Antibiotic Resistance The European perspective Dik Mevius
Antibiotic Resistance Surveillance EU n
Legal Basis: Zoonoses Directive 2003/99/EC l Target organisms: l
• Salmonella, Campylobacter and other organisms of PHconcern (eg. MRSA) • E. coli, enterococci (indicator or sentinel organisms) l
EFSA-guidelines
n
Broth microdilution (NEN-EN-ISO 16256:2012 ≅ CLSI) l No clinical MICbreakpoints l EUCAST ECOFF’s l
Indicator organisms (E. coli)
n
Provide optimum information about acquired resistance in populations and associations with antibiotic usage or interventions Sampling can randomized l No isolation rates or species/serotype influences on R% l
n
Currently under debate in EC to make this mandatory Isolates from faecal samples taken at/close to slaughter l and meat l
European reports
S, F, N, Fr, De, It, Es, ‌
Resistance from 1998 - 2011 (E. coli as commensal in the GI-tract ) (MARAN-2012)
Expressed as multi-drug resistance
MDR to 8 – 9 classes ABs
Antibiotic usage in humans and animals in Europe ESAC versus ESVAC
Antibiotic use in animals in NL (Source FIDIN) 700
600
kg active ingredient x 1.000
500
400
90% oral administration by group/flock mediation AMGPs (growth promoters) Antibiotics (therapeutic use)
300
200
Increase up to 2007 was the basis for mandatory reduction policy of the government of 20/50% Total
100
0 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Animal versus human use in kg
van Geijlswijk, et al, TvD, 2009
What does this mean n
Dutch food-producing animals are an ideal environment for multidrug resistant organisms l
Risk?? • Animal health? – Yes, if they cause infections • Public health? – Yes if:
» Food-borne pathogens » Zoonotic organisms » Transferable genes
Relation between resistance in animals and humans?
n n
In spite of long term differences in usage, the resistance levels in Dutch Health care are low! So does a relation with resistance in animals exist? l
Unfortunately, yes • MRSA! • ESBLs!
EARSS-net 2010 report (ECDC) on MRSA and ESBLs in invasive infection in hospitals MRSA
ESBLs
Extended Spectrum Beta-lactamases (ESBLs) n
Enzymes that inactivate beta-lactam antibiotics l Penicillin, ampicillin, amoxicillin l All cefalosporins
n
Consequence for infections with ESBL-producers: l
n
Impaired treatment, increased risk for patients
Genes are transferable on plasmids (E. coli/Salmonella) l Transmission of ESBLs also via the food-chain!!!
Types of Beta-Lactamases n
Beta-Lactamase Penicillinase blaz (S. aureus) l TEM-1, SHV-1 (Enterobacteriaceae) l
n
ESBLs l
n n
TEM-derivatives, SHV-2 and derivatives, CTX-M,OXA, PER, VEB, GES
AmpC-group (CMY, DHA etc) Carbapenemases (KPC, OXA, IMP, VIM, NDM) > 1000 variants known
EU: CTX-M-1, TEM-52 dominant in poultry US: CMY-2
Cefotaxime resistance in E. coli (MARAN) Cefotaxime R% in E. coli 25
Dairy cattle Veal calves
20
Pigs Broiler chickens
R%
15
10
5
0 1998
1999
2001
2002
2003
2004
2005
2006
2007
2008
2009
ESBL-genes and plasmids in Broiler isolates (Dierikx et al. 2010) S. enterica (n=21) 18
E. coli (n=23)
16
100% farms positive, 96% of the animals
14
12
10
Humans:
8
CTX-M15, 14/9, 3‌..
6
4
2
0 CTXM-1
TEM-52
IncI1
IncI1 + nt
CMY-2
IncK
TEM-20
IncI1
CTXM-2
ACC-1
IncHI2/P
Nt
SHV-2
IncK
Transmission in the Poultry production pyramidUK, US AmpC
ESBL + AmpC
GPS
PS
Broilers Vertical transmission and recirculation in all layers of the pyramid Broilers app. 100% positive in one week!!
