Blackwell Publishing LtdOxford, UKEMIEnvironmental Microbiology 1462-2912 2006 The Authors; Journal compilation 2006 Society for Applied

d Microbiology and Blackwell Publishing Ltd? 20068711371144Review Article

Aquaculture and antibiotic resistance bacteriaF. C. Cabello

Environmental Microbiology (2006) 8(7), 11371144 doi:10.1111/j.1462-2920.2006.01054.x

Minireview

Heavy use of prophylactic antibiotics in aquaculture:

a growing problem for human and animal health and
for the environment

Felipe C. Cabello many developed and developing countries. It is expected

Department of Microbiology and Immunology, New York that this growth will increase at an even faster rate in the
Medical College, Valhalla, NY 10595, USA. future, stimulated by the depletion of fisheries and the
market forces that globalize the sources of food supply
(Goldburg et al., 2001; Goldburg and Naylor, 2005). The
Summary
last 20 years have seen a fourfold growth in industrial
The accelerated growth of finfish aquaculture has aquaculture worldwide (Naylor et al., 2000; 2003; Naylor
resulted in a series of developments detrimental to and Burke, 2005). This impressive industrial development
the environment and human health. The latter is illus- has been accompanied by some practices potentially
trated by the widespread and unrestricted use of pro- damaging to human and animal health (Goldburg and
phylactic antibiotics in this industry, especially in Naylor, 2005; Naylor and Burke, 2005) that include pass-
developing countries, to forestall bacterial infections ing large amounts of veterinary drugs into the environ-
resulting from sanitary shortcomings in fish rearing. ment (Haya et al., 2000; Boxall et al., 2004). For example,
The use of a wide variety of antibiotics in large the aquaculture of shrimp and salmon has been accom-
amounts, including non-biodegradable antibiotics panied by an important use of prophylactic antibiotics in
useful in human medicine, ensures that they remain the aquatic environment of rivers, lakes and oceans
in the aquatic environment, exerting their selective (Grave et al., 1999; Le and Munekage, 2004; Le et al.,
pressure for long periods of time. This process has 2005). As expected, and as has occurred in other indus-
resulted in the emergence of antibiotic-resistant bac- trial settings of animal husbandry (Angulo and Griffin,
teria in aquaculture environments, in the increase of 2000; Witte, 2000; Anderson et al., 2003; Angulo et al.,
antibiotic resistance in fish pathogens, in the transfer 2004; Nandi et al., 2004), this use has resulted in an
of these resistance determinants to bacteria of land increased antibiotic resistance of bacteria in the environ-
animals and to human pathogens, and in alterations ment (Rhodes et al., 2000a; Miranda and Zemelman,
of the bacterial flora both in sediments and in the 2002a,b; Petersen et al., 2002; Alcaide et al., 2005).
water column. The use of large amounts of antibiotics Moreover, this development has been accompanied by an
that have to be mixed with fish food also creates increase of antibiotic resistance in fish pathogens (Davies
problems for industrial health and increases the et al., 1999; Rhodes et al., 2000a,b; Schmidt et al., 2000;
opportunities for the presence of residual antibiotics 2001a,b; Srum, 2000; 2006; LAbee-Lund and Srum,
in fish meat and fish products. Thus, it appears that 2001). The emergence of antibiotic resistance among fish
global efforts are needed to promote more judicious pathogens undermines the effectiveness of the prophylac-
use of prophylactic antibiotics in aquaculture as tic use of antibiotics in aquaculture (LAbee-Lund and
accumulating evidence indicates that unrestricted Srum, 2001; Srum, 2006) and increases the possibili-
use is detrimental to fish, terrestrial animals, and ties for passage not only of these antibiotic-resistant bac-
human health and the environment. teria but also of their antibiotic resistance determinants to
bacteria of terrestrial animals and human beings, includ-
ing pathogens.
Introduction

