Use of Extra-label Drugs in Commercial Aquaculture

The present study focused on the use of extra-label drugs in commercial aquaculture. Data was collected through questionnaire interview with 30 drug retailers and 30 commercial aqua farmers in Mymensingh Sadar and Trishal upazila of Mymensingh district. All together 94 extra-label drugs of different groups were identified which included antibiotics, disinfectants, nutritional supplements, probiotics, gas remover and saline. Six groups of antibiotics having 10 different active compounds with 46 trade names were found in the drug retailer shops. These drugs were primarily prepared either for the use in veterinary or poultry but were found using indiscriminately in aquaculture. All these drugs were marketed by 18 companies in the study areas. It was observed that 83% drugs were not labeled for aquaculture purpose. Majority (77%) of the commercial aqua farmers used extra-label drugs in their farms and 73% of them never received any prescription from qualified personnel before use. Most of the farmers were unable to calculate appropriate doses and had no idea about risk, safety issue and toxicity reaction of using extra-label drugs. Farmers generally got suggestion from the drug retailer regarding application of drugs. The results also revealed that extra-label use of veterinary and poultry drugs in aquaculture is a common practice by commercial aqua farmers. Thus, the use of drugs in aquaculture should have a sufficient regulatory system in place. It is important to produce and use appropriate labeled drugs under a sufficient regulatory system for safe fish production in the aquaculture of Bangladesh. Article history Received: 28 Nov 2020 Accepted: 21 Jan 2021 Published: 30 Mar 2021


Introduction
Bangladesh has made a tremendous breakthrough in sustainable aquaculture through securing 56% contribution to the total fish production (DoF, 2018). The recent and rapid development has boosted Bangladesh to 5 th in world aquaculture production (DoF, 2018). The shift of aquaculture towards the use of intensive culture systems during the last decades has led to several serious problems, particularly the misuse of extra-label veterinary medicines and chemicals used for the treatment of disease outbreaks, consequently raising concern with regard to the safety of aquaculture products (Baoprasertkul et al., 2012).
A wide variety drugs, chemicals and biological have been using in different aquaculture activities for various purposes. Vast majority of the drugs are used for health management and treatment of fish diseases. Other major uses including water quality management, hatchery management and feed formulation. However, due to indiscriminate use of drugs, aqua farmers are not getting expected result. Also, antimicrobials used in aquaculture cause negative impact on aquatic environment, contribute to the development of antimicrobial-resistance and the presence of residue in aquaculture products (WHO, 2006;Jaime et al., 2012).
Extra label drug use describes the use of a drug in a manner for which it was not approved. It occurs when a drug approved for one species of animal is used in another animal, or when a drug is used to treat a condition for which it was not approved. Extra label use of veterinary or poultry drugs have now become a common practice in commercial aquaculture of Bangladesh. When an approved human or animal drug is used in a manner other than what is stated on the drug's label, then it is called an extra-label use, because the drug is used in a way that is "off the label" (FDA, 2020).
In most of the countries, government agencies exert some controlling actions on the use of drugs. In Bangladesh, the uses of drugs are rising tremendously and concern is now growing on the use of unapproved drugs in aquaculture. There are a number of reports on the use of extra-label veterinary drugs in aquaculture in other countries (Breton, 2009;Yang and Zheng, 2007;Bravo, 2012;Zarza, 2012;Love et al., 2020). However, although few works have been carried out in Bangladesh on the use of aqua-drugs (Faruk et al., 2008;Ahmed et al., 2014;Ahmed et al., 2015;Hassan, 2016), but there is hardly any study conducted on the use of extra label drugs in aquaculture of the country. The objective of the present study was therefore to identify type, source and status of use of extra-label drugs in commercial aquaculture.

Materials and Methods
The study was carried out in Trishal and Mymensingh sadar upazila under Mymensingh district of Bangladesh for six from February to July 2017. Data were collected from 30 drug retailers and 30 commercial fish farmers through questionnaire interview. The major topic of questionnaire included types, constituents, sources, uses, price and label of drugs. In addition, idea about extra label use, receiving prescription, dose calculation ability and proper application methods were also included. Data were analyzed using descriptive statistics.

