Patrick Whittaker, Timothy S. Kniffen, and Simon Otto As the human population and income continue to grow, so too does the demand for high‐quality protein sources, including seafood. The ability to meet the increasing global seafood demand from wild‐caught resources is unsustainable and untenable. Aquaculture has rapidly grown globally to meet this additional demand for high‐quality protein to the extent that in 2018, almost 50% of all seafood consumed was provided by aquaculture (Food and Agricultural Organization, 2020). As with any other farmed food animal species, it is the moral and ethical obligation of the farmer and veterinarian to ensure the health and welfare of the animals in their care. One of the key tenets of this obligation is the prudent treatment of illness with antimicrobials when necessary and appropriate. Prudent is the key word in this statement, considering that products from aquaculture are destined for human consumption and present a potential transmission pathway for antimicrobial resistance (AMR) from the aquatic environment and products to humans. All antimicrobial use (AMU) must be evaluated via a One Health lens wherein human medicine, terrestrial animal agriculture, and aquaculture all contribute antimicrobials to the environment, resulting in potential effects on nontarget organisms as well as the risk of bacterial AMR development. Salmonid aquaculture is the largest contributor as far as tonnage produced and economic relevance in North America, South America, and western Europe are concerned. Due to efforts by governments, third‐party certification groups and data reporting by publicly traded companies, salmonid aquaculture has the most robust data collected and reported on annual antimicrobial usage. Salmonid aquaculture is also an example of an industry that has shown an impressive ability to reduce AMU. The largest global salmon producer, Norway, has reduced AMU by 99% over the last 25 years while simultaneously increasing total salmon production (Norwegian Veterinary Institute (Veterinaerinstituttet), 2021). Effective vaccines, improved biosecurity, and management changes and improvements have nearly eliminated the need for antimicrobials in Norwegian salmon production. However, viral diseases of Atlantic salmon remain a formidable challenge. In other Atlantic salmon‐farming regions around the globe, there are gaps in successful vaccine development to address local bacterial challenges. Ongoing research will hopefully find and develop solutions to guide the use of biologics and the best management practices to mitigate these challenging diseases, as the industry recognizes the need to reduce AMU for sustainability. This chapter focuses on the prudent use of antimicrobials guided by the ethical treatment of disease while avoiding residues, as well as minimizing environmental impacts and the risk of the development of AMR. Due to a lack of research and robust data regarding AMU and AMR in many aquatic species and geographic regions, the chapter will primarily focus on salmonid production. There is a common but erroneous belief that antimicrobials are used in aquatic species for growth promotion. The cost of antimicrobials is high relative to the cost of production and market value of most aquatic species. There are no approved indications for any antimicrobial to improve production parameters in any aquatic species. For example, one study demonstrated that oral administration of oxytetracycline to channel catfish, hybrid striped bass, Nile tilapia, and rainbow trout for eight weeks did not improve survival, average daily gain, or feed conversion ratio (Trushenski et al., 2018). With no economic value to feeding antimicrobials to healthy finfish, there is no reason or incentive to utilize antimicrobials in a nontherapeutic fashion. The use of antimicrobials in all types and forms of aquaculture is and must remain limited to the treatment of disease due to susceptible pathogenic bacteria. Globally, over six hundred different aquatic species are under cultivation in aquaculture compared to terrestrial agriculture, which produces approximately one dozen species, albeit with multiple breeds (Henriksson et al., 2018). Forty‐four ectothermic species make up 90% of total global aquaculture production, in comparison to five predominant terrestrial livestock species. Modern aquaculture is conducted in both fresh‐water and salt‐water (marine) environments. Animals raised in aquaculture systems are classified as cold‐water, warm‐water, or tropical species. Therefore, an entire book, not just one chapter, could be dedicated to pharmacology in all the aquaculture applications, not to mention aquarium species and marine mammals. However, the focus of this chapter is finfish aquaculture, with emphasis on the most economically relevant species. The authors