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CHALLENGES FACING THE PRODUCER IN THE USE OF VETERINARY PRODUCTS IN AQUACULTURE Workshop for OIE National Focal Points for Aquatic Animals, Lisbon, 9-11 April 2013 Luz Arregui Maraver President ESACUA – ADSG OP 65 ATRUGAL

Challenges facing the producer in the use of veterinary products in aquaculture

• About Veterinary Products

• Some differences between Aquaculture and other terrestrial food animals

• Legislative Framework in Europe

• Availability

• The cascade system

• Antimicrobials

• Medicated Feed

• Vaccines

• Conclusions

About Veterinary Products

• In Europe, fish oral drugs, as well as external antibacterial and antiparasitic compounds, are considered as Veterinary Medicinal Products (VMP).

• Veterinary medicines are substances intended for use to prevent or cure disease in animals. They support both the health and welfare of both food-producing animals and pets. There are 3 main types:

• Vaccines: They are made from a killed or weakened disease organism or part of it which does not cause disease when administered to the patient, but stimulates the body to produce antibodies and protective cells that can combat the disease.

• Antibiotics: These are substances that kill or inhibit the growth of bacteria. • Parasiticides: These are substances that destroy parasites, which can be either

internal or external. • Veterinary medicines are licensed.


• A licence means that veterinary medicines only reach the marketplace once their safety, quality and efficacy are clearly demonstrated, and after review by the relevant authorities.

• Each EU Member State has its own independent regulatory authority, which performs independent scientific evaluations of veterinary medicines.

• Additionally, the European Medicines Agency, is a pan-EU regulatory agency for human and veterinary medicines.

• The registration requirements for all EU Member States have been harmonised. Licence can be obtained by:

The national procedure

The mutual recognition procedure

The centralised procedure

The decentralised procedure.


Alternatives to the use of antimicrobial agents include:

• Adequate Vaccination Programs

• Biological control and movement restrictions through sanitary plans (EU, national, or regional/local level).

• Good husbandry

• Adequate feed composition

So we need:

• Vaccine development, immunostimulants and probiotics

• Level playing field: • Use of Medicines/antibiotics/

disinfectants/additives differs between EU states as well as at the global level.

• 3rd countries can use raw

materials that are forbidden in EU or member states for use in feeds.

Some differences between Aquaculture and other terrestrial food animals

Farmed “fish” are not one specie but many.

• These species evolved at different times, have different life cycles', live in different waters, in different temperatures, have different physiological needs and are farmed in different environments.

• Because of these innate species differences, health and welfare indicators cannot be the same for all fish species. Therapies are different as well.


Farmer

Social Competent authorities

Clients

Consumers

Labs & Research

Environment VETERINARIAN

Fish


• Metabolism and feed intake reduces with temperature.

• High temperature and other environment factors as well can reduce feed intake.

• Sick fish reduces his feed intake drastically. Oral treatments have to be administered immediately.

• But we have delays in oral treatments:

• Distance between aquaculture feed mills and farms

• Treatment volumes (too big or too small)

• Administrative burdens ( e.g. NM aprovals when imported VM)

• In some species /life cycle stages (e.g. larvae's feeded with microalgae), only way of practical treatment is medicated baths.


• In aquaculture isolation and identification of a certain pathogen does not always warrant treatment. Relevant variables:

- Pathogens involved

- Morbidity/mortalitity rate

- Value of the production/ fish population

- Possible treatment sequela

- Cost of treatment

- Effect of the disease on the farmed fish welfare

- Legal Considerations

Legislative framework in Europe

• The Commission is considering a revision of the legal framework for veterinary medicinal products:

• Directive 2001/82/EC and in Regulation (EC) No 726/2004.

Requirements and procedures for the marketing authorisation for veterinary medicinal products.

• Regulation (EC) No 470/2009. MRL for veterinary medicinal products. To ensure the protection of consumers against possible harmful effects resulting from the exposure to residues of veterinary medicinal products present in foodstuffs.

• All Community legislation in the area of veterinary medicinal products is contained in volume 5 of "The Rules Governing Medicinal Products in the European Union".

