Σ ε ώ Λ ώ εω ό Π ε ά

. Θε ε Π

Γδώλγομ Λ. Δα εομ

Ια λδεά Σχοζά Παθεπδ βηέου γβθώθ, ΄ΠΠΚ Λαϊεό Νο οεοηεέο

Α α 2ί1ζ

Κα α ο ή ω MICs

Π ι α α ι ές οι ώ ις

PK/PD

Κ ι ι ά ο έ α

Percentages of MRSA and MSSA isolates with a vancomycin (Van) MIC of 1 gήml from 2ίίί to 2004.

Wang G et al. J. Clin. Microbiol. 2006;44:3883-3886

Distribution of Vancomycin MICs for MRSA Blood

Isolates (N=300)

Success Rate of Vancomycin in the

Treatment of MRSA BSIs

MIC g/ml

%S

ucc

es

s

Sakoulas JCM 2004; 42:2398

P=0.02

Forest plot (using Mantel-Haenszel analysis) of events denoting methicillin-resistant S. aureus mortality (irrespective of source of infection and minimum inhibitory concentration

[MIC] methodology used) comparing high vancomycin MIC (≥1έη  gήmL) with low MIC (<1έη  gήmL) infectionsέ

van Hal S J et al. Clin Infect Dis. 2012;54:755-771

Pk/Pd Targets for Optimizing

Treatment with Vancomycin

• Targets

– AUCήεIC ≥ 4ίί

– Trough 15-20 ηg/ml

• Trough levels < 10 ηg/ml are suboptimal

and may promote resistance

Probability of achieving AUCήMIC ratio ≥ζίί for vancomycin regimens of varying intensity when Cmin values were between 10 and 15 mg/L.

Patel N et al. Clin Infect Dis. 2011;52:969-974

Vancomycin is Inferior to anti-staphylococcal

penicillins for the Treatment of Infections

Caused by MSSA

• Endocarditis

• Bacteremia

• Pneumonia

Small and Chambers, AAC 1990; Korzeniowski et

al, Ann Intern Med 1982;Levine et al, Ann Intern

Med 1991; Chambers et al Ann Intern Med 1988

MSSA: staphylococcal penicillins

MRSA: Vancomycin MIC

– εIC ≤ 1ηg/ml Vancomycin

– MIC > 1ηg/ml newer agent

• Pneumonia: Linezolid

• Bacteremia or ΙΕμ Daptomycin

• SSTI: Linezolid or Daptomycin

Detection and reporting of ESBL-producing

Enterobacteriaceae

Until 2009. Approach by resistance mechanism

- Search for ESBLs by phenotypic tests and correct

antibiogram according to the findings; ESBL-

producing organisms are reported as resistant to

all cephalosporins

Revised CLSI and EUCAST breakpoints. MIC approach

- The revised breakpoints eliminate the need to

perform screening for ESBLs for making treatment

decisions. The MIC correlates better with clinical

outcome than the resistance mechanism

Breakpoints for Enterobacteriaceae

CLSI EUCAST

S R S R

Cefotaxime ≤1 ≥4 ≤1 >2

Ceftriaxone ≤1 ≥4 ≤1 >2

Ceftazidime ≤4 ≥1θ ≤1 >4

Cefepime ≤κ ≥γβ ≤1 >4

The presence or absence of an ESBL does not in itself influence the categorization

of susceptibility

ι ι ή α α CLSI/EUCAST

α έα ό ια α οσ ο ού σ α ί σ ο ο ί ο α ισ ού α ά σ α ί σ ς α ο ής

ο ί αι ι ι ά σ α ι ή αι ι έ ι ήσ ο α ιβιο ι ού

Η σ ύ α ο ώ ιαφο ι ώ ύ ί αι σ ή σή α αι αθισ ά οσ άθ ια α ί σ ς ο ς φαι ο ι ά σ ο ύ ο , ο οβό α αι α α ιό ισ

Κ ι ι ές έ ς, ι α α ι ά ο έ α αι ώσ PK/PD ι ιο ή α ιβιο ι ώ ι έ ο ήσ ο ς σ σ έ α ές MIC α ά α ο σία α ισ ού α ο ής

Η MIC Κα ο ε ο Κ ό Απο ε α α όχ ο Μ χα ό Α οχ

Ceftazidime susceptibility of ~ 100 E. coli

producing CTX-M type ESBLs

Williamson DA Eur J Clin Microbiol Infect Dis 2011

Π οβ α ισ οί

Πα ά ί σ ο ί έ α οσοσ ό οβα ια ώ ο α ά ο ESBL έ ο

MIC ός ο ί αισθ σίας αι θα α ύο αι Α Η Α

Α ο ή σ ία φα οσ ο ί ς ιάς θέ ι ο ία ό ι ο σ έ ος α ά ι ESBL

Ποια ί αι α ο έ α ο οσ ί ο ό ι ήσ φα οσ ο ι ώ ί αι ασφα ής σ α ές

ις ι ώσ ις?

