y

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a
r
b
i
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e

www.EUCAST.org

r
u
t
c
e TESTING
SUSCEPTIBILITY
r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M

EXPERT RULES IN ANTIMICROBIAL

C
S
E

Dr. Rafael Cantn

Hospital Universitario Ramn y Cajal
SERVICIO DE MICROBIOLOGA Y PARASITOLOGA

Departamento de
Microbiologa II
Universidad
Complutense. Madrid

y
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r
b
i
L
e

Antimicrobial susceptibility testing

r
u
t
Based on clinical
breakpoints
c
e r
L
o
e
h
Interpretive reading
t
n
i
u
l
a
n
O Basedbony resistance mechanisms knowledge
D
I
Application
of expert rules
M
C
S
Based both on clinical evidence and
E
Clinical categorization (S, I, R)

resistance mechanisms knowledge

y
r
a
r
b
Clinical breakpoints
i
L
The ultimate goal of clinical breakpointsre
is using MIC values to
u
separate strains where there is a high
likelihood of treatment
t
c is more likely to fail (R)
success (S) from those where e
treatment
r
L
o
e
h
They are not primarilyn
defined totdetect
resistant bacteria
i
u
l
a
n
y prospective human clinical studies
They are mainlyO
derived from
b
comparingIoutcomes
with the MICs of the infecting pathogen
D

and supported
with MIC distributions and Pk/Pd studies
M
C
E
If S
breakpoints are well established no actions (expert rules) are
needed beyond MIC interpretation
Antimicrobial susceptibility testing

This has not been always the case in the past!

y
r
a of the
r
During more than twenty years interpretive reading
b
i
antibiogram have been used to:
L
e phenotypes
- infer resistance mechanisms behind rresistant
u
t
- identify resistant organisms forcinfection control purposes
e
r
L
- apply an expert rule* and modify (when
needed!) previous
o
e
h
t
n
clinical categorization
i
u
l
a
n
O by
D
I
M
This approach was partially needed
C
S
due to inadequate breakpoints!
E
Antimicrobial susceptibility testing

Courvalin P. ASM News 19921992;58:368-75

Livermore et al. J Antimicrob Chemother 2001;48(Suppl 1):87-102
Cantn R. Enferm Infecc Microbiol Clin 2002; 20: 176-86
Cantn R. Enferm Infecc Microbiol Clin 2010; 28:375-85
Leclercq et al. Clin Microbiol infect 2011; Oct 21.

*Action to be taken (normally S or I to R), based on current clinical

or microbiological evidence, in response to specific AST results

y
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b
i
Interpretative reading: the classical example
L
e
r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
expert rule
D
I
M
C
S
E
Antimicrobial susceptibility testing

ESBL positive isolate

resistant to all
cephalosporins
and azthreonam

(irrespective of MICs)

y
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a
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b
i
1.- To establish the susceptibility phenotypeL
e
r
u
t
c
e r
L
o
2.- To infer the potential resistance
mechanism
e
h
t
n
i
u
l
a
n
O by
D
I

3.- To predict previously

defined phenotype from the
M
resistance
mechanisms
C
S
E

Interpretive reading of the antibiogram

Courvalin P, ASM News, 1992

Livermore DM et al. J Antimicrob Chemother 2001; 48 (Suppl 1): 87-102
Cantn R. Enferm Infecc Microbiol Clin 2010; 28:375-385

y
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b
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Importance of bacterial identification
L
e
r
u
t
c
Antimicrobial MIC
Organisms
Potential phenoype
e
r
L
o
Ampicillin
>64
E.e
coli
AmpC hyperproduction
h
t
n
Amox/clav
>32/16
plasmid AmpC
i
u
l
a
n
Ticarcillin
>64
ESBL + porin deficiency
y
Piperacillin
32 O
b
Piper/Tazo
16/4
D
I
K. pneumoniae ESBL + porin deficiency
Cefuroxime M >64
Cefoxitin C
>32
S
Cefotaxime
4
E
Ceftazidime
8
E. cloacae
ESBL
Antibiogram interpretative reading

(mg/L)

Cefepime

y
r
a
r
b
i
L
e

Proteus vulgaris
hyperproduction of chromosomal b-lactamase (Class A)

r
u
t
Ampicillin
c
e Ticarcillin
r
L
o
Piperacillin
e
h
t
Piper/Tazo
n
i
u
l
Amox/clav
a
n
Cefalotin
O by
Cefoxitin
D
I

Cefuroxime
M

AMP

CXM

CTX

C
S
E

PIP

CAZ

AMC

ATM

CEF

FOX

FEP

IPM

Cefotaxime
Ceftazidime
Cefepime
Imipenem

MIC

Interp.

