Shift to European (EUCAST)
breakpoints – the impact on the
BSAC recommendations
Alasdair MacGowan
Southmead Hospital
BRISTOL
Topics
Process
what is EUCAST? what does it do? why does it do it?
what are the advantages? (if any), Do I care?
Definitions
clinical breakpoints and wild type cut offs
 categorical results (S, R, I)
 non- species specific breakpoints
How a clinical breakpoint is assessed/decided
Changes in BSAC breakpoints so far
The future
Summary
EUCAST
Is European Committee on Antimicrobial Susceptibility Testing
formed in 1997, restructured into present form in 2002
convened by –
European Society for Clinical Microbiology and Infectious Diseases (ESCMID)
and
National Breakpoint Committees of Europe (France, CA-SFM; Germany;
DIN; Netherlands, CRG; Norway, NWGA; Sweden, SRGA; UK, BSAC WP)
Financed by –
ESCMID
National Committees
DG-SANCO of the EU for 3years until May 07
EUCAST objectives
 set common European antimicrobial breakpoints for
surveillance
 to harmonise breakpoints for existing and new drugs
(all agents)
 (promote standardisation of methodologies)
 (encourage I and E QA)
 (collaborate with other groups in AST and epidemiology)
 advise EU institutions
 (training)
EUCAST
General Committee
 one representative of each European country (n=32),
ISC and FESCI (n=2)
 Chair/Scientific Secretary/Clinical Co-ordinator (n=3)
appointed by ECCMD
Steering Committee
 one representative of each European national breakpoint
committee (n=6)
 two representatives of the EUCAST General Committee.
Chair/Scientific Secretary/Clinical Co-ordinator (as above)
EUCAST website
www.eucast.org
constitution & organisation
Committees & meetings
documents & MIC breakpoints
MIC distributions
Impact of EUCAST on the BSAC standardised method
• definitions of S, R and I
• changed clinical breakpoints to define susceptibility
• introduction of “wild type cut-offs”
• listing of non-species specific clinical breakpoints
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 dependency on CLSI/NCCLS and FDA
Definitions
Clinical breakpoints
susceptible
a micro organism is defined as susceptible of inhibited in
vitro by a concentration of an antimicrobial agent that is
associated with a high likelihood of therapeutic success.
Resistant
a micro organism 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
Definitions – cont’d
Intermediate
a micro organism is defined as intermediate by a level of
antimicrobial agent activity associated with uncertain effect.
It implies –
 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.
The intermediate category (I)
 re-introduction for BSAC users (previous M is Stoke’s
methodology).
 most other breakpoint committees have I category.
 until now I and R combined in BSAC methodology
- both called R.
 usually a doubling tube dilution higher than S/I
breakpoint.
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, example
urinary testing for uncomplicated UTI.
Problems
: definitions of tissue penetration
: most bps based on blood levels for the
treatment of tissue infection
: little evidence to support an I/R breakpoint
Intermediate - cont’d
• if you can use a bigger dose, 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
Intermediate - cont’d
the clinical outcome is truly indeterminate
i.e. H. influenzae and macrolides
problem - good quality clinical data
- ethics of relevant studies
Intermediate - cont’d
• acts as a buffer zone to prevent major blunders
related to minor methodological changes
i.e. I  S mis categorisation less of a problem than
R  S.
• helps explain day-to-day variation in results.
Problems:- difficult for epidemiological capture
Is the intermediate category a useful adjunct
Yes because:• allows consideration of high dose, addition of a second
agent, novel dosing.
(much more data needed, i.e. MIC value)
• allows consideration of tissue penetration (be very careful)
• allows a blunder zone
• can continue to lump I/R together for epidemiological
purposes
Main problems:• understanding what I means at a clinical level
• coping with S/I/R in epidemiological capture of
laboratory data
• others
Epidemiological cut of values
• a micro organism is defined as wild type (WT) by the
absence of acquired or mutational resistance mechanisms
WT is presented as WT < Xmg/L
Wild type organisms may or may not respond clinically
to antimicrobial treatment
Graph shown in the EUCAST program for display of
MIC distributions of wild type bacteria.
Values >1% show on graph!
Non species specific breakpoint
(clinical breakpoint)
-these are 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.
Relevant factors in setting clinical breakpoints
• national similarities and differences regarding dosing
and dose size
• national differences in target organisms
• dose/concentration effect relationships in animals, in vitro
and man (pK/pD data).
• modelling process such as Monte Carlo simulation may
be used to assess breakpoints
• clinical outcome data related to MICs, drug exposures
and pD indices
• breakpoints are tested against MIC distribution data
to ensure wild type MIC distributions not split
• consensus is sought through the General Committee
and National Committees
EUCAST procedure for
setting breakpoints
1. Data on dosing, formulations, clinical indications and target organisms
are reviewed and differences which might influence breakpoints are
highlighted
BSAC
UK
CA-SFM
France
CRG
Netherlands
DIN
Germany
NWGA
Norway
SRGA
Sweden
Most common dose
500 x 2 oral
400 x 2 iv
500 x 2 oral
200 x 2 iv
250 x 2 oral
200 x iv
500 x 2 oral
200 x 2 iv
200-400 x 2
oral
400 x 2 iv
500 x 2 oral
400 x 2 iv
Maximum dose schedule
750 x 2 oral
400 x 3 iv
750 x 2 oral
400 x 3 iv
750 x 2 oral
400 x 3 iv
750 x 2 oral
400 x 2 iv
data pending
750 x 2 oral
400 x 3 iv
oral, iv
oral, iv
oral, iv
oral, iv
oral, iv
oral, iv
Dosage
Available formulations
EUCAST procedure for
setting breakpoints
2. Multiple MIC-distributions are collected, the wild type MIC
distribution is defined and tentative epidemiological cut-off values
determined (WT <X mg/L)
Epidemiological cut
off: WT<0.064 mg/L
EUCAST procedure for
setting breakpoints
3. Existing national clinical breakpoints are compared
Breakpoints prior to harmonisation (mg/L) S< R>
General breakpoints
BSAC
CA-SFM
CRG
DIN
NWGA
SRGA
ND
1/2
1/2
1/2
0.125/2
1/2
Species related breakpoints
not yet
NCCLS
no
Enterobacteriaceae
1/1
0.12/2
0.12/1
1/2
Pseudomonas spp.
