EUCAST 2003

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Antimicrobial susceptibility testing in Europe
- the role of national breakpoint committees and
EUCAST
Gunnar Kahlmeter, EUCAST gunnar.kahlmeter_at_ltkronob
erg.se
NCCLS (USA)
BSAC wp
DIN
CA-SFM
CRG
NWGA
SRGA
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Simulated local outbreak!
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The breakpoint compromise!
Clinical aspects breakpoints must have
clinical value!
Epidemiological aspects breakpoints must allow
(early) detection of acquired resistance
mechanisms!
Methodological aspects breakpoints must allow
reproducible S-, I- and R-categorization in the
lab!
lt2.0
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EUCAST
European Committee on Antimicrobial
Susceptibility Testing formed in 1997 and
restructured in 2002 convened by European
Society for Clinical Microbiology and Infectious
Diseases (ESCMID) National Breakpoint Committees
in Europe and financed by ESCMID National
Breakpoint Committees in Europe DG-SANCO of the
European Union (3 year grant from May 2004)
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EUCAST

• EUCAST General Committee
• - one representative, appointed by the
  appropriate medical associations, from each
  European country - one representative each from
  ISC and FESCI- Chairperson and Scientific
  secretary (appointed by ESCMID)- meets once a
  year at ECCMID - all Steering Committee
  proposals are referred to the General Committee
  for comments before decision
• EUCAST Steering Committee
• - Chairperson and a Scientific Secretary
  (appointed by ESCMID)- one representative each
  from the European national breakpoint committees
  (presently 6)- two representatives from the
  EUCAST General Committee - Czech Republic and
  Greece 2002-2004 - Russia and Spain 2004 -2006
• EUCAST industry network - The network consists
  of all interested manufacturers of
  pharmaceuticals and susceptibility testing
  devices. All are invited to take an active part
  in EUCAST activities - Steering Committee
  proposals are referred to the industry network
  for comments before decision
• - relevant industry members can apply for
  inclusion on the email list by contacting the
  EUCAST secretariat

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EUCAST General Committee 2004

• Portugal Prof Jose Melo Cristino
• Romania no official representative
• Russia Dr Olga Stetsiouk
• Serbia Dr Lazar Ranin
• Slovak Republic Prof. Milan Niks
• Slovenia Dr Jana Kolman
• Spain Dr Francisco Soriano
• Sweden Dr Barbro Olsson-Liljequist
• Switzerland Prof Jaques Bille
• Turkey Dr Deniz Gür
• UK Prof Alasdair MacGowan
• Yugoslavia no official representative
• ISC Prof Paul Tulkens
• FESCI Prof David Livermore
• Email network of industry with interest in
  antimicrobials

• Austria Prof Helmut Mittermayer
• Belgium Prof Jan Verhaegen
• Bosnia Dr Selma Uzunovic-Kamberovic
• Bulgaria Prof Krassimir Metodiev
• Croatia Dr Arjana Tambic-Andrasevic
• Czech Republic Dr Pavla Urbaskova
• Denmark Dr Niels Frimodt-Møller
• Estonia Dr Paul Naaber
• Finland Dr Antti Nissinen
• France Prof Claude-James Soussy
• Germany Prof Bernd Wiedemann
• Greece Prof Alkiviadis Vatopoulos
• Hungary Dr Éva Bán
• Iceland Dr Karl Gustaf Kristinsson
• Ireland Dr Martin Cormican
• Italy Prof Pietro Emanuele Varaldo
• Latvia Dr Arta Balode
• Lithuania Prof Arvydsa Ambrozaitis
• Netherlands Prof John Degener

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EUCAST Steering Committee Membership

• Chairperson Gunnar Kahlmeter 2002 - 05
• Scientific Secretary Derek Brown 2002 -
  05
• BSAC (The UK) Alasdair MacGowan 2002 - 05
• CA-SFM (France) Fred Goldstein 2002 - 05
• CRG (The Netherlands) Johan W. Mouton 2002 -
  05
• DIN (Germany) Arne Rodloff 2002 - 05
• NWGA (Norway) Martin Steinbakk 2002 - 05
• SRGA (Sweden) Anders Österlund 2002 - 05
• General Committee rep Olga Stetsiouk
  (Russia) 2004 - 06
• General Committee rep Francisco Soriano
  (Spain) 2004 - 06

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EUCAST definitions of clinical breakpointsavailab
le at www.eucast.org

