Antimicrobial use in aquaculture and antimicrobial resistance, Notas de estudo de Engenharia Biológica

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DEPARTMENT OF FOOD SAFETY, ZOONOSES AND FOODBORNE DISEASES WORLD HEALTH ORGANIZATION GENEVA, SWITZERLAND CONSULTATIONS AND WORKSHOPS Antimicrobial Use in Aquaculture and Antimicrobial Resistance Report of a Joint FAO/OIE/WHO Expert Consultation on Antimicrobial Use in Aquaculture and Antimicrobial Resistance Seoul, Republic of Korea, 13–16 June 2006 Issued by the World Health Organization in collaboration with the Food and Agriculture Organization of the United Nations and the World Organisation for Animal Health PA N I SF I A T PA N I SF I A T WHO Library Cataloguing-in-Publication Data: Report of a joint FAO/OIE/WHO expert consultation on antimicrobial use in aquaculture and antimicrobial resistance : Seoul, Republic of Korea, 13-16 June 2006. 1.Anti-infective agents - utilization. 2.Drug resistance, Microbial - prevention and control. 3.Aquaculture. 4.Risk management. I.World Health Organization. II.Food and Agriculture Organization of the United Nations. III.International Office of Epizootics. ISBN 92 4 159512 4 (NLM classification: QW 45) ISBN 978 92 4 159512 4 © World Health Organization 2006 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: permissions@who.int). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. 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This publication contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the World Health Organization. Printed by the WHO Document Production Services, Geneva, Switzerland. i EXECUTIVE SUMMARY It is well recognized that the issues of antimicrobial use in food animals are of global concern. International interdisciplinary cooperation is essential, and FAO, OIE and WHO have organized a number of consultations to address the issues related to antimicrobial use, the emergence of resistant pathogens and the potential public health impact. Previous consultations have judged that antimicrobial resistance is a problem related to all types of antimicrobial usages, including use in humans and animals. Antimicrobial resistance in human pathogens is largely the consequence of use in human medicine and terrestrial animal agriculture. While difficult to assess in aquaculture the relative risk to humans is likely to be lower. The previous consultations did not address thoroughly the use of antimicrobials in aquaculture and the public health impact of such use. FAO, OIE and WHO therefore organized the present consultation to evaluate the usage patterns, and public health impact of this use, and to develop strategies to minimize the risk. Although data on quantities of antimicrobials used in aquaculture are not available in most countries, available evidence suggests that the amount of antimicrobials used in aquaculture in most developed countries is limited and in some countries the quantity has been decreasing. Nevertheless, large quantities of antimicrobials are used in aquaculture in some countries, often without professional consultation or supervision. Furthermore, an important proportion of aquatic animals raised for the global aquaculture industry are raised in countries with insufficient regulations and limited enforcement for the authorization of antimicrobial agents used in animals. In some countries availability of registered antimicrobials is insufficient which contributes to illegal use. The public health hazards related to antimicrobial use in aquaculture include the development and spread of antimicrobial resistant bacteria and resistance genes, and the occurrence of antimicrobial residues in products of aquaculture. The greatest potential risk to public health associated with antimicrobial use in aquaculture is thought to be the development of a reservoir of transferable resistance genes in bacteria in aquatic environments from which such genes can be disseminated by horizontal gene transfer to other bacteria and ultimately reach human pathogens. However, a quantitative risk assessment on antimicrobial resistance in aquaculture is difficult to perform owing to lack of data and the many different and complex pathways of gene flow. Prevention and control of bacterial diseases in aquatic animals is essential to minimize the use of antimicrobials and avoid the negative impact of antimicrobial resistance. Efficacious vaccines and improved systems for mass vaccination of finfish should be developed, and an optimization of vaccine licensing procedures should be promoted. Programmes to monitor antimicrobial usage and antimicrobial resistance in bacteria from farm-raised aquatic animals and their environment should be implemented and national databases should be developed to achieve efficient communication. A practical, feasible and cost-effective approach should be developed and implemented, building on the work of FAO, the Network of Aquaculture Centres in Asia-Pacific (NACA) and others to strengthen aquaculture extension support and technical advice and assistance to small-scale aquaculture to increase awareness, implement good aquaculture practices1, and 1 FAO is currently working on technical guidelines for the improvement of safety and quality in aquaculture, which will be field-tested in early 2007 and finalized the same year. ii strengthen government and industry institutions for aquatic animal health. The strategies should be integrated within an overall approach for poverty alleviation with particular emphasis on access to credit (micro-credit) and to extension support services. The WHO Global Principles for Containment of Antimicrobial Resistance in Animals Intended for Food, the OIE International Standards on Antimicrobial Resistance, the Codex Code of Practice to Minimize and Contain Antimicrobial Resistance (CAC/RCP 61-2005) and the Codex Code of Practice for Fish and Fishery Products (Section 6 - Aquaculture Production) (CAC/RCP 52-2003) provide recommendations on the responsible and prudent use of antimicrobial agents in veterinary medicine to reduce the over-use and mis-use of antimicrobials in animals for the protection of human health. (Although aquaculture was not specifically considered when the WHO Principles, OIE Guidelines and the Codex Code of Practice (CAC/RCP 61-2005) were adopted, and the Codex Code of Practice for Fish and Fishery Products does not cover extensive fish-farming systems or integrated livestock and fish culture systems that dominate aquaculture production in the world, they also pertain to the use of antimicrobial agents in aquaculture. Antimicrobial agents used in aquaculture should therefore be used in accordance with the WHO Global Principles and with the relevant provisions of the OIE Terrestrial Animal Health Code and Codex texts made applicable to aquatic animals. Antimicrobial agents defined as “critically important for human medicine” by WHO will require special risk assessment and management in respect of non-human antimicrobial use. The use of antimicrobials in aquaculture should be seen within a general framework for risk analysis of antimicrobial resistance in relation to the use of antimicrobials in animals. The future Codex Ad-Hoc Intergovernmental Task Force on Antimicrobial Resistance with respect to Food Safety should work in close collaboration with OIE to develop risk analysis principles and risk assessment guidelines. Within this process a full risk assessment should be developed in priority areas iii PREAMBLE A Joint FAO/OIE/WHO Expert Consultation on Antimicrobial Use in Aquaculture and Antimicrobial Resistance was held in Seoul, Republic of Korea, from 13 to 16 June 2006. The meeting was hosted by the Korean Food and Drug Administration and was attended by 25 experts from 19 countries (see Annex 1 - list of participants). Following the delivery of opening remarks by Dr C. J. Moon, Commissioner, Korean Food and Drug Administration, and Dr Jørgen Schlundt, Director, Department of Food Safety, Zoonoses and Foodborne Diseases, World Health Organization, a silence of one minute was observed in memory of the late Dr Lee Jong Wook, who had passed away suddenly in Geneva, Switzerland, on 22 May 2006, during his term of office as Director-General of the World Health Organization. Dr Gun Jo Woo was elected as Chairman of the meeting, and Dr Herbert Schneider and Dr Peter Smith were elected as Vice-Chairman and Rapporteur respectively. It was decided to address the main issues of concern in two working groups. Dr Hilde Kruse and Dr Iddy Karunasagar were elected as Chairman and Rapporteur of Working Group 1, which would be dealing with assessment of the risk; and Dr Fred Angulo and Dr Carl Uhland were elected as Chairman and Rapporteur of Working Group 2, which would be dealing with risk management options. vi 1 REPORT OF A JOINT FAO/OIE/WHO EXPERT CONSULTATION ON ANTIMICROBIAL USE IN AQUACULTURE AND ANTIMICROBIAL RESISTANCE Seoul, Republic of Korea, 13-16 June 2006 PART I - ASSESSING THE RISK ON PUBLIC HEALTH OF THE USE OF ANTIMICROBIALS IN AQUACULTURE Antimicrobial resistance represents an extremely complex area of microbiology, particularly because of the promiscuity of resistance genes, the importance of horizontal gene transfer and the many different and complex pathways of gene flow. It is therefore not possible to perform a quantitative risk assessment on antimicrobial resistance in aquaculture. Here we are assessing the risk using the common framework for risk assessment as laid down by the Codex Alimentarius Commission, while taking into account certain aspects mentioned in the OIE framework for risk assessment. 1. Hazard identification The public health hazards related to antimicrobial use in aquaculture include the development and spread of antimicrobial resistant bacteria and resistance genes, and the occurrence of antimicrobial residues in products of aquaculture. 1.1. Antimicrobial resistance Today, development and spread of antimicrobial resistance has become a global public health problem that is impacted by both human and non-human antimicrobial usage (OIE/FAO/WHO 2004a). It is generally acknowledged that any use of antimicrobial agents can lead to the emergence of antimicrobial resistant microorganisms and further promote the dissemination of resistant bacteria and resistance genes (OIE/FAO/WHO 2004a). Furthermore, resistance genes neither respect phylogenetic, geographical nor ecological borders. Thus, the use of antimicrobials in one area, such as aquaculture, can have an impact on the resistance situation in another area, such as in human medicine, and resistance problems in one country can spread to another country. Antimicrobial resistance deriving from usage of antimicrobials in aquaculture presents a risk to public health owing to either: • Development of acquired resistance in bacteria in aquatic environments that can infect humans. This can be regarded as a direct spread of resistance from aquatic environments to humans. • Development of acquired resistance in bacteria in aquatic environments whereby such resistant bacteria can act as a reservoir of resistance genes from which the genes can be further disseminated and ultimately end up in human pathogens. This can be viewed as an indirect spread of resistance from aquatic environments to humans caused by horizontal gene transfer. 2 1.1.1. Resistant human bacteria The use of antimicrobial agents in aquaculture can result in an increase in the prevalence of resistant bacteria that can be transmitted to and cause infections in humans. Such direct spread of resistance from aquatic environments to humans may occur owing to (1) consumption of aquaculture food products or through drinking water, and (2) direct contact with water or aquatic organisms, or through the handling of aquaculture food products. These bacteria include: (1) Motile Aeromonas spp, Edwardsiella tarda, Escherichia coli, Plesiomonas shigelloides, Salmonella spp., Shigella spp., Vibrio cholerae, V. parahaemolyticus, and V. vulnificus (alphabetised list), (WHO, 1999) (2) Motile Aeromonas, Erysipelothrix rhusiopathiae Mycobacterium marinum, Streptococcus iniae,and Vibrio vulnificus (alphabetized list). In most countries human infections caused by Vibrio spp. and Aeromonas spp. are uncommon compared to E.coli and Salmonella spp. However, motile Aeromonas and Vibrio vulnificus, and to a lesser extent non-O1 Vibrio cholerae and Plesiomonas shigelloides, can cause bloodstream infections, especially in individuals with risk factors such as chronic liver disease and iron overload, as well as in people with immune disorders. Fluoroquinolones are important as first or second line treatment for these potentially fatal infections. Vibrio vulnificus, Vibrio parahaemolyticus and some non-O1 V.cholerae serogroups are well-recognized causes of gastrointestinal illnesses, despite the incidence being low in some countries. Motile Aeromonas are common causes of self-limiting diarrhoeal illnesses although there is notable geographical variation in incidence, possibly reflecting differences in strains involved. Antimicrobials in general are not required or recommended in the case of self-limiting gastrointestinal illnesses. Bacteria listed under (2) above are infrequent causes of soft tissue infections that require antimicrobial treatment. In some cases, disseminated infections may also occur. 1.1.2. Resistance genes (horizontal gene transfer) Development and spread of antimicrobial resistance as a consequence of exposure to antimicrobial agents is widely documented in both human and veterinary medicine. It is also well documented that fish pathogens and aquatic bacteria can develop resistance as a consequence of antimicrobial exposure (Sørum 2006). Examples include Aeromonas salmonicida, Aeromonas hydrophila, Edwardsiella tarda, Citrobacter freundii, Lactococcus garviae, Yersinia ruckeri, Photobacterium damselae subsp. piscicida, Vibrio anguillarum, Vibrio salmonicida, Photobacterium psychrophilum and Pseudomonas fluorescens. For example Aeromonas salmonicida, which causes disease in fish of temperate and colder areas, easily develops resistance. Acquired sulfonamide resistance in Aeromonas salmonicida was reported already in 1955 in the USA and, in the 1960s, multiresistant strains were observed in Japan. Later on, multiresistant Aeromonas salmonicida have been described from many countries in various parts of the world, and transferable resistance plasmids are commonly detected in these strains (Sørum 2006). Typical transferable resistance determinants are those conferring resistance to sulphonamide, tetracycline, trimethoprim, and streptomycin. The use of quinolones in the 5 2. Hazard characterization 2.1. Antimicrobial resistance The consequences of antimicrobial resistance in bacteria causing human infections include: (1) Increased frequency of treatment failures and increased severity of infection as a result of antimicrobial resistance may be manifested by prolonged duration of illness, increased frequency of bloodstream infections, increased hospitalization, or higher mortality (OIE/FAO/WHO 2004a). Although there are no examples involving cases from aquaculture products, prolonged duration of illness has been demonstrated in case-control studies of fluoroquinolone-resistant Campylobacter (Smith et al, 1998; Neimann et al, 2003). Prolonged duration of illness has also been demonstrated among persons infected with nalidixic acid resistant Salmonella Typhi treated with fluoroquinolones. The association between an increased frequency of antimicrobial resistance Salmonella and an increased frequency of hospitalization has been demonstrated in several studies. The same phenomenon as demonstrated for Salmonella and Campylobacter can occur with other resistant human pathogens, in which resistance might have originated in aquaculture. (2) Antimicrobial agent use in humans disturbs the microbiota of the intestinal tract, placing such individuals at increased risk of certain infections. Individuals taking an antimicrobial agent, for any reason, are therefore at increased risk of becoming infected with pathogens resistant to the antimicrobial agent. 2.2 Antimicrobial residues If present in concentrations above the established maximum residue limits, or if the drug is used without appropriate authorization based on scientific assessment of the benefit and risk of the treatment, residues can present a hazard in products from aquaculture. 