Sales survey of veterinary medicinal products containing antimicrobials in France in Annual report

Sales survey of veterinary medicinal products containing antimicrobials in France in 2016 Annual report October 2017 Scientific edition

Sales survey of veterinary medicinal products containing antimicrobials in France in 2016 Rapport annuel October 2017 Scientific edition

Sales survey of veterinary medicinal products containing antimicrobials in France in 2016 Authors: French Agency for Food, Environmental and Occupational Health & Safety (ANSES) - French Agency for Veterinary Medicinal Products (ANMV) Delphine Méheust, Anne Chevance and Gérard Moulin, ANSES-ANMV

CONTENTS CONTENTS... 1 I. Abstract... 5 II. Introduction... 9 III. Materials and Methods... 10 1. Data used in this report... 10 2. Calculations and interpretation of indicators... 11 3. Important points concerning the 2016 annual report... 12 IV. Tonnages of antimicrobials sold and exposure indicators in 2016... 14 1. Tonnages by antimicrobial class and route of administration... 14 2. Tonnages by species... 15 3. Indicators by antimicrobial class and route of administration... 16 4. Indicators by species... 18 V. Change in sales and exposure to antimicrobials between 1999 and 2016... 19 1. Change in sales and exposure to antimicrobials by pharmaceutical form... 19 2. Change in sales and exposure to antimicrobials by class... 22 VI. Change in exposure to antimicrobials by species... 26 1. Cattle... 26 2. Pigs... 31 3. Poultry... 36 4. Rabbits... 40 5. Domestic carnivores... 44 VII. Update on exposure to fluoroquinolones, third- and fourth-generation cephalosporins and colistin 48 1. Change in exposure to fluoroquinolones... 48 2. Change in exposure to newer-generation cephalosporins... 52 3. Change in exposure to colistin... 55 VIII. Comparison of exposure calculations and indicators between the French and European approaches... 60 1. Publication of the DDDvet and DCDvet values by the ESVAC... 60 2. Differences in the calculations between the French and European approaches... 60 1

3. Comparison by species for 2016... 60 4. Change in exposure indicators since 2011... 62 IX. Discussion... 64 1. Indicators of sales and indicators of exposure... 64 2. Collection of data on prescription and use... 64 3. Change in exposure of animals to antimicrobials... 65 X. Conclusion... 67 XI. Annexes... 68 1. Data on animal populations... 69 2. Change in sales and exposure to antimicrobials between 1999 and 2016... 75 3. Change in exposure to antimicrobials by species... 81 XII. Guide to indicators... 96 2

Table of illustrations Figure 1: Relative average proportions of pharmaceutical forms in the body weight treated by different classes of antimicrobials in 2016... 17 Figure 2: Change in ALEA by pharmaceutical form since 1999... 21 Figure 3: Change in animal exposure by antimicrobial class (ALEA)... 24 Figure 4: Change in exposure of cattle by antimicrobial class (ALEA)... 27 Figure 5: Change in exposure of cattle by routes of administration since 1999 (ALEA)... 29 Figure 6: Change in the number of intramammary treatments per dairy cow during the lactation period and at dry-off since 1999... 29 Figure 7: Change in exposure of pigs by antimicrobial class (ALEA)... 32 Figure 8: Change in exposure of pigs by pharmaceutical forms since 1999 (ALEA)... 34 Figure 9: Change in the estimated percentage of pigs treated with newer-generation cephalosporins since 1999... 34 Figure 10: Change in exposure of poultry by antimicrobial class (ALEA)... 37 Figure 11: Change in exposure of poultry by pharmaceutical forms since 1999 (ALEA)... 39 Figure 12: Change in exposure of rabbits by antimicrobial class (ALEA)... 41 Figure 13: Change in exposure of rabbits by pharmaceutical forms since 1999 (ALEA)... 43 Figure 14: Change in exposure of domestic carnivores by antimicrobial class (ALEA)... 45 Figure 15: Change in exposure of domestic carnivores by routes of administration since 1999 (ALEA)... 47 Figure 16: Change in exposure to fluoroquinolones (ALEA)... 48 Figure 17: Change in body weight treated with fluoroquinolones according to the species (in tonnes) 49 Figure 18: Change in body weight treated parenterally with fluoroquinolones (in tonnes)... 50 Figure 19: Change in the body weight treated parenterally with fluoroquinolones as a percentage of the body weight treated parenterally with antimicrobials... 50 Figure 20: Change in body weight treated orally with fluoroquinolones (in tonnes)... 51 Figure 21: Change in the body weight treated orally with fluoroquinolones as a percentage of the body weight treated orally with antimicrobials... 51 Figure 22: Change in exposure to newer-generation cephalosporins (ALEA)... 52 Figure 23: Change in body weight treated with newer-generation cephalosporins (in tonnes)... 53 Figure 24: Change in the body weight treated with newer-generation cephalosporins as a percentage of the body weight treated parenterally with antimicrobials... 54 Figure 25: Change in exposure to colistin according to the pharmaceutical forms (ALEA)... 55 Figure 26: Change in body weight treated with colistin according to the species (in tonnes)... 55 Figure 27: Change in body weight treated by premixes based on colistin (tonnes)... 57 Figure 28: Change in body weight treated by oral forms (excluding premixes) based on colistin (tonnes)... 58 Figure 29: Change in body weight treated parenterally with colistin (in tonnes)... 58 3

Figure 30: Comparison of body weight treated in 2016 according to the French and European approaches (tonnes)... 61 Figure 31: Comparison of body weight treated day in 2016 according to the French and European approaches (tonnes)... 61 Figure 32: Change in body weight treated since 2011 according to the French and European approaches (tonnes)... 62 Figure 33: Change in body weight treated day since 2011 according to the French and European approaches (tonnes)... 63 Table 1: Breakdown of sales for 2016 in tonnage of active ingredient for each antimicrobial class by route of administration... 14 Table 2: Breakdown of sales for 2016 between the different species in tonnage of active ingredient and quantity of active ingredient per kilogram of body weight... 15 Table 3: Body weight treated for 2016 according to the classes of antimicrobials and routes of administration (in tonnes)... 16 Table 4: Breakdown of sales for 2016 between the different species in tonnage of body weight treated and ALEA exposure indicator... 18 Table 5: Change in the indicator of exposure by pharmaceutical form (ALEA)... 20 Table 6: Change in sales by antimicrobial class since 1999 in mg of active ingredient per kilogram of body weight (mg/kg)... 22 Table 7: Change in animal exposure in France by antimicrobial class since 1999 (ALEA calculated for the oral and parenteral routes only)... 25 Table 8: Change in exposure of cattle by antimicrobial class since 1999 (ALEA calculated for the oral and parenteral routes only)... 28 Table 9: Change in exposure of pigs by antimicrobial class since 1999 (ALEA calculated for the oral and parenteral routes only)... 33 Table 10: Change in exposure of poultry by antimicrobial class since 1999 (ALEA calculated for the oral and parenteral routes only)... 38 Table 11: Change in exposure of rabbits by antimicrobial class since 1999 (ALEA calculated for the oral and parenteral routes only)... 42 Table 12: Change in exposure of domestic carnivores by antimicrobial class since 1999 (ALEA calculated for the oral and parenteral routes only)... 46 Table 13: Change in the quantities of colistin sold according to the European indicator (mg/pcu)... 59 4

