Transcript EUCAST breakpoints - UNIPATH 2014 CONGRESS

Screening Criteria for Carbapenem
Resistant Enterobacteriaceae
Fernando Baquero, Rafael Cantón
Department of Microbiology
Ramón y Cajal University Hospital, IRYCIS
28034 Madrid, Spain
Screening Criteria for Carbapenem
Resistant Enterobacteriaceae
Carbapenem-resistant………………For Therapy?
Carbapenem-resistant….. = Carbapenemase producers?
Carbapenem resistance and carbapenemases
 Most carbapenemase producing Enterobacteriaceae are
R to carbapenems but can be also S or I
Carbapenemase
producing
Enterobacteriaceae
(CPE)
Susceptible
(S)
Intermediate
(I)
Resistant
(R)
Categories for clinical response to carbapenems
Carbapenemase producing Enterobacteriaceae
FDA
CLSI (2010-2014)
EUCAST (EMA) (2009-2014)
S
S
R
S
R
ECOFF
Imipenem
≤4
≤1 (4)*
≥4 (16)
≤2
>8
≤0.5; ≤1**
Meropenem
≤4
≤1 (4)
≥4 (16)
≤2
>8
≤0.12
Ertapenem
≤2
≤0.5 (2)
≥1 (8)
≤0.5
>1
≤0.06
Doripenem
≤0.5
≤1 (ND)
≥4 (ND)
≤1
>4
≤0.12
*2009; **E. coli y K. pneumoniae; ND: not defined
 MICs associated with carbapenemases might be below current
breakpoints (… even below the ECCOFs)
Carbapenemase producing Enterobacteriaceae
S
R
carbapenemases
ECOFF
The carbapenem breakpoints for Enterobacteriaceae will detect all clinically important resistance
mechanisms (including the majority of carbapenemases). Some isolates that produce carbapenemase
are categorised as susceptible with these breakpoints and should be reported as tested, i.e. the
presence or absence of a carbapenemase does not in itself influence the categorisation of susceptibility.
In many areas, carbapenemase detection and characterisation is recommended or mandatory for
infection control purposes.
EUCAST breakpoint tables v4.0, 2014
Imipenem MIC distributions
EUCAST
Meropenem MIC distributions
EUCAST
Ertapenem MIC distributions
EUCAST
A) Imipenem
ECOFF
Eco
E. coli
K. pneumoniae
E. cloacae
Carbapenems
susceptibility criteria
EUCAST
Kp/Ecl
Clinical breakpoints
S
R
mg/L
B) Meropenem
ECOFF
Clinical breakpoints
S
Eco/Kp/Ecl
mg/L
C) Ertapenem
ECOFF
Eco/Kp/Ecl
mg/L
Clinical breakpoints
S
R
R
Carbapenem breakpoint (mg/L) evolution in Enterobacteriaceae over time
FDAb
EMA and EUCASTc
CLSI
Yeara
S
R
≤4
≥16
≤1
≥4
≤1
≥16
≤1
≥4
≤2010e
≤2
≥8
2010f
≤0.25
≥1
≤0.5
≥2
≤2010e
2010f-2014
Meropenem
Ertapenem
≤4
≤2010e
2010f-2014
2012-2014
≤4
≤2
Doripenem
2010f-2014
screening
Yeara
S
Imipenem
EUCAST
≤0.5
≤1
≥4
S
R
ECOFF
cut offsd
2006-2014
≤2
>8
≤0.5; ≤1**
>0.12
2006-2014
≤2
>8
≤0.125
1
2006-2014
≤0.5
>1
≤0.06
>0.12
2008-2013
≤1
>4
≤0.12
2014
≤1
>2
≤0.12
ND
FDA: Food and Drug Administration; CLSI: Clinical and Laboratory Standards Institute; EUCAST: European Committee on Antimicrobial Susceptibility Testing;
EMA: European Medicines Agency; ECOFF: epidemiological cut-off values; S: susceptible; R: resistant; ND: not defined. Bold numbers indicate currently identical
breakpoints for CLSI and EUCAST.
