1 13 September 2018 2 EMA/CVMP/AWP/842786/2015 3 Committee for Medicinal Products for Veterinary Use (CVMP) 4 Reflection paper on the use of aminopenicillins and their 5 beta-lactamase inhibitor combinations in animals in the 6 European Union: development of resistance and impact 7 on human and animal health 8 Draft Draft agreed by Antimicrobials Working Party (AWP) 9 July 2018 Adopted by CVMP for release for consultation 13 September 2018 Start of public consultation 21 September 2018 End of consultation (deadline for comments) 21 December 2018 9 Comments should be provided using this template. The completed comments form should be sent to [email protected] 10 Keywords aminopenicillins, antimicrobial resistance 11 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2018. Reproduction is authorised provided the source is acknowledged. 12 13 Table of contents 14 Executive summary ..................................................................................... 4 15 CVMP Recommendations for action ............................................................. 6 16 1. Background ............................................................................................. 7 17 2. General drug characteristics .................................................................... 8 18 2.1. Structure and mechanism of action ....................................................................... 8 19 2.2. Antimicrobial spectrum ....................................................................................... 8 20 2.3. Pharmacodynamics ............................................................................................. 9 21 2.4. Pharmacokinetics ............................................................................................. 10 22 3. Resistance mechanisms and susceptibility testing ................................ 12 23 3.1. Resistance mechanisms .................................................................................... 12 24 3.1.1. Enzymatic degradation of beta-lactams by beta-lactamases ................................. 12 25 3.1.2. Modification of the target site .......................................................................... 17 26 3.1.3. Other resistance mechanisms .......................................................................... 17 27 3.2. Susceptibility testing ........................................................................................ 17 28 4. Sales and use of aminopenicillins and their inhibitor combinations in 29 veterinary medicine ................................................................................... 19 30 4.1. Sales .............................................................................................................. 19 31 4.2. Use and indications in food-producing animals ...................................................... 19 32 4.3. Use and indications in horses ............................................................................. 20 33 4.4. Use and indications in companion animals ........................................................... 21 34 5. The use of aminopenicillins and their inhibitor combinations in human 35 medicine .................................................................................................... 25 36 5.1. Indications in human medicine ........................................................................... 25 37 5.2. Consumption of aminopenicillins in humans in the EU ............................................ 26 38 6. Occurrence of resistance ....................................................................... 29 39 6.1. Resistance in bacteria of animal origin covered by EU surveillance ........................... 30 40 6.2. Resistance in animal target pathogens ................................................................ 31 41 6.3. Resistance in human pathogens ......................................................................... 34 42 7. Possible links between the use of aminopenicillins and their inhibitor 43 combinations in animals and resistance in bacteria of animal origin ......... 36 44 8. Impact of resistance on animal and human health ................................ 37 45 8.1. Animal health .................................................................................................. 37 46 8.2. Human health .................................................................................................. 38 47 9. Transmission of resistance or resistance determinants between animals 48 and humans ............................................................................................... 39 49 9.1. Transmission of resistant bacteria ....................................................................... 39 50 9.2. Transmission of resistance determinants ............................................................. 41 Reflection paper on the use of aminopenicillins and their beta-lactamase inhibitor combinations in animals in the European Union: development of resistance and impact on human and animal health EMA/CVMP/AWP/842786/2015 Page 2/65 51 10. Discussion ........................................................................................... 44 52 11. Conclusions ......................................................................................... 46 53 12. References .......................................................................................... 53 54 Appendix ................................................................................................... 65 55 56 Reflection paper on the use of aminopenicillins and their beta-lactamase inhibitor combinations in animals in the European Union: development of resistance and impact on human and animal health EMA/CVMP/AWP/842786/2015 Page 3/65 57 Executive summary 58 The objective of this document is to review available information on the use of aminopenicillins and 59 their beta-lactamase inhibitor combinations in veterinary medicine in the EU, their effect on the 60 emergence of antimicrobial resistance (AMR) and the potential impact of resistance on human and 61 animal health. The document provides information for the risk profiling, as recommended by the 62 Antimicrobial Advice ad hoc Expert Group (AMEG) of the EMA, to assist with placing these substances 63 within the AMEG’s categorisation (EMA/AMEG, 2014). The focus of this paper is on veterinary 64 aminopenicillins authorised in the EU, which are ampicillin (ATC J01CA01), amoxicillin (ATC J01CA04), 65 and their beta-lactamase inhibitor combination amoxicillin-clavulanic acid (J01CR02). 66 The WHO classifies penicillins (natural, aminopenicillins and antipseudomonal) as critically important 67 antimicrobials (CIA) for humans. According to the WHO, the CIA status is justified due to limited 68 therapy options for listeriosis and infections caused by Enterococcus spp., and the likelihood of 69 transmission of resistant Enterococcus spp. and Enterobacteriaceae, including both Salmonella spp. 70 and Escherichia coli, from non-human sources to humans. 71 Although aminopenicillins are seldom among the sole treatment options, with the exception of for 72 Listeria and enterococci, they are often used as first line antimicrobials for many infections in animals 73 and humans. In animals aminopenicillins are used for infections caused by species belonging to 74 Pasteurellaceae, Streptococcus spp., Staphylococcus spp., Erysipelothrix rhusiopathiae, Listeria 75 monocytogenes, Clostridium spp. and other anaerobic species, Bordetella bronchiseptica and species 76 belonging to the Enterobacteriaceae. Aminopenicillins and their inhibitor combinations are very 77 valuable drugs for treating respiratory infections in humans caused by Streptococcus pneumoniae, 78 Haemophilus influenzae, and Branhamella catarrhalis. Due to the abundant presence of beta- 79 lactamases in E. coli and in many other Enterobacteriaceae, aminopenicillins are combined with beta- 80 lactamase inhibitors for the treatment of infections caused by these bacteria. Inhibitor combinations 81 can also be useful in certain infections caused by ESBL-producing E.coli provided that an isolate is 82 susceptible to the combination in vitro. The combination is ineffective against AmpC-mediated 83 resistance. 84 Ampicillin, amoxicillin, and to a lesser extent amoxicillin-clavulanic acid combinations have been widely 85 used for decades for the treatment of infections in several animal species in European countries. 86 Measured in mg/PCU (population correction unit), penicillins were the second most used antimicrobial 87 class in food-producing animals in the EU in 2015 and accounted for 25% of the total sales. 88 Aminopenicillins (amoxicillin) made up the major proportion (88%) of the total penicillin use, while 89 their inhibitor combinations formed a very limited fraction of the total penicillin use. There are 90 substantial differences between the uses of different beta-lactam drug classes in animals in Nordic 91 countries, where benzyl penicillin and its pro-drugs dominates, vs. in other European countries, where 92 aminopenicillins are the prevailing beta-lactams used. This may be due to differences in treatment 93 guidelines, availability of authorised products, production systems (including dominant animal species), 94 herd sizes, disease occurrences, and production