recognize there is concern regarding both the type and quantity of antimicrobials used with crustaceans; however, this will not be addressed in the chapter as robust data for this use are sparse. The chapter focuses primarily on data from Atlantic salmon as they are generally available and robust in quality. Atlantic salmon aquaculture could be a model for many forms of aquaculture and terrestrial agriculture where biosecurity, technology (e.g, vaccines), management practices, regulation, and third‐party certification have reduced or eliminated the need for antimicrobials in production systems. In 2017, over 80% of global aquaculture biomass produced was consumed in China (57.9%), India (11.3%), Indonesia (8.6%), and Vietnam (5%) (Schar et al., 2020). In these countries, accurate data regarding the types and quantities of AMU are difficult to access. For example, carp represent more than one‐third of global aquaculture production tonnage by species, but only one survey of farms in Vietnam explicitly identified carp among the species for which AMU data were collected (Schar et al., 2020). Antimicrobial use also crosses socioeconomic boundaries, emphasizing the need to teach and use a One Health policy to evaluate AMU in humans, terrestrial agriculture, and aquaculture (Ayukekbong et al., 2017). Medicated feed with oral delivery is the route of administration used to treat the major aquaculture species discussed here. This mode of antimicrobial administration presents its own challenges, similar to those faced in all other species, in that the affected animal must be consuming feed in order to obtain the medication, and the need to treat groups of animals rather than the individual. The challenge to the aquaculture veterinarian responsible for treating aquatic species is to evaluate the population, prescribe an efficacious dose of an approved product, and ensure that a very high proportion of the population consumes the prescribed dose. Homeotherms are organisms that have the ability to maintain a relatively constant body temperature independent of their environmental temperature. Some examples of homeotherms are humans, terrestrial and marine mammals, and birds. Poikilotherms are organisms that do not have the ability to regulate their body temperature because they lack the physiological ability to generate heat. Examples of poikilotherms include amphibians, reptiles, insects, and aquatic animals such as fish and shrimp. The body temperature of aquatic species equilibrates with the temperature of the water in which they are located. Water temperature must be considered in the production and management of any aquatic species. Each species, whether cold‐water, warm‐water, or tropical, will have a preferred optimal water temperature range. Exposure to water temperatures outside the optimal range results in a decreased rate of biological functions, physiological stress, or death. The impact of water temperature on drug metabolism and elimination is crucial in establishing drug withdrawal recommendations. An Atlantic salmon can survive in an environment from approximately 0 °C to temperatures in the low 20 °C range. This wide range of temperatures is a predicament for the prescribing veterinarian as an equivalent amount of antimicrobial will be metabolized more slowly with low water and body temperatures. Some approved product labels include instructions that the drug is not to be used if water temperature is <10 °C. For example, in winter in Atlantic Canada, ocean water temperatures routinely go below 5 °C. This low temperature necessitates an increased withdrawal time in Atlantic salmon for oxytetracycline treatment of bacterial kidney disease (BKD) caused by Renibacterium salmoninarum. Degree days (DD) is an important concept to understand in aquaculture and aquatic medicine. Degree days is a metric calculated by the product of average water temperature during a 24‐hour period (°C) multiplied by the number of days. A fish in a body of water with an average water temperature of 15 °C over a 24‐hour period would accumulate 15 DD. Degree days determine or influence nearly every aspect of aquatic animal biology from egg hatching, growth, reproduction, and onset of immunity after vaccination, to withdrawal times for antimicrobials. Many antimicrobials have withdrawal recommendations based on number of days and are often based on a minimum assumed temperature. In this way, the DD concept is built into antimicrobial drug label withdrawal periods. A more logical path forward would be to utilize DD for a more accurate prediction of drug withdrawal given the variety of water temperatures that are encountered. For further discussion on antimicrobial residues in aquaculture, see Okocha et al. (2018) and Chapter 26. The approach to AMU and regulation is very highly variable across the different