Therapeutic Considerations - The Merck Veterinary Manual

Therapeutic Considerations

Therapeutic options in fish are limited. FDA-approved drugs commercially available for use in food fish are listed in Table: FDA-approved Drugs for Aquaculture Use in the USA (2002). In addition, the FDA has listed several compounds as being of “low regulatory concern” (Table: Drugs Designated as Low Regulatory Priority for Aquaculture by the FDA). These compounds, though 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 used in aquaculture under the provision of “moderate regulatory concern.” Finally, there are several non-FDA approved compounds that are used in pet fish practice under controlled conditions. These have no legal status at present and have no place in food animal practice. In addition to being aware of FDA concerns, fish practitioners should be familiar with state environmental regulations. Federal and state environmental regulations are of greatest concern when treating outdoor ponds.

FDA-approved Drugs:

FDA-approved drugs for use in aquaculture in the USA include 2 antibiotics, 1 parasiticide, 1 anesthetic, and 1 spawning hormone. In many cases, therapeutic management of fish other than catfish or salmonids requires extra-label use of drugs.

Oxytetracycline is approved for use in Pacific salmon (for marking bony tissue), salmonids, catfish, and lobsters. It is widely available and has a broad spectrum of activity against gram-negative bacteria. Clinical evidence suggests that it is quite effective against myxobacteria, which do not grow on Müller-Hinton agar, making sensitivity testing difficult. Its main disadvantage is that it is only available in sinking feeds, which may make it difficult to determine whether it has been eaten, especially when treating fish in ponds. Because oxytetracycline has been used extensively for several decades, significant bacterial resistance has developed. Reliance on bacterial sensitivity test results is recommended.

A potentiated sulfonamide is approved for use in salmonids with furunculosis ( Aeromonas salmonicida ) and in channel catfish infected with Edwardsiella ictaluri . It should be fed at a dosage of 50 mg/kg for 5 days. The drug binds to the skin, and salmonid products are generally sold with intact skin, so longer withdrawal times (42 days) are required. This drug is available in floating feed, which makes it easier to determine whether it has been eaten. Clinical evidence suggests that it is not always effective against myxobacteria; therefore, it is not recommended as the drug of choice if columnaris is an important component of an epizootic.

Formalin is FDA approved for use in finfish and penaeid (saltwater) shrimp. Parasite-S^® is labeled for all finfish and penaeid shrimp; 2 other brands, Formalin-F^® and Paracide-F^® are labeled for select finfish species (table 7, Table: FDA-approved Drugs for Aquaculture Use in the USA (2002)). Methanol may be added to formalin products as a preservative. Formalin eliminates protozoan parasites and monogenean trematodes from the external surface of fish. 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 removes dissolved oxygen from the water. Vigorous aeration during formalin treatment is essential. A concentration of 25 mg/L is equal to 2 drops/gal. (useful for delivering formalin to aquarium fish). When treating at ≤25 mg/L, a water change is not necessary following chemical 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 observed for several days. This is an artifact caused by the interaction of the 2 compounds. Short-term baths with formalin can be provided at concentrations up to 250 mg/L for 30-60 min. At water temperatures >77°F (25°C), the concentration should be decreased to ~170 mg/L. Fish should never be left unattended during treatment and 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 observed. 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.

Tricaine methanesulfonate (MS-222) is FDA approved for use as a sedative and anesthetic in food fish and is often used to sedate broodstock for handling and injection of hormones for spawning. It is also useful for pet fish and is effective for sedation, surgical anesthesia, and euthanasia. Sedation can generally be achieved with concentrations between 50-100 mg/L, although species-specific sensitivities should be expected. Induction for most species may be near 125 mg/L; however, when working with unfamiliar species it is best to start at a lower concentration (ie, 50 mg/L) and increase the concentration until the desired effect is achieved. Because MS-222 is an acid, the chemical should be buffered (2 parts sodium bicarbonate by weight to 1 part MS-222). Following induction, the concentration may be decreased to 50-100 mg/L to maintain the desired depth of anesthesia. Respiration should be monitored; if opercular movement ceases, fish should be immediately moved to clean water. MS-222 can also be used to euthanize fish at concentrations of 1,000-10,000 mg/L. For small animals, a squirt bottle with a stock solution of 10,000 mg/L can be used to quickly apply a lethal dose of chemical to the gills. The compound will not remain stable for more than a few weeks when used in this manner. As it degrades, the color of the solution will change from clear to brownish. MS-222 is light sensitive and should be kept in a brown bottle when stored as a solution.