Introduction

• No definitions for minor species (MS) or minor uses (MU).

• Salmonidae are classed as Major animal food producing species for MLRs ; other fish are then considered Minor Species

• The market for aquaculture VMPs is small and the approval process for new compounds is expensive.

2010 Second ESVAC report



• No harmonised, specific, defined procedure for authorising medicines for MSMU. 1

• Few countries have a procedure, is usually a case-by-case basis.

• But even for substances with LMR fixed, there is still no VM available in the market, so there are other reasons involved.2

• Increased data requirements have led to reduction of range of authorized products for species and indications of smaller market sectors.

• The animal health industry needs incentives: e.g. longer protection periods, adittion of species or indications in existing products...2

• 1: European Medicines Agency EMEA Position Paper regarding availability of Products for minor uses and minor species

• 2: Recomendaciones para incrementar la disponibilidad de medicamentos veterinarios. Plataforma Vet+I

Availability

• There is a complete lack of Veterinary Medicines with Market Authorization for treatment of many fresh-water and sea-water parasitic and fungal conditions affecting farmed fish.

Examples include treatments for

• Argulus sp., Ichthyophthirius multifiliis (white spot),

• Cryptocaryon irritans,

• Saprolegnia sp.,

• Tetracapsula bryosalmonae (proliferative kidney disease),

• gill amoebae

• monogeneans infections (both in marine and freshwater fish)

• Uronema sp.

• other internal ciliates.

Availability

DG SANCO

2011

Aquaculture drug examples

from Rodgers et al., 2009

Availability

Antimicrobial class Antimicrobial subclasses Active ingredient

Aminocyclitol Aminoglycosides Spectinomycin

Streptomycin

2 Deoxystreptamine Kanamycin

Bicozamycin

Coumarin Fusidane Glycophospholipid Novobiocin

Kirromycin lincosamides Lincomycin

Macrolides Macrolides C14 Erythromycin

Macrolides C16 Josamycin

Macrolides C16 Kitasamycin

Macrolides C16 Spiramycin

Macrolides C16 Mirosamicin

Penicillins Aminopenicillin Amoxicillin

Ampicillin

Carboxypenicillin Tobicillin

Antimicrobial class Antimicrobial subclasses Active ingredient

Phenicols Florfenicol

Thiamphenicol

Phosphonic acid Pleuromutilins Fosfomycin

Quinolones Quinolone 1G Oxolinic acid

Miloxacin

Flumequine

Quinolone 2G (Fluoroquinolones) Enrofloxacin

Sarafloxacin

Sulfonamides Sulfadimethoxine

Sulfafurazole

Sulfamonomethoxine

Sulfonamides + diaminopyrimidines

Sulfonamides + trimethoprim

Tetracyclines Doxycycline

Oxytetracycline

Tetracycline

Antimicrobials available for use in food producing animals (fish), authorised in at least one country .

Source: Antimicrobial Resistance in animal and public health. Rev. sci.tech.Off. Int. Epiz. 2012,31(1) 15-21 OIE.

Antimicrobials use in aquaculture

• Total lack of specific authorised MV to treat any condition in many of the food fish species farmed within member states (depending on the country : sturgeon, perch, cod, char, turbot, etc...) ;

• Restricted number of antibiotic with MA to treat bacterial disease in several countries

• Minimum withdrawal period of 500 °C/day for « off label use » of MV or for extemporaneously prepared substances. This reduces the availability of treatments for fish when required too closely to their harvest.

Availability

Antimicrobials available for use in fish. Source: FEAP, last update 2011. Known changes since then: Bronopol (DK), FORMALDEHIDE AQUACEN (E). There might be other

changes since 2011.

Pharmacological principle/ Trade Name

CZ N H GR IR UK I E FIN DK NL F D

AN

EST

HET

ICS

BENZOAK VET. (BENZOCAIN) X

FINQUEL (METACAIN) X MS 222 (TRICAINE METHANE SULPHONATE) X X X X X X

AN

TIB

IOTI

C

AMOXYCILLIN X X

CHLORTETRACYCLIN X

FLORFENICOL X X X X

FLUMEQUINE X X X X X X X

OXYTETRACYCLINE X X X X X X X X X

OXILINIC ACID X X X X X

SULFAMID + TRIMETHOPRIM X X X X X X X

Availability

Antimicrobials available for use in fish. Source: FEAP, last update 2011. Known changes since then: Bronopol (DK), FORMALDEHIDE AQUACEN (E). There might be other

changes since 2011.

