Sales survey of Veterinary Medicinal Products containing Antimicrobials in France Volumes and estimated exposure of animals to antimicrobials

Sales survey of Veterinary Medicinal Products containing Antimicrobials in France - 2013 Volumes and estimated exposure of animals to antimicrobials October 2014 Scientific Edition

Sales survey of Veterinary Medicinal Products containing Antimicrobials in France - 2013 Volumes and estimated exposure of animals to antimicrobials October 2014 Scientific Edition

Authors: French Agency for Food, Environmental and Occupational Health & Safety (ANSES) French Agency for Veterinary Medicinal Products (ANMV) Anne Chevance and Gérard Moulin, ANSES ANMV

CONTENTS I. Abstract... 2 II. Introduction... 7 III Materials and methods... 8 IV. Results for 2013... 12 1. Results presented by antimicrobial class and by route of administration... 12 2. Results by species... 15 V. Change in sales and exposure to antimicrobials between 1999 and 2013... 16 1. Change in sales and exposure to antimicrobials by pharmaceutical form... 16 2. Change in sales and exposure to antimicrobials by class... 19 VI. Change in exposure to antimicrobials by species... 21 1. Results for cattle... 21 2. Results for domestic carnivores... 26 3. Results for rabbits... 30 4. Results for pigs... 34 5. Results for poultry... 38 VII. Update on exposure to fluoroquinolones and third- and fourth-generation cephalosporins... 41 VIII. Discussion... 48 IX. Conclusion... 51 X. ANNEXES... 52 A. Animal population... 53 B. Guide to indicators... 56 C. Sales expressed in ADDkg for 2013... 65 D. Change in antimicrobial sales for all species by class between 1999 and 2013... 66 E. Change in antimicrobial sales by species in ADDkg... 67 F. Exposure of cattle to antimicrobials... 69 G. Exposure of domestic carnivores to antimicrobials... 70 H. Exposure of rabbits to antimicrobials... 71 I. Exposure of pigs to antimicrobials... 72 J. Exposure of poultry to antimicrobials... 73 Page 1 of 73

I. Abstract The French Agency for Veterinary Medicinal Products (ANSES-ANMV) began monitoring sales of veterinary antimicrobials in 1999. This survey is based on the recommendations of the OIE guideline on "Monitoring of the quantities and usage patterns of antimicrobial agents used in food producing animals" from the OIE Terrestrial Animal Health Code 2014 - Chapter 6.8. It is carried out in collaboration with the French Union for the Veterinary Medicinal Product and Reagent Industry (SIMV), based on annual reporting of antimicrobial sales by the pharmaceutical laboratories marketing them. These companies also provide an estimated breakdown of the drugs sold by target species. The information collected from the laboratories covers 100% of authorised drugs 1. The information gathered through this national monitoring scheme is one of the essential elements, together with monitoring of bacterial resistance, needed for assessing the risks associated with antimicrobial resistance. Tonnage of active ingredient sold In 2013, total sales of antimicrobials amounted to 699 tonnes, the lowest since monitoring began. The results from 2013 confirm the decrease in sales volumes seen in previous years (-46.7% since 1999, -34% over the last five years, -10.6% between 2012 and 2013). Exposure to antimicrobials Given the differences in potency and dose between different antimicrobials, the sales in weight of antimicrobials do not accurately reflect their use. Recent antimicrobials are generally more potent and require the administration of a smaller dose. To assess animal exposure to antimicrobials, it is necessary to consider the dosage and duration of administration, but also changes in the animal population over time. By relating the estimates of body weight treated to the mass of the animal population potentially treated with antimicrobials, we obtain an estimate of the level of exposure (ALEA: Animal Level of Exposure to Antimicrobials). This indicator is correlated to the percentage of animals treated relative to the total population and is an objective indicator of exposure to antimicrobials. Change in exposure to antimicrobials compared to the previous year All animal species combined, overall exposure in 2013 fell by 7.3% compared to 2012. However, this overall trend must be qualified according to the target species and classes of compounds. Between 2012 and 2013, exposure to antimicrobials decreased by 6.6% for cattle, 5.4% for poultry, 4% for pigs and 1.7% for domestic carnivores. It rose by 3.6% for rabbits. Main trends observed All animal species combined, the level of exposure of animals to antimicrobials in 2013 was for the first time lower than that of 1999, the year the monitoring plan was launched (-5.5%). Since 2007, there has been a steady decline. More precisely, there has been an overall reduction of 15.7% in exposure over the last five years. 1 The off-label use of veterinary medicinal products is partly taken into consideration in the manufacturers declarations. Exceptional prescription and off-label use of human drugs or extemporaneous preparations containing antibiotics under the provisions of the cascade approach (Article L. 5143-4 of the French Code of Public Health) are not taken into account. Page 2 of 73

