atb en dialisis[1]
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Clin Pharmacokinet 2007; 46 (12): 997-1038REVIEW ARTICLE 0312-5963/07/0012-0997/$44.95/0
© 2007 Adis Data Information BV. All rights reserved.
Pharmacokinetic Considerations forAntimicrobial Therapy in PatientsReceiving Renal Replacement TherapyFederico Pea,1 Pierluigi Viale,2 Federica Pavan1 and Mario Furlanut1
1 Institute of Clinical Pharmacology and Toxicology, Department of Experimental and ClinicalPathology and Medicine, Medical School, University of Udine, Udine, Italy
2 Clinic of Infectious Diseases, Department of Medical and Morphological Research, MedicalSchool, University of Udine, Udine, Italy
ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9971. Principles of Drug Removal during Renal Replacement Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 999
1.1 Working Differences between Haemodialysis and Haemofiltration . . . . . . . . . . . . . . . . . . . . . . . 9991.2 Characteristics of Drugs and Continuous Renal Replacement Therapy (CRRT) Devices
Affecting Extracorporeal Clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10012. Rationales for Appropriate Dosage Adjustment of Antimicrobials during CRRT: the Importance
of Pharmacokinetic-Pharmacodynamic Relationships . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10043. Pharmacokinetics of Antimicrobials during CRRT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1005
3.1 Hydrophilic Antimicrobials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10053.1.1 Carbapenems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10053.1.2 Penicillins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10183.1.3 Cephalosporins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10203.1.4 Aminoglycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10253.1.5 Glycopeptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1026
3.2 Lipophilic Antibacterials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10283.2.1 Fluoroquinolones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10283.2.2 Oxazolidinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10313.2.3 Others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1032
3.3 Antifungal Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10323.3.1 Polyenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10323.3.2 Triazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1033
4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1034
Continuous renal replacement therapy (CRRT), particularly continuousAbstractvenovenous haemofiltration (CVVH) and continuous venovenous haemodiafiltra-tion (CVVHDF), are gaining increasing relevance in routine clinical managementof intensive care unit patients. The application of CRRT, by leading toextracorporeal clearance (CLCRRT), may significantly alter the pharmacokineticbehaviour of some drugs. This may be of particular interest in critically ill patientspresenting with life-threatening infections, since the risk of underdosing withantimicrobial agents during this procedure may lead to both therapeutic failureand the spread of breakthrough resistance. The intent of this review is to discussthe pharmacokinetic principles of CLCRRT of antimicrobial agents during theapplication of CVVH and CVVHDF and to summarise the most recent findings on
998 Pea et al.
this topic (from 1996 to December 2006) in order to understand the basis foroptimal dosage adjustments of different antimicrobial agents.
Removal of solutes from the blood through semi-permeable membranes duringRRT may occur by means of two different physicochemical processes, namely,diffusion or convection. Whereas intermittent haemodialysis (IHD) is essentiallya diffusive technique and CVVH is a convective technique, CVVHDF is acombination of both. As a general rule, the efficiency of drug removal by thedifferent techniques is expected to be CVVHDF > CVVH > IHD, but indeedCLCRRT may vary greatly depending mainly on the peculiar physicochemicalproperties of each single compound and the CRRT device’s characteristics andoperating conditions. Considering that RRT substitutes for renal function inclearing plasma, CLCRRT is expected to be clinically relevant for drugs withdominant renal clearance, especially when presenting a limited volume of distri-bution and poor plasma protein binding. Consistently, CLCRRT should be clinical-ly relevant particularly for most hydrophilic antimicrobial agents (e.g. β-lactams,aminoglycosides, glycopeptides), whereas it should assume much lower relevancefor lipophilic compounds (e.g. fluoroquinolones, oxazolidinones), which general-ly are nonrenally cleared. However, there are some notable exceptions: ceftriax-one and oxacillin, although hydrophilics, are characterised by primary biliaryelimination; levofloxacin and ciprofloxacin, although lipophilics, are renallycleared. As far as CRRT characteristics are concerned, the extent of drug removalis expected to be directly proportional to the device’s surface area and to bedependent on the mode of replacement fluid administration (predilution orpostdilution) and on the ultrafiltration and/or dialysate flow rates applied.