>256
8->256
8->256
8-32
4-8
>256
2-4
>256
2-8

0,12-0,5
0,5-2
0,5-2

R
R
S/R
S/R
S/I
R
S
R
R
S
S/I
S

EUCAST expert rules: definition

y
r
a
r
b
i
Expert rules in antimicrobial susceptibility
testing (AST)
L
e
r
u
- describe actions to be taken on the basis
of specific AST results
t
c
e
r
L
- based on clinical breakpoints & resistance
mechanism knowledge
o
e
h
t
n
i
u
- assist clinical microbiologists
in the
interpretation of AST results
l
a
n
y by highlighting anomalous results
O assurance
- contribute to quality
b
D
I
M
- should be
in agreement with clinical breakpoints
C
S
E
Winstanley T, Courvalin P. Clin Microbiol Rev 2011; 24: 51556
Leclercq R et al. Clin Microbiol Infect 2011 Oct 21 [Epub ahead of print]
http://www.eucast.org

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e

C
S
E

r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M

y
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a
r
b
i
L
e

r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M

C
S
E

Clin Microbiol Infect, 2011 Oct 21 [Epub ahead of print]

EUCAST expert rules

y
r
a
r
b
i
L
The EUCAST expert rules in antimicrobial
e susceptibility
r
u
testing are divided into:
t
c
e r
L
- intrinsic resistances
o
e
h
t
n
i
u
l
a
n
- exceptional
phenotypes
O by
D rules
I
- interpretive
M
C
S
E
Leclercq R et al. Clin Microbiol Infect 2011 Oct 21 [Epub ahead of print]
http://www.eucast.org

EUCAST expert rules v2: intrinsic resistance

y
r
a
r
Characteristic of all or almost all isolates of the bacterial
species
b
i
L
The antimicrobial activity of the drug is clinically
insufficient or
e
r
antimicrobial resistance is innate, rendering
it clinically useless
u
t
c
Antimicrobial susceptibility is unnecessary
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M
C
S
E
ECOFF

ECOFF

www.eucast.org

EUCAST expert rules v2: intrinsic resistance

y
r
a
r
b
i
L
e

r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M
S

C
S
E

ECOFF

www.eucast.org

EUCAST expert rules v2: intrinsic resistance

y
r
a
r
b
i
L
e

r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M

C
S
and
E non-fermentative Gram-negative bacteria listed are
Gram-negative bacteria other than Enterobacteriaceae
also intrinsically resistant to

glycopeptides, lincosamides, daptomycin, and linezolid

EUCAST expert rules v2: exceptional phenotypes

y
r
a
r
b
i
Exceptional phenotypes
L
e
r
Resistances of some bacterial speciesuto particular antimicrobial
t
agents which have not yet been reported
or are very rare
c
e r
L
o
They should be checked asethey mayh
also indicate an error in
t
n
i
identification or susceptibility
testing.
If they are confirmed locally:
u
l
a
n
- the isolate should
studied
y
Obe further
b
- sent to a reference
laboratory
D for independent confirmation
I
M
The may
change with time as resistance may develop and
C
S
increase
E over time
There may also be local or national differences. Very rare in one
hospital, area or country, may be more common in another

EUCAST expert rules v2: exceptional phenotypes

y
r
a
r
b
i
L
e

C
S
E

r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M

y
r
a
r
b
i
Actions to be taken on the basis of specific AST
results
L
e
r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
Agents ID

testedMAgents
C
affected
S
E
EUCAST expert rules v2

IF THEN

Exceptions,
scientific basis
and comments
www.eucast.org

EUCAST expert rules v2: interpretive rules

y
r
a
r
b
i
Evidences of expert rulesL
e
r
u
t
A. There is good clinical evidence
that reporting the test
c
results as susceptible leadseto clinical failures
r
L
o
e
h
t
n
i
u
l
B. Evidence is weak
and based
only on a few case reports
a
n
y It is presumed that reporting
O models.
or on experimental
b
the testID
result as susceptible may lead to clinical failures