Over the last five years, oral exposure has fallen by 24.3% while an increase of 9.4% has been observed for injections. This decrease in oral exposure is mainly due to a decline in the use of medicated premixes (-45.9% over 5 years, and -15.4% in 2013 compared to 2012). These changes probably reflect a decline in antimicrobials used in prevention. This overall trend (all species combined) must be qualified according to the target species and classes of compounds. Third- and fourth-generation cephalosporins and fluoroquinolones Over the 15 years of monitoring, the level of animal exposure to cephalosporins has been multiplied by 2.5. Over the last five years, exposure to third- and fourth-generation cephalosporins has grown by 14.1%. Following a stable period between 2010 and 2012, a large fall in exposure to cephalosporins was observed in 2013 (-9.8% compared to 2012). Between 2012 and 2013, exposure decreased by 11% in cattle and 9.3% in pigs, although a very large increase in exposure (+25%) was observed in domestic carnivores in this year. Over the 15 years of monitoring, the level of animal exposure to fluoroquinolones has doubled. Over the last five years, exposure to fluoroquinolones has remained virtually stable (0.4% increase over this period). Between 2012 and 2013, exposure to fluoroquinolones decreased slightly (-1.5%) when taking all animal species into account. It fell in poultry (-7.3%) and in cattle (-3.1%), and increased by 1.6% in pigs and by 12.2% in domestic carnivores. Exposure of cattle to antimicrobials In cattle, the estimated exposure (ALEA) to antimicrobials has increased by 0.2% in the past five years and in 2013 was still at a significantly higher level than in 1999 (+14.7%). In 2013, a 6.6% decrease in exposure was observed compared to 2012. Over these last five years, exposure to newer-generation cephalosporins has grown by 26.9% and exposure to fluoroquinolones has increased by 15.4%. Exposure to macrolides has decreased by 19.4% over the same period. Between 2012 and 2013, exposure to newer-generation cephalosporins and fluoroquinolones fell by respectively 11% and 3.1%. Exposure of domestic carnivores to antimicrobials In cats and dogs, estimated exposure (ALEA) increased until 2007 and has been declining since. In 2013, a 1.7% decrease in exposure was observed compared to 2012. The level of exposure of domestic carnivores to antimicrobials has decreased by 10% over the last five years. In 2013, overall exposure was 7.9% lower than that estimated when monitoring began. Exposure of cats and dogs to antimicrobials belonging to the class of newer-generation cephalosporins increased constantly from 2006 to 2011, decreased in 2012, and then increased dramatically between 2012 and 2013 (+25% compared to 2012). Exposure to fluoroquinolones has increased by 69.3% since the start of monitoring, although a 5.2% decrease in this exposure has been observed over the last five years. However, a 12.2% increase was observed between 2012 and 2013. This increase needs to be examined in the light of the marketing in 2013 of generic drugs belonging to this class of antimicrobials. Page 3 of 73

Exposure of rabbits to antimicrobials In rabbits, the estimated exposure to antimicrobials increased between 1999 and 2004 and has declined since, with the ALEA falling by 30% over the last five years. The results obtained should be considered in the context of efforts to reduce the use of antimicrobials, and in particular the interprofessional charter established in December 2011. However, a 3.6% increase was observed between 2012 and 2013. This increase is mainly related to an increase for the tetracyclines class, with use in the other classes being stable or declining. Over the last five years, the decrease in exposure to pleuromutilins, quinolones, sulfonamides, tetracyclines and trimethoprim has been particularly noticeable. Exposure of pigs to antimicrobials In pigs, the estimated exposure to antimicrobials has decreased by 25% over the monitoring period, by 27.7% over the last five years and by 4% between 2012 and 2013. Exposure fell for most classes of antimicrobials. Over the last five years, exposure to newer-generation cephalosporins has decreased by 60.3%. Following the initiative in the pig sector to voluntarily restrict the use of newer-generation cephalosporins, the reduction in the use of this class of critical antimicrobials continued in 2013, with estimated exposure of pigs to this class falling by 65.5% between 2010 and 2013. An estimate was made of the number of pigs treated with newer-generation cephalosporins that took into account the weight of the animals at the time of treatment (from field surveys conducted by ANSES Ploufragan). This showed a decrease of 82.5% in the number of growers treated between 2010 and 2013. The use of fluoroquinolones has increased by 37% since monitoring began. After a significant drop in 2010 (-40% compared to 2009), an increase has been observed since 2012 (a 1.6% increase in 2013 compared to 2012); however over the last 5 years, exposure has fallen by 26.4%. Exposure of poultry to antimicrobials Estimated exposure of poultry to antimicrobials increased from 1999 to 2006 and remained relatively stable until 2011. It has fallen since then. Exposure has decreased by 12.3% over the last five years and by 5.4% between 2012 and 2013. In 2013, exposure remained at a level significantly higher than that of 1999 (+41.8%). While exposure of poultry to fluoroquinolones increased steadily from 2005 to 2011 (+62.9%), it has fallen since then (-7.3% between 2012 and 2013). Discussion Expressing sales in terms of the amount of active ingredient is an accurate measurement when applied to all species combined. When it is defined by species, it is based on an estimate of the breakdown of sales between different species potentially treated with antimicrobials and becomes an estimated measurement. All expressions of sales in terms of exposure indicators are estimated measurements, resulting from the pharmaceutical laboratories estimates of the breakdown of sales by species, and dosages and durations of treatment specified by the MA that are sometimes unrelated to the dosages and durations actually applied in the field. In France, the approach in place for many years provides an estimate of exposure for the main animal species; however the current system cannot allocate sales by category of animals or by physiological stage. In particular, veal calves cannot be distinguished from adult cattle. Similarly, some species are grouped together; this is the case with poultry, for instance. It is necessary to be able to distinguish the different species: broilers, turkeys, layers, etc. Page 4 of 73

At European level, the European Surveillance of Veterinary Antimicrobial Consumption (ESVAC) scheme currently allows harmonised collection of antimicrobial sales data without distinguishing between animal species. A reflection paper 2 was published in 2013 to propose a system for collecting data by species and the establishment of "consumption" indicators. At national level, the French bill on the future of farming provides for the mandatory reporting of sales of antimicrobials by the veterinary pharmaceutical companies, as well as reporting by the parties entitled to dispense these drugs. The need for more accurate data on the use of antimicrobials by species and category of animals is regularly reiterated at European level. In its Opinion published in April 2014, ANSES recommended the introduction of long-term tools for monitoring more closely the administration of antimicrobials on farms, by animal species, by sector and type of production. Initiatives are being introduced to improve the estimation of exposure to antimicrobials by category of animals, physiological stage or species, in the case of poultry. The measures in Axis 4 of the national plan to reduce the risks of antimicrobial resistance in veterinary medicine, which include conducting surveys by sector, will provide some answers in the near future to improve the documenting of actual use in the production sectors. Conclusion In France, many measures have been taken since late 2010 to promote the prudent use of antimicrobials: initiative in the pig sector on limiting the use of cephalosporins, charter on correct use of drug therapies in rabbit farming, raising awareness in many sectors about good practice and the rational use of antimicrobials, introduction in veterinary medicine of the EcoAntibio 2017 national plan, which is aiming to reduce use of antimicrobials (all classes combined) by 25% in 5 years, while preserving the therapeutic arsenal, ANSES internal request to assess the risk of emergence of antimicrobial resistance associated with patterns of antimicrobial use in the field of animal health, draft bill on the future of farming, food and forestry, which has set a target of a 25% reduction in the use of fluoroquinolones and third- and fourth-generation cephalosporins by December 2016, taking 2013 as the reference year. etc. In 2013, the level of exposure was lower than that in 1999, the year the antimicrobial sales monitoring plan was launched (-5.5%). Over the last five years, overall animal exposure to antimicrobials has decreased by 15.7%. In 2013, animal exposure to antimicrobials fell by 7.3% compared to 2012. Exposure of animals to critical antimicrobials (third- and fourth-generation cephalosporins and fluoroquinolones) has stabilised over the past few years. In 2013 there was a significant fall in the use of cephalosporins and a smaller decrease in the use of fluoroquinolones. The increases observed in certain animal species should be monitored carefully however, in particular domestic carnivores in which disturbing increases have been observed (25% for cephalosporins, 12.2% for fluoroquinolones). 2 ESVAC reflection paper on collecting data on consumption of antimicrobial agents per animal species, on technical units of measurement and indicators for reporting consumption of antimicrobial agents in animals. http://www.ema.europa.eu/docs/en_gb/document_library/scientific_guideline/2012/12/wc500136456.pdf Page 5 of 73