I. Abstract The French Agency for Veterinary Medicinal Products (ANSES-ANMV) has been monitoring sales of veterinary antimicrobials in France since 1999. Its survey is based on the recommendations of Chapter 6.8 of the OIE Terrestrial Animal Health Code: "Monitoring of the quantities and usage patterns of antimicrobial agents used in food-producing animals". It is carried out with the participation of the French Union for the Veterinary Medicinal Product and Reagent Industry (SIMV), based on annual reporting of antimicrobial sales by the pharmaceutical companies marketing them. The companies also provide an estimated breakdown of the drugs sold by target species. The information collected from the companies covers 100% of authorised drugs 1. The information gathered in the context of 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. Background The first EcoAntibio plan was published in November 2011. This plan aimed to reduce the use of antimicrobials by 25% in five years, with particular attention being paid to the use of antimicrobials of critical importance in veterinary and human medicine. The results for 2016 correspond to the last year of the plan and help provide a quantified assessment of how the use of antimicrobials has evolved over this period. The Act on the future of agriculture, food and forestry (LAAAF 2, Act No. 2014-1170 of 13 October 2014) added specific objectives for antimicrobials of critical importance in human medicine. It thus set a target of a 25% reduction in three years in the use of antimicrobials belonging to the classes of fluoroquinolones and third- and fourth-generation cephalosporins, taking 2013 as the reference year. With effect from 1 January 2015, this Act brought an end to discounts, rebates and reductions for veterinary medicinal products containing antimicrobials. The data on the sales of veterinary medicinal products containing antimicrobials have been interpreted for 2014 and 2015 based on the average for the two years, in order to smooth the phenomenon of drug stockpiling by the players involved in distribution and/or prescription, which was observed in 2014. Tonnage of active ingredient sold In 2016, the total sales volume for antimicrobials amounted to 530 tonnes, a fall of 18.5% compared to the average for 2014 and 2015 (651 tonnes). While 1311 tonnes of antimicrobials were sold in France in 1999, the figure was 910 tonnes in 2011, the EcoAntibio plan s year of reference. The 530 tonnes recorded in 2016 reflect a reduction of 41.8% compared with 2011. 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 antimicrobials under the provisions of the cascade approach (Article L. 5143-4 of the French Public Health Code) is not taken into account. 2 http://www.legifrance.gouv.fr/affichloipubliee.do;jsessionid=5691bba0e2987b8fcbb6195e53853f64.tpdjo07v_2?type=gene ral&iddocument=jorfdole000028196878 5

Exposure to antimicrobials Given the differences in potency and dose between different drugs, 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 of active ingredient. 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. In 2016, the ALEA fell by 20.5% compared with the average for 2014 and 2015. Since monitoring began in 1999, the ALEA has declined by 31.4% in France. Over the last five years, overall exposure has decreased by 36.6%. The objective of the first EcoAntibio plan to reduce the use of antimicrobials by 25% in five years has therefore been achieved and even greatly exceeded. The decline in exposure to antimicrobials was observed for all species compared to 2011 (cattle: -24.3%, pigs: -41.5%, poultry: -42.8%, rabbits: -37.6%, cats and dogs: -19.4%). Exposure to fluoroquinolones and newer-generation cephalosporins Third- and fourth-generation cephalosporins and fluoroquinolones are considered as particularly important in human medicine because they are among the only alternatives for the treatment of certain infectious diseases in humans. The Act on the future of agriculture, food and forestry set a target of a 25% reduction in three years in the use of antimicrobials belonging to each of these classes. The year 2013 was taken as a reference for this objective, which is to be achieved by the end of December 2016 at the latest. Exposure to newer-generation cephalosporins decreased by 81.3% in 2016 compared to 2013, all species combined. The ALEA for this class of antimicrobials decreased for cattle (-81.6%), pigs (- 85.1%) and domestic carnivores (-71.6%). A 74.9% decrease in exposure to fluoroquinolones was observed in 2016 compared to 2013. The ALEA for this class of antimicrobials decreased for cattle (-82.6%), pigs (-72.7%), poultry (-45.3%) and domestic carnivores (-57.4%). The objective to reduce the use of fluoroquinolones and third- and fourth-generation cephalosporins by 25% in three years has therefore been achieved and even greatly exceeded. Exposure to colistin The article published in November 2015 describing the first plasmid-mediated mechanism of resistance to colistin led to the establishment of reinforced surveillance for this antimicrobial. At European level, in July 2016, the Antimicrobial Advice Ad Hoc Expert Group (AMEG) 3 recommended reducing the use of colistin to less than 5 mg/pcu (Population Correction Unit) in 3 to 4 years for European countries that are high or moderate consumers, and less than 1 mg/pcu for European countries with the lowest use of colistin. 3 http://www.ema.europa.eu/docs/en_gb/document_library/scientific_guideline/2016/07/wc500211080.pdf 6

