Introduction
Antibiotic resistance problem
Antimicrobial resistance is the resistance of micro-organism to antimicrobial preparations, through which these preparations become ineffective as treatment for microbial infections. The consequences of antimicrobial resistance can be increased mortality, prolonged hospital stays, longer illnesses and higher costs (Smith & Coast, 2013). According to the World Health Organization (WHO) antibiotic resistance is one of the biggest threats to global health, development and food security. The WHO states that without a prudent use of antibiotics (in the human public health care and veterinary health care), antibiotic resistance will flourish and will become a major threat, not only affecting poor countries but affecting every country in the world (“WHO | Antibiotic resistance,” 2016).
Antibiotics have been used extensively for the last 60-70 years in human health care, which result nowadays in the problem of growing antibiotic resistance. Even though the use of antibiotics in animals has a slight effect on the resistant pathogens in humans, the use of antibiotics in animals is under restriction. Antibiotic resistance has been under the attention for the last 20-25 years, and has led to changes in the veterinary world like the abundance of growth promotors in 1999 by the European Union (Prescott, 2008).
Three groups of bacteria are the main focus because of their threat to the public health; vancomycine-resistant enterococci (VRE), the methicillin-resistant Staphylococcus aureus (MRSA) and the bacteria that produce extended spectrum beta-lactamase (ESBL). Whereas VRE and MRSA are mainly a hospital-bound issue, ESBL-producing bacteria are also found outside of the hospital and have the ability to spread quickly (Health Council of the Netherlands, 2011). You see a shift from a hospital-bound problem to a more community-bound problem (Prescott, 2008).
‘Prudent use’
The definition of ‘a prudent use of antibiotics’ according to the WHO is the usage of antibiotics which minimizes the development of antimicrobial resistance and maximizes the therapeutic effect (World Health Organization, 2000). A prudent use of antibiotics in veterinary medicine according to the World Organization of Animal Health (OIE) described in Terrestrial Code, 2008 contains practical measures and recommendations, with a One Health approach, intended to benefit animal, human and environmental health while preserving and maintaining the therapeutic efficiency of these antibiotics (World Organization for Animal Health (OIE), 2016). Therefor a prudent use of antibiotics is reached by minimizing the misuse and overuse of antibiotics (Teale & Moulin, 2012).
European guidelines
In 2012 the Action Plan on Antimicrobial Resistance of the European Commission Communication and the Conclusions of the European Union Council encouraged member states of the European Union to establish monitoring and evaluating plans, national guidelines and strategies to fight the antibiotic resistance (European Commission, 2016).
The Action plan has a ‘One Health’ approach, covering human health care and veterinary health care. This action plan consists of 12 key strategic actions that had to be taken to fight the antimicrobial resistance. A period of five years (2011-2015) was set, and after that period a rapport was published on the progress made in this period of time (Plan Nacional Resistencia Antibióticos., 2015)(European Commission, 2016).
The European Medicines Agency (EMA) is a decentralized body of the European Union (EU). The EMA evaluates and supervises medicines for human and veterinary use, for the protection and promotion of human and animal health. In the report ‘CVMP strategy on antimicrobials 2011-2015’ of the EMA the Committee for Medicinal Products for Veterinary Use (CVMP) gives a list of recommendations for actions to limit the risk of the evolving antimicrobial resistance. The first recommendation is the development of risk assessment guidelines, where the CVMP is the responsible body. The second recommendation is the assessment of critically important antimicrobial (CIA) for public health, where the CVMP, applicants and National Competent Authorities have the responsibly. Establishment of guidelines for a prudent use of antibiotics is part of this recommendation, here the professional bodies, universities and veterinary practitioners are responsible. The third recommendation is to record and monitor the off-label use of human CIAs in companion animals, here the National Competent Authorities are responsible. The fourth recommendation is to extend AMR surveillance programs that are significant to companion animals, the responsible bodies are the Member States (Committee for Medicinal Products for Veterinary Use (CVMP), 2015).
