We have all heard the old adage that “if a little is good, then more is better.” It is easy to understand how a shrimp farmer facing serious disease losses due to bacterial diseases, such as vibriosis and necrotizing hepatopancreatitis, might be tempted to up the dose a little in attempting to control these diseases by treating with medicated feeds containing oxytetracycline (OTC). Errors in calculating the amount of OTC premix to be added during the formulation and manufacture of medicated feeds can also occur resulting in dose rates higher or lower than the recommended rate. For these reasons, the U.S. Food and Drug Administration (FDA) requires that a “Target Animal Safety (TAS)” study be done in support of any new animal drug application (NAD). The FDA considers the results of the TAS, along with the results of other required studies, prior to official approval of a new animal drug (or new use of an existing animal drug in the case of OTC) for the U.S. market. When a drug is approved, the label must clearly indicate how the drug may be used (i.e., in feed at specific dose rate and time for a specific animal species, give the withdrawal time prior to harvest, etc.).
The major portion of the TAS study was carried out by Bill Bray, Addison Lawrence, and the staff at the Texas Agriculture Experiment Station, Texas A&M System, Shrimp Mariculture Laboratory (TAES) in Port Aransas. Rod Williams coordinated the design of the TAS study and served as the “Study Monitor.” As the Study Monitor, Rod interfaced with personnel at FDA to ensure that the study’s protocol was approved by the FDA prior to initiating the study and that the study was run according to the principles of “good laboratory practices (GLP).” Industry collaborators included Cargill (Giddings, Texas), Rangen Feeds, Inc., and Phibro, Inc. (the current manufacturer and distributor of TM-100 for aquatic animals). UAZ performed histopathological analyses
on shrimp sampled at the termination of the study.
The dose levels and dosing time in the TAS study were much greater than would be used in treating shrimp with OTC responsibly. Not surprisingly, TAES and UAZ found that shrimp treated with the higher dose rates and extended continuous exposure to OTC in the feed showed a toxic response syndrome that could be potentially serious in terms of survival, growth rate, and product quality. Such overdosing would also produce shrimp that would be
considered adulterated by FDA in terms of drug residue.
The Center for Veterinary Medicine of the FDA is the Federal Agency responsible for insuring the safety and efficacy of drugs and chemicals used for disease control purposes in the culture of aquatic animals. For a “new animal drug” to be approved for use with food animals in the U.S., data for four major studies are required. The central topics of the four study areas are 1) efficacy - the therapeutant (a drug or chemical) must be effective at the recommended dose or use rate for treating or preventing the disease(s) identified by the therapeutant’s sponsor; 2) human food safety - the use of the therapeutant for its intended use does not result in residues or the therapeutant or its metabolites which pose a hazard to humans; 3) target animal safety - the therapeutant does not pose a significant adverse effect to the animals being treated at the recommended dose or use level, and 4) environmental safety - that the therapeutant does not present adverse environmental effect such as harming non-target species or accumulating in the farm’s
environment.
No antibiotics are currently approved by the FDA for use with shrimp, but OTC may be the first. Research on OTC use in shrimp in the U.S. began 30 years ago. This research has had as its intent the eventual FDA approval of the drug for use in treating bacterial diseases in shrimp. During that 30-year period, funding and in-kind assistance for OTC studies have come from the USDA Marine Shrimp Farming Consortium, the Texas Shrimp Farmers Association, the National Coastal Research Institute (NOAA), USDA Center for Tropical and Subtropical Aquaculture, the U.S. FDA Office of Science, the National Marine Fisheries Service (NOAA), Marine Culture Enterprises, Harlingen Shrimp Farms, and from companies like Pfizer and Phibro that have been in the business of making and selling OTC. Most of the studies required by FDA for the eventual approval of the drug for use in shrimp have been completed and a plethora of data reports, supporting data and formal publications on OTC use in shrimp have been submitted to CVM/FDA. The Target Animal Safety Study may be the last major study required by CVM/FDA to complete the data package (called the “Master File”). Once the Master File is complete and accepted by FDA, the data generation process for OTC use in shrimp will be completed. The last antibacterial drug approved by the FDA for use in U.S. aquaculture was Romet 30, and that was more than 20 years ago. An approval for OTC use in managing certain bacterial diseases of shrimp could be the next approved drug if the Master File (when it is completed in 2004 with the TAS and Environmental Assessment Reports) is deemed by FDA to meet its data
requirements.
Getting back to the findings of the Target Animal Safety Study: As was indicated earlier, the experimental OTC medicated feeds were made and fed to shrimp in controlled laboratory studies at TAES. UAZ did the pathological examinations of the treated shrimp. The TAS study was designed so that four (one control and three experimental) groups of shrimp were fed the drug at dose rates ranging from 0 to 5 times the recommended dose for treating certain bacterial diseases for a time period of 3 times the normal dosing period. Hence, one group of shrimp (the negative control receiving the 0X dose) received only normal shrimp feed; a second group received the recommended dose (the 1X dose or 4.5g OTC/kg feed); and a third and fourth group were fed feed at 3X (13.5 g OTC/kg feed) and 5X (22.5 g OTC/kg feed) the normal dose rate, respectively. All three groups received the medicated feed for 6 weeks (42 days), which is 3 times the recommended treatment duration of 14 days for OTC medicated feed use in shrimp.
Representative samples of experimental shrimp in this TAS study were preserved for histopathology at the termination of the study. Shrimp fed the highest (the 3Xand 5X) OTC doses presented some significant signs of toxicity, while the shrimp fed the 1X dose were similar to the control group in their health status. The over-dosing of OTC in shrimp as demonstrated in this study results in shrimp with soft shells and an atrophied hepatopancreas with very low or totally depleted lipid reserves. Along with the gross signs presented by over-medicated shrimp, the histopathological changes in such shrimp can be used to diagnose OTC toxicity when the case history suggests that a misuse (due to an error in formulation of the OTC medicated feed or to deliberate over-dosing) of the drug may have occurred. This important information will very likely be incorporated into the FDA approved label for any OTC product intended for use in medicated feeds for shrimp in order to warn users of the consequences and signs of overdosing. Such information can also be used by the shrimp culture industry to ensure that OTC is used responsibly to treat bacterial diseases of shrimp and to aid shrimp disease specialists in diagnos
ing OTC toxicity when it occurs.