The cascade system

Member States use cascade system to meet the need of using necessary but unauthorized drugs.

They interpretation of the cascade is different among MS.

Directive 2001/82/EC Article 11

• 1. Member States shall take the necessary measures to ensure that, if there is no authorised veterinary medicinal product in a Member State for a condition affecting a food-producing species, by way of exception, the veterinarian responsible may, under his direct personal responsibility and in particular to avoid causing unacceptable suffering, treat the animals concerned on a particular holding with:

(a) a veterinary medicinal product authorised in the Member State for use with another animal species, or for another condition in the same species; or

(b) if there is no product as referred to in point (a), either:

(ii) a veterinary medicinal product authorised in another Member State in accordance with this Directive for use in the same species […]

The cascade system

Directive 2001/82/EC Article 11

• 1. Member States shall take the necessary measures to ensure that, if there is no authorised veterinary medicinal product in a Member State for a condition affecting a food-producing species, by way of exception, the veterinarian responsible may, under his direct personal responsibility and in particular to avoid causing unacceptable suffering, treat the animals concerned on a particular holding with:

(a) a veterinary medicinal product authorised in the Member State for use with another animal species, or for another condition in the same species; or

(b) if there is no product as referred to in point (a), either:

(ii) a veterinary medicinal product authorised in another Member State in accordance with this Directive for use in the same species […]

The cascade system

Factsheet on cascade procedure (EPRUMA)

(…)Only if these conditions are met, the veterinarian may make use of the cascade, as visualised in the following decision-tree3.

1 These conditions only apply for food producing animals. 2 If no withdrawal period for the medicine for use in the food-animal species concerned is available, the withdrawal period should not be less than 7 days for eggs and milk, 28 days for meat from poultry and mammals or 500 degree days for meat from fish. 3 The Small Animal Exemption Scheme additionally allows veterinarians to use a product in a different way than its recommended use if in her/his professional judgment this would provide a safer or better option for treatment. 4 Administration of a medicine prescribed in accordance with the cascade is only allowed by the prescribing veterinarian or by a person acting under their direction. Responsibility for the prescription and use remains with the prescribing veterinarian.

The cascade system

• The application of the "cascade" involves different risks if is used for:

• a drug approved in another MS (import)

• or in the case of the use of a VM approved in other species

the risks are significantly lower in the first case, as pharmacovigilance is active, although in another Country

• Lack of harmonisation in the interpretation of the veterinary cascade system from one country to another by their respective government authorities (particularly for the importation of MV with MA in another member state)

• Difficulties to convince a pharmaceutical company to spend time on importation procedures without attractive commercial benefits in the target country ;

Biocides

In order to control parasites, bacteria and fungi, the water and the farm surfaces have to be disinfected. Substances with biocide activity such as formaldehyde, hydrogen peroxide, chloramine T, copper sulphate, and others have been widely used in aquaculture, in some cases for decades...e.g. formaldehyde They are Veterinary Medicines, Biocides or both?

BIOCIDES: DIR 1998/08 REG 1451/2007 Reg . 528/2012 (22 may 2012) will substitute the Dir. 98/08 from September, 2013, it includes major number of requirements to register a biocide.

The cascade system

The cascade system

• According to the current EU legislation this use is only allowed according to the cascade system of VM prescription or as a water disinfectant under the biocide legislation.

• Prescription of extemporaneous preparations. European legislation don´t offer a definition of extemporaneous preparations.

• Use of these substances is inconsistently regulated in different EU Member States, and there would be benefit from simpler legislation facilitating a more consistent approach.

The cascade system

• VM with inadequate concentration of active substance especially when feeding ratios are very low (too cold/warm water, broodstock etc...) ;

• Autogenous vaccine use is very difficult with very bureaucratic procedures in several member states

• Emergency licenses have been issued for some products in some member states but the preliminary procedures are very long, if successful these remain temporary (3 – 12 months) and specific for one site and quantity.