According to the World Organization of Animals Health (OIE) in Terrestrial Code, 2008 (World Organization for Animal Health (OIE), 2016) the responsibilities of prudent use of antibiotics lie with all those involved in all stages of production, distribution and use of veterinary antibiotics. The following groups are therefor held responsible; the competent authority, veterinary pharmaceutical industry, wholesale and retail distributors, the veterinarians, food-animal producers and animal feed manufacturers (Teale & Moulin, 2012).
European guidelines
The evaluation rapport of the Action Plan on Antimicrobial Resistance of the European Commission Communication stated that in 2015 the European commission published guidelines on the prudent use of antimicrobials in veterinary medicine (European Commission, 2016). These guidelines were produced by the Federation of Veterinarians and the Federation of European Companion Animal Veterinary Association (FECAVA, 2013)(FECAVA, 2013) the use of antibiotics in companion animals (Committee for Medicinal Products for Veterinary Use (CVMP), 2015).
European monitoring and surveillance
Specific on the antimicrobial resistance problem the EMA launched the European Surveillance of Veterinary Antimicrobial Consumption (ESVAC) in 2009 to collect data on sales of antibiotics from EU countries. Their last report of 2014 included data of 29 EU countries, the EMA stated that Spain has one of the highest consumptions of antibiotics of all 29 countries participating. The data collected is mainly focused on food-producing animals, and a little is known about the antibiotic use in companion animals. The EMA states that the use of antibiotic tablets is mostly used with companion animals. The data of tablets in the Netherlands, Denmark and Spain is 3.1, 0.9 and 1.6 tonnes per year respectively. Although in the 2014 report of the EMA all injectable preparation used for companion animals where excluded from these numbers, which makes these numbers not fully representable for the total use of antibiotics in companion animals, but gives good indication (European Medicines Agency, 2016).
Food-producing animals vs companion animals
The use of antibiotics in food-producing animals is under much stricter regulation compared to the use of antibiotics in companion animals. Even though companion animals live close with their human owner through which they can share resistant bacteria, amplify resistant bacteria and act as a reservoir for human infection (Prescott, 2008).
Introduction of the main question
On European level there are lots of rapports and measures established to battle the antimicrobial resistance. The European Commission states that all member states of the European Union should take their responsibility and compose monitoring & evaluating systems and guidelines for a prudent use of antibiotics in the veterinary field.
In this literature review three European policies on antibiotics for companion animals will be researched and compared. The first country is the Netherlands; with their unique classification of antibiotics and their formularies. The second country is Denmark; a country ahead of time when introducing their policies with the use of antibiotics in food-producing animals and their monitoring and surveillance system. The third country is Spain; a country with one of the highest uses of antibiotics in food-producing animals in Europe (European Medicines Agency, 2016).
A small part of this literature review will focus on pet owners related factors that can interfere with a prudent use of antibiotics with companion animals.
REVIEW METHODOLOGY
A literature research was performed in Google Scholar, PubMed and Google for the period of the 6th of February 2017 and the … of March 2017. The following keywords were used: Antibiotics policy, Antibiotic stewardship, Denmark, Netherlands, Spain, Companion animals, Pets, Antimicrobial resistance, Guidelines, Prudent use, Responsible use, Veterinary medicine. These keywords were used as a single keyword or in a combination of keywords. Articles were selected based on relevance and publication date. Referenced cited in selected articles were also used. Apart from the articles found in databases, several website and rapports were used which were found through Google.
