Screening Criteria for Carbapenem Resistant Enterobacteriaceae

Fernando Baquero, Rafael CantónDepartment of Microbiology

Ramón y Cajal University Hospital, IRYCIS28034 Madrid, Spain

Screening Criteria for Carbapenem Resistant Enterobacteriaceae

Carbapenem-resistant………………For Therapy?Carbapenem-resistant….. = Carbapenemase producers?

Most carbapenemase producing Enterobacteriaceae are R to carbapenems but can be also S or I

Carbapenem resistance and carbapenemases Carbapenem resistance and carbapenemases

Susceptible (S)

Intermediate (I)

Resistant (R)

Categories for clinical response to carbapenems

Carbapenemase Carbapenemase producing producing

EnterobacteriaceaeEnterobacteriaceae(CPE)(CPE)

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 EnterobacteriaceaeCarbapenemase producing Enterobacteriaceae

Carbapenemase producing EnterobacteriaceaeCarbapenemase producing Enterobacteriaceae

S R

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.

carbapenemases

EUCAST breakpoint tables v4.0, 2014

Imipenem MIC distributions

EUCAST

Meropenem MIC distributions

EUCAST

Ertapenem MIC distributions

EUCAST

ECOFF

S R Eco Kp/Ecl

A) ImipenemClinical breakpoints

mg/L

ECOFF

S R Eco/Kp/Ecl

B) MeropenemClinical breakpoints

mg/L

ECOFF

S R Eco/Kp/Ecl

C) ErtapenemClinical breakpoints

mg/L

E. coli K. pneumoniaeE. cloacae

Carbapenems susceptibility criteria

EUCAST

 

Yeara

FDAb CLSI

Yeara

EMA and EUCASTc EUCAST

screening

cut offsdS S R S R ECOFF

Imipenem ≤2010e

  ≤4 ≥16          

  2010f-2014 ≤4 ≤1 ≥4 2006-2014 ≤2 >8 ≤0.5; ≤1** >0.12

                   

Meropenem ≤2010e

  ≤1 ≥16          

  2010f-2014 ≤4 ≤1 ≥4 2006-2014 ≤2 >8 ≤0.125 1

                   

Ertapenem ≤2010e

  ≤2 ≥8          

  2010f

  ≤0.25 ≥1          

  2012-2014 ≤2 ≤0.5 ≥2 2006-2014 ≤0.5 >1 ≤0.06 >0.12                   

Doripenem         2008-2013 ≤1 >4 ≤0.12  

  2010f-2014 ≤0.5 ≤1 ≥4 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.

Carbapenem breakpoint (mg/L) evolution in Enterobacteriaceae over time

The concept of resistance … pharmacologistsThe concept of resistance … pharmacologists

Probabilities of Target Attainment (PTA) for Meropenem

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

fAUC/MIC currently use by EUCAST and carbapenems

Carbapenems pharmacokinetic criteria

Daikos et al. Antimicrob Agents Chemother

2009; 53:1868-73

Survival probability (Kaplan-Meier curves) of patients with VIM-producing

K. pneumoniae bloodstream infections according with susceptibilityto 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

Carbapenemase producing EnterobacteriaceaeCarbapenemase producing Enterobacteriaceae

VIM (+) MIC>4

VIM (+) and (-) MIC <4

Interpretive reading of AST resultsInterpretive reading of AST results

Interpretative reading: do we have to apply to carbapenemase producing Enterobacteriaceae (CRE)?

Carbapenemase positive isolate

resistant to all carbapenems (irrespective of MICs)

expert rule*

*Currenty, both CLSI and EUCAST recommend to “report as tested” an do not have specific expert rules for CRE

0

1

2

3

4

5

6

7

8

9

10

0 1 2 4 6 8 12 24

Log

10 C

FU/m

L

Time (hours)

control

IMI 2X

MER 2X

ERT 2X

DOR 2X

0

1

2

3

4

5

6

7

8

9

10

0 1 2 4 6 8 12 24

Log

10 C

FU/m

L

Time (hours)

control

IMI 4X

MER 4X

ERT 4X

DOR 4X

Bactericidal activity against CPE (VIM-1-producing K. pneumoniae)