M
C
S
C.
is no clinical evidence, but microbiological data
E There
suggest that clinical use of the agent should be discouraged
Leclercq R et al. Clin Microbiol Infect 2011 Oct 21 [Epub ahead of print]
http://www.eucast.org

EUCAST expert rules v2

Evidences

y
r
a
r
b
i
L
e

r
u
A. There is clinical evidence that treporting the test result as
c
susceptible leads to clinicale
failures
r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M
C
S
E

EUCAST expert rules v2

Evidences

y
r
a
r
b
i
L
e

r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M

B. Evidence is weak and based only on a few case reports or

on experimental models. It is presumed that reporting the
test result as susceptible may lead to clinical failures

C
S
E

EUCAST expert rules v2

Evidences

y
r
a
r
b
i
L
e

r
u
C. There is no clinical evidence, butt microbiological data
c
suggest that clinical use of e
the agent should be discouraged
r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M
C
S
E

y
r
a
r
b
i
Some major modifications
L
e
r
Old 9.1 and 9.8 expert rules have been
deleted
u
t
c
- ESBL detection and clinical category
modification in extended
e
r
L
spectrum cephalosporins no longer
existo(report as found)
e
h
t
n
i
u
l
- carbapenemase detection
and a
clinical
category modification in
n
carbapenems no
(report as found)
y
Olonger exist
b
D
I

Haemophilus and -lactams

expert rules have been reworded
M
C
OldS
13.7 expert rule (now 13.6)
E- nalidixic acid disk diffusion screen test for Salmonella and clinical
EUCAST expert rules v2

failure of fluoroquinolones due to acquisition of at least one target

mutation in gyrA has been substituted for ciprofloxacin MIC criteria
of >0.06 mg/L

y
r
a
r
CLSI (2010-12)
EUCAST
(2009-12)
b
i
Cefalosporins
L
S
R
S
R
e
r
1
4
1
>2
u
Cefotaxime
t
c
r
1
4Le
1
>2
Ceftriaxone
o
e
h
t
n
1
>4 (8)
Ceftazidime 4 li 16 u
a
n
y
32
1
>4 (8)
Cefepime O8
b
D
I
M
4 (8) 16
1
>4 (8)
Aztreonam
C
S
E
3rd/4th gen. cephalosporin breakpoints in Enterobacteriaceae

(8)*

(64)

(8)

(64)

(8)

(32)

(32)

*2009

Remember!

R category is in CLSI while > in EUCAST

y
r
a
r
b
i
CLSI and EUCAST new breakpoints were supported
on Pk/Pd
L
data, animal models and clinical outcomee
data
r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M
C
S
E
3rd/4th gen. cephalosporin breakpoints in Enterobacteriaceae

Monte-Carlo simulations and target

attainment rate (TAR) for intravenous
ceftriaxone 2 g every 24 h

Enterobacteriaciae in a murine thigh

infection model: Cephalosporin %
T>MIC and microbiological efficacy

MacGowan. CMI 2008; 14(Suppl 1):166-8

Andes & Craig. CMI 2005; 11(Suppl 6):10-7

y
r
a
Probability of target attainment (PTA) for ceftazidime
r
b
i
- 2 log drop in L
viable Gram-negatives
e fT>MIC
requiresr50%
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D ceftazidime
I
EUCAST decreased
and cefepime breakpoints due to

