and integrative conjugative elements) that
can recombine, mobilise, and generate original and
mobile assortments of ARGs and generate bacteria better
adapted to an environment containing variable amounts
of naturally occurring and added antimicrobials.14,39
In fact, bacteria from the aquatic environment share
genetically related plasmids, integrons, and integrative
conjugative elements with fish, shellfish, and human
pathogens and are thus in a position to link the resistomes
of aquatic bacteria and human pathogens.14,55,57–61
Several emerging plasmid-encoded quinolone resistance
genes (eg, qnrA, qnrB, qnrS, and aac[6´]-1b-cr) in Escherichia
coli and klebsiella and the macrolide-resistance genes

(mef[C], mef[G]) in vibrio and photobacterium appear to
have an aquatic origin.55,56,62,63 Similarly, the tetC gene in the
Chlamydia suis genome might have come from the genome
of the salmon pathogen Aeromonas salmonicida.64 The
readily recombinable and transmissible broad host range
IncA/C plasmids shared between aquatic bacteria and
piscine and human pathogenic yersinia, salmonella, and
vibrios,57,58,65,66 contain resistances to multiple antimicrobials
(eg, β lactams, aminoglycosides, chloramphenicol,
sulphonamides, trimethoprim, quinolones, and tetra-
cycline), and can successfully replicate in many genera of
aquatic and terrestrial bacteria.57,65,67,68 IncU plasmids are
also widely shared by piscine pathogenic, human
pathogenic, and non-pathogenic aeromonas.57,69 Con-
tamination of the aquatic environment with animal and
human pathogens and the selective pressure of
antimicrobials that facilitate horizontal gene transfer
between bacteria of these dissimilar and geographically
separated environments have been suggested to underlie
these and many similar findings.52,70–74
The composition of microbiota in the aquatic
environment can be altered by the microbiota of stools
and secretions of fish and shellfish treated with
antimicrobials through the addition of high levels of
commensals and potential pathogens containing
ARGs.23,24,75 These ARG-containing bacteria might
colonise marine shelter species, including zooplankton
and phytoplankton. Such species function as loci for
magnifying genetic variability and genetic processes in
the aquatic environment, and provide large basal popu-
lations in which spontaneous and induced mutations to
antimicrobial resistance can arise and spread by
horizontal gene transfer.76 The aquatic environment also
contains high concentrations of bacteriophages and
other gene transfer agents able to mediate and stimulate
horizontal gene transfer by transduction and generate
naked DNA for transformation by bacterial lysis.14,77 Such
naked DNA can be taken up by many bacterial species
(eg, by animal pathogens such as vibrio).60 Moreover,
aquatic animals might concentrate antimicrobials in
their tissues and organs where antimicrobials can
interact with their normal flora.76 Biofilms, with their
ability to mediate horizontal gene transfer and
persistence, are common in the aquatic environment
both on organisms living there and on the inanimate
components of these environments.78 These charac-
teristics potentially convert the intestinal tract and
integuments of fish and shellfish and the inanimate
aquatic environment into dynamic hotspots for
generating novel arrangements of ARGs and new
antimicrobial-resistant bacteria (figure).14,18,76,79 In some
ways, this situation is similar to that in terrestrial manure
in which an increase in ARGs and horizontal gene
transfer can be caused by antimicrobials in the presence
of high concentrations of organic matter.80,81
The use of antimicrobials in aquaculture has
differences and similarities to their use in terrestrial
www.thelancet.com/infection Published online April 12, 2016 http://dx.doi.org/10.1016/S1473-3099(16)00100-6
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animal husbandry. One of the important differences is
that the study of this effect is in its infancy in aquaculture
as compared with the study of antimicrobial resistance in
terrestrial animal husbandry.14,32 Although multidrug-
resistant R plasmids were detected in Japanese
aquacultural environments in the 1970s,82,83 it was not
until the early 1990s that these plasmids were intensively
studied in this setting.84 Initial assumptions regarding
the power of aquatic environments to degrade and
dilute antimicrobials have proved to be erroneous.44
As previously mentioned, many antimicrobials remain
highly active and able to select for resistance in these
environments, especially in areas of heavy use.33,42,52 The
spatial separation of terrestrial and aquatic habitats
initially suggested that both bacterial populations
would remain genetically separated. Unfortunately, con-
tamination of the aquatic environment in large parts of
the world with human and terrestrial animal pathogens
has negated this assumption.70 These apparently
separated populations are actually biologically continuous