In France, in its report 4 on the subject published in October 2016, ANSES recommended a 50% reduction in the use of colistin. Following this opinion, the EcoAntibio2 plan (Action 12) set the goal of a 50% reduction in five years in exposure to colistin in the cattle, pig and poultry sectors, taking as a reference the average ALEA for 2014-2015. With an ALEA of 0.064 for 2016, exposure to colistin has decreased by 40.3% compared to the average exposure calculated for 2014 and 2015. Exposure in 2016 decreased for cattle (-43.4%), pigs (-51.6%) and poultry (-26.7%) compared to the average exposure for the years 2014-2015. A 55.1% decrease in exposure was observed compared to 2011 (all species and routes of administration combined). Calculating the results in mg/pcu according to the standards defined by the European Surveillance of Veterinary Antimicrobial Consumption (ESVAC) scheme, the value obtained for colistin in 2016 was 2.82 mg/pcu while it was 5.96 mg/pcu in 2013. In 2016, the quantities of colistin sold in France were therefore less than 5 mg/pcu threshold advocated by the AMEG. Comparison of exposure calculations and indicators between the French and European approaches In April 2016, the ESVAC scheme published reference values (DDDvet and DCDvet) for three animal species: cattle, pigs and broilers (poultry). A comparative analysis was performed for the last five years, using on the one hand the European reference values and on the other the French reference values. Analysis of the indicators reveals differences that can be explained by different methodological choices: the European reference values were established on the basis of marketing authorisation data from nine Member States, whereas the specific dosages of each drug sold in France are used for the national monitoring. Nevertheless, when examining the comparative changes in the indicators calculated with the French and European reference values, a similar trend can be observed. Conclusion The objectives laid down by the first EcoAntibio plan and by the Act on the future of agriculture, food and forestry (No. 2014-1170 of 13 October 2014) have been achieved and even greatly exceeded: - 36.6% decrease in five years in exposure to antimicrobials - Decrease compared to 2013 in the use of third- and fourth-generation cephalosporins (-81.3%) and fluoroquinolones (-74.9%). These positive results reflect the effective commitment of all the stakeholders in the fight against antimicrobial resistance. Over the last five years, significant changes in the use of antimicrobials have been observed, with in particular a reduction in the use of antimicrobials by the oral route and a limited use of antimicrobials of critical importance in human medicine. The impact of the significant decrease in the use of third- and fourth-generation cephalosporins, fluoroquinolones and colistin should be analysed over the next few years. The results for 2016 suggest that there has been a limited transfer of uses to other classes of antimicrobials. It will be particularly important in the next few years to monitor these changes in the use of antimicrobials and assess their consequences on the evolution of bacterial resistance. 4 https://www.anses.fr/fr/system/files/mv2016sa0160.pdf 7

This assessment of the impacts of the first plan is one of the aims of the second EcoAntibio plan published in April 2017. This new plan also aims to consolidate the achievements and ensure that progress is sustained. All stakeholders need to continue their mobilisation and efforts regarding the prudent and responsible use of antimicrobials in veterinary medicine. 8

II. Introduction Antimicrobial resistance is a major 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. ANSES-ANMV has been monitoring sales of veterinary antimicrobials in France since 1999. Its survey is based on the recommendations of Chapter 6.8 of the OIE Terrestrial Animal Health Code: "Monitoring of the quantities and usage patterns of antimicrobial agents used in food-producing animals". 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 reports by holders of marketing authorisations (MAs) obtained in conjunction with the French Union for the Veterinary Medicinal Product and Reagent Industry (SIMV) and made mandatory by Act No 2014-1170 of 13 October 2014. All antimicrobials sold in France are recorded through this annual monitoring. The present report describes the veterinary antimicrobial sales for 2016 and includes a comparison with results from previous years. 9

III. Materials and Methods 1. Data used in this report a) Data on sales of medicinal products containing antimicrobials Monitoring of sales is based on an annual declaration by each marketing authorisation (MA) holder marketing veterinary medicinal products containing antimicrobials authorised in France. Information on the number of units sold for each presentation of each medicinal product is thus sent to ANSES-ANMV. Since 2009, MA holders have also been required to provide information, for each presentation, on the breakdown of sales by target animal species. These figures are supplied for the period from 1 January to 31 December and therefore cover all veterinary antimicrobials marketed in the calendar year. 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 also subject to a specific audit. b) Data on the French animal populations To take into account fluctuations in the animal population when interpreting the data, the information published by Agreste 5 is used for food-producing animals. For domestic pets, data are provided by statistics from FACCO 6 (the French trade federation of food manufacturers for dogs, cats, birds and other pets), which are published every two years. In order to evaluate the biomasses of animals potentially treated with antimicrobials, different weights have been selected: the weights of adult animals for those with a life cycle of more than one year, and the weights at slaughter for the others. The data on animal populations used for this report are available in the Annex (Table 1 and Table 2). c) Data on veterinary medicinal products containing antimicrobials A variety of information on the medicinal products containing antimicrobials is available in the Index of veterinary medicinal products authorised in France 7. Some data from the Summary of Product Characteristics (SPC) have been used for each veterinary drug: - qualitative and quantitative composition in antimicrobials, - pharmaceutical form, - dosage and route of administration. For each drug and each species, the dosage selected is the one defined in the MA: - the daily dose, expressed in mg of antimicrobials per kg of body weight treated, - the duration of treatment, expressed in days. 5 http://agreste.agriculture.gouv.fr/ 6 http://www.facco.fr/ 7 http://www.ircp.anmv.anses.fr/ 10

In the framework of this national monitoring, dosage data were used when multiple doses and durations are described in the SPC for the same species: - When multiple doses are possible, the highest dose was chosen, for the drug s main indication. - When multiple treatment durations are possible, the longest treatment duration was chosen. 2. Calculations and interpretation of indicators 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. In this report, two types of indicators are presented: - sales indicators, used to monitor the change in the weights of antimicrobials sold over time, - exposure indicators, used to better represent the use of antimicrobials to treat animals. a) Tonnages of antimicrobials sold The weight of antimicrobial sold by drug presentation is an exact measurement obtained by multiplying the quantitative composition of active ingredient for each presentation by the number of units sold. For some active ingredients expressed in IU (International Units), a conversion coefficient (WHO standard value) has been used to calculate the quantity of antimicrobials by drug presentation. The coefficients used for the national monitoring scheme are those recommended by the European Medicines Agency (EMA) in the framework of the European Surveillance of Veterinary Antimicrobial Consumption (ESVAC) scheme 8. In this report, the quantities of antimicrobials sold (expressed in tonnes) are presented according to the pharmaceutical forms of the drugs and/or the classes of antimicrobials. The weight of antimicrobials sold by species is calculated using the estimates provided by the MA holders on the shares of sales for each animal species. This estimated amount is therefore calculated by multiplying the weight of antimicrobials sold by presentation by the percentage of reported sales for a given species. b) Weight of antimicrobials sold related to the animal biomass In order to take into account the fluctuations in medicinal product sales and animal populations over time, the ratio between the weights of antimicrobials sold and the biomass of the population potentially using antimicrobials can be calculated. This indicator is expressed in mg of active ingredient per kg of body weight. 8 http://www.ema.europa.eu/docs/en_gb/document_library/other/2015/06/wc500188365.pdf 11

