Workshop for OIE national Focal Points for Veterinary Products (2 nd cycle) Vienna (Austria), 20-22 November 2012 Antimicrobial use and Antimicrobial resistance: chapter 6.7 and 6.8 of the OIE Terrestrial Animal Health Detailed presentation and implementation Dr. Gérard Moulin Anses/ANMV OIE Collaborating Centre on Veterinary medicinal products (French agency for veterinary medicinal products / French Agency for Food, Environmental and Occupational Health and Safety) 8 rue Claude Bourgelat - Parc d'activités de la Grande Marche - Javené - BP 90203-35302 Fougères France gerard.moulin@anses.fr
OIE International standards on antimicrobial resistance Terrestrial Animal Health Code (2012) Section - 6: Veterinary Public Health Chapter 6.7: Harmonisation of antimicrobial resistance surveillance and monitoring programmes (2003 - updated in 2012) Chapter 6.8: Monitoring of the quantities and usage patterns of antimicrobial agents used in food producing animals (2003 - updated in 2012) Chapter 6.9: Guidelines for the responsible and prudent use of antimicrobial agents in veterinary medicine (2003 - updated 2005) Chapter 6.10: Risk assessment for antimicrobial resistance arising from the use of antimicrobials in animals (2004) Manual of Diagnostic Tests and vaccines for Terrestrial Animals Chapter 4.1: Laboratory methodologies for bacterial antimicrobial susceptibility testing (2003 - updated in 2012)
OIE International standards on antimicrobial resistance Aquatic Animal Health Code (2012) Section - 6: Veterinary Public Health Chapter 6.2: Introduction to the recommendations for controlling antimicrobial resistance (2011) Chapter 6.3: Principles for responsible and prudent use of antimicrobial agents in aquatic animals (2011) Chapter 6.4: Monitoring of the quantities and usage patterns of antimicrobial agents used in aquatic animals (2012) Chapter 6.5: Development and harmonisation of national antimicrobial resistance surveillance and monitoring programmes for aquatic animals (2012)
Chapter 6.7: Harmonisation of antimicrobial resistance surveillance and monitoring programmes
Chapter 6.7: Harmonisation of antimicrobial resistance surveillance and monitoring programmes Content Objective / Purpose The development of antimicrobial resistance surveillance and monitoring programmes 1. General aspects 2. Sampling strategies 3. Sample size 4. Sample sources 5. type of sample to be collected 6. Bacterial isolates 7. Storage of bacterial strains 8. Antimicrobial susceptibility testing 9. Recording, storage and interpretation of data 10. Reference laboratory and annual reports
Chapter 6.7: Harmonisation of antimicrobial resistance surveillance and monitoring programmes Objective To provides criteria for the development and harmonisation of antimicrobial resistance surveillance and monitoring programmes Purpose: why surveillance and monitoring are necessary? NEW introduce the notions of active (targeted) and passive surveillance encourage regional cooperation between members 1. To assess and determine the trends and sources of antimicrobial resistance in bacteria 2. To detect the emergence of new antimicrobial resistance mechanism 3. To provide data for conducting risk analysis 4. To provide a basis for policy recommendations for animal and human health 5. To provide information for evaluating antimicrobial prescribing practices and for prudent use recommendations
Chapter 6.7: Harmonisation of antimicrobial resistance surveillance and monitoring programmes General aspects: National AMR monitoring and surveillance programmes should be scientifically based and may include the following components: a) statistically based surveys; b) sampling and testing of food producing animals on the farm, at live animal market or at slaughter; c) an organised sentinel programme (targeted sampling of food producing animals, herds, flocks and vectors; d) analysis of veterinary practice and diagnostic laboratory records.
