Antibiotic Resistance A Global Problem. Dik Mevius

Transcription

1 Antibiotic Resistance A Global Problem Dik Mevius

2 Content History of AMR with focus at ESBLs What are ESBLs The Dutch situation Antibiotic use Antimicrobial resistance ESBLs in animals Public health risks Measures initiated in The Netherlands Effect on use and AMR Critical success factors

3 Beta-lactam antibiotics Photo from slide by Christine L. Case, Ed.D, Professor of Microbiology, Skyline College, California First was penicillin (1928) Active against Gram positive bacteria (a.o. staphylococci, streptococci) Newer beta-lactam antibiotics also active against Gram negative bacteria (e.g. E. coli, Salmonella) Very important class for treatment of both humans and animals Source:

4 Different beta-lactams Penicillins (e.g. benzylpenicillin, ampi/amoxicilline) Cephalosporins 1st and 2nd generation cephalosporins (bv. cefalexin,cefapirine) 3rd and 4th generation cephalosporins (Extended Spectrum Cephalosporins (ESC), e.g. cefaperazone. ceftiofur, cefquinome, cefovecin Cephamycins (e.g. cefoxitin, cefepime) Monobactams (e.g. aztreonam) Carbapenems and penems (e.g. imi/mero/ertapenem)

5 Resistance against beta-lactam antibiotics Two mechanisms: Reduced affinity for the binding site (penicillin binding protein (PBP)) Inactivation by enzymes (beta-lactamases) Narrow spectrum beta-lactamases Penicillinase (S. aureus) TEM-1 (E. coli) Extended Spectrum beta-lactamases (ESBL) / AmpC betalactamases Metallo beta-lactamases Carbapenemases

6 ESBL/AmpC beta-lactamases Inactivate All penicillins (pen, ampi, amox), and all cephalosporins (ceftiofur, cefovecin, cefquinome) In vitro inhibited by clavulanic acid (not AmpCs) Most important families are CTX-M (cefotaximase, first found in a patient in München) SHV (sulfhydryl reagent variable) TEM (Greek patient Temoneira) CIT (Citrobacter (CMY)) Chromosomal ampc promoter mutants Always present but are not part of the ESBL-problem

7 AmpC ESBL Carbapenemases Now > 1000 variants known

8 Where do ESBLs orginate Beta-lactamases exist in environmental organisms to: protect antibiotic producing organisms Including bacteria that live in the same environment soil, water E.g. Kluyvera, Shewanella, Rahnella,.

9 Evolution of ESBLs determined by selection!! OXA-48 NDM-1 Penicillin Ampi/Amox 3rd/4th-gen Cefalosporines Carbepenems Bla-z TEM-1 ESBL Carb.

10 Canton & Coque The CTX-M ß-lactamase pandemic Current Opinion in Microbiology Volume 9, Issue

11 Since 2000: CTX-M pandemic Canton & Coque`, 2006

12 How do ESBL spread? ESBL-genes are often plasmid located Facilitates horizontal transfer within (E. coli -> E. coli) but also between bacterial species (E. coli -> Salmonella) No limits to possibilities to spread Food-safety issue!!

13 Plasmids Plasmids: self-replicerating Mobile DNA In E. coli more than 20 plasmid families known: Most important ESBL-carrying plasmid in animals is: IncI1, but also: IncHI2, IncK, IncB/O, IncN, IncA/C

14 ESBL-epidemiology is determined by: Genes (via transposons, jumping genes) Chrom > plasmide, plasmid > plasmid (vb TEM-1) Plasmids Conjugation, addiction factors (e.g. IncF/CTX-M-15, IncI1/CTX-M-1) Strains Clonal spread Evolutionary tools Eg. Uropathogenic E. coli O25b:H4-B2-ST131 with IncF/CTX-M-15 Pandemic spread also outside hospitals

15 Epidemiology of CTX-M-1 versus CTX-M-15

16 ESBLs in Animals Publicaties Predominant in EU The predominant ESBL families encountered are CTX-M, TEM, and SHV; the predominant AmpC family is CMY. The most common genes associated with this resistance in animals are CTX-M-1 (the most commonly identified ESBL), and CTX-M-14, followed by TEM-52 and SHV-12. Among the genes encoding AmpCtype β-lactamases, CMY-2 is the most common

