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 21^st century^1–5. The critical relevance of this problem has been widely discussed by international and national health organizations, governments, private foundations, professional societies, and increasingly, by consumers^1–6. 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 produced^7–9.

Not surprisingly, ARB are most likely to emerge in hotspots with concentrated multiple antimicrobial usage such as hospitals and industrial animal husbandry, including aquaculture^1,2,3,6,9. 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 costs^1–3,6–12. 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 medicine^2–5, and this veterinary use is widely agreed to play an important role in the emergence of antimicrobial resistance in animal and human pathogens^2,5. 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 genes^1,5,10–14. 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 infections^{1,2,6,12,14,15}.

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 impact^1,12,17. We have previously published our findings in numerous reports^1,17,18, 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 Plan^1,17,19,20.

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 used^1,10–13. 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 use^12,17,19,20. 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 farming^12,17,18,20. 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 period^12,17,18,20. We have also shown that the importation of these antimicrobials to the country has been directly proportional to the expansion of salmon aquaculture production^12,17.

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 medicine^12,17,18,20. 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 restricted^12,17,18,20. 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 use^12,17.

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 genes^18,21. 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 bacteria^18,22–25. 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 environment^18,22–25.

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 pathogens^18,23–25.

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 pathogens^{1,12,17,23–25}. Human health is also affected by the contamination of wild fish for human consumption with antimicrobial residues. These can potentially alter the human microbiome^26,27 and select for ARB in the meat of wild fish and aquacultural products, factors all able to stimulate horizontal gene transfer of antimicrobial resistance genes^1,26,27.

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 worldwide^{1,11,12,17,18,22–24}.

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 origin^12,28,29.

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 industry^1,31,32. 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 impacts^12,17. 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 humans^1,3,33. 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 interactions^{1,3,12,33,34,35}. 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.