2.2.1 Toxicological aspects Chloramphenicol was evaluated by JECFA on several occasions as well as other agencies (IARC and CVMP). Concerns have been expressed about the genotoxicity of chloramphenicol and its metabolites, its embryo- and fetotoxicity, its carcinogenic potential in humans and the lack of dose response relationship for aplastic anemia in humans. It has been concluded that chloramphenicol is not suitable for use in food producing animal species as no ADI or MRLs could be established. However, there are no reported cases of aplastic anaemia attributed to consumption of chloramphenicol residues in foods. JECFA also concluded that there was no evidence that chloramphenicol could be synthesized naturally in detectable amounts in soil. Chloramphenicol presents a particular threat to human health as it can cause an idiosynchratic dose-independent aplastic anemia in humans, which can be induced by low concentrations of chloramphenicol. (Sundlof, 1993). Aplastic anemia is irreversible and has a 70% case fatality rate. Those who recover experience a high incidence of acute leukaemia. The probability is about 1 in 25 000 if exposed to oral treatment with chloramphenicol. Drug allergies are generally considered to be type 1 immune response mediated through IgE. Symptoms include urticaria, angioedema and might include anaphylaxis. Penicillin is the 6 most commonly implicated antimicrobial in adverse reactions from foodborne residues, causing penicillin hypersensitivity or skin disease unrelated to penicillin allergy. Penicillin residues as low as 5-10 IU are capable of producing allergic reactions in previously sensitized persons (Sundlof 1993). The extent of use of penicillin in aquaculture is most probably low due to the fact that penicillin rapidly degrades in aqueous solutions. Many antimicrobials other than penicillin – including other beta-lactams, streptomycin (and other aminoglycosides), sulfonamides and, to a lesser extent, tetracyclines - are known to cause allergic reactions in sensitive persons. But, apart from a single report of a reaction to meat suspected of containing streptomycin residues, we are not aware of any reports of foodborne allergic reactions resulting from residues of any antimicrobial other than penicillin (Sundlof 1993). Increasing concern about the carcinogenic and mutagenic potential and their thyroid toxicity has led to decreased use of sulfonamides. Research has shown that chronic dietary exposure to sulfamethazine produces a statistically significant increase in thyroid follicular cell adenomas in both rats and mice, and a statistically significant increase in thyroid follicular cell adenocarcinomas in rats (Sundlof 1993). 2.2.2. Effects on human intestinal flora The principal concern is to which degree antimicrobial residues in food may affect human health either by: (i) exerting a selective pressure on the dominant intestinal flora; (ii) favouring the growth of micro-organisms with natural or acquired resistance; (iii) promoting, directly or indirectly, the development of acquired resistance in pathogenic enteric bacteria; (iv) impairing colonization resistance; or (v) altering metabolic enzyme activity of the intestinal microflora (Hernandez, 2005). Although limited knowledge is available in this area, a few studies indicate that at low level of exposure effects on the human intestinal microflora might occur (EMEA 2001). However, the risk assessment performed to establish a microbiological ADI takes into account the potential for development of resistance, using models with human faecal material or in vivo studies. 3. Exposure assessment 3.1. Prevalence of antimicrobial resistant human pathogens The risk of human infections from the organisms listed in 1.1.2 has been assessed by FAO and WHO and determined to be low or very low (WHO 1999). However, although there are large variations depending on regions and environmental conditions, antimicrobial resistance in many of these bacteria from aquatic environments is widespread. It is uncertain to what degree the resistance is a result of antimicrobial usage in aquaculture. It is likely that usage in other areas such as human medicine and terrestrial animals play a role. Salmonella spp. and E. coli strains, including resistant strains, can be found in aquatic environments as a result of contamination with such bacteria from human, animal or agricultural environments. The resistance is caused by usage of antimicrobials in humans or terrestrial food animals. Sewage contamination or run-off from agricultural areas with grazing animals to aquaculture operations can result in the presence of resistant Salmonella spp. and E. coli in products of aquaculture. The similar picture applies to Shigella spp., but for this 7 pathogen, which is a strictly human pathogen, antimicrobial usage in humans is the promoter of resistance development and spread. In some aquaculture environments, human pathogens deriving from terrestrial animal or human wastes may be incapable of extensive cell division, limiting the extent to which usage of antimicrobial agents in aquaculture can exert a selective pressure for the emergence of resistant variants. However, in some climatic and aquaculture systems, there might be cell division and usage of antimicrobial agents in aquaculture can exert a selective pressure for the emergence of resistant variants. Vibrio spp. are marine bacteria of which some can be pathogenic to humans. Resistance in Vibrio cholerae and Vibrio parahaemolyticus can be a result of human usage of antimicrobials, but may also be a consequence of use of antimicrobials in aquaculture. The risk that resistant bacteria from aquaculture may be present in treated drinking water supply is remote. In areas where drinking water is not treated, resistant bacteria from aquaculture may reach drinking water supply (Hernandez, 2005). 3.2 Prevalence of antimicrobial resistance genes It is well documented that antimicrobial resistance develops and spreads in fish pathogens as a consequence of exposure to antimicrobials. Available literature shows that resistance is widespread in fish pathogens and, in general, that resistance is more prevalent where the usage is high. The resistance genes in fish pathogens are often the same as those found in human pathogens, and most of these genes are transferable. Thus, fish pathogens act as a reservoir of resistance genes that can be transmitted horizontally to human pathogens through different pathways. Transfer of R Plasmid and emergence of new drug resistance gene cassettes have been reported in human and fish pathogenic bacteria in aquatic environments. Because antimicrobials used in aquaculture can be deposited in the environment, there is potential for a selective pressure on environmental bacteria. As a result, there is also potential for the establishment of a reservoir of resistance genes for further dissemination, which could ultimately reach humans. 3.3 Antimicrobial residues The public health risk associated with antimicrobial residues depends on the quantity of the antimicrobial encountered or consumed, i.e. the exposure. In general, the lower the exposure, the lower the risk. Public perception that foodborne residues pose a major health risk is not supported by actual case reports. The FAO/OIE/WHO consultation on scientific issues related to non-human usage of antimicrobials held in Geneva, in December 2003, concluded that residues of antimicrobials in foods, under present regulatory regimes, represent a significantly less important human health risk than the risk related to antimicrobial resistant bacteria in food. The use of water and food as the most common administration route in aquaculture helps to obtain a uniform dose and avoid any potential for high localized concentration that might accumulate at the site of injection during intramuscular or subcutaneous routes of administration, such as in terrestrial animals. Strict adherence to withdrawal times is nevertheless critical. 10 • Member countries should undertake development, harmonization and implementation of methods for monitoring the prevalence of resistant bacteria, resistance genes and antimicrobial residues in products from aquaculture and in the aquatic environment. • Given the lack of data, in respect of many aspects of antimicrobial use in aquaculture, a preliminary study designed to prioritize the various risks that have been identified should be performed. Risks with a high priority should then be investigated in a full qualitative risk assessment. References Ababouch, L., Gandini, G., Ryder, J., 2005. Detentions and rejections in international fish trade. FAO Fisheries Technical Paper No. 473, 110 pages. FAO, Rome, Italy. Andersen SR and Sandaa RA., 1994, Distribution of tetracycline resistance determinants among gram-negative bacteria isolated from polluted and unpolluted marine sediments. 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Oslo, Norway, 10-13 September 2001. http://www.who.int/emc/diseases/zoo/antimicrobial.html 15 (5) Since in many countries an important proportion of antimicrobial agents used in aquaculture are administered with limited or no professional supervision or guidance, the development of extension services is needed. 2.2 Disease prevention and infection control To minimize the use of antimicrobials and avoid the negative impact of antimicrobial resistance, it is essential to prevent and/or control bacterial diseases of aquatic organisms. (1) Infection control and prevention requires accurate diagnosis of disease conditions to ensure the proper application of antimicrobial therapy (OIE Manual of Diagnostic tests for Aquatic Animals). Another aspect in the prevention and control of infectious disease in aquaculture is the need for improvement of diagnostic practices including the development and implementation of rapid diagnostic methods. Many areas lack adequate veterinary and diagnostic support. (2) Implementing periodical disease surveillance and management health plans is important to maintain the health status of the aquatic organisms including ornamental fish. Knowledge concerning the nature of pathogens, source of infection, carriers, mode of transmission, epidemiology, etc, of disease is needed for disease management. (3) Monitoring of the health status of ornamental fish is encouraged as it may act as a source of infection and antimicrobial resistance for aquatic animals and humans. In order to maximize the ability to withstand disease, it is important to maintain optimal environmental conditions such as stocking densities, good water quality, proper feeding and high standards of hygiene for aquatic animals. (4) Effective environmental management such as optimal site selection, water source, facility design, fish handling, transport system and the efficient waste removal are important for successful fish culture and disease prevention (CAC/RCP 61-2005). (5) Proper feeding (quantity and quality) is important, not only for growth and prevention of nutritional diseases, but also for overall health. Using animal by-products may constitute fish health problems and public health hazard through transmission of zoonotic diseases and antimicrobial resistance genes. (6) Sanitation and disinfection of aquaculture and hatchery facilities are very important to control both vertical and horizontal transmission of diseases. (7) Vaccination is an important measure in relation to disease prevention in finfish. Vaccines are available for many of the major infectious diseases problematic in aquaculture, and by the application of such vaccines the need for antimicrobials can be reduced substantially. (8) Other methods for improving the immunity of aquatic animals against diseases may be helpful. These include: (i) Selective breeding is an important approach to obtaining more tolerant strains of aquatic animals against infectious pathogens. (ii) Immunostimulants, including bioactive natural products, may represent a new approach for the control of disease in aquaculture, but need further evaluation. 16 (9) Biosecurity practices used for disease control are necessary. Adoption of quarantine measures together with establishment and enforcement of national and international regulations will help prevent the transfer of infectious agents (CAC/RCP 52-2003). (10) Regulatory measures together with an appropriate legal framework with the necessary powers for policy decision making and for the practical application of regulations that are accepted by aquaculture industry are essential for disease prevention and control in aquatic animals. 2.3 Environmental management 2.3.1 Manure Human and animal waste can be added to aquaculture ponds as a fertilizer to increase plant and phytoplankton growth, which fish then eat. This manure may carry antimicrobial agents. Since manure contains enteric bacteria, some of which may be antibiotic resistant, particularly if the animals or people have received antibiotics, the use of manure should be avoided whenever possible. If manure is used, it should be processed to reduce enteric bacteria. 2.3.2 Waste There will be an antimicrobial fraction that is lost to the water column following leaching of the medicated feed, and a portion of non-absorbed medication excreted by the aquatic organism in the urine and faeces. Recuperation of the faecal portion by using waste recuperation techniques such as sedimentation or filtration will help reduce the quantity of antimicrobial released to receptor watersheds. The binding of certain antimicrobials with benthic sediments, as well as degradation by microbial processes and exposure to sunlight, will decrease the quantity of available active medication in the environment. Care will be needed with any sludge or waste water released for ponds if used for people or animals as it may contain resistant bacteria and/or traces of antimicrobials. Care will also be needed with waste water and sludge applied to foods (e.g. vegetables). 2.3.3 Location of fish farms The rates of water exchange need to be taken into account and dilution factors for any antibiotics that will leech from feeds and may be present in effluents as these will otherwise be deposited into and accumulate in the layers below the “fish farm”. Thus the relevant national authorities should take into consideration the environmental impact in decisions on where to locate and/or how often to move [aquatic ponds, net pens, containers and sea farms]. 2.4 Risk analysis framework The use of antimicrobials in aquaculture should be seen within a general framework for risk analysis of antimicrobial resistance in relation to the use of antimicrobials in animals. A future Codex Ad-Hoc Task Force on Antimicrobial Resistance with respect to Food Safety should work with input from OIE to develop such principles as well as guidelines for risk assessment. Guidelines for risk assessment could be harmonized between the existing OIE guidelines, Risk assessment for antimicrobial resistance arising from the use of antimicrobials in animals, (http://www.oie.int/eng/normes/mcode/en_chapitre_3.9.4.htm) and general guidelines from Codex. Risk assessment to support the risk analysis process 17 could be envisaged within the framework of the Joint FAO/WHO Expert Meeting on Microbiological Risk Assessment (JEMRA) with the additional expertise of OIE. The development of capacity to assess the relative importance of human antimicrobial use as compared to animal use is an important area for future work. There is a need for increased scientific and surveillance efforts to provide data to fit the risk assessment frameworks developed. Data input for these efforts could be sought from national authorities as well as scientific institutions and industry. 3. Risk management: implementation (1) The establishment of regulations which concern the use of antimicrobials should be promulgated. These should establish permitted antimicrobial products as well as allowable withdrawal times. (2) The development of extension services, in collaboration with producers and producer associations where they exist, are necessary to provide information to producers concerning applicable regulations and appropriate antimicrobial usage. The importance of this professional expertise is also relevant concerning the application of judicious use principles. Expertise with the different aquatic species, as well as pathology, pharmacology, immunology, physiology and other connected disciplines is a vital resource when planning disease control strategies. (3) Control measures for the importation or antimicrobials and dispensing their use in aquaculture should be established. (4) The imposition and enforcement of regulations concerning antimicrobial residues in aquaculture products for domestic and export markets may help to reduce the use of forbidden substances. (5) The intervention of trained professionals (veterinarians and veterinary paraprofessionals) on the aquaculture site is vital for the dissemination of information concerning appropriate antimicrobial usage as well its enforcement. (6) The imposition of food safety standards by importing countries and/or enterprises are likely to have a positive reinforcement effect upon avoidance of antimicrobial residues. 