c) Indicators of exposure of the animal population For drugs administered by the oral and parenteral routes, three exposure indicators can be calculated: the body weight treated day, the body weight treated, and the ALEA. The body weight treated for a given drug, also called the "Number of ACDkg", is calculated by dividing the weight of antimicrobials sold by the dose required to treat a typical animal over the entire duration of treatment. This ACD (Animal Course Dose) corresponds to the daily dose multiplied by the duration of treatment (see Section 1.c of this Materials and Methods chapter for the daily doses and durations selected). The body weight treated for a given species is calculated by adding together the numbers of ACDkg calculated for all the drug presentations sold for this species. The indicator of exposure of animals to antimicrobials or ALEA (Animal Level of Exposure to Antimicrobials) is calculated by dividing the body weight treated by the biomass of the animal population potentially using antimicrobials. The ALEA indicator has no unit and is based on the assumption that all the antimicrobials sold during the year were administered to animals in France during this year. The body weight treated day for a given drug, also called the "Number of ADDkg", is calculated by dividing the weight of antimicrobials sold by the daily dose chosen for this drug. This ADD (Animal Daily Dose) corresponds to the dose required to treat a typical animal for one day (see Section 1.c of this Materials and Methods chapter for the daily doses selected). The body weight treated day for a given species is calculated by adding together the numbers of ADDkg calculated for all the drug presentations sold for this species. The ratio between the numbers of ADDkg and numbers of ACDkg calculated for a species gives an estimate of the average number of days per antimicrobial treatment for this species. The total per year in body weight treated is lower than the sum of body weight treated per class of antimicrobials, due to combinations of antimicrobials in some veterinary drugs. The same is true for the total body weight treated day and the total ALEA, when the results are presented by class of antimicrobials. 3. Important points concerning the current annual report Changes to the SPC were implemented in 2016 for certain veterinary medicinal products authorised in France. These changes have been incorporated in the analysis of sales for 2016 but do not affect the results of previous years. The biomass data for the different animal populations were updated for the years 2014, 2015 and 2016 according to the Agreste website. 12

Given the stockpiling by the beneficiaries of the medicinal products, related to the publication of the Act on the future of agriculture, food and forestry, the sales data for 2014 and 2015 have been interpreted taking into account the average of the indicators calculated for the two years (tonnage, body weight treated day, body weight treated). The indicator of exposure of animals to antimicrobials for 2014 and 2015 was calculated according to this formula: ALEA2014-15 = (body weight treated2014 + body weight treated2015) / (Biomass2014 + Biomass2015) To assess the change in light of the objective to reduce antimicrobial use by 25% as stipulated by the EcoAntibio plan, the results on exposure to antimicrobials for 2016 were compared to those from 2011. For fluoroquinolones and third- and fourth-generation cephalosporins, the results were compared to 2013, the reference year mentioned in the Act on the future of agriculture, food and forestry, which sets a goal of reducing the use of these classes of antimicrobials by 25% in three years. Given the current interest in resistance to colistin, there was a focus on how exposure to this compound has evolved. Following publication of reference values for the doses and treatment durations at European level (ESVAC), a comparative analysis was performed for the last six years, using on the one hand the European reference values and on the other the French reference values. 13

IV. Tonnages of antimicrobials sold and exposure indicators in 2016 1. Tonnages by antimicrobial class and route of administration In 2016, the total volume of sales amounted to 530.14 tonnes of antimicrobials. Five antimicrobial classes (tetracyclines, sulfonamides, penicillins, aminoglycosides and macrolides) accounted for around 88% of total antimicrobial sales (Table 1). Tetracyclines alone represented 35.0% of tonnage sold. Critical antimicrobials (newer-generation cephalosporins and fluoroquinolones) accounted for nearly 0.4% of the tonnage of active ingredient sold. Table 1: Breakdown of sales for 2016 in tonnage of active ingredient for each antimicrobial class by route of administration MEDICATED PREMIXES ORAL FORMS EXCLUDING PREMIXES INJECTIONS INTRAMAMMARY & INTRAUTERINE TOTAL SHARE OF THE CLASS (%) AMINOGLYCOSIDES 14.45 10.99 28.67 1.65 55.76 10.52% OTHER CLASSES 9-1.21-0.05 1.26 0.24% CEPHALOSPORINS 1&2G - 4.21 0.05 2.14 6.40 1.21% CEPHALOSPORINS 3&4G - - 0.33 0.07 0.39 0.07% FLUOROQUINOLONES - 1.17 0.53 0.00 1.70 0.32% LINCOSAMIDES 0.73 1.64 0.61 0.02 3.01 0.57% MACROLIDES 8.04 19.23 9.56-36.84 6.95% PENICILLINS 8.72 35.69 30.82 2.32 77.55 14.63% PHENICOLS - 0.33 5.26 0.00 5.59 1.05% PLEUROMUTILINS 2.30 2.21 0.02 0.00 4.53 0.85% POLYMYXINS 3.94 15.71 0.46 0.13 20.25 3.82% QUINOLONES 0.27 2.93 - - 3.21 0.60% SULFONAMIDES 52.43 53.18 5.44-111.04 20.95% TETRACYCLINES 100.32 73.28 10.08 1.72 185.40 34.97% TRIMETHOPRIM 7.96 8.23 1.04-17.23 3.25% TOTAL 199.15 230.00 92.88 8.10 530.14 100.00% PERCENTAGE 37.57% 43.39% 17.52% 1.53% 100.00% Sales of antimicrobials administered in local forms (sprays, creams, ear or eye solutions) are not presented in this report. They account for around 0.5% of the tonnage of active ingredient sold. 9 Other classes: dimetridazole, metronidazole, pyrimethamine, rifaximin 14

2. Tonnages by species According to the information on the breakdown by species transmitted to ANSES-ANMV by the pharmaceutical companies, around 36% of the tonnage of antimicrobials sold is intended for pigs, 23% is intended for cattle and around 20% is destined for poultry (Table 2). In 2016, 33.70 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. Table 2: Breakdown of sales for 2016 between the different species in tonnage of active ingredient and quantity of active ingredient per kilogram of body weight Cattle Pigs Poultry Rabbits Cats & Dogs Sheep & Goats Horses Fish Other Total Tonnage sold 124.19 189.40 105.57 44.22 15.63 38.94 8.51 2.54 1.19 530.14 Percentage 23.42% 35.73% 19.91% 8.34% 2.95% 7.34% 1.61% 0.48% 0.22% 100.0% Sales in mg/kg 13.13 66.22 47.19 432.68 95.33 70.92 29.33 56.24 34.14 33.70 15