Industrial aquaculture is a rapidly growing industry in

Antibiotic use in aquaculture

In the aquaculture of fish, especially that of salmon and

Received 31 January, 2006; accepted 4 April, 2006. *For correspon-
dence. E-mail cabello@nymc.edu; Tel. (+1) 914 594 4182; Fax trout, nearly all manipulations undergone by the fish as
(+1) 914 594 4176. they are being raised are stressors (Barton and Iwama,

2006 The Author

Journal compilation 2006 Society for Applied Microbiology and Blackwell Publishing Ltd
1138 F. C. Cabello
1991). Because these manipulations decrease the effec-
tiveness of the fishess immune system to clear up bacte-
rial colonization and infection (Barton and Iwama, 1991;
Cabello, 2003; Naylor and Burke, 2005), it has become
common to increase the use of prophylactic antibiotics.
Moreover, hygienic shortcomings in fish raising methods,
including increased fish population densities, crowding of
farming sites in coastal waters, lack of sanitary barriers
and failure to isolate fish farming units with infected ani-
mals (Naylor et al., 2000; Naylor and Burke, 2005), have
increased the possibility of rapid spread of infections. This
scenario also results in an augmented use of prophylactic
antibiotics, often with the misplaced goal of forestalling
these sanitary shortcomings (Grave et al., 1996; Cabello,
2003; Srum, 2006). Fish are given antibiotics as a com-
ponent of their food, and occasionally in baths and injec-
tions (Markestad and Grave, 1997; Srum, 2006). The
unconsumed food, and fish faeces, containing antibiotics
reach the sediment at the bottom of the raising pens;
antibiotics are leached from the food and faeces and
diffuse into the sediment and they can be washed by
currents to distant sites (Hektoen et al., 1995; Kerry et al.,
1996; Coyne et al., 1997; Holten et al., 1999; Guardabassi
et al., 2000; Srum, 2000; Srum and LAbe-Lund, 2002;
Boxall et al., 2004; Srum, 2006). Once in the environ-
ment, these antibiotics can be ingested by wild fish and
other organisms including shellfish (Hektoen et al., 1995;
Kerry et al., 1996; Coyne et al., 1997; Holten et al., 1999;
Srum, 2000; Srum and LAbe-Lund, 2002; Boxall et al.,
2004; Srum, 2006). These residual antibiotics will remain
in the sediment, exerting selective pressure, thereby
altering the composition of the microflora of the sediment
and selecting for antibiotic-resistant bacteria (Kruse and
Srum, 1994; Hektoen et al., 1995; Davison, 1999;
Miranda and Zemelman, 2002a,b; Burrus and Waldor,
2003; Balaban et al., 2004; Beaber et al., 2004; Hasting
et al., 2004; Kim et al., 2004; Srum, 2006). There are a
number of important studies that indicate that the bacterial
flora in the environment surrounding aquaculture sites
contain an increased number of antibiotic-resistant bacte-
ria (Huys et al., 2000; Schmidt et al., 2000; 2001a,b;
Srum, 2000; Miranda and Zemelman, 2002a,b; Furush-
ita et al., 2005; Srum, 2006), and that these bacteria
harbour new and previously uncharacterized resistance
determinants (Miranda et al., 2003; Furushita et al., 2005;
Poirel et al., 2005a,b; Roberts, 2005; Saga et al., 2005).
The determinants of antibiotic resistance that have
emerged and selected in this aquatic environment have
the potential of being transmitted by horizontal gene trans-
fer to bacteria of the terrestrial environment, including
human and animal pathogens (Kruse and Sorum, 1994;
Sandaa and Enger, 1994; Rhodes et al., 2000a,b; LAbee-
Lund and Srum, 2001; Srum, 2006). The exchange of
resistance determinants between the aquatic and terres-
Journal compilation 2006 Society for Applied Microbiology and Blackwell Publishing Ltd, Environmental Microbiology, 8, 11371144
trial environment can also stem from the movement of
antibiotic-resistant bacteria between these two environ-
ments, a result of transporting fish between bodies of
freshwater and the ocean, a step that is needed to fulfil
the developmental requirements of salmonids (Cabello,
2003; Goldburg and Naylor, 2005; Naylor and Burke,
2005). Horizontal gene transfer mechanisms involved in
exchanging resistance determinants between aquatic and
terrestrial bacteria include conjugation and conjugative
transposition (Bushman, 2002a,b; Agerso and Guarda-
bassi, 2005; Casas et al., 2005). However, transduction
also has the potential to play an important role in these
processes because of the high concentrations of viruses
in seawater and the marine sediment (Fuhrman, 1999;
Bushman, 2002a). In many aquaculture settings in devel-
oping countries, the possibilities of these exchanges have
been amplified by the high level of contamination of sea-
water and freshwater with untreated sewage and agricul-
tural and industrial wastewater containing normal
intestinal flora and pathogens of animals and humans
usually resistant to antibiotics (Miranda and Zemelman,
2001; Cabello, 2003; Srum, 2006). This is also the case
in settings in which aquaculture is integrated with agricul-
ture (Petersen et al., 2002), and such practices such as
the use of manure and other agricultural residues as fish
feed are widespread (Petersen et al., 2002).
Aquaculture as a source of antibiotic resistance in
human pathogens
Not unexpectedly, exchange of genes for resistance to
antibiotics between bacteria in the aquaculture environ-
ment and bacteria in the terrestrial environment, including
bacteria of animals and human pathogens has recently
been shown (Srum, 1998; Rhodes et al., 2000a,b;
Schmidt et al., 2001a,b; Srum, 2006). For example,
strong epidemiological and molecular evidence exists
indicating that fish pathogens such as Aeromonas can
transmit and share determinants for resistance to antibi-
otics with pathogens such as Escherichia coli isolated
from humans (Rhodes et al., 2000a,b; Srum, 2000;
LAbee-Lund and Srum, 2001; Srum and LAbe-Lund,
2002; Srum, 2006). Incompatibility IncU plasmids con-
taining determinants for resistance to tetracycline
encoded by Tn1721, have been disseminated between
Aeromonas salmonicida, a fish pathogen, and the human
pathogens Aeromonas hydrophila, Aeromonas caviae
and E. coli obtained from different geographical locations
in Europe (Rhodes et al., 2000a). Similar molecular epi-
demiology studies in A. salmonicida have shown that
plasmids that contain class 1 integrons found in human
pathogenic bacteria, and are able to transfer with high
frequency to E. coli and Salmonella, are responsible for
the resistance to trimethoprim, sulfonamide and strepto-
2006 The Author