Conversely, drug removal by means of CVVH or CVVHDF is unaffect-ed by the drug size, considering that almost all antimicrobial agents have molecu-lar weights significantly lower (<2000Da) than the haemofilter cut-off(30 000–50 000Da). Drugs that normally have high renal clearance and thatexhibit high CLCRRT during CVVH or CVVHDF may need a significant dosageincrease in comparison with renal failure or even IHD. Conversely, drugs that arenormally nonrenally cleared and that exhibit very low CLCRRT during CVVH orCVVHDF may need no dosage modification in comparison with normal renalfunction. Bearing these principles in mind will almost certainly aid the manage-ment of antimicrobial therapy in critically ill patients undergoing CRRT, thuscontaining the risk of inappropriate exposure. However, some peculiar pathophys-iological conditions occurring in critical illness may significantly contribute tofurther alteration of the pharmacokinetics of antimicrobial agents during CRRT(i.e. hypoalbuminaemia, expansion of extracellular fluids or presence of residualrenal function). Accordingly, therapeutic drug monitoring should be considered avery helpful tool for optimising drug exposure during CRRT.
Renal replacement therapy (RRT) is an approach and so some of these techniques, particularly contin-originally employed mainly for blood purification in uous venovenous haemofiltration (CVVH) and con-the presence of chronic renal impairment, as in the tinuous venovenous haemodiafiltration (CVVHDF),case of intermittent haemodialysis (IHD). More re- are gaining increasing relevance in routine clini-cently, continuous RRT (CRRT) has been intro- cal management of intensive care unit (ICU) pa-duced as adjunctive therapy to treat critically ill tients.[1,2] Additionally, some researchers have be-patients in the presence of multiple organ failure, lieved that the excessive production of pro-inflam-
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Disposition of Antimicrobials during CRRT 999
matory cytokines as a host response to infection 1. Principles of Drug Removal duringRenal Replacement Therapiesduring sepsis may be responsible for the cascade of
events leading to multiple organ failure.[3] Consist-ently, removal of such cytokines by means of CRRT 1.1 Working Differences betweenhas been proposed as powerfully effective pathoge- Haemodialysis and Haemofiltrationnetic treatment of sepsis to protect patients fromunfavourable outcomes.[4] Removal of solutes from blood through semi-
permeable membranes during RRT may occur byRegardless of opinion on the role of CRRT, itmeans of two different physicochemical processes:has been proven that the growing confidence innamely, diffusion or convection (table I).CRRTs has resulted in improved survival of critical-
Diffusion, which represents the typical workingly ill patients with acute renal failure.[5] However, principle of haemodialysis (figure 1), occurs pas-it should not be overlooked that the application sively in counter-current with respect to blood flowof CRRT, by leading to extracorporeal clearance and is driven by the gradient of concentration. Addi-(CLCRRT), may significantly alter the pharmacokin- tionally, the clearance efficiency during IHD isetic behaviour of some drugs. greater for small drugs (figure 2). However, the cut-
off of modern synthetic dialyser membranes (the so-Of note, the extent of CLCRRT may be of particu-called high-flux membranes) is significantly largerlar interest in critically ill patients presenting withthan that of the old cuprophane dialyser membraneslife-threatening infections, since the risk of un-(<1000Da). This means that although high molecu-
derdosing with antimicrobial agents during this pro- lar weight may protect some large molecules (name-cedure may lead to both therapeutic failure and the ly, the glycopeptides vancomycin and teicoplanin,spread of resistance. the streptogramin combination of quinupristin/dal-
fopristin, and the polimixin colistin) from removalIt is now widely accepted that the definition ofwhen using old cuprophane membranes, this no‘inappropriate antimicrobial therapy’ in the treat-longer occurs when using modern high-flux mem-ment of critically ill patients refers not only to anbranes.unsuitable drug choice in terms of the spectrum of
Conversely, convection, which represents theactivity, but also to potential underexposure at thetypical working process of haemofiltration (figure
infection site as a consequence of an inadequate 3), occurs actively and more rapidly thanks to adosing regimen due to the patient’s particular patho- pump-driven pressure gradient. Interestingly, drugphysiological status and/or iatrogenic conditions.[6,7]
removal by means of haemofiltration is independentfrom drug molecule size, considering that almostThe aim of this review is to discuss the pharma-
cokinetic principles of CLCRRT of antimicrobialagents during the application of CVVH and CV-VHDF and to summarise the most recent findingson this topic in order to understand the basis foroptimal dosage adjustments of different antimicro-bial agents. The literature search was done throughMEDLINE and refers to articles published from1996 to December 2006.