3. Indicators by antimicrobial class and route of administration Sales expressed in body weight treated show that animals are treated primarily with tetracyclines, penicillins, polymyxins, aminoglycosides and macrolides, followed by sulfonamides (Table 3). Nearly 2% of body weight treated in veterinary medicine is treated with fluoroquinolones or newer-generation cephalosporins. Table 3: Body weight treated for 2016 according to the classes of antimicrobials and routes of administration (in tonnes) MEDICATED PREMIXES ORAL POWDERS & SOLUTIONS OTHER ORAL FORMS* INJECTIONS TOTAL PERCENTAGE AMINOGLYCOSIDES 61,625 68,061 5,422 646,747 781,855 10.57% OTHER CLASSES 0 4 5,991 0 5,995 0.08% CEPHALOSPORINS 1&2G 0 0 9,032 600 9,632 0.13% CEPHALOSPORINS 3&4G 0 0 0 57,291 57,291 0.77% FLUOROQUINOLONES 0 21,331 3,507 61,709 86,547 1.17% LINCOSAMIDES 7,270 27,035 583 23,418 58,306 0.79% MACROLIDES 67,971 143,645 3,937 541,034 756,587 10.23% PENICILLINS 64,787 488,101 47,149 946,793 1,546,830 20.91% PHENICOLS 0 6,019 0 140,665 146,684 1.98% PLEUROMUTILINS 28,949 17,274 0 617 46,840 0.63% POLYMYXINS 115,920 817,865 5,003 64,969 1,003,757 13.57% QUINOLONES 3,805 40,838 55 0 44,698 0.60% SULFONAMIDES 211,961 280,203 15,702 131,311 639,177 8.64% TETRACYCLINES 257,824 862,663 9,288 538,092 1,667,867 22.55% TRIMETHOPRIM 173,461 237,921 4,910 129,193 545,485 7.37% TOTAL (in tonnes) 794,288 2,747,416 91,579 2,465,645 6,098,928 100.00% PERCENTAGE 13.02% 45.05% 1.50% 40.43% 100.00% * tablets, oral pastes, boluses, etc. Medicated premixes are generally medicinal products containing older compounds administered over a long period. Although they accounted for 38% of the tonnage of active ingredient sold, they represented around 13% of body weight treated. Oral powders and solutions represented 45% of total body weight treated, and injections around 40% of total body weight treated with antimicrobials. For medicated premixes, the tetracycline class accounted for 32% of body weight treated, and the sulphonamides class for 27% of body weight treated. Around 30% of the body weight treated with oral powders or solutions was treated with polymyxins, and 31% with tetracyclines. For parenteral administration, in terms of body weight treated, penicillins were the class most commonly used (38%), followed by aminoglycosides (26%). Fluoroquinolones and third- and fourth-generation cephalosporins were used to treat respectively 2.5% and 2.3% of the total body weight treated by the parenteral route. 16

Figure 1: Relative average proportions of pharmaceutical forms in the body weight treated by different classes of antimicrobials in 2016 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% MEDICATED PREMIXES ORAL POWDERS & SOLUTIONS OTHER ORAL FORMS INJECTIONS Polymyxins, tetracyclines, sulfonamides and trimethoprim are mainly administered orally (Figure 1). Aminoglycosides, penicillins, macrolides and fluoroquinolones are primarily administered by the parenteral route, while newer-generation cephalosporins are not administered orally. 17

4. Indicators by species More than 38% of the body weight of animals treated relates to cattle, 30% to pigs and 21% to poultry (Table 4). These percentages should be considered in the context of the biomass of each animal species in France (Table 2 in the Annex). Table 4: Breakdown of sales for 2016 between the different species in tonnage of body weight treated and ALEA exposure indicator Cattle Pigs Poultry Rabbits Cats & Dogs Sheep & Goats Horses Fish Other Total Body weight treated (tonnes) 2,348,450 1,843,734 1,284,657 202,397 98,527 211,128 91,715 10,196 8,124 6,098,928 Percentage 38.51% 30.23% 21.06% 3.32% 1.62% 2.29% 3.46% 0.17% 0.13% 100.00% ALEA 0.248 0.645 0.574 1.980 0.601 0.385 0.316 0.226 0.233 0.388 The ALEA indicator best reflects exposure to antimicrobials as it takes into account information on the treatments (dose and duration) and also 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 (produced) of the animal population. An ALEA of 0.248 for cattle means that sales of antimicrobials intended for this animal sector were used to treat 24.8% of the total body weight of cattle. According to the ALEA calculated for 2016, rabbits, pigs, cats and dogs, and poultry are the species most exposed to antimicrobials (Table 4). However, the ALEA does not take into account the potential differences between the treatment of young and adult animals. 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. 18

V. Change in sales and exposure to antimicrobials between 1999 and 2016 1. Change in sales and exposure to antimicrobials by pharmaceutical form a) Change in weights of active ingredients Over the 18 years of monitoring, the tonnage of antimicrobials sold has fluctuated between 514 in 2015 and 1383 tonnes in 2000 (Table 3 in the Annex). The tonnage of antimicrobials sold in 2016 has decreased by 18.5% compared to the average tonnage for the years 2014-2015 (with a decrease mainly recorded for medicated premixes, and oral powders and solutions). The weight of antimicrobials sold in 2016 was compared to the tonnage in 2011, the reference year for the beginning of the National EcoAntibio Plan: a decrease of 41.7% has been observed over these last five years. This decrease is largely attributable to lower sales of orally administered antimicrobials. b) Change in the body weight treated by antimicrobials 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 body weight treated in 2016 decreased by 20.7% compared to the average body weight treated for the years 2014-2015, and by 37.7% compared to 2011, the reference year for the national EcoAntibio plan (Table 5 in the Annex). Since 1999, the body weight treated with medicated premixes has decreased by 78.9%, the body weight treated with oral powders and solutions has fallen by 16.3% and the body weight treated parenterally has fallen by 17.1%. Over the last five years, the body weight treated with medicated premixes has decreased by 61.0%, the body weight treated with oral powders and solutions has fallen by 43.5% and the body weight treated parenterally has decreased by 11.6% (2016 variations compared to 2011). The change in sales by pharmaceutical form is presented in the annexes: Table 4 for the change in the body weight treated day and Table 5 for the change in the body weight treated. c) Change in animal exposure to antimicrobials (ALEA) Since monitoring of sales began, the level of exposure of animals to antimicrobials, all routes and species combined, has decreased by 31.5% (variation between 1999 and 2016). Over the last five years, overall exposure has decreased by 36.6% (Table 5). 19