1/4
ND
1/1
1/2
1/1
1/2
0.12/2
0.06/2
1/2
Acinetobacter spp.
Staphylococci
1/1
Streptococci
1/1
excluded
0.12/2
0.12/2
excl
2/2 (I)*
excluded
0.12/2 (I)*
0.12/2 (I)*
excl
excluded
excluded
0.12/2
0.12/2
1/2
0.12/0.5
0.12/0.25
1/-
S. pneumoniae
Enterococci
Haemophilus/Moraxella spp.
1/1
Corynebacteria
excl
N. Meningitidis
1/1
N. Gonorrhoeae
0.06/-
P. Multocida
Anaerobes
0.06/0.12
0.03/0.25
0.06/0.12
0.06/0.25
ND
ND
0.12/0.25
excluded
ND
excluded
no
no
Campylobacter spp.
1/1
Helicobacter pylori
2/2
0.06/1
no
no
0.06/0.5
200
180
160
140
120
100
80
60
40
20
0
0.25
ciprofloxacin 500 mg q12h oral
fAUC/MIC
fAUC/MIC
4. Using available Pk/Pd data, Monte Carlo simulations are performed
and a Pk/Pd breakpoint calculated based on conventional dosing regimens
99% CI
Average
0.5
1
2
4
8
MIC mg/L
S = 0.5 mg/L
200
180
160
140
120
100
80
60
40
20
0
0.25
levofloxacin 500 mg q24h oral
99% CI
Average
0.5
1
2
MIC mg/L
Pk/Pd
S = 1 mg/L
4
8
EUCAST procedure for
setting breakpoints
5. Clinical data relating outcome to MIC-values, wild type and resistance
mechanisms are assessed in relation to the tentative breakpoint
6a. Tentative breakpoints are checked against target species wild type MIC
distributions to avoid splitting the wild type to obtain tentative breakpoints
Epidemiological cut
off: WT<2.0
…the breakpoints were set
at S≤0.125 and R>2 mg/L,
rendering wild type S.
pneumoniae intermediate
in susceptibility to
ciprofloxacin.
<2 mg/L
Splitting the wild
type must be avoided
to permit reproducible
susceptibility testing
6b. Tentative breakpoints are checked against target species wild type MIC
distributions to avoid splitting the wild type to obtain tentative breakpoints example levofloxacin
… a break-point of 2 mg/L
was acceptable with a
footnote that this relates
to high dose therapy.
Epidemiological
cut off: WT<2.0
Splitting the wild
type must be avoided
to permit reproducible
susceptibility testing!
<2 mg/L
EUCAST procedure for
setting 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
EUCAST breakpoint tables
available at http://www.eucast.org
Click on name to
directly access
MIC distributions
”Dashed” – laboratories are
recommended not to test
against this species
Insufficient
evidence
Changes to BSAC breakpoints so far
Agreed breakpoints for –
aminoglycosides
aztreonam
carbapenems
cephalosporins
fluoroquinolones
glycopeptides
linezolid
New agents –
daptomycin
tigecycline
Draft/consultation breakpoints for
macrolides
penicillins
garenoxacin
Summary of changes
aminoglycosides
aztreonam
carbapenems
cephalosporins
fluoroquinolones
glycopeptides
linezolid
n=63
lower
0
2
9
9
11
0
2
33
(53%)
EUCAST vs BSAC
same
higher
3
9
0
0
2
0
6
0
2
0
6
0
2
0
21
9
(33%)
(14%)
  1diln
0
2
3
4
0
0
0
9
(14%)
Which pathogen groups have changed the most?
Enterococcus
Pseudomonas
Staphylococcus
Enterobacteriacae
B. haemolytic streps
H. influenzae/
M. catarrhalis
lower
0
3
3
8
9
same
4
4
5
5
2
higher
0
3
3
3
0
10
1
0
Impact on susceptibility rates: BSAC surveillance 2005
%S
gentamicin
E coli (n=247)
S. aureus (n=244)
P. aeruginosa (n=216)
BSAC
( 1mg/L)
87.4
97.9
57.4
EUCAST
( 2mg/L)
92.7
98.8
81.9
%S
ciprofloxacin
E coli
P. aeruginosa
H. influenzae
BSAC
( 1mg/L)
93.5
82.4
99.8
EUCAST
( 0.5mg/L)
93.5
79.2
99.8
%S
entapenem
E coli
K. pneumoniae
Ent cloacae
BSAC
( 2mg/L)
100
99.5
96.5
EUCAST
( 0.5mg/L)
100
99.5
86.7
The future
 complete set of clinical breakpoints and wild type
cut offs based on European process (EUCAST)
 mapping of breakpoints into standard methods
(France, Norway, Sweden, UK)
 ?standardised methodologies ISO/SEN standard
for MIC testing
 relationship with EMEA means EUCAST will set
breakpoints for new agents in Europe and for new
drug SPC
 relationship with CLSI/NCCLS
Summary
 EUCAST is a functional EU funded national collaboration!
 Professionally based
 improved credibility for UK clinical breakpoints
 improved cross Europe epidemiology
 some different concepts for BSAC users: I,
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