The reductions observed are greater in certain animal sectors where specific measures have been introduced. For instance, following the initiative in the pig sector to voluntarily restrict the use of newergeneration cephalosporins, exposure of pigs to this class fell by 66% between 2010 and 2013. In its Opinion (published in April 2014) on the risk of emergence of antimicrobial resistance associated with patterns of antimicrobial, ANSES repeated its recommendation to reserve the use of newergeneration cephalosporins and fluoroquinolones as a last resort for specific situations that need to be identified for each sector and strictly regulated. The French bill on the future of farming sets a new target for reducing the use of cephalosporins and fluoroquinolones by 25% in three years (taking 2013 as the reference year). Reaching this target will require the continuation of measures taken and the introduction of new actions, especially in sectors where the use of these classes of compounds is high. The EcoAntibio 2017 plan is aiming to reduce the use of all antimicrobials by 25% in five years. The fall in exposure to antimicrobials observed in recent years, both overall and for certain species, seems to confirm the positive impact of the various measures taken regarding the rational use of antimicrobials. In two years, a 12.7% reduction has been observed, which is currently in line with the EcoAntibio 2017 target. Page 6 of 73

II. Introduction Antimicrobial resistance is a public health issue concerning both human and veterinary medicine. Monitoring of sales of antimicrobials is one of the important sources of information used for the assessment and management of risks related to antimicrobial resistance. The French Agency for Veterinary Medicinal Products (ANSES-ANMV) began monitoring sales of veterinary antimicrobials in 1999. This survey is based on the recommendations of the OIE guideline on "Monitoring of the quantities and usage patterns of antimicrobial agents used in food producing animals" from the OIE Terrestrial Animal Health Code 2014 - Chapter 6.8. France also participates in the European Surveillance of Veterinary Antimicrobial Consumption (ESVAC) scheme which was launched by the European Medicines Agency (EMA) at the request of the European Commission, with the aim of collecting harmonised data on antimicrobial sales for all countries in the European Union. In France, monitoring of antimicrobial sales is based on reporting by holders of marketing authorisations (MAs) obtained as a result of an agreement with the French Union for the Veterinary Medicinal Product and Reagent Industry (SIMV). All antimicrobials sold in France are recorded through this monitoring. Antimicrobial sales data are compared with other sources of information such as reported turnover from the companies marketing the veterinary drugs and data from epidemiological surveys of antimicrobial consumption. The present report describes the veterinary antimicrobial sales for 2013 and includes a comparison with results from previous years. Page 7 of 73

III. Materials and Methods a) Data used in this report Data provided by the Marketing Authorisation holders Monitoring of sales is based on a questionnaire sent annually to each Marketing Authorisation (MA) holder which has registered in France a veterinary medicinal product containing antimicrobials. MA holders are asked to declare the number of units sold for each commercial presentation of each veterinary medicinal product. Since 2009, MA holders have also been required to provide information, for each medicinal product, on the breakdown of sales by target species. These figures are supplied for the period from 1 January to 31 December and therefore cover all veterinary antimicrobials sold in 2013. Data on the French animal population To take into account fluctuations in the animal population when interpreting the data, the information published by Agreste 3 is used for food-producing animals. For domestic pets, data are provided by statistics from FACCO 4 (the French trade federation of food manufacturers for dogs, cats, birds and other pets), which are published every two years. Data on dosage and treatment duration For each drug and for each species, the dosage and treatment duration used are those defined in the Marketing Authorisation (MA). b) Data validation To avoid the risk of any reporting errors, sales volumes are compared with annual turnover reported independently by the MA holders. Any discrepancies are investigated. Significant differences compared to previous years are subject to a special audit. c) Calculation and interpretation of data Sales volumes for each commercial presentation are cross-referenced with data available in the ANSES-ANMV veterinary medicinal product database (qualitative and quantitative composition, pharmaceutical form, target species, etc.). In this annual report, critical antimicrobials are those belonging to the classes of newer-generation cephalosporins and fluoroquinolones. Conversion Calculations are then performed to express the sales in weight of active ingredient. For some active ingredients expressed in IU (international units), as recommended by the European Medicines Agency (EMA) in the framework of the ESVAC scheme, a conversion factor (WHO standard value) is used: - 74 IU for 1 mg of Bacitracin - 12700 IU for 1 mg of Colistin methanesulfonate sodium - 20500 IU for 1 mg of Colistin sulfate 3 http://agreste.agriculture.gouv.fr/ 4 http://www.facco.fr/ Page 8 of 73

