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Revista chilena de infectología

versión impresa ISSN 0716-1018

Rev. chil. infectol. vol.35 no.3 Santiago  2018

http://dx.doi.org/10.4067/s0716-10182018000300299 

Viewpoint

Antimicrobial resistance in Chile and The One Health paradigm: Dealing with threats to human and veterinary health resulting from antimicrobial use in salmon aquaculture and the clinic

Ana R. Millanao5 

Carolina Barrientos-Schaffeld5 

Claudio D. Siegel-Tike5 

Alexandra Tomova6 

Larisa Ivanova6 

Henry P. Godfrey7 

Humberto J. Dölz5 

Alejandro H. Buschmann8 

Felipe C. Cabello6 

5Instituto de Farmacia, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile

6Department of Microbiology and Immunology, New York Medical College, Valhalla, New York, USA

7Department of Pathology, New York Medical College, Valhalla, New York, USA

8Centro i~mar and CeBiB, Universidad de Los Lagos, Puerto Montt, Chile

ABSTRACT

The emergence and dissemination of antimicrobial-resistant bacteria (ARB) is currently seen as one of the major threats to human and animal public health. Veterinary use of antimicrobials in both developing and developed countries is many-fold greater than their use in human medicine and is an important determinant in selection of ARB. In light of the recently outlined National Plan Against Antimicrobial Resistance in Chile, our findings on antimicrobial use in salmon aquaculture and their impact on the environment and human health are highly relevant. Ninety-five percent of tetracyclines, phenicols and quinolones imported into Chile between 1998 and 2015 were for veterinary use, mostly in salmon aquaculture. Excessive use of antimicrobials at aquaculture sites was associated with antimicrobial residues in marine sediments 8 km distant and the presence of resistant marine bacteria harboring easily transmissible resistance genes, in mobile genetic elements, to these same antimicrobials. Moreover, quinolone and integron resistance genes in human pathogens isolated from patients in coastal regions adjacent to aquaculture sites were identical to genes isolated from regional marine bacteria, consistent with genetic communication between bacteria in these different environments. Passage of antimicrobials into the marine environment can potentially diminish environmental diversity, contaminate wild fish for human consumption, and facilitate the appearance of harmful algal blooms and resistant zoonotic and human pathogens. Our findings suggest that changes in aquaculture in Chile that prevent fish infections and decrease antimicrobial usage will prove a determining factor in preventing human and animal infections with multiply-resistant ARB in accord with the modern paradigm of One Health.

Key words: Resistance; antimicrobials; antibiotics; aquaculture; salmon; One Health

Emergence of antimicrobial-resistant bacteria (ARB) and their worldwide dissemination has been recognized as one of the major human and animal public health threats of the 21st century15. The critical relevance of this problem has been widely discussed by international and national health organizations, governments, private foundations, professional societies, and increasingly, by consumers16. This latter group includes customers of health care organizations and consumers of animal food products and their derivatives who increa singly are demanding that retailers distribute foodstuffs certified to have been sustainably produced79.

Not surprisingly, ARB are most likely to emerge in hotspots with concentrated multiple antimicrobial usage such as hospitals and industrial animal husbandry, including aquaculture1,2,3,6,9. It has long been recognized that infections produced by resistant bacteria are associated with increased mortality, augmented morbidity, and greater numbers of complications leading to prolonged hospitalizations and higher treatment costs13,612. It has also been repeatedly demonstrated in almost every country, both developed and developing, that many-fold more antimicrobials are used in production of animals for food and for other veterinary uses than in human medicine25, and this veterinary use is widely agreed to play an important role in the emergence of antimicrobial resistance in animal and human pathogens2,5. Passage of antimicrobials into the terrestrial and aquatic environments as a result of these activities select resistant bacteria and increase the frequency of genetic variation in them by fostering mutation, DNA recombination and horizontal gene transfer of variants and new antimicrobial resistance genes1,5,1014. This panoply of molecular variation also facilitates the capture of new and unrecognized antimicrobial resistance genes from the environmental resistome by animal and human pathogens, further undermining the therapy of infections1,2,6,12,14,15.