RESULTS
Dutch Antibiotic Policy and Measures
In 2011 the recommendations of the Health Council of the Netherlands in ‘Antibiotics in food animal production and resistant bacteria in humans’ became a leading recommendation for the Dutch veterinarian antibiotic policy (Ministry of Economic Affairs, 2014). These recommendations were adapted by the Veterinary Antibiotics Policy Working Group (WVAB) of the Royal Dutch Society for Veterinary Medicine (KNMvD) into a guideline ‘smal-, versus breed spectrum antibiotica en eerste, tweede en derde keus op basis van Gezondheidsraad-advies’ (Werkgroep Veterinair Antibioticum Beleid KNMvD, 2013). Former guidelines focused on narrow spectrum, broad spectrum and ‘last resort’-agents. While this new guideline focuses on avoiding selection pressure on ESBL and AmpC producing micro-organisms (KNMvD, 2015). This guideline became the foundation for the guideline ‘Formularies for Companion Animals’ by the KNMvD (Werkgroep Veterinair Antibioticum Beleid KNMvD, 2013).
Classification of antibiotics
Antimicrobial agents where classified in line with the recommendation of the Health Council of the Netherlands (Ministry of Economic Affairs, 2014). This classification in first, second and third choice antibiotics is unique in Europe (KNMvD, 2015):
• First choice antibiotics; are antibiotics for a specific indication. These antibiotics do not have a specific effect on the appearance of resistance by ESBL and/or AmpC producing organisms (Werkgroep Veterinair Antibioticum Beleid KNMvD, 2013).
• Second choice antibiotics; are antibiotics for a specific indication. These antibiotics are not part of the first-choice antibiotics because of their co-selection for ESBL and/or AmpC producing organisms. For the use of these antibiotics there is a ‘no-unless rule’: the necessity for using second choice antibiotics needs to be well-founded (Werkgroep Veterinair Antibioticum Beleid KNMvD, 2013).
• Third choice antibiotics; are antibiotics which are of critical importance for human health care. For the use of these antibiotics there is a ‘no-unless rule’: these antibiotics can only be used on individual animals, with bacteriological and sensitivity research which indicate that there are no other alternatives to treat the animal (Werkgroep Veterinair Antibioticum Beleid KNMvD, 2013). Bacteriological research is obligatory by law (KNMvD, 2015).
Formularies
In 2012 the Dutch (and UK) had a different unique aspect of their policy concerning antibiotics; the formularies (Teale & Moulin, 2012). The guideline ‘Formularies for Companion Animals Dogs and Cats’ is meant to create a responsibly antibiotic use in dogs and cats. The goal of this guideline is to advise primary care companion animal veterinarians with prescribing antibiotics to companion animals to reach an optimal effectivity and to prevent the creation and spreading of resistant bacteria and resistance genes (Werkgroep Veterinair Antibioticum Beleid KNMvD, 2013).
The formularies committee made a list of relevant indications for dogs and the cats. With these indications, the committee choose suitable and permanent registered pharmaceutical preparations for specific species and the concerning indication with the appropriate route of administration. The chosen antibiotics per indication per animal are based on the proven effectivity in clinical pharmaceutical studies. If there are no clinical pharmaceutical studies available the decision is based on scientific data of pharmacokinetics, pharmacodynamics, in vitro activity and toxicity of the pharmaceutical preparation (Werkgroep Veterinair Antibioticum Beleid KNMvD, 2013).
Monitoring & Surveillance
Monitoring of Antimicrobial Resistance and Antibiotic Usage in Animals in The Netherlands (MARAN) monitors the use of antibiotics in the veterinary field, every year they publish a report to gain insight in the prevalence and spreading of antimicrobial resistance (MARAN, 2016).
The Veterinary Medicines Authority (SDa) is an independent organ which sets bench markers for the use of antibiotics in animal health care.
The SDa also set a unit of measurement ‘the defined daily dose animal’ (DDDA) for the determination of the annual antibiotic drug consumption in the veterinary field. The DDDA is established per species per antimicrobial veterinary medicinal product (AVMP) and represents the amount of AVMP used for treatment of one kg of animals for one day. These data are used to give an impression on the use and sales of antibiotics in the Netherlands (Taverne et al., 2015).