4. Risk management: capacity building (1) The development of adequate diagnostic support is essential for aquaculture industries in order to ensure the appropriate utilization of antimicrobials. (2) The development of an adequate enforcement infrastructure is necessary to assure adherence to existing regulations concerning antimicrobial use in aquaculture. (3) The development of surveillance infrastructure will be necessary to evaluate the development of antimicrobial resistance as well as to obtain information concerning antimicrobial use. This data is necessary for risk analysis. (4) The approval process for antimicrobials and vaccines specifically designed for aquatic animal species should be optimized for rapid movement through the regulatory process, 20 6. Recommendations (not listed in order of priority) • WHO has defined a list of “critically important drugs for human medicine” that require special risk assessment and management, and this list should be considered in the use of antimicrobials in animal health. • An OIE list of antimicrobials of veterinary importance for animal use is in the process of further refinement according to the type of usage. OIE should specifically address antimicrobial use in aquaculture. • Regulations at the national level should be established for the approval of antimicrobials used in aquaculture with a view to international harmonization. These should include approval of antimicrobials for all relevant aquatic species as well as recommending allowable withdrawal times. • All uses of antimicrobials, including off-label and extra-label use should also be regulated. Governments should ensure these regulations are enforced. Controls of import and dispensing of antimicrobials should also be established. Drug residue surveillance programs for aquaculture products should be implemented. • Antimicrobial agents used in aquaculture should be used prudently and in accordance with the WHO Global Principles and with the relevant Provisions of the OIE Terrestrial Animal Health Code and Codex texts made applicable to aquatic animals (appendix 4, 5 and 6: guidelines for prudent use of the three organizations). • A practical, feasible and cost effective approach should be developed and implemented, building on the work of FAO, NACA (Network of Aquaculture Centers in Asia) and others to strengthen aquaculture extension support and technical advice and assistance to small scale aquaculture to increase awareness, implement good aquaculture practices 4 , and strengthen government and industry institutions for aquatic animal health. The strategies should be integrated within an overall approach for poverty alleviation with particular emphasis on access to credit (micro-credit) and to extension support services. • Provision of basic diagnostic services and tools should be the joint responsibility of governments and the private sector to ensure that they are accessible to producers and the aquaculture sectors at all levels. Governments should promote appropriate aquatic animal health management framework through national centers, farmer associations and extension services is available for aquaculture at local, national and regional level including on farm diagnostic services, rapid diagnostic kits, simple tests such as disk diffusion, as well as high technology diagnostic centres. This framework should include trained professionals as well as specialized diagnostic centres that will monitor pathogen emergence and clinical relevance. • Programs to monitor usage and antimicrobial resistance in bacteria from farm-raised aquatic animals and their environment should be implemented based on existing guidelines (OIE Guidelines for the harmonization of antimicrobial resistance surveillance and monitoring programmes, which may be found at the following 4 FAO is currently working on technical guidelines for the improvement of safety and quality in aquaculture, which should be field-tested in early 2007 and finalized the same year. 21 website: http://www.oie.int/eng/normes/mcode/en_chapitre_3.9.1.htm and for the monitoring of the quantities of antimicrobials used in animal husbandry, which may be found at: http://www.oie.int/eng/normes/mcode/en_chapitre_3.9.2.htm) • Veterinarians, veterinary paraprofessionals (e.g. aquatic animal health specialists), fish farmers, medical practitioners and authorities, should be kept regularly informed, at least annually, about surveillance results and trends. National databases should be developed to achieve efficient communication. Antimicrobial susceptibility testing should be performed according to standardized methods using appropriate quality controls and be reported quantitatively to allow comparisons of results. Susceptibility testing methods in aquatic bacterial species should be harmonized. • Training and technical assistance should be provided to build capacity and infrastructure particularly in developing countries to strengthen government institutions, industry support services and extension services in the areas of prudent antimicrobial use, good aquaculture practices and food safety. Veterinary institutions should be encouraged to promote aquatic animal health in the training of veterinarians. • Producer associations should be promoted at national or regional levels to improve management strategies for aquatic animal farming, reduce usage of antimicrobials and improve economic viability of small farmers. • Programme should be developed to increase aquatic animal fitness for aquaculture. Such a programme should include selective breeding for optimal aquatic animal performance, disease resistance and other parameters of importance to farming success. • Tools should be developed that foster optimal rearing environments for aquatic animal production. Special consideration should be given biocontrol opportunities and improvements in biosecurity. • Efficacious vaccines and improved systems for mass vaccination of finfish should be developed and implemented in order to reduce antimicrobial utilization. Optimization of vaccine licensing procedures should be promoted. • Post-marketing antimicrobial surveillance programmes should be developed to monitor changes in clinical efficacy and frequency of treatment failures. Veterinarians, veterinary paraprofessionals and aquatic animal farmers should be kept regularly informed about surveillance results and trends. A standardized database should be developed to achieve efficient communication and allow comparisons. • There is a need for a coherent framework for risk analysis of antimicrobial resistance in relation to the use of antimicrobials in animals intended for food including aquatic animals. This framework should also enable future linkages to broader evaluations, including comparisons of the relative importance of animal versus human use as well as risk-benefit evaluations. • The future Codex Ad-Hoc Intergovernmental Task Force on Antimicrobial Resistance with respect to Food Safety should work in close collaboration with OIE to develop risk analysis principles and risk assessment guidelines. Within this process a full risk assessments should be developed in priority areas. 22 Annex 1 Joint FAO/OIE/WHO Expert Consultation on Antimicrobial Use in Aquaculture and Antimicrobial Resistance, Seoul, Republic of Korea, 13-16 June 2006 LIST OF PARTICIPANTS Dr Salah Mesaly ALY, Professor of Fish Pathology, Faculty of Veterinary Medicine, Suez Canal University, Senior Researcher and Programme Leader of Fish Health for Africa, World Fish Center, Abbassa, Sharkia, Egypt (Mobile: 002012-1057688, E-mail: S.mesalhy@cgiar.org) Dr Fred ANGULO, Chief, FoodNet/NARMS Unit, Foodborne and Diarrhoeal Diseases Branch National Centers for Infectious Diseases, Mailstop A-38, 1600 Clifton Road, 30333 Atlanta, Georgia, USA (Tel.+ 404-639-3315, Email: fja0@cdc.gov) Professor Takashi AOKI, Laboratory of Genome Science, Graduate School of Marine Science and Technology, Tokyo University Of Marine Science and Technology, Konan 4-5-7, Minato-Ku, Tokyo 108-8477, Japan (Tel. 81-3-5463-0556 Fax. 81-3-5463-0690 E-Mail. Aoki@S.Kaiyodai.Ac.Jp) Dr Panos CHRISTOFILGIANNIS, AQUARK, General Manager, Management Solutions for Aquatic Resources, 143 Papagou Avenue, 15773 Zografou, Athens, Greece (Tel/Fax:+30 210 7470147; Mobile:+30 6944 418566, Email: panos@aquark.gr and/or panosvet@otenet.gr) Professor Peter COLLIGNON, Director, Infectious Diseases Unit and Microbiology Department, The Canberra Hospital, PO Box 11, Woden, ACT 2607, Australia (Fax: +61 2 6281 0349, Tel.:+ 61 2 6244 2105, E-mail: peter.collignon@act.gov.au) Dr Anders DALSGAARD, Professor in Food Safety and Food Security in Developing Countries, Department of Veterinary Pathobiology, The Royal Veterinary and Agricultural University, Grønnegårdsvej 15, 1870 Frederksberg C, Denmark (Tel.: +45 35 282720, Fax +45 35 282755, Email: ad@kvl.dk) Dr Jorge ERRECALDE (Professor of Pharmacology and Toxicology, Faculty of Veterinary Science. National University of La Plata, 12 St Nº 219 (1900), La Plata, Buenos Aires, Argentina (Tel./Fax. + 54 2214247813, Email: jerrcal@yahoo.com/jerecal@fcv.unlp.edu.ar) Dr Kari GRAVE, Norwegian School of Veterinary Science, P. O Box 8146, Dep.N-0033, Oslo, Norway (Tel.+ 47 22 96 49 88, Fax: 47 22 96 47 52, Email: kari.grave@veths.no) Dr Benjamin GUICHARD, AFSSA-ANMV, Pharmaceuticals Assessment Unit, B. P. 90203, Fougères cedex, France (E-mail: b.guichard@anmv.afssa.fr) Dr Ole E. HEUER, Research Scientist, Department of Microbiology and Risk Assessment, Danish Institute for Food and Veterinary Research, 19 Mørkhøj Bygade, 2860 Søborg, Denmark (Tel: +45 7234 7080, Fax: +45 7234 7028, E-mail: oeh@dfvf.dk) 25 Secretariat of the World Health Organization (WHO): Dr Awa AIDARA-KANE, Scientist, Department of Food Safety, Zoonoses and Foodborne Diseases, Sustainable Development and Healthy Environments, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (Tel: +41 22 791 12403, Fax. +41 22 791 4893, E-mail: aidarakanea@who.int) Dr Jørgen SCHLUNDT, Director, Department of Food Safety, Zoonoses and Foodborne Diseases, Sustainable Development and Healthy Environments, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (Tel: +41 22 791 3445, E-mail: schlundtj@who.int) Secretariat of the Codex Alimentarius Commission: Dr Annamaria BRUNNO, Food Standards Officer, Codex Alimentarius Commission Secretariat, Joint FAO/WHO Food Standards Programme (Tel: + 39 06 5705 6254; Fax: +39 06 5705 4593, E-mail: annamaria.bruno@fao.org) 26 Annex 2 Joint FAO/OIE/WHO Expert Consultation on Antimicrobial Use in Aquaculture and Antimicrobial Resistance, Seoul, Republic of Korea, 13-16 June 2006 AGENDA Tuesday, 13 June 2006 09.00 – 10.00 SESSION I: OPENING OF MEETING • Welcome and opening remarks • Election of chairperson and vice- chairperson • Appointment of rapporteur • Adoption of the agenda Introductory statement on behalf of FAO, OIE, WHO and CODEX Dr C. J. Moon, Commissioner, KFDA Chairperson Dr Jørgen Schlundt, WHO 10.00 – 10.30 Tea/Coffee break 10.30 - 12.30 SESSION II: DRAFTING GROUP PAPERS Presentation of draft paper on aquaculture production and utilization - World aquaculture production and contribution to food security (production volume and value, producing countries, species, consumption, utilization, trade) - Aquaculture technology and aquaculture systems, use of antimicrobials in aquaculture - Technological developments and future trends DISCUSSION P. Christofilogiannis C. Lavillapitogo D. Prater 12.30 – 13.30 Lunch 27 13.30 – 15.30 Presentation of draft paper on animal health issues - Benefit assessment for animal health - Exposure assessment - Hazard identification - Risk assessment (Animal Health risk and human exposure to antimicrobial residues and antimicrobial resistance) - Risk Management (Prudent use) DISCUSSION B. Guichard P. Smith V. Aldaysanz C. Uhland 15.30 – 16.00 Coffee break 16.00 – 18.00 Presentation of draft paper on public health issues: - Risk assessment : human health consequences of use of antimicrobials in aquaculture (considering resistant bacteria, resistant genes, residues, environmental aspects) - Hazard identification, hazard characterization, exposure assessment - Establishment of a risk profile including consideration of factors that might contribute to an increase in antimicrobial resistance - Identify gaps , needs for future research and capacity building - Risk management options DISCUSSION F. Angulo H. Kruse P. Collignon I. Karunasagar O. Heuer Wednesday, 14 June 2006 0900 – 10.30 SESSION III: WORKING GROUP SESSIONS Plenary: Formation of Working Groups 1 and 2 Election of chairpersons and rapporteurs Working Group 1: Risk assessment approach Working Group 2: Risk management options 10.30 – 11.00 Coffee break 11.00 – 13.00 Working Group 1: Risk assessment approach Working Group 2: Risk management options 13.00 – 14.00 Lunch 30 Aquaculture has grown more rapidly than either capture fisheries or the terrestrial food animal production sector with average annual growth rates of 8.8%, 1.2% and 2.8% per cent respectively. Processed product from aquaculture has also outpaced population growth since 1970, with per capita supply increasing from 0.7 kg in 1970 to 7.1 kg in 2004, an average annual growth rate of 7.1%. In 2004 the global production of food fish and aquatic plants was valued at over US$ 70 billion on production of 59.4 million tons. This is compared with production of less than a reported one million tons in the early 1950s. In addition to increases in production there has also been an increase in the total value of the aquaculture crop as high-value species have come under intensive culture. Aquaculture occurs in many regions of the globe but is most significant in the Asia-Pacific region, especially China. According to FAO, countries in the Asia-Pacific region accounted for 91.5% of the production volume and 80.5% of the value in 2004. Furthermore, of the world total, China produced 69.6% of the total volume and 51.2% of the total value of aquaculture production, a significant proportion of which is consumed domestically. Understanding the contribution of aquaculture product from the developing countries of the Asia-Pacific region is important when considering approaches to antimicrobial therapy. In 2004 global aquaculture consisted of approximately 51% mariculture, 43% freshwater culture, and 6% culture in brackishwater environments. About two-thirds of brackishwater production consists of penaeid shrimps with finfish making up the difference. Freshwater culture consists largely of finfish which make up over 94%. Mollusks and aquatic plants on the other hand almost evenly make up most of the mariculture at 43% and 46%, respectively. Species Diversity Aquaculture is very diverse and there has been an increase in the number of cultured species and culture systems over the years. According to the FAO FishStat database, 442 different species have been cultured at sometime between 1950 and 2004. Since 1950 the number of species cultured has grown from 72 to 336 in 2004, for an average annual introduction of approximately five new species each year. The introduction of new species often results in the development of new or modified culture systems and a learning curve during which producers may experience increased disease outbreaks in species under intensive culture. Production statistics can be examined by volume (tons of production) or by value (dollar value of production). Finfish are the top group by quantity or by value at 47% and 54% respectively. Aquatic plants are second in quantity at 23%, but only fourth in value at 9.7%. Crustaceans are fourth by quantity at 6%, but second by value at 20%. Molluscs are third by quantity or by value at 22% and 14%, respectively. Not well described by current FAO statistics is the production of cultured ornamental fish. Ornamental fish present challenges similar to other intensively reared species, including risk of disease and potential need for antimicrobial therapy. However, handling not withstanding, they do not pose the same exposure profile as food fish with respect to human consumption. Cyprinids are the most important finfish family by volume and total value. On an individual basis, their value is lower than some species, such as Atlantic salmon, which suggests that many farmed cyprininds are raised for local consumption, rather than for export. This highlights the important role of aquaculture in food security. It also highlights the situation in some developing countries where relatively low-value species are produced for domestic consumption and high-value species are produced for an export market, typically in developed 31 countries with significant regulation of the imported product. Production of a product for a highly-regulated market may influence the use of antimicrobial therapies for certain species. After finfish, oysters are a distant second by volume at 4.6 million tons and are followed closely by kelps at 4.5 million tons. Crustaceans represented by penaeid shrimps and grapsid crabs have high total values relative to their production volumes and are another example of high value species. Seafood Consumption Global per capita seafood consumption has increased over the past four decades, from 9.0 kg in 1961 to an estimated 16.5 kg in 2003 according to FAO statistics. As nutritional standards have increased worldwide, particularly in developing countries, so has protein intake, rising from 65.1 grams in 1970 to 75.7 grams in 2003. In recent years, fish has been widely recognized as a highly nutritious source of protein, essential fatty acids, micronutrients and minerals. In many countries, especially developing countries, the average per caput fish consumption may be low, but, even in small quantities; fish can have a significant positive impact in improving the quality of dietary protein by complementing the essential amino acids that are often present in low quantities in vegetable- based diets according to FAO. During the last few years, major increases in the quantity of fish consumed originated from aquaculture, which in 2004 is estimated to have contributed 43% of the total amount of fish available for human consumption. Aquaculture production has pushed the demand and consumption for several high value species as shrimps, salmon and bivalves. During the last two decades, these species shifted from being primarily wild-caught to being primarily aquaculture-produced, with a decrease of their prices and a strong increase in their commercialization. Aquaculture has also a major role in terms of food security in several developing countries, particularly in Asia, for the significant production of some low-valued freshwater species, which are mainly destined to domestic consumption. Culture Systems Contributing to the diversity of aquaculture is the number of different culture systems employed to produce an increasing number of species. A wide variety of culture systems are employed to meet the production needs of the cultured species and maximize the resources available in the region. Each culture system has aspects that affect the production densities and risk for disease, as well as