- 820 IU for 1 mg of Dihydrostreptomycin - 920 IU for 1 mg of Erythromycin - 620 IU for 1 mg of Gentamicin - 755 IU for 1 mg for Neomycin - 8403 IU for 1 mg of Polymyxin B - 3200 IU for 1 mg of Spiramycin These coefficients are applied to sales from 1999 to 2013. Breakdown by species The interpretation of sales figures by species is made difficult by the fact that the same veterinary medicinal product may be intended for several animal species. It is therefore necessary to make an estimate of sales by species. Since the 2009 sales survey, MA holders have been asked to provide an estimate of the breakdown by target species for each drug. This estimate has been provided for all medicinal products. d) Expression of results To correctly interpret the data in this report, it is necessary to understand what information is used as a basis for the calculations of the proposed indicators. Several indicators are proposed because the results of this study may be used for different purposes. Some indicators may be preferred for assessing the correlation between sales of antimicrobials and antimicrobial resistance. Others will be more appropriate for monitoring global changes over time in prescription of veterinary medicinal products and for attempting to measure the impact of actions implemented at national level. For more details concerning the calculation of the various indicators, an indicator calculation guide is provided in Annex B of this report. Information used to calculate the indicators All the indicators are calculated using some or all of the following information: Quantity of active ingredient, Dosage, Duration of treatment, Weight of treated animals, Weight of adult animals or body weight at slaughter. These indicators can be calculated for all animal species, by species, by route of administration, by class of antimicrobials. In this study, the following information has been used: Quantity of active ingredient: calculated from sales figures for presentations of veterinary medicinal products and their quantitative composition in antimicrobials. Dosage: the dosage used is that from the Marketing Authorisation (MA). When multiple doses are possible, the highest dose is chosen, for the drug s main indication. Duration of treatment: the duration of treatment used is that from the MA. When multiple treatment durations are possible, the longest treatment duration is chosen, for the drug s main indication. Page 9 of 73

Weight of the animal population: the weights used correspond to the weights of adult animals for those with a life cycle of more than one year, and to the body weights at slaughter for others. Weight of animals at the time of treatment: currently, this weight is only taken into account in special cases when more detailed observations are needed. The weights at treatment chosen come from field surveys conducted by ANSES (for the study of exposure to newergeneration cephalosporins in pigs) or weights recorded in pharmacovigilance reports (for the study on exposure to antimicrobials in veal calves). Indicators of antimicrobial sales 1. Numerators used in the national sales monitoring plan QAI; the quantity of active ingredient in a unit of weight (mg, kg, tonne or international unit of activity) is easily deduced from trade of commercial units (boxes, cans, bottles, etc.). The active ingredient composition of each commercial unit is multiplied by the number of units sold (from national monitoring of sales) or acquired (from monitoring of antimicrobial uses) to obtain the corresponding weight of active ingredient. The ADDkg (Animal Daily Dose kilogram) is the dose needed to treat one kilogram of body weight during one day. The number of ADDkg is calculated by dividing the quantity of active ingredient by the value selected for the ADDkg (daily dosage from the MA under national monitoring of antimicrobial sales). The ADD (Animal Daily Dose) is the dose required to treat a typical animal for one day. The ACDkg (Animal Course Dose kilogram) is the dose required to treat one kilogram of body weight over the entire duration of treatment. The number of ACDkg (=WAT [Weight of animals treated]) is calculated by dividing the quantity of active ingredient by the value selected for the ACDkg (daily dose and duration of treatment from the MA under national monitoring of antimicrobial sales). The ACD (Animal Course Dose) is the dose required to treat a typical animal for the entire duration of treatment. Page 10 of 73

2. Denominator used in the national sales monitoring plan The denominator should represent the population of users or potential users of antimicrobials and enables population changes over time to be taken into account. The denominator used for the national monitoring of antimicrobial sales is the weight of animals potentially treated with antimicrobials (in kilograms produced). For some specific analyses, such as estimating the number of calves treated orally or estimating the number of pigs treated with newer-generation cephalosporins, the denominator is the number of animals potentially treated with antimicrobials. 3. Indicators Amount of active ingredient in mg of active ingredient per kg of body weight produced: by dividing the weight of the active ingredient by the animal mass potentially treated with antimicrobials, we obtain a quantity of active ingredient expressed in milligrams per kilogram of body weight. ALEA: by dividing the body weight treated (number of ACDkg) by the animal mass that could potentially be treated with antimicrobials, we obtain an expression of sales in ALEA (Animal Level of Exposure to Antimicrobials), the exposure indicator used by ANSES-ANMV. The mean duration of a treatment is obtained by dividing the number of ADDkg by the number of ACDkg. e) Important points concerning the 2013 survey Some dosages and treatment durations used to calculate the treated body weight have been revised and applied to earlier years. Some results are presented as a percentage of animals treated (sales of antimicrobials administered orally to calves and administration of newer-generation cephalosporins in the pig sector). The totals per year in body weight treated (in ADDkg or ACDkg) and ALEA are lower than the sum of body weight treated and ALEA per class, due to combinations of antimicrobials. Page 11 of 73

MEDICATED PREMIXES ORAL POWDERS AND SOLUTIONS OTHER ORAL FORMS (tablets, boluses, oral pastes) INJECTIONS INTRAMAMMARY & INTRAUTERINE TOTAL PERCENTAGE ANSES annual report Veterinary medicinal products containing antimicrobials in France in 2013 IV. Results for 2013 1. Results presented by antimicrobial class and route of administration - Results expressed in weight of active ingredient Table 1* Breakdown of sales (tonnage) of active ingredient for each antimicrobial class by route of administration AMINOGLYCOSIDES 10.28 7.69 0.17 34.72 1.54 54.40 7.78% CEPHALOSPORINS 1&2G 0 0 4.74 0.07 1.59 6.40 0.92% CEPHALOSPORINS 3&4G 0 0 0 1.80 0.33 2.13 0.31% OTHERS 0 0 1.53 0.05 0.13 1.73 0.25% FLUOROQUINOLONES 0 1.97 0.38 2.40 0 4.76 0.68% LINCOSAMIDES 2.21 1.48 0.29 0.57 0.03 4.58 0.65% MACROLIDES 15.08 25.27 0.98 10.53 0.08 51.94 7.43% PENICILLINS 12.72 33.00 4.58 33.76 2.56 86.62 12.39% PHENICOLS 0 0.15 0 4.55 0 4.69 0.67% PLEUROMUTILINS 2.53 3.09 0 0.02 0 5.64 0.81% POLYMYXINS 16.44 25.40 0.34 0.51 0.14 42.82 6.13% QUINOLONES 0.54 4.14 0.02 0 0 4.70 0.67% SULFONAMIDES 62.05 66.58 4.25 3.39 0 136.27 19.49% TETRACYCLINES 125.90 136.04 0.38 7.94 1.95 272.22 38.94% TRIMETHOPRIM 10.40 9.14 0.12 0.55 0 20.21 2.89% GENERAL TOTAL 258.15 313.94 17.78 100.86 8.36 699.09 100.00% PERCENTAGE 36.92% 44.90% 2.54% 14.43% 1.20% 100.00% * Sales of antimicrobials administered in local forms (sprays, creams, ear or eye solutions) are not presented in this report. They account for less than 0.5% of the tonnage of active ingredient sold. In 2013, the total volume of sales amounted to 699.09 tonnes of antimicrobials. Five antimicrobial classes (tetracyclines, sulfonamides, penicillins, aminoglycides and macrolides) accounted for around 86% of total antimicrobial sales. Tetracyclines alone represented approximately 39% of tonnage sold. Critical antimicrobials (newer-generation cephalosporins and fluoroquinolones) accounted for 1.0% of the tonnage of active ingredient sold. Page 12 of 73