Extra-label drugs
In this study, 94 extra label drugs were found in the drug shops which were used by the commercial aqua farmers. The drugs could be grouped as antibiotics, disinfectant, ammonia reducer, probiotics, nutritional supplements, saline and pesticides. All these drugs were provided by 18 companies. Drugs from ACI, Eon, Acme, Square, Renata, SK+F and Novartis were found prominently at drug shops. Group wise description of identified extralabel drugs are given below:

Antibiotics
Six groups of antibiotics having 10 different compounds with 46 trade names were found in drug shops. The groups included beta-lactams, macrolides, fluroquinolones, tetracyclines, sulfonamides and quinolones. Major compound and trade names of extralabel antibiotics under different groups are summarized in Table1.
Seven various trade named antibiotics were found under the group of beta-lactams. The major constituent of this group was amoxicillin and their price varied from Tk. 110-270 per 100g. Major companies that provide these products included Acme, ACI, Navana, Square and Reneta (Table1). In poultry and veterinary, this broad spectrum antibiotic is used for preventing and treating different bacterial and mycoplasmic diseases. In dairy industry, they are effectively used against Mycoplasmosis, Streptococcus and Staphylococcus infection. They are also found to retard growth against bacteria those are sensible to penicillin. In aquaculture, beta-lactams have been using against red mouth, septicemia infection and epizootic ulcerative syndrome in fish.
Under the group of macrolides, twelve various trade named antibiotics were found. Major constituents of this group were erythromycin, azithromycin and tylosin. Generally, macrolides antibiotics are used for the treatment of Mycoplasmosis, associated with secondary bacterial infections in poultry. They are also effective against bacteria those are responsible for respiratory and genetic disorder. In aquaculture, they have been using to control mortality associated with enteric septicemia in catfish and forthe treatment of secondary bacterial infections. Ten trade named extra-label antibiotics of the group fluroquinolones were found also identified in the drug shops. These were found effective against Streptococcus infection in tilapia and carps. Under the group of tetracycline, 11 different trade named antibiotics were found.
Major constituents were oxytetracycline, doxycycline and chlortetracycline. In poultry, they were generally used against Colibacillosis, Cholera, Streptococcosis and Staphylococcosis and also effective against bacterial infection like respiratory and genetic disorder, Clostridium, CRD, Mycoplasma and Entarytis infection. According to drug seller and information leaflet, these antibiotics were effective against fin rot, Edwardsiellosis, Columnaris and some other bacterial diseases found in freshwater fishes of Bangladesh. Moreover, five trade named sulfonamids with sulfadiazine and trimethoprim as their major active ingredients were also found in the shops. According to the package these extra label drugs could be useful in killing all kind of bacterial, viral and fungal infections. Finally, under the group of quinolones, one antibiotic, peflox vet was found. The price of this antibiotic was 140 Tk. per 100 ml. In aquaculture, it could be effective against Columnaris, Vibriosis and bacterial gill disease.

Ammonia remover
Four ammonia removing substances were found in the drug shops (Table 3). There major constituents were glycocomponent, saponins, extract of Yucca and the price varied from 315-350 Tk. per 100 ml with different doses.

Probiotics
Probiotics of 3 different trade names like FRAC 12, protexin and protimin were found (Table 4). According to the information leaflet and drug retailer information, major constituents are well balanced mixture of 1monolaurim and essential oils, amino acids and minerals. Major companies those provided these products were ACI, SK+F and Novartis.

Saline
A number of extra label saline were found with different trade names (Table 5). Their major constituents were dextrosenhydrus, ascorbic acid, sodium bicarbonet, sodium chloride, potassium chloride, dextrosenhydrus and vit-Aacitet. Doses of saline also varied during fry transportation. Major companies those provided these products were ACI, Eon, Acme and AV agro Ltd. In aquaculture, it is used for particularly for giving instant energy of fish fry during fry transportation.

Nutritional supplements
A great variety of nutritional supplements with various trade named were found. According to their constituents, nutritional supplements with vitamin premix are summarized in Table 6. About 17trade names of such products were found in the drug shops.

Other micronutrients
The component of calcium, zinc and phosphorus supplements were listed from drug shops (Table 7). In aquaculture, they are used for prevention and treatment of deficiency of calcium, phosphorus and vitamin D3. It also helps for sexual maturity and bone development of fish. Moreover, information provided in the label indicates that it enhances neurological system and hormonal production and reduces fat deposition in fish.