The concept of resistance … pharmacologists
Probabilities of Target Attainment (PTA) for Meropenem
fAUC/MIC currently
use by EUCAST
and carbapenems
Pharmacokinetic parameters used to obtain the PTA:
- Volume of distribution (Vd): 20.8 L,CV 13% - Fraction unbound (Fu): 91%
- Elimination half-life (t): 1.04 h, CV 19%
- Infusion time: 0.5 h
Eucast Rationale Document, 1.5, June 2009
Carbapenems pharmacokinetic criteria
Carbapenemase producing Enterobacteriaceae
 Survival probability (Kaplan-Meier curves) of patients with VIM-producing
K. pneumoniae bloodstream infections according with susceptibility
to carbapenems (imipenem or meropenem):
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)
… but not all patients
were treated with
carbapenems
Daikos et al. Antimicrob Agents Chemother
2009; 53:1868-73
VIM (+) and (-) MIC <4
VIM (+)
MIC>4
Interpretive reading of AST results
 Interpretative reading: do we have to apply to carbapenemase
producing Enterobacteriaceae (CRE)?
Carbapenemase positive isolate
expert rule*
resistant to all carbapenems
(irrespective of MICs)
*Currenty, both CLSI and EUCAST recommend to “report as tested”
an do not have specific expert rules for CRE
Carbapenemase producing Enterobacteriaceae
 Bactericidal activity against CPE (VIM-1-producing K. pneumoniae)
MIC: imipenem, meropenem, doripenem = 8 mg/L, ertapenem = 1 mg/L
10
10
9
9
8
8
7
IMI 4X
IMI 2X
6
MER 2X
5
ERT 2X
4
DOR 2X
Log 10 CFU/mL
Log 10 CFU/mL
control
control
7
6
MER 4X
5
ERT 4X
4
DOR 4X
3
3
2
2
1
1
0
0
0
1
2
4
6
Time (hours)
8
12
24
0
1
2
4
6
Time (hours)
8
12
24
Morosini et al. 2011
 Presence of KPC in Enterobacteriaceae with carbapenem MICs 1-16
mg/L had no impact on the PD (%T>MIC) necessary for bacteriostasis
by carbapenems
Craig et al. 48th ICAAC, 2008, abstract A-029
 Animal models corroborates in vitro studies with MBL or KPC producing
isolates
Tzouvelekis et al. Clin Microbiol Infect 2014 May 29 [Epub ahead of print]
Carbapenemase producing K. pneumoniae
Combination therapy with 2 active drugs,
A: one of which
was a carbapenem
B: not including
a carbapenem
Inapropriate
therapy
Monotherapy with
C:
aminoglycoside
D:
carbapenem
E:
tigecycline
F:
colistin
Tzouvelekis et al. Clin Microbiol Rev 2012; 25: 682-707
Carbapenemase producing K. pneumoniae
Results of carbapenem monotherapy in 50 infected patients with K.
pneumoniae harboring carbapenemases from 15 studies
(most VIM producers)
80
75.0%
70
P = 0.02
60
% of
failures
50
28.6%
40
30
20
10
5/17
3/12
2/7
2/6
6/8
≤1
2
4
8
>8
0
MIC (mg/L)
Tzouvelekis et al. Clin Microbiol Rev 2012; 25: 682-707
Mortality in bloodstream infections and KPC-K. pneumoniae
 Higher 30-day mortality rate in patients treated with monotherapy
(54.3%) that those with combination (34.1%) therapy (P=0.02)
 Significant decreased of mortality in patients treated with
combination therapy including meropenem
 Kaplan-Meier curves (survival)
Combination therapy
Monotherapy
 Mortality (%): monotherapy
50
45
40
35
30
25
20
15
10
5
0
Colistin
Tigecycline
Aminoglycoside
Carbapenem
Tumbarello et al. Clin Infect Dis 2012; 55: 943-50
Mortality in bloodstream infections and KPC-K. pneumoniae
 Higher 30-day mortality rate in patients treated with monotherapy
(54.3%) that those with combination (34.1%) therapy (P=0.02)
 Significant decreased of mortality in patients treated with
combination therapy including meropenem
 Kaplan-Meier curves (survival)
 Mortality (%): combination therapy
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
Carbapenem resistance for clinicians:
MIC, mechanisms, what matters?