M
evidences
on clinical and MIC correlations:
C
S
E
3rd/4th gen. cephalosporin breakpoints in Enterobacteriaceae

ceftazidime 1000 mg x3

100

fT >MIC

80
60
40
20

. dose

99% percentile
95% percentile
Mean

0
0.25 0.5

MIC mg/L

1 mg/L
2-4 mg/L
>4 mg/L

16

32

64

PTA achieved
for MIC of

criteria

1 g x 3 IV

4 mg/L

2 g x 3 IV

8 mg/L

Ceftazidime rationale document, 2010

no difference ESBL and non-ESBL producers

variable successful outcomes
poor outcomes

Paterson et al. JCM 2001; 3; 9:2206-12; Andes & Craig. CMI 2005; 11 (Suppl. 6):10-7
Bin et al. DMID 2006; 56:351-7; Bhat et al. AAC 2007; 51:4390-5

y
r
The current situation on Enterobacteriaceae ra
b
i
L
FDA
CLSI (2011)
EUCAST (EMA) (2011)
e
r
u
S
S
R t
S
R
ECOFF
c
e r2 >8 0.5; 1**
4
Imipenem
1
4
L
o
e
4
Meropenem
1 n
4 th 2
>8
0.125
i
u
l
a
n
2
Ertapenem
0.25
1 (8)
0.5
>1
0.06
y
O
b
0.5
Doripenem
1
>4
0.12
D 1 4
I
M
C
S
EUCAST breakpoint are higher than those of CLSI!
E
CLSI & EUCAST carbapenem clinical breakpoints

(4)*

(16)

(4)

(16)

(2)

(ND)

(ND)

*2009; **E. coli y K. pneumoniae; ND: not defined

y
r
a
r
CLSI
EUCAST
b
i
L
New breakpoints published in
Breakpoints
published in 2006
e
r
June 2010 and January 2011*
anduwith
doripenem in 2008*
t
c
- to capture carbapenemase
- define as clinical breakpoints
e
r
L
(mainly KPCs) producers
noto
to detect carbapenemases
e
h
t
n
- Rationale:
- Rationale:
i
u
l
a
- Pk/Pd tools avoiding
PK
- MIC distribution of wild-type
n
O(inflatedby
subject variability
isolates, MBL-KPC producers
variance) ID
- Pk/Pd data

- Review of clinical data

M
C
Modified
Hodge test no longer
Carbapenemase detection no
S
necessary
unless for infection
longer necessary for clinical
E
control and epidemiological
categorization unless for
CLSI & EUCAST carbapenem clinical breakpoints

purposes

*Documents M100-S20-U; M100-S21

infection control purposes

*Version 1.3, January 2011

y
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r
b
i
L
e

Carbapenem breakpoints and Enterobacteriaceae

IMIPENEM*

C
S
E

r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M
EUCAST,

S 2

R: >8

*Imipenem Rationale Documment, 2009

y
r
Probability of target attainment (PTA) for Enterobacteriaceae for
a500 mg x 4 i.v.
r
b
i
L
e
r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M
C
S
E
EUCAST RD: Imipenem (Monte Carlo simulation)

PTA: % fT>MIC for 2 log experimental reduction = 35-55; % fT>MIC from clinical data = 54
Pk parameters used to obtained the PTA:
- Volume of distribution (Vd): 1.5 L, CV 15% - Elimination half life (t): 1.05h, CV 20%
- Fraction unbound (Fu): 80%;
- Infusion time: 0.5 h

Imipenem rationale documment, 2009

y
r
a
r
What has been the impact of these new breakpoints?
b
i
L
e microbiological
- on-desk studies (mainly on ESBLs) calculated
r
u
impact on % of S-R isolates using CLSI
and EUCAST breakpoints
t
c
e r
L
o
e
h
t
n
- critical voices alerting on
negativeuconsequence for no further
i
l
detection and reportn
of ESBLs a
and carbapenemases
O by
D
I

- analysis and meta-analysis

of different impact on mortality
M
of ESBL
and carbapenemase producing organisms
C
S
E

Cephalosporin / carbapenem breakpoints -Enterobacteriaceae

Howser et al. AAC 2010; 54:3043-6; Hoban et al. AAC 2010; 54:3031-4
Howser et al. EJCMID 2011; 30:173-9; Rodriguez-Bao et al. CMI 2012; 18:894-900

