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SRAC Publication No. 473 Southern regional
Medicated Feed for Food Fish
Anita M. Kelly1
Medicated feed is frequently recommended to control drugs for use in aquaculture, preventing bacterial disease bacterial disease outbreaks in cultured fish. Medicated outbreaks with proper disease management strategies is feeds are commercially prepared, and contain an anti- the best method to avoid bacterial diseases in fish. For biotic to control specific bacterial infections by either more information on preventing diseases on fish farms killing the bacteria or preventing the bacteria from see SRAC Publication No. 4703, Disease Prevention on reproducing. Antibiotics do not control parasites, fungus, Fish Farms; SRAC Publication No. 4707, Biosecurity in Aquaculture, Part 1: An Overview; and SRAC Publication No. 4708, Biosecurity in Aquaculture, Part 2: Recirculating Bacterial disease
Bacterial diseases of fish are usually a result of a Bacterial infections occur in fish just like any other stressful event such as periods of low dissolved oxygen or animal. Several different pathogenic bacteria are associ- spawning stress. In nature, fish are generally less prone ated with disease in cultured freshwater food fish such as to bacterial disease outbreaks as they can seek the least channel catfish, hybrid striped bass, and salmon. For spe- stressful conditions. In aquaculture, fish often are unable cific information on bacterial diseases see SRAC Publica- to reduce their own stressful conditions, and thus, are tion No. 477, ESC - Enteric Septicemia of Catfish; SRAC weakened by increased fish density, inadequate nutrition, Publication No. 478, Aeromonas Bacterial Infections - poor water quality (i.e., low dissolved oxygen or high Motile Aeromonad Septicemia; and SRAC Publication No. ammonia and nitrite), parasite infestation, and handling.
479b, Columnaris Disease: Flavobacterium columnare. When stress occurs in fish, their immune system is Fortunately, many bacterial diseases of cultured fish suppressed, increasing susceptibility to bacterial infec- can be successfully treated with medicated feeds that con- tions. As a result, cultured fish are more susceptible to tain U.S. Food and Drug Administration (FDA) approved disease than free-ranging animals. Minimizing stressful antibacterial drugs. These compounds have undergone conditions often reduces the incidence of disease. Fail- extensive animal, human-food, and environmental test- ing to correct stressful conditions that lead to a disease ing prior to approval for use in fish. Unfortunately, there outbreak, even while treating sick fish with medicated are very few drugs approved by the FDA for use in fish feed, will usually prevent the medication from being fully in the United States. Compounding this issue can be the effective or will result in a reinfection of disease after improper use of antibiotics which has resulted in devel- treatment is completed. Therefore, medications should opment of many antibiotic resistant strains of bacteria. only be thought of as part of the strategy in controlling Therefore, medicated feeds should only be used when and preventing disease. Prior to and during medication, absolutely necessary and according to label or veteri- fish culturists should review all husbandry and environ- narian instructions. Because there are so few approved mental factors that may have contributed to the disease outbreak and correct them to prevent the disease from continuing or reoccurring.
1 University of Arkansas at Pine Bluff Bacteria are either opportunistic or obligate patho- ensure that the antibiotic is out of the fish and that it is gens. Opportunistic bacteria are present in the water and safe for human consumption. It is a good idea to designate inside the fish, and generally cause no problem. When this date on the pen, tank, or raceway with a clearly visible culture conditions deteriorate, these bacteria will take the and prominent sign in order to eliminate any potential opportunity to cause disease in infected fish. Common error of a premature harvest. examples of opportunistic bacteria which can cause dis- The U.S. Food and Drug Administration (FDA) has ease and death of food fish include: Aeromonas hydroph- approved only four antibiotics for use in food fish. The ila, Flexibacter columnaris, and Pseudomonas fluorescens. three antibiotics that are commercially available are Ter-
Obligate pathogenic bacteria can cause disease even ramycin® (Terramycin® 200 for Fish), Romet® (Romet®30
in the absence of stressors. Examples include Aeromonas and Romet® TC) and Florfenicol (Aquaflor®). Sulfamera-
salmonicida, Edwardsiel a ictaluri, Renibacterium salmo- zine® is also approved but is no longer available. FDA ninarum, and Yersinia ruckeri. However, they can become approves specific products that contain the antibiotics more problematic under stressful environmental condi- and only those specific products can be purchased and used for species listed on the label. For example, if the fish species is not listed in Table 1 for use with Terramycin®, Use of medicated feeds