In 2016 the SDa published a report ‘Usage of antimicrobial drug in companion animals 2012-2014; Result of a survey of veterinary practices in the Netherlands’ in which they stated that the usages levels of antibiotics have been declining, and the levels of usage where comparable with the human antibiotic usage based on GP prescriptions. There was also a notable shift from third- and second-choice antibiotics usage towards first-choice antibiotics (The Netherlands Veterinary Medicines Authority, 2017).
Although there is a good monitoring and surveillance system working, it is not mandatory to report data which can be used by the EMA (European Medicines Agency, 2016).
Danish antibiotic policy and measures
Guidelines
In 2012, the Danish Small Animal Veterinary Association (a division of the Danish Veterinarian Association), motivated by the increasing antibiotic resistance problems, formed the guideline ‘Antibiotic Use Guidelines for Companion Animal Practice’. The goal of this guideline, which is only a recommendation, is to guide practical veterinarians in their antibiotics choice, so that a bacterial infection can be treated with an as specific as possible choice of antibiotics to avoid the development of multi-resistant bacteria. A different goal of the guideline is to promote the use of culture and sensitivity testing. The guideline focusses especially on skin and urinary tract infection, because of their commonness with appearance and multi-resistant bacteria (Danish Veterinary Ophthalmologic Association (DSVO), a division of SvHKS et al., 2012).
The guideline includes data of antibiotic resistant bacteria in Denmark and data of the prescription of antibiotics to companion animals. The guideline also includes information about pharmacokinetics & pharmacodynamics of different antibiotics, the route of application, the treatment duration, toxicity and side-effects of antibiotics, information about resistant bacteria, information about preforming and interpreting microbiological testing and includes a classification of antibiotics (Danish Veterinary Ophthalmologic Association (DSVO), a division of SvHKS et al., 2012).
This classification is based on the clinical importance in human and veterinary medicine and the risk of antibiotics resistance and is divided in five categories:
• First category; antibiotics (like penicillin) with a narrow working spectrum and with a limited risk of producing or spreading resistant bacteria.
• Second category; antibiotics (like aminopenicilline) with a broader working spectrum and with a limited risk of producing or spreading resistant bacteria.
• Third category; antibiotics (like first-generation cephalosporins and amoxicilline/clavulanate) with a broader working spectrum and a bigger risk of producing or spreading resistant bacteria.
• Fourth category; antibiotics (like third-generation cephalosporins) which should be used with caution to preserve the effectivity in veterinary medicine and to bigger risk of producing of spreading resistant bacteria.
• Fifth category; antibiotics (like vancomycin) which should be used very restricted and should only be used in rare cases with multi-resistant infections which cannot be treated differently.
The guideline recommends that broad-spectrum antibiotics are only being used based on sensitivity testing and that they should be reserved for infections that do not respond to narrow-spectrum antibiotics treatment. Based on this classification the guideline gives a list of recommended antibiotics for specific infections of specific organs or systems (Danish Veterinary Ophthalmologic Association (DSVO), a division of SvHKS et al., 2012).
Surveillance and monitoring
In 1995 Denmark was the first country to establish a systematic and continuous monitoring program of antimicrobial drug consumption and antimicrobial resistance in animals, food and humans. The program was called the Danish Integrated Antimicrobial Resistance Monitoring and Research Program (DANMAP). DANMAPs result are still reported annually, and if the results are relevant they are being published in scientific journals (Bager, 2000). The data obtained by DANMAP is especially focused on food-producing animals and the data available of companion animals are not as detailed as the data of food-producing animals (Bager, 2016).
The Danish national surveillance program adopted the use of animal defined daily dosages (ADD) to enable standardization of drug dosage, per animal species, per day to correct for differences in dosing between antibiotics and animal species. (Guardabassi, Schwarz, & Lloyd, 2004). The ADDs are used for the annual reports of DANMAP for the period from 2009-2011. Since 2012 DANMAP uses the Defined Animals Daily Dose (DADD), which is a measure at the level of active ingredient, route of administration and pharmaceutical form (Taverne et al., 2015).