Livermore et al. JAC 2012; 67:1569-77

Bonten et al. JAC 2012; 67:1311-20; Falagas et al. AAC 2012; 4214-22

y
r
a
What has been the impact of these new breakpoints?
r
b
i
L
- On-desk studies (mainly on ESBLs) calculated
microbiological
e
r
impact on % of S-R isolates using CLSI
and EUCAST breakpoints
u
t
c
e r
L
o
e
h
t
n
i
- major impact when lusing
CLSIuthan EUCAST
a
n
y and cefepime than for cefotaxime
Oceftazidime
- major impact for
b
D
I

- geographic dependent
impact (different ESBL epidemiology)
M
C
- origin
(hospital or community-onset) dependent impact
S
E
3rd/4th gen. cephalosporin breakpoints in Enterobacteriaceae

Howser et al. AAC 2010; 54:3043-6; Hoban et al. AAC 2010; 54:3031-4
Howser et al. EJCMID 2011; 30:173-9; Rodriguez-Bao et al. CMI 2012; 18:894-900

y
r
a
r
% of ESBL-E. coli isolates susceptible to 3 / 4 b
gen. ceph. when
i
using CLSI and EUCAST breakpoints in different
studies
L
e
r
u
t
c
e r
L
CTX hoCAZ
FEP
e
t
n
i
u
l
a
n
O by
D
I
M
C
S
E
3rd/4th gen. cephalosporin breakpoints in Enterobacteriaceae
rd

th

60

52

50

38

% S isolates

40
30

19

20

14,7 14,7

10

Rodriguez-Bao
(CLSI)

Spain

Hoban (CLSI)

USA

7,5 8,7

2,3

Chen (CLSI)

Asia

Rodriguez-Bao
(EUCAST)

Spain

y
r
a
r
Impact of CLSI & EUCAST breakpoints in ESBL-E. b
coli blood isolates
i
L
e
r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M
C
S
E
3rd/4th gen. cephalosporin breakpoints in Enterobacteriaceae

CTX-M-9

CTX-M-1 group

SHV group

MIC (mg/L)

S-EUCAST
S-CLSI
0%

MIC (mg/L)

S-EUCAST
14.7%

S-CLSI
35.1%
Rodriguez-Bao et al. Clin Microbiol Infect 2012; 18:894-900

y
r
a
r
Ceftazidime susceptibility of prevalent CTX-M producing
E. coli
b
i
L
e
r
u
t
c
e r
% of CAZ-S isolates
L
o
e
h
CLSI EUCAST
t
n
i
u
l
a
n
CTX-M-14 93
74
O by
CTX-M-15 11
2
D
I

M
C
S
E
3rd/4th gen. cephalosporin breakpoints in Enterobacteriaceae

Willamson et al. EJCMID 2012; 31:821-4

Critical voices

y
r
a
r
b
i
L
e

r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M

1.- Similar number of clinical cases on record where cephalosporins and

carbapenems have proved effective and ineffective against infections
due to low-MIC ESBL and carbapenemase producers, respectively
2.- Routine susceptibility testing is less precise than in research: ESBL
and carbapenemase producers with MICs of 18 mg/L will oscillate
between susceptibility categories according to who tests them and how.

C
S
E

3.- Although breakpoint committees advocate ESBL and carbapenemase

detection for epidemiological purposes, some laboratories will abandon
seeking these enzymes for treatment purposes, leading to a loss of
critical infection control information

y
r
a
r
Clinical data on outcome for ESB L producers indicates
that
b
i
outcome decrease when MICs are > 2 mg/L L
e
r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M
C
S
E
3rd/4th gen. cephalosporin breakpoints in Enterobacteriaceae

Clinical outcome in patients with ESBL-producing Klebsiella spp.

or E. coli bacteraemia and treated with cephalosporin monotherapy
80

% of success

% of success

80
60
40
20
0

60
40

20

16

CMI (mg/L)

Paterson et al. JCM 2001; 39:2206-12

CMI (mg/L)

Andes & Craig. CMI 2005; 11 (Suppl. 6):10-7

y
r
a
r
b
i
L
a higher mortality rate was observed for patients
infected with
e CI, 1.05-3.92)
strains with high MICs (Risk ratio 2.03; r
95%
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M
C
S
E
differences
on mortality were not statistically significant in patients

Impact of antibiotic MIC on infection outcome in patients with

susceptible Gram-negative bacteria

infected with ESBLs (Risk ratio 1.89; 95% CI, 0.94-3.92)