affect the ways in which antimicrobials are administered and handled with respect to uptake by the cultured species and excretion into the environment. In addition, economic factors may influence the predominant type of culture system in a particular region. For example, subsistence farmers and domestic producers may utilize predominantly extensive systems, particularly in China, Asia and developing countries, while producers for export, those producing high-value species, utilize more intensive systems. As economic efficiencies improve, there has been a trend towards an increase in the proportion of intensive systems. While the current FAO reporting system for aquaculture works well for describing production and utilization, the classification system by environment creates a challenge for determining the relative importance of each culture system in the respective regions. However, the dominant system may be inferred for each region using the dominant species produced. Cyprinids are most likely produced in freshwater fishponds, salmons in sea cages, shrimps in 32 brackish water or marine ponds, and channel catfish in raceways or freshwater ponds. On the other hand marine bivalves are mostly produced using lines, racks and stakes and seaweeds are primarily produced using lines. By inference this would mean that freshwater fishponds, sea cages, lines and racks are all important in Asia, while sea cages are dominant in Europe. There are also land-based, industrial-type hatchery and nursery aquaculture production systems where temperature is controlled and where liquid oxygen may be used. These systems are energy intensive and are used primarily for grow-out for very high value products intended for niche markets. For example, this system is used for abalone culture in Australia, for tilapia culture for the live market, and for hybrid striped bass in the United States of America. The commercial aquaculture of marine finfish is expanding and likely to take place in more offshore locations than have traditionally been used. Cages developed specifically for offshore culture have been put into commercial use in recent years. More development in this area is envisioned. Earthen pond and limited-flow culture systems are widely used throughout the world. Freshwater ponds are a principal system for the culture of cyprinids in Asia and channel catfish in the United States of America, while brackish water or marine ponds are the predominant system for shrimps. Ponds can be of any size, typically ranging from 0.2 ha (0.5 acre) to 8 ha (20 acres) with a depth of 1.0m to 2.0m. Ponds may be managed as extensive systems with low stocking densities and low nutrient input relying on natural sources of feed; as semi- intensive systems with supplemental feeding of artificial diets and a consequent increase in production; or as intensive systems with high stocking densities, large inputs of feed, and a higher level of monitoring and control to maintain appropriate water conditions. High stocking densities and reduced water quality are key factors associated with the potential for disease outbreaks, and are important in other culture systems as well. Pond culture systems are sensitive to environmental conditions particularly temperature. Flow-through tanks and raceways. Salmonids and other coldwater species require access to clean, highly oxygenated water meaning that static pond water is not suitable for these species. Freshwater salmonids are grown in raceways or tanks with continuous water flow through. The simplest gravity fed system for trout farming includes earthen ponds, typically 30m x 10m x 1.5m, employing as a water source an adjacent stream. Circular tanks or concrete raceways represent a more intensive approach with higher water flow and at least 10-fold increased stocking densities. With a usual length of up to 100m, with a depth of 1m and width of 3m, raceways are segmented by fish screens or, depending on gradient, smaller splashdown raceways. Circular tanks with a diameter of 4m to 5m and a depth of 0.7m are made of concrete, fibreglass or coatings that resist erosion, prevent algal accumulation and employ water exchange of at least three times per hour. Water inlets are peripheral inducing a vortex action and self-cleaning properties, especially in slightly sloped bottom tanks. Net pen and cage culture systems share the fundamental characteristic of utilizing an enclosure to rear aquatic species in open bodies of water. Net pens are the predominant marine culture system for salmonids in Norway, Scotland and Chile. Net pens vary from flexible net bags to semi-rigid with flexible internal construction to rigid boxlike structures. Net pen volumes range from 1000 m3 to over 20 000 m3 and are typically moored in natural bays or near-shore locations. Cages differ from net pens in that they are typically smaller and have rigid frames. Cages may be used in a variety of environments such as ponds, streams and coastal waters. When feeding fish in net pens or cages particular attention must be paid to sinking feed falling through the bottom of the cage or floating feed leaving the sides or top of the enclosure. 35 mitigation strategies. Traceability and product labeling may decrease off label use and residues. WORKING GROUP 2: Animal health issues: towards a risk analysis of antimicrobial use in aquaculture (Prepared by Victoria Alday, Benjamin Guichard, Peter Smith and Carl Uhland) Introduction An antimicrobial agent has never been developed specifically for an aquaculture application. Given the cost of drug development and licensing and the economics of aquaculture it is unlikely that any will be in the near future. The antimicrobial agents used in aquaculture are, therefore, those that have been developed for and are used to treat humans or other land-based animals. This raises the question of whether antimicrobial agent use in aquaculture can have a negative impact on the therapeutic value of these agents for human disease - and if this negative effect is evident, how big is it and what can be done to minimize it? In addressing the risks to human health represented by the use of antimicrobial agents in aquaculture, three major problems have to be confronted. The first is related to the very diversity of aquaculture systems, the second is related to the paucity of information, and the third relates to the complexity of the exposure pathways involved. Diversity It is impossible to overstate the diversity of activities that must be included under the term "aquaculture". Although in 2000, 29 species belonging to a number of different phyla accounted for 78% of global aquaculture production, the farming of an additional 180 different aquatic animal and plant species was also reported. This vast range of species is reflected in the diversity of culture systems used in aquaculture. From the perspective of microbial ecology the diversity is just as great. Temperatures encountered in aquaculture can vary over at least a 30°C range and salinity can vary from 40 g/l to 0. The nutrient levels in aquaculture systems also vary over a wide range. Some systems operate with pure spring water whilst, at the other end of the spectrum, some involve the deliberate eutrophication of the water. Equally systems vary with respect to their exposure to bacteria present in human or animal wastes. The socioeconomic environments within which aquaculture operates also vary over the full range found in the world. The bulk of aquacultural production occurs in Asia, often in LIFDC’s where it plays a major role in meeting subsistence nutritional requirements, as a vital source of employment, profit and of foreign exchange earnings. Aquaculture is also practiced in the developed world where it is often run by sophisticated multinational companies. Thus, the scientific and technical infrastructure available to aquaculture producers and the regulatory environments within which they operate show wide variations. Treating aquaculture, and therefore antimicrobial agents use in aquaculture, as a single category has the automatic result that only very broad generalizations can be made. 36 Paucity of information Antimicrobial use Amounts of antimicrobials used in aquaculture In general it has been difficult to obtain accurate data on antimicrobial agent use in aquaculture. However, estimates can be offered for some European countries. In Norway, which has been collecting accurate statistics for some years, and in Sweden, recent estimates suggest that approximately 2 g of antimicrobials were used per tonne of aquaculture product. Data from the UK would suggest an aquaculture usage of 10-20 g/t and those from Denmark, France and Greece would indicate a slightly higher use of between 40 - 100 g/t. With respect to Canada and Chile, best estimates (157 g/t and >200 g/t respectively) would suggest that usage is higher than in most European countries. Data from Asia, where the vast majority of aquacultural production takes place, has been even more difficult to obtain. However, an indirect estimate of usage in Viet Nam would suggest a figure of 700 g/t. This might suggest that European data would provide a poor guide to usages in other countries. Range of antimicrobials used in aquaculture In countries such as those of Europe and northern America, where licensing and regulation of the use of antimicrobials are strictly enforced and where use is always under veterinary guidance, it would be typical that 2-4 agents would be available to aquaculture. Those most commonly licensed would be oxytetracycline, trimethoprim-sulfadiazine (or ormetoprim/sulfadimethoxine in American countries), oxolinic acid and/or flumequine, and florfenicol. It is probable that, in these countries, off-label use will only be involved in a small minority of administrations. In highly-regulated countries, low sales volumes and high cost of licensing have already resulted in companies deciding not to renew their licenses and to withdraw their compounds from the market, thereby further reducing the therapeutic option open to veterinarians to treat fish diseases. This high degree of regulation occurs in countries that account for only a small percentage of world aquaculture production. In contrast, licensing, enforcement of regulations (where they exist) and use under veterinary guidance is less common in those countries that account for the vast bulk of world aquaculture production and an even greater proportion of antimicrobial agent use in aquaculture. The unregulated nature of use in these countries precludes any accurate identification of the agents used. It should also be noted that in many of these countries the lack of regulation also extends to the use of antimicrobials in human and veterinary medicine. Rationale and style of administrations In some systems antimicrobial agents are almost exclusively administered in feed; in others, administration via water is common. Again a wide variation is seen in the rationale for antimicrobial use. At one end of the spectrum antimicrobials are used only in response to epizootics and then only under veterinary prescription and after diagnosis and susceptibility tests have been performed. At the other end of the spectrum antimicrobials are used in an ad hoc manner and selection of agents is made based on price and availability in an unregulated market. It was the opinion of many with experience in the field that, in all countries, the use of antimicrobials was more common in small production units with no or low knowledge and advice in fish pathology and therapeutics. Fate of antimicrobials 37 The extent and quality of the data on the fate of antimicrobial agents used in aquaculture again shows extreme variation. Adequate data is available for marine salmonid farms and these indicate that the distribution is local and transitory. In under-farm sediments, where the maximal concentrations occur, these may not reach levels capable of exerting selection for resistance. Concentration is the water bodies leaving farms are also unlikely to reach selective levels. In contrast, little data is available concerning the fate of antimicrobials used in other aquacultural systems which are responsible for the vast majority of aquaculture production world-wide. Selection exerted by antimicrobial use There is clear evidence that the use of antimicrobials in aquaculture has been accompanied by the emergence of resistant variants of bacteria associated with fish disease. There is also ample evidence that, in these bacteria, the resistances may be encoded in plasmid located genes that can be transferred to terrestrial bacteria. Current evidence would indicate that the genes encoding resistance in aquatic bacteria are similar to those encountered in terrestrial bacteria. There are also extensive data demonstrating that the presence of bacteria resistant to many antimicrobials occur with high frequencies in many aquatic environments. Evidence that antimicrobial use in aquaculture has exerted a selective pressure for the enrichment of resistance variants in terrestrial or aquatic bacteria present in the environment of farms is less convincing. The very few studies that have adequately addressed the complex methodological problems and that have included adequate controls provide contradictory evidence as to the extent of any selective pressure on these bacteria. Aquatic animals do not have a commensal intestinal microflora of the type encountered in land-based animals. This may account for the conflicting evidence as to whether there is even any selection for resistant variants in the intestines of fish receiving oral therapy. At present, there are no data that demonstrate selective enrichment, in the environment of aquaculture facilities, of bacteria possessing resistance genes. Examination of scientific literature reveals a very significant shortage of data on the extent to which antimicrobial agents use in aquaculture result in the enrichment of bacteria possessing resistance to those agents. Hazards and exposure pathways The adverse health effects that might occur in humans as a result of antimicrobial use in aquaculture are those associated with residues in the food produced or with resistance in bacteria associated with human disease. Resistance in bacteria associated with human disease may arise either directly via enrichment for these bacteria in the aquaculture environment or indirectly via the enrichment for genes that encode such resistance and which may subsequently be transferred to bacteria associated with human disease. Residues The pathways by which antimicrobial residues in aquaculture products may pass to human are direct and for the purposes of risk analysis relatively easy to model. It should be noted that no case of an adverse reaction resulting from the consumption of aquacultural products contaminated with residues has ever been reported. It should also be noted that market forces 40 same strategies as used in other areas of animal production are employed, including the application of antimicrobial agents. The most common fish infections treated with antimicrobials are skin ulcers and septicaemia. The use of antimicrobials in aquaculture differs to how they are used in people and terrestric animals. In aquaculture, antimicrobials are often added to the feed, which is then placed in the water where the fish are kept, or antimicrobials may be added directly to the water. These practices result in a selective pressure in the exposed environments (mainly water). Consequently, the use of antimicrobials in aquaculture results in a broad environmental application impacting a wide variety of bacteria. Aquatic bacteria are not different from other bacteria in their responses to exposure to antimicrobials. Genetic mobility is just as common and widespread in this ecological environment as in others. Furthermore, there is overlap between the various ecological niches, including aquaculture and human environments, which means that bacteria and the resistance genes they contain may circulate between these different environments. Thus, addressing risks in relation to aquaculture requires a holistic approach. Many antimicrobials used in human medicine are also applied in aquaculture. Table 1 summarizes the main antimicrobials that are used in aquaculture worldwide and their importance in human medicine as identified during the WHO Expert Consultation on Critically Important Antibacterial Agents for Human Medicine for Risk Management Strategies of Non- Human Use, in Canberra, Australia, in 2005 (WHO 2005). Table 1: Major antimicrobial drugs (and classes) used in aquaculture Drug (and class) Administration Importance of antimicrobial classes in human medicine Amoxicillin (aminopenicillins) Oral Critically important Ampicillin (aminopenicillins) Oral Critically important Chloramphenicol (amphenicols) Oral/bath/injection Important Florfenicol (amphenicols) Oral Important 1) Erythromycin (macrolides) Oral/injection/bath Critically important Streptomycin, neomycin (aminoglycosides) Bath Critically important Furazolidone (nitrofurans) Oral/bath Important Nitrofurantoin (nitrofurans) Oral Important Oxolinic acid (quinolones) Oral Critically important 1) Enrofloxacin (fluoroquinolones) Oral, bath Critically important 1) Flumequine (fluoroquinolone) Oral Critically important 1) Oxytetracycline, chlortetracycline, tetracycline (tetracyclines) Oral/bath/injection Highly important Sulphonamides, (sulphonamides) Oral Important N.B. These drug classes were defined in the report of the Canberra meeting. However, some of the individual drugs were not specifically