• Clinically Susceptible (S)
• a microorganism is defined as susceptible by a
  level of antimicrobial activity associated with a
  high likelihood of therapeutic success
• a microorganism is categorized as susceptible (S)
  by applying the appropriate breakpoint in a
  defined phenotypic test system
•  
• Clinically Intermediate (I)
• a microorganism is defined as intermediate by a
  level of antimicrobial activity associated with
  indeterminate therapeutic effect
• a microorganism is categorized as intermediate
  (I) by applying the appropriate breakpoints in a
  defined phenotypic test system
•  
• Clinically Resistant (R)
• a microorganism is defined as resistant by a
  level of antimicrobial activity associated with a
  high likelihood of therapeutic failure.
• a microorganism is categorized as resistant (R)
  by applying the appropriate breakpoint in a
  defined phenotypic test system
• Clinical breakpoints may be altered with
  legitimate changes in circumstances
• Clinical breakpoints are presented as Sltx mg/L
  Igtx, lty mg/L Rgty mg/L

EUCAST has re-defined susceptible, intermediate
and resistant and defined the terms wild type and
non-wild type microorganism.. and agreed
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EUCAST definitions of epidemiological cut off
values available at www.eucast.org

• 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.
• wild type microorganisms may or may not respond
  clinically to antimicrobial treatment.
•  
• Microbiological resistance - non-wild type (NWT)
• a microorganism is defined as non-wild type (NWT)
  for a species by the presence of an acquired or
  mutational resistance mechanism to the drug in
  question.
• a microorganism is categorized as non-wild type
  (NWT) for a species by applying the appropriate
  cut-off value in a defined phenotypic test
  system.
• non-wild type microorganisms may or may not
  respond clinically to antimicrobial treatment.
• Epidemiological cut-off values will not be
  altered by changing circumstances.
• The wild type is presented as WTltz mg/L and
  non-wild type as NWT gtz mg/L

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EUCAST publications

• 1. European Committee on Antimicrobial
  Susceptibility Testing. (2000). Terminology
  relating to methods for the determination of
  susceptibility of bacteria to antimicrobial
  agents. EUCAST Definitive Document E.Def 1.2.
  Clinical Microbiology and Infection 6, 503-8.
• 2. European Committee on Antimicrobial
  Susceptibility Testing. (2000). Determination of
  antimicrobial susceptibility test breakpoints.
  EUCAST Definitive Document E.Def 2.1. Clinical
  Microbiology and Infection 6, 570-2.
• 3. European Committee on Antimicrobial
  Susceptibility Testing. (2000). Determination of
  minimum inhibitory concentrations (MICs) of
  antibacterial agents by agar dilution. EUCAST
  Definitive Document E.Def 3.1. Clinical
  Microbiology and Infection 6, 509-15.
• 4. European Committee on Antimicrobial
  Susceptibility Testing. (2001). Linezolid
  breakpoints. EUCAST Definitive Document E.Def
  4.1. Clinical Microbiology and Infection 7,
  283-4.
• 5. European Committee on Antimicrobial
  Susceptibility Testing. (2003). Determination of
  minimum inhibitory concentrations (MICs) of
  antibacterial agents by broth microdilution.
  EUCAST Discussion Document E.Def 5.1. Clinical
  Microbiology and Infection 9 (issue 7 insert)
  1-10.
• 6. Ridgway, G.L., Bébéar, C., Bébéar, C.M, et al.
  (2001). Antimicrobial susceptibility testing of
  intracellular and cell-associated pathogens.
  EUCAST Discussion Document E.Dis 6.1. Clinical
  Microbiology and Infection 7 (issue 12
  insert),1-10.
• 7. Rodriguez-Tudela, J.L., Barchiesi, F., Bille,
  J. et al. (2003). Determination of minimum
  inhibitory concentrations by broth microdilution
  of fermentative yeasts. EUCAST Discussion
  Document E.Dis 7.1. Clinical Microbiology and
  Infection 9 (issue 8 insert), 1-8.
• Drobniewski, F. (2002). Antimicrobial
  susceptibility testing of Mycobacterium
  tuberculosis. EUCAST Discussion Document E.Dis
  8.1. Clinical Microbiology and Infection 8 (issue
  10 insert),1-10.
• Kahlmeter G, Brown DFJ, Goldstein FW et al.
  (2003) European harmonization of MIC breakpoints
  for antimicrobial susceptibility testing of
  bacteria. Journal of Antimicrobial Chemotherapy
  52, 145-148.
• Kahlmeter G Brown D. Harmonisation of European
  breakpoints can it be achieved? Clinical
  Microbiology Newsletter, in press.

