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Reflection Paper 1 15 November 2010 2 EMA/CVMP/SAGAM/741087/2009 3 Committee for Medicinal Products for Veterinary Use (CVMP) 4 Reflection paper on the use of macrolides, lincosamides 5 and streptogramins (MLS) in food-producing animals in 6 the European Union: development of resistance and 7 impact on human and animal health 8 9 Draft Agreed by Scientific Advisory Group on Antimicrobials (SAGAM) 2-3 June 2010 Adoption by CVMP for release for consultation 10 November 2010 End of consultation (deadline for comments) 28 February 2011 10 11 Comments should be provided using this template. The completed comments form should be sent to [email protected] 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8416 E-mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2010. Reproduction is authorised provided the source is acknowledged. 12 Reflection paper on the use of macrolides, lincosamides 13 and streptogramins (MLS) in food-producing animals in 14 the European Union: development of resistance and 15 impact on human and animal health 16 CVMP recommendations for action 17 Macrolides and lincosamides are used for treatment of diseases that are common in food producing 18 animals and for medication of large groups of animals (mass medication). They are critically important 19 for animal health and therefore it is highly important that they are used prudently to contain resistance 20 against major animal pathogens. In addition, MLS are listed by WHO (AGISAR 2009) as critically 21 important for the treatment of certain zoonotic infections in humans and risk mitigation measures are 22 needed to reduce the risk for spread of resistance from animals to humans. 23 Macrolides have been used for group and flock medication since several decades. Before the 24 authorisation of growth promoters expired in EU these molecules were added in low doses in animal 25 feed to increase feed conversion. Such use is not allowed in EU today but there are products approved 26 for preventive treatment using low doses for long time. 27 Data recently published shows great differences between different countries on the use of 28 antimicrobials in general - including macrolides - which indicates that there might be options to reduce 29 use of these antimicrobials that are available without compromising animal health and welfare. 30 The recommendations below have been prepared following SAGAM’s review on macrolides, 31 lincosamides and streptogramins. 32 33 For veterinary medicinal products for food producing animals the CVMP concluded that the following 34 recommendations are for consideration by Competent Authorities: 35 Prudent use of antimicrobials should be strongly promoted. It is acknowledged that macrolides 36 are first line treatment against a number of animal diseases but still there is a need to avoid 37 overuse, for e.g. general prophylaxis where no specific diagnose is evident or where the 38 disease in question would self cure without antimicrobials. 39 Duration of treatment should be limited to the minimum required time for treatment of 40 diseases. There might be a need to review certain SPCs to reduce the approved treatment 41 duration in cases where it is found unnecessarily long in relation to the severity of the disease. 42 Doses should preferably be selected considering AMR related risks. In case of old products 43 where data on dose selection are sparse doses should anyway be reviewed and in case they 44 are obviously too low (e.g. compared to other products containing the same active substance) 45 this should be addressed. Notably there are often several different doses approved for different 46 indications and thus there is an option to increase doses where relevant without asking for new 47 tolerance or safety data. 48 Indications for use should preferably be restricted to those for which efficacy has been proven 49 and general indications without a solid clinical basis should be avoided. In case of old products 50 where data are sparse indications should be reviewed and revised where appropriate to be as 51 accurate as possible. In particular, combination products are of concern as there seems to be 2/39 52 products on the market for which the choice of included active components cannot be justified 53 as their combined use lacks scientific rational. 54 Notwithstanding the list of recommendations above, the CVMP is of the opinion that antimicrobial 55 resistance should not be considered in isolation but a global approach to the problem is needed. 56 Implementation of prudent use principles remains a cornerstone to contain resistance together with 57 biosecurity and other measures to promote animal health and thereby reduce the need for treatment. 3/39 58 Table of contents 59 CVMP recommendations for action.........................................................................................2 60 1. Mandate .............................................................................................................................5 61 2. Introduction.......................................................................................................................5 62 3. Objective............................................................................................................................6 63 4. Classification, mechanism of action, spectrum of activity and pharmacokinetics ...............6 64 4.1. Classification ................................................................................................................... 6 65 4.2. Mechanism of action and spectrum of activity ....................................................................... 7 66 4.3. Pharmacokinetics ............................................................................................................. 8 67 5. Use of macrolides, lincosamides and streptogramins.........................................................8 68 5.1. Use in human medicine ..................................................................................................... 8 69 5.2. Macrolides, lincosamides and streptogramins authorised for animals in the EU .......................... 9 70 5.3. Use of macrolides, lincosamides and streptogramins for animals in the EU .............................. 10 71 6. Mechanisms of resistance to macrolides, lincosamides and streptogramins ....................12 72 6.1. Natural resistance .......................................................................................................... 12 73 6.2. Acquired resistance ........................................................................................................ 13 74 6.3. Horizontally transferable resistance................................................................................... 13 75 6.4. Non-horizontally transferable resistance ............................................................................ 15 76 6.5. Resistance in bacteria from food producing animals............................................................. 16 77 6.6. Emergence of resistance among animal pathogens .............................................................. 16 78 6.6.1. Brachyspira ................................................................................................................ 16 79 6.6.2. Anaerobic bacteria other than Brachyspira....................................................................... 17 80 6.6.3. Family Pasteurellaceae ................................................................................................. 17 81 6.6.4. Staphylococcal and streptococcal species ........................................................................ 17 82 6.6.5. Other bacteria and Mycoplasma ..................................................................................... 18 83 6.7. Emergence of resistance among zoonotic and commensal bacteria ........................................ 19 84 6.7.1. Campylobacter spp ...................................................................................................... 19 85 6.7.2. Enterococcus spp......................................................................................................... 20 86 6.8. Influence of use of macrolides, lincosamides and streptogramins in human medicine on resistance 87 .......................................................................................................................................... 21 88 6.9. Influence of macrolide use in food animals on occurrence of macrolide resistant Campylobacter.22 89 6.10. Influence of use of macrolides in food animals on occurrence of macrolide resistant enterococci22 90 6.11. Influence of macrolide use in food animals on resistance among Gram-positive cocci other than 91 enterococci .......................................................................................................................... 22 92 6.12. Influence of macrolides use in food animals on resistance among other bacterial species......... 23 93 7. Impact of MLS resistance on human and animal health ...................................................23 94 7.1.1. Impact on human health............................................................................................... 23 95 7.1.2. Impact on animal health ............................................................................................... 25 96 8. Summary assessment ......................................................................................................26
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