17 Trends in veal calves in NL

18 Selection in animals by: Initiated by use of beta-lactams Ampi/amoxicilline 3rd/4th gen cefalosporins (3rd choice drugs) Ceftiofur Preventive use at hatcheries, young piglets, Dairy cows irt 0 days withdrawal time for milk Cefquinome: Dry cow treatment Cefovecin Very long acting drug in dogs and cats Other antibiotic use Co-selection

19 EFSA Baseline report: trade and MRSA positivity

20 Antibiotic usage in humans and animals in NL

21 kg active ingredient x Antibiotic use in animals in NL (Source FIDIN) % oral administration by group/flock mediation Increase up to 2007 was the basis for mandatory reduction policy of the government of 20/50% AMGPs (growth promoters) Antibiotics (therapeutic use) Total

22 Animal versus human use in kg van Geijlswijk, et al, TvD, 2009

23 EARSS-net 2010 report (ECDC) MRSA ESBLs

24 Resistance in 2009 (E. coli as commensal in the GI-tract ) (MARAN-2009)

25 Expressed as multi-drug resistance MDR to 8 9 classes

26 What does this mean Dutch food-producing animals are an ideal environment for multidrug resistant organisms Risk?? Animal health? Yes, if they cause infections Public health? Yes if:» Food-borne pathogens» Zoonotic organisms» Transferable genes ESBLs!!

27 Cefotaxime resistance in E. coli Ban of ceftiofur use at hatcheries

28 ESBL-genes and plasmids in Broiler isolates (Dierikx et al. 2010) S. enterica (n=21) 18 E. coli (n=23) Humans: CTX- M15, 14/9, CTXM-1 TEM-52 CMY-2 TEM-20 CTXM-2 ACC-1 SHV-2 IncI1 IncI1 + nt IncK IncI1 IncHI2/P Nt IncK

29 Prevalence of ESBLs on Dutch broiler farms (Dierikx et al. 2010) 100 % of the farms: ESBL-positive On 85 % (22/26) within-farm prevalence > 80% Percentage ESBL-positieve monsters per bedrijf A B C D E F G H I J K L M N O P Q R S T U V W X Y Z Bedrijfscodes

30 Which types of ESBLs in humans in NL? National ESBL reference study (RIVM, UMCU, CVI) analysing 692 human clinical isolates from 29 diagnostic laboratories (Voets et al. 2012) 25% Klebsiella (CTX-M-15) 75% E. coli App. half was CTX-M-15 ( pandemic variant in humans no relation with farm animals!!) (CTX-M-9/14, 2, 3; SHV-12) Partially (30%) either CTX-M-1 or TEM-52 (Paltansing LUMC, 24% CTX-M-1 P054) (Al Naimi et al. JCM 2006, 18% CTX-M-1) Potential relation with poultry!!!

31 Association with humans CMI, 2011

32 Association with humans EID, 2011

33 94 100% poultry meat pos for ESBLs Beef/pork incidentally positive Conclusion: Attribution from animal production is likely Poultry meat is the most likely source

34 ESBLs in other animals in The Netherlands Animal species ESBLs-Prevalence ESBL subtypes Companian animals > 50% in dogs (Dierikx et al 2012) Hordijk 2015: 45% healthy dogs CTX-M-1, 2, 9, 14, 15, TEM-30, 52, 80, OXA-1, CMY-2, 39 (qnr) Slaughter pigs 75% slaughter batches CTX-M-1, 14, 15, 32, TEM- 52, SHV-12, CMY-2, OXA-1 Vleeskalveren 70% slaughter batches CTX-M-1, 2, 14, 15, 32, TEM-52, CMY-2, OXA-1 Melkkoeien 7% individual cows CTX-M-1, 14, 15 Kalkoenen 50% flocks CTX-1,15, CMY-2

35 ESBLs in other animals in The Netherlands Wild bird Species ESBL Wilde eend Anas platyrhynchos 4 Rotsduif Columbia livia 1 Kemphaan Philomachus pugnax 1 Tureluur Tringa totanus 5 Kokmeeuw Chroicocephalus ridibundus 2 Zilvermeeuw Larus argentatus 1 Zwarte zwaan Cygnus atratus 1 Grote mantelmeeuw Larus marinus 1 Jan van Gent Morus bassanus 1 Total 17 (22%) ESBLs in all animal species and the environment. Poultry is the largest reservoir but part of the problem!!