Published documents, discussion documents and
tentative decisions are posted on the EUCAST
website. Tentative decisions and discussion
documents - after a period of consultation they
will be submitted for publication and/or be made
available on the EUCAST website as final
documents or decisions (www.eucast.org).
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EUCAST Subcommittee on Antifungal Susceptibility
Testing (EUCAST AFST)

• develop reference methods for antifungal
  susceptibility testing
• set breakpoints for antifungal drugs
• Financed through EUCAST
• EUCAST processes for breakpoint setting,
  decisions and consultation

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EUCAST collaborations

• EMEA SOP being developed which renders EUCAST
  the official European breakpoint committee
  (EUCAST breakpoints in the SPCs).
• Expert groups and reference laboratories
  (Neisseria, Salmonella, European Veterinary
  working group, NEQAS)
• EARSS
• EUCAST permanently on the EARSS advisory board
• NCCLS
• NCCLS/EUCAST broth dilution method for the
  determination of MIC-values harmonised through
  CEN and ISO finished document end of 2004.
• NCCLS/EUCAST common QC type strain MIC-target
  values and ranges
• NCCLS/EUCAST harmonised FQ breakpoints for
  staphylococci.
• Collaborative process for revision of
  cephalosporin and carbapenem MIC breakpoints
  (first joint meeting in Tampa, January 2005).
• Pharmaceutical industry information and
  consultation network

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Liaison with NCCLS
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Breakpoints for new antimicrobials

• Daptomycin
• Tigecycline

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EUCAST procedure for setting breakpoints
The next 9 slides describe the EUCAST procedure
for harmonising European breakpoints.
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1. Data on dosing, formulations, clinical
indications and target organisms are reviewed and
differences which might influence breakpoints are
highlighted
National breakpoint committees

Example ciprofloxacin
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2. Multiple MIC-distributions are collected, the
wild type MIC distribution is defined and
tentative epidemiological cut-off values
determined (WT lt X mg/L)
Epidemiological cut off WTlt2.0
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3. Existing national clinical breakpoints are
compared
Ciprofloxacin was used in this example
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4. Using available PK/PD data, Monte Carlo
simulations are performed and a tentative
breakpoint calculated
Minimum requirement for S-category is that the
high MIC value of the wild type MIC-distribution
is consistent with the MIC derived from the PK/PD
index needed for optimal efficacy based on free
drug.
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5. Clinical data relating outcome to MIC-values
and resistance mechanisms are assessed in
relation to the tentative breakpoint
.and youve just heard Professor MacGowan
adress that issue
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6. Tentative breakpoints are checked against
target species wild type MIC distributions to
avoid splitting the wild type
Epidemiological cut off WTlt2.0
it was decided to set the break-point at S0.125
and Rgt2 mg/L, rendering wild type S.pneumoniae
inter-mediately susceptible to ciprofloxacin.
To permit reproducible susceptibility
testing, splitting of the wild type must be
avoided 0.5 and 1 mg/L were not acceptable.and
2 mg/L was considered too high
lt2 mg/L
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8. Re-appraisal of tentative breakpoints
following comments
7. Consultation process on tentative
breakpoints - national committees- EUCAST
general committee- pharmaceutical industry, AST
device manufacturers - others via EUCAST
website
9. Further consultation if required
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EUCAST has now finalised breakpoints for
fluoroquinolones, glycopeptides, aminoglycosides
and linezolid and is now working on
cephalosporins, carbapenems and aztreonam.
EUCAST breakpoint tables are published at
www.eucast.org
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EUCAST websites are found at www.eucast.org

• The EUCAST website is a section of the official
  ESCMID website it gives details of all EUCAST
  activities including
• - constitution and organisation
• - committee member lists
• - meetings
• - EUCAST documents
• - EUCAST power-point presentation
• - clinical MIC breakpoint tables
• - MIC distributions for wild type bacteria and
  fungi
• - epidemiological MIC cut-off values.

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www.eucast.org
This is the first screen of the EUCAST general
website.
28
Choose to display in English, French or German
First screen of the EUCAST program for the
display of wild type MIC distributions in
microorganisms.
www.eucast.org
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EUCAST aggregated wild type MIC distributions

• - the fact that wild type microrganisms of the
  same species exhibit identical MIC (and
  inhibition zone) distributions irrespective of
  origin provides an opportunity to aggregate
  multiple distributions and define a reference.

