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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)