Although improvement of water quality, nutrition, and other general husbandry factors may be enough to improve the health of a population, chemotherapeutics are often required to ameliorate disease outbreaks. Management of fish diseases is challenging because of basic logistics, including the aquatic environment, numbers of fish, and routes of administration, and also because of the pharmacologic and regulatory complexities of chemotherapeutic usage in fish.
One major point of confusion among veterinarians, more critical because of impacts on the aquatic environment, is the difference between a drug and a pesticide. Drugs are regulated by the FDA, whereas pesticides are regulated by the Environmental Protection Agency (EPA). According to the Federal Food Drug and Cosmetic Act, the term "drug" can be defined four ways:
articles recognized in the official United States Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them
articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals
articles (other than food) intended to affect the structure or any function of the body of man or other animals
articles intended for use as a component of any of the aforementioned articles
The EPA regulates water and effluents and controls the use of pesticides against “pests.” A “pest” is defined by the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) as “any insect, rodent, nematode, fungus, weed” or “any other form of terrestrial or aquatic plant or animal life or virus, bacteria, or other microorganism (except viruses, bacteria, or other microorganisms on or in living man or other living animals).”
Legally, a drug is a compound that works in or on the fish, whereas a pesticide works in the water. Challenges occur for one of two reasons: 1) certain pathogens, and in particular some parasites, including the fish louse Argulus spp and anchorworm Lernaea spp, have life stages off the host and in the environment; and 2) certain compounds, such as copper and diquat, are legal pesticides but are also drugs effective against some pathogens.
FDA-approved Drugs, Indexed Drugs, Pesticides, and Regulatory Concerns
FDA-approved therapeutic options for fish are limited but increasing. The FDA is the best resource for basic information on the status of drugs and chemicals, particularly those intended for aquaculture use. In addition, the FDA has listed several compounds as being of “low regulatory concern.” These compounds, although not fully approved, are considered innocuous enough for use in food fish. Of these, salt is the most important. A few compounds, including copper sulfate and potassium permanganate, are not FDA approved but are legally available for limited use in food fish under the category "regulatory action deferred" pending further study. For more information, see the SRAC website, specifically SRAC Fact Sheet 4709 (Investigational New Animal Drug [INAD] Exemptions and the National INAD Program [NIP]), as well as FDA CVM Program Policy and Procedures Manual 120.4200 "Enforcement Priorities for Drug Use in Aquaculture."
Another category is drugs on the Index of Legally Marketed Unapproved New Animal Drugs for Minor Species (the Index). Fish are considered by the FDA to be a minor species. The process of placing drugs on the Index involves the use of an expert panel and is intended to increase legal access to unapproved drugs intended for non-food-producing minor species (including non-food fish) and non-food early life stages of food-producing minor species. Currently, the only two fish drugs on the Index are metomidate, a fish sedative/anesthetic, and GnRH + domperidone, a spawning aid also used to “spawn out” egg-bound females under some conditions. See table: Drugs Used in Aquaculture in the US – Approval Status and Withdrawal Times for a summary of the approval status and withdrawal times of drugs used in aquaculture in the US. Practitioners are encouraged to visit the FDA website frequently for the most current information.
Finally, a number of compounds that are not FDA approved are used in pet fish practice under controlled conditions. These drugs have no legal status and have no place in food animal practice. A term formerly used by the FDA, “regulatory discretion,” has fallen out of favor, but it does provide some explanation of the FDA’s current approach to use of unapproved, non-Indexed drugs. The primary concerns are degree and magnitude of impact on human and environmental safety, and regulatory action against any illegal use will be weighed against those two measures. (See the Center for Veterinary Medicine Program Policy and Procedures Manual on the FDA website for additional guidance).