Antimicrobials

• Medicated feed legislation

• Medicated feed contains a premix of veterinary medicines and requires veterinary prescription. Almost always is the only way and the most effective way for a farmer to give medicine to farmed fish .

• The Commission regulated the conditions for mixing veterinary medicine into feed, its marketing and use across the EU in Directive 90/167/EEC .

• Its transposition in EU countries led to differences throughout the EU for manufacturers and farmers.

• This directive will be revised

• Some provisions are not in line with developments in feed and veterinary medicinal products legislation.

Antimicrobials

Open Issues:

• Reduced feed intake – Anorexia

• Cost

• Reduced efficacy of tetracyclines and sulphonamides orally.

• Range of reduced choice - administered only orally (medicated feed)

• Selection of resistant strains of bacteria - antimicrobial resistance

• Withdrawal period - commercial size fish / temperature dependant

• Environmental compatibility

• Important differences in treating different fish species

Vaccination

Potential benefits

• Less outbreaks

• Reduction of drug use

• Reduction of bacterial drug resistance risk

• Better food conversion rates in vaccinated fish, Increased appetite and growth.

• Potential of growing vaccinated fish at higher densities

• Improvement of fish health & environment of the farm.

Potential costs

• Post-vaccination mortality as a result of:

• Fish are latent carriers of pathogen which "emerges".

• Fish are weakened by improper handling or rearing practices.

• Decrease in growth caused by side effects such as those produced by some adjuvant vaccines.

IMMERSION

Vaccination methods

Immersion vaccination:

1. Dip Immersion

2. Long term bath

3. Spraying

Advantages

• Suitable for large quantities of small fish (<5g)

• Cost effective for small fish (nº 1 , 3)

• Protective immunity for 3-5 months dependind on antigens

Disadvantages

• Difficult to aply on ongrowing units

• Expensive for large fish

• Costly (nº2)

INJECTION

Vaccination methods

Injection vaccination:

1. IP

2. IM

Advantages

• Good Protective immunity, up to 1 year)

• Suitable for large fish(broodstocks)

• Possibility of automatization.

• Good for weak antigens, for vaccination at low temperature

• Disadvantages

• Stressful method

• Labor and time consuming

• Use of anesthesic required

• Side lesions

ORAL

Vaccination methods

Oral vaccination:

Advantages • No stress, no time

consuming • Easy to apply on all

production facilities • For all sizes of fish (>10g)

and large batches.

• Disadvantages • Monovalent vaccines

only • Protection slightly

shorter than injection (8 months)

• Needs to be planned and requires ood feeding practice.

Conclusions

• FEAP, its National Member Associations , the Vets working in fish farms support the review of the veterinary medicines legislation and the need to ensure a stable and robust regulatory framework which aims to promote the development of new veterinary medicines, increase their availability in Europe, improve the functioning of the internal market, but underline that:

• The peculiarities of the aquaculture sector see above all in relation to issues of animal health and welfare, but also in terms of technological problems (such as route of administration) must be taken into great consideration.

• Cascade off label use of veterinary products should remain an option to guarantee animal health. The lack of specific veterinary medicines available on the market at Member State level, especially for minor species and minor uses, is still a critical point.

Conclusions

Farmers and Fish Vets, should be responsible for ensuring that animals satisfy the requirements of the animal health provisions.

Fish Farm Health Management Planning/Codes of Practices:

voluntary and flexible management procedures which integrate :

• improvements in animal health and animal welfare,

• animal productivity & farm profitability,

• veterinarian/farmer relationships,

• improvements in sustainable and safe food production,

• optimization in the use of preventive veterinary/animal health procedures.

They are most successful when they are bespoke and tailored to the farm, which requires historic, in-depth knowledge of the farm, its marketplace, resources, geographical location and animals.

Thanks for your attention! Special thanks to Andrea Fabris (API) and other FEAP fish health comittee members for their contributtions to this presentation.

www.feap.info Luz Arregui Maraver President ESACUA – ADSG OP 65 ATRUGAL [email protected]

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