by author ESCMID Online Lecture Library Epidemiological cutoff values (ECOFFs) and Low Level resistance Gunnar Kahlmeter

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1 Epidemiological cutoff values (ECOFFs) and Low Level resistance ECCMID 2010 Gunnar Kahlmeter Sweden

2 The epidemiological cutoff value ECOFF When breakpoints fail to detect t resistance as a biological phenomenon, the ECOFF will.

3 Wild type MIC distribution ECOFF Organism with MIC above ECOFF: - erroneous identification - erroneous MIC-determination - resistance mechanism If the wild type distribution of the species is deemed a good target for the drug, the ECOFF is the lowest possible value for the clinical breakpoint.

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5 A species totally corrupted for an antibiotic almost all individuals have resistance mechanisms!

6 .and the corresponding zone diameter distribution

7 0 S.pneumoniae & Cotrimoxazole % strains Pondicherry, India Kronoberg county, Sweden Zone diameter (mm) C.Larsson et al, Clin Microbiol Infect, 1999

8 Some people collect stamps. others collects quantitative susceptibility data (MICand Zone diameter values) and organises the data in aggregated g distributions..

9 MIC- and Zone diameter distributions in the database on Data from many investigators Data from many timeperiods Data from many geographical areas Data from many origins human from resistance surveillance programs, studies, pharmaceutical development etc Veterinarian Food safety programs Wild life etc

10 S.pneumoniae vs ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin i Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin i Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin i Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin

11 EUCAST definitions of wild type MIC distributions and epidemiological i i l cut off values (ECOFFs) Wild type (WT) a microorganism is defined as wild type (WT) for a species by the absence of acquired and mutational resistance mechanisms to the drug in question. a microorganism is categorized as wild type (WT) for a species by applying the appropriate cut-off value in a defined phenotypic test system. ECOFF wild type microorganisms may or may not respond clinically to antimicrobial treatment.

12 The relationship between ECOFF and clinical breakpoint. There is NO inherent relationship between ECOFF and clinical i l breakpoint. A clinical breakpoint may be higher (cefotaxime v. S. pneumoniae), the same (ampicillin v. E. coli) lower (gentamicin v. Enterococci)

13 CBP higher than ECOFF Cefotaxime v. S. pneumoniae

14 CBP = ECOFF Ampicillin v. E. coli

15 CBP lower than ECOFF Ciprofloxacin v. S. pneumoniae

16 Wild type distributions ib ti and ECOFFs. Do not change over time Do not change with geographical origin Do not vary between man and animals Contain very little biological variation vis-à-vis the drug in question

17 No of obs Biological variation in the wild type? S.aureus - clinical isolates vs S.aureus ATCC clinical isolates vs. 125 determinations of one type strain S.aureus - clinical isolates S.aureus ATCC Zone diameter (mm)

18 0 % strains S.pneumoniae vs. oxacillin 1 µg Geography Kronoberg county, Sweden Pondicherry, India Zone diameter (mm) C.Larsson et al, Clin Microbiol Infect, 1999

19 Sjölund et al, CMI, 2009

20 Wild type MIC-distributions and ECOFFs for antifungal drugs as one of several tools for determining breakpoints Principle authors: J-L. Tudela, P. Donnelly, M. Arendrup, M. Cuenza-Estrella, C. Lass-Flörl.

21 Wild-type MIC distributions and epidemiological cut-off values for antibiotics used for the treatment of Mycobacterium tuberculosis Principle authors: K Ängeby, P Jurén, T Schön. and with E Sturegård, E Chryssanthou, CG Giske, J Werngren, M Nordvall, A Johansson, G Kahlmeter, S Hoffner.

22 The use of ECOFFs As a tool in the determination of clinical breakpoints To avoid dividing wild type MIC distributions of important target organisms As a surrogate breakpoint when Pk/Pd data is incomplete To exclude resistance oxacillin to exclude all penicillin-r in S. pneumoniae cefoxitin to exclude methicillin resistance in S. aureus nalidixic to exclude quinolone resistance in several organisms (cave qnr) For detection of low-level resistance. For surveillance of antimicrobial resistance when clinical breakpoints change over time differ between systems differ between animals and humans between animals Food safety in the development of functional foods to screen candidate organisms for presence of possible resistance genes.

23 To exclude resistance S. aureus vs. cefoxitin By comparing S. aureus with and without the meca-gene it has been shown that cefoxitin clearly separates organisms with from those without the gene.

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28 Ciprofloxacin MIC distributions and clinical breakpoints and ECOFFs. The use of ECOFFs to find low level-resistance (

29 Cefotaxime MIC distributions and clinical breakpoints and ECOFFs. The use of ECOFFs to find low level-resistance resistance. (

30 Meropenem MIC distributions and clinical breakpoints and ECOFFs. The use of ECOFFs to find low level-resistance. (

31 *Clinical Break Point = Epidemiological Cutoff Species/antibiotic combinations where CBP = ECOFF* Antibiotic Species ECOFF WT CBP S Ampicillin E.coli 8 8 Ciprofloxacin Salmonella spp Ciprofloxacin S. aureus 1 1 Cefoxitin S. aureus 2 2 Vancomycin* S. aureus 2 2 Gentamicin P. aeuruginosa Chloramphenicol H. influenzae 1 1 Meropenem P. aeruginosa 2 2 Trimethoprim E. coli 2 2 Piperacillin P. aeruginosa Levofloxacin S. pneumoniae 2 2 Erythromycin S. pneumoniae

32 Species/antibiotic combinations where CBP* >> ECOFF* Antibiotic Species ECOFF EUCAST Meropenem** Ciprofloxacin E.coli / 8 K.pneumoniae /8 S. pneumoniae / 2 H. influenzae / 2 E. coli K. pneumoniae etc / 1 Pseudomonas - - Staphylococci - - Enterococci - - *Clinical Break Point much higher than Epidemiological Cutoff **And with slightly different values imipenem and doripenem

33 Programs officially utilizing ECOFFs European Food Safety Project screening for functional food microorganism candidates to exclude transferable resistance

34 Use of ECOFF s in Resistance surveillance in animals EU As a direct of spin-off of collaboration of EU NRLs on antimicrobial resistance in animals and EUCAST, EFSA guidelines were prepared for standardized resistance surveillance Salmonella, Campylobacter E. coli, enterococci Courtesy of Dik Mevius, NL

35 Harmonized sampling strategies Broth microdilution according to ISO :2006 as standard method List of required antibiotics to include in the tests and ECOFF s as interpretive criteria for sensitive and harmonized interpretation of surveillance results in the EU see table A EFSA Guidelines Courtesy of Dik Mevius, NL

36 Thank you!

37 . of ob bs. No E. coli wild type; generation times (min) (n=100) Expected Normal min