MIC: imipenem, meropenem, doripenem = 8 mg/L, ertapenem = 1 mg/L

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 EnterobacteriaceaeCarbapenemase producing Enterobacteriaceae

Carbapenemase producing Carbapenemase producing K. pneumoniaeK. pneumoniae

Combination therapy with 2 active drugs,

B: not including a carbapenem

C: aminoglycoside

D:carbapenem

E:tigecycline

F:colistin

Monotherapy with

A: one of which was a carbapenem

Inapropriate therapy

Tzouvelekis et al. Clin Microbiol Rev 2012; 25: 682-707

Carbapenemase producing Carbapenemase producing K. pneumoniaeK. pneumoniae

Tzouvelekis et al. Clin Microbiol Rev 2012; 25: 682-707

0

10

20

30

40

50

60

70

80

≤1 2 4 8 >8

% of failures

75.0%

28.6%

P = 0.02

MIC (mg/L)

Results of carbapenem monotherapy in 50 infected patients with K. pneumoniae harboring carbapenemases from 15 studies

(most VIM producers)

5/17 3/12 2/7 2/6 6/8

Mortality in bloodstream infections and KPC-Mortality in bloodstream infections and KPC-K. pneumoniaeK. pneumoniae

Monotherapy

Combination therapy

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

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

Kaplan-Meier curves (survival) Mortality (%): monotherapy

05

101520253035404550

Colistin Tigecycline Aminoglycoside Carbapenem

Monotherapy

Combination therapy

0

10

20

30

40

50

60

COL + GEN

TIG + GEN

TIG + COL

TIG + GEN + MER

TIG + COL + MER

Mo

rta

lity

(%

)

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

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

Kaplan-Meier curves (survival) Mortality (%): combination therapy

Mortality in bloodstream infections and KPC-Mortality in bloodstream infections and KPC-K. pneumoniaeK. pneumoniae

Carbapenem resistance for clinicians: Carbapenem resistance for clinicians:

MIC, mechanisms, what matters?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

Clinical breakpoints and screening cut-off valuesscreening cut-off values for

carbapenemase-producing Enterobacteriaceae

Guidelines for detection of resistance mechanismsGuidelines for detection of resistance mechanisms and specific resistances of clinical and specific resistances of clinical and/or epidemiological importance and/or epidemiological importance

www.eucast.org

Acknowledgments 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)

Problems with carbapenem susceptibility and CPE 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

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

. Failure . MIC (mg/L) Vitek Etest . ≤2 1 / 2 2 / 4 4 4 / 7 --- 8 --- 3 / 4 ≥16 2 / 2 2 / 3

Outcome in patients treated with carbapenems in monotherapy

0

10

20

30

40

50

60

70

80

90

100

1 2 4 8 ≥16

%30-day mortality rate in patients treated with combination therapy

including meropenem stratified by meropenem MIC values

1/1 4/4 8/10 3/4 11/17

MIC (mg/L)

Nonsurvivors

Survivors

2/10 1/10 6/17

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

Mortality in bloodstream infections and KPC-Mortality in bloodstream infections and KPC-K. pneumoniaeK. pneumoniae

PK/PD breakpoints (expressed as mg/L) based on Monte Carlo simulations in healthy volunteers and in critically ill patients without renal dysfunction

Agent Dosing regimen

Actual variance1Inflated

variance1

Critically ill patients

without renal dysfunction

40%f T>MIC 40%f T>MIC 40%f T>MIC Reference

Ertapenem 1000 mg x 1 IV0.25 0.125 0.25 41

Imipenem 1000 mg x 3 IV1 1 2 42

Meropenem 1000 mg x 3 IV1 0.5 2 39

Doripenem 500 mg x 3 IV 1 0.5 2 43

Bhavnani SM, Dudley MN, Landersdorfer L, Drusano GL, Craig WA, Jones RN, et al. Pharmacokinetic-pharmacodynamic basis for CLSI carbapenem susceptibility breakpoint changes, abstr A-1382. Abstr. 50th Intersci. Conf. Antimicrob. Agents Chemother, Boston, MA. 2010

Efficacy of antimicrobial regimens used to treat infections caused by carbapenemase-producing Klebsiella pneumoniae

Clin Microbiol Infect 2011; 17: 1135-41