In order to better understand the rationales fordosage adjustments of antimicrobials during RRT, itmay be useful to describe the working principles ofthe most frequently applied techniques and to definewhich factors may affect drug removal.
Table I. Comparison of characteristics of drug removal duringhaemodialysis vs haemofiltration
Characteristic Haemodialysis HaemofiltrationDrug removal By diffusion across By convection across
a semi-permeable a semi-permeablemembrane membrane
Process Passive Active
Principle Counter current flow Pump-driven pressuregradient
Conditioning Conditioned by drug Unconditioned by drugmolecular weight molecular weight
Equilibrium Long Rapidtime
Replacement Not needed Needed to reconstitutefluid blood volume (pre- or
postdilution mode)
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
1000 Pea et al.
On the basis of the type of body access and therelative role of diffusion and/or convection, RRTsmay be classified into several different types (tableII). The most frequently applied techniques are sure-ly represented by IHD on the one hand and CVVHor CVVHDF on the other hand. Whereas IHD isessentially a diffusive technique, CVVH is a con-vective technique and CVVHDF is a combination ofboth. Interestingly, CVVHDF is sometimes applied
Dialysate
Dialysate
BFR
Dialysis fluid in Dialysate out
BFR
Fig. 1. Schematic representation of intermittent haemodialysis.BFR = blood flow rate.
in very critically ill patients presenting with sepsisand acute renal failure, with the intent of enablingall antimicrobial agents have molecular weights sig-sufficient removal of metabolites through perfusionnificantly lower than the haemofilter cut-offof the haemofilter with the dialysate.[2] Indeed, al-(30 000–50 000Da), whose high value has the intentthough this approach is currently still a very ques-of enabling removal of inflammatory cytokines. Ad-tionable issue, what should be mentioned is the factditionally, since (similarly to the glomerular filtra-that in these circumstances, very high flow rates oftion in the kidney) the haemofiltration process pro-up to 6 L/h may be applied.duces an ultrafiltrate, refilling with a substitution
fluid is required in order to preserve an adequate As a general rule, the efficiency of drug re-circulatory volume. Of note, replacement may be moval by the different techniques is expected to beapplied before or after blood filtration, that is in CVVHDF > CVVH > IHD, but indeed CLCRRT maypredilution or in postdilution mode, and this may vary greatly, mainly depending on the peculiarobviously affect the entity of drug clearance to a physicochemical properties and pharmacokineticdifferent extent. behaviour of each single compound.
0 500 1000
Molecular weight (Da)
1500 2000
MetronidazoleImipenem
CiprofloxacinLinezolid
AmpicillinAmoxicillin
LevofloxacinGatifloxacinClindamycin
AztreonamMeropenemMoxifloxacinCefotaxime
CefepimeCefpiromePiperacillin
CeftazidimeCeftriaxoneRifampicin
ColistinVancomycin
Q/DTeicoplanin
Fig. 2. Molecular weight of some antimicrobial agents. Q/D = quinupristin/dalfopristin.
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Disposition of Antimicrobials during CRRT 1001
Replacement fluid
Post-dilution Pre-dilution
BFRBFR
UF
Fig. 3. Schematic representation of continuous venovenous haemofiltration. BFR = blood flow rate; UF = ultrafiltrate.