it cannot be legally used to treat the bacterial infection in Once a bacterial infection has been diagnosed in Each of the currently approved antibiotics and the fish, an approved antibiotic feed can be determined. The approved product is discussed separately below. This list treatment should always be the maximum recommended may change as new antibiotics obtain approval for use dose for that species and should be fed for the total in food fish. To determine if an antibiotic not on the list number of days recommended (even if the fish appear to below has obtained approval, please visit the FDA Center have recovered before the end of the treatment period). for Veterinary Medicines website at: http:/ www.fda.gov/ Feeding lower concentrations of antibiotics or decreas- ing the number of days the drug is fed can allow bacterial pathogens to develop a resistance to the antibiotic. If this occurs, the antibiotic would likely not be able to control certain infections that may occur later at a fish farm or Terramycin® has been used for treatment of food fish for many years. The approved product for fish is Terra- Fish often stop eating as a bacterial disease pro- mycin®200 for Fish, which contains the active ingredient gresses, so early diagnosis and treatment are essential to oxytetracycline dihydrate. This drug is usually effective ensure that infected fish consume the medicated feed. against a number of bacteria which cause disease in food Once a bacterial disease is diagnosed, and the appropri- ate medicated feed is determined, the feed should be used Terramycin® 200 for Fish is incorporated into the feed immediately. Furthermore, doses have been calculated by commercial feed mills licensed by the FDA. The label for an antibiotic to maintain a certain level in the blood- (Table 2) includes a feeding rate to achieve the desired stream for a certain period of time in order to be effective. dosage levels required to attain adequate therapeutic Depending upon the compound, it takes a day or so to treatment. Terramycin® must be fed for 10 days to control reach this level. Treatment should be done for the pre- the infection. Once the treatment is completed, the fish scribed time and never stopped prematurely because the must be held for an additional 21 days before they can be fish "look better".
marketed for food or released into the wild in order to Prophylactic use of antibiotics is prohibited. Such use allow elimination of the drug from the fish. Marketing can lead to increased disease resistance and higher resi- fish for human consumption before the end of the 21-day dues of the antibiotic in the tissues of fish. Prophylactic withdrawal period is a violation of federal law. As a result, use of antibiotics has not been shown to increase growth marketing plans must be considered before treating fish rates in fish. For these reasons, only use antibiotics when with Terramycin®. Once treated, fish cannot be sold for a absolutely necessary to treat a bacterial infection.
minimum of 31 days (10-day treatment period plus 21-day It is important to emphasize to all involved, the withdrawal period). An additional consideration when proper withdrawal time for the antibiotic used (see Table feeding Terramycin® medicated feed manufactured at a 1), and that all understand that no food fish harvest will feed mill is that it is only available as a sinking feed. The occur prior to that period being completed. This is to drug is broken down by the higher temperatures needed Table 1: Antibiotics approved for use in medicated feed for foodfish.
Trade name
Indications
(For the control of:)
2.5 – 3.75 g per 100 21-day withdrawal time lbs fish per day for furunculosis (Aeromonas salmonicida), bacterial hemorrhagic septicemia (A. liquefaciens), and pseudomonas disease Freshwater-raised Mortality due to 3.75 g per 100 lbs 21-day withdrawal time coldwater disease caused fish per day for 10 by Flavobacterium Mortality due to columnaris 3.75 g per 100 lbs 21-day withdrawal time fish per day for 10 Oncorhynchus Bacterial hemorrhagic 2.5 - 3.75 g per 100 Water temperature not septicemia (A. liquefaciens) lbs fish per day for and pseudomonas disease 21-day withdrawal time Furunculosis due to 50 mg per kg fish per 42-day withdrawal time Enteric septicemia due to 50 mg per kg fish per 3-day withdrawal time Edwardsiel a ictaluri Mortality due to enteric 10 mg per kg fish per 15-day withdrawal time septicemia associated with Edwardsiel a ictaluri Freshwater-raised 1) Mortality due to 10 mg per kg fish per 15-day withdrawal time furunculosis associated with Aeromonas 2) Mortality due to coldwater disease associated with F. Mortality due to columnaris 15-day withdrawal time disease associated with per kg fish per day for 10 daysOthers – 10 mg per kg fish per day for 10 Freshwater-raised 1) Mortality due to 15 mg per kg fish per warmwater finfish streptococcal septicemia 15-day withdrawal time Table 2: Label rates of Terramycin® 200 for fish to use at various feeding rates.