mentioned as those drugs are not used in humans. Other antimicrobials in the same class, however, are used in humans. Resistance to all members of the class will result from their use if resistant bacteria develop. Assessment of the risks associated with antimicrobial use in aquaculture 41 Hazard identification The public health hazards related to antimicrobial use in aquaculture include the development and spread of antimicrobial resistant bacteria, the occurrence of antimicrobial residues in aquaculture products, and a negative impact on the environment. Development and spread of antimicrobial resistant bacteria Today, development and spread of antimicrobial resistance has become a global public health problem that is impacted by both human and non-human antimicrobial usage (OIE/FAO/WHO 2004a). It is generally acknowledged that any use of antimicrobial agents can select for the emergence of antimicrobial resistant microorganisms and further promote the dissemination of resistant bacteria and resistance genes (OIE/FAO/WHO 2004a). Furthermore, resistance neither respects phylogenetical, geographical nor ecological borders. Thus, use of antimicrobials in one ecological niche, such as in aquaculture, can have impact on the occurrence of antimicrobial resistance in another ecological niche, such as human medicine. Antimicrobial resistant bacteria in aquaculture present a risk to public health owing to either: • Development of acquired resistance in fish pathogens and other aquatic bacteria whereby such resistant bacteria can act as a reservoir of resistance genes from which genes can be further disseminated and ultimately end up in human pathogens (e.g. the spread of a resistance genes from Aeromonas spp. to E. coli). This can be viewed as an indirect spread of resistance from aquatic environments to humans caused by horizontal gene transfer. • Development of acquired resistance in aquatic bacteria able to infect humans. This can be regarded as a direct spread of resistance from aquatic environments to humans. Indirect spread of resistance by horizontal gene transfer Development and spread of antimicrobial resistance as a consequence of exposure to antimicrobial agents is well documented in both human medicine and veterinary medicine. It is also well documented that fish pathogens and other aquatic bacteria can develop resistance as a consequence of antimicrobial exposure (Sørum 2006). Examples include Aeromonas salmonicida, Aeromonas hydrophila, Edwardsiella tarda, Citrobacter freundii, Yersinia ruckeri, Photobacterium damselae subsp. piscicida, Vibrio anguillarum, Vibrio salmonicida, Photobacterium psychrophilum and Pseudomonas fluorescens. For example Aeromonas salmonicida, which causes disease in fish of temperate and colder areas, easily develop resistance when exposed to antimicrobials. Acquired sulfonamide resistance in Aeromonas salmonicida was reported in 1955 in USA, and in the 1960s multiresistant strains were observed in Japan. Later on, multiresistant Aeromonas salmonicida have been described by many countries in various parts of the world, and transferable resistance plasmids are commonly detected in these strains (Sørum 2006). Typical transferable resistance determinants among Aeromonas salmonicida are those conferring resistance to sulphonamide, tetracycline, trimethoprim, and streptomycin. The use of quinolones in aquaculture in the control of bacterial infections from the 1980s resulted in the development of quinolone resistance in strains of Aeromonas salmonicida. This resistance was mainly mediated by mutation in the gyrase A gene (gyrA). So far genes resulting in quinolone 42 resistance in bacteria associated with fish have not been shown to be transferable (Sørum 2006). Development of resistance by shrimp pathogens such as Vibrio harveyi due to exposure to antimicrobials has also been reported (Karunasagar et al., 1994). Resistance to norfloxacin, oxolinic acid, trimethoprim and sulphamethoxasole was found to be high in bacteria in mud samples from shrimp farming locations in Viet Nam, and Bacillus and Vibrio were predominant among bacteria resistant to antimicrobials (Lee et al., 2005). A high prevalence of resistance to sulphonamide in bacteria from shrimp hatcheries in India was reported by Otta et al (2001). The fact that the bacteria responsible for infections in fish often belong to bacterial families that also cause infections in humans increases the probability of spread from aquaculture to humans. Several studies have demonstrated that plasmids harbouring resistance determinants are often transferable from fish pathogens and aquatic bacteria to not only other bacteria within the same genus, but also to E. coli. For example, multi-resistance plasmids have been shown to be transferable to E. coli from Aeromonas salmonicida, Aeromonas hydrophila, Edwardsiella tarda, Citrobacter freundii, Photobacterium damselae subsp. piscicida, Vibrio anguillarum, and Vibrio salmonicida (Sørum 2006). A large multi-resistance plasmid conferring resistance to six antimicrobials was shown to be transferable from Vibrio cholerae O1 to A. salmonicida, A. hydrophila, V. parahaemolyticus, V. cholerae, V. anguillarum, Shigella spp., Salmonella spp. and E. coli (Kruse 1995). Plasmids with varying resistance genes have been transferred in vitro from fish pathogens to human pathogens, including Vibrio cholerae and Vibrio parahaemolyticus (Angulo 1999). A 21kb plasmid coding for resistance to cephalothin that could be transferred to E. coli was isolated from Vibrio strains from shrimp ponds (Molina-Aja et al., 2002). Furushita et al. (2003) noted that genes coding for tetracycline resistance in fish farm bacteria and human clinical isolates in Japan showed high similarity suggesting that they may be derived from the same source. Further, in laboratory experiments, transfer of tetracycline resistance from marine strains of Photobacterium, Vibrio, Altromonas and Pseudomonas could be transferred to E. coli by conjugation suggesting that transfer of resistance from marine bacteria to bacteria associated with the human gut is possible. The transfer of resistance plasmids between fish pathogens and other aquatic bacteria illustrates that these bacteria can act as reservoirs of antimicrobial resistance genes that can be further disseminated and ultimately reach human pathogens, and thereby add to the burden of antimicrobial resistance in human medicine. Molecular characterization supports the suggestion that some of the antimicrobial resistance determinants in multiresistant Salmonella Typhimurium DT104 may have emerged, perhaps in Asia, in the early 1980s in aquaculture and were transferred horizontally to DT104 (Angulo et al. 2000). Tetracycline resistance in MR DT104 is due to a class G resistance gene. The class G resistance determinant is rare and had not previously been reported from Salmonella isolates. It was first identified in 1981 in tetracycline resistant isolates of Vibrio anguillarum. Chloramphenicol resistance in MR DT104 is encoded by a flo-like gene that confers resistance to both chloramphenicol and florfenicol. Flo was first identified in Pasteurella piscicida, the causative agent of pseudotuberculosis, a common disease of marine fish in Asia. Florfenicol was evaluated as a therapeutic agent in fish in the early 1980s. Kim and Aoki (Kim E.H., 1994) reported the emergence of florfenicol resistant strains of Pasteurella piscicida due to the acquisition of transferable resistance plasmids containing the flo-gene, in addition to other antimicrobial resistance marker genes (ampicillin, kanamycin, sulphonamides, tetracycline). Furthermore, nucleotide sequence analysis of the DNA region in MR DT104 containing the florfenicol resistance gene and two tetracycline resistance genes showed a 94% similarity to a sequence found in a plasmid from P. piscicida (Sørum 2006). In bovine E. coli, a florfenicol 45 (Graslund et al.2003), showed that a large proportion of shrimp farmers along the Thai coast used antimicrobials in their farms. Of the 76 farmers interviewed, 74% used antimicrobials in shrimp pond management. Most farmers used them prophylactically, some on a daily basis. At least 13 different antimicrobials were used. The authors concluded that a more restrictive use of antimicrobials could have positive effects for the individual farmer and simultaneously decrease impacts on regional human medicine and adjacent coastal ecosystems. Although data are limited on antimicrobial use in Asia, available evidence indicate that countries in Asia with large aquaculture sectors use very large amounts of antimicrobials in aquaculture often without veterinary or other professional supervision, and often purchase directly from drug company salespersons without regulatory oversight. In contrast, available evidence indicates that in Europe and North America, use of antimicrobials in aquaculture is well regulated. In a study of ready-to-eat shrimp (Dura N 2005), 13 brands from four countries were obtained from local grocery stores. A total of 1564 isolates representing 162 bacterial species were recovered during screening of resistance to 10 antimicrobials. 42% of the isolates and 81% of the species had acquired resistance to antimicrobials. Numerous resistant human pathogens were isolated, including Escherichia coli, Enterococcus spp., Salmonella, Shigella flexneri, Staphylococcus spp., and Vibrio spp. Ready-to-eat shrimp is sold with instructions to thaw the product before serving and without the need for cooking, which is likely to result in consumer exposure to antimicrobial resistant bacteria. The authors concluded that widespread trade of this product provides an avenue for international dissemination of antimicrobial resistant pathogens. Antimicrobial residues The public health risk associated with antimicrobial residues depends on the quantity of the antimicrobial encountered or consumed, i.e. the exposure. In general, the lower the exposure, the lower the risk. In a FAO/OIE/WHO consultation on scientific issues related to non-human usage of antimicrobials held in Geneva, in December 2003, it was concluded that residues of antimicrobials in foods, under present regulatory regimes, represents a significantly less important human health risk than the risk related to antimicrobial resistant bacteria in food. The use of water and food as the administration route helps to obtain a uniform dose and avoid high localized concentration that might arise from use of injection. In most countries where antimicrobials are licensed for use in aquaculture, withdrawal times that ensure safety to the consumers are set. Non-compliance with these withdrawal times presents a risk to public health. Risk characterization The greatest risk to public health associated with antimicrobial use in aquaculture is the development of a reservoir of transferable resistance genes in fish pathogens and other aquatic bacteria. From these bacteria such genes can disseminate by horizontal gene transfer to other bacteria and ultimately reach human pathogens. Horizontal gene transfer to human pathogens may occur in the aquaculture environment, in the food chain, or in the human intestinal tract. When human pathogens are antimicrobial resistant this can cause treatment problems. The risk of horizontal gene transfer from fish pathogens and other aquatic bacteria ultimately to human pathogens is considered significant and of large magnitude. Therefore efforts are needed to prevent such development and spread of resistance genes. 46 The second greatest risk associated with antimicrobial use in aquaculture is the development of resistance in aquatic bacteria that are pathogenic for people and these resistant pathogenic bacteria are ultimately transferred to humans. In contrast to aquaculture, in terrestrial food producing animals (cattle, chickens, pigs, turkeys), transfer of resistant pathogenic bacteria, such as Salmonella, to humans is a more important risk than horizontal gene transfer. Antimicrobial residues under current regulatory regimes represent a smaller, but still significant public health risk. It is important that efforts are made to ensure that regulations that prevent residues are complied with and enforced. Risk management options Prevention and control of infectious diseases in aquaculture The most effective means to prevent development and spread of antimicrobial resistance is to reduce the need for antimicrobial treatment (Haastein 2000). The main components of disease prevention and control may be summarised as follows: • legal basis for disease control in aquatic animals; • highly qualified personnel at the aquaculture, laboratory and administrative level; • stocking programmes and management practices to avoid disease outbreaks; • disease prevention techniques to avoid the introduction of pathogens; • control measures if disease occurs; • eradication of certain pathogens from a facility and, if possible, from wild stocks. An important measure in relation to disease prevention is the introduction of vaccines. Today, vaccines are available for many of the major infectious disease agents in aquaculture, and by the application of such vaccine the need for antimicrobials can be reduced substantially. In Norway, introduction of effective vaccines as well as improved health management had a major impact on antimicrobial consumption. The annual usage of antimicrobial agents in farmed fish declined by 98% from 1987 to 2004 (Figure 1). 47 Regulatory control of antimicrobial usage Countries should have a regulatory approval and control system for all antimicrobial agents and products containing antimicrobial agents used in animals, including aquaculture. Such a system could include, but not be limited to, listing of all available antimicrobial agents in the country and an approval mechanism. A pre-licensing safety evaluation of antimicrobials to be used in aquaculture with consideration of potential resistance to antimicrobials used in human medicine is important. Data show that when there is no regulatory control of antimicrobial use in aquaculture, farmers tend to use any antibiotic they might obtain (Hernandez 2005). It is recommended that antimicrobial usage, also in aquaculture, be under obligatory prescriptions. Implementation of prudent use guidelines Development and implementation of guidelines on prudent use of antimicrobials to veterinarians and other professionals prescribing antimicrobials as well as to those working in the aquaculture industry is essential. The WHO Global Principles for the Containment of Antimicrobial Resistance in Animals Intended for Food (Global Principles) provide a framework of recommendations to reduce the overuse and misuse of antimicrobials in food animals for the protection of human health. The Global Principles were developed with the participation of FAO and OIE, as part of a comprehensive WHO Global Strategy for the Containment of Antimicrobial Resistance and are available at http://www.who.int/emc/diseases/zoo/who_global_principles/index.htm Figure 1. Antimicrobial Usage vs Salmon and Trout Production in Norway 0 100 000 200 000 300 000 400 000 500 000 600 000 700 000 1981 1984 1987 1990 1993 1996 1999 2002 Vo lu m e (to ns w fe ) 0 10 000 20 000 30 000 40 000 50 000 60 000 A nt ib io tic s (k g ac tiv e su bs ta nc e) Volume salmon and trout Consumption antibiotics 50 World Health Organization, 2000. WHO Global principles for the containment of antimicrobial resistance in animals intended for food. Report of a WHO Consultation with the participation of the Food and Agriculture Organization of the United Nations and the Office International des Epizooties. Geneva, Switzerland, 5-9 June 2000. http://whqlibdoc.who.int/hq/2000/WHO_CDS_CSR_APH_2000.4.pdf 51 Annex 4 WHO GLOBAL PRINCIPLES FOR THE CONTAINMENT OF ANTIMICROBIAL RESISTANCE IN ANIMALS INTENDED FOR FOOD Report of a WHO Consultation with the participation of the Food and Agriculture Organization of the United Nations and the Office International des Epizooties Geneva, Switzerland, 5-9 June 2000 Full report available at : http://www.who.int/emc/diseases/zoo/who_global_principles/index.htm). Purpose To minimize the negative public health impact of the use of antimicrobial agents in food- producing animals while at the same time providing for their safe and effective use in veterinary medicine. General National governments should adopt a proactive approach to reduce the need for antimicrobials in animals and their contribution to antimicrobial resistance and to ensure their prudent use (including reducing overuse and misuse), as elements of a national strategy for the containment of antimicrobial resistance. Relevant authorities should develop strategies that reduce the actual and potential risk to public health from antimicrobial-resistant bacteria and resistance genes, prolong the efficacy of veterinary antimicrobial products, ensure the maintenance of animal health, and establish systems for controls and interventions to ensure compliance with the developed strategies and regulations on the use of antimicrobials. Responsibilities of regulatory and other relevant authorities. A. Pre- and post-approval Decisions concerning the licensing of veterinary antimicrobial substances should consider the impact on human health of antimicrobial resistance developing in food animals in which antimicrobials have been used. No antimicrobial should be administered to animals unless it has been evaluated and authorized for such use by relevant authorities. Exceptionally, where no antimicrobial drug for use in a species or for a specific