1.2 Characteristics of Drugs and Continuous According to this distinction, it seems clearRenal Replacement Therapy (CRRT) Devices that CLCRRT should be clinically relevant forAffecting Extracorporeal Clearance most hydrophilic agents, whereas it should assume
much lower relevance for the lipophilic compoundsConsidering that RRT substitutes for renal func- which, in general, are nonrenally cleared. Obvi-
tion in clearing plasma, CLCRRT is expected to be ously, some notably exceptions to this general ruleclinically relevant for drugs with dominant renal may exist. Ceftriaxone and oxacillin, although hy-clearance (CLR), especially when presenting a limit- drophilics, are characterised by primary biliaryed volume of distribution (Vd) and poor plasma elimination, and so they are not expected to beprotein binding. significantly removed by CRRT; on the other hand,
The pharmacokinetic parameters of the most rel-levofloxacin and ciprofloxacin, although lipophilics,
evant antimicrobial agents assessed in healthy vol-are renally cleared, and so they might be removed byunteers are shown in table III. Comparison of theseCRRT.data with those observed during the application of
CRRT enhances understanding of the relevance thatCRRT may have for extracorporeal removal of eachsingle drug.
In this respect, it may be useful to split an-timicrobials, according to their solubility, into hy-drophilic or lipophilic compounds (figure 4).[6,7] Hy-drophilic compounds, which include β-lactams, gly-copeptides and aminoglycosides, are unable topassively cross the plasmatic membrane of theeukaryotic cell, and so their distribution is limitedonly to the plasma and to the extracellular space, andthey are usually excreted via the renal route asunchanged drug. On the contrary, lipophilic agents,which include macrolides, fluoroquinolones, tetra-cyclines, chloramphenicol, rifampicin (rifampin)and linezolid, may freely cross the plasmatic mem-brane of the eukaryotic cells, and so they are widelydistributed into the intracellular compartment andmust often be metabolised through different path-ways before elimination.
Table II. Characteristics of some renal replacement therapies(adapted from Joy et al.,[8] with permission)
Procedure Removal by Removal by Vasculardiffusion convection access
IHD + + + + + Fistula or VV
IHDF + + + + + + Fistula or VV
CAPD + + + + + None
CAVH – + + + + AV
CVVH – + + + + VV
CAVHD + + + + + AV
CVVHD + + + + + VV
CAVHDF + + + + + + AV
CVVHDF + + + + + + VVAV = artery and vein; CAPD = continuous ambulatory peritonealdialysis; CAVH = continuous arteriovenous haemofiltration;CAVHD = continuous arteriovenous haemodialysis; CAVHDF =continuous arteriovenous haemodiafiltration; CVVH = continuousvenovenous haemofiltration; CVVHD = continuous venovenoushaemodialysis; CVVHDF = continuous venovenoushaemodiafiltration; IHD = intermittent haemodialysis; IHDF =intermittent haemodiafiltration; VV = vein and vein; – indicates notoccurring; + indicates mild; + + indicates moderate; + + + indicatesmarked; + + + + indicates intense.
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
1002 Pea et al.
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Tab
le I
II. O
verv
iew
of
the
phar
mac
okin
etic
(P
K)
para
met
ers
of s
ome
antim
icro
bial
age
nts
in h
ealth
y vo
lunt
eers
a
Dru
gM
W (
Da)
t1 /2
(h)
Vss
(L)
CL
(mL/
min
)C
L R (
mL/
min
)C
L R:
CL
ratio
PB
(%
)A
nti
bac
teri
als
Car
bape
nem
s
mer
open
em[9
]38
3.47
1.0
14–2
1b18
6.67
140
0.75
9
imip
enem
[9]
317.
370.
9–1.
11b
14–2
1b25
0.0
112.
5–12
5.0b
0.45
–0.5
0b9
Pen
icill
ins
flucl
oxac
illin
[10]
453.
882.
120
.612
2.5
880.
7296
pipe
raci
llin[1
1]51
7.56
0.75
10.6
418
1.72
102.
580.
5630
tazo
bact
am[1
1]30
0.29
0.89
11.9
184.
8712
5.44
0.68
30
Cep
halo
spor
ins
cefe
pim
e[12]
480.
572.
3218
.414
313
20.