Feeding Rate
To achieve a dose rate of 2.5 – 3.75 g/100 pounds of fish
Pounds feed/
Terramycin in
Terramycin for Fish
Total biomass that one ton
100 Pounds fish (%)
Finished Feed
per ton of feed
of medicated feed will treat
to make a floating pellet. Feeding a sinking food to sick pond fish makes it difficult to determine if they are eating the medicated feed. Terramycin® 200 can be top dressed The Veterinary Feed Directive (VFD) is a new cat- on floating feeds with vegetable oil, but the stability of the egory of medicated feeds created by the Animal Drug antibiotic on the feed may be inferior to the stability in a Availability Act of 1996. It provides an alternative to pre- manufactured feed.
scription status for certain animal drugs for use in feed, while requiring participation of a veterinarian to issue a directive to enable producers to acquire VFD medicated feeds. Antibiotics listed under the VFD listing cannot be Romet® (Romet-30®, Romet-TC®) is approved for used as extra label, meaning it cannot be used on fish spe- use in salmonids and catfish. This product contains two cies other than those listed on the label. drugs, sulfadimethoxine and ormetoprim. These drugs Florfenicol, sold under the trade name of Aquaflor®, in combination are more effective than either drug used is the first antibiotic used in aquaculture that falls within alone, with both acting on different parts of the folic acid the VFD. This means that florfenicol can only be used metabolism pathway. Bacteria need to manufacture folic under the supervision of a licensed veterinarian in the acid for cell reproduction, where fish and humans can context of a valid veterinarian-client relationship. Addi- receive theirs from the diet. This makes the compound tionally, florfenicol cannot be used under extra-label drug very safe for animals use options unless the producer is using it under an FDA Romet® is specifically approved for treatment of Investigational New Animal Drug (INAD). bacterial diseases listed in Table 1. Romet® medicated Florfenicol is specifically approved for treatment of feed is only fed for 5 days as opposed to the 10 days for bacterial diseases listed in Table 1. Florfenicol medicated Terramycin®. The withdrawal period for Romet® is 3 days feed is fed for 10 days. The withdrawal period for flor- for channel catfish. With a 5-day treatment period and fenicol is 15 days for channel catfish, salmonids raised in a 3-day withdrawal period, catfish treated with Romet® freshwater, and warmwater finfish raised in freshwater. can be slaughtered in as little as eight days after the drug As a result, fish cannot be sold for human consumption or treatment is initiated. Salmonids have a required 42-day stocked into natural waters for 25 days (10 day treatment withdrawal period from Romet® before being slaughtered. period and 15 day withdrawal time).
Another advantage of Romet® is its availability from com- mercial mills in a floating pellet. This allows direct pond observation of the fish eating the medicated feed.


Selecting the proper medicated feed
salmoninarum, which is the cause of bacterial kidney disease in salmonids, or Mycobacterium species, which To optimize the response to medicated feed, the can occur in many food fish species including salmon and causative agent needs to be identified and a sensitivity test hybrid striped bass. This is why it is important to work should be performed to ensure that the correct antibiotic with a fish health specialist/fish veterinarian for proper is used. A sensitivity test (Fig. 1) shows the relative suscep- tibility of the disease-causing bacteria to various antibiot- ics. Small discs, each containing a different antibiotic are Treatment strategies
placed on an agar plate that has been recently inoculated with the isolated disease causing bacteria. If bacteria are Economics and other factors also help to determine unable to grow in the presence of a particular antibiotic, a the appropriateness of using medicated feed. If the cost clear area is present surrounding the disc. If the drug has of the treatment is more than the cost of the fish, it does no effect, the bacteria will grow up to or over the top of the not make economic sense to treat the fish. When possible, disc. The clear area is measured and compared to a stan- expensive treatments should be avoided unless they are dard to determine if the antibiotic would be effective in likely to save money for the producer. A good example is treating the bacterial infection. A fish health professional the treatment strategy for Enteric Septicemia of Catfish or disease diagnostic laboratory can perform the sensitiv- (ESC) caused by Edwardsiel a ictaluri. This disease occurs ity test for you and recommend an antibiotic to be used. when temperatures are between 68 and 82 °F (20 and 28 There are situations when antibiotic treatment may be °C) when the bacteria are in their optimum growth range. ineffective. Some disease outbreaks are caused by bacte- Fish dying from ESC will usually stop dying as tempera- ria that are resistant to particular antibiotics and some tures rise above 82 °F (28 °C) or fall below 68 °F (20 °C). bacterial diseases cannot be controlled with currently- Medicating fish just before temperatures are forecast to approved medicated feed. For example, there are no FDA be in the 90s, for example, is often not advised, because approved antibiotics currently available that are effective the disease stops on its own due to the high temperatures. against an active outbreak associated with Renibacterium Using this type of strategy can save a significant amount of money on medicated feed purchases. Mixing medicated feeds