Table 5: Change in the indicator of exposure by pharmaceutical form (ALEA) MEDICATED PREMIXES ORAL POWDERS & SOLUTIONS OTHER ORAL FORMS INJECTIONS TOTAL 1999 0.210 0.183 0.007 0.166 0.566 2000 0.217 0.217 0.007 0.162 0.604 2001 0.202 0.248 0.006 0.159 0.616 2002 0.192 0.286 0.007 0.160 0.645 2003 0.186 0.313 0.007 0.166 0.672 2004 0.174 0.322 0.007 0.157 0.659 2005 0.179 0.365 0.007 0.173 0.725 2006 0.179 0.348 0.007 0.182 0.716 2007 0.196 0.348 0.007 0.168 0.719 2008 0.168 0.305 0.007 0.169 0.649 2009 0.156 0.311 0.007 0.161 0.634 2010 0.148 0.315 0.007 0.169 0.639 2011 0.127 0.304 0.007 0.174 0.612 2012 0.100 0.289 0.006 0.181 0.575 2013 0.085 0.266 0.006 0.175 0.532 2014 0.085 0.321 0.007 0.190 0.602 2015 0.070 0.158 0.005 0.141 0.374 2016 0.050 0.175 0.006 0.157 0.388 Variation 2016 / ALEA 2014-2015 -0.027-0.064 0.000-0.009-0.100-34.8% -26.9% -3.7% -5.3% -20.5% Variation 2016 / 2011-0.077-0.129-0.001-0.017-0.224-60.3% -42.5% -14.6% -10.0% -36.6% Exposure to antimicrobials via medicated premixes has fallen by 76.0% since 1999 (Figure 2). Over the last five years, there has been a 60.3% decrease in exposure to this form of antimicrobials. Exposure to antimicrobials via oral powders and solutions has decreased by 4.5% since 1999 and by 42.5% since 2011. Exposure to antimicrobials via other orally administered forms (pastes, tablets, boluses, etc.) has been relatively stable since 1999. Exposure to injections has decreased by 5.5% since monitoring of sales began, and by 10% over the last five years. 20

Figure 2: Change in ALEA by pharmaceutical form since 1999 0,800 0,700 0,600 0,500 0,400 0,300 0,200 0,100 INJECTABLES AUTRES FORMES ORALES POUDRES ET SOLUTIONS ORALES PREMELANGES MEDICAMENTEUX - 21

2. Change in sales and exposure to antimicrobials by class a) Change in the tonnage related to the biomass of the animal population Since 1999, sales expressed in mg of antimicrobials per kg of body weight produced have fluctuated between 32.52 and 80.04 mg/kg (Table 6). Table 6: Change in sales by antimicrobial class since 1999 in mg of active ingredient per kilogram of body weight (mg/kg) AMINOGLYCOSIDES OTHER CLASSES CEPHALOSPORINS 1&2G CEPHALOSPORINS 3&4G FLUOROQUINOLONES LINCOSAMIDES MACROLIDES PENICILLINS PHENICOLS PLEUROMUTILINS POLYMYXINS QUINOLONES SULFONAMIDES TETRACYCLINES TRIMETHOPRIM TOTAL 1999 4.55 0.05 0.29 0.05 0.18 0.33 4.43 5.04 0.24 1.73 3.74 1.10 14.45 34.76 2.09 73.04 2000 4.95 0.05 0.29 0.06 0.20 0.44 4.88 5.35 0.26 1.82 3.90 0.91 14.98 36.28 2.14 76.53 2001 5.01 0.05 0.28 0.06 0.22 0.50 5.52 5.11 0.24 1.40 3.90 0.80 13.31 36.09 1.96 74.46 2002 5.03 0.05 0.35 0.07 0.23 0.61 6.04 5.44 0.31 1.41 3.79 0.88 12.74 35.12 1.89 73.95 2003 4.70 0.02 0.39 0.07 0.25 0.59 5.86 5.29 0.25 1.26 3.87 0.81 12.02 37.15 1.87 74.40 2004 4.60 0.05 0.39 0.08 0.25 0.56 5.65 4.94 0.29 0.94 3.69 0.73 12.27 37.31 1.98 73.71 2005 4.68 0.04 0.44 0.10 0.27 0.61 6.10 5.42 0.29 0.50 4.05 0.81 13.15 40.49 2.17 79.12 2006 4.74 0.06 0.39 0.11 0.29 0.55 6.28 5.66 0.37 0.61 4.08 0.80 12.92 36.68 2.03 75.59 2007 4.48 0.04 0.43 0.12 0.28 0.55 5.89 5.65 0.35 0.60 4.45 0.66 13.55 40.94 2.04 80.04 2008 4.39 0.04 0.43 0.13 0.29 0.47 5.71 5.12 0.30 0.48 3.95 0.48 11.72 35.17 1.78 70.45 2009 3.95 0.04 0.43 0.11 0.30 0.43 5.08 5.28 0.29 0.50 4.05 0.46 11.09 30.76 1.73 64.49 2010 3.85 0.04 0.37 0.14 0.33 0.41 5.02 5.59 0.32 0.47 4.01 0.50 10.78 29.12 1.63 62.57 2011 3.97 0.04 0.44 0.14 0.33 0.34 4.40 5.64 0.29 0.42 3.79 0.39 10.70 24.35 1.56 56.81 2012 3.64 0.04 0.42 0.15 0.31 0.30 3.87 5.47 0.29 0.36 3.25 0.34 9.21 20.82 1.35 49.81 2013 3.45 0.04 0.41 0.14 0.30 0.29 3.30 5.50 0.30 0.36 2.72 0.30 8.65 17.90 1.28 44.93 2014 3.66 0.04 0.47 0.13 0.31 0.29 3.71 6.24 0.37 0.41 3.27 0.35 9.33 20.06 1.45 50.11 2015 3.06 0.03 0.28 0.09 0.17 0.20 2.31 4.07 0.24 0.34 1.93 0.18 6.75 11.88 0.98 32.52 2016 3.54 0.08 0.41 0.03 0.11 0.19 2.34 4.93 0.36 0.29 1.29 0.20 7.06 11.79 1.10 33.70 Variation 2016 / Average 2014-2015 Variation 2016 / 2011 0.18 0.04 0.03-0.09-0.13-0.05-0.67-0.22 0.05-0.09-1.31-0.06-0.98-4.17-0.12-7.59 5.5% 121.0% 9.2% -77.4% -55.1% -22.1% -22.2% -4.4% 15.5% -23.4% -50.5% -23.3% -12.2% -26.1% -9.8% -18.4% -0.43 0.04-0.03-0.12-0.22-0.15-2.06-0.71 0.07-0.13-2.51-0.19-3.64-12.56-0.47-23.11-10.8% 95.2% -7.6% -82.6% -67.3% -43.6% -46.8% -12.5% 24.4% -31.9% -66.1% -47.7% -34.0% -51.6% -30.0% -40.7% A decrease of 53.9% in the quantity of active ingredient in mg per kilogram of body weight can be observed between 1999 and 2016. This decrease is largely attributable to lower sales of antimicrobials from the classes of tetracyclines (-66.1%) and sulfonamides (-51.1%). A decrease of 40.7% in the quantity of active ingredient in mg per kilogram of body weight has been observed over the last five years (by comparing sales for 2011 to those of 2016). This decrease is largely 22