mycin in this bacterium (Srum and LAbe-Lund, 2002;
Srum, 2006). The sulfonamide-resistant determinant
SulI has also been found in plasmids present in
A. salmonicida and bacteria of other niches including
Erwinia (a plant pathogen), Vibrio cholerae and E. coli,
thereby suggesting the transfer of genetic information
between all these bacteria of the terrestrial and aquatic
environment (LAbee-Lund and Srum, 2001; Srum,
2006).
Molecular and epidemiological evidence has demon-
strated that antibiotic resistance determinants of resistant
Salmonella enterica serotype Typhimurium DT104, an
emergent pathogen and the cause of several outbreaks
of salmonellosis in humans and animals in Europe and
the USA, probably originated in aquaculture settings of
the Far East (Angulo, 2000; Angulo and Griffin, 2000;
Angulo et al., 2004). The antibiotic resistance determi-
nants of S. Typhimurium DT104 are encoded by a trans-
missible genetic element in the chromosome that contains
a resistance gene for florfenicol, an antibiotic extensively
used in aquaculture in the Far East (Briggs and Fratamico,
1999; Angulo, 2000). This florfenicol determinant, floR,
was detected for the first time in the fish pathogen Vibrio
damsela (Bolton et al., 1999). The tetracycline resistance
determinant carried by this Salmonella genetic element
belongs to the class G that was also, for the first time,
detected in the fish pathogen Vibrio anguillarum (Briggs
and Fratamico, 1999; Angulo, 2000; Angulo and Griffin,
2000). Moreover, the DNA sequence of the transmissible
element harbouring these antibiotic resistance determi-
nants has an important DNA sequence similarity to a
plasmid of Pasteurella piscicida, which is also a fish
pathogen (Kim and Aoki, 1993; Angulo, 2000; Angulo and
Griffin, 2000). This molecular evidence strongly suggests
that there was horizontal transmission of antibiotic resis-
tance determinants from bacteria in the aquaculture envi-
ronment to a human and terrestrial veterinary pathogen
(Angulo, 2000; Angulo and Griffin, 2000). The epidemiol-
ogy of the dissemination of S. Typhimurium DT104 also
suggests this pathogen could have been spread by fish
meal as has happened with the Salmonella Agona that
originated in Peru several years ago (Clark et al., 1973;
Angulo, 2000; Boyd et al., 2001). This process illustrates
the potential role of transport of antibiotic-resistant bacte-
ria as an alternative mechanism responsible for the
spread of antibiotic resistance determinants from the
aquatic environment to the terrestrial environment (Clark
et al., 1973; Angulo and Griffin, 2000).
The presence of antibiotics in the aquatic environment
can result in the appearance of resistance among human
pathogens forming part of its microbiota (Angulo, 2000).
For example, V. cholerae of the Latin American epidemic
of cholera that started in 1992 appeared to have acquired
antibiotic resistance as a result of coming into contact with
2006 The Author
Journal compilation 2006 Society for Applied Microbiology and Blackwell Publishing Ltd, Environmental Microbiology, 8, 11371144
Aquaculture and antibiotic resistance bacteria 1139
antibiotic-resistant bacteria selected through the heavy
use of antibiotics in the Ecuadorian shrimp industry
(Weber et al., 1994; Angulo, 2000). The widespread trans-
mission of antibiotic resistance determinants between
bacteria of the aquatic and terrestrial environment has
been recently demonstrated by the emergence of
plasmid-mediated quinolone resistance among human
Gram-negative pathogens (Jacoby, 2005; Li, 2005; Nord-
mann and Poirel, 2005; Robicsek et al., 2005; 2006), and
the potential tracing of the origin of these resistant deter-
minants to the aquatic bacteria Shewanella algeae and
Vibrio (Poirel et al., 2005a,b). Interestingly, one of these
quinolone-resistant determinants has been recently
detected in Japan and in Chile in the emergent human
pathogen Vibrio parahaemolyticus (Gonzalez-Escalona
et al., 2005; Poirel et al., 2005a; Saga et al., 2005; F.C.
