Professional Documents
Culture Documents
Best antibiotic
Optimum effect
Bacterial eradication
&
clinical efficacy
Avoid toxicity
&
adverse effects
N = 2154
Kumar.
Kumar. Crit Care Med 2006;34:15892006;34:1589-1596
Underdosing
Toxicity
Immunocompromised
host
Resistance
Severe
infections
Reduced
elimination
Nosocomial pathogens
CRRT
Clinical data
Lipophilic antibiotics
General PK
Low Vd
Predominant renal Cl
Low intracellular penetration
High Vd
Predominant hepatic Cl
Good intracellular
penetration
Altered ICU PK
Increased Vd
Cl higher or lower
dependent on renal function
Vd largely unchanged
Cl higher or lower
dependent on hepatic
function
Examples
Beta-lactams
Aminoglycosides
Glycopeptiden
Linezolid
Colisitin
Fluoroquinolones
Macrolides
Lincoamides
Tigecycline
Sepsis
Increased Cardiac
Output
Leaky Capillaries
&/or altered
protein binding
Normal organ
function
End Organ
Dysfunction (e.g.
renal or hepatic)
Increased Cl
Increased Vd
Unchanged Vd
Decreased Cl
Normal plasma
concentrations
High plasma
concentrations
Low plasma
concentrations
T1/2 = 0.693 x Vd
Cl
Gold-standard: creatinine
clearance (2-hours CL?)
Hypalbuminemia
(e.g. cetriaxone 95%
albumin bound in normal
subjects)
Aanvoer
Aanvoer
SCUF
Effluent
CVVH
Teruggave
Substitutie
Substitutie
(pre of
of post
dilutie
dilutie)
Effluent
Aanvoer
Teruggave
teruggave
Teruggave
Dialysaat
Dialysaat
(pre of
of
post dilutie
dilutie)
Effluent
CVVHD
Effluent
CVVHDF
ClCVVH = SC X
QUF
[UF]
SC =
[Blood]
membrane
Hemofilter
Blood
Blood flow in
Ultrafiltrate
Basic principles
Extracorporeal clearance (ClEC) is usually considered clinically
significant only if its contribution to total body clearance
exceeds 25 - 30%
FrEC =
ClEC
ClEC + ClR + ClNR
Loading dose
Bouman.
Bouman. Curr Opin Crit Care;14:654Care;14:654-659
Unacceptable toxicity
Peak
IC90
Peak
Trough
Cmax
Cmin
IC50
Poor activity
Poor activity
Time after taking drug
Cmax / MIC
AUC0-24 / MIC
Time-dependent
Concentration-dependent
Penicillins
Aminoglycosides
Cephalosporins
Fluoroquinolones
Fluoroquinolones
Carbapenems
Metronidazole
Metronidazole
Monobactams
Daptomycin
Quinupristin
Macrolides
Azithromycin
Lincoamides
Glycopeptides
Linezolid
Tetracyclines
Ciprofloxacin
[ciprofloxacin]
80
70
60
50
40
30
20
10
0
t in hours
Cmax/MIC (>10)
AUC24/MIC
Ciprofloxacin: 100100-125
Schentag. J Chemother 1999 Dec;11(6):426Dec;11(6):426-39
AUC
200
180
160
140
120
100
80
60
40
20
0
1
11 13 15 17 19 21 23 25 27 29 31
patient
at MIC 0.25, 0.5, 1.0 and 2.0 mg/l for ciprofloxacin dosages ranging from 8003200 mg/day based on ICU patient population pharmacokinetics obtained at 800
mg/day
-lactam Pk/Pd
Time above MIC
How long?
For all bacteria?
For all -lactams?
Influence pharmacokinetics?
MIC90
Time above MIC
Time
10
20
30
40
50
60
70
80
90
10
20
30
40
50
60
70
80
90
Enterobacteriacieae
% T > MIC
S. Pneumoniae
% T > MIC
Ceftriaxon
38 (34-42)
39 (37-41)
Cefotaxime
38 (36-40)
38 (36-40)
Ceftazidime
36 (27-42)
39 (35-42)
Meropenem
22 (18-28)
Imipenem
24 (17-28)
P<0.05
The jury is still out on continuous infusion of betalactam antibiotics in critically ill patients
Advantages
Disadvantages
Time
required
(SD) (min:s)
Hourly
wages
()
Time costs
()
Materials
costs ()
Total costs
()
Volumetric
pump
5:04 (2:29)
21.90
01.85
02.06
03.91
Syringe pump
4:56 (2:03)
21.58
01.78
01.45
03.23
Bolus injection
9:21 (2:16)
74.09
11.59
00.10
11.69
Piggyback
infusion
5:51 (3:33)
19.75
01.93
03.47
05.40
Insertion of IV
catheter
10:15 (6:31)
23.51
04.02
04.30
08.32
Removal of IV
catheter
02:22 (0:36)
19.41
00.74
01.00
01.74
Dose
(mg)
Dosages
(n)
Drug
costs
() (A)
Average
time
(min:s)
Staff
costs ()
(B)
Material
costs ()
(C)
Admini
stration
costs ()
(B+C)
Total
daily
costs ()
(A+B+C)
Amoxicillin/
clavulanic acid
1000
/
200
07.35
12:21
03.99
04.35
08.34
15.69
Cefotaxime
1000
49.40
18:48
06.08
05.80
11.88
61.28
Erythromycin
1000
54.44
36:44
11.88
05.80
17.68
72.12
Gentamicin
320
20.34
03:39
01.18
01.45
02.63
22.97*
Pip/Tazo
2250
43.14
16:31
05.40
04.35
09.75
52.89
Data presented are the medication costs, the time expenditure required, the staff wage and the disposable
material costs for each of the antibiotics per day administrated via syringe pump. The figures quoted refer to
the total time for preparation and administration of each medication per day, averaged over wards and
indications studied. Costs are based on list prices provided by Dutch health care authorities. *If therapeutic
drug monitoring costs for gentamicin based on 24-hourly intervals would be included, the total costs would be
58.97 per day.
The jury is still out on continuous infusion of betalactam antibiotics in critically ill patients
Advantages
Disadvantages
Risk of underdosing
Hydrophylic antibiotic
Thank you!