indication is authorized, or an authorized product is demonstrated to be no longer effective, then a product authorized for another indication or other species may be used under direct supervision of a veterinarian. However, relevant authorities which regulate extra label use of antimicrobials in food animals should consider restricting such use of those drugs deemed highly important in human medicine. The authorization of veterinary antimicrobial products should take account of data on antimicrobial resistance among relevant bacterial strains and should ensure that recommended dosages are optimal for therapy, taking into consideration pharmacokinetics, clinical efficacy, residues, and, if available, other relevant data in order to minimize the development of 52 resistance. Existing product labelling should also be reviewed, when necessary, by regulatory authorities to ensure that the recommended dose and duration of use are consistent with current knowledge of efficacy, antimicrobial resistance, pharmacokinetics, pharmacodynamics and prudent use. A risk-based evaluation of the potential human health effects of all uses of antimicrobial drugs in food producing animals should be conducted, including currently approved products. In the evaluation of currently approved products, priority should be given to those products considered most important in human medicine. Characterization of the risk should include consideration of the importance of the drug or members of the same class of drug to human medicine, the potential exposure to humans from antimicrobial-resistant bacteria and their resistance genes from food animals, as well as other appropriate scientific factors. Those antimicrobials judged to be essential for human medicine should be restricted and their use in food animals should be justified by culture and susceptibility results. Decisions regarding registration of antimicrobials for use in food animals should be based on scientific data and, unless otherwise justified, should include the potential rate and extent of resistance in relevant bacteria associated with the proposed use in food animals in the pre- approval evaluation. Post-approval surveillance is indispensable and surveillance of resistance to antimicrobials belonging to classes considered important in human medicine should be closely monitored so as to be able to detect emergence of antimicrobial resistance in time to allow corrective strategies to be implemented as part of an efficient post-licensing review. Post-approval surveillance of antimicrobial resistance should include identification of the appropriate bacteria and methods of collection. Relevant antimicrobials to be included in such post-approval surveillance programmes should be guided by a risk-based priority list under the direction of the relevant authority. The methods and data should be made publicly available. Such surveillance may be carried out with the participation of the veterinary pharmaceutical industry. Epidemiological and/or experimental investigations to identify risk factors may be needed if resistance increases above levels of concern, and proportionally incremental mitigation strategies*, such as education, infection control, labelling changes, changes in dosing and duration of use, should then be implemented. If, and when the ongoing assessment of the risk demonstrates it to be unacceptable, withdrawal of an antimicrobial for veterinary use from the market should be considered. Relevant authorities should ensure that all antimicrobials for disease control in animals are classified as prescription-only medicines unless, under exceptional circumstances, veterinary advice is not available and alternative means of disease control must be facilitated. Under such exceptional circumstances, relevant authorities should take steps to ensure that veterinary advice becomes available in the future. B. Quality/Manufacturing Antimicrobial products, including generic products, should be manufactured in accordance with the current good manufacturing practices (GMP) and following the specifications laid out * increasingly strict measures proportional to the risk identified 55 Antimicrobials should be prescribed only when indicated, using antibiotics directed against the causative agent/s, given in optimal dosage, dosage intervals and length of treatment to ensure maximum concordance with the treatment regimen. It is the responsibility of the producers to ensure that production systems promote animal health and welfare. Antimicrobial usage, if necessary, should always be a part of, not a replacement for, an integrated animal health programme. Such a programme is likely to involve hygiene and disinfection procedures, bio-security measures, management alterations, changes in stocking rate, vaccination and other relevant components. Veterinarians together with producers should be jointly responsible for the health of animals on the farm. Veterinarians and producers should agree on policies and protocols on preventive strategies, health and treatment programmes and veterinary involvement in ongoing animal health management. These policies and protocols should comply with prudent use principles, good farming practice, and quality assurance programmes. Prophylactic use of antimicrobials Use of antimicrobials for prevention of disease can only be justified where it can be shown that a particular disease is present on the premises or is likely to occur. The routine prophylactic use of antimicrobials should never be a substitute for good animal health management. Prophylactic use of antimicrobials in control programmes should be regularly assessed for effectiveness and whether use can be reduced or stopped. Efforts to prevent disease should continuously be in place aimed at reducing the need for the prophylactic use of antimicrobials. Education and training Veterinary undergraduate, postgraduate and continuing education should be evaluated to en- sure that preventive medicine, prudent antimicrobial use and antimicrobial resistance are given high priority. Ongoing education strategies should be developed by entities such as professional associations, relevant authorities, appropriate international organizations and/or educational institutions to provide relevant professional bodies and stakeholders with appropriately targeted information about infections, the role and benefits of prudent antimicrobial use and the risks of inappropriate use. All relevant stakeholders including the veterinary pharmaceutical industry and public health sectors should be encouraged to support this effort. Continuous evaluation of the effectiveness of educational strategies for prudent use should be conducted. Education strategies emphasizing the importance and benefits of prudent use principles must be developed and implemented to provide relevant information on antimicrobial resistance for producers and stakeholders. Emphasis must also be given to the importance of optimizing animal health through implementation of disease prevention programmes and good management practices. The public should be informed of the human health aspects of antimicrobial use in food animals, so that they can support efforts to control antimicrobial resistance. 56 Research Stakeholders should identify research priorities to address public health issues of antimicrobial resistance from antimicrobial use in food animals. Governments, universities, research foundations and industry should give high priority to supporting research in these areas. 57 Annex 5 GUIDELINES FOR THE RESPONSIBLE AND PRUDENT USE OF ANTIMICROBIAL AGENTS IN VETERINARY MEDICINE ( International Animal Health Code - 2006 APPENDIX 3.9.3.) Article 3.9.3.1. Purpose These guidelines provide guidance for the responsible and prudent use of antimicrobial agents in veterinary medicine, with the aim of protecting both animal and human health. The Competent Authorities responsible for the registration and control of all groups involved in the production, distribution and use of veterinary antimicrobials have specific obligations. Prudent use is principally determined by the outcome of the marketing authorisation procedure and by the implementation of specifications when antimicrobials are administered to animals. Article 3.9.3.2. Objectives of prudent use Prudent use includes a set of practical measures and recommendations intended to prevent and/or reduce the selection of antimicrobial-resistant bacteria in animals to: 1. maintain the efficacy of antimicrobial agents and to ensure the rational use of antimicrobials in animals with the purpose of optimising both their efficacy and safety in animals; 2. comply with the ethical obligation and economic need to keep animals in good health; 3. prevent, or reduce, as far as possible, the transfer of micro-organisms (with their resistance determinants) within animal populations; 4. maintain the efficacy of antimicrobial agents used in food-producing animals; 5. prevent or reduce the transfer of resistant micro-organisms or resistance determinants from animals to humans; 6. maintain the efficacy of antimicrobial agents used in human medicine and prolong the usefulness of the antimicrobials; 7. prevent the contamination of animal-derived food with antimicrobial residues that exceed the established maximum residue limit (MRL); 8. protect consumer health by ensuring the safety of food of animal origin with respect to residues of antimicrobial drugs, and the ability to transfer antimicrobial drug resistant micro-organisms to humans. Article 3.9.3.3. Responsibilities of the regulatory authorities 1. Marketing authorisation The national regulatory authorities are responsible for granting marketing authorisation. This should be done in accordance with the provisions of the Terrestrial Code. They have a significant role in specifying the terms of this authorisation and in providing the appropriate information to the veterinarian. 2. Submission of data for the granting of the marketing authorisation The pharmaceutical industry has to submit the data requested for the granting of the marketing authorisation. The marketing authorisation is granted only if the criteria of safety, quality and efficacy are met. An assessment of the potential risks and benefits to both animals and humans resulting from the use of antimicrobial agents in food-producing animals should be carried out. The evaluation should focus on each individual antimicrobial product and the findings not be generalised to the class of antimicrobials to which the particular active principle belongs. 60 i. the MRL established for the antimicrobial agent under consideration; ii. the composition of the product and the pharmaceutical form; iii. the target animal species; iv. the dosage regimen and the duration of treatment; v. the route of administration. d. The applicant should provide methods for regulatory testing of residues in food. 9. Protection of the environment An assessment of the impact of the proposed antimicrobial use on the environment should be conducted. Efforts should be made to ensure that the environmental impact of antimicrobial use is restricted to a minimum. 10. Establishment of a summary of product characteristics for each veterinary antimicrobial product (VAP) The summary of product characteristics contains the information necessary for the appropriate use of VAPs and constitutes the official reference for their labelling and package insert. This summary should contain the following items: a. active ingredient and class; b. pharmacological properties; c. any potential adverse effects; d. target animal species and age or production category; e. therapeutic indications; f. target micro-organisms; g. dosage and administration route; h. withdrawal periods; i. incompatibilities; j. shelf-life; k. operator safety; l. particular precautions before use; m. particular precautions for the proper disposal of un-used or expired products; n. information on conditions of use relevant to the potential for selection of resistance. o. 11. Post-marketing antimicrobial surveillance The information collected through existing pharmacovigilance programmes, including lack of efficacy, should form part of the comprehensive strategy to minimise antimicrobial resistance. In addition to this, the following should be considered: a. General epidemiological surveillance The surveillance of animal micro-organisms resistant to antimicrobial agents is essential. The relevant authorities should implement a programme according to the Terrestrial Code. b. Specific surveillance 61 Specific surveillance to assess the impact of the use of a specific antimicrobial may be implemented after the granting of the marketing authorisation. The surveillance programme should evaluate not only resistance development in target animal pathogens, but also in food-borne pathogens and/or commensals. Such surveillance will also contribute to general epidemiological surveillance of antimicrobial resistance. 12. Supply and administration of the antimicrobial agents used in veterinary medicine The relevant authorities should ensure that all the antimicrobial agents used in animals are: a. prescribed by a veterinarian or other authorised person; b. supplied only through licensed/authorised distribution systems; c. administered to animals by a veterinarian or under the supervision of a veterinarian or by other authorised persons; The relevant authorities should develop effective procedures for the safe collection and destruction of unused or expired VAPs. 13. Control of advertising All advertising of antimicrobials should be controlled by a code of advertising standards, and the relevant authorities must ensure that the advertising of antimicrobial products: a. complies with the marketing authorisation granted, in particular regarding the content of the summary of product characteristics; b. is restricted to authorised professionals, according to national legislation in each country. 14. Training of antimicrobial users The training of users of antimicrobials should involve all the relevant organisations, such as regulatory authorities, pharmaceutical industry, veterinary schools, research institutes, veterinary professional organisations and other approved users such as food-animal owners. This training should focus on: a. information on disease prevention and management strategies; b. the ability of antimicrobials to select for resistance in food-producing animals; c. the need to observe responsible use recommendations for the use of antimicrobial agents in animal husbandry in agreement with the provisions of the marketing authorisations. 15. Research The relevant authorities should encourage public- and industry-funded research. Article 3.9.3.4. Responsibilities of the veterinary pharmaceutical industry 1. Marketing authorisation of VAPs The veterinary pharmaceutical industry has responsibilities to: a. supply all the information requested by the national regulatory authorities; b. guarantee the quality of this information in compliance with the provisions of good manufacturing, laboratory and clinical practices; c. implement a pharmacovigilance programme and on request, specific surveillance for bacterial susceptibility and resistance. 2. Marketing and export of VAPs For the marketing and export of VAPs: 62 a. only licensed and officially approved VAPs should be sold and supplied, and then only through licensed/authorised distribution systems; b. the pharmaceutical industry should provide quality certificates prepared by the Competent Authority of the exporting and/or manufacturing countries to the importing country; c. the national regulatory authority should be provided with the information necessary to evaluate the amount of antimicrobial agents marketed. 3. Advertising The veterinary pharmaceutical industry should: a. disseminate information in compliance with the provisions of the granted authorisation; b. ensure that the advertising of antimicrobials directly to the food animal producer is discouraged. 4. Training The veterinary pharmaceutical industry should participate in training programmes as defined in point 14 of Article 3.9.3.3. 5. Research The veterinary pharmaceutical industry should contribute to research as defined in point 15 of Article 3.9.3.3. Article 3.9.3.5. Responsibilities of wholesale and retail distributors 1. Retailers distributing VAPs should only do so on the prescription of a veterinarian or other suitably trained person authorised in accordance with national legislation, and all products should be appropriately labelled. 2. The guidelines on the responsible use of antimicrobials should be reinforced by retail distributors who should keep detailed records of: a. date of supply; b. name of prescriber; c. name of user; d. name of product; e. batch number; f. quantity supplied. 3. Distributors should also be involved in training programmes on the responsible use of antimicrobials, as defined in point 14 of Article 3.9.3.3. Article 3.9.3.6. Responsibilities of veterinarians The concern of the veterinarian is to promote public health and animal health and welfare. The veterinarian’s responsibilities include preventing, identifying and treating animal diseases. The promotion of sound animal husbandry methods, hygiene procedures and vaccination strategies (good farming practice) can help to minimise the need for antimicrobial use in food-producing animals. Veterinarians should only prescribe antimicrobials for animals under their care. 1. Use of antimicrobial agents The responsibilities of veterinarians are to carry out a proper clinical examination of the animal(s) and then: 65 viii. result of laboratory tests; ix. effectiveness of therapy; k. inform the responsible veterinarian of recurrent disease problems. 