aquaculture‐producing countries. Some countries ban the use of antimicrobials with potential for carcinogenic or mutagenic effects (e.g, nitrofurans, nitroimidazoles, malachite green, chloramphenicol) while permitting the use of others that are categorized as critical for human health (Henriksson et al., 2018). Other highly regulated countries monitor AMU and control quantities used or ban use. The following information discusses a variety of aquaculture industries in several countries but is by no means exhaustive. In some countries, the quality of data does not exist as to the types or amounts of products that are used. In New Zealand aquaculture, no antimicrobials are approved for use in finfish. To this point, no New Zealand food fish has ever received antimicrobial treatment (Zac Waddington, New Zealand King Salmon, personal communication, 2021). In Australia, there are no approved antimicrobials for use in the salmon‐farming industry; however, oxytetracycline has been used extra‐label for the treatment of Rickettsia‐like organisms in Atlantic salmon (Christine Hunyh, Petuna, personal communication, 2021). In Norwegian salmon farming, AMU has declined drastically from the mid to late 1980s (Solveig Nygaard, Grieg Seafood, personal communication, 2021). In 1990, an effective vaccine was developed against many of the common bacterial diseases which eliminated most antimicrobial treatments. Today, most antimicrobial use in aquaculture in Norway is for the treatment of bacterial diseases of lumpsucker fish, which are stocked on salmon farms to accomplish lice removal from the salmon. Oxytetracycline, oxolinic acid, and florfenicol are approved for use in Norway. However, their use is minimal due to poor bioavailability (oxytetracycline) and oxolinic acid being on the World Health Organization’s list of critically important antimicrobials for human medicine. Only one feed manufacturer regularly produces antimicrobials in feed, and only florfenicol is currently available. A special order is required, including regulatory requirements for justification, to prescribe either of the other two antimicrobials. In Canada and the United States, florfenicol, oxytetracycline, and potentiated sulfonamides are approved for aquaculture use. In eastern North America, AMU in salmonid aquaculture is primarily for the control of BKD. Vaccines exist to aid in the prevention and control of BKD but oxytetracycline is still used for treatment of clinical cases. In western North America, AMU is driven by the environmental bacterium Tenacibaculum maritimum, the causative agent of a disease most commonly diagnosed in smolts called “yellow mouth.” This disease occurs early in the marine phase of the production cycle and is typically over within a few months of smolts being transferred to sea. The primary antimicrobial of choice is florfenicol, which is used at lower drug weights due to the small size of the affected fish and lower label mg/kg dosage. Research is ongoing to develop an effective vaccine or management strategy for yellow mouth to further reduce the need for antimicrobials. One of the strategies utilized for minimizing AMR is practicing “all‐in all‐out” management of a farm. In this case, antimicrobials are given early in the production cycle, and new salmon are not restocked into the area until all the treated fish are removed and a fallow period for the region is observed. Implementation of this management strategy results in a minimum of 18–20 months between antimicrobial treatments in a given region. The practice of “all‐in all‐out” management has been exemplified through area‐based management which is a management tool where all the farms in the region have coordinated fish stocking and harvesting. This allows for coordinated treatments when necessary, and fallowing of the entire region, not just the farm. The relevant geographical region can be complicated to assess as adequate hydrological data may not exist in all areas of farming and therefore distance between sites has been used as a proxy where data do not exist. In some regions of British Columbia, salmonid rickettsial septicemia (SRS), caused by Piscirikettsia salmonis, occurs and may be controlled through antimicrobial therapy. Florfenicol and oxytetracycline are the primary antimicrobials used to treat SRS. Vaccine development for SRS is ongoing as it is the most common reason for antimicrobial therapy in Chile and AMU there is amongst the highest in salmonid aquaculture (Miranda et al., 2018). A variety of vaccines are available in Chile for SRS, but they have been unable to eliminate antimicrobial treatments to date. Twenty different antimicrobials were reportedly used in Chinese aquaculture production but of those, 12 are not officially approved for use. China banned erythromycin use in aquaculture in 2002 but its use