Pesticides
Extra label pesticides including sumithion, energy and rise 10 EC were available in the drug shops (Table 8).
Major companies that provided these pesticides were Eon and Setu Corporation Ltd. In agriculture, pesticides are used to prevent or control of pest. In aquaculture, they are used to control noxious organisms like Hash poka in the pond. Sumithion is used particularly to control Argulus sp. in fish pond.

Labeling of the packet and information leaflet
Most of the packet and information leaflet were not well labeled for use in aquaculture. Most information provided on the labels focused either use in veterinary or poultry. About 83% drugs were unlabeled for aquaculture having no information for use in fish though they were found to be used by commercial fish farmers and only 7% were well labeled and about 10% had little labeling (Fig. 2).

Extra-label drugs used by commercial fish farmers
All the 30 interviewed commercial fish farmers practiced polyculture system for growing fish.

Most frequently used extra-label drugs by the farmers
Majority (77%) of the commercial fish farmers used a number of extra-label drugs in their farms. They used these drugs because of the availability and effectiveness in their culture system. Most frequently used extra-label drugs by farmers were antibiotic (66.66%), nutritional supplement (50%) and disinfectant (40%) followed by saline (26.66%), ammonia remover (23.33%), probiotics (10%) and pesticides (6.66%) (Fig. 3). Individually, Renamycin and Timsen were the mostly used drugs by the farmers followed by Pondkleen, Acmezyme and Oralyte.

Misuse of drugs
It was found that about 73% farmers used drugs without having any prescription from any qualified person while 27% accepted counseling sometimes in case of disease problem or any other environmental problems of their farms. Farmers usually received prescription from different sources including technical personnel of drug company and upazila fisheries officers. Farmers were questioned about whether they could calculate the amount of drugs needed before use and it was found that 87% farmers were unable to calculate whereas 13% farmers were quite able to calculate the dose. Using over dose and dosage of drugs was found as very common phenomena in commercial fish farming. Most of the time, farmers practiced over dose intentionally without following any guidelines. It was noticed that overall 90% farmers did not maintain the guideline of applying dose and dosages while 10% did that practice. Majority (88%) of farmers mentioned that they had no idea about risk, safety issue and toxicity reaction of using these drugs and only 7% farmers had little idea about it. When farmers became unable to use any drugs, they took suggestions from drug sellers and it was reported that most (60%) of the farmers took suggestion from the drug retailers although literally they had no right to suggest. About 72% farmers of Mymensingh Sadar received suggestion from drug sellers and 45% in Trishal did the same.