Falagas et al. Antimicrob Agents Chemother 2012; 56 4214-22

y
r
a
r
b
i
ESBL production in Enterobacteriaceae bacteremia
is associated
L
with higher mortality (OR 2.35; 95% CI, 1.90-2.91), although it is
e
r
reduced after adjustment by inadequate
empirical therapy
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M
C
S
E
Association of bacteraemia caused by ESBL-producing
Enterobacteriaceae and patient outcome

Rottier et al. J Antimicrob Chemother 2012; 67:1311-20

Carbapenem breakpoints in Enterobacteriaceae

y
r
Survival probability (Kaplan-Meier curves) of patients with a
VIM-producing
r
K. pneumoniae bloodstream infections according withib
susceptibility
L
to carbapenems (imipenem or meropenem):
e
r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
Not allM
patients were
C
treated with
S
E carbapenems
Patients infected with a VIM-(+)
organism for which the MICs of
both imipenem and meropenem
were >4 mg/L were more likely
to die than those infected with a
VIM-(+) carbapenem-susceptible
of VIM-negative organisms
(P 0.044)

Daikos et al. Antimicrob Agents Chemother

2009; 53:1868-73

Carbapenem breakpoints in Enterobacteriaceae

y
r
a
r
Clinical correlation of carbapenem treatment in b
monotherapy
i
L
e
r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M
C
S
44 pacientes with K. pneumoniae
E
with VIM, NDM or KPC
80

70
60

% of
efficacy

50
40

30
20

10

0,5

>8

22 patients with K. pneumoniae

without carbapenemasa

Daikos et al.Clin Microbiol Infect 2011; 17: 1135-41

y
r
a
r
b
i
L
e

r
u
Efficacy of antimicrobial regimens usedtto treat infections caused
c
by carbapenemase-producing
Klebsiella
pneumoniae
e
r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M
C
S
E

y
r
Higher mortality (30-day) rate in patients treated with monotherapy
(54.3%)
a
r
that those with combination (34.1%) therapy (P=0.02)ib
L
Significant decreased of mortality in patients treated
with combination
e
r
therapy including meropenem
u
t
c
e
r
L
Mortality
(%): combination therapy
Kaplan-Meier curves (survival)
o
e
h
t
n
i
u
l
a
n
O by
D
I
M
C
S
E
Mortality in bloodstream infections and KPC-K. pneumoniae

60

Monotherapy

Mortality (%)

Combination therapy

50
40
30
20
10
0

COL + TIG +
GEN GEN

TIG + TIG + TIG +

COL GEN + COL +
MER MER

Tumbarello et al. Clin Infect Dis 2012; 55: 943-50

y
r
a
r
30-day mortality rate in patients treated with combination
therapy
b
i
including meropenem stratified by meropenemL
MIC values
e
r
u
t
Nonsurvivors
c
e r
L
o
e
h
t
n
i
u
l
a
n
Survivors
O by
D
I
M
C
S
E
Mortality in bloodstream infections and KPC-K. pneumoniae

100
90

2/10

1/10

6/17

80

70
60
50
40
30

1/1

4/4

8/10

3/4

11/17

16

20
10
0

MIC (mg/L)

Tumbarello et al. Clin Infect Dis 2012; 55: 943-50

EUCAST expert rules v2: major modifications

C
S
E

y
r
a
r
-lactams and Haemophilus influenzae
b
i
L
Rule 10.1 v2 (evidence grade
e A)
r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M

EUCAST expert rules v2: major modifications

C
S
E

y
r
a
r
-lactams and Haemophilus influenzae
b
i
L
Rule 10.2 v2 (evidence grade
e C)
r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M

EUCAST expert rules v2: major modifications

C
S
E

y
r
a
r
-lactams and Haemophilus influenzae
b
i
L
Rule 10.3 v2 (evidence grade
e C)
r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M