Chapter 6.7: Harmonisation of antimicrobial resistance surveillance and monitoring programmes Sampling strategy: Representativeness of the population, robustness of the method Criteria: sample source, animal species and category, health status, sample selection, type of sample Sample size: Table 1. Sample size estimates for prevalence of antimicrobial resistance in a large population Expected prevalence 90% Level of confidence 95% Level of confidence Desired precision Desired precision 10% 5% 1% 10% 5% 1% 10% 24 97 2,429 35 138 3,445 20% 43 173 4,310 61 246 6,109 30% 57 227 5,650 81 323 8,003 40% 65 260 6,451 92 369 9,135 50% 68 270 6,718 96 384 9,512 60% 65 260 6,451 92 369 9,135 70% 57 227 5,650 81 323 8,003 80% 43 173 4,310 61 246 6,109 90% 24 97 2,429 35 138 3,445
Chapter 6.7: Harmonisation of antimicrobial resistance surveillance and monitoring programmes Sampling sources: Examination of the livestock production system (Animal feed, Food producing animals, Food) Type of samples to be collected: Source Herd or flock of origin Abattoir Processing, packing Point of sales (Retail) Table 2. Examples of sampling sources, sample types and monitoring outcomes Sample type Faecal or bulk milk Faecal Caeca or intestine Carcass Food products Food products Outcome Prevalence of resistant bacteria originating from animal populations (of different production types) Relationship resistance antimicrobial use Prevalence of resistant bacteria originating from animals at slaughter As above Hygiene, contamination during slaughter Hygiene, contamination during processing and handling Prevalence of resistant bacteria originating from food, exposure data for consumers Additional information required or additional stratification Age categories, production types, etc. Antimicrobial use over time Various origins Animal feed Prevalence of resistant bacteria originating from animal feed, exposure data for animals
Chapter 6.7: Harmonisation of antimicrobial resistance surveillance and monitoring programmes Which bacteria to monitor? Animal bacterial pathogens Zoonotic bacteria Salmonella Campylobacter Other emerging bacterial pathogens (MRSA, Listeria monocytogenes ) Commensal bacteria Escherichia coli and enterococci
Chapter 6.7: Harmonisation of antimicrobial resistance surveillance and monitoring programmes Which antimicrobials to be used in susceptibility testing? Reference to the OIE list of antimicrobials of veterinary importance Recommendations on: Storage of bacterial strains Recording, storage and interpretation of data Reference laboratory and annual reports Need to designate a National Reference Centre
Examples: France, Europe Surveillance of bacterial pathogens (France) Resapath: http://www.resapath.anses.fr Surveillance of zoonotic and commensal bacteria (Europe, EFSA) http://www.efsa.europa.eu/en/efsajournal/doc/2597.pdf
Chapter 6.8: Monitoring of the quantities and usage patterns of antimicrobial agents used in food producing animals
Chapter 6.8: Monitoring of the quantities and usage patterns of antimicrobial agents used in food producing animals Content Purpose Objectives Development and standardisation of antimicrobial monitoring systems Sources of antimicrobial data Types end reporting formats of antimicrobial use data Interpretation
Chapter 6.8: Monitoring of the quantities and usage patterns of antimicrobial agents used in food producing animals Purpose: To describe an approach to the monitoring of the quantities of antimicrobial agents used in food producing animals In order to evaluate antimicrobial exposure, need for quantitative information to monitor usage patterns by animal species, antimicrobial agents or class, type of use and route of administration
Chapter 6.8: Monitoring of the quantities and usage patterns of antimicrobial agents used in food producing animals Objectives: This information is necessary: - For interpreting antimicrobial resistance surveillance data - For risk management to evaluate the effectiveness of efforts to ensure responsible prudent use and mitigation strategies - For risk communication purposes