Cabello and L. Dubytska, unpublished), a marine bacte-
rium transmitted to humans by the ingestion of raw shell-
fish and that is most likely able to exchange genetic
information with other bacteria of the marine environment
(Srum, 2006). Thus, the commonality of antibiotic resis-
tance determinants and of genetic elements between
aquatic bacteria, fish pathogens and bacteria from the
terrestrial environment strongly supports the concept that
antibiotic usage in aquaculture will influence the appear-
ance of resistance in bacteria of other niches, including
resistance in pathogens able to produce a variety of
human and animal diseases (Wegener, 1999; Angulo,
2000; Rhodes et al., 2000a; LAbee-Lund and Srum,
2001; Cabello, 2003; Poirel et al., 2005a,b; Srum, 2006).
Additional effects of the excessive use of antibiotics
in aquaculture
Another problem created by the excessive use of antibi-
otics in industrial aquaculture is the presence of residual
antibiotics in commercialized fish and shellfish products
(Grave et al., 1996; 1999; Goldburg et al., 2001; Cabello,
2003; 2004; Angulo et al., 2004; Srum, 2006). This prob-
lem has led to undetected consumption of antibiotics by
consumers of fish with the added potential alteration of
their normal flora that increases their susceptibility to bac-
terial infections and also selects for antibiotic-resistant
bacteria (Grave et al., 1996; 1999; Alderman and Hast-
ings, 1998; McDermot et al., 2002; Greenlees, 2003;
Cabello, 2004; Salyers et al., 2004). Moreover, undetec-
ted consumption of antibiotics in food can generate prob-
lems of allergy and toxicity, which are difficult to diagnose
because of a lack of previous information on antibiotic
ingestion (Alderman and Hastings, 1998; Cabello, 2004).
Allergy to antibiotics and problems of toxicity can also be
created for the unprotected workers in the aquaculture
industry through the use of large amounts of antibiotics
that come in contact with the skin, and intestinal and
1140 F. C. Cabello
bronchial tracts as workers medicate the food in food mills,
distributing it, and administer it to fish (Grave et al., 1996;
1999; Lillehaug et al., 2003). In aquaculture, the passage
into and permanent existence of large amounts of antibi-
otics in the environment of water and sediments also have
the potential to affect the presence of the normal flora and
plankton in those niches, resulting in shifts in the diversity
of the microbiota (Davies et al., 1999; Miranda and Zemel-
man, 2001; Cabello, 2003; Hunter-Cevera et al., 2005;
Srum, 2006). These shifts can be amplified by the
eutrophication produced in the aquaculture environment
by the increased input of N, C and P generated by the
non-ingested food and fish faeces (Goldburg et al., 2001;
Cabello, 2003; Hunter-Cevera et al., 2005). As the micro-
biota carries important trophic and metabolic functions in
aquatic and sediment niches, this heavy use antibiotics
also has the potential to alter the ecological equilibria at
those levels, thus creating situations that may impact fish
and human health by promoting, for example, algal
blooms and anoxic environments (Valiela, 1995; Sellner
et al., 2003; Hernandez et al., 2005; Hunter-Cevera et al.,
2005).
Policies of antibiotic use in aquaculture
Evidence indicating that antibiotic-resistant bacteria and
antibiotic resistance determinants pass from the aquatic
to the terrestrial environment has resulted in a drastic
restriction of the use of antibiotics in aquaculture in many
countries (Markestad and Grave, 1997; Lillehaug et al.,
2003; Angulo et al., 2004; Cabello, 2004; Goldburg and
Naylor, 2005; Srum, 2006). Restrictions have included,
increased control of the prescription of therapeutic antibi-
otics (Grave et al., 1996; 1999; Markestad and Grave,
1997; Lillehaug et al., 2003; Srum, 2006), almost total
elimination of the use of antibiotic prophylaxis in this set-
ting (Grave et al., 1996, 1999; Srum, 2006) and proscrip-