Discussion
Aquaculture activities in Bangladesh are being influenced by huge number of drugs and chemicals. The present study was conducted in Trishal and Sadar upazillas of Mymensingh district to know the present status of use of extra-label drugs in commercial aquaculture. It was found that a wide range of extra label drugs were marketed by various companies for use in aquaculture. Most of the drugs were seen to use mainly for disease treatment, disinfecting aquaculture facilities, as nutrient supplements, during pond preparation and water management and as probiotics. Fish health management and disease treatment were the major areas where farmers were seen to use a lot of such extra label-drugs.
Only few approved and conditionally approved drugs are available to use in aquaculture. Therefore, a number of extra-label drugs are allowed to apply in fish under specified conditions with the supervision of a qualified veterinarian (FDA, 2020). It is evident that extra-label drugs have commonly been usingin different countries in different aquaculture systems (Zarza, 2012;Baoprasertkul et al., 2012). The primary benefit of the use of extra label veterinary drugs in aquaculture is that their prudent and responsible use supports the development of intensive, industrial-scale food production systems. In addition, they are indispensable for the treatment of epizootic disease outbreaks having the potential to cause mass mortalities, the failure of individual aquaculture enterprises and the occasional collapse of entire industries (FAO, 2019).
In the present study, 6 groups of antibiotics with 46 different trade names were recorded in the drug shops of the study areas. Fish farmers usually bought these antibiotics from drug shops without any prescription by qualified person. Among the antibiotics, the following active compounds were found which included tetracyclines (oxytetracycline), amoxicillin, erythromycin, ciprofloxacin, sulfadiazine and chlortetracycline. The occasional uses of tylocin, azithromycin, pefloxacin, enrofloxacin etc were also reported. Antibiotics like oxytetracycline and Percentage sulfonamides (sulfadiazine and trimethoprim) had been used widely to treat several diseases such as Vibriosis and ulcerative diseases in aquaculture (Nogueira-Lima et al., 2006), although other broad spectrum antibiotics such as oxolinic acid and flumequine were also used (Sapkotaet al., 2008). Yang and Zheng (2007) reported that the extra-label veterinary medicines in China were classified by their functions and ingredients. Five different kinds of veterinary medicine were reported to be used in aquaculture which included disinfectants, antiparasitics, water-quality treatments, antimicrobial agents and herbal treatments. Bravo (2012) also informed the use of extra label veterinary medicines at the beginning of the salmon industry to control Piscirickettsia salmonis in Chile.
Antibacterial substances are utilized in aquaculture production to combat bacterial diseases. They are mainly applied through medicated feed and enter the environment as a result of leaching from feces and uneaten treated feed (Lalumera et al., 2004). Among the chemicals used in aquaculture, special oversight should be given to veterinary drugs used to prevent and treat bacterial diseases. Only three fish grade antibiotics including oxytetracycline, sulfadimethoxine and sulfamerazine are approved by the FDA to use in aquaculture (FDA, 2020). In the present study, almost all the identified antibiotics were made for use in poultry and veterinary but were being used indiscriminately in aquaculture for disease treatment of fish. These antibiotics were not approved by appropriate authority to user in aquaculture. In recent study, Hassan (2016) also found some poultry and veterinary drugs used immensely at the farm level to produce fish.
Hazards due to the use of unapproved or banned antibiotics differ depending on the type of antibiotic, dose level, national regulations and there are no harmonised regulations yet to deal properly with this situation at an international level. Unapproved antibiotics or extra-label uses of antibiotics were used in two main situations which included extra label use of an approved antibiotic in aquaculture and extra-label use of an antibiotic not specifically approved for use in aquaculture (Subasinghe, 2009). Use of unapproved extra-label drugs in commercial fish farming can create potential human health hazard. These substances may be toxic, allergenic and carcinogenic. Presence of drug residue because of drug abuse in fish products may create negative impact on export business and even products may be rejected by the foreign buyers. Also, farmers are to pay additional money for the extra drugs and they lose financially. Okocha et al., 2018;Beyene, 2016).
According to the Aqua Medicinal Products (AMPs) guideline of the Department of Fisheries, certain information of the name of drugs, amount of purchased drugs, name and address of drug retailer, date of drug application, amount of applied drugs, harvesting date after drug application, batch number, expired date, followed withdrawal period, description of aquatic animal have to be recorded during drug application (DoF, 2015). Also, records have to be stored for two years. Record keeping activity of farmers and retailers were found very poor. The present study also revealed a lack of information regarding the leaflets of particular drugs with dose, dosage, withdrawal period and method of application. Consequently, most of the farmers were found to be unable to calculate proper dose and dosages before using and hence, drug abuse happened. Even in some instances, there were wrong information on the leaflet like the disease mentioned there might not exist in Bangladesh aquaculture at all.
As per the guideline, it is mandatory to receive prescription from the authorized person before using antibiotics and other drugs. Majority of commercial farmers used drugs without receiving any prescription from qualified personnel. There was a lack of qualified personnel, providing prescription, in Bangladesh as well as in the study area. As a result, majority of the farmers could not receive proper prescription and they used to use drugs indiscriminately and thus drug abuse happened regularly.

Conclusion
The practice of using drugs and chemicals in aquaculture operations in Bangladesh are not fully regulated and controlled by competent authorities. Hence, the extralabel use of veterinary and poultry drugs in aquaculture is a common practice of commercial fish farmers. The uncontrolled and indiscriminate use of drugs in aquaculture may lead to the emergence of antimicrobial resistant organisms, loses of aquatic ecosystem and make negative impact on human health. Thus, the use of drugs in aquaculture should have a sufficient regulatory system in place. It is also important to produce and use appropriate labeled drugs in aquaculture for safe fish production. Further in-depth research is needed to understand the impact of extra-label drug on fish, aquatic ecosystem and human health.