- Results expressed in ACDkg (taking into account the dosage and duration of treatment) Table 2 5 Breakdown of sales in ACDkg for each antimicrobial class by route of administration (oral and parenteral routes only) MEDICATED PREMIXES ORAL POWDERS AND SOLUTIONS OTHER ORAL FORMS INJECTIONS TOTAL PERCENTAGE AMINOGLYCOSIDES CEPHALOSPORINS 1&2G CEPHALOSPORINS 3&4G OTHERS FLUOROQUINOLONES LINCOSAMIDES MACROLIDES PENICILLINS PHENICOLS PLEUROMUTILINS POLYMYXINS QUINOLONES SULFONAMIDES TETRACYCLINES TRIMETHOPRIM TOTAL (in tonnes) PERCENTAGE 57,065 69,944 4,782 620,978 752,770 9.01% - - 8,622 668 9,289 0.11% - - - 306,104 306,104 3.66% - 111 38,333 6,104 44,548 0.53% - 41,494 14,773 288,754 345,021 4.13% 20,745 38,833 468 19,979 80,025 0.96% 124,323 207,876 4,194 560,258 896,652 10.73% 99,498 542,055 38,841 938,432 1,618,826 19.37% - 2,794-116,935 119,729 1.43% 31,598 41,028-367 72,993 0.87% 338,677 1,363,116 16,048 70,609 1,788,450 21.40% 6,355 55,114 227-61,696 0.74% 271,152 342,006 21,883 69,228 704,268 8.43% 408,161 1,517,367 7,413 434,772 2,367,714 28.33% 232,166 274,349 4,095 65,726 576,336 6.90% 1,318,682 4,181,204 100,129 2,758,422 8,363,438 100.00% 15.78% 50.02% 1.20% 33.00% 100.00% Sales expressed in ACDkg show that animals are treated primarily with tetracyclines, polymyxins, penicillins and macrolides, followed by aminoglycosides and sulfonamides. More than 7.8% of body weight treated in veterinary medicine is treated with a critical antimicrobial. Medicated premixes are generally medicinal products containing older compounds administered at high doses and over a long period. Although they account for nearly 37% of the tonnage of active ingredient sold, they represent less than 16% of body weight treated. Oral powders and solutions represent 50% of total body weight treated, and injections around 33% of total body weight treated with antimicrobials. For medicated premixes, the tetracycline class accounts for over 30% of body weight treated, and the polypeptide class for around 25% of body weight treated. Over 36% of the body weight treated with oral powders or solutions is treated with tetracyclines, and nearly 33% with polymyxins. For parenteral administration, in terms of body weight treated, penicillins are the class most commonly used, followed by aminoglycosides, macrolides and tetracyclines. 5 The totals per year in body weight treated (in ADDkg or ACDkg) are lower than the sum of body weight treated per class, due to combinations of antimicrobials. Page 13 of 73

Fluoroquinolones and third- and fourth-generation cephalosporins were used to treat respectively 10.5% and 11.1% of the total body weight treated by the parenteral route. Figure 1 Relative proportions of pharmaceutical forms in the body weight treated by different classes of antimicrobials 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% MEDICATED PREMIXES OTHER ORAL FORMS ORAL POWDERS AND SOLUTIONS INJECTIONS Polymyxins, tetracyclines, sulfonamides and trimethoprim are mainly administered orally. Aminoglycosides, penicillins, macrolides and fluoroquinolones are primarily administered by the parenteral route, while newer-generation cephalosporins are not administered orally (no marketing authorisation in France). Page 14 of 73

2. Results by species - Results expressed in weight of active ingredient Table 3 Breakdown of sales for 2013 between the different species in tonnage of active ingredient and quantity of active ingredient per animal kg Cattle Cats & Dogs Horses Fish Rabbits Sheep & Goats Pigs Poultry Other Total Tonnage sold 147.17 15.17 15.31 2.86 52.46 45.16 262.12 156.57 2.27 699.09 Percentage 21.1% 2.2% 2.2% 0.4% 7.5% 6.5% 37.5% 22.4% 0.3% 100.0% Sales in mg/kg 15.81 96.68 51.44 63.57 517.57 78.93 91.30 85.60 65.25 45.95 Body weight treated According to the information on the breakdown by species transmitted to ANSES-ANMV by the pharmaceutical companies, more than 37% of the tonnage of antimicrobials sold is intended for pigs, more than 22% is intended for poultry and 21% is destined for cattle. In 2013, 45.95 mg of antimicrobials were sold per kilogram of body weight, with differences depending on the species. When expressed in weight of active ingredient, the results are not representative of the exposure to antimicrobials of the animal species. - Results expressed in body weight treated (ACDkg) Table 4 Breakdown of sales for 2013 between the different species in body weight treated (ACDkg) and ALEA exposure level indicator Cattle Cats & Dogs Horses Fish Rabbits Sheep & Goats Pigs Poultry Other Total 2,839,593 104,770 108,806 8,027 273,824 231,361 2,730,607 2,043,147 18,300 8,363,438 Percentage 34.0% 1.3% 1.3% 0.1% 3.3% 2.8% 32.6% 24.4% 0.2% 100% ALEA 0.305 0.668 0.366 0.178 2.701 0.404 0.951 1.117 0.525 0.550 More than 34% of body weight of animals treated corresponded to cattle, over 32% to pigs and more than 24% to poultry. The ALEA indicator best reflects exposure to antimicrobials as it takes into account information on the treatments (dose and duration) and on potential users (weight of the animal population potentially treated with antimicrobials). If the ALEA is equal to 1, it means that, for a given species, the estimated body weight treated is exactly the same as the total body weight (product) of the animal population. An ALEA of 0.305 for cattle means that in 2013, sales of antimicrobials intended for this animal sector were used to treat 30.5% of the total body weight of cattle. It thus appears that rabbits, poultry and pigs are the species most exposed to antimicrobials. This indicator does not take into account potential differences in treatment between young animals and adults; so according to our estimates (see VI.1 Oral exposure of calves to antimicrobials), the ALEA for veal calves is similar to the ALEA for rabbits. To better assess the use of antimicrobials, the weight of the animals during treatment should be taken into account and not the adult weight or weight at slaughter. Page 15 of 73

