5. Success Rate of Vancomycin in the
Treatment of MRSA BSIs
%Success
P=0.02
MIC g/ml
Sakoulas JCM 2004; 42:2398
6. 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
7. 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
8. 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
9. 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
10. MSSA: staphylococcal penicillins
MRSA: Vancomycin MIC
Vancomycin
– εIC ≤ 1ηg/ml
– MIC > 1ηg/ml
newer agent
• Pneumonia: Linezolid
• Bacteremia or ΙΕμ Daptomycin
• SSTI: Linezolid or Daptomycin
11. 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; ESBLproducing 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
13. 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 MIC Κα ο ε ο Κ
ό Απο ε α α
Ησ ύ α
ο ώ ιαφο ι ώ
ύ
ί αι σ ή
όχ ο Μ χα
ό Α οχ
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
14. Ceftazidime susceptibility of ~ 100 E. coli
producing CTX-M type ESBLs
Williamson DA Eur J Clin Microbiol Infect Dis 2011
15. Π οβ
Πα ά
α ισ οί
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
ς
Α ο ή σ ία φα οσ ο ί
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?
16.
17. f %T>MIC
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)
19. Monte Carlo Simulations and Target Attainment
Rates for IV Ceftriaxone 2g q24 h
MIC
0.5
1
2
4
8
40%
100
100
100
87
8
% T >MIC
50%
60%
100
100
100
100
99
93
58
25
1
0
D. Andes and W. A. Craig CMI 2005; 11 (Suppl 6): 10-17
70%
100
99
74
6
0
23. ~ 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
ο ού αι α σ σ ά οσο ο ι ά σ ή α α
Οι σ
θ α
ασ οί α ασ ο έα ί αι α ά
α βα έ
φόσο
ά
ίας
ο ί αι ο ή σ σ
άσ ο ς ασθ ίς
ασ ού
ι
ά
ι
αισθ σία αι
ι ο ή ια α ο ι ά σ
ς
αισθ σία σ ο α ιβιό α α
ίς α ιβιό α
α αι σ βα έ ς
Clin Infect Dis 2012; 54:167
24. 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
25. 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
26. Rule No
9.1
Rule
Comments
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
27. 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
Deescalate to
Carbapenem-spare regimen
ESBL-positive
Continue with
carbapenems
28. 2012
• α ι ι ά
ο έ α α φισβη ού η ασφά ια ο ή σ ς
ς αι
ς
ιάς σ σοβα ές οι ώ ις α ό ESBL
φα οσ ο ι ώ
•
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
29. New CLSI and EUCAST Breakpoints
for Enterobactericeae
CLSI
S
EUCAST
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
30. Comparison of the efficacies of two different doses of doripenem against carbapenemaseproducing K. pneumoniae isolates in immunocompromised and immunocompetent animals.
MIC: 354=4, 356=8, 359=16
Bulik C C , Nicolau D P Antimicrob. Agents Chemother.
2010;54:4112-4115
31. Simulated concentration–time
profiles of three different dosing
regimens of meropenem
Markogiannakis & Daikos CMI 2011
Simulated target attainment
probabilities for 50% time above
the MIC (50% T > MIC) of three
different regiments of meropenem
32. Carbapenem Monotherapy in 50 Patients with
Serious CPE Infections
(Results compiled from 15 studies)
MIC
( g/ml)
≤1
No. of
patients
17
No. of
No. of
successes failures
12
5
% failure
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
33. 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
34. 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)
35. 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
36. 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)
37. Outcome of Patients with CPKP
BSIs According to Treatment
Daikos GL (unpublished data)
38. Effect of treatment against CPKP BSIs
(monotherapy vs combination therapy)
By severity of underlying disease
Daikos GL (unpublished data)
By severity of sepsis
39.
40. Proposed Algorithm for the Treatment of
CPE Infections
Daikos GL Expert Review Anti-infective Therapy (December 2013)