36 Eight o clock news, September

37 Measures implemented by government Mandatory reduction of antibiotic usage of 20% in 2012 and 50% in 2013 (compared to 2009) New target in 2012 = 70% All antibiotic use on farms registered (VetCis) Mandatory since 2012 Preventive use not legal Independent control institute Netherlands Veterinary Medicines Authority (SDa, Tasks» Report usage data publically,» Define target for usage» Identify frequent users» Control measures to improve usage

38 BENCHMARKINDICATORS ACTION LEVEL Direct measures necessary to reduce antibiotic usage SIGNALING LEVEL Please be aware TARGET LEVEL No direct measures necessary to reduce antibiotic usage

39 Broilers usage data 2011in (N = 737) ATD/Y nr of treatment days per year on each farm Median 20% P75 Denmark 3 ATDs Germany NRW 50 ATDs

40 Pig-production farms (> 2000 top), veal calves (app. 1000bottom) Animal Defined Daily dosages (ADDD/Y)

41 Health Council report

42 ESBLs in animals considered the most important PH threat Ban usage of new classes in animals: Carbapenems, tigecycline, daptomycine, oxazolidones, mupirocine etc. 3rd/4th generation Cefalosporins Not for group treatment Not for mastitis prevention in dry cow treatment Solely allowed for individual treatment based on antibiogram Colistin, beta-lactams, fluoroquinolones, aminoglycosides Usage needs to be reduced in time FQ solely based on antibiogram

43 Veterinary Antibiotics Working Party-guideline 1 st, 2 nd and 3 rd choice drugs defined based on Health Council advice 1 st Choice Allowed for empiric therapy with no direct effect on ESBLs 2 nd Choice No unless, appropriate argumentation provided by a vet 3 rd Choice No unless, no alternatives based on ABG Banned Not allowed for FP-animals UDD-rule July In Drug Law by

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45 Formularia adjusted based on this guideline Formularia now essential parts of quality chain managementsystems for animal production sectors Basis for controllable prescription behaviour Basis for treatment plans on each farm Only first choice drug allowed Stichting Geborgde dierenarts Foundation for Certified Vets

46 Foundation for Certified Veterinarians Contractual 1-in-1 relation between vet and farmer Responsible for prescription and supply of antibiotics Mandatory on each farm Treatment plan on all farms based on formularies Only 1 st choice drugs allowed on farms (max 1 treatment) 2 nd choice AB: no unless argumentation by vet 3 rd choice AB (cefs and FQs): no unless there is no alternative, based on antibiogram Health plan Ultimate sanction possibility that a vet looses his/hers certificate Need to be adjusted if AB-use is in action level!!

47 Benchmarking of veterinarians (January 2014) Based on population of farms of each vet By animal species Criteria are based on the chance that on the farms of a vet AB-use is higher than the action level

48 Trends in Sales of antibiotics for animals in NL 56% reduction from 2007 to % 50% 50% reduction from target for 2013 met in % 24% reduction from FQ and 3rd/4th-gen cefs use reduced to a minimum

49 Sales of antibiotics for (mg) per kg biomass produced (PCU) in Europe

50 ESVAC less than 100 mg/pcu

51 Critical success factors in NL Clear targets defined by the government Created a sense of urgency Measures were initiated and implemented by private animal production sectors and veterinary association Urgent need for collaboration Use fully transparent Farms (on > farms ADDDs available) Vets Independent control Institute Accepted by all parties involved

52 Effect on resistance??

53 Acknowledgements CVI: Cindy Dierikx, Kees Veldman, Marga, Japing, Joop Testerink, Alieda van Essen, Arie Kant, Apostolos Liakopoulos, Yvon Geurts, Mike Brouwer Veterinary Faculty: Jaap Wagenaar, Joost Hordijk, Angela Bosman SDa: Dick Heederik, Johan Mouton, Inge van Geijlswijk, Marian Bos, Femke Taverne, Hetty van Beers