The EU Antimicrobial Resistance Strategy -The Italy experience-

The EU Antimicrobial Resistance Strategy -The Italy experience- Maurizio Ferri, Paola Romagnoli Official veterinarians, SIMeVeP Multi-beneficiary Workshop on Veterinary Drugs Residue and Antimicrobial Resistance. Zagreb, 9-10 February 2015 1

Outline - AMR Global risk - AMR healthcare infection - AMR in food-producing animals and food - AMR and food-borne diseases - The EU strategy: monitoring and surveillance of AMR - Joint ECDC-EFSA-EMA report - Drug Consumption data in Italy - AMR strategy in Italy (human and food animals) - One-health concept in AMR 2

Scenario The Antibiotic Era (health benefits) helped to fight bacterial infections and bolstered the modern medicine Today AMR is an emerging problem and a threat to the modern healthcare system AMR as public health consequence of overuse and misuse of antimicrobial in animal productions and human medicine 3

WHO 4

AMR as Global Risk World Economic Forum (2014) Societal risk: the impact and the probability of the AMR is deemed as high as t e r r o r i s m o r c l i m a t e change. 5

OIE 6

Health-Economic Impact of AMR in the EU 25.000 deaths/year Healthcare cost (direct and indirect ) over 1,5 billion and 600 millions for lost of productivity 7

Health-Economic Impact of AMR in the US 2.000.000 infections 23.000 deaths (bacteria and fungi) Healthcare cost (direct and indirect): from 21 to 34 billions dollars (WHO, 2014) 8

AMR and Healthcare Related Infections (From WHO, AMR Report 2014)

AMR and healthcare related infections ECDC (Ears-Net) 2013. Drug-resistant strains of: - Klebsiella - Escherichia - Pseudomonas - meticillin-resistant S. aureus (MRSA) Increasing multi-drug resistance to fluoroquinolones, 3 generation cephalosporins and aminoglycosides (from 15% in 2010 to 21% in 2013). 10

AMR and healthcare related infections K. pneumoniae carbapenems resistant (29%) (50% death mortality rate) multi-resistant S.thyphimurium (DT 104- ACSSuT) 35% of Staphylococcus resistant to methicillin (MRSA) 11

The AMR cycle

Environmental community of AMR pathogens Presence of tetk gene driver for the tetracycline-resistance phenotype on NYC subways surfaces microbioma

AMR in Food-producing Animals and Food Chain overuse and misuse of antibiotics in animal productions risk of spreading of AMR zoonotic strains to humans through direct contact and consumption of food of animal origin zoonoses pathogens: Salmonella newport, S. DT104, Campylobacter, E. coli, Enterococcus vancomicin-resistent many studies showed the transmission of AMR to humans. 13

EFSA/ECDC. The European Union Summary Report on antimicrobial resistance in zoonotic and indicator bacteria from humans, animals and food in 2012 Salmonella and E. coli strains resistent to ampicillin s u l f o n a m i d e s a n d fluoroquinolones Campylobacter isolated from poultry, pork and beef meat with high resistance to ciprofloxacin, nalidixic acid and tetracycline 14

AMR and Food Safety resistance to more than one antibiotic represents a common feature of Campylobacter and Salmonella EU Campylobacteriosis: 214,268 confirmed human cases in 2012 EU Salmonella: 91,034 human cases reported in 2012. prevalence of MRSA in the primary production of pigs 15

AMR and Food Safety AMR strains resistant to environmental stress (heat, refrigeration, ph, Aw, etc..): eg. thermotolerant S. typhimurium DT104 Potential transmission animal-humans of Clostridium difficile via food? 16

Clostridium difficile an emerging food safety risk? USA: high mortality in hospitalized patients potential transmission of the bacteria from livestock to humans isolated from retail meat sold in Canada, Sweden and the USA. 17

The AMR and foodborne diseases (potential association) Netherlands Institute for Public Health, Food and Environment (RIVM 2011) (2003) significant increase in the incidence of strains of S. enteritidis phage type 1 quinolone-resistant (nalidixic acid) associated with the importation of eggs from Spain. (2005): a tenfold rise of cases of Salmonella Typhimurium DT104 multi-resistant associated with the importation of beef from a third country. 18

