fabio silvio taccone, md department of intensive care ... · fabio silvio taccone, md department of...
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Fabio Silvio TACCONE, MDDepartment of Intensive Care
Hôpital Erasme - ULBBrussels (BELGIUM)
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Critical Illness
Adapted from : Roberts and Lipman. Springer 2007
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AUCAUC
TimeINJECTION
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DIFFUSION
CONVECTION
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Is it so simple?
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Drug’s Charge
Gibbs-Dohan Effect
Membrane absorption
Sulfonated Polyacrylonitrile - Amikacin
Sieving Coefficient
Amikacin (CAT) if albumin retention (AN)
Charged particles across the membrane
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Q filtration / Q dyalisate
Protein Binding
Residual CL
CVVHDF > CVVH
Renal and Hepatic
Oxacillin, Ceftriaxone, Micafungine
Too High = Decreased Sc
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Malone, AAC 2001
12 ICU septic pts12 ICU septic pts
4 x MIC4 x MIC
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ATB Dosing Pts Membrane Technique Results
Traunmuller2002
CEFTA 2g q8h 12 PSF CVVHMIC 4 OKMIC 8 NO
Allaouchich1997
CEFE 2g q12h 6 AN69 CVVH MIC 8 = 2/6 PK
Capellier1998
PIP 4g q8h 10 NR CVVH MIC 16 = OK
Valtonen2001
PIP 4g q8h 6 PSFCVVHDCVVH
MIC 16 OK
Valtonen2000
MERO0.5g q12h1g q12h
6 PSFCVVHDCVVH
MIC 2 OK
Krueger2000
MERO 0.5g q12h 8 PSF CVVHMIC 1 OKMIC 2 = 5/8
Robatel2003
MERO0.5g q12h1g q12h
15 PSF CVVHDF MIC 2 = 1g q12h
Giles2000
MERO 1g q 12h 10 PANCVVHCVVHDF
MIC 2 = OK
Ververs2000
MERO 0.5g q12h 5 NR CVVH MIC 2 = OK
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Trotman, Clin Infect Dis 2005
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0 20 40 60 80 100
Ade
quat
eC
once
ntra
tion
s(%
)
Piperacilline
Ceftazidime
Cefepime
Meropenem
Seyler, Crit Care 2011
DOSING < 48 hrs
n = 7
n = 7
n = 8
n = 12
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Seyler, Crit Care 2011
DOSING > 48 hrs
n = 15
n = 4
n = 7
n = 9
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Insufficient doses of -lactams in Early phase (day 1-2) especially in Cephalo / PTAZ (12g/d) Higher MIC pathogens
PTAZ : 2.25g q6h CEFE: 1-2g q12h MERO: 1g q12h CEFTA: 1-2g q12h
4g q6h4g q6h2g q8h2g q8h1g q8h1g q8h2g q8h2g q8h
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Beumier,Critical Care 2014
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Beumier,Critical Care 2014
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Beumier,Critical Care 2014
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Beumier,Critical Care 2014
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Inhibition of GABA-A receptor function
Neurons hyper-excitability
Depolarization of the post-synaptic membrane
Seizure threshold lowered
Mechanism of β-lactams neurotoxicity
Fujimoto Br J Pharmacol. 1995Sugimoto Neuropharmacology 2003Chow Eur J Microbiol Infect Dis 2005
Competitive vs. non-competitive binding
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TimeTime
MICMIC8 8 g/g/mLmL
Cmax/MIC > 8Cmax/MIC > 8--1010
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Taccone FS et al. Int J Antimicrob Agents 2011Taccone FS et al. Int J Antimicrob Agents 2011
MICMIC
8 x MIC8 x MIC9/13 pts9/13 pts
Median time to < 5 g/mL : 34 [15-76] hrsMedian time to < 5 Median time to < 5 g/mL : 34 [15g/mL : 34 [15--76] hrs76] hrs
3/13 non-toxic Cmin
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CMI: 0.25 µg/ml
CMI: 0.50 µg/ml
CMI: 1 µg/ml
Drusano et al.
MIC: 16 g/mL ??
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Layeux, Antimicrob Agents Chemoth 2010
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Layeux, Antimicrob Agents Chemoth 2010
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TimeTime
MICMIC
AUC = dose 24h / CLAUC = dose 24h / CL
AUC/MIC > AUC/MIC > 400400
Moise-Broder, Clin Pharmacokin 2004
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But this strategy is poorly effective against MIC > 1 But this strategy is poorly effective against MIC > 1 g/mLg/mL
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CI = 20 CI = 20 –– 30 mcg/mL 30 mcg/mL (= AUC/MIC > 400)(= AUC/MIC > 400)
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TimeTime
MIC = 1MIC = 1
AUCAUC00--2424 = (20x24)/1 = 480= (20x24)/1 = 480
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No evidence of better clinical outcome when CI is used
Reduced incidence of nephrotoxicity
No studies in septic patients about which is the best regimen during CRRT
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LD = 15 mg/kgLD = 15 mg/kgDD = 20DD = 20--30 mg/kg30 mg/kg
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Beumier, J Antimicrob Agents 2013Beumier, J Antimicrob Agents 2013
35 mg/kg LD + 14 mg/kg daily
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200 mg tidIs it enough?
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Colistin concentrations were below the current MIC breakpoints, and the area under the concentration-time curve for the free, unbound fraction of the drug
over 24 h in the steady state divided by the MIC (fAUC/MIC) was lower than recommended, suggesting that a dosage regimen of 160 mg CMS every 8 h (q8h)
is inadequate
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Daptomycin once-daily dosing is appropriate in patients undergoing CRRT
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Loading dose only depends on: Target plasma level Vd Not require adaptation
No dosage adaptations: High protein binding Non renal elimination
Increase of maintenance dose: Clinical relevant CRRT removal
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-lactams Higher than recommended drug regimens to treat less susceptible GNB Rapid adjustment of daily dose (48 hrs?) Intensity of CRRT ? Continuous Infusion ?
Aminoglycosides Loading dose of at least 25 mg/kg Dose adjustment on pathogen susceptibility (MIC) TDM to avoid drug accumulation
Vancomycin Insufficient drug concentrations with standard regimens CI > II … but not better clinical response
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We know everything about antibiotics except how much to give …
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