Looking into the future: routine TDM for beta-lactams in ICU · Looking into the future: routine...
Transcript of Looking into the future: routine TDM for beta-lactams in ICU · Looking into the future: routine...
14/10/2015 14th ICTDMCT - Rotterdam, The Netherlands 1
Looking into the future: routine TDM for beta-lactams in ICU ?
Paul M. Tulkens, MD, PhD
Cellular and Molecular Pharmacology& Center for Clinical Pharmacy
Louvain Drug Research InstituteHealth Science Sector
Université catholique de LouvainBrussels, Belgium
14/10/2015 14th ICTDM&CT - Rotterdam, The Netherlands
Do we have a problem ?
1. Infections are (most often) treated with an antibiotic dosing regimen related to the severity of the disease rather than the susceptibility of the micro-organism ...
What is a "severe disease" ?
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Problem ... #2 (of many)
Clinicians tend to ask (and clinical microbiologists to provide only) "S – I – R" answers based on accepted breakpoints …
But, what is a breakpoint ?
GoodEvil
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In the good old time…
MIC (mg/L)
1 2 4 8 16 6432 2561280.50.250.125
mean serum concentration
Good !!
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No so old but still good time ….
MIC (mg/L)
Good !!
Bad !!
1 2 4 8 16 6432 2561280.50.250.125 1 2 4 8 16 6432 2561280.50.250.125
effective serum concentration
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Still good old time ….
MIC (mg/L)
Good !!
Bad !!
1 2 4 8 16 6432 2561280.50.250.125 1 2 4 8 16 6432 2561280.50.250.125
effective serum concentration
This is why microbiologists used the 2-fold dilution progression !
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But now, what do you do with this ?
MIC (mg/L) May be?
effective serum concentration ?
1 2 4 8 16 6432 2561280.50.250.125
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But now, what do you do with this ?
MIC (mg/L)
effective serumconcentration ?
1 2 4 8 16 6432 2561280.50.250.125or here ?
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But now, what do you do with this ?
MIC (mg/L)
1 2 4 8 16 6432 2561280.50.250.125
This where we have
problem #2
effective serumconcentration ?
or there ?
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Breakpoints do not make things easy
what do you do
with that ?
Problem #3: which is the correct parameter to take into account ?
• Why are β-lactams time-dependent ?
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oxacillin
-2 -1 0 1 2
-5
-4
-3
-2
-1
0
1
2
3
MIC
log concentration (mg/L)
∆lo
g C
FU (2
4h -
0h)
gentamicin
-2 -1 0 1 2
-5
-4
-3
-2
-1
0
1
2
3
MIC
log concentration (mg/L)
∆lo
g C
FU (2
4h -
0h)
phamacodynamic model of antibiotic response24 incubation at fixed concentrations
full susceptible MSSA
Problem #3: which is the correct parameter to take into account ?
• Why are β-lactams time-dependent ?
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phamacodynamic model of antibiotic response24 incubation at fixed concentrations
oxacillin
-2 -1 0 1 2
-5
-4
-3
-2
-1
0
1
2
3
Cmin - CmaxCmin - Cmax
MIC
log concentration (mg/L)
∆lo
g C
FU (2
4h -
0h)
gentamicin
-2 -1 0 1 2
-5
-4
-3
-2
-1
0
1
2
3
Cmin - Cmax
MIC
log concentration (mg/L)
∆lo
g C
FU (2
4h -
0h)
maximal activity in the Cmin-Cmax range
activity is concentration-dependent in the Cmin-Cmax
range
full susceptible MSSA
Problem #3: which is the correct parameter to take into account ?
• Why are β-lactams time-dependent ?
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phamacodynamic model of antibiotic response24 incubation at fixed concentrations
meropenem
-2 -1 0 1 2
-5-4-3-2-101234
Cmin - Cmax
MIC
log concentration (mg/L)
∆lo
g C
FU (2
4h -
0h)
What do you do
with this ?
Clinical P. aeruginosa
the Cmin/MIC ratio
becomes critical !
Problem #3: which is the correct parameter to take into account ?
• Are β-lactams really time-dependent ?