The AMR and foodborne diseases (potential association) complexity of the transmission routes between species (human-human), intra-species (humananimal) and crossing regional borders more epidemiological evidence (phenotypic and molecular typing) to confirm the same ARM isolates good strong of associations (human isolates-animal strains) FQR Campylobacter MRSA ESBLs 20

AMR: which strategy? Holistic approach (multi-sector) 21

AMR: which strategy? Holistic approach (multi-sector) We must start from the farms (sensitivity test, traceability 21

AMR: which strategy? Holistic approach (multi-sector) We must start from the farms (sensitivity test, traceability Analysis of development and spread of AMR bacterial strains through the whole food-chain 21

AMR: which strategy? Holistic approach (multi-sector) We must start from the farms (sensitivity test, traceability Analysis of development and spread of AMR bacterial strains through the whole food-chain Parliament resolutions: "By 2018 the use of antimicrobials for veterinary use in the European must be halved". 21

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AMR: which strategy? Community Action Plan against the rising threats from AMR 2011. 1 Strengthen the promotion of the appropriate use of antimicrobials in all Member States. 2 Strengthen the regulatory framework on veterinary medicines and on medicated feed via the review package foreseen for 2013 3 Introduce recommendations for prudent use in veterinary medicine, including follow-up reports, using the same approach as 2002 Council Recommendation on prudent use of antimicrobial agents in human medicine. 4 Strengthen infection prevention and control in healthcare settings 5 Introduction of the new Animal Health Law, which will focus on prevention of diseases, reducing the use of antibiotics and replacing current Animal Health provisions based on disease control. 6 To promote, in a staged approach, unprecedented collaborative research and development efforts to bring new antibiotics to patients 7 Promote efforts to analyze the need for new antibiotics into veterinary medicine 8 Develop and/or strengthen multilateral and bilateral commitments for the prevention and control of AMR in all sectors. 9 Strengthen surveillance systems on AMR and antimicrobial consumption in human medicine 10 Strengthen surveillance systems on AMR and antimicrobial consumption in animal medicine 11 Reinforce and co-ordinate research efforts 12 Survey and comparative effectiveness research 23

AMR: which strategy? The EU Commission relies on: EFSA, ECDC and EMA 5 surveillance networks on AMR and antibiotic consumption (as part of European Surveillance System -TESSy): for humans (FWD-Net, ESAC-Net, EARS-Net) animals (EFSA Scientific Network for Zoonosis Monitoring and ESVAC) 24

The EU AMR Roadmap Strengthen the regulatory framework on veterinary medicines and on medicated feed Prudent use of antimicrobials in human and veterinary medicine Development of new antimicrobials or alternatives for treatments Monitoring and reporting Communication, education and training International cooperation. 25

AMR EU monitoring on zoonotic and commensal bacteria

Joint report EFSA-ECDC-EMA on AMR (2014) Main findings consumption of antimicrobial agents in foodproducing animals is lower than in humans in half of the countries Positive associations food-producing animalshumans 27

Joint report EFSA-ECDC-EMA on AMR (2014) Positive associations Food-producing animals: consumption and occurrence of resistant bacteria (Escherichia coli. Salmonella spp. and Campylobacter spp.) Humans: consumption and resistance for 3rd, 4rd generation cephalosporins and fluoroquinolones resistance in E. coli. Animals-human indicator E. Coli macrolides (animals) and human cases of resistant Campylobacter spp. tetracyclines (animals) and human cases of resistant Salmonella spp. and Campylobacter spp. 28

Drug Monitoring and Antimicrobial Resistance Strategy in Italy

Consumption of antibiotics in Italy (AIFA, 2013) AIFA (OsMed) - Humans - Monitoring of drug consumption/selling Ministry of Health - Animals Drug surveillance National monitoring and traceability of veterinary medicine extension of current human database to veterinary products with electronic prescription and computerized flow (pilot project) 30

