Veterinarians' role in the use of veterinary feed directive drugs in aquaculture

Patricia S. Gaunt Department of Pathobiology-Population Medicine, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762; and the Delta Research and Extension Center, Mississippi State University, Stoneville, MS 38776.

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 DVM, PhD, DABVT

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The US FDA has approved a limited number of treatments for use in food fish. Two commercial aquaculture antimicrobials (oxytetracycline and sulfadimethoxine-ormetoprim combinations) were approved more than 20 years ago.1 Since these drugs are not effective against all bacteria and are not approved for use in many fish species, additional antimicrobials for use in aquaculture are needed. Because of the expensive drug approval process, pharmaceutical companies have been reluctant to develop new animal drugs for use in aquaculture. Passage of the MUMS Health Act in 2004 has given pharmaceutical manufacturers financial incentives to invest in development of new aquaculture treatments.2,3 In addition, increased global demand for farm-raised fish has encouraged farmers to seek effective treatments that will protect their fish crop. Because medicated feeds are easy to administer, fish farmers prefer that additional treatments become available in that form.

Prior to 1996, the FDA's options for regulating animal drugs were “over the counter” and “by prescription.”4 At that time, antimicrobials approved for use in aquaculture were marketed as over-the-counter drugs. Public concern regarding issues such as environmental contamination, residues in food, and antimicrobial resistance has prompted the FDA to propose tighter regulations that would require veterinary supervision of drugs used in animal feed. Because of these concerns and because many states prohibited feed mills from dispensing prescription drugs, a coalition of government and industry workers laid the groundwork for the ADAA in 1996. The ADAA is an amendment to section 512(b) of the Federal Food, Drug, and Cosmetic Act that created a new class of therapeutic drugs, the VFD drug.4 Established in 1996, the VFD is an approval that the FDA may assign to any new antimicrobial for use in or on animal feed. Orders for VFD drugs are available to fish producers only from licensed veterinarians. In 2005, florfenicola became the first VFD drug approved for use in catfish.5 Veterinary feed directives are a new concept in aquaculture, and specific requirements are needed for veterinarians issuing VFD orders.

Types of animal feed drugs

Medicated animal feeds are classified as category I or II drugs.6 Category I drugs require no withdrawal period at the lowest concentration at which they are approved for each species. Category II drugs require a withdrawal period at the lowest concentration for which they are approved or are regulated on a noresidue (zero tolerance) basis for at least 1 species.

Within each category, there are 3 types of medication: A, B, and C.6 Type A is any new animal drug used in the manufacture of other medicated articles or type B or C medicated feeds. Type B is a concentrated form of medicated feed used in the manufacture of other medicated feeds. There are restrictions on the concentration of this feed, and it is not to be fed directly to animals. Type C medicated feed is either the final form of complete feed or a supplement to another animal feed. Type C medicated feed is manufactured from a type A medicated article or type B medicated feed. All VFD drugs will be labeled as category II, type A medicated article used to manufacture type B or C medicated feed.6

Currently approved VFD drugs

Presently, 2 VFD antimicrobials are commercially available: tilmicosin,b which is labeled for use in swine feed,7 and florfenicol,a which is labeled for use in catfish feed.5 Tilmicosinb was approved in 1996 for control of swine respiratory tract disease, and veterinarians in swine practice are accustomed to issuing VFD orders. Florfenicola was approved in October 2005 as a VFD drug for the control of mortality due to ESC associated with Edwardsiella ictaluri. Numerous other antimicrobials for use in aquaculture, as well as additional label claims for florfenicol,a are presently being investigated as investigational new animal drugs (INADs) and could be approved as VFD drugs3,8 for treating commercial, recreational, or hobby fish.