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phamacodynamic model of antibiotic response24 incubation at fixed concentrations
Clinical P. aeruginosa of increasing MIC
meropenem vs P. aeruginosa
-2 -1 0 1 2
-5-4-3-2-101234
Cmin - Cmax
MIC = 1
log concentration (mg/L)
∆lo
g C
FU (2
4h -
0h)
meropenem vs P. aeruginosa
-2 -1 0 1 2
-5-4-3-2-101234
Cmin - Cmax
MIC = 4MIC = 1
log concentration (mg/L)
∆lo
g C
FU (2
4h -
0h)
meropenem vs P. aeruginosa
-2 -1 0 1 2
-5-4-3-2-101234
Cmin - Cmax
MIC = 8
MIC = 1
log concentration (mg/L)
∆lo
g C
FU (2
4h -
0h)
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Solution for β-lactams: T > MIC…
• The same for all beta-lactams ?(Free fractions of the drug [Fu] ) ?
• The same for all micro-organisms ?• The same for all infections ?• Can you apply to all patients ?• How much / How frequent ?
(Static dose vs maximum effect ?)
You know it is "time above MIC", but…
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Concentration-time profile of a beta-lactam in volunteersVd = 20 L, ka = 1.2 h-1, ke = 0.3 h-1
There are variations of PK in individuals...
Unlike the Belgian 400 m run team, we are not all
(almost) equal
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What is, indeed, a standard patient ?
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Mouton, Int J Antimicrob Agents april 2002
0.20
1.20
2.20
3.20
4.20
5.20
6.20
7.20
8.20
9.20
10.20
11.20
12.20
13.20
14.20
15.20
16.20
17.20
18.20
19.20
0.00
1.25
2.50
3.75
5.00
6.25
7.50
8.75
10.0
0
11.2
5
12.5
0
13.7
5
15.0
0
16.2
5
17.5
0
18.7
5
20.0
0
21.2
5
22.5
0
23.7
5
0.95-1.000.90-0.950.85-0.900.80-0.850.75-0.800.70-0.750.65-0.700.60-0.650.55-0.600.50-0.550.45-0.500.40-0.450.35-0.400.30-0.350.25-0.300.20-0.250.15-0.200.10-0.150.05-0.100.00-0.05
Conc
Time
Prob
4h
10h
Concentration-time profile of a beta-lactam in patients with a simulation with a coefficient var. of 20 %
Variation of PK in individuals...
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What is, indeed, a standard patient ?
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Continuous Infusion of Ceftazidime (4 g/day) vs Conventional Schedule and Dosis (3 X 2 g/day) for Treatment of Ventilator-associated Pneumonia in Intensive Care
Units.P.F. Laterre, N. Baririan, H. Spapen, T. Dugernier, M. Simon, D. Pierard, H. Servais, C. Seral and P.M. Tulkens
Cliniques universitaires St-Luc & Université catholique de Louvain, Brussels; Akademische Ziekenhuis, Vrije Universiteit Brussel, Brussels; Clinique St-Pierre, Ottignies; Clinique St Joseph, Arlon; Belgium.
• ICAAC 2002 Poster no. A1 1402
• target level: 24 mg/L (max. MIC: 6 mg/L [EUCAST bkpt = 8 mg/L])
• loading dose: 10.8 mg/kg (assumed Vd: 0.4 L/kg)
• infusion: 4 g/day • assumed clearance: 102 ml/min (6.12 L/h)• drug diluted in 48 ml of water• infusion through motor-operated syringe at a
rate of 2 ml/h; • temperature 25°C or lower
target
observed(mean)
patients with continous administration of ceftazidime
But even then, serum levels remain difficult to predict with accuracy…
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Solution for β-lactams: T > MIC…
• The same for all beta-lactams ?(Free fractions of the drug [Fu] ) ?
• The same for all micro-organisms ?• The same for all infections ?• Can you apply to all patients ?• How much / How frequent ?
(Static dose vs maximum effect ?)
You know it is "time above MIC", but…
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How much time above MIC ?
• cefotaxime
• neutropenic mice
• K. pneumoniae
• pulmonary infection
100 % - Maximal effect ?
40 %Static dose ?
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It all depends on your patient !
40 %
Moderately severe infectionin a non-immunosuppressed patient
100 % ?
Severe infectionin an immunosuppressedpatient
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It all depends on your patient !