Consumption of antibiotics in Italy (AIFA, 2013) National drugs expenditure: 26,1 billion euros (+2,3% compared to 2012) 436 euro pro-capite 75,4% reimbursed by the State Cardiovascular in the lead Problems? inappropriateness for antibiotics, d r u g s a s c o n s u m p t i o n c o m m o d i t y, ennvironmental contamination. 31

Consumption of antibiotics in Italy (AIFA, 2013 and ECDC- EMA-EFSA report 2014) Italy ranked second in Europe (after France) > 44% of EU average consumption North-South gradient: higher consumption in the southern regions (Campania, Calabria, Puglia, Sicily) 32

Consumption of veterinary antimicrobial agents in Italy ESVAC (European Surveillance of Veterinary Antimicrobial consumption) third report 2012 33

Consumption of veterinary antimicrobial agents in Italy sales (tonnes of active ingredient): 1,543 (third country) (137%: 3 times higher the EU average) volume of sales of veterinary antimicrobial (farms animals) decreased by 13% between 2010 and 2011 similar (20% in EU, 2013-2014) positive trend but not be confirmed in the long run 34

Consumption of veterinary antimicrobial agents in Italy Legal basis for the monitoring of sales T h e c o l l e c t i o n o f s a l e s d a t a b y pharmaceutical companies is based on the National Law 193/2006 (art. 32(3)) transposing EC Directive 2004/28. 35

Consumption of veterinary antimicrobial agents in Italy tetracyclines (37%) penicillins (22%) sulfonamides (10%) CIAs: 3 rd, 4th-generation cephalosporins, fluoroquinolones and macrolides (horses, a c c o u n t e d f o r 0. 2 %, 1. 7 % a n d 8 %, respectively, of the total sales in the 26 countries in 2012). 36

Selling of veterinary antimicrobial agents in Italy antimicrobial agents for use in animals are prescription-only medicines the retail sale of veterinary medicinal products containing antibiotics can occur only at pharmacies and only under veterinary prescription 37

Selling of veterinary antimicrobial agents in Italy Decoupling (highly debated in EU) No: France and Holland Yes: Denmark Yes: Italy (Veterinarians cannot sell veterinary drugs, including antibiotics). 38

Selling of veterinary antimicrobial agents in Italy Farms cannot hold stocks of antibiotics in the form of medicated feed or veterinary drugs administered in feed, water or liquid feed. Only small quantities not exceeding a treatment period of 7 days are allowed to be held. 39

AMR reduction strategy in Italy (human) Ministry of Health Decision n.2119/98/ec of the European Parliament and of the Council of 24 September 1998 setting up a network for the epidemiological surveillance and control of communicable diseases in the Community National surveillance network of AMR (humans) managed by the Health Institute (ISS) AR- ISS " Antibiotic Resistance project 40

AMR surveillance system Ministry of Health AR- ISS " Antibiotic Resistance project not funded by the pharmaceutical industry involving 40 sentinel labs linked to 60 hospitals throughout the country The protocol Ar-Iss meets the information needs of EARS-Net. 41

AMR surveillance system Ministry of Health AR- ISS " Antibiotic Resistance project: Covers invasive pathogens: Staphylococcus a u r e u s, S t r e p t o c o c c u s p n e u m o n i a e, Enterococcus faecalis/faecium, Klebsiella oxytoca/pneumoniae, E.coli, P. aeruginosa. Regional surveillance system (eg. Lombardia, Emilia Romagna, Toscana) 42

AMR surveillance system AMR-ISS (2011-2013) High resistance in Italy over the European average Increase trend of Gram-: E.coli and K.pneumoniae resistent to fluoroquinolones, 3 generation cephalosporins and aminoglycosides Pseudomonas aeruginosa resistent to piparacillina +tazobactam, ceftazidime, aminoglycosides Carbapenems resistent K. pneumoniae increased from 1% (2008) to al 34% nel 2013. 43

AMR surveillance system AMR-ISS (2011-2013) Gram +: trend are generally stable, but still high: increase resistance of S. pneumoniae to penicillin (14% in 2013) resistance to macrolides (25% in 2013) is slightly lower MRSA stable (36% in 2013) 44