continued in 2012 (Liu et al., 2017). Vietnam has 27 approved antimicrobials for use in aquaculture, many of which are critical to human medicine, while Thailand has five (Henriksson et al., 2018). There are no data on the extent of use of unapproved antimicrobials in many other countries. There are also concerns about the potential for antimicrobial residues in aquaculture food products in countries with few to no regulations on their use in aquaculture, such as India, Bangladesh, Nigeria, and Iran (Okocha et al., 2018). This is in contrast to North America, specifically Canada, where government surveillance finds greater than 96% compliance for drug residues in food products, meaning that the vast majority do not contain antimicrobial residues over acceptable levels (Government of Canada, 2022). These examples demonstrate the uncertainty and variability regarding the type and quantity of AMU in aquaculture at the global level. Our experience suggests that AMU in Atlantic salmon production in North America and western Europe is judicious, highly regulated and viewed with an emphasis on reduction. Many salmon‐farming companies in these countries conduct internal assessments of environmental impacts and monitor for AMR. Conversely, from a One Health perspective, a variety of factors in developing countries and those with fewer regulations contribute to a lack of awareness, education, or other tools to address environmental concerns, AMR development, and food safety impacts of AMU in all forms of food production and human medicine (Ayukekbong et al., 2017). Pharmacokinetics (PK) is the science of quantitatively describing the disposition of an antimicrobial through the animal, and includes drug absorption, distribution, metabolism, and excretion. When evaluating and comparing pharmacokinetic parameters reported between different aquaculture studies, it is important to be aware that there may be significant variability in the experimental design of one study compared to another. Factors such as dose, dosage form, sampling times, water temperature, salinity, health/disease status, species and other factors may have a substantial or even significant impact on PK values for any particular study (see Chapter 4). The two most commonly used antimicrobials in aquaculture systems around the world are oxytetracycline and florfenicol. Tables 39.1 and 39.2 provide pharmacokinetic parameters for those two antimicrobial compounds in select aquaculture species. It is important to note that not all data are available for all possible pharmacokinetic parameters for all species listed or routes of administration. As a general rule, the tables include the information from studies where the antimicrobials were delivered orally and the data selected for the table were generated from the highest dose of the antimicrobial used in the event that multiple doses were evaluated. One of the considerations for antimicrobial therapy in aquatic animals is whether the fish will be treated in fresh water, salt water, or brackish water. In a fresh‐water environment, fish are hyperosmotic relative to their aqueous environment, and therefore absorb water via this osmotic gradient primarily via the gills. Passive absorption of water results in fresh‐water fish producing relatively large volumes of dilute urine. Fish in salt water are hypoosmotic relative to their aqueous environment and therefore must actually consume water orally on a continuous basis to prevent dehydration. Additionally, fish in a salt‐water environment produce low volumes of urine. The gut contents of marine fish species include plenty of sea water and associated ions in addition to whatever the fish consumes, including antimicrobials. Table 39.1 Select florfenicol pharmacokinetic parameters in selected aquatic species.
39
Antimicrobial Therapy in Aquaculture
Introduction
Aquaculture Definition
Poikilotherms versus Homeotherms
Degree Days
Antimicrobial Use in Aquaculture
Pharmacokinetics/Pharmacodynamics of Antimicrobials Used in Aquaculture
Fresh‐water versus Salt‐water Effects
Species
Dose
(mg/kg)
Route of administration
Water temperature (°C) & salinity (ppt)
t1/2 (hours)
Cmax (μg/ml)
Tmax
(hours)
F (%)
Reference
Channel catfish (Ictalurus punctatus)
10
PO (feed gavage)
25.4 / fresh water
9.1
7.6
9.2
109
(Gaunt et al., 2012)
Channel catfish (Ictalurus punctatus)
10
IV
25.4 / fresh water
8.3
22.3
0.2
(Gaunt et al., 2012)
Crucian carp (Carassius auratus)
10
PO (feed gavage)
10 / fresh water
22.9
2.4
3.7
(Yang et al., 2019)
Crucian carp (Carassius auratus)
10
PO (feed gavage)
20 / fresh water
12.3
2.8
3.2
(Yang et al., 2019)
Crucian carp (Carassius auratus)
10
PO (feed gavage)
25 / fresh water
9.6
3.6
2.9
(Yang et al., 2019)
Atlantic salmon (Salmo salar)
10
PO
10.8 / sea water (30)
12.2
4.0
10.3
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