40 %
Moderately severe infectionin a non-immunosuppressed patient
100 % ?
Severe infectionin an immunosuppressedpatient
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But back to MIC …!
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But back to MIC …!
an ICU patient may require Cminat 4 x MIC !
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And do not forget about changes in MIC (low-level resistance) during treatment !
meropenem (n=28)
D0 DL0.125
0.25
0.5
1
2
4
8
16
32
64
128
256
*
piperacillin-tazobactam (n=31)
D0 DL
2
4
8
16
32
64
128
256
512
1024
*
MIC
(mg/
L)
Change in MIC of antibiotics used in empiric antipseudomonal therapy (nosocomial pneumonia; intensive care units) towards the isolate identified before onset of therapy (D0) vs. the last isolate (DL) collected from the same patient and with clonal similarity with the first isolate. Differences were analyzed using both raw and log2 transformed data and found significant by both non-parametric (Wilcoxon matched pair test) and parametric (two-tailed paired t-test) analysis.
Riou et al. Int J Antimicrob Agents. 2010 Dec;36(6):513-22.
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And do not forget about changes in MIC (low-level resistance) during treatment !
meropenem (n=28)
D0 DL0.125
0.25
0.5
1
2
4
8
16
32
64
128
256
*
piperacillin-tazobactam (n=31)
D0 DL
2
4
8
16
32
64
128
256
512
1024
*
MIC
(mg/
L)
Change in MIC of antibiotics used in empiric antipseudomonal therapy (nosocomial pneumonia; intensive care units) towards the isolate identified before onset of therapy (D0) vs. the last isolate (DL) collected from the same patient and with clonal similarity with the first isolate. Differences were analyzed using both raw and log2 transformed data and found significant by both non-parametric (Wilcoxon matched pair test) and parametric (two-tailed paired t-test) analysis.
Riou et al. Int J Antimicrob Agents. 2010 Dec;36(6):513-22.
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As a result, monitoring the serum levels of β-lactams has been proposed …
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But available methods are slow and complex,and do not measure the free concentration ...
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A clinical algorithm or a path to success...
Knowledge or ou “educated” suspicion of the causative agent
Pathology andepidemiology Local MIC data
Obtain an MICand free serum
levels
no
Use common dosage but with attention to PK/PD
yes
Adjust the dosage on a full PK/PD basis and continue
monitoring free blood levels
S / I / Ris
insufficient !!
Is the organism probably highly
susceptible ?
But what do we need ?
• a fast and reliable assay of the serum free fraction… results available within the period of the medical shift !
• a clear definition of the desired target for efficacy … and prevention of emergence of resistance… Cmin (or Css) at 4 x the MIC ?
• a clear definition of the maximal doses without unacceptable toxicity (convulsions…) … Cmax not exceed the value of an approved mode of administration ?
• an algorithm that calculates the next dose based on population PK but also on real data from the previous administration… adaptive PK/PD modeling
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Adjust the dosage on a full PK/PD basis and continue
monitoring free blood levels
A clinical algorithm or a path to success...
in ICU, the patient's situation changes rapidly !
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We can always dream …
difficult machinery
acrobatic algorithms
dead ends…
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But at the end …
light at the end of the tunnel…
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But at the end …
light at the end of the tunnel…
… and far above sea levelhttp://www.spiegel.de/international/zeitgeist/peak-of-insanity-dutch-dream-of-building-artificial-mountain-a-784085.htmlLast accessed: 13-10-2015
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Back-up
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But even then, serum levels remain are difficult to predict with accuracy…
Mouton, unpublished
5 10 15 2010
100
time h
conc
entra
tion
mg/
Lpatients with continous administration of ceftazidime
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0 1 3 42
Free
ser
um c
once
ntra
tion
(mg/
L)
Time after administration (h)
Which pharmacokinetic parameter drives the activity of β-lactams ?
MICfT > CMI
Time during whichthe free concentrationremains > MIC
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Solution for β-lactams: fT > MIC…
• The same for all beta-lactams ?(Free fractions of the drug [Fu] ) ?
• The same for all micro-organisms ?• The same for all infections ?• Can you apply to all patients ? • How much / How frequent ?
(Static dose vs maximum effect ?)
You know it is "free time above MIC", but…