V. Change in sales and exposure to antimicrobials between 1999 and 2013 1. Change in sales and exposure to antimicrobials by pharmaceutical form - Results expressed in weight of active ingredient See Table 5 Change in the weight of active ingredient by pharmaceutical form (in tonnes) Over 15 years of monitoring, the tonnage of antimicrobials sold has fluctuated between 699.09 and 1383.64 tonnes. The tonnage of antimicrobials sold in 2013 was the lowest since monitoring of sales began. The total sold in 2013 fell by 10.6% compared to the total sold in 2012 and has declined by 34.0% over the last five years. This decrease is largely attributable to lower sales of orally administered antimicrobials, and medicated premixes in particular. - Results expressed in body weight treated 6 See Table 6, Change in body weight treated (ACDkg) annually by pharmaceutical form and Table 8, Change in the number of treatments by the intramammary route The body weight treated was calculated by drug for the different oral forms and injections. For intramammary drugs, the results are expressed in number of animals treated with antimicrobials. The tonnage of body weight treated in 2013 was the lowest estimate since monitoring of sales began. The body weight treated in 2013 decreased by 17.6% compared to 1999, by 19.6% over the past five years and by 7.7% compared to the total sold in 2012. This decrease is largely attributable to lower sales of antimicrobials in the form of medicated premixes. Over the 15 years of monitoring, the body weight treated with medicated premixes has decreased by 65.0%, the body weight treated with oral powders and solutions has increased by 27.4% and the body weight treated parenterally has decreased by 7.1%. Over the last five years, the body weight treated with medicated premixes has decreased by 48.4%, the body weight treated with oral powders and solutions has fallen by 17.9% and the body weight treated parenterally has increased by 4.5%. Between 2012 and 2013, the body weight treated with medicated premixes decreased by 15.7%, the body weight treated with oral powders and solutions fell by 7.9% and the body weight treated parenterally fell by 3.2%. 6 This year, some dosages and treatment durations used for the calculation of body weight treated have been revised; these changes have been applied to earlier years to make the results from different years comparable. Page 16 of 73

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 ANSES annual report Veterinary medicinal products containing antimicrobials in France in 2013 Figure 2 Change in treatments (oral and parenteral) by pharmaceutical form since 1999 14 000 000 12 000 000 10 000 000 8 000 000 6 000 000 4 000 000 2 000 000 INJECTIONS OTHER ORAL FORMS ORAL POWDERS AND SOLUTIONS MEDICATED PREMIXES 0 The number of intramammary treatments decreased by 25.6% between 1999 and 2013, while over the same period the total number of dairy cows decreased by 16.4%. While the estimated number of intramammary treatments per dairy cow was 1.58 in 2012, it was 1.50 in 2013. - Results expressed in exposure level indicator See Table 7 Change in exposure level indicator (ALEA) by pharmaceutical form The level of animal exposure to antimicrobials, all routes and animal species combined, fell by 5.5% between 1999 and 2013. Over the last five years, overall exposure has decreased by 15.7%. In 2013, exposure decreased by 7.3% compared to the previous year. Exposure to antimicrobials via medicated premixes has fallen by 59.9% since 1999. Over the last five years, there has been a 45.9% decrease in exposure to this form of antimicrobials. In 2013, exposure decreased by 15.4% compared to the previous year. Over the 15 years of monitoring, exposure to antimicrobials via oral powders and solutions has risen by 46.2%. Over the last five years, animal exposure to oral powders and solutions has decreased by 13.9%. In 2013, exposure decreased by 7.6% compared to the previous year. Exposure to antimicrobials via other orally administered forms (pastes, tablets, boluses, etc.) has been relatively stable since 1999. Exposure via injections has risen by 6.4% over the 15 years of monitoring and by 9.4% over the last five years. In 2013, exposure decreased by 2.8% compared to the previous year. Page 17 of 73