9216
–19b
cefp
irom
e[13]
514.
591.
7618
.114
211
3.6
0.80
10
cefta
zidi
me[1
4]54
6.58
1.58
12.4
613
1.83
122.
50.
9318
.7
ceftr
iaxo
ne[1
5,16
]55
4.59
8.8
10.7
14.2
8.6
0.61
90
Am
inog
lyco
side
s
netil
mic
in[1
7,18
]47
5.58
247
.691
670.
740
Gly
cope
ptid
es
vanc
omyc
in[1
9,20
]14
49.2
78.
141
.16
84.8
0.70
37
teic
opla
nin[2
1,22
]18
77.6
692
.347
.614
.70
140.
9596
Flu
oroq
uino
lone
s
cipr
oflo
xaci
n[23]
331.
344
137.
944
8.33
318.
330.
7120
–40b
levo
floxa
cin[2
4,25
]37
0.38
6–8b
7713
310
6.4
0.80
24–3
8b
mox
iflox
acin
[26,
27]
401.
4313
222
248.
3350
.50.
2030
–50b
oflo
xaci
n[28,
29]
361.
376.
6713
4.4
227.
519
00.
7415
Oxa
zolid
inon
es
linez
olid
[30,
31]
337.
354.
830
–50b
97.3
25.9
0.27
31
An
tifu
ng
als
Pol
yene
s
amph
oter
icin
B[3
2,33
]92
4.08
357
15.3
4.78
0.32
90–9
5b
amph
oter
icin
B li
pid
com
plex
[33]
924.
0891
7043
6
lipos
omal
am
phot
eric
in B
[32,
33]
924.
087.
711
.30.
580.
05
Azo
les
fluco
nazo
le[3
4]30
6.27
29.7
5221
.03
12.9
10.
6111
–12b
aT
he v
alue
s ar
e ex
pres
sed
as m
eans
unl
ess
spec
ified
oth
erw
ise.
bR
ange
.
CL
R =
ren
al c
lear
ance
; C
L =
tot
al b
ody
clea
ranc
e; M
W =
mol
ecul
ar w
eigh
t; P
B =
pla
sma
prot
ein
bind
ing;
t1 /2
= e
limin
atio
n ha
lf-lif
e; V
ss =
vol
ume
of d
istr
ibut
ion
at s
tead
y st
ate.
Disposition of Antimicrobials during CRRT 1003
As far as the Vd is concerned, the larger it is, theless likely it is that the drug will be removed byRRT, considering that the Vd reflects where a givendrug is compartmentalised in the body. According-ly, during RRT, extracellularly located hydrophilicagents will be much more promptly removable fromthe body than intracellularly accumulated lipophilicones.
This means that although for most hydrophiliccompounds, supplemental dosing may often be ne-cessary during CRRT in comparison with anephricpatients, for most lipophilic drugs with a wide Vd,even if the extraction across the RRT filter is 100%,only a small fraction of the drug present in the bodywill be removed, thus rendering supplemental dos-ing unnecessary.
Hydrophilic
• β-lactams • penicillins • cephalosporins • carbapenems • monobactams• Glycopeptides• Aminoglycosides
• Limited volume of distribution• Inability to passively diffuse through plasmatic membrane of eukariotic cells• Inactive against intracellular pathogens• Eliminated renally as the unchanged drug
Lipophilic
• Macrolides• Fluoroquinolones• Tetracyclines• Chloramphenicol• Rifampicin• Linezolid
• Large volume of distribution• Freely diffuse through plasmatic membrane of eukariotic cells• Active against intracellular pathogens• Eliminated often after hepatic metabolism
Fig. 4. Classification of antimicrobials according to their physico-chemical properties.