AMR surveillance system Klebsiella pneumoniae multi resistant to fluorochinolons, cephalosporins and amynoglicosides EU-EARS-Net 2013 50 40 41,8 % 30 20 20,9 Italy EU average 10 0 Italy EU average

AMR surveillance system Escherichia coli, multi resistent to fluorochinolons, aminoglycosides and cephalosporins EU EARS Net 2013 25 20 % 15 12,2 Italy EU average 10 5 4,6 0 Italy EU average

AMR surveillance system Staphylococcus aureus meticillin resistent (MRSA) EU EARS Net 2013 50 40 35,8 30 20 18 Italy EU average 10 0 Italy EU average

AMR surveillance system Pseudomonas aeruginosa, multiresistent to piperacillina/tazobactam, ceftazidime,fluorochinolons, aminoglycosides and carbapenems EU-EARS-Net 2013 30 25 24,5 % 20 15 13 Italy EU average 10 5 0 Italy EU average

AMR surveillance system Klebsiella pneumoniae resistent to carbapenems EU-EARS-Net 2013 80 60 % 40 34,3 Italy EU average 20 8,3 0 Italy EU average

AMR surveillance system Carbapenem-resistant Klebsiella pneumoniae 80 treatment options are extremely scarce % 60 40 20 34,3 8,3 Italy EU avera one possibility is colistin, an old antibiotic with toxicity problems 0 Italy EU average strains of K. pneumoniae are developing resistance to colistin Colistin resistance superimposed endemic to carbapenem-resistant Klebsiella pneumoniae: a Rapidly evolving problem in Italy, November 2013 to April 2014 Eurosurveillance October 23, 2014

AMR reduction strategy in Italy (animals/food) Legal framework Directive 2003/99/EC on the monitoring of zoonoses and zoonotic agents (Regulation CE 2160/2003) implemented in Italy with Legislative Decree 191/2006 The C o m m i s s i o n D e c i s i o n 2 0 0 7 / 4 0 7 / E C - requirements for an harmonized monitoring and reporting of resistant strains of Salmonella isolated Decision 2013/652/EU to improve the monitoring and reporting of AMR in food-producing animals and food thereof 52

AMR reduction strategy in Italy (animals/food) Ministry of Health Official controls on the correct use of the active ingredients and medications including antibiotics, are performed by public health veterinarians Tools: National drug surveillance plan National residue plan NPAA Traceability (pilot project-piemonte Region- ASCOFARVE) National surveillance network of AMR in food producing animals and food thereof 51

AMR reduction strategy in Italy (animals/food) CRAB: National reference center for AMR in foodproducing animals and food managed by IZS Lazio e Toscana (D.M. 8-5-2002, G. U. 22 maggio 2002, n. 118) (NRL, Reg. CE 882/2004) Data from 10 public vet labs (IZS and IZSAM) (Collaborate with National Zoonoses Reference Centres and ISS (MoH) Web oriented application for data uploading 54

AMR reduction strategy in Italy (animals/food) develop standards diagnosis confirmation deliver training and organize inter-laboratory network 15,000 determinations in MIC susceptibility testing of pathogenic bacterial isolates from animal (samples from IZZS) molecular techniques for zoonotic pathogens (Salmonella and Campylobacter): Single Locus sequencing, Multilocus Sequence Typing, Phylogrouping, PFGE, Array Testing) 55

AMR reduction strategy in Italy (animals/food) primary production of pigs a high prevalence of MRSA equal to or greater than 60% resistance to FQs and macrolides in Campylobacter spp. primary production of poultry equal to or greater than 60% FQs and macrolides resistent Campylobacte spp. MRSA in turkeys and poultry ranges from 0 to 79%. 53

Veterinary and Human Medicine Collaboration on AMR Surveillance and Monitoring Activities 56