because of bidirectional horizontal gene transfer.14,18,79
Preliminary evidence indicates that the resistome of
pristine aquatic environments and aquaculture-
influenced aquatic environments contain genes coding
for new mechanisms of resistance that differ from those
of terrestrial environments.14,17,19,54,85–87
Knowledge of the role of large amounts of fish excreta,
undigested feed, and fish intestinal flora in sediments at
aquaculture sites in stimulating genetic variation and
horizontal gene transfer is preliminary compared with
knowledge of the role of manure in terrestrial
farming.18,23,24,80 Little is also known about the biological role
of wild aquatic animals in fostering genetic variation and
horizontal gene transfer or the role of currents in
transporting antimicrobials, ARGs, and antimicrobial-
resistant bacteria.14,52,85 As with foodstuffs originating in
terrestrial animals, foodstuffs from aquaculture might be
contaminated with antimicrobial-resistant bacteria,
including human pathogens of aquatic origin, such as
vibrios and aeromonas, and terrestrial pathogens, such as
salmonella and E coli.30,31 The potential of antimicrobial-
resistant emergent piscine pathogens such as Streptococcus
agalactiae,88 Streptococcus phocae,89 Flavobacterium
araucanum, Rhodococcus erythropolis,91 and Francisella
90
philomiragia92 (at least some of which are opportunistic
human pathogens93–95) to spread to the altered microbiomes
of workers in aquacultural activities exposed to anti-
microbials needs increased assessment.14 Although some
knowledge regarding the use of antimicrobials and
antimicrobial-resistant bacteria in terrestrial farm animals
might be partly applicable to the situation in aquaculture,
the obvious differences between aquatic and terrestrial
environments and their different microscopic and
macroscopic flora and fauna create unforeseen situations.
Once a single ARG exchange event has occurred
between bacteria of the aquatic and terrestrial environ-
ments at a particular geographical location, further
3
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selection and spread of the ARG among bacterial
populations, including human pathogens, is facilitated
by the presence and selective activity of antimicrobials in
the local environment where the event happened.96
Antimicrobial-resistant bacteria containing these new
combinations of ARG might then spread globally
through transport of aquacultural products, ova, and
seeds, as well as through travel of workers and people
living in the areas from where these bacteria had
originated.8,10,97 As previously mentioned, sharing of
IncA/C plasmids between piscine and human
pathogenic vibrios and yersinia,65,67 dissemination of the
multi-drug resistant IncU plasmid pRAS1 in piscine and
human pathogenic aeromonas,69,98 and emergence of
plasmid-encoded quinolone resistance genes in Gram-
negative bacteria,55,56 are examples of globalisation of
aquatic-generated ARGs. The worldwide emergence of
epidemic Salmonella enterica serovar Typhimurium
DT104 and dissemination of S enterica serovar Kentucky
198-X1 from Egypt to other countries in the Middle East,
Africa, and Europe provide additional examples of this
process. 14,97,99,100 The plasmid-associated colistin resistance
mediated by the mcr-1 gene is another transmissible
antimicrobial resistance that might have originated in
aquacultural environments.87,101 This gene has already
spread widely among animals and human beings in
China and has been recently found in Denmark in
imported chicken meat and in an infected patient.101,102
Local action and One Health
The occurrence of novel ARGs, new ARG assortments,
and the antimicrobial-resistant bacteria that harbour
them in local aquacultural environments indicates that
prevention of their globalisation might be first
approached as a regional issue.13,14,52,103,104 Local approaches
to prevent globalisation are also suggested by the widely
variable amounts of antimicrobials used in aquaculture
in different geographical areas and jurisdictions, and by
the crucial role that this local antimicrobial use has on
the globalisation of ARGs and antimicrobial-resistant
bacteria.14,52,105,106 For example, quantities of antimicrobials
used to produce 1 tonne of salmon in different
jurisdictions vary from 0·0008 kg to 1·4 kg.14,105 One
industrial concern uses 279 g of antimicrobials to
produce 1 tonne of salmon in Chile but only 4·8 g to
produce the same amount of salmon in Norway.106 Such
differences in antimicrobial use probably reflect
substantial differences in animal health and animal
wellbeing, local differences in disease risks in different
regions, and the knowledge and awareness of all the
various stakeholders with respect to the detrimental
effects of excessive antimicrobial use. These
stakeholders include (in addition to physicians) fish
farmers, veterinarians, government regulators, workers,
consumers, and international organisations fostering