EUCAST expert rules v2: major modifications

y
r
a issues
-lactams and Haemophilus influenzae: practical
r
b
i
L
Test for -lactamase and report positive isolates
R to penicillins
e
r
without -lactamase inhibitors
u
t
c
Use ampicillin and amoxicillin breakpoints
only to -lactamase
e
r
L
negative isolates
o
e
h
t
n
i
u
Isolates may be R to penicillins,
aminopenicillins
and/or
l
a
n
cephalosporins due to
in PBPs (BLNAR)
y
O changes
b
D positive
A few -lactamase
isolates may have also PBP changes
I

M
(BLPACR)
C
S
Isolates
S to ampicillin and amoxicillin are also S to amoxicillin
E
-clavulanate, piperacillin and piperacillin-tazobactam
Isolates S to amoxicillin-clavulanate are also S to piperacillin
tazobactam

EUCAST expert rules v2: major modifications

-lactamase test

y
r
a
r
b
i
L
e

r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M

Positive
Ampicillin-R
(BLP)
Expert rule
10.1

Report R to:
Ampicillin
Amoxicillin
Piperacillin

C
S
E

Negative

Amox/clav-R
(BLPACR)

Ampicillin-R
(BLNAR)

Expert rule
10.3

Expert rule
10.2

Report R to:
Ampicillin
Amoxicillin
Amox/clav
Amp/sulb
Piperacillin
Pip/tazb
Cefaclor
Cefuroxime

Report R to
Ampicillin
Amoxicillin
Amox/clav
Amp/sulb
Piperacillin
Piper/tazb
Cefaclor
Cefuroxime

Ampicillin-S
(BLN)

Benzylpenicillin
1 unit
screen test

EUCAST expert rules v2: major modifications

y
r
a
r
b
i
L
e

Benzylpenicillin- 1 unit screen test

r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M
R < 12 mm

S 12 mm
Ampicillin-S
(BLN)

Negative

Ampicillin-R
(BLNAR)

Expert rule 10.2

C
S
E

-lactamase test

Report R to
Ampicillin, Amoxicillin
Amox/clav, Amp/sulb
Piperacillin, Piper/tazb
Cefaclor, Cefuroxime

Ampicillin-R
Amox/clav-S
(BLP)
Expert rule
10.1

Report R to:
Ampicillin
Amoxicillin
Piperacillin

Positive
Ampicillin-R
Amox/clav-R
(BLPACR)
Expert rule 10.3

Report R to:
Ampicillin, Amoxicillin
Amox/clav, Amp/sulb
Piperacillin, Pip/tazb
Cefaclor, Cefuroxime

y
r
a
r
Salmonella spp. and fluoroquinolones
b
i
L
e
r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
y recommended for detection of
O bpreviously
Nalidixic ac. (zone diameter),
Dresistance,
fluoroquinolone
had been removed in breakpoint tables
I

- it doesM
not detect qnr-mediated resistance
C
-S
low-level resistance in Enterobacteriaceae (exception Salmonella spp)
E is no longer of major interest since high-level resistance is now
EUCAST expert rules v2

common in species

y
r
a
r
Salmonella spp. and fluroquinolones
b
i
L
e
r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
There is clinical evidence
for ciprofloxacin
to indicate a poor response in
y
O
b
systemic infections caused by
Salmonella spp. with low-level quinolone
D
I
resistance (MIC>0.064
mg/L).
This mainly to S. typhi but there are also

M
case reports
of poor response with other Salmonella species
C
S
E
EUCAST expert rules v2

Future modification of fluoroquinolones breakpoints?

y
r
a
r
b
i
L
e

Salmonella spp., nalidixic acid and fluoroquinolones

r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M
ECOFF

C
S
E

ECOFF

S R EUCAST, 2011

y
r
a
r
b
i
L
e

r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M

C
S
E

Clin Microbiol Infect, 2011 Oct 21 [Epub ahead of print]

Acknowledgements

y
r
a
r
b
i
L
e

C
S
E

r
u
t
c
e r
L
o
e
h
t
n
i
u
l
a
n
O by
D
I
M
Petra Apfalter
Derek F.J. Brown
Rafael Cantn
Luc Dubrueil
Christian Giske
Gunnar Kahlmeter
Alasdair P. MacGowan
Johan W. Mouton
Robert Skov
Martin Steinbakk
Luis Martnez-Martnez
Claude-James Soussy

Hospital Universitario Ramn y Cajal

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