The Chilean government has recently proposed an outline for a national plan to prevent and combat antimicrobial resistance following the recommendations of the World Health Organization (WHO), the Food and Agricultural Organization (FAO), the Office International des Epizooties (OIE), and the United Nations General Assembly16. We have been actively involved in studying the amounts of antimicrobials used in veterinary medicine in Chile for the past 15 years, especially in salmon aquaculture, and their potential impact1,12,17. We have previously published our findings in numerous reports1,17,18, and would now like to revisit this data, extend our findings to 2015, and discuss their relevance to the emergence of antimicrobial resistance in Chile in light of the proposed National Plan1,17,19,20.

Determination of the amounts of antimicrobials used in a defined area in a well-defined period of time is the cornerstone for preventing and combatting antimicrobial resistance because levels of resistance are directly related to the amounts of antimicrobial used1,1013. Since no antimicrobials are produced in Chile, all antimicrobials used in this country must be imported. Between 1998 and 2015, our analysis indicated that 95% (7,775 tonnes) of tetracyclines, phenicols and quinolones imported into Chile were for veterinary use12,17,19,20. Of these imported antimicrobials, 19% (1,480 tonnes) were quinolones, 35% (2,683 tonnes) were phenicols and 46% (3,612 tonnes) were tetracyclines. Of the quinolones imported for veterinary use, 1,132 tonnes (77%) were used in aquaculture. Interestingly, phenicols for veterinary use increased from 3.2 tonnes between 2000-2003 to 1,606 tonnes between 2012-2015, probably reflecting increased use in aquaculture and more specifically mainly in salmon farming12,17,18,20. During this same period, 381 tonnes of antimicrobials (5% of the total) were imported for human clinical use: 312 tons (82%) quinolones, 28 tonnes (7%) phenicols, and 41 tons (11%) tetracyclines. A further illustration of the difference between veterinary and human clinical use is that while an average of 226 tons of tetracyclines per year were imported for veterinary use between 2000-2015, only 2.5 tons, a hundred times less, were imported each year for human clinical use in the same time period12,17,18,20. We have also shown that the importation of these antimicrobials to the country has been directly proportional to the expansion of salmon aquaculture production12,17.

These findings indicate that, as in other nations, antimicrobial use in animals, specifically salmon aquaculture in this case, likely drives selection for ARB for these three groups of antimicrobials as well as for others others given that the total of this antimicrobial use in Chile is almost 20 times higher than its use in human medicine12,17,18,20. Moreover, these results indicate that highly relevant antimicrobials such as quinolones have been used indiscriminately in veterinary medicine in Chile, in stark contrast with international recommendations that veterinary use of antimicrobials useful in human medicine should be restricted12,17,18,20. A positive development has been the recent decrease of the use of highly effective quinolones in aquaculture after demands from government regulators and retailers, suggesting that antimicrobial use can be modified relatively quickly in response to market requirements20.

Unfortunately, our studies suggested that the amounts of antimicrobials determined to be used in veterinary medicine might be underestimations as we found that the governmental regulatory services responsible for assessing this use authorized lower amounts in some years than the amounts actually imported for that use12,17.

Our documentation of the presence of residual antimicrobials in marine sediments as well as ARB in water and sediments in areas 8 km distant from the areas of application, and the presence of antimicrobial resistance genes in these ARB to the antimicrobials mostly used in this activity, i.e. tetracyclines, phenicols and quinolones18, is consistent with our and others’ conclusions that passage of antimicrobials used in Chilean aquaculture into fresh water and marine environments underlie these observations since bacteria in these environments contain multiple antimicrobial resistance genes18,21. We have shown that ARB from the marine environment contain their antimicrobial resistance genes in mobile genetic elements such as plasmids and integrons, and that they can transfer these genetic structures and their resistance genes to other bacteria18,2225. Marine bacteria and human pathogenic bacteria from aquaculture regions share antimicrobial resistance genes and mobile genetic elements, suggesting that they can exchange these genetic elements by horizontal gene transmission, probably in the aquatic environment18,2225.