attributable to lower sales of antimicrobials from the classes of tetracyclines (-51.6%) and sulfonamides (-34.0%), but also the classes of polymyxins and macrolides. Since 2011, a decrease of 67.3% has been observed for the class of fluoroquinolones, and a decline of 82.6% for the class of third- and fourth-generation cephalosporins. Compared to sales in 2013, a decrease of 64.6% has been observed over the last three years for the class of fluoroquinolones, and a decline of 81.5% for the class of third- and fourth-generation cephalosporins. In 2016, the tonnage sold of newer-generation cephalosporins, fluoroquinolones and colistin decreased compared to the average tonnage sold in 2014-15, by respectively 77.4%, 55.2% and 50.5%. At the same time, sales of aminoglycosides, first- and newer-generation cephalosporins and phenicols increased (by respectively 5.5%, 9.2% and 15.5%). The change in the tonnage sold by class is presented in Table 6 in the Annex. b) Change in animal exposure to antimicrobials (ALEA) Since 1999, the level of animal exposure to antimicrobials, all classes and animal species combined, has fallen by 31.5%. The average ALEA for 2014 and 2015 was 0.488, and that for 2016 was 0,388, a variation of -20.5% (Table 7). Since 2011, overall exposure has fallen by 36.6%. The trend in exposure varies according to the class considered (Figure 3). Between 2014-15 and 2016, exposure to antimicrobials decreased for all classes except for aminoglycosides, phenicols, first- and second-generation cephalosporins and penicillins. Over the last three years, exposure to third- and fourth-generation cephalosporins has fallen by 81.3% while exposure to fluoroquinolones has decreased by 74.9% (see VII. Update on exposure to fluoroquinolones, third- and fourth-generation cephalosporins and colistin). Exposure to colistin has decreased by 40.3% compared to the average exposure calculated for 2014 and 2015. 23

Figure 3: Change in animal exposure by antimicrobial class (ALEA) 0,300 0,250 0,200 0,150 0,100 0,050 0,000 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2014-2015 2015 2016 24

Table 7: Change in animal exposure in France by antimicrobial class since 1999 (ALEA calculated for the oral and parenteral routes only) AMINOGLYCOSIDES OTHER CLASSES CEPHALOSPORINS 1&2G CEPHALOSPORINS 3&4G FLUOROQUINOLONES LINCOSAMIDES MACROLIDES PENICILLINS PHENICOLS PLEUROMUTILINS POLYMYXINS QUINOLONES SULFONAMIDES TETRACYCLINES TRIMETHOPRIM TOTAL 1999 0.059 0.000 0.000 0.008 0.011 0.006 0.052 0.096 0.006 0.024 0.110 0.013 0.070 0.178 0.053 0.566 2000 0.061 0.000 0.000 0.010 0.012 0.009 0.059 0.102 0.006 0.025 0.117 0.011 0.072 0.186 0.054 0.604 2001 0.061 0.000 0.000 0.009 0.014 0.011 0.065 0.098 0.006 0.020 0.120 0.010 0.067 0.199 0.052 0.616 2002 0.060 0.000 0.001 0.011 0.017 0.013 0.072 0.096 0.008 0.020 0.123 0.011 0.065 0.212 0.049 0.645 2003 0.060 0.000 0.001 0.012 0.019 0.012 0.071 0.098 0.006 0.018 0.131 0.010 0.061 0.234 0.047 0.672 2004 0.062 0.000 0.001 0.013 0.018 0.011 0.067 0.092 0.007 0.014 0.128 0.009 0.061 0.238 0.049 0.659 2005 0.065 0.000 0.001 0.016 0.021 0.011 0.076 0.102 0.007 0.008 0.144 0.010 0.065 0.264 0.053 0.725 2006 0.064 0.001 0.001 0.018 0.023 0.010 0.077 0.106 0.009 0.008 0.148 0.010 0.064 0.242 0.051 0.716 2007 0.061 0.000 0.001 0.019 0.021 0.009 0.069 0.105 0.009 0.008 0.153 0.008 0.066 0.251 0.052 0.719 2008 0.058 0.000 0.001 0.020 0.022 0.009 0.070 0.095 0.008 0.006 0.143 0.006 0.059 0.210 0.047 0.649 2009 0.052 0.000 0.001 0.017 0.022 0.008 0.067 0.096 0.008 0.006 0.146 0.006 0.055 0.202 0.045 0.634 2010 0.050 0.000 0.001 0.021 0.022 0.007 0.068 0.102 0.008 0.006 0.148 0.006 0.054 0.194 0.044 0.639 2011 0.051 0.000 0.001 0.021 0.023 0.006 0.065 0.105 0.007 0.005 0.142 0.005 0.054 0.177 0.043 0.612 2012 0.048 0.000 0.001 0.022 0.022 0.005 0.061 0.103 0.008 0.005 0.127 0.004 0.047 0.172 0.038 0.575 2013 0.048 0.000 0.001 0.019 0.022 0.005 0.057 0.103 0.008 0.005 0.114 0.004 0.045 0.152 0.037 0.532 2014 0.050 0.000 0.001 0.017 0.021 0.005 0.066 0.115 0.010 0.004 0.134 0.005 0.050 0.175 0.042 0.602 2015 0.034 0.000 0.000 0.013 0.013 0.004 0.043 0.070 0.006 0.004 0.080 0.002 0.036 0.104 0.029 0.374 2016 0.050 0.000 0.001 0.004 0.006 0.004 0.048 0.098 0.009 0.003 0.064 0.003 0.041 0.106 0.035 0.388 Variation 2016 / Average 2014-2015 Variation 2016 / 2011 0.008 0.000 0.000-0.012-0.012-0.001-0.006 0.006 0.001-0.001-0.043-0.001-0.002-0.033-0.001-0.100 18.9% 10.1% -76.2% -67.7% -13.8% -11.3% 6.1% 18.0% -26.7% -40.3% -19.9% -5.0% -24.0% -2.0% -20.5% -0.002 0.000 0.000-0.018-0.017-0.002-0.017-0.007 0.002-0.002-0.078-0.002-0.013-0.071-0.008-0.224-3.2% 11.0% -8.3% -82.9% -75.6% -39.4% -26.1% -6.5% 25.8% -44.1% -55.1% -43.5% -24.8% -40.0% -19.7% -36.6% The change in sales by class of antimicrobials is presented in the annexes: Table 7 for the change in the body weight treated day and Table 8 for the change in the body weight treated. 25