Chorionic gonadotropin is FDA approved as a spawning aid for finfish. Veterinarians may work as part of a team for fish hatcheries and may be asked to assist in obtaining spawning hormones.

Salt:

Salt can be used for many purposes, including destruction of single-celled protozoans and management of osmoregulation. Seawater is 3% salt, which is 30,000 ppm. By increasing or decreasing the amount of salt to which a freshwater fish or marine fish, respectively, is exposed, osmoregulatory stress can be minimized and many parasites eliminated. For freshwater fish, a 3% dip is an effective ectoparasiticide and is strongly recommended when moving fish. However, tolerance varies by species. Most freshwater fish will tolerate 3% salt for 30 sec up to several minutes, after which they show signs of stress, commonly manifest by rolling on their side. Recovery is rapid if fish are promptly removed from the salt solution. The use of salt is a quick, effective, inexpensive, and readily available means of minimizing the introduction of protozoans into a system with new fish. A solution of 0.5-1.0% salt is recommended for transportation of freshwater fish, and most species will tolerate this concentration for several hours or days. A solution of 0.02-0.2% (200-2,000 ppm) salt can be added to freshwater recirculating systems as a continuous treatment to minimize parasitic protozoa in the system. Salt is less caustic than other parasiticides and seems to optimize healing of epithelial surfaces. Unfortunately, it is not practical for use in ponds (other than for control of nitrite toxicity) because of the massive quantities that would be required to achieve a nominal level of salinity. Addition of salt may be practical in small ornamental ponds of a few thousand gallons. Less information is available on lowering salinity for marine fish, but it is a technique that should not be overlooked.

Non-FDA-approved Compounds:

Copper sulfate (CuSO₄) is not approved by the FDA; however, a number of compounds containing CuSO₄ have been approved by the US Environmental Protection Agency (EPA) as algicides for use in aquatic sites. CuSO₄ is currently designated as “of moderate regulatory concern” and is used in food fish practice; however, practitioners must keep themselves informed of possible changes in the status of this chemical. 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 its interaction with carbonate salts in water. In freshwater systems, the concentration of CuSO₄ applied should be based on the total alkalinity (TA) of the water. If TA is <50 mg/L, copper cannot be used safely without performing a bioassay. 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. Other concerns when treating a pond with CuSO₄ (in addition to its direct toxicity to fish) relate to its algicidal activity. Rapid death of an algal bloom can precipitate a 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 disc ≤18 in.) or if the water is already deficient in oxygen due to other factors, (eg, cloudy weather or high water temperature). CuSO₄ is efficacious against most protozoal parasites, is economical, and despite these concerns, may be an excellent choice when multiple treatments are required (eg, in an epizootic of Ichthyophthirius multifiliis ). In saltwater systems, copper is sometimes applied in a chelated form because it stays in concentration longer. Chelated compounds may be difficult to use safely and require careful monitoring. CuSO₄ can be used to treat marine fish, but the concentration of active copper must be closely monitored (test kits are available) and should be maintained at 0.2 mg/L for up to 3 wk. Safe and effective use of copper in marine systems requires that Cu²⁺ concentrations be tested at least once a day. Copper is extremely toxic to invertebrates, so these must be removed before the water is treated. Copper is also toxic to plants and should not be used in ornamental ponds that have been stocked with valuable plants. Finally, copper will impact bacteria in biofilters and a transient increase in ammonia should be expected for several days following treatment. Monitoring ammonia until measurable concentrations subside is recommended.

Potassium permanganate (KMnO₄) is not approved by the FDA but is also in the group designated “of moderate regulatory concern.” 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 the fish. Overuse, particularly multiple uses within a short period of time, will kill fish. Use of KMnO₄ no more than once a week seems safe for many fish. The concentration of KMnO₄ used varies with the permanganate demand of the water. Permanganate demand is greater in water with a high organic load than in water with little organic matter. 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 at least 8 hr. A practical method is to apply KMnO₄ at 2 mg/L in the morning—if the color changes from pink to brown or clear in <8 hr, the treatment should be repeated. If the concentration of KMnO₄ required to maintain a pink color for at least 4 hr is >6 mg/L, then the organic load is excessive, and sanitation practices should be evaluated. In large production ponds, little can be done to decrease the accumulation of organic material in ponds other than draining the pond, drying the bottom, and discing it. This is not done very often, perhaps once in 10-15 yr. In smaller systems (<0.1 acre), mechanisms may be in place to facilitate cleaning and removal of debris. KMnO₄ has little impact on biofilters when applied at 2 mg/L or less.