Figure 1 Metric tonnes of phenicols, tetracyclines and quinolones imported to Chile for use in veterinary medicine mainly in aquaculture, 1998-2015. The information has been obtained from references 12, 17, 19 and 20

This work has also indicated that the marine environment contains bacteria harboring undescribed and new antimicrobial resistance genes that can potentially pass to the resistome of piscine and human pathogens18,2325.

Antimicrobial use in veterinary medicine and specifically in aquaculture can thus have negative impact on human health by selecting ARB in the aquatic environment and facilitating transfer of antimicrobial resistance genes between marine bacteria and human pathogens1,12,17,2325. Human health is also affected by the contamination of wild fish for human consumption with antimicrobial residues. These can potentially alter the human microbiome26,27 and select for ARB in the meat of wild fish and aquacultural products, factors all able to stimulate horizontal gene transfer of antimicrobial resistance genes1,26,27.

Our studies strongly suggest that the extended geographical areas used by aquacultural activities in Chile are hotspots for the generation of ARB and the dissemination of these bacteria and their antimicrobial resistance genes worldwide1,11,12,17,18,2224.

Use of antimicrobials in aquaculture has other impacts on the environment besides its impact on human health produced by selection of ARB and antimicrobial resistance genes. Their use can decrease biological diversity in the environment with the theoretical potential of facilitating the appearance of toxic algal blooms and selection for epidemic resistant human pathogens of marine origin, i.e., Vibrio parahaemolyticus and zoonotic pathogens of aquatic origin12,28,29.

It has been recently found that the bacterial diversity in a salmon farming area is reduced compared to that from a control site lacking salmon aquaculture activities, and it appears that the function of these bacteria in the ecosystem is also different30. The decrease in biological diversity produced by this excessive use of antimicrobials also facilitates bacterial infections of the cultured fish with new and emerging fish pathogens resistant to antimicrobials, i.e., Piscirickettsia salmonis, that together with algal blooms constitute a major menace to the aquaculture industry1,31,32. For example, approximately, half of the isolated P. salmonis in Chile, are resistant to quinolones reflecting the previous heavy use of these therapeutics in the industry32.

Our investigations have thus indicated that the indiscriminate use of antimicrobials constitute a risk to human, animal and environmental health as well as to the aquaculture industry itself. For this reason, we proposed a set of measures in 2011 that needed to be implemented by the Chilean aquaculture industry and by the Chilean animal and human health regulatory entities to ameliorate these impacts12,17. Many of our recommendations coincide with those of the proposed National Plan to Prevent and Combat Antimicrobial Resistance. However, we would like to suggest that the plan should also incorporate measures based on the One Health paradigm to register and control antimicrobial use in animals and humans1,3,33. The One Health paradigm specifies that protection of human health is achieved through the implementation of hygienic measures in the industrial rearing of fish that decrease the use of antimicrobials, because as we and others have shown, animal and human health are interlocked and have reciprocal interactions1,3,12,33,34,35. The most important elements facilitating emergence of ARB and dissemination of antimicrobial resistance genes impacting human health in Chile could be prevented by appropriate veterinary attention to the hygiene and well-being of animals, especially those of fish under aquaculture.

Acknowledgements:

This work has been supported by grants from the Lenfest Ocean Program/Pew Charitable Trusts (F C C and A H B), FONDECYT, Núcleo de Investigation (NU02/2016, Universidad de Los Lagos and Basal Program-CONICYT FB001) (A H B), and by a fellowship from the John Simon Guggenheim Foundation (F C C).

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Received: February 06, 2018; Accepted: February 27, 2018

Corresponding Author: Felipe C. Cabello, Department of Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, U.S.A. cabello@nymc.edu

Conflict of interest: The authors do not have any conflicts of interest to declare.

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