tion of the use of antibiotics in therapeutics that are still
very useful in the therapy of human infections (Grave
et al., 1996; 1999; Markestad and Grave, 1997; Goldburg
et al., 2001; Lillehaug et al., 2003). In this way, the use of
quinolones has been totally restricted in aquaculture in
industrialized countries, not only because they are a
highly effective group of antibiotics for human infections
but also because of their ability to generate cross-resis-
tance among all the members of this group (Grave et al.,
1996; 1999; Gorbach, 2001; Cabello, 2004; Moellering,
2005; Srum, 2006). Quinolones also remain active in
sediments for prolonged periods of time as they are not
readily biodegradable (Hansen et al., 1992; Samuelsen
et al., 1992; 1994; Jacoby, 2005). This increased control
of antibiotic use, accompanied by sanitary measures that
include the use of vaccines, have drastically reduced the
use of antibiotics in the aquaculture industry of developed
Journal compilation 2006 Society for Applied Microbiology and Blackwell Publishing Ltd, Environmental Microbiology, 8, 11371144
countries, therefore indicating that it is economically fea-
sible to develop a productive aquaculture industry without
excessive prophylactic use of antibiotics (Grave et al.,
1996; 1999; Markestad and Grave, 1997; Lillehaug et al.,
2003; Srum, 2006). However, the use of quinolones and
many other antibiotics remains totally unrestricted in
aquaculture in countries with growing aquaculture indus-
tries such as China and Chile (Cabello, 2004; Jacoby,
2005). For example, in Chile, statistics indicate that annu-
ally 1012 metric tons of quinolones are used in human
medicine and approximately 100110 metric tons of these
antibiotics are used in veterinary medicine per year, most
of them in aquaculture (Cabello, 2004; Bravo et al., 2005).
In this country the use of flumequine, a fluoroquinolone
used exclusively in aquaculture, has increased from
approximately 30 metrics tons in 1998 to close to 100
metric tons in 2002 (Bravo et al., 2005). This increase in
the use of this broad-spectrum fluoroquinolone parallels
the increase in the production of salmon from 258 000
metric tons in 1998 to 494 000 metric tons in 2002 (Bravo
et al., 2005). This suggests that in Chile, aquaculture use
of quinolones and not human use will probably be the
most important selective pressure to generate the emer-
gence of quinolone-resistant bacteria (Bakken, 2004;
Cabello, 2004; Bravo et al., 2005; Hernandez et al.,
2005). Similarly in China, quinolone resistance has
emerged as an important public health problem as result
of the unrestricted use of this group of antibiotics in aquac-
ulture and in industrial animal husbandry (Wang et al.,
2001; Jacoby, 2005). The potential of these events to
precipitate the emergence of antibiotic-resistant bacteria
across the globe is already illustrated in the appearance
and global distribution of S. Typhimurium DT104
described above (Angulo, 2000; Angulo et al., 2004).
Conclusions
This brief review suggests that the unrestricted use of
antibiotics in aquaculture in any country has the potential
to affect human and animal health on a global scale, and
further suggests that this problem should be dealt through
unified local and global preventive approaches (Grave
et al., 1996; 1999; Cabello, 2004; Bravo et al., 2005). The
use of antibiotics in aquaculture shares characteristics
with a heavy use of antibiotics in alternative industrial
processes of animal husbandry. It, nonetheless, has spe-
cific characteristics (Cabello, 2004; Srum, 2006). It would
appear that the transfer of antibiotic resistance determi-
nants among bacteria of the aquatic and terrestrial envi-
ronment would be readily attained, simply as a result of
the high concentrations of bacteria in seawater and
aquatic sediments and the abundant presence of bacte-
riophages to facilitate such a transfer (Fuhrman, 1999;
Bushman, 2002a). Contamination of the bodies of water
2006 The Author