Hydrogen peroxide (H₂O₂, 3%) is currently used to control protozoan parasites in both food and ornamental species as an alternative to CuSO₄ and KMnO₄ . H₂O₂ is categorized as “low regulatory priority” by the FDA and is used in the salmonid and hybrid striped bass industries. Food grade H₂O₂ is 35% active and is the best product for aquaculture use. The primary use of H₂O₂ is the control of sea lice and aquatic fungi on fish or fish eggs. It may also help control bacterial gill disease and columnaris. Dosages are variable and some fish may not tolerate this chemical. It is applied as a short-term bath, often for 15-30 min intervals. A dosage of 250 mg/L would be 2.7 mL of the 35% solution/gal. of water. Practitioners unfamiliar with use of this compound should experiment with it in a bioassay before applying it to a valuable group of fish. Efficacy can be monitored by evaluation of gill and skin biopsy material before and after treatment.

Erythromycin is not FDA approved but has been used in management of bacterial kidney disease of salmonids and streptococcal infections in food and nonfood species. It can be incorporated into fish food at a dosage of 100 mg/kg body wt and fed for 14 days. FDA permission is required for use in food animals.

Another group of compounds have been designated by FDA as “high regulatory priority,” ie, their use is likely to result in enforcement action by the FDA. The most important of these compounds are chloramphenicol, the nitrofurans, and malachite green. These compounds should never be used in food animals for any reason, and their use in nonfood species is discouraged.

Pet Fish Practice:

Some drugs are used in pet fish practice that are not appropriate for aquaculture use, including both antibiotics and parasiticides. None of these compounds are approved for the uses described, and safety and efficacy data are sparse. Nonetheless, these treatments are considered somewhat routine in the practice of ornamental fish medicine.

Kanamycin has been used with some success to treat bacterial diseases of ornamental fish, including koi. It can be administered orally at 20 mg/kg, by injection at 20 mg/kg, or in a bath at a concentration of 750 mg/L for 2 hr. Anorectic fish can be medicated with a bath treatment or by injection, repeated daily, until fish begin to eat, at which time the drug can be incorporated into the feed to complete the treatment period. Treatment should be continued for 7 days beyond the alleviation of clinical signs. Aminoglycosides are toxic to fish and should be used with caution. Severe kidney lesions have been reported in goldfish treated with gentamicin. Toxicity may be exacerbated by a high ammonia concentration in the water.

Organophosphates have been used in nonfood fish practice for decades to control monogenea, crustaceans, and leeches. Historically, there was an approved compound, Masoten (used at a concentration of 0.25 mg/L active ingredient), for use in ponds stocked with nonfood fish, however the label expired and was not renewed. Use of organophosphates in aquaria is still practiced, and the dosage is often increased slightly in marine systems due to the higher pH. Use of organophosphates in outdoor ponds is not generally recommended because of legal and environmental concerns.

Metronidazole is used to control flagellated protozoans and can be delivered in a medicated food or as a bath when fish are anorectic. A concentration of ~7 mg/L (~250 mg metronidazole dissolved in 10 gal. of water) can be administered daily for 5 days. A daily water change a few hours after treatment is recommended. Metronidazole can be administered at 50 mg/kg PO, for 5 days. Anecdotal information suggests that excessive treatment (10 times the recommended dosage for 30 days) with metronidazole may be associated with reproductive failure in some fish.

Fenbendazole has been used to control intestinal helminths in fish. A dosage of 25 mg/kg, delivered in food for 3-5 days, has been commonly recommended, but this regimen has not been evaluated in controlled trials.

Praziquantel has also been used successfully in fish to control intestinal cestodes as well as monogenean trematodes on the gills and skin. The most common use of praziquantel is as a prolonged bath in large marine aquaria for control of monogenean trematodes, particularly Neobenedenia spp . It is applied at a concentration of 2 mg/L, and limited work indicates that the compound remains active for several weeks. Praziquantel can also be administered PO at a dosage of 35-125 mg/kg for up to 3 days or as a short-term bath treatment at a concentration of 10 mg/L for 3 hr.

Chloroquine has been used to control Amyloodinium sp in ornamental marine fish. It is applied as a prolonged bath at concentrations of 2 mg/L. Efficacy in recirculating systems seems to be very good; however, there are essentially no data on treatment intervals, effects on biofilters, or other basic husbandry data.