ANSES annual report Veterinary medicinal products containing antimicrobials in France in 2013 Table 5 Change in the weight of active ingredient by pharmaceutical form (in tonnes) 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 MEDICATED PREMIXES 853.26 878.05 821.24 732.31 687.18 650.55 652.56 626.16 712.16 626.55 535.11 494.96 406.69 303.90 258.15 ORAL POWDERS AND SOLUTIONS 284.61 331.51 383.59 430.96 450.67 464.90 495.34 459.45 473.87 404.73 392.95 388.01 369.15 345.42 313.94 OTHER ORAL FORMS 20.18 19.43 19.29 18.66 18.58 18.97 20.18 21.43 20.91 21.39 19.50 20.10 19.69 18.77 17.78 INJECTIONS 138.98 139.53 137.06 131.05 123.93 114.42 116.34 120.10 110.05 108.73 101.70 101.86 104.12 104.70 100.86 INTRAMAMMARY & INTRAUTERINE 14.25 15.13 13.68 13.63 13.49 11.82 11.71 10.58 10.92 10.99 9.60 9.77 10.11 9.05 8.36 TOTAL 1,311.29 1,383.65 1,374.86 1,326.60 1,293.84 1,260.66 1,296.14 1,237.71 1,327.92 1,172.38 1,058.86 1,014.69 909.76 781.84 699.09 Table 6 Change in body weight treated (ACDkg) by pharmaceutical form (in tonnes) 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 MEDICATED PREMIXES 3,772,128 3,923,173 3,737,925 3,443,259 3,233,197 2,969,194 2,926,738 2,927,973 3,256,544 2,789,002 2,557,471 2,390,104 2,031,075 1,564,014 1,318,682 ORAL POWDERS AND SOLUTIONS 3,281,358 3,925,447 4,582,477 5,135,194 5,435,511 5,498,621 5,975,769 5,689,430 5,762,853 5,071,699 5,095,696 5,097,669 4,853,442 4,541,864 4,181,204 OTHER ORAL FORMS 121,235 126,215 115,841 116,409 118,511 116,248 121,817 120,184 115,886 120,640 111,028 115,800 108,743 101,022 100,129 INJECTIONS 2,975,540 2,933,253 2,927,698 2,872,108 2,893,532 2,678,733 2,837,273 2,983,572 2,777,476 2,803,620 2,640,436 2,741,226 2,788,408 2,850,535 2,758,422 TOTAL 10,150,261 10,908,087 11,363,942 11,566,971 11,680,752 11,262,796 11,861,597 11,721,160 11,912,759 10,784,960 10,404,631 10,344,800 9,781,667 9,057,434 8,363,438 Table 7 Change in exposure level indicator (ALEA) by pharmaceutical form 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 MEDICATED PREMIXES 0.216 0.223 0.208 0.197 0.191 0.178 0.184 0.183 0.202 0.172 0.160 0.152 0.131 0.102 0.087 ORAL POWDERS AND SOLUTIONS 0.188 0.223 0.255 0.294 0.321 0.330 0.375 0.356 0.357 0.314 0.319 0.324 0.312 0.297 0.275 OTHER ORAL FORMS 0.007 0.007 0.006 0.007 0.007 0.007 0.008 0.008 0.007 0.007 0.007 0.007 0.007 0.007 0.007 INJECTIONS 0.170 0.167 0.163 0.164 0.171 0.161 0.178 0.187 0.172 0.173 0.165 0.174 0.179 0.187 0.181 TOTAL 0.581 0.619 0.633 0.662 0.690 0.676 0.744 0.734 0.738 0.667 0.652 0.657 0.629 0.593 0.550 Table 8 Change in the number of treatments by the intramammary route 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 NUMBER OF INTERMAMMARY TREATMENTS 7,450,793 7,586,776 6,854,031 7,092,073 7,181,681 6,330,748 6,363,945 6,358,545 6,070,081 6,282,949 5,368,714 5,578,901 6,141,693 5,739,498 5,542,965 NUMBER OF TREATMENTS PER DAIRY COW 1.68 1.83 1.63 1.72 1.79 1.66 1.61 1.64 1.57 1.63 1.43 1.49 1.68 1.58 1.50 Page 18 of 73

2. Change in sales and exposure to antimicrobials by class See table in annex. Change in the mass of the animal population by species from 1999 to 2013 in tonnes (Annex A, Table A2) - Results expressed in weight of active ingredient relative to the weight of the animal population See table in annex. Change in antimicrobial sales in tonnes of active ingredient sold per class between 1999 and 2013 (Annex D, Table D1) See Table 9 Change in sales by antimicrobial class from 1999 to 2013 in mg of active ingredient per kilogram of body weight (mg/kg) In 2013, the equivalent of 45.95 mg of antimicrobial per kg of body weight produced was sold, the lowest amount in mg/kg of antimicrobials over the last 15 years. Over the last five years, the amount in mg/kg of antimicrobials sold has decreased by 30.7%. These results, expressed in mg of active ingredient per kilogram of body weight, show that the observed decrease is essentially due to a decline in sales of tetracyclines and sulfonamides. Compared to 1999, and expressed in this way, the amount of fluoroquinolones sold has increased by 65.7% while that of first-generation quinolones has decreased by 72.7%. Over the last five years, the amount of fluoroquinolones sold in mg/kg has increased by 2%. Compared to 1999, sales of third- and fourth-generation cephalosporins in mg/kg have increased by 165.8% and those from the first and second generations have risen by 39.9%. Over the last five years, the amount in mg/kg of third- and fourth-generation cephalosporins sold has risen by 22.4%, while the amount in mg/kg of first- and second-generation cephalosporins has fallen by 4.2%. - Results expressed as Animal Level of Exposure to Antimicrobials (ALEA) See table in annex. Change in antimicrobial sales by class in tonnes of body weight treated (WAT or ACDkg) between 1999 and 2013 (Annex D, Table D2) See Table 10. Change in sales by antimicrobial class from 1999 to 2013 expressed in ALEA (oral and parenteral routes only) The level of animal exposure to antimicrobials, all classes and animal species combined, fell by 5.5% between 1999 and 2013. Over the last five years, overall exposure has decreased by 15.7%. And in 2013, exposure decreased by 7.3% compared to the previous year. Over the 15 years of monitoring, the number of MAs for fluoroquinolones or cephalosporins has increased. Over the same period, exposure to newer-generation cephalosporins has increased by 145.4% and exposure to fluoroquinolones has doubled. Over the last five years, exposure to third- and fourth-generation cephalosporins has increased by 14.1% and exposure to fluoroquinolones has stabilised. Compared with 2012, in 2013, exposure to the newer-generation cephalosporins fell by 9.8% and exposure to fluoroquinolones fell by 1.5% (see VII. Update on exposure to fluoroquinolones and third- and fourth-generation cephalosporins). Page 19 of 73