Animal model studies suggest that the PD target associated with efficacy in treatment of ESBL-producing organisms is the same as that in therapy against non-ESBL-producing bacteria (>50% T>MIC)

f %T>MIC

40%

Βα ηρ ο α ό

απ έ ε α, α εί α έ α α η α ε

ε α επα εί

70%

Βα ηρ ο όνο απ έ ε α, απα αί η α

α ε έ ε α α α α α έ υ

Monte Carlo Simulations and Target Attainment

Rates for IV Ceftriaxone 2g q24 h

D. Andes and W. A. Craig CMI 2005; 11 (Suppl 6): 10-17

% T >MIC

MIC 40% 50% 60% 70%

0.5 100 100 100 100

1 100 100 100 99

2 100 99 93 74

4 87 58 25 6

8 8 1 0 0

42 cases

Impact of cefepime therapy on mortality among patients with

bloodstream infections caused by ESBL-producing

K.pneumoniae and E.coli

Α α ο ι ή έ βα ιαι ί ς

ο α α ο ι ή α ά σ

Κα βα έ ς ς ι ι ή θ α ία, ι ό θ ό α ό ι OR=0.61,95% CI 0.26-1.50

Κ φ ί ς ι ι ή θ α ία, α ύ θ ό α ό ι OR= 1.66, 95% CI 0.71-3.87

Chopra et al. AAC 2012

Lee N et al. Clin Infect Dis. 2013;56:488-495

17 ε φ πέηβ vs 161 εαλίαπ θΫηβ Μδελκίδκζκΰδεά απκτυχέα

Κζδθδεά απκτυχέα

ΑυιβηΫθβ γθβτστβτα

Κ φ πέηβ: Αθ ιΪλτβτκμ παλΪΰωθ εδθ τθκυ ΰδα γθβτστβτα (OR 9.9; 95% CI, 2.8–31.9; P < .001)

Μ ε εί ε Κεφε ί έ τ ESBL- ετ ώ Ε τε τ ώ

Clin Infect Dis 2012; 54:167

~ 9 ασθ ίς βα ιαι ία UTI ή ο α ιϊ ι α α ό έ ς

Η ο οθ α ία ΑMC ή TZP φόσο ί αι ασ ι ά βάσ ο α ιβιό α α, σ ο ύ αι α ό α ό οια θ ό α αι ιά ια οσ ίας ό ς θ α ία

α βα έ

Η θ α ία σ ασ ό ί αι ασφα ής φόσο ά ι αισθ σία αι ο ού αι α σ σ ά οσο ο ι ά σ ή α α

Οι σ ασ οί α ασ ο έα ί αι α ά ι ο ή ια α ο ι ά σ ς θ α ίας α βα έ φόσο ά ι αισθ σία σ ο α ιβιό α α

ο ί αι ο ή σ σ ασ ού ίς α ιβιό α α αι σ βα έ ς άσ ο ς ασθ ίς

Forest plot depicting the RRs of all-cause mortality of patients with ESBL-positive bacteraemia treated empirically with carbapenems versus BL/BLIs.

Vardakas K Z et al. J. Antimicrob. Chemother. 2012;67:2793-2803

Forest plot depicting the RRs of all-cause mortality of patients with ESBL-positive bacteraemia treated definitively with carbapenems versus BL/BLIs.

Vardakas K Z et al. J. Antimicrob. Chemother. 2012;67:2793-2803

Rule No Rule Comments

9.1 For Enterobacteriaceae intermediate

or resistant to any third-generation

(cefotaxime, ceftriaxone, ceftazidime)

or fourth-generation (cefepime)

oxyimino-cephalosporin, AND

susceptible to amoxycillin–clavulanate,

ampicillin–sulbactam or piperacillin–tazobactam, THEN report as tested and

enclose a warning on uncertain

therapeutic outcome for infections

other than urinary tract infections

(GRADE B)

With the exception of urinary

tract infections and

bloodstream infections

secondary to this origin, the

use of these combinations in

infections caused by ESBL

producers remains

controversial, and should be

approached with caution.