Distribution in Europe in poultry
CMY ESBL + CMY
CMI, 2011
Association with humans EID, 2011
84 – 100% of poultry meat pos for ESBLs Pork/beef incidentally pos n
Conclusion: l l
Yes an animal attribution is apparent Poultry meat was considered to be the most likely source
ESBLs in other animals in The Netherlands Animal species
ESBLs-Prevalence Wild bird
Companion animals Slaughter pigs Veal calves
Wilde eend
Species Anas platyrhynchos
? Increasing
Rotsduif (Dierikx et al Columbia livia 2012) Kemphaan Philomachus pugnax Tureluur
Kokmeeuw >
Tringa totanus
50% slaughter batches Chroicocephalus ridibundus
Zilvermeeuw
Larus argentatus
Zwarte zwaan
Cygnus atratus
Grote mantelmeeuw > 50% Jan van Gent
Larus marinus slaughter batches Morus bassanus
Total
ESBL subtypes detected ESBL 4
CTX-M-1, 2, 9, 14, 15, 1 TEM-30, 52, 80, OXA-1, 1 CMY-2, 39 (qnr) 5
CTX-M-1, 14, 15, 32, 2 TEM-52, SHV-12, CMY-2, 1 OXA-1 1 1 CTX-M-1, 2, 14, 15, 32, 1 TEM-52, CMY-2, OXA-1
17 Â (22%)
Dairy cows
11% individual animals
CTX-M-1, 2
Turkeys
50% flocks
CTX-1,15, CMY-2
Is poultry the source or part of the problem??
Measures implemented by the government 2008 memoranda of understanding signed
n
Mandatory reduction of antibiotic usage of 20% in 2012 and 50% in 2013 (compared to 2009) • New target = 70% l
All antibiotic use on farms registered • Mandatory since 2012
Preventive use not legal l Restrictions on use of FQ and Cefs l Independent control institute l
• Animal Drug Authority (SDa, www.autoriteitdiergeneesmiddelen.nl) – Tasks » » » »
Report usage data publically, Define targets for usage Identify frequent users Control measures to improve usage
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
Broilers usage data 2011in (N = 737) ADDD/Y ≈ nr of treatment days per year on each farm Median –20% P75 Denmark 3 ADDDs Germany NRW 50 ADDDs
Is it all about targets and control?? n
Not only Stimulate the responsibility of both farmers and vets to control and improve the health status of the animals without strategic usage of preventive antibiotics l ADDD’s are a tools to visualize the effects of measures aimed at: l
• • • • • •
Infection control Improved management, climate etc. Feed quality Drinking water Housing density Other preventive measures…
Ceftiofur use in Dutch poultry
n
Not licenced in poultry in EU because no MRL for poultry >> administration in poultry only legal according to the cascade rule
n
Used in: l
Reproduction animals (GP, P) (until 2010 in NL, other EUMSs??) • In day-old chicks SC injection • In-ovo
l
Broilers hatcheries • Spray in NL and B (until March 2010)
Cefotaxime resistance in E. coli Ban of ceftiofur use at hatcheries
Impact of withdrawal of in ovo use of ceftiofur in QuĂŠbec Voluntary withdrawal in QuĂŠbec*
80%
S. Heidelberg retail chicken isolates
Percentage of ceftiofur resistance
70%
S. Heidelberg human isolates 60%
E. coli retail chicken isolates
50% 40% 30% 20% 10% 0% 3
4
1
2
3
2004
29
4
1
2
3
4
1
2005
2
3
2006
4
1
2
3
4
2007
Year and quarter Dutil et al.
Trends in Sales of antibiotics in NL Reduction Targets
(FIDIN/LEI 2012) www.maran.wur.nl
Sales of antibiotics for animals (mg) per kg biomass produced (PCU) in Europe 2007
2010
Will we succeed? Antibiotic reduction
Antimicrobial resistance l ?????
l
Most likely, yes!!
l
l
Will it be enough??
Why? • Global problem • More determinants than antibiotic usage • May need structural changes in animal husbandry practices
Thanks to Manon Houben, PorQ