where aquaculture is practised with bacteria of the normal
flora and pathogens of the intestine of humans and ani-
mals will also accelerate this transfer (Miranda and Zemel-
man, 2001; Cabello, 2003; Srum, 2006). Approximately
20 years after industrial aquaculture had begun, evidence
emerged of the transfer of antibiotic resistance determi-
nants between aquatic bacteria, including fish pathogens
and human pathogens (Srum, 2006). Historical evidence
appears to indicate that in terrestrial animal husbandry
this process took a longer time (Srum, 2006). The accel-
eration of this process strongly suggests that heavy anti-
biotic use in aquaculture needs to be reduced drastically
and replaced with improved sanitation in fish husbandry
to avoid the emergence of antibiotic resistance in fish
pathogens and environmental bacteria and the passing of
this resistance to human pathogens, thus endangering
effective therapy to treat human bacterial infections
(Angulo, 2000; Srum, 2006). Experience with alternative
processes of animal husbandry and aquaculture itself
(Srum, 2006) indicates that these much-needed
changes to protect human and animal health can be
achieved without detrimental effects, in financial terms, to
the industry (Grave et al., 1996; 1999; Wierup, 2001;
Srum, 2006).
Acknowledgements
The author thanks a USACanada 2004 fellowship from the
John Simon Guggenheim Foundation that allowed him to
travel to Norway and Chile to obtain information about the
use of antibiotics in aquaculture. He would also like to thank
many colleagues in Norway, especially Henning Srum and
Kari Grave, and in Chile, Alejandro Buschman, Juan C.
Cardenas, Marcel Claude and Humberto Dolz for stimulating
informative discussions about the use of antibiotics in aquac-
ulture and its public health implications and environmental
consequences. He would also like to thank Fred Angulo for
providing information with regard to S. Typhimurium DT104,
and Henry P. Godfrey, Mrs Harriett V. Harrison, Mrs Melody
Steinberg and Mrs Leonor Delgado for the preparation of the
manuscript.
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