Chapter 6.8: Monitoring of the quantities and usage patterns of antimicrobial agents used in food producing animals Data sources: sources of data will vary from country to country Basic sources Direct sources End-use sources Other sources customs, import and export data, manufacturing and sales data Veterinary medicinal products registration authorities, wholesalers, retailers, pharmacists, veterinarians, feed stores, feed mills Pharmaceutical industry associations veterinarians food animal producers Non conventional (internet sales )
Chapter 6.8: Monitoring of the quantities and usage patterns of antimicrobial agents used in food producing animals Type of antimicrobial use data: - Weight in kilograms of the active ingredient per year - Number of food producing animals by species, type of production and their weight in kilograms for food production per year - Information on dosage regimen and route of administration Reporting formats of antimicrobial use data: - Organised by species, route of administration and type of use
Example: French Antimicrobial Sales/Use Monitoring system Started in 1999 In accordance with OIE guideline agreement Industry ANMV/AFSSA sponsorship Ministry of Agriculture Principles System based on Marketing Authorisation Holder declarations Confidentiality ensured Simple questionnaire 100 % answers Check quality of data Annual report http://www.anses.fr/documents/anmv-ra-antibiotiques2010.pdf
Example: French Antimicrobial Sales/Use Monitoring system Based on sales declaration by Marketing Authorisation Holder (MAH) For each sale package of each VMP containing antimicrobial : ID number Number of sales Species repartition estimate Data base on Veterinary Medicinal Products Data on number of animals in the country
Database Fields VMP Name MAH name Id Sale package Sale package description Number of sold units Active ingredient Quantity of active expressed in mass of the active entity of the molecule. Convertion factor IU/g for some Active ingredients Pharmaceutical form Route of administration Target Species Posology mg/kg Treatment duration 21
How to interpret results? Crucial to distinguish between: - Sales volume - Exposure to antimicrobials - Antimicrobial sales volumes do not represent precisely their use Recent antimicrobials are more potent than old ones, and less active is needed to be administered to treat animals. -To estimate animal exposure to antimicrobials it is need to take into account other factors such as the posology (mg/kg) and the duration of administration. It is also needed to take into account the change in the total animal population according to time Therefore a decrease in sales volume does not mean obligatorily that there is a decrease in Antimicrobial use
Theoritical example(1) Time 1 Time 2 25 Total animal population (animal number) 1000 1000 20 15 Population treated (animal number) 110 205 10 including treated with oxytétracycline (Animal nb) 10 5 5 treated with fluoroquinolones (Animal nb) 100 200 0 Exposure Time 1 Time 2 In this example, the percentage of treated animals jump from 11% to 20,5 % meaning that globally the exposure increase from 86.4 % How do antimicrobial quantities vary?
Theoritical example (2) Calculation performed according to the following elements: Animal weight: 50 Kg Posology: Oxytétracycline : 20 mg/kg during 3 days Posology: Fluoroquinolone: 2 mg/kg for 1 day Calculation: Nb animals x 50 Kg x posology x treatment duration Results: 30 Time 1 Time 2 25 Oxytétracycline quantity (mg) 30000 15000 20 Fluoroquinolone quantity (mg) 10000 20000 15 10 Total anttimicrobial quantity (mg) 40000 35000 5 0 In this example, the antimicrobial quantity decrease from 12.5 % 45 40 35 Antimicrobial quantity (g) Time 1 Time 2
Theoritical example (3) In this example, an increase in animal exposure of 86.5 % results in a decrease of antimicrobial quantity of 12.5 % 45 40 35 30 25 20 15 Time 1 Time 2 10 5 0 Antimicrobial quantity (mg) Exposure Need to define an exposure indicator (see later ALEA (Animal Level of Exposure)). This indicator is directly correlated to the number of animals treated.