In addition to being aware of FDA concerns, fish practitioners should be familiar with environmental regulations for drugs and pesticides. Federal and state environmental regulations are of greatest importance when treating outdoor ponds. Considerations include potential for entry of treated water into natural water bodies or the water table and potential effects to nontarget species. Compounds labeled pesticides are regulated in the US by the EPA and therefore cannot be used under extra-label drug use provisions regulated by the FDA (ie, these compounds cannot be used in a manner beyond their specific label, which would have to include an aquatic use section).
Veterinarians should be familiar with the Veterinary Feed Directive (VFD). This is of particular interest to practitioners in rural areas, who may be asked to write prescriptions for aquacultured fish. For a veterinarian to issue a VFD order, there must be a valid veterinarian-client-patient relationship, and the veterinarian must have examined the fish and identified a bacterial disease that would be treatable with the VFD drug (eg, florfenicol). Extra-label use of the VFD drug, including use for species or pathogens not indicated on the label, is prohibited by law. However, VFD drugs may be allowed and prescribed under conditions described below.
Three FDA-approved antibiotics are currently available for use in aquacultured food fish in the US, and all of these specific products are now Veterinary Feed Directive (VFD) drugs. Some of these approved products can be useful in ornamental fish, especially koi. Legally, extra-label use of FDA-approved medicated feeds is not permitted under current law. However, recognizing the need to deliver some medications in a medicated food for fish, the FDA has indicated that it would not normally consider regulatory action against a veterinarian using medicated fish food (ie, VFD drugs in medicated feed) in an extra-label manner if the following criteria are met:
extra-label use is only with expressed prior written recommendation under a licensed veterinarian's oversight within a valid veterinarian-client-patient relationship
the extra-label use is for treatment of a minor species as defined by federal law
the Type A medicated article is approved for use in or on feed and manufactured and labeled as per law
in an aquatic species, the use of medicated feed in an extra-label manner is limited to products approved for use in other aquatic species
extra-label use is limited to farmed or confined species
extra-label use is limited to therapeutic treatment when animal health is threatened, and suffering or death may result from failure to treat
medicated feed has not been promoted or advertised by any party for an extra-label use
In addition, the veterinarian must have properly diagnosed and evaluated the therapeutic indication, no other legal products are available, treated animals can be identified, and withdrawal periods have been properly determined and will be followed to avoid drug residues.
For more specifics, see the FDA CVM Compliance Policy Guide Sec 615.115 and CVM GFI #120. Additionally, these VFD drugs may be available through enrollment in the appropriate INAD (Investigational New Animal Drug) program . Registering under an INAD requires an initial, annual fee and has specific reporting requirements.
A small group of compounds have been designated by the FDA as “high regulatory priority,” meaning their use is likely to result in enforcement action. These drugs either have human or environmental safety concerns or are related to compounds considered critical for human health and disease. The most important of these compounds are chloramphenicol, the nitrofurans, fluoroquinolones and quinolones, steroid hormones, and malachite green. These compounds should never be used in food animals for any reason, and their use in nonfood species is discouraged.
Antimicrobials
Aquaflor® is an approved medicated feed containing florfenicol for use against specific pathogens in enteric septicemia (Edwardsiella ictaluri) in channel catfish, coldwater disease (Flavobacterium psychrophilum) in salmonids, furunculosis (Aeromonas salmonicida) in freshwater-reared salmonids, streptococcal septicemia in freshwater-reared warmwater finfish, and columnaris disease (Flavobacterium columnare) in freshwater-reared finfish. It is marketed as a VFD drug. This broad-spectrum antimicrobial has excellent efficacy against many gram-negative bacteria and gram-positive streptococci. As discussed earlier, use may be permitted in other species and for other indications in certain situations or use may be available through registration in the appropriate INAD program. The withdrawal time is 15 days.
Oxytetracycline dihydrate is an in-feed VFD drug approved: 1) to control mortality in freshwater-reared salmonids due to coldwater disease associated with F psychrophilum; 2) to control mortality in freshwater-reared rainbow trout due to columnaris disease associated with F columnare; and 3) to mark skeletal tissue in Pacific salmon. All approved uses require a 21-day withdrawal period for harvest-size food fish species. As discussed earlier, use may be permitted in other species and for other indications in certain situations or use may be available through registration in the appropriate INAD program.