 Carbapenem MICs should be determined if clinically necessary
 Do not use the clinical breakpoints to detect resistance
mechanisms but the ECOFFs (or screening cut-off values)
 Combine adequate susceptibility testing methods and go beyond
MIC values to infer resistance mechanisms (interpretive reading)
 In carbapenemase producing Enterobacteriaceae MIC values
seem to be necessary to better define combination therapies
 New clinical data are waiting for further supporting EUCAST and
CLSI views
 There are still unresolved problems in susceptibility testing of
carbapenemase producing Enterobacteriaceae
 EUCAST created a subcommittee in 2012 to establish guidelines
for the detection of resistance mechanisms of clinical and/or
epidemiological importance
www.eucast.org
Guidelines for detection of resistance mechanisms
and specific resistances of clinical
and/or epidemiological importance
Clinical breakpoints and screening cut-off values for
carbapenemase-producing Enterobacteriaceae
Acknowledgments
Breakpoints for carbapenemase-producing
Enterobacteriaceae: Is the problem solved?
Rafael Cantón,a,b Andrés Canut,c María Isabel
Morosini,a,b Antonio Oliverb,d (submitted)
www.eucast.org
Problems with carbapenem susceptibility and CPE
 Carbapenemase genes in isolates within the wild type population
 Common hetero-resistance: difficulties to define MICs when using
different and even the same inoculum
Tato et al. J Clin Microbiol 2010; 48:4089-93
 Difficult correlation of MICs and outcome due to MIC variation
when using different methods
.
Failure
.
Outcome in patients treated with
carbapenems in monotherapy
MIC (mg/L)
≤2
4
8
≥16
Vitek
1/2
4/7
--2/2
Etest .
2/4
--3/4
2/3
Weisenberg et al. Diagn Microbiol Infect Dis 2009; 64:233-5
 Difficult detection of certain carbapenemases (OXA-48) by
commercial automatic systems when using MIC values
Woodford et al. J Clin Microbiol 2010; 48: 2999-3002
Mortality in bloodstream infections and KPC-K. pneumoniae
 30-day mortality rate in patients treated with combination therapy
including meropenem stratified by meropenem MIC values
100
2/10
90
1/10
6/17
Nonsurvivors
80
70
%
60
Survivors
50
40
1/1
4/4
8/10
3/4
11/17
1
2
4
8
≥16
30
20
10
0
MIC (mg/L)
Tumbarello et al. Clin Infect Dis 2012; 55: 943-50
PK/PD breakpoints (expressed as mg/L) based on Monte Carlo simulations
in healthy volunteers and in critically ill patients without renal dysfunction
Actual
Agent
Ertapenem
Imipenem
Meropenem
Doripenem
variance1
Inflated
Critically ill patients
variance1
without renal dysfunction
Dosing regimen
40%f T>MIC
40%f T>MIC
40%f T>MIC
Reference
0.25
0.125
0.25
41
1
1
2
42
1
0.5
2
39
1
0.5
2
43
1000 mg x 1 IV
1000 mg x 3 IV
1000 mg x 3 IV
500 mg x 3 IV
Bhavnani SM, Dudley MN, Landersdorfer L, Drusano GL, Craig WA, Jones RN, et al. Pharmacokineticpharmacodynamic basis for CLSI carbapenem susceptibility breakpoint changes, abstr A-1382. Abstr. 50th
Intersci. Conf. Antimicrob. Agents Chemother, Boston, MA. 2010
Clin Microbiol Infect 2011; 17: 1135-41
Efficacy of antimicrobial regimens used to treat infections caused
by carbapenemase-producing Klebsiella pneumoniae