Results 2010: Sales
Evolution of antimicrobial sales between 1999 and 2010 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 1014 tons sold in 2010 Evolution des ventes d'antibiotiques 1999-2010 (Tonnes) The lowest sales figure during the survey period (-23% in comparison to1999) (-3,6 % in 2010 compared to 2009) 1 600,00 1 400,00 1 200,00 1 000,00 800,00 600,00 400,00 200,00 0,00 Decrease due mainly to 2 antimicrobial classes: Tetracyclines (-153T,-24.5%) Sulfonamides (-86T, -33%) compared to 1999
Estimate of antimicrobial exposure
Change in antimicrobial exposure 1999-2010 (oral + parenteral route) 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 The animal exposure to antimicrobials: - has increased between 1999 and 2007 (+21.8%) 0,8 0,7 Evolution de l'exposition aux antibiotiques 1999-2010 (ALEA) - has decreased in 2008 and 2009 (-12.3)% - was stabilised in 2010 0,6 0,5 0,4 0,3 0,2 0,1 0
Change in Exposure 1999-2010 (oral + parenteral route) 0,8 Analysis by route of administration and pharmaceutical form 10 000 000 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0 1 2 3 4 5 6 7 8 9 10 11 12 Injectable oral 9 000 000 8 000 000 7 000 000 6 000 000 5 000 000 4 000 000 3 000 000 2 000 000 1 000 000 0 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 oral Other oral forms oral solutions oral powders Premixes
Change in Exposure 1999-2010 (oral + parenteral route) 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 Analysis by antimicrobial class Antimicrobials most often used: 0,3 0,25 Tetracyclines Polymyxins Penicillins Macrolides Aminoglycosides 0,2 0,15 0,1 0,05 0
Change in Exposure 1999-2010 (oral + parenteral route) Analysis by animal species 1,6 1,4 1,2 1 0,8 0,6 0,4 Bovine Porcine Poultry Cat dogs 0,2 0
1999 2000 2001 2002 2003 2004 2005 Change in Exposure 1999-2010 (oral + parenteral route) 2006 2007 2008 2009 2010 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 Analysis by animal species by route of administration and antimicrobial classes Example: Porcine Parenteral route Oral route 40% 40% 35% 35% 30% Pénicillines 30% Fluoroquinolones 25% Aminoglycosides Macrolides 25% Tétracyclines Polypeptides Tétracyclines Pleuromutilines 20% Polypeptides Sulfamides 20% Sulfamides Triméthoprime 15% 10% Céphalosporines 3&4G Triméthoprime Lincosamides Pleuromutilines Quinolones Phénicolés 15% 10% Macrolides Pénicillines Aminoglycosides Quinolones Lincosamides 5% 5% 0% 0%
Poultry oral route Fluoroquinolones - generics 0,02500 0,02000 0,01500 0,01000 0,00500 REF AUTRE GEN TOTAL - -0,00500
Field surveys Performed by another Anses Laboratory based in Ploufragan Field survey for Poultry, Porcines, Rabbits Field survey gives complementary and more precise information
Example: fluoroquinolones, oral route, Poultry 120,00% National survey 100 % = mean value 1999-2005 100,00% 80,00% 60,00% 40,00% Generics Reference products 20,00% 0,00% 2003 2004 2005 2006 2007 2008 Field studies
European example ESVAC: European Surveillance of Veterinary Antimicrobial Consumption European project started in 2009 in order to collect harmonized data on antimicrobial use in animals at the European level 1 st report: Trends in the sales of veterinary antimicrobial agents in nine European Countries Reporting period: 2005-2009 http://www.ema.europa.eu/docs/en_gb/document_library/other/2010/04/wc500089584.pdf 2 nd Report: Sales of veterinary antimicrobial agents in 19 EU/EEA countries in 2010 http://www.ema.europa.eu/docs/en_gb/document_library/report/2012/10/wc500133532.pdf
Conclusion Tool enabling to follow trends in use of antimicrobials Is to be analysed in conjunction with fields surveys This tool and the data obtained is a basis to: - Make a comparison with antimicrobial resistance data - To analyse the potential impact or risk management measures
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 Exposure Recent example of Management measures Volontary ban of Cephalosporines in Pigs in France in 2010 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% 39
Thank you for your attention Organisation mondiale de la santé animale World Organisation for Animal Health Organización Mundial de Sanidad Animal 12 rue de Prony, 75017 Paris, France - www.oie.int oie@oie.int