Ormetoprim sulfadimethoxine is an in-feed treatment approved by the FDA to control furunculosis (A salmonicida) in salmonids, for which a 42-day withdrawal period is required, and to control enteric septicemia of catfish (E ictaluri) in channel catfish for which a 3-day withdrawal period is required. Romet-30 can be used extra-label as long as there is a veterinarian-client-patient relationship and veterinary oversight. As discussed earlier, use may be permitted in other species and for other indications in certain situations, or use may be available through registration in the appropriate INAD program.
Aquaculture grade hydrogen peroxide 35% is administered by immersion and is FDA approved for use in finfish to control bacterial gill disease (caused by F branchiophilum) in salmonids, external columnaris (caused by F columnare) in freshwater-reared coolwater finfish and catfish, and fungal infection (saprolegniasis) of freshwater-reared finfish eggs. These are common external infections in fish that may follow handling or be associated with high organic load or other water quality perturbations for the affected species. Hydrogen peroxide is used as a short-term, continuous-flow bath. Treatments are administered daily or on consecutive alternate days for three treatments. An initial bioassay is recommended before treating a large group of fish. Paddlefish are sensitive, and use of hydrogen peroxide is not recommended. Other sensitive species include northern pike, pallid sturgeon, and in some instances, walleye. Hydrogen peroxide can be used extra-label, and experimental use has been attempted in other species and for other indications, including as a parasiticide (see UF/IFAS EDIS publication Use of Hydrogen Peroxide in Finfish Aquaculture ). There is no required withdrawal time after treatment with this product.
Other Chemotherapeutic Drugs
Formalin in Aquaculture
Formalin is FDA approved for use in finfish and penaeid (saltwater) shrimp. Several brands have received FDA approval for aquaculture use. Methanol may be added to formalin products as a preservative. “Pure” 100% formalin is, technically, water saturated with ~37%–40% formaldehyde gas. Formalin eliminates protistan parasites and monogeneans from the external surface of fish. It also has some efficacy against external fungal (specifically, water mold or oomycete) infections. It can be used as a prolonged bath at concentrations of 15–25 mg/L. The lower concentration is recommended for pond use, because formalin, an algicide, may remove dissolved oxygen from the water, especially if phytoplankton are present. Vigorous aeration during formalin treatment is essential.
When treating with formalin at ≤25 mg/L, a water change is not necessary after administration. At this concentration, formalin has minimal impact on biofiltration; however, if ammonia is tested using Nessler’s reagent, a very high reading may be seen for several days. This is an artifact caused by the interaction of the two compounds. Use of the salicylate method to test ammonia is suggested when formalin has been used in a system. Short-term baths with formalin can be provided at concentrations up to 250 mg/L for 30 minutes, but a bioassay and close observation during treatment is essential because 250 mg/L may be lethal in some fish. At water temperatures >77°F (25°C), the concentration should not exceed ~170 mg/L. If adverse reaction to the chemical becomes apparent, the fish should be immediately placed in clean water. If formalin is allowed to chill to < 45°F, a white precipitate, paraformaldehyde, will form. Because paraformaldehyde is highly toxic to fish, formalin should never be used if a precipitate or cloudiness is seen. Formalin is carcinogenic and potentially toxic to workers; material safety data sheets should be on hand in businesses where the chemical is used, and employees should be informed of appropriate safety precautions. There is no required withdrawal time after treatment with formalin.
Chloramine-T in Aquaculture
Chloramine-T, a biocide and mild disinfectant, is approved by the FDA for three indications: 1) to control mortality in freshwater-reared salmonids caused by bacterial gill disease associated with Flavobacterium spp, 2) to control mortality in walleye due to external columnaris disease (F columnare), and 3) to control mortality in freshwater-reared warmwater finfish due to external columnaris disease (F columnare). No withdrawal period is required before harvest.