aquacultural activities (eg, UN and Food and Agriculture
Organization).9,13,14,103
4 www.thelancet.com/infection Published online April 12, 2016 http://dx.doi.org/10.1016/S1473-3099(16)00100-6
If globalisation of ARGs and antimicrobial-resistant
bacteria originating in aquaculture is to be prevented, the
evolving concept of One Health at the animal and
human interface needs to be strengthened.107–109 This
strengthening in turn means that the health of fish and
shellfish and preservation of the integrity of the health
of the local ecosystem and its microbiota become
paramount goals.85,107,108 Improvements in the health of
fish and shellfish will require increasing the levels of
awareness in farmers and local veterinarians in countries
with large aquacultural industries of the counter-
productive results of excessive antimicrobial use.110
In Norway, for example, regulation of antimicrobial use
in salmon aquaculture, improvements in diagnostics,
including susceptibility testing and use of vaccines, and
use of probiotics have reduced the use of antimicrobials
to negligible levels.111,112 Similarly, use of collectors under
pens to catch uneaten medicated feed and monitoring
when fish stop eating precludes its passage to the
bottoms of pens and reduces exposure of the bacteria in
the sediment to antimicrobials and their metabolites.40,41
Consumers also need to be educated about antimicrobial
use in aquaculture and its potential impact on
human health and the environment. The potential for
antimicrobial overuse to degrade the environment to the
extent that aquaculture itself as well as other economic
activities (eg, tourism) are negatively impacted needs to
be stressed so that collapse of these industries with wide
economic and social repercussions can be avoided.38,110
As in terrestrial animal husbandry, education needs to
be accompanied by other actions if emergence of
antimicrobial-resistant bacteria from aquaculture is to
be avoided. Clinical and laboratory diagnosis of infection
and antimicrobial resistance must be improved.
This advancement includes more widespread use of
microbiological culture, determination of antimicrobial
susceptibilities, implementation of molecular methods
of bacterial identification and susceptibilities, and the
use of ecofriendly preventive and therapeutic measures
that include vaccines, probiotics, and bacteriophages.110–113
Improvements also need to include better tracking of
the amounts of aquacultural antimicrobial use and
determination of marine and human resistomes in
areas of intensive aquaculture with heavy use of
antimicrobials.14,114 Human risk assessments regarding
the potential of various concentrations of antimicrobials
in the aquatic environment to stimulate genetic
diversity (including mutagenesis, new assortments of
antimicrobial resistances, and horizontal gene transfer)
should be encouraged.14,20,50 New policies regarding fish
hygiene and epizootic control, to improve therapeutic
use and ameliorate prophylactic use of antimicrobials,
will need to be developed and instituted in place of
present policies encouraging prophylactic antimicrobial
use. These new policies will need to be complemented
by an increased restriction of aquacultural use of
antimicrobials used in human medicine, as well as by

improved and more transparent surveillance and
reporting of antimicrobial resistance in regions where
aquaculture takes place, and revised policies for
therapeutic use of antimicrobials in veterinary and
human medicine.39,99,115–117
A time for change
The increasing numbers of infections caused by
antimicrobial-resistant bacteria in human and veterinary
medicine have led to the current emphasis on
development of new antimicrobials.118 The notion of One
Health, with its linkage of human, animal, and environ-
mental health and its emphasis on education and local
approaches, provides a crucial supplement to the
development of these new antimicrobials. The recognised
contribution of aquaculture and the aquatic environment
to the emergence of antimicrobial-resistant infections
needs to be determined, delineated, and countered. In
the absence of any such efforts, increases in the stockpile
of new antimicrobials will not be sufficient to prevent a
major crisis in the treatment of bacterial infectious
diseases in both human and veterinary populations.
Contributors
FCC and HPG wrote the first draft and managed all subsequent revisions.
All authors provided conceptual discussions, did literature searches,
analysed literature, and provided critical comments on the draft.
Declaration of interests
We declare no competing interests.
Acknowledgments
FCC and AHB were supported by grants from the Lenfest Ocean
Program/Pew Charitable Trusts, AHB by the FONDECYT and Basal
Program (FB001), and FCC by a fellowship from the John Simon
Guggenheim Foundation. We thank Nataliya Timoshevskaya for
assistance with the figure.
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