• Data from scientific papers, breakpoint
  committees, reference laboratories,
  pharmaceutical industry, surveillance networks
  (EARSS, Sentry, Alexander Project, National
  surveillance networks)
• All submitted full-range MIC distributions
  accepted
• To date no systematic exclusions.
• October, 2004 3500 MIC distributions

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S. pneumoniae and ciprofloxacin MIC distributions
This slide shows a portion of the data set for
S.pneumoniae and ciprofloxacin. Each MIC
distribution is from a different investigator,
surveillance program, breakpoint committee or
pharmaceutical company. The median of the uni-
or of the first part of the bi- or multi-modal
distribution has been marked in blue.
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Aggregated S.pneumoniae ciprofloxacin
MIC-data.Values of gt1 are shown in graph as
bars.
32
Choose to display in English, French or German
www.eucast.org
33
Specify the drug or the bug (never both) - after
a moment a table of MIC-distributions is shown.
Click on any species in the left hand column to
display the data as a bar chart, with EUCAST
epidemiological cut-off values and harmonised
European clinical breakpoints.
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(1) To define epidemiological cut-off values
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(2) As a template for calibration of methodology
(accuracy and imprecision). We have defined the
result of antimicrobial susceptibility testing!
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(3) Reference MIC database for breakpoint setting
- to avoid clinical breakpoints that divide wild
type bacteria
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(4) As MIC reference database
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EUCAST wild type MIC distributions templates
for calibration of MIC determinations
Laboratories which cannot fit their own MIC data
to the the EUCAST reference distribution should
look into the following possibilities

• The method used for MIC determination in the
  local set of data is not adequately standardised
  or calibrated,
• The species identification is incomplete
• There are too few determinations to allow
  identification of the part of the distribution
  that constitutes the wild type microorganisms
  (which usually corresponds to the four lowest
  dilution steps).

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Examples from the EUCAST wild type MIC
distribution program.
1
40

• The objectives of EUCAST are
• to form in EUCAST, under the auspices of the
  European Society of Clinical Microbiology and
  Infectious Diseases", a professional network of
  - the national breakpoint committees and experts
  on antimicrobial susceptibility testing and -
  industry involved in the production and marketing
  of antimicrobial agents or of in-vitro
  diagnostic medical devices used in antimicrobial
  susceptibility testing
• to set common European breakpoints for
  surveillance of antimicrobial resistance
• to identify national differences in clinical
  breakpoints and to harmonise breakpoints for
  existing and new antimicrobial drugs
• to produce, disseminate and update a series of
  documents on the technology of in-vitro
  antimicrobial susceptibility testing, promoting
  standardisation of methods used in different
  parts of Europe and comparability of results
  obtained by different technologies
• to encourage internal and external national and
  international quality assessment schemes
• to collaborate with European and international
  groups concerned with antimicrobial
  susceptibility testing and/or the epidemiology of
  antimicrobial resistance
• to advise European Community Institutions on the
  technology and interpretation of antimicrobial
  susceptibility testing
• to work with groups outside Europe (eg NCCLS) to
  achieve international consensus on susceptibility
  testing
• to devise and participate in educational and
  training programmes for antimicrobial
  susceptibility testing (workshop with EARSS in
  2005, two workshops for national breakpoint
  committees in 2005 2006).

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The End
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E.coli and ciprofloxacin in ECOSENS
Wildtype distributions do not vary with
geographical origin!
G Kahlmeter, JAC, 2003.
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Wildtype distributions do not vary with
geographical origin!
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Origin
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Origin
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Summary of EUCAST procedure for setting clinical
breakpoints

• Data on dosing, formulations, clinical
  indications and target organisms are reviewed and
  differences which might influence breakpoints are
  highlighted.
• Multiple MIC-distributions are collected, the
  wild type MIC distribution is defined and
  tentative epidemiological cut-off values
  determined (WT lt X mg/L).
• Existing national clinical breakpoints are
  compared.
• Using available PK/PD data, Monte Carlo
  simulations are performed and a tentative
  breakpoint calculated. Minimum requirement for
  S-category is that the high MIC value of the
  wild type MIC-distribution is consistent with the
  MIC derived from the PK/PD index needed for
  optimal efficacy based on free drug.
• Clinical data relating outcome to MIC-values and
  resistance mechanisms are assessed in relation to
  the tentative breakpoint.
• Tentative breakpoints are checked against target
  species wild type MIC distributions to avoid
  splitting the wild type.
• Consultation process (national committees, EUCAST
  general committee and pharmaceutical industry and
  AST device manufacturers).
• EUCAST clinical breakpoint tables are published
  on the internet (www.eucast.org) with links to
  tables and graphs of wild type distributions of
  MIC values.

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How to implement EUCAST breakpoints

• The national breakpoint committees have committed
  themselves to implementing EUCAST breakpoints
  which means that anyone using the national
  European systems will gradually adhere to the
  EUCAST breakpoint system
• Breakpoints as presented in EUCAST tables can be
  directly applied to MIC distributions (local and
  national surveillance, EARSS, etc)
• Systems for automated susceptibility testing can
  be set up with EUCAST MIC breakpoints.