ANSES annual report Veterinary medicinal products containing antimicrobials in France in 2013 Table 9 Change in sales by antimicrobial class from 1999 to 2013 in mg of active ingredient per kilogram of body weight (mg/kg) 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 AMINOGLYCOSIDES 4.68 5.09 5.15 5.16 4.83 4.72 4.81 4.86 4.60 4.51 4.06 3.97 4.09 3.76 3.58 CEPHALOSPORINS 1&2G 0.30 0.30 0.29 0.35 0.40 0.40 0.45 0.40 0.44 0.45 0.44 0.38 0.45 0.43 0.42 CEPHALOSPORINS 3&4G 0.05 0.06 0.06 0.07 0.08 0.08 0.10 0.12 0.12 0.13 0.11 0.14 0.15 0.15 0.14 OTHERS 0.09 0.09 0.09 0.09 0.06 0.09 0.09 0.13 0.12 0.12 0.12 0.13 0.12 0.11 0.11 FLUOROQUINOLONES 0.19 0.21 0.23 0.24 0.26 0.26 0.27 0.30 0.29 0.30 0.31 0.33 0.34 0.32 0.31 LINCOSAMIDES 0.34 0.46 0.52 0.62 0.60 0.57 0.63 0.56 0.56 0.48 0.45 0.43 0.35 0.31 0.30 MACROLIDES 4.55 5.01 5.67 6.19 6.03 5.79 6.27 6.43 6.05 5.87 5.22 5.17 4.53 3.99 3.41 PENICILLINS 5.18 5.49 5.25 5.58 5.43 5.06 5.56 5.80 5.80 5.26 5.43 5.75 5.81 5.64 5.69 PHENICOLS 0.25 0.26 0.25 0.32 0.25 0.29 0.29 0.38 0.36 0.31 0.30 0.32 0.29 0.30 0.31 PLEUROMUTILINS 1.78 1.87 1.44 1.45 1.30 0.97 0.52 0.63 0.62 0.49 0.51 0.48 0.44 0.37 0.37 POLYMYXINS 3.85 4.00 4.01 3.89 3.98 3.79 4.16 4.18 4.58 4.06 4.16 4.13 3.91 3.36 2.81 QUINOLONES 1.13 0.94 0.83 0.91 0.83 0.75 0.83 0.82 0.68 0.49 0.47 0.51 0.40 0.35 0.31 SULFONAMIDES 14.84 15.36 13.66 13.07 12.35 12.58 13.50 13.22 13.91 12.05 11.35 11.05 10.98 9.51 8.96 TETRACYCLINES 35.73 37.23 37.08 36.05 38.17 38.29 41.58 37.56 42.06 36.14 31.63 29.97 25.07 21.17 17.89 TRIMETHOPRIM 2.14 2.19 2.01 1.94 1.92 2.03 2.23 2.07 2.10 1.83 1.76 1.67 1.60 1.39 1.33 TOTAL 75.11 78.56 76.53 75.93 76.48 75.67 81.30 77.46 82.30 72.49 66.33 64.42 58.54 51.19 45.95 Table 10 Change in sales by antimicrobial class from 1999 to 2013 expressed in ALEA (oral and parenteral routes only) 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 AMINOGLYCOSIDES 0.061 0.062 0.063 0.062 0.061 0.064 0.066 0.066 0.063 0.060 0.054 0.052 0.053 0.050 0.049 CEPHALOSPORINS 1&2G 0.000 0.000 0.000 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 CEPHALOSPORINS 3&4G 0.008 0.010 0.009 0.011 0.013 0.013 0.016 0.019 0.019 0.021 0.018 0.022 0.022 0.022 0.020 OTHERS 0.003 0.002 0.002 0.002 0.002 0.002 0.002 0.003 0.003 0.003 0.003 0.003 0.003 0.003 0.003 FLUOROQUINOLONES 0.011 0.012 0.015 0.017 0.020 0.019 0.022 0.024 0.021 0.023 0.023 0.023 0.023 0.023 0.023 LINCOSAMIDES 0.007 0.009 0.011 0.013 0.012 0.011 0.011 0.010 0.009 0.009 0.008 0.007 0.006 0.005 0.005 MACROLIDES 0.054 0.061 0.067 0.074 0.073 0.069 0.078 0.079 0.071 0.071 0.068 0.070 0.067 0.063 0.059 PENICILLINS 0.098 0.105 0.101 0.098 0.101 0.094 0.105 0.108 0.107 0.097 0.098 0.105 0.108 0.106 0.106 PHENICOLS 0.006 0.007 0.006 0.008 0.006 0.007 0.007 0.009 0.009 0.008 0.008 0.008 0.008 0.008 0.008 PLEUROMUTILINS 0.024 0.026 0.020 0.020 0.018 0.014 0.008 0.008 0.008 0.006 0.006 0.006 0.005 0.005 0.005 POLYMYXINS 0.113 0.120 0.123 0.126 0.135 0.131 0.148 0.152 0.157 0.147 0.150 0.153 0.147 0.131 0.118 QUINOLONES 0.013 0.012 0.010 0.011 0.010 0.009 0.010 0.010 0.008 0.006 0.006 0.006 0.005 0.005 0.004 SULFONAMIDES 0.072 0.074 0.069 0.066 0.062 0.063 0.067 0.065 0.068 0.060 0.056 0.055 0.055 0.048 0.046 TETRACYCLINES 0,183 0,191 0,204 0,217 0,241 0,244 0,271 0,248 0,258 0,216 0,208 0,199 0,182 0,177 0,156 TRIMETHOPRIM 0.054 0.056 0.053 0.050 0.049 0.050 0.055 0.052 0.054 0.048 0.046 0.045 0.044 0.039 0.038 TOTAL 0.581 0.619 0.633 0.662 0.690 0.676 0.744 0.734 0.738 0.667 0.652 0.657 0.629 0.593 0.550 Page 20 of 73

VI. Change in exposure to antimicrobials by species 1. Results for cattle See Tables 11a and 11b. Change in sales of antimicrobials for cattle - Results expressed in weight of active ingredient Between 1999 and 2005, the tonnage intended for cattle increased considerably; since then it has declined, reaching its lowest level since 1999 in 2013. The tonnage of newer-generation cephalosporins has risen by 154% over the 15 years of monitoring, and the tonnage of fluoroquinolones has increased by 119%. - Results expressed in body weight treated The body weight treated (ACDkg) in 2013 fell by 6.1% compared to 2012 and by 4.2% compared to 2009. However, the body weight treated in 2013 was higher than that estimated in 1999 (the year when monitoring began). Figure 3. Change in body weight of cattle treated according to the route of administration (in tonnes) 2500000 2000000 1500000 1000000 Oral Injection 500000 0 Page 21 of 73