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

Received 31 January, 2006; accepted 4 April, 2006. *For correspondence. E-mail cabello@nymc.edu; Tel. (+1) 914 594 4182; Fax (+1) 914 594 4176.

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1138 F. C. Cabello 1991). Because these manipulations decrease the effectiveness of the shess immune system to clear up bacterial 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 sh raising methods, including increased sh population densities, crowding of farming sites in coastal waters, lack of sanitary barriers and failure to isolate sh farming units with infected animals (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 component of their food, and occasionally in baths and injections (Markestad and Grave, 1997; Srum, 2006). The unconsumed food, and sh 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 environment, these antibiotics can be ingested by wild sh and other organisms including shellsh (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 microora 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 ora in the environment surrounding aquaculture sites contain an increased number of antibiotic-resistant bacteria (Huys et al., 2000; Schmidt et al., 2000; 2001a,b; Srum, 2000; Miranda and Zemelman, 2002a,b; Furushita 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 transfer to bacteria of the terrestrial environment, including human and animal pathogens (Kruse and Sorum, 1994; Sandaa and Enger, 1994; Rhodes et al., 2000a,b; LAbeeLund and Srum, 2001; Srum, 2006). The exchange of resistance determinants between the aquatic and terrestrial environment can also stem from the movement of antibiotic-resistant bacteria between these two environments, a result of transporting sh between bodies of freshwater and the ocean, a step that is needed to full 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 Guardabassi, 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 developing countries, the possibilities of these exchanges have been amplied by the high level of contamination of seawater and freshwater with untreated sewage and agricultural and industrial wastewater containing normal intestinal ora 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 agriculture (Petersen et al., 2002), and such practices such as the use of manure and other agricultural residues as sh 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 environment 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 sh pathogens such as Aeromonas can transmit and share determinants for resistance to antibiotics 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 containing determinants for resistance to tetracycline encoded by Tn1721, have been disseminated between Aeromonas salmonicida, a sh 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 epidemiology 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-

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Aquaculture and antibiotic resistance bacteria 1139 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 demonstrated 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 Grifn, 2000; Angulo et al., 2004). The antibiotic resistance determinants of S. Typhimurium DT104 are encoded by a transmissible genetic element in the chromosome that contains a resistance gene for orfenicol, an antibiotic extensively used in aquaculture in the Far East (Briggs and Fratamico, 1999; Angulo, 2000). This orfenicol determinant, oR, was detected for the rst time in the sh 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 rst time, detected in the sh pathogen Vibrio anguillarum (Briggs and Fratamico, 1999; Angulo, 2000; Angulo and Grifn, 2000). Moreover, the DNA sequence of the transmissible element harbouring these antibiotic resistance determinants has an important DNA sequence similarity to a plasmid of Pasteurella piscicida, which is also a sh pathogen (Kim and Aoki, 1993; Angulo, 2000; Angulo and Grifn, 2000). This molecular evidence strongly suggests that there was horizontal transmission of antibiotic resistance determinants from bacteria in the aquaculture environment to a human and terrestrial veterinary pathogen (Angulo, 2000; Angulo and Grifn, 2000). The epidemiology of the dissemination of S. Typhimurium DT104 also suggests this pathogen could have been spread by sh 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 bacteria 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 Grifn, 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 antibiotic-resistant bacteria selected through the heavy use of antibiotics in the Ecuadorian shrimp industry (Weber et al., 1994; Angulo, 2000). The widespread transmission 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; Nordmann and Poirel, 2005; Robicsek et al., 2005; 2006), and the potential tracing of the origin of these resistant determinants 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 bacterium transmitted to humans by the ingestion of raw shellsh and that is most likely able to exchange genetic information with other bacteria of the marine environment (Srum, 2006). Thus, the commonality of antibiotic resistance determinants and of genetic elements between aquatic bacteria, sh pathogens and bacteria from the terrestrial environment strongly supports the concept that antibiotic usage in aquaculture will inuence the appearance 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 antibiotics in industrial aquaculture is the presence of residual antibiotics in commercialized sh and shellsh products (Grave et al., 1996; 1999; Goldburg et al., 2001; Cabello, 2003; 2004; Angulo et al., 2004; Srum, 2006). This problem has led to undetected consumption of antibiotics by consumers of sh with the added potential alteration of their normal ora that increases their susceptibility to bacterial infections and also selects for antibiotic-resistant bacteria (Grave et al., 1996; 1999; Alderman and Hastings, 1998; McDermot et al., 2002; Greenlees, 2003; Cabello, 2004; Salyers et al., 2004). Moreover, undetected consumption of antibiotics in food can generate problems of allergy and toxicity, which are difcult 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