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EUCAST wild type MIC distributions and
epidemiological cut-off values the concept JAC
2003 52 145-148

• EUCAST developed the concept of antimicrobial
  wild type MIC distributions and epidemiological
  cut-off values (JAC 52145-148, 2003).Software
  was created to receive and display large volumes
  of MIC data for bacteria and fungi over the
  Internet. It is freely available at
  http//www.eucast.org.
• Distributions are displayed in an aggregated
  format. Tables and graphs show the part of the
  MIC distribution which, when EUCAST defines the
  epdemiological cut-off value, is defined as the
  wild type distribution. The epidemiological
  cut-off value separating microorganisms without
  (wild type) and with acquired or mutational
  resistance (non-wild type) and clinical
  breakpoints are, if defined, shown on the bottom
  line of the graph.
• The epidemiological cut-off value (left hand
  lower corner) is shown as WT X mg/L.
• The clinical breakpoints (right hand lower
  corner) are shown as S Y mg/L and Rgt Z mg/L.

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EUCAST wild type MIC distributions and
epidemiological cut-off values methods and data

• Origin of MIC data
• Each distribution is comprised of aggregated MIC
  data including individual MIC distributions from
  
• - publications in international journals
• - breakpoint committees
• - antimicrobial surveillance systems such as
  EARSS, SENTRY, the Alexander Project
• - pharmaceutical companies and susceptibility
  testing device manufacturers.
• Thus, unless otherwise specifically stated,
  distributions include results obtained with
  different methods. These methods do not give
  exactly the same results but the results rarely
  vary by more than one doubling dilution step. In
  this way the aggregated EUCAST MIC distributions
  contain the random variation between different
  investigators and the systematic variation seen
  between different methods.
• Origin of the organisms included in the MIC
  distributions
• The data are from tests on bacteria and fungi
  collected from man and animals, of any geographic
  origin and over a wide timeframe.
• MIC methods represented Species-specific
  distributions of MIC values collected from all
  over the world are included in the database. The
  distributions shown represent full range MIC
  values determined with methods described by
  EUCAST, BSAC (UK), CA-SFM (France), CRG (The
  Netherlands), DIN (Germany), NCCLS (USA), NWGA
  (Norway), and SRGA (Sweden) or methods calibrated
  to these methods (eg. commercial methods which
  give full range MIC values).

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EUCAST wild type MIC distributions templates
for calibration of MIC determinations
Exclusion of data All submitted full-range MIC
distributions have been accepted. There has been
no systematic exclusion of data from one
contributor or from one method. The contributions
are screened by the EUCAST Steering Committee and
less than 10 have been excluded from the
aggregated distributions. However, all data are
held in the database and are accessible to the
Steering Committee. The most common reason for
exclusion has been that the data were not
full-range MICs so that a significant proportion
of MICs were outside the tested range.

• Laboratories which cannot fit their own MIC data
  to the the EUCAST reference distribution should
  look into the following possibilities
• The method used for MIC determination in the
  local set of data is not adequately calibrated,
• The species identification is incomplete,
• There are too few determinations to allow
  identification of the part of the distribution
  that constitutes the wild type microorganisms.
  This usually corresponds to the four lowest
  dilution steps.

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EUCAST wild type MIC distributions why are
only the MICs of wild type microorganisms
displayed?

• The distributions consist of MIC-values
  determined over 30 years or more.
• Resistance frequencies obtained through the
  aggregated MIC distributions would not be
  representative of current antimicrobial
  resistance frequencies and would be confusing and
  misleading.
• When the epidemiological cut-off value has been
  determined by the EUCAST Steering Committee it
  blocks display of the non-wild type
  microorganisms (red bars, upper figure) and shows
  only the part representing the wild type (lower
  fig).

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EUCAST wild type MIC distributions how to
contribute data

• Everyone is invited to contribute data
• All who have full-range MIC data for bacteria or
  fungi are invited to contribute data as long as
  MICs are determined with an accepted standardised
  method, which should be named. Once entered on
  the database the data will not be identifiable as
  separate distributions but will help build the
  aggregate reference distributions. The
  biologically resistant (non-wild type) part of
  the distribution will be seen only by the EUCAST
  Steering Committee.
• Submitting data to the EUCAST database does not
  interfere with publication of data.
• Where can I get more information?
• Contact EUCAST email addresses and information
  can be obtained through the EUCAST website at
  http//www.eucast.org