It is mandatory to report data of sales which can be by the EMA for their annual report (European Medicines Agency, 2016).
A different program called VetStat monitors all medicines used for veterinary purpose. Vetstat collects data including date of sale, prescribing veterinarian and practice, quantities, recipient, species and age of the animal which the medicine is prescribed to. In contrast to veterinarians prescribing medicines to food-producing animals, veterinarian prescribing medicines to companion animals are not responsible for recording information on antibiotics (Danish Veterinary Ophthalmologic Association (DSVO), a division of SvHKS et al., 2012).
In 2003 VetStat stated that the consumption of antibiotics in companion animals where substantial compared to consumption of antibiotics in food-producing animals (Heuer, Jensen, & Hammerum, 2005).
Different measures
To raise awareness for the antibiotic problems the National Antibiotic Council organizes a yearly Awareness Seminar on European Antibiotic Awareness Day.
To promote the use of vaccines instead of antibiotics there are no taxes on vaccines. There are higher taxes on CIA antibiotics and lower to no taxes on vaccines and narrow-spectrum antibiotics (European Commission, 2015). Pharmacies have the exclusiveness of selling antibiotics to veterinarians. These antibiotics are prescription-only medicines. The veterinarian can sell the antibiotics with a maximum of 5% profit, this limit is set by law (Bager, 2000).
Spanish antibiotic Policy and Measures
Guidelines
In 2015 the Spanish Agency of Medicines and Medical Devices (AEMPS) published a national fine year plan (2014-2018) ‘Plan Nacional Resistencia Antibióticos’ to reduce the risk of producing and spreading of resistant bacteria. The rapport focusses on both human and veterinary health and recommends on specific measures and specific actions, structured into six strategic lines:
1. Surveillance of antibiotic consumption and antimicrobial resistance
2. Control of bacterial resistance
3. Identification and spearheading of alternative and/or complementary measures of prevention and treatment
4. Defining research priorities
5. Training and information for healthcare professionals
6. Communication and raising awareness in the population as a whole and in population subgroups
The total plan consists of twenty measures and seventy-four actions. Each group of measures and actions are assigned to a specific coordinator and institutions, bodies, societies or participating groups for development. The actions are specified if there are focused on humans, animals or both (Plan Nacional Resistencia Antibióticos., 2015).
The first strategic line ‘Surveillance of antibiotic consumption and antimicrobial resistance’ has a few implemented actions as ‘Improved vigilance systems of antibiotics sales, including data at distribution level’ which is performed under the European surveillance of Veterinary Antimicrobial Consumption project (ESVAC), Spain has joined this project since 2009 (Plan Nacional Resistencia Antibióticos., 2015). Although it is not mandatory to report the collected data to the EMA (European Medicines Agency, 2016).
A different action under the first strategic line is to develop and implement an electronic prescription and control system, with specific fields like pet/other, medicated feed, etc. The Spanish Medicines Agency (AEMPS) is developing a Vademecum, a specific handbook for the use of antibiotics. (Madero, Navas, Alvarez, & others, 2016)
The second strategic line ‘Control of bacterial resistance’ includes the following actions; develop specific online guidelines for clinical veterinarians where all the information can be found to make a proper decision with prescribing antibiotics. (Madero et al., 2016)
Monitoring and Surveillance
Inspired by DANMAP in 1997 the Spanish Veterinary Antimicrobial Resistance Surveillance Network (VAV) was established to surveillance the following critical areas; bacteria from sick animals, bacteria from healthy animals and bacteria from food animals (Moreno, Domı́nguez, Teshager, Herrero, & Porrero, 2000).
Different measures
Species specific prescription guidelines have been drawn up in collaboration with veterinary organizations, animal producer organizations, academia and other partners. These guidelines consists of a specific list of critically important antibiotics, which should be used only under critically important situations after sensibility testing. By law veterinarians are not able to benefit economically from the prescribing of antibiotics. And all antibiotics are available under prescription by the veterinarian only (Madero et al., 2016).