All of the approved antibiotics for use in food fish are Type A medicated feeds. Producers may purchase Type A premixes only if they hold a valid feed mill license. The VFD form issued by the veterinarian will contain mix- ing or dilution instructions. Medicated feed mill license applications (Forms FDA 3448) may be obtained from the Public Health Service, Consolidated Forms and Publica- tions Distribution Center, Washington Commerce Center, 3222 Hubbard Rd., Landover, MD 20785, or electroni- cally from the Center for Veterinary Medicine home page at http:/ www.fda.gov/cvm. Additionally, a set of guidelines for manufacturing feed, referred to as Good Manufacturing Practices (GMPs), are designed to prevent feed contamination and provide reasonable assurance that medicated feed additives are used properly. These guidelines serve as Food and Drug Administration (FDA) Figure 1. Antibiotic discs on a bacterial plate (white circles). Clear area
regulations. Everyone involved in producing medicated around the disc (highlighted by the dash lines) indicates that the antibiotic or non-medicated feed, whether at a commercial off-farm is useful in fighting the infection. Clear areas are measured in mil imeters plant or with an on-farm mill or grinder/mixer, must and compared with standards in order to determine if antibiotic is effective comply with the GMPs.
against the bacteria disease.
Storage of medicated feed
Use of medicated feed
As with all fish food, medicated feed should be stored in alternative species
in a cool, dry place. If available, a freezer is ideal for stor- ing fish feed for extended periods provided it does not At the time of this writing, FDA will allow veterinar- get moist or wet. Antibiotics and essential nutrients will ians to prescribe the use of Terramycin® 200 for Fish and deteriorate rapidly in a warm, moist environment. Exces- Romet®30 or Romet® TC medicated feed for fish species or sive decomposition of antibiotics as a result of improper diseases other than those listed on the label. For example, storage can result in unsuccessful treatment. Any unused Terramycin® 200 for Fish, medicated feed that has been medicated feed, stored at room temperature, should be approved for use in catfish, may be prescribed extra-label discarded after 3 to 4 months. However, a VFD medicated for hybrid striped bass by a licensed veterinarian. Flor- feed is not valid 5 days after the prescribed treatment fenicol (Aquaflor®) cannot be legally used on species other terminates. Thus florfenicol (Aquaflor®) is a one-time use than those on the label, unless it is used under an INAD. purchase and any extra feed must be discarded and not Check with a qualified fish health professional or veteri- kept for future use. Be sure to follow all state guidelines narian on the current status of medicated feed use regula- for disposal of unused or old medicated feed.
tions before treating your fish. Additional information on use of medicated feeds approved for use in food fish can be found at: http:/ www.fda.gov/AnimalVeterinary/Development http:/ www.fws.gov/fisheries/aadap/home.htm Quick Reference Guide to Approved Drugs for Use in Aquaculture. 2011. http:/ www.fws.gov/fisheries/aadap/ SRAC fact sheets are reviewed annual y by the Publications, Videos and Computer Software Steering Committee. Fact sheets are revised as new knowledge becomes available. Fact sheets that have not been revised are considered to reflect the current state of knowledge.
The work reported in this publication was supported in part by the Southern Regional Aquaculture Center through Grant No. 2010-38500-21142 from the United States Department of Agriculture, National Institute of Food and Agriculture.

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100 The Open Nutrition Journal, 2008, 2, 100-105 Open Access Alkaline Mineral Supplementation Decreases Pain in Rheumatoid Arthri-tis Patients: A Pilot Study Regina Maria Cseuz1, Istvan Barna2, Tamas Bender3 and Jürgen Vormann*,4 1Revita Klinik, Budapest, Hungary; 2Institute of Experimental Medicine of the Hungarian Academy of Sciences, Budapest, Hungary; 3Hospital Brothers of St. John of God, Budapest, Hungary, 4Institute for Prevention and Nutrition, Ismaning, Germany