Veterinarians and VFD orders in aquaculture

In the United States, few veterinarians are trained in the field of aquaculture, compared with other veterinary medical specialties. Although most aquaculture veterinarians are associated with universities and aquaria in large cities, most commercial food fish operations are located in rural areas near diagnostic laboratories served by few veterinarians. Fish farmers in rural areas will likely depend on local practitioners in companion or food animal practice to properly diagnose and recommend treatments for fish diseases treatable with VFD drugs. Because extensive courses in aquatic veterinary medicine are not offered at all veterinary colleges, most veterinarians are not adequately trained in disease and diagnostic procedures for fish. For veterinarians interested in aquatic diseases, continuing education courses in aquatic animal medicine are offered at many local and national veterinary meetings as well as fishery meetings. The Southern Regional Aquaculture Center9 and the Aquaculture Network Information Center (AquaNIC)10 provide information on fish husbandry, diseases, and treatments. In addition, aquatic veterinarians and fishery extension agents are cooperating to educate veterinary practitioners on diagnostic tests available for fish diseases treatable by a VFD drug.

VFD regulations that apply to veterinarians

For a veterinarian to issue a VFD order, a valid veterinary-client-patient relationship must exist.11 The veterinarian must examine the producer's fish and ascertain that they are ill on the basis of clinical signs, lesions, or results of diagnostic tests such as bacterial culture. If the fish have a bacterial disease that is treatable with a VFD drug and the farmer chooses to use this treatment, the veterinarian will issue a medicated feed order. The VFD order can only be written for treatment of a disease in that fish species for which there is a label claim. Extralabel use of a VFD drug is prohibited by law.11 Although the active ingredient in the VFD drug may be approved for use in other animal species (eg, florfenicol injectablec in cattle), only the approved formulation can be used to manufacture the VFD medicated feed (eg, florfenicola type A medicated article for catfish).12

By law, the veterinarian must discuss proper use of the medicated feed, including dose rate, duration of treatment, and withdrawal time. The quantity of medicated feed ordered is based on the weight of the fish in the pond as estimated by the fish farmer from fish stocking and growth rates.13

The farmer must agree to use the drug in accordance with VFD regulations as explained by the veterinarian.11 Either the veterinarian or the farmer may present the original VFD order for filling. The veterinarian must be available to provide follow-up evaluation or emergency coverage in the event of an adverse reaction or failure of the treatment regimen.

VFD drug currently approved for use in aquaculture

Florfenicola is currently approved only for catfish with a diagnosis of ESC, which is caused by E ictaluri, a gram-negative coccobacillus member of Enterobacteriaceae.5 This disease is typically detected in the fall and spring in the southeastern United States, when pond temperatures range from 22° to 28°C (71.6° to 82.4°F).14 Lesions compatible with ESC include inflammation through the sutra fontanel of the skull (commonly known as “hole in the head”), hemorrhages on the skin and fins, exophthalmia, gastrointestinal tract and hepatic hemorrhage, ascites, and swollen kidneys.15 For a definitive diagnosis, postmortem examinations of affected fish should include bacterial culture specimens obtained from the brain or posterior kidney tissues for E ictaluri. Culture swabs, sent to a diagnostic laboratory with experience in performing diagnostic tests on samples from fish, are plated on Mueller Hinton medium with 5% sheep blood and incubated at 25°C for 24 to 48 hours. Colonies of E ictaluri are small, white, punctate, and weakly b-hemolytic and are negative for oxidase and indole.16

Following diagnosis, the veterinarian and producer discuss treatment options. If florfenicola is indicated, the veterinarian writes a VFD order. The drug's manufacturer usually provides standardized VFD order forms to veterinarians, although a veterinarian has the option to create his or her own form.11 The form must be filled out in triplicate and contain certain information (Appendix).

The approved regimen for treating ESC with florfenicola is a dose rate of 10 mg of florfenicol/kg (4.5 mg/lb) of body weight fed once a day for 10 days.17 The preslaughter withdrawal time for florfenicola is 12 days.18

The feed distributor must retain the original VFD record, and the veterinarian and the fish farmer must each retain a copy of the order for a minimum of 2 years.11 Although VFD order forms can be faxed, the original order must be received by the distributor with-in 5 working days. Veterinary feed directive orders can-not be provided to the feed distributor via telephone. The veterinarian, fish farmer, and feed distributor must make VFD records available for review and copying in the event of an FDA inspection.