Hypersalinity and Hyposalinity in Aquaculture
Hypersalinity (for freshwater systems) and hyposalinity (for marine systems) are often used in aquaculture and can be effective methods for control of some parasites. Hypersalinity in freshwater typically involves use of sodium chloride, which is considered “low regulatory priority.” In some instances, dilution of seawater may be used. Sodium chloride effectively mitigates nitrite toxicity ( see Aquatic Systems) to reduce osmoregulatory stress in freshwater fish and to control some protistan and copepod parasite infestations. In some instances, seawater may be used. Salt is not generally practical for use in production ponds because of their large volume, except for control or prevention of nitrite toxicity, but it can be used in ornamental ponds that are not more than several thousand gallons. Salt is commonly used in recirculating aquaculture systems.
Copper Sulfate in Aquaculture
Copper sulfate (CuSO4) is currently categorized as "regulatory action deferred" and not approved by the FDA; however, a number of compounds containing CuSO4 have been approved by the EPA as algicides for use in aquatic sites, and copper sulfate can be used in food fish species. Technically, the chemical form of the commonly used blue crystal copper sulfate is CuSO4•5H2O (copper sulfate pentahydrate), but for purposes of brevity, the formula CuSO4 will be used here, and this blue compound referred to as “copper sulfate.”
CuSO4 has been used for many years as a parasiticide and is particularly useful in large production ponds because of its relatively low cost. Copper is highly toxic to fish, and safe use depends on knowing both the volume of water to be treated and the total alkalinity, as well as potential species sensitivities.
In freshwater systems, the concentration of CuSO4 is considered 100% active, and application should be based on the total alkalinity (TA) of the water. If TA is < 50 mg/L, copper sulfate cannot be used safely. If TA is 50–250 mg/L, a safe concentration of CuSO4 can be determined by dividing the TA by 100. For example, if TA = 100 mg/L, a safe concentration of CuSO4 would be 1 mg/L. If TA is >250 mg/L, the concentration of CuSO4 should not exceed 2.5 mg/L. CuSO4 also has algicidal activity. Rapid death of an algal bloom can precipitate catastrophic oxygen depletion. Use of CuSO4 in ponds not equipped with supplemental aeration is risky. Use of CuSO4 is hazardous if a pond has a heavy algal bloom (secchi disk ≤18 inches in diameter) or if the water is already deficient in oxygen because of other factors (eg, cloudy weather, heavy stocking density, or high water temperature).
Copper in marine systems, by contrast, is dosed according to level of free copper ion (Cu2+). Therapeutic concentrations are based on maintaining a longterm dosage range of 0.15–0.2 mg/L of free Cu2+. As discussed earlier, “blue” copper sulfate is actually CuSO4•5H2O, so for purposes of marine systems, copper sulfate is considered 25% active ingredient (the molecular weight of free copper is ~25% of the entire compound). Because copper is toxic and because treatment periods for susceptible marine pathogens often last for ≥2–4 weeks, copper should be added to a system slowly at 0.05 ppm/day to reach the target range of 0.15–0.2 mg/L over the course of 3–4 days. This allows the fish’s body to acclimate and activate detoxifying pathways to reduce toxic effects. Free copper levels should be monitored daily. Copper is highly toxic to many invertebrates, and even with slow acclimation some saltwater species are still fairly sensitive. The following formula can be used to calculate the grams of copper sulfate required to treat a marine tank: volume (in gallons) × 0.0038 × desired concentration × 4 = g of CuSO4.
Chelated copper compounds (copper sulfate or copper ion chelated with another chemical) have also been used in some circumstances, but caution should be used for legal reasons and when dosing for treatment. Copper can be removed from a system with water changes or by filtering water through activated carbon. Food fish must undergo a 7-day withdrawal period after treatment before harvest.