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1140 F. C. Cabello bronchial tracts as workers medicate the food in food mills, distributing it, and administer it to sh (Grave et al., 1996; 1999; Lillehaug et al., 2003). In aquaculture, the passage into and permanent existence of large amounts of antibiotics in the environment of water and sediments also have the potential to affect the presence of the normal ora and plankton in those niches, resulting in shifts in the diversity of the microbiota (Davies et al., 1999; Miranda and Zemelman, 2001; Cabello, 2003; Hunter-Cevera et al., 2005; Srum, 2006). These shifts can be amplied by the eutrophication produced in the aquaculture environment by the increased input of N, C and P generated by the non-ingested food and sh faeces (Goldburg et al., 2001; Cabello, 2003; Hunter-Cevera et al., 2005). As the microbiota 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 sh 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 antibiotics (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 setting (Grave et al., 1996, 1999; Srum, 2006) and proscription 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-resistance 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 countries, therefore indicating that it is economically feasible 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 industries such as China and Chile (Cabello, 2004; Jacoby, 2005). For example, in Chile, statistics indicate that annually 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 umequine, a uoroquinolone 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 uoroquinolone 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 emergence 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 aquaculture 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 unied 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 specic characteristics (Cabello, 2004; Srum, 2006). It would appear that the transfer of antibiotic resistance determinants among bacteria of the aquatic and terrestrial environment would be readily attained, simply as a result of the high concentrations of bacteria in seawater and aquatic sediments and the abundant presence of bacteriophages to facilitate such a transfer (Fuhrman, 1999; Bushman, 2002a). Contamination of the bodies of water

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Aquaculture and antibiotic resistance bacteria 1141 where aquaculture is practised with bacteria of the normal ora and pathogens of the intestine of humans and animals will also accelerate this transfer (Miranda and Zemelman, 2001; Cabello, 2003; Srum, 2006). Approximately 20 years after industrial aquaculture had begun, evidence emerged of the transfer of antibiotic resistance determinants between aquatic bacteria, including sh 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 acceleration of this process strongly suggests that heavy antibiotic use in aquaculture needs to be reduced drastically and replaced with improved sanitation in sh husbandry to avoid the emergence of antibiotic resistance in sh 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 nancial 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 aquaculture 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. agents in food animals in the United States. Microb Drug Resist 9: 373379. Angulo, F.J. (2000) Antimicrobial agents in aquaculture: potential impact on health. APUA Newsletter 18: 16. Angulo, F.J., and Grifn, P.M. (2000) Changes in antimicrobial resistance in Salmonella enterica serovar Typhimurium. Emerg Infect Dis 6: 436438. Angulo, F.J., Nargund, V.N., and Chiller, T.C. (2004) Evidence of an association between use of anti-microbial agents in food animals and anti-microbial resistance among bacteria isolated from humans and the human health consequences of such resistance. J Vet Med 51: 374379. Bakken, J.S. (2004) The uoroquinolones: how long will their utility last? Scand J Infect Dis 36: 8592. Balaban, N.Q., Merrin, J., Chait, R., Kowalik, L., and Leibler, S. (2004) Bacterial persistence as a phenotypic switch. Science 305: 16221625. Barton, B.A., and Iwama, G.K. (1991) Physiological changes in sh from stress in aquaculture with emphasis on the response and effects of corticosteroids. Annu Rev Fish Dis 1: 326. Beaber, J.W., Hochhut, B., and Waldor, M.K. (2004) SOS response promotes horizontal dissemination of antibiotic resistance genes. Nature 427: 7274. Bolton, L.F., Kelley, L.C., Lee, M.D., Fedorka-Cray, P.J., and Maurer, J.J. (1999) Detection of multidrug-resistant Salmonella enterica serotype Typhimurium DT104 based on a gene which confers cross-resistance to orfenicol and chloramphenicol. J Clin Microbiol 37: 13481351. Boxall, A.B., Fogg, L.A., Blackwell, P.A., Kay, P., Pemberton, E.J., and Croxford, A. (2004) Veterinary medicines in the environment. Rev Environ Contam Toxicol 180: 191. Boyd, D., Peters, G.A., Cloeckaert, A., Boumedine, K.S., Chaslus-Dancla, E., Imberechts, H., and Mulvey, M.R. (2001) Complete nucleotide sequence of a 43-kilobase genomic island associated with the multidrug resistance region of Salmonella enterica serovar Typhimurium DT104 and its identication in phage type DT120 and serovar Agona. J Bacteriol 183: 57255732. Bravo, S., Dolz, H., Silva, M.T., Lagos, C., Millanao, A., and Urbina, M. (2005) Informe Final. Diagnostico del uso de frmacos y otros productos qumicos en la acuicultura. Universidad Austral de Chile. Facultad de Pesquerias y Oceanograa, Instituto de Acuicultura. Casilla 1327. Puerto Montt, Chile. Proyecto No. 2003-28. Briggs, C.E., and Fratamico, P.M. (1999) Molecular characterization of an antibiotic resistance gene cluster of Salmonella Typhimurium DT104. Antimicrob Agents Chemother 43: 846849. Burrus, V., and Waldor, M.K. (2003) Control of SXT integration and excision. J Bacteriol 185: 50455054. Bushman, F. (2002a) Conjugation, transposition, and antibiotic resistance. In Lateral DNA Transfer. Mechanisms and Consequences. Cold Spring Harbor, NY, USA: Cold Spring Harbor Laboratory Press, pp. 2772. Bushman, F. (2002b) Phage transduction and bacterial pathogenesis. In Lateral DNA Transfer. Mechanisms and Consequences. Cold Spring Harbor, NY, USA: Cold Spring Harbor Laboratory Press, pp. 73128.

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