EUCAST 2003

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Shift to European (EUCAST) breakpoints - impact
on BSAC recommendations Derek Brown HPA,
Addenbrookes Hospital, Cambridge
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Outline

• EUCAST
• what is it? what does it do? how does it do it?
• what are the advantages?
• Definitions
• categorical results (S, I, R)
• clinical breakpoints and epidemiological (wild
  type) cut-offs
• Non-species-specific breakpoints
• How breakpoints are assessed/decided
• Changes in BSAC breakpoints so far
• The future

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EUCAST
European Committee on Antimicrobial
Susceptibility Testing formed in 1997 and
re-structured 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 objectives
• to form a professional network of national
  breakpoint committees and experts on
  antimicrobial susceptibility testing and
  pharamaceutical and device manufacturing
  industries
• to harmonise European breakpoints for existing
  antimicrobial agents
• to set common European breakpoints for new agents
• to promote standardisation of methods
• to encourage internal and external quality
  assessment
• to collaborate with other groups concerned with
  susceptibility testing and epidemiology
• to work with groups outside Europe (eg CLSI) to
  achieve wider international consensus

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EUCAST

• EUCAST Steering Committee
• one representative from each active European
  national breakpoint committees (UK, France,
  Germany, Netherlands, Sweden, Norway)
• two representatives from the EUCAST General
  Committee
• Chairperson, Scientific Secretary and Clinical
  Data Coordinator appointed by ESCMID

• EUCAST General Committee
• one representative from each European country
  (n32)
• one representative each from ISC and FESCI
• Chairperson, Scientific secretary and Clinical
  Data Coordinator as above

• EUCAST industry email network
• proposals are referred for comment

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EUCAST Subcommittees

• Antifungal Susceptibility Testing
• Expert Rules
• Anaerobes
• Mycobacteria

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EUCAST websites www.eucast.org

• - constitution
• - organisation
• - committee member lists
• - meetings
• - EUCAST documents
• - MIC breakpoints
• - MIC distributions

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Impact of EUCAST on the BSAC method

• definitions of S, I and R
• changed clinical breakpoints
• introduction of epidemiological (wild type)
  cut-offs
• listing of non-species-specific clinical
  breakpoints

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Definitions of clinical breakpoints

• Susceptible
• A microorganism is defined as susceptible if
  inhibited in vitro by a concentration of an
  antimicrobial agent that is associated with a
  high likelihood of therapeutic success.
• Resistant
• A microorganism is defined as resistant if
  inhibited in vitro by a concentration of an
  antimicrobial agent that is associated with a
  high likelihood of therapeutic failure

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Definitions of clinical breakpoints (cont.)

• Intermediate
• A microorganism is defined as intermediate by a
  level of antimicrobial agent activity associated
  with uncertain effect
• It implies that infection may be treated in body
  sites where the drug is concentrated or when a
  high dosage can be used
• it indicates a buffer zone to prevent small
  uncontrolled technical factors causing major
  discrepancies in interpretation

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The intermediate category (I)

• Re-introduction for BSAC users (previous M in
  Stokes method)
• Until now I and R combined in BSAC methodology -
  both called R
• Most other breakpoint committees have I
  category
• Usually a doubling tube dilution higher than S/I
  breakpoint.

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What does intermediate mean? All things to all
men?

• If drug is concentrated at a body site, can use
  the I/R breakpoint to define susceptibility, for
  example urinary testing for uncomplicated UTI
• Problems
• definitions of tissue penetration
• little evidence to support an I/R breakpoint
• most breakpoints based on blood levels for the
  treatment of tissue infection

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What does intermediate mean? (cont.)

• if you can use a bigger dose or novel dosing
  strategy this will overcome the resistance level.
  Twice the dose, doubles the clinical breakpoint
• also could add a second agent to overcome low
  level resistance e.g. P. aeruginosa therapy
  with meropenem if MIC 2-8mg/L
• Problems
• emergence of resistance may be more common
  efflux mutants and fluoroquinolones
• what if the mechanism is an enzyme in contrast to
  efflux pump or target site mutation
• more data needed than disc diffusion result, i.e.
  MIC value?

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What does intermediate mean? (cont.)

• the clinical outcome is truly indeterminate e.g.
  H. influenzae and macrolides
• Problems
• good quality clinical data
• ethics of relevant studies

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What does intermediate mean? (cont.)

• acts as a buffer zone to prevent major blunders
  related to minor methodological changes
• R ? I or I ? S mis-categorisation less
  significant than R ? S
• Problems
• difficult for epidemiological capture

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Is the intermediate category useful?