Potassium Permanganate in Aquaculture
Potassium permanganate (KMnO4) is also "regulatory action deferred," and KMnO4 is used as an external parasiticide, fungicide, and bactericide. It is a strong oxidizing agent and “burns” organic material off the external surface of fish. Overuse, particularly multiple uses within a short period of time (more than once a week) will kill fish. The concentration of KMnO4 used varies with the permanganate demand of the water. In aquaria or ornamental ponds with very clear water, a concentration of 1–2 mg/L is usually safe and effective. Permanganate demand is greater in water with a high organic load.
To determine the permanganate demand, a bioassay can be performed: the water to be treated is placed in small containers, and KMnO4 is added in incremental concentrations of 2 mg/L. The correct concentration for therapeutic use will be the lowest concentration that maintains a pink color for 4–8 hours. If the concentration of KMnO4 required is >6 mg/L, then the organic load is excessive, and sanitation practices should be evaluated. KMnO4 has little impact on biofilters when applied at ≤2 mg/L. Potassium permanganate is more toxic as salinity of the water increases, and use in marine systems is not recommended. Food fish must undergo a 7-day withdrawal period after treatment before harvest.
Diquat in Aquaculture
Diquat, first registered as a contact herbicide (pesticide), has been used for many years to control columnaris disease (F columnare) in fish. Only recently has it come under greater FDA scrutiny and become an INAD for control of Flavobacterium species associated with bacterial gill disease and columnaris disease. Withdrawal times for harvestable food fish species are 5 days for channel catfish, muskellunge, tiger muskellunge, and northern pike, and 30 days for all other fish species.
Diflubenzuron in Aquaculture
Diflubenzuron, a chitinase inhibitor used to control crustacean parasites, is a restricted-use pesticide that can be applied only by licensed pesticide applicators. Dimilin is labeled for control of anchorworms on ornamental fish and baitfish commercially produced in ponds and tanks. Fish being raised for human consumption should not be exposed to diflubenzuron.
Anesthetics/Sedatives
Tricaine Methanesulfonate in Aquaculture
Tricaine methanesulfonate is a benzocaine derivative and is the only FDA-approved fish anesthetic. TMS is approved for the temporary immobilization of fish, amphibians, and other aquatic, cold-blooded animals. In fish intended for human consumption, TMS can only be used in members of the Ictaluridae, Salmonidae, Esocidae, and Percidae, and water temperature should not exceed 10°C (50°F). Withdrawal period if used in these species is 21 days.
Eugenol in Aquaculture
Eugenol, one component of several found naturally in clove oil, is currently available through an INAD and is intended for use as an anesthetic/sedative. Although eugenol is not approved, it is currently allowed for use in freshwater and marine fisheries work as a zero-withdrawal fish anesthetic. However, if used in aquaculture, the withdrawal time is 72 hours. A related compound, isoeugenol, is not allowed for use in the US because of carcinogenicity concerns.
Metomidate in Aquaculture
Metomidate hydrochloride is a fish sedative on the FDA CVM Index of Legally Marketed Unapproved New Animal Drugs for Minor Species (the Index), labeled for the sedation and anesthesia of ornamental finfish. It is not legal for use in food fish species.
Spawning Compounds
Chorionic Gonadotropin in Aquaculture
Chorionic gonadotropin is FDA approved for use as an aid to improve spawning function in male and female brood finfish. This is the only spawning aid approved by the FDA for use in food fish species. There is no withdrawal time if used according to label instructions on broodfish. Veterinarians may work as part of a team for fish hatcheries and may be asked to help obtain spawning hormones. Chorionic gonadotropin is a prescription drug and is restricted to use by or on the order of a licensed veterinarian.
Gonadotropin-releasing Hormone + Domperidone in Aquaculture
Salmonid GnRH analogue + domperidone is on the Index and labeled for use as a spawning aid in ornamental finfish broodstock. This product cannot be used in food fish species.