VI. Change in exposure to antimicrobials by species 1. Cattle a) Change in sales and exposure to antimicrobials by class The tonnage intended for cattle increased considerably between 1999 and 2005 but has been declining since (Table 9 in the Annex). In 2016, it was around 124 tonnes, or 18.2% lower than the average tonnage for the years 2014 and 2015, and 32.3% lower than in 2011. The body weight treated day relative to the biomass has decreased by 33.7% compared to 2011 (Table 10 in the Annex). The body weight treated in 2016 was 15.1% lower than in 1999 and 23.4% lower than in 2011 (Table 11 in the Annex). The ALEA for cattle was 0.248 in 2016 (Table 8). Taking into account the variations in the population of cattle potentially treated with antimicrobials, exposure of cattle to antimicrobials has decreased by 6.6% since 1999. Exposure has fallen by 24.3% over the last five years (compared to 2011). Cattle were treated mainly with penicillins, tetracyclines, aminoglycosides, macrolides, and then with sulfonamides, trimethoprim and polymyxins (Figure 4). Between 2014-15 and 2016, exposure to antimicrobials decreased for all classes except for aminoglycosides, sulfonamides, trimethoprim and penicillins. Exposure to newer-generation cephalosporins has declined by 81.6% over the last three years (compared to 2013). Exposure to fluoroquinolones has fallen by 82.6% over this same period. 26

Figure 4: Change in exposure of cattle by antimicrobial class (ALEA) 0,140 0,120 0,100 0,080 0,060 0,040 0,020 0,000 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2014-2015 2015 2016 27

Table 8: Change in exposure of cattle by antimicrobial class since 1999 (ALEA calculated for the oral and parenteral routes only) AMINOGLYCOSIDES CEPHALOSPORINS 3&4G FLUOROQUINOLONES LINCOSAMIDES MACROLIDES PENICILLINS PHENICOLS POLYMYXINS QUINOLONES SULFONAMIDES TETRACYCLINES TRIMETHOPRIM TOTAL 1999 0.065 0.012 0.009 0.002 0.045 0.080 0.010 0.029 0.004 0.013 0.072 0.007 0.266 2000 0.064 0.015 0.009 0.002 0.046 0.079 0.011 0.030 0.004 0.015 0.070 0.007 0.271 2001 0.062 0.014 0.013 0.002 0.046 0.077 0.010 0.031 0.004 0.014 0.062 0.007 0.263 2002 0.060 0.017 0.016 0.002 0.050 0.075 0.013 0.033 0.005 0.014 0.067 0.007 0.284 2003 0.062 0.020 0.019 0.002 0.051 0.076 0.011 0.033 0.005 0.013 0.076 0.007 0.299 2004 0.066 0.021 0.017 0.002 0.049 0.079 0.012 0.031 0.004 0.014 0.098 0.007 0.321 2005 0.070 0.025 0.020 0.003 0.056 0.087 0.013 0.035 0.005 0.014 0.117 0.007 0.368 2006 0.068 0.026 0.022 0.003 0.053 0.085 0.016 0.034 0.005 0.014 0.106 0.007 0.357 2007 0.065 0.027 0.020 0.002 0.044 0.079 0.015 0.031 0.004 0.016 0.104 0.007 0.335 2008 0.062 0.029 0.020 0.002 0.053 0.074 0.013 0.031 0.003 0.016 0.081 0.008 0.317 2009 0.053 0.024 0.019 0.002 0.053 0.069 0.011 0.031 0.003 0.013 0.086 0.007 0.305 2010 0.053 0.030 0.023 0.002 0.057 0.079 0.012 0.027 0.004 0.014 0.098 0.007 0.340 2011 0.062 0.033 0.024 0.001 0.062 0.085 0.011 0.021 0.002 0.021 0.075 0.010 0.328 2012 0.059 0.034 0.023 0.002 0.064 0.085 0.011 0.015 0.002 0.016 0.081 0.008 0.327 2013 0.057 0.030 0.022 0.002 0.062 0.084 0.011 0.018 0.002 0.016 0.062 0.008 0.304 2014 0.060 0.027 0.020 0.002 0.074 0.077 0.013 0.028 0.003 0.018 0.095 0.012 0.354 2015 0.040 0.021 0.013 0.002 0.048 0.053 0.009 0.015 0.001 0.013 0.069 0.008 0.239 2016 0.059 0.006 0.004 0.002 0.056 0.071 0.011 0.012 0.002 0.018 0.070 0.015 0.248 Variation 2016 / Average 2014-2015 Variation 2016 / 2011 0.008-0.018-0.013 0.000-0.005 0.006 0.000-0.009 0.000 0.002-0.012 0.005-0.048 16.9% -76.6% -77.2% -12.2% -7.7% 9.2% -0.1% -43.4% -20.6% 14.5% -15.1% 48.0% -16.3% -0.003-0.027-0.020 0.001-0.006-0.015 0.000-0.009-0.001-0.003-0.005 0.004-0.080-5.1% -83.1% -83.7% 127.1% -9.0% -17.2% 2.4% -41.5% -22.3% -16.1% -7.0% 41.0% -24.3% b) Change in exposure by pharmaceutical form and average treatment durations Cattle are treated primarily by the parenteral route, and then by the oral route (Figure 5) mainly with the use of oral powders and solutions. The ratio between the numbers of ADDkg and numbers of ACDkg provides information on the average number of days per antimicrobial treatment. Between 1999 and 2005, this average number of days per treatment intended for cattle increased slightly to reach 4.0 days in 2005. Since then, this number has fallen and was equal to 2.6 days in 2016 (close to the value for 1999, equal to 2.9). Oral treatments generally last between 4 and 5 days while the average number of days per parenteral treatment is around 2.5 days. 28