• Individual project: Influencing factors for a prudent use of antibiotics (500 words)
DISCUSSION (1500 words)
Comparing the guidelines
The Federation of Veterinarians and the Federation of European Companion Animal Veterinary Association established documents for the use of antibiotics in companion animals. In addition the European Union recommends that every Member State of the EU should establish their own guidelines in the use of antibiotics to guide the veterinarian in making a decision regarding the best antibiotics choice for a specific infection.
In the Netherlands and Denmark these guidelines are public and easily accessible for every veterinarian. Although these countries both have guidelines, the focus is different.
The Danish guidelines on antibiotic divides the antibiotics in five categories with a focus
on the broad spectrum working versus the narrow spectrum working mechanism of the antibiotics and the risk of producing resistance.
The Dutch guidelines take a different and unique approach in the establishment of the guidelines. The guidelines are in line with the recommendation of the Health Council of the Netherlands and focuses especially on the risk of the ESBL and AmpC producing bacteria.
Spain has the intention to make guidelines for the veterinarian, and although some sources mention that the guidelines are made, they are not easily accessible and not available in English.
In addition of the guidelines there are documents made called Formularies. The Netherlands were one of the first countries introducing formularies, and now Denmark has followed their example, and they integrated the formulary information in the ‘Antibiotic Use Guidelines for Companion Animal Practice’. In Spain there is not something available like formularies.
Although the guidelines are a good guide for the veterinarian, the formularies contain much more detailed information. And especially for a country like Spain, where the use of antibiotics in food-producing animals is very high, documents like a formulary should be available for every veterinarian.
Comparing the monitoring & surveillance system
In the Netherlands, Denmark and Spain there is a monitoring system in use for the monitoring of the antimicrobial drug consumption and antimicrobial resistance. Denmark was one of the first countries to develop DANMAP, the Netherlands followed with MARAN and Spain with VAV. The monitoring and surveillance of antimicrobial drug consumption and antimicrobial resistance is seen as an important action in the battle against antimicrobial resistance. But in all three countries the focus of the monitoring program is mainly on food-producing animals.
The EMA collects all the data of the sales of antibiotics of several European countries, including Spain, the Netherlands and Denmark. These data are important to get an idea of the sales of antibiotics and of the possible antimicrobial resistance risk. But although these data are important, only Denmark has a mandatory to collect this data which the EMA van use.
The data of EMA suggest that Spain has the highest antibiotic use in food-producing animals. But this is not in line with the level of antibiotics in companion animals. Here the Netherlands have the highest number. Although these data are also not fully representable because they only count the tablets and not the injected antibiotics.
An different point of discussion is the comparability of the obtained data by the EMA. Both Denmark and the Netherlands have a different approach on how to define the total use of sales of antibiotics by different measure tactics. The Netherlands uses the DDDA and Denmark uses DADD, where in the Netherlands the sales is based on the AVMP and in Denmark the sales is based on the active ingredient. This makes the obtained data not comparable, although the EMA compares these data in their annual reports (Taverne et al., 2015).
Comparing different measures like taxes
A different approach between the three countries is the tax on the antibiotics. In all three countries antibiotics are prescription only medicines, which gives the veterinarian a unique position according to the selling of antibiotics.
In Denmark the veterinarian can only ask 5% tax on top the antibiotics, and the government makes the use of vaccines more attractive to make them without tax. This approach makes the prescription of antibiotic not necessarily attractive to the veterinarian, so an economically drive in prescribing antibiotics is not in place. The same is true in Spain, where by law the veterinarian can’t benefit economically with the selling and prescription of antibiotics.
In the Netherlands the opposite is true, there the veterinarian can benefit economically from the selling and prescribing of antibiotics. This makes the prescription of antibiotics by veterinarians vulnerable for a wrong use.
CONCLUSION (250 words)
ACKNOWLEDGEMENT
REFERENCES