66 Annex 6 CODEX CODE OF PRACTICE TO MINIMISE AND CONTAIN ANTIMICROBIAL RESISTANCE CAC/RCP 61-2005 INTRODUCTION ................................................................................................................................... AIMS AND OBJECTIVES ..................................................................................................................... RESPONSIBILITIES OF THE REGULATORY AUTHORITIES ................................................... Quality Control of veterinary antimicrobial drugs ........................................................................ Assessment of efficacy .................................................................................................................. Assessment of the potential of veterinary antimicrobial drugs to select for resistant microorganisms ......................................................................................................... Establishment of ADIs (acceptable daily intake). MRLs (maximum residue limit), and Withdrawal periods for veterinary antimicrobial drugs ................................................................ Establishment of a summary of product characteristics for each veterinary antimicrobial drug for food-producing animals............................................................ Surveillance programmes ............................................................................................................. Distribution of veterinary antimicrobial drugs in veterinary medicine ........................................ Control of advertising ................................................................................................................... Training of veterinary antimicrobial drug users ............................................................................ Development of research .............................................................................................................. Collection and destruction of unused veterinary antimicrobial drugs ........................................... RESPONSIBILITIES OF THE VETERINARY PHARMACEUTICAL INDUSTRY..................... Marketing authorisation of veterinary antimicrobial drugs for food-producing animals ............. Marketing and export of veterinary antimicrobial drugs .............................................................. Advertising ................................................................................................................................... Training ........................................................................................................................................ Research ........................................................................................................................................ RESPONSIBILITIES OF WHOLESALE AND RETAIL DISTRIBUTORS .................................... RESPONSIBILITIES OF VETERINARIANS .................................................................................... Off-label use ................................................................................................................................. Recording ...................................................................................................................................... Training ..................................................................................................................................................... RESPONSIBILITIES OF PRODUCERS ............................................................................................. CONCLUSIONS ...................................................................................................................................... Endnotes .................................................................................................................................................... List of Abbreviations ................................................................................................................................. Glossary and Definitions of Terms ........................................................................................................................... 67 INTRODUCTION 1. This document provides additional guidance for the responsible and prudent use of antimicrobials in food-producing animals, and should be read in conjunction with the Recommended International Code of Practice for Control of the Use of Veterinary Drugs CAC/RCP 38-1993. Its objectives are to minimize the potential adverse impact on public health resulting from the use of antimicrobial agents in food-producing animals, in particular the development of antimicrobial resistance. It is also important to provide for the safe and effective use of veterinary antimicrobial drugs in veterinary medicine by maintaining their efficacy. This document defines the respective responsibilities of authorities and groups involved in the authorization, production, control, distribution and use of veterinary antimicrobials such as the national regulatory authorities, the veterinary pharmaceutical industry, veterinarians, distributors and producers of food-producing animals. 2. The marketing authorization procedure has a significant role in establishing the basis for prudent use of veterinary antimicrobial drugs in food-producing animals through clear label indications, directions and warning statements. 3. A number of codes of practice relating to the use of veterinary antimicrobial drugs and the conditions thereof have been developed by different organisations. These codes were taken into consideration and some elements were included in the elaboration of this Code of Practice to Minimize and Contain Antimicrobial Resistance. 4. In keeping with the Codex mission, this Code focuses on antimicrobial use in food– producing animals. It is recognized that antimicrobial resistance is also an ecological problem and that management of antimicrobial resistance may require addressing the persistence of resistant microorganisms in the environment. Although this issue is most relevant for CCRVDF with respect to food-producing animals, the same principles apply to companion animals, which also harbor resistant microorganisms. AIMS AND OBJECTIVES 5. It is imperative that all who are involved in the authorisation, manufacture, sale and supply, prescription and use of antimicrobials in food-producing animals act legally, responsibly and with the utmost care in order to limit the spread of resistant microorganisms among animals so as to protect the health of consumers. 6. Antimicrobial drugs are powerful tools for the management of infectious diseases in animals and humans. This Code and existing guidelines for the responsible use of antimicrobial drugs in food-producing animals include recommendations intended to prevent or reduce the selection of antimicrobial resistant microorganisms in animals and humans in order to: • Protect consumer health by ensuring the safety of food of animal origin intended for human consumption. • Prevent or reduce as far as possible the direct and indirect transfer of resistant microorganisms or resistance determinants within animal populations and from food-producing animals to humans. • Prevent the contamination of animal derived food with antimicrobial residues which exceed the established MRL. • Comply with the ethical obligation and economic need to maintain animal health. 70 15. Countries without the necessary resources to implement an efficient authorisation procedure for veterinary antimicrobial drugs and whose supply of veterinary antimicrobial drugs mostly depends on imports from foreign countries should: • ensure the efficacy of their administrative controls on the import of these veterinary antimicrobial drugs, • seek information on authorizations valid in other countries, and • develop the necessary technical cooperation with experienced authorities to check the quality of imported veterinary antimicrobial drugs as well as the validity of the recommended conditions of use. Alternatively, a national authority could delegate a competent institution to provide quality certification of veterinary antimicrobial drugs. 16. All countries should make every effort to actively combat the manufacture, advertisement, trade, distribution and use of illegal and/or counterfeit bulk active pharmaceutical ingredients and products. Regulatory authorities of importing countries could request the pharmaceutical industry to provide quality certificates or, where feasible, certificates of Good Manufacturing Practices prepared by the exporting country’s national regulatory authority. Quality Control of Antimicrobial Agents 17. Regulatory authorities should ensure that quality controls are carried out in accordance with international guidance and in compliance with the provisions of good manufacturing practices, in particular: • to ensure that the quality and concentration (stability) of veterinary antimicrobial drugs in the marketed dosage form(s) is maintained and properly stored up to the expiry date, established under the recommended storage conditions. • to ensure the stability of veterinary antimicrobial drugs when they are mixed with feed or drinking water. • to ensure that all veterinary antimicrobial drugs are manufactured to the appropriate quality and purity. Assessment of Efficacy 18. Preclinical data should be generated to establish an appropriate dosage regimen necessary to ensure the efficacy of the veterinary antimicrobial drug and limit the selection of microbial resistant microorganisms. Such preclinical trials should, where applicable, include pharmacokinetic and pharmacodynamic studies to guide the development of the most appropriate dosage regimen. 19. Important pharmacodynamic information may include: • mode of action; • the spectrum of antimicrobial activity of the substance; • identification of bacterial species that are naturally resistant relevant to the use of the veterinary antimicrobial drugs; • antimicrobial minimum inhibitory and/or bactericidal concentrations; 71 • determination of whether the antimicrobial exhibits time or concentration- dependent activity or co-dependency, • evaluation of activity at the site of infection. 20. Important pharmacokinetic information may include: • bio-availability according to the route of administration; • concentration of the veterinary antimicrobial drug at the site of infection and its distribution in the treated animal; • metabolism which may lead to the inactivation of veterinary antimicrobial drugs; • excretion routes. 21. The use of fixed combinations of veterinary antimicrobial drugs should be justified taking into account: • pharmacodynamic (additive or synergistic effects towards the target microorganism); • pharmacokinetics (maintenance of the concentrations of associated antimicrobials responsible for additive or synergistic effects at the site of infection throughout the treatment period). 22. Clinical data should be generated to confirm the validity of the claimed indications and dosage regimens established during the preclinical phase. 23. Criteria to be considered include: • parameters for qualitatively and quantitatively assessing efficacy; • diversity of the clinical cases met when carrying out clinical trials; • compliance of the protocols of clinical trials with good clinical practice, such as VICH guidelines7; • eligibility of the studied clinical cases based on appropriate clinical and microbiological criteria. Assessment of the potential of veterinary antimicrobial drugs to select for resistant microorganisms 24. Where applicable, data from preclinical or clinical trials should be used to evaluate the potential for target microorganisms, foodborne and/or commensal microorganisms to develop or acquire resistance. 25. Appropriate information should be provided to support an adequate assessment of the safety of veterinary antimicrobial drugs being considered for authorisation in food-producing animals. The regulatory authorities should develop criteria for conducting such assessments and interpreting their results. Existing guidelines for antimicrobial resistance risk assessment, such as the OIE Guideline 8 may be used for more comprehensive information. The type of information to be evaluated in these assessments may include, but is not limited to, the following: 7 VICH Good Clinical Practice Guideline , http://vich.eudra.org/pdf/2000/Gl09_st7.pdf 8 Antimicrobial resistance: risk analysis methodology for the potential impact on public health of antimicrobial resistant bacteria of animal origin, http://www.oie.int/eng/publicat/rt/2003a_r20314.htm 72 • the route and level of human exposure to food-borne or other resistant microorganisms; • the degree of cross resistance within the class of antimicrobials and between classes of antimicrobials; • the pre-existing level of resistance, if available, in pathogens causing gastrointestinal infections in humans (baseline determination); • the concentration of active compound in the gut of the animal at the defined dosage level. Establishment of ADIs (acceptable daily intake), MRLs (maximum residue limit), and withdrawal periods for veterinary antimicrobial drugs 26. When setting ADIs and MRLs for veterinary antimicrobial drugs, the safety evaluation is carried out in accordance with international guidelines and should include the determination of microbiological effects (e.g., the potential biological effects on the human intestinal flora) as well as toxicological and pharmacological effects. 27. An acceptable daily intake (ADI) and a maximum residue limit (MRL) for appropriate food stuffs (i.e., meat, milk, eggs, fish and honey) should be established for each antimicrobial agent. MRLs are necessary in order that officially recognised control laboratories can monitor that the veterinary antimicrobial drugs are being used as approved. Withdrawal periods should be established for each veterinary antimicrobial drug, which make it possible to produce food in compliance with the MRLs. 28. Withdrawal periods have to be established for each veterinary antimicrobial drug by taking into account: • the MRLs established for the considered veterinary antimicrobial drug; • the pharmaceutical form; • the target animal species; • the dosage regimen and the duration of treatment; • the route of administration. Establishment of a summary of product characteristics for each veterinary antimicrobial drug for food-producing animals 29. The summary of product characteristics contains the information necessary for the appropriate use of veterinary antimicrobial drugs. It constitutes, for each veterinary antimicrobial drug, the official reference of the content of its labelling and package insert. This summary contains the following items: • pharmacological properties; • target animal species; • indications; • target microorganisms; • dosage and administration route; • withdrawal periods; 75 Development of research 37. The relevant authorities should encourage public and private research to: • improve the knowledge about the mechanisms of action of antimicrobials in order to optimise the dosage regimens and their efficacy; • improve the knowledge about the mechanisms of selection, emergence and dissemination of resistance determinants; • develop practical models for applying the concept of risk analysis to assess the public health concern precipitated by the development of resistance; • further develop protocols to predict, during the authorisation process, the impact of the proposed use of the veterinary antimicrobial drugs on the rate and extent of resistance development; and • develop and encourage alternative methods to prevent infectious diseases. Collection and destruction of unused veterinary antimicrobial drugs 38. The relevant authorities should develop effective procedures for the safe collection and destruction of unused or out-of-date veterinary antimicrobial drugs. RESPONSIBILITIES OF THE VETERINARY PHARMACEUTICAL INDUSTRY Marketing authorisation of veterinary antimicrobial drugs for food-producing animals 39. It is the responsibility of the veterinary pharmaceutical industry: • to supply all of the information requested by the national regulatory authority in order to establish objectively the quality, safety and efficacy of veterinary antimicrobial drugs; and • to ensure the quality of this information on the basis of the implementation of procedures, tests and trials in compliance with the provisions of good manufacturing, good laboratory and good clinical practices. Marketing and export of veterinary antimicrobial drugs 40. Only officially licensed/authorized veterinary antimicrobial drugs should be marketed, and then only through approved distribution systems. • Only veterinary antimicrobial drugs meeting the quality standards of the importing country should be exported from a country in which the products were produced; • The information necessary to evaluate the amount of veterinary antimicrobial drugs marketed should be provided to the national regulatory authority. 