Expiration dates, refills, and reorders of VFD orders

According to regulations of the ADAA, the expiration dates of a VFD order may be extended to medicate multiple production groups and provide efficient treatment of sick animals.11 However, the FDA reserves the right to regulate expiration dates on a drug-by-drug basis. For florfenicol,a the FDA regulations state that the expiration of a VFD order is 15 days from the date of issuance.5

Although ADAA regulations allow refills of VFD orders at the veterinarian's discretion, the FDA has mandated that refills are not available for florfenicol.5,a If catfish infected with E ictaluri are treated with florfenicola for 10 days and the farmer requests additional treatment of fish in the same pond, a new VFD order must be issued by the veterinarian. Concurrent ESC outbreaks from multiple ponds on 1 farm may be treated with florfenicola on the basis of results of examination of ill fish from a representative pond at the discretion of the attending veterinarian.5 The veterinarian assumes responsibility and liability for diagnosis of fish in all treated ponds.

Manufacture of VFD medicated feeds

Only feed mills that hold a medicated feed mill license and are registered with the FDA can manufacture VFD medicated feeds.11 A licensed feed mill purchases the drug from its manufacturer, which will supply any special instructions on mixing the medication with fish feed. Veterinarians are not responsible for supervising the preparation of the VFD medicated feed.

Commercial fish feed is often manufactured in lots of 5 tons or more, rather than on an individual basis. For practical reasons, the feeding rate (calculated as a percentage of body weight) for medicated feed is pre-determined by the feed mill on the basis of local feeding practices.13 The percentage feeding rate and dosage will determine the concentration that medication is blended into feed, according to the following formula:

Concentration of medication in feed = dose rate/percentage feeding rate19

For florfenicol,a the dose rate is 10 mg of active ingredient/kg of body weight17 and the feeding rate used in the Mississippi Delta is 2% of body weight. Therefore, the drug would be blended as a 500-ppm (500 mg/kg) concentration in fish feed.

The feed mill can manufacture VFD medicated feeds in advance but cannot dispense them without a signed VFD order from a licensed veterinarian.20 Medicated feeds are typically supplied to fish producers in lots ranging from 25-lb bags to truck loads that weigh several tons. Veterinary feed directive medicated feeds must be clearly labeled with ingredient statements, cautionary statements, and withdrawal information.11

Distribution of VFD medicated feeds

A distributor is defined as the person or company who sells a VFD medicated feed to a farmer or other distributor.21 Prior to selling VFD medicated feeds, the distributor must file a onetime notice to the FDA. When the distributor sells the medicated feed to a fish farmer, he or she must retain the original VFD order.11 If the feed mill serves as the manufacturer as well as the distributor of the VFD medicated feed, the original VFD order will be maintained at the feed mill. A veterinarian can become a distributor of VFD medicated feeds provided that the veterinarian has filed the required notice with the FDA.

Future outlook

The Office of MUMS Animal Drug Development was created by the FDA Center for Veterinary Medicine to oversee and facilitate approval of new minor species drugs granted by the MUMS Act.22 With financial incentives for drug manufacturers, additional VFD drugs will hopefully be available for use in aquaculture.3 Improved cooperation with extension agents and additional continuing education programs available through veterinary meetings, fish health meetings, and Web sites will be important in helping veterinarians correctly use VFD drugs in fish medicine practice.

ABBREVIATIONS

MUMS

Minor use and minor species

ADAA

Animal Drug Availability Act

VFD

Veterinary feed directive

ESC

Enteric septicemia of catfish

a.

Aquaflor, Schering-Plough Animal Health, Summit, NJ.

b.

Pulmotil, Elanco Animal Health, Greenfield, Ind.

c.

Nuflor, Schering-Plough Animal Health, Summit, NJ.

References

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Appendix

Appendix

Information required on VFD order forms.

Farmer's name, address, and phone number
Veterinarian's name, address, phone number, and state license number
Name of VFD drug
Identification of animals to be treated, including species, number, and location
Date of treatment and date of ordering the VFD drug (if different) Expiration date of the VFD order
No. of refills or reorders (if permitted by the approval)
Condition or disease being treated
Feeding directions with the withdrawal time
Amount of drug to be mixed and amount of feed required to treat fish
Any warning or cautionary statements or special instructions
Veterinarian's signature
The following statement: “Extralabel use is strictly prohibited”
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