AMR integrated reduction strategy Key points International cooperation: resistant bacteria are borderless and an ineffective management by a single country could endanger other countries Holistic approach: interdisciplinary collaboration Structured surveillance systems which integrate animal, human and food chain surveillance First joint report of EFSA-EMA-ECDC on human-animal AMR 57

Ministry of Health Department of Veterinary Public Health, Nutrition and Food Safety ECDC EFSA ISS CRAB AMR isolates Local Health Units (228) Abruzzo AUSL 5 Public Health laboratories (Hospitals) Public Vet laboratories (IZS) Public health Animal health (vet. service) Food of animal origin (vet. service) Food of non animal origin (medical service) 3

AMR integrated reduction strategy The Council of Health Ministers in December 2014 invited the Commission and MS to further strengthen the cooperation between the human health and the veterinary sectors in order to address the rising threat from antimicrobial resistance. 59

AMR integrated reduction strategy in Italy 2013 Minister of Health Guidance Manual on "Biosafety and correct and rational use of antibiotics in animal husbandry. National Drug surveillance include the notification of failed efficacy (adverse effect) Limitation of use of human drugs in animal productions 60

Harmonized Monitoring plan for AMR in Italy Decision 652/2013 Involved institutions IZSLT-CRAB-National center for AMR IZS Teramo- Campy NRC IZS Padova- Salmonella NRC Ministry of Health 60

Harmonized Monitoring plan for AMR in Italy Decision 652/2013 Period: 2014-2016-2018-2020 laying hens, broiler, relate fresh meat, fattening turkey Period: 2015-2017-2019 Pigs, cattle < 1 year, pork meat/beef 61

Harmonized Monitoring plan for AMR in Italy Decision 652/2013 - identification, typing, AMR profile of the following bacterial species: - isolates of Salmonella on laying hens, broiler, fattening turkeys with samples taken in the framework of National control plan for Salmonella (possible to use isolated from FBO) - isolates of C.jejuni, and E.coli (indicator and ESBL, Ampc and Carbapenemasi) from caecum sampled from poultry and turkey at slaughterhouse. 61

Harmonized Monitoring plan for AMR in Italy Decision 652/2013 - Number of samples is related to the expected AMR isolates - 850 broiler - 850 fattening turkey - The sampling include regions with high density of farms and animal population - Emilia Romagna, Lombardia, Marche, Abruzzo, Piemonte (broiler) - Veneto, Emilia Romagna, Toscana (fattening turkey) 61

Harmonized Monitoring plan for AMR in Italy Decision 652/2013 Stratified regional sampling according to annual volume of slaughtering Casual sampling every three months Preferable to sample a farm once a year 61

Harmonized Monitoring plan for AMR in Italy Decision 652/2013 Ministry of Health Recommendations isolates form National control plan for Salmonella to be submitted to CRAB for AMR profile isolates of Salmonella obtained from microbiological monitoring (process hygiene a s f o r R e g u l a t i o n 2 0 7 3 / 2 0 0 5 ) a t slaughterhouse to be submitted to CRAB for AMR profile sampling and submitting procedures according to instructions of Annex 1 61

Harmonized Monitoring plan for AMR in Italy Decision 652/2013 61

AMR integrated reduction strategy in Italy Structured surveillance systems ISS Network of IZZ vet laboratories Zoonoses national references centers CRAB (IZSLT) partners in EU cofunded projects EFFORT against antimicrobial resistance. EU EMIDA-ERANET MRSA lineages in primary productions: multi-host pathogen, spill-over and spill-back between animals and humans? 62

AMR integrated reduction strategy in Italy EU Funded AMR projects Ecology from Farm to Fork Of microbial drug Resistance and Transmission (9 mil euro) Nanotherapeutics for antibiotic resistant emerging bacterial pathogens (9,6 mil euro) Nanotherapeutics to treat antibiotic resistant Gram-negative bacteria caused pneumonia Infections: 5,6 mil euro Targeting the HIV-1 Nucleocapsid Protein to fight Antiretroviral Drug Resistance. IT coordinator. University of Siena: 5,7 mil.

Minister of Health Responsible use of antibiotics in pet An handbook for veterinarians

One Health? Thank you for the attention 65