76 Advertising 41. It is the responsibility of the veterinary pharmaceutical industry to advertise veterinary antimicrobial drugs in accordance with the provisions of Paragraph 35 on the Responsibilities of the Regulatory Authorities, Control of Advertising and to not inappropriately advertise antimicrobials directly to the food animal producer. Training 42. It is the responsibility of the veterinary pharmaceutical industry to participate in the training of users of veterinary antimicrobial drugs as defined in Paragraph 36. Research 43. It is the responsibility of the veterinary pharmaceutical industry to contribute to the development of research as defined in Paragraph 37. RESPONSIBILITIES OF WHOLESALE AND RETAIL DISTRIBUTORS 44. Retailers distributing veterinary antimicrobial drugs should only do so on the prescription of a veterinarian or other suitably trained person authorized in accordance with national legislation and all products should be appropriately labelled. 45. Distributors should encourage compliance with the national guidelines on the responsible use of veterinary antimicrobial drugs and should keep detailed records of all antimicrobials supplied according to the national regulations including: • date of supply • name of prescribing veterinarian • name of user • name of medicinal product • batch number • quantity supplied 46. Distributors should participate in the training of users of veterinary antimicrobial drugs as defined in Paragraph 36. RESPONSIBILITIES OF VETERINARIANS 9 47. The veterinarian is responsible for identifying recurrent disease problems and developing alternative strategies to prevent or treat infectious disease. These may include changes in husbandry conditions and vaccination programs where vaccines are available. 48. Veterinary antimicrobial drugs should only be prescribed for animals under his/her care, which means that: 9 Under some circumstances, this may refer to a suitably trained person authorized in accordance with national legislation. 77 • the veterinarian has been given responsibility for the health of the animal or herd/flock by the producer or the producer’s agent; • that responsibility is real and not merely nominal; • that the animal(s) or herd/flock have been seen immediately before the prescription and supply, or • recently enough for the veterinarian to have personal knowledge of the condition of the animal(s) or current health status of the herd or flock to make a diagnosis and prescribe; and • the veterinarian should maintain clinical records of the animal(s) or the herd/flock. 49. It is recommended that veterinary professional organizations develop for their members species-specific clinical practice guidelines on the responsible use of veterinary antimicrobial drugs. 50. Veterinary antimicrobial drugs should only be used when necessary and in an appropriate manner: • A prescription for veterinary antimicrobial drugs must precisely indicate the treatment regimen, the dose, the dosage intervals, the duration of the treatment, the withdrawal period and the amount of antimicrobial to be delivered depending on the dosage, the number, and the weight of the animals to be treated; • All veterinary antimicrobial drugs should be prescribed and used according to the conditions stipulated in the national legislation. 51. The appropriate use of veterinary antimicrobial drugs in practice is a clinical decision which should be based on the experience and local expertise of the prescribing veterinarian, and the accurate diagnosis, based on adequate diagnostic procedures. There will be occasions when a group of animals, which may have been exposed to pathogens, may need to be treated without recourse to an accurate diagnosis and antimicrobial susceptibility testing in order to prevent the development of clinical disease and for reasons of animal welfare. 52. Determination of the choice of a veterinary antimicrobial drug by: • The expected efficacy of the treatment based on: - the clinical experience of the veterinarian; - the spectrum of the antimicrobial activity towards the pathogens involved; - the epidemiological history of the rearing unit particularly in regards to the antimicrobial resistance profiles of the pathogens involved. Ideally, the antimicrobial profiles should be established before the commencement of treatment. Should a first antimicrobial treatment fail or should the disease recur, the use of a second veterinary antimicrobial drug should be based on the results of microbiological tests; - the appropriate route of administration; - results of initial treatment; - known pharmacokinetics/tissue distribution to ensure that the selected veterinary antimicrobial drug is active at the site of infection; - prognosis. 80 - withdrawal periods; - result of laboratory tests; - result of treatment; - name of the prescribing veterinarian or other suitably trained person authorized in accordance with national legislation. • To ensure sound management of animal wastes and other materials to avoid dissemination of antimicrobial agents and resistance determinants into the environment; • To prevent the unnecessary contact with and transmission of resistant bacteria to all personnel, including farm workers; • To assist the relevant authorities in surveillance programs related to antimicrobial resistance. CONCLUSIONS 60. Veterinary antimicrobial drugs are very important tools for controlling a great number of infectious diseases in both animals and humans. It is vital that all countries put in place the appropriate systems to ensure that veterinary antimicrobial drugs are manufactured, marketed, distributed, prescribed and used responsibly, and that these systems are adequately audited. 61. This document is designed to provide the framework that countries may implement in accordance with their capabilities but within a reasonable period of time. A stepwise approach may be appropriate for a number of countries to properly implement all of the elements in this document. 62. The continued availability of veterinary antimicrobial drugs, which are essential for animal welfare and animal health and consequently human health, will ultimately depend on the responsible use of these products by all those involved in the authorisation, production, control, distribution and use of antimicrobials in food-producing animals. ______________________________ ENDNOTES: ¹A. Franklin, J. Acar, F. Anthony, R. Gupta †T. Nicholls, Y. Tamura, S. Thompson, E.J. Threlfall, D. Vose, M. van Vuuren, D.G. White, H. C. Wegener & M.L. Costarrica. Antimicrobial resistance: harmonization of national antimicrobial resistance monitoring and surveillance programmes in animals and in animal-derived food. Rev. sci. tech. Off. Int. Epiz., 20 (3), 859-870. http://www.oie.int/eng/publicat/rt/2003/a_r20318.htm ²D.G. White, J. Acar, F. Anthony, A. Franklin, R. Gupta, †T. Nicholls, Y. Tamura, S. Thompson, E.J. Threlfall, D. Vose, M. van Vuuren, H. C. Wegener & M.L. Costarrica. Antimicrobial resistance: standardization and harmonization of laboratory methodologies for the detection and quantification of antimicrobial resistance. Rev. sci. tech. Off. Int. Epiz., 2001, 20 (3), 849-858. http://www.oie.int/eng/publicat/rt/2003/a_r20317.htm 81 LIST OF ABBREVIATIONS USED IN THIS CODE ADI Acceptable Daily Intake CAC Codex Alimentarius Commission CAC/RCP Codex Alimentarius Commission/Recommended Code of Practice CCRVDF Codex Committee on Residues of Veterinary Drugs in Foods FAO Food and Agriculture Organization of the United Nations MRL Maximum Residue Limit OIE World Organisation for Animal Health VICH International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products WHO World Health Organization GLOSSARY AND DEFINITION OF TERMS Veterinary Antimicrobial Drug Veterinary antimicrobial drug(s) refers to naturally occurring, semi-synthetic or synthetic substances that exhibit antimicrobial activity (kill or inhibit the growth of microorganisms). Where anticoccidial products have antibacterial activity, they should be considered as veterinary antimicrobial drugs, except where this is precluded by national legislation. Disease Treatment/Therapeutic Use Treatment/Therapeutic Use refers to use of an antimicrobial(s) for the specific purpose of treating an animal(s) with a clinically diagnosed infectious disease or illness. Disease Prevention/Prophylactic Use Prevention/Prophylactic Use refers to use of an antimicrobial(s) in healthy animals considered to be at risk of infection or prior to the onset of clinical infectious disease. This treatment includes: • control of the dissemination of a clinically diagnosed infectious disease identified within a group of animals, and • prevention of an infectious disease that has not yet been clinically diagnosed. Growth Promotion Growth Promotion refers to the use of antimicrobial substances to increase the rate of weight gain and/or the efficiency of feed utilization in animals by other than purely nutritional means. The term does NOT apply to the use of antimicrobials for the specific purpose of treating, controlling, or preventing infectious diseases, even when an incidental growth response may be obtained. 82 Annex 7 THE CODEX CODE OF PRACTICE FOR FISH AND FISHERY PRODUCTS (CAC/RCP 52-2003, Rev. 2-2005. Sections relevant to Aquaculture CONTENTS Introduction …………………………………………….. How to use this Code …………………………………… Section 1: Scope …………………………………… Section 2: Definitions …………………………….. Section 2.2 Aquaculture ……………………….…… Section 6 Aquaculture production …………...…. Section 6.1 General …………………………..……. Section 6.2 Identification of hazards and defects ….. Section 6.3 Production operations …………………… 85 (g) Sections 9 to 16 – Processing of Specific Fish and Shellfish Products – Processors operating in particular sectors will need to consult the appropriate Section to find additional information specific to that sector*. (h) Sections 17 to 18 - Transportation and Retail cover general transportation and retail issues. Transportation and retail apply to most if not all sections for processing of specific products. They should be considered with the same care as the other processing steps*. (i) Additional information will be found in the Appendices*. SECTION 1 - SCOPE This Code of practice applies to the growing, harvesting, handling, production, processing, storage transportation and retail of fish, shellfish and aquatic invertebrates and products thereof from marine and freshwater sources, which are intended for human consumption. SECTION 2 - DEFINITIONS 2.2 AQUACULTURE Aquaculture means the farming during part or the whole of their life cycle of all aquatic animals, except mammalian species, aquatic reptiles and amphibians intended for human consumption, but excluding species covered in section 7 of this code. These aquatic animals are hereafter referred to as “fish” for ease of reference in section 2.2 and section 6. Aquaculture Establishment is any premises for the production of fish intended for human consumption, including the supporting inner infrastructure and surroundings under the control of the same management. Chemicals includes any substance either natural or synthetic which can affect the live fish, its pathogens, the water, equipment used for production or the land within the aquaculture establishment. Colouring means obtaining specifically coloured feature (e.g. flesh/shell/gonad) of a targeted organism by incorporating into the fish food a natural or artificial substance or additive approved for this purpose by the agency having jurisdiction. Diseased Fish means a fish on or in which pathological changes or other abnormalities that affect safety and quality are apparent. Extensive farming means raising fish under conditions of little or incomplete control over the growing process and production conditions where their growth is dependent upon endogenously supplied nutrient inputs. Feed Additives means chemicals other than nutrients for fish which are approved for addition to their feed. Fish farm is an aquaculture production unit (either land-or water based); usually consisting of holding facilities (tanks, ponds, raceways, cages), plant (buildings, storage, processing), service equipment and stock. Fish Feed means fodder intended for fish in aquaculture establishments, in any form and of any composition. Good Aquaculture (or Fish Farming ) are defined as those practices of the aquaculture sector that are necessary to produce quality and safe food products conforming to food laws and regulations 86 Practices Harvesting Operations involving taking the fish from the water. Intensive farming means raising fish under controlled growing process and production conditions where their growth is completely dependent on externally supplied fish feed. Official Agency Having Jurisdiction means the official authority or authorities charged by the government with the control of food hygiene (sometimes referred to as the competent authority) as well as/or with sanitation in aquaculture. Pesticide means any substance intended for preventing, destroying, attracting, repelling or controlling any pest including unwanted species of plants or animals during the production, storage, transport, distribution and processing of food, agricultural commodities, or animal feeds or which may be administered to animals for the control of ectoparasites. The term normally excludes fertilisers, plant and animal nutrients, food additives, and veterinary drugs. Pesticide Residue means any specified substance in food, agricultural commodities, or animal feed resulting from the use of a pesticide. The term includes any derivatives of a pesticide, such as conversion products, metabolites, reaction products, and impurities considered to be of toxicological significance. Residues means any foreign substances including their metabolites, which remain in fish prior to harvesting as a result of either application or accidental exposure. Semi-intensive farming means raising fish under conditions of partial control over the growing process and production conditions where their growth is dependent upon endogenously supplied nutrient inputs and externally supplied fish feed. Stocking density is the amount of fish stocked per unit of area or volume. Veterinary Drug means any substance applied or administered to any food-producing animal, such as meat or milk-producing animals, poultry, fish or bees, whether used for therapeutic, prophylactic or diagnostic purposes or for modification of physiological functions or behaviour. Withdrawal Time is the period of time necessary between the last administration of a veterinary drug to fish, or exposure of these animals to a veterinary drug, and harvesting of them to ensure that the concentration of the veterinary drug in their edible flesh intended for human consumption, complies with the maximum permitted residue limits. SECTION 6 - AQUACULTURE PRODUCTION Preamble Aquaculture establishments should operate in a responsible way such that they comply with the recommendations of the Code of Conduct for Responsible Fisheries (FAO, Rome, 1995) in order to minimize any adverse impact on human health and environment including any potential ecological changes. Fish farms should operate effective fish health and welfare management. Fry and fingerlings should be disease free and should comply with the OIE Codes of Practice (International Aquatic Animal Health Code, 6th Edition, 2003). Growing fish should be monitored for disease. When using chemicals at fish farms, special care should be exercised so that these substances are not released into the surrounding environment. Whilst the fish health, environment, and ecological aspects are important considerations in aquaculture activities, this section focuses on food safety and quality aspects. 87 This Section of the Code applies to industrialised and commercial aquaculture production, producing all aquatic animals, except mammalian species, aquatic reptiles and amphibians for direct human consumption, but excluding bivalve molluscs covered in section 7 of the code, hereafter referred to as “fish that are intended for direct human consumption. Such intensive or semi-intensive aquaculture systems use higher stocking densities, stock from hatcheries, use mainly formulated feeds and may utilise medication and vaccines. This Code is not intended to cover extensive fish farming systems that prevail in many developing countries or integrated livestock and fish culture systems. This section of the code covers the feeding, growing, harvesting and transport stages of aquaculture production. Further handling and processing of fish are covered elsewhere in the code. In the context of recognising controls at individual processing steps, this section provides examples of potential hazards and defects and describes technological guidelines, which can be used to develop control measures and corrective action. At a particular step only the hazards and defects, which are likely to be introduced or controlled at that step, are listed. It should be recognised that in preparing a HACCP and/or DAP plan it is essential to consult Section 5 which provides guidance for the application of the principles of HACCP and DAP analysis. However, within the scope of this Code of Practice it is not possible to give details of critical limits, monitoring, record keeping and verification for each of the steps since these are specific to particular hazards and defects. The following example flow diagram will provide guidance to some of the common steps in aquaculture production. The flow chart is for illustrative purpose only. For implementation of HACCP principles, a complete and comprehensive flow chart has to be drawn up for each product. References correspond to relevant Sections of the Code. Ice /Water Growing water Feed reception & storage Feed Veterinary drugs Growing/Culture Harvesting Transportation Figure 6.1 Example of a flow chart for aquaculture production Section 6.3.1 Section 6.3.3 Section 6.3.4 Section 6.1.2 Section 6.3.5 Section 6.3.8 Section 6.3.2