• Yes because
• Allows consideration of high dose, addition of a
  second agent, novel dosing
• Allows consideration of tissue penetration (be
  very careful)
• Provides a blunder zone
• Can continue to lump I/R together for
  epidemiological purposes if required
• Problems
• Understanding what Intermediate means at a
  clinical level
• Coping with S/I/R in epidemiological capture of
  laboratory data

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Wild type (epidemiological) cut-off values and
MIC distributions

• A microorganism is defined as wild type (WT) by
  the absence of acquired or mutational resistance
  mechanisms
• The upper limit of the WT MIC distribution is
  the wild type (epidemiological) cut-off value
• WT is presented as WT lt Xmg/L
• Wild type organisms may or may not respond
  clinically to treatment

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Wild type MIC distributions

• Reference material for epidemiological cut-off
  values for antimicrobial resistance surveillance
• Reference distributions for committees involved
  in decisions on clinical breakpoints
• Reference MIC ranges of wild type organisms for
  a wide spectrum of species and antimicrobials
• Reference for calibration of antimicrobial
  susceptibility testing methods

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Non-species specific breakpoint(clinical
breakpoint)

These are clinical breakpoints determined on the
basis of Pharmacokinetic/Pharmacodynamic data and
are independent of MIC distributions of any
bacterial species. They may be used only for
species that have not been given a clinical
breakpoint
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(No Transcript)
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1. National data on dosing, formulations,
clinical indications and target organisms are
reviewed and differences which might influence
breakpoints are highlighted
EUCAST procedure for setting harmonising
breakpoints
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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 ltX mg/L)
EUCAST procedure for setting harmonised
breakpoints
Epidemiological cut- off WTlt0.064 mg/L
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3. Existing national clinical breakpoints are
compared
EUCAST procedure for setting harmonised
breakpoints
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EUCAST procedure for setting harmonised
breakpoints
4. Using available Pk/Pd data, Monte Carlo
simulations are performed and a Pk/Pd breakpoint
(non-species-specific) calculated based on
conventional dosing regimens
S 0.5 mg/L
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EUCAST procedure for setting harmonised
breakpoints
5. Clinical data relating outcome to MIC values,
wild type and resistance mechanisms are assessed
in relation to the tentative breakpoint
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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
the breakpoints were set at S0.125 and Rgt2
mg/L, rendering wild type S. pneumoniae
intermediate in susceptibility to ciprofloxacin.
Splitting the wild type must be avoided to
permit reproducible susceptibility testing
lt2 mg/L
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EUCAST procedure for setting harmonised
breakpoints
7. Tentative breakpoints proposed by the
EUCAST Steering Committee are referred to the
national breakpoint committees for
comments. When Steering Committee and national
committees agree the tentative breakpoints are
subjected to the EUCAST consultation process
8. Consultation process on tentative
breakpoints - EUCAST General Committee -
Expert groups (eg Neisseria, anaerobes)-
Pharmaceutical industry, AST device
manufacturers - Others via EUCAST website
9. Rationale document prepared and published on
website
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EUCAST breakpoint tablesavailable at
http//www.eucast.org
Click on name to access MIC distributions
Dashed labs are recommended not to test
these organisms
Insufficient evidence
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EMEA SOP for setting breakpoints through EUCAST
Available from the EUCAST (www.eucast.org) and
EMEA websites
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Advantages of the EUCAST process for BSAC users

• Vigorous process for reviewing clinical
  breakpoints based on Pk, Pd, MIC distributions,
  clinical trials, medical experience
• Consultation with 5 other National Committees and
  open consultation across Europe
• Harmonised breakpoints for old agents
• Improved data (Pk, Pd, MIC, clinical trial) for
  new agents
• Link with EMEA
• Improved international acceptance of UK
  breakpoints
• Epidemiological advantages
• Reduced significance of CLSI (NCCLS) and FDA

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Changes to BSAC breakpoints

• Agreed harmonized breakpoints for
• Aminoglycosides
• Aztreonam
• Carbapenems
• Parenteral cephalosporins
• Fluoroquinolones
• Glycopeptides
• Linezolid
• Agreed breakpoints for new agents
• Daptomycin
• Tigecycline

• Draft/consultation breakpoints for
• Macrolides
• penicillins
• Oral cephalosporins
• Miscellaneous agents
• New agents under consideration
• Doripenem
• Ceftobiprole
• Dalbavancin

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Summary of changes to BSAC breakpoints
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Which pathogen groups have changed the most?
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Impact on susceptibility rates BSAC
surveillance 2005Gentamicin
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Impact on susceptibility rates BSAC
surveillance 2005Ciprofloxacin
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Impact on susceptibility rates BSAC
surveillance 2005Ertapenem
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The future

• Complete set of clinical breakpoints and wild
  type cut-offs based on European (EUCAST) process
• Mapping of breakpoints into routine disc methods
  (France, Norway, Sweden, UK) and automated
  systems
• Standardised methodologies
• ISO/CEN standard for MIC testing?
• European diffusion method?
• Relationship with EMEA means EUCAST will set
  breakpoints for new agents in Europe and for new
  drug SPC
• Relationship with CLSI (NCCLS)

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Summary

• EUCAST is a functional EU funded international
  collaboration!
• Professionally based
• Improved credibility for UK clinical breakpoints
• Improved cross Europe epidemiology
• Some different concepts more intermediate, wild
  type cut-offs, non-species-specific breakpoints
• Some different breakpoints but less direct impact
  than you may think
• Major focus for BSAC in medium term is on
  implementation/education