Leclercq R et al. CMI 2011

Definitive treatment of infections

In critically ill patients

Use ECOFF for Rx guidance

≤0.25

Cephalosporins

or BLBLIs

Carbapenem

Request for ESBL testing

ESBL-negative ESBL-positive

Deescalate to

Carbapenem-spare regimen

Continue with

carbapenems

2012

• α ι ι ά ο έ α α φισβη ού η ασφά ια ο ή σ ς φα οσ ο ι ώ ς αι ς ιάς σ σοβα ές οι ώ ις α ό ESBL

• ά ο αθό ο ο έ α ια βα έως άσχο ς ασθ ίς αι α οσο α ασ α έ ο ς

• H ο ή σ φα οσ ο ι ώ ί αι ασφα ής φόσο MIC<0.25 g/ml

• ά ο ο έ α ο οσ ί ο ήσ σ ασ ώ α ασ ο ίς βάσ ο α ιβιό α α α ό α αι σ βα ιαι ία ( ύ ισό ο ο ο οιη ι ό ή χο ηφό α φόσο ο ού αι οι

έ ισ ς όσ ις αι ο ασθ ής ί αι βα έ ς άσ

New CLSI and EUCAST Breakpoints

for Enterobactericeae

CLSI EUCAST

S R S R (>)

Imipenem 1 4 2 8

Meropenem 1 4 2 8

Doripenem 1 4 1 4

Ertapenem 0.5 2 0.5 1

Comparison of the efficacies of two different doses of doripenem against carbapenemase-producing K. pneumoniae isolates in immunocompromised and immunocompetent animals.

Bulik C C , Nicolau D P Antimicrob. Agents Chemother. 2010;54:4112-4115

MIC: 354=4, 356=8, 359=16

Simulated concentration–time

profiles of three different dosing

regimens of meropenem

Simulated target attainment

probabilities for 50% time above

the MIC (50% T > MIC) of three

different regiments of meropenem

Markogiannakis & Daikos CMI 2011

Carbapenem Monotherapy in 50 Patients with Serious CPE Infections

(Results compiled from 15 studies)

MIC

( g/ml)

No. of

patients

No. of

successes

No. of

failures

% failure

≤ 1 17 12 5 29.4

2 12 9 3 25

4 7 5 2 28.6

8 6 4 2 33.3

> 8 8 2 6 75

Tzouvelekis et al CMR 2012; 25: 682-707

Outcomes of infections caused by carbapenemase-producing Klebsiella pneumoniae, according to treatment regimen.

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

CID 2012

A significantly higher mortality rate

was observed among patients

treated with monotherapy (54.3% vs

34.1% in those who received combined

drug therapy; P = .02)

Combination of tigecycline, colistin,

and meropenem was associated with

lower mortality

(OR: 0.11; 95% CI: .02–.69; P = .01)

Treatment of Patients Infected with CPKP

• 12 pts received no active therapy

• 72 pts received one active drug

• 103 pts > 1 active drug

• 18 pts received Rx for <48 h and were excluded from the

analysis

• The pts who received 1 active drug were comparable

with those who received > 1 active drug in terms of

severity of underlying diseases, severity of sepsis, ICU

or no ICU stay

Cox Proportional Hazards Model of Factors Associated with

Mortality in 175 Patient with CPKP BSIs

Variable Hazards ratio P

Age 1.01 0.37

Mc Cabe

Ultimately fatal/non fatal

Rapidly fatal/non fatal

3.25

4.20

0.001

<0.001

Severity of sepsis

Severe sepsis/sepsis

Septic shock/sepsis

1.63

2.15

0.2

0.015

1 active vs >1 active

2.08

0.006

Daikos GL (unpublished data)

Outcome of Patients with CPKP

BSIs According to Treatment

Daikos GL (unpublished data)

Effect of treatment against CPKP BSIs (monotherapy vs combination therapy)

By severity of underlying disease

By severity of sepsis

Daikos GL (unpublished data)

Proposed Algorithm for the Treatment of

CPE Infections

Daikos GL Expert Review Anti-infective Therapy (December 2013)