Finally, considering that because of the haemofil-ter’s cut-off, only the unbound moiety of a given membrane, a process whose extent is expected to bedrug is available for extracorporeal elimination, the maximal immediately after starting RRT and then tohigher the plasma protein binding is (figure 5), the progressively decrease over time until filter exhaus-lower the drug clearance will be. This concept is tion.exemplified by the sieving coefficient (Sc), which is
Accordingly, caution was expressed regardingthe ratio between the drug concentrations in thecalculation of the supplemental dose of a given drugultrafiltrate and in plasma, and may be defined byduring haemofiltration only on the basis of the theo-equation 1:retical unbound fraction instead of the Sc.[39]
As far as the CRRT device characteristics areconcerned, the extent of drug removal is expected to
CUF
CPSc =
be directly proportional to the device’s surface area(Eq. 1)and to be dependent on the mode of replacementwhere CUF is the drug concentration in the ultrafil-fluid administration and on the ultrafiltration and/ortrate and Cp is the drug concentration in the plasma.dialysate rates applied.The Sc values of some antimicrobials are shown in
figure 6. When the replacement fluid to reconstitute bloodvolume is added in the postdilution mode, name-Interestingly, whereas in most cases the Sc duringly after haemofiltration, drug clearance duringCVVH in humans should equate to the unboundhaemofiltration (CLHF) will equate to the ultrafiltra-moiety of the drug[35] (as documented, for example,tion rate (QUF) [equation 2]:for 66 different compounds by Golper)[36] it may,
however, sometimes be significantly different. CLHF(postdilution) = QUF × ScIndeed, some factors might explain this finding.
(Eq. 2)First, in critically ill patients presenting with hy-poalbuminaemia, the unbound fraction of normally Conversely, in the predilution mode, consideringmoderately to highly bound drugs may vary, and that plasma has been diluted by the substitution fluidso drug clearance may be increased in these circum- before entering the haemofilter, drug clearance willstances.[36,37] Interestingly, it has recently been be lower due to a dilution factor (DF; equation 3):shown that this may be clinically relevant especial-ly for the glycopeptides teicoplanin[38] and van- DF =
QBF
QBF + QRFcomycin.[35] Additionally, drug extraction may befurther increased by adsorption to the haemofilter (Eq. 3)
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
1004 Pea et al.
where QBF is the blood flow rate and QRF is the ing which concentrations are maintained above thereplacement flow rate. Therefore, drug clearance minimum inhibitory concentration of the aetiologi-will be (equation 4): cal agent (T>MIC) is considered the most rele-
vant pharmacodynamic parameter. In this regard,exposure may be optimised by maintaining the mini-CLHF(predilution) =
QUF × Sc × QBF
QBF + QRFmum plasma concentration above the MIC(Eq. 4)(Cmin>MIC),[7] maximal efficacy being ensured inthe presence of a Cmin four to five times the MIC.2. Rationales for Appropriate DosageAccordingly, for these agents, the most suitableAdjustment of Antimicrobialsapproach to preserve efficacy during CRRT is toduring CRRT: the Importance ofmaintain the frequency of drug administration whilePharmacokinetic-Pharmacodynamicmodifying the amount of each single dose.Relationships
Conversely, for concentration-dependent antimi-Drugs that are significantly cleared during CV-crobials, namely aminoglycosides and fluoroquino-VH or CVVHDF may need significant dosage in-lones, the most important pharmacodynamic para-creases in comparison with renal failure or evenmeters are represented by the ratios between theIHD. This may be performed by increasing thepeak plasma concentration (Cmax) and the MIC,amount of each single dose, or conversely by short-with optimal exposure in the presence of a Cmax/ening the dosing interval. The approach taken willMIC ratio of >8–10, and between the area under thediffer according to the type of antimicrobial activi-plasma concentration-time curve (AUC) and thety, which may be time dependent or concentra-MIC, with optimal exposure in the presence of antion dependent. For time-dependent antimicrobials,AUC/MIC ratio of >100. Accordingly, to optimisenamely β-lactams, macrolides, glycopeptides, ox-efficacy with these agents during CRRT, it may beazolidinones and azole antifungals, the time dur-
Plasma protein binding (%)
0 20 40 60 80 100
Meropenem
Metronidazole
Ceftazidime
Cefepime
Amoxicillin
Imipenem
Gatifloxacin
Ampicillin
Piperacillin
Ciprofloxacin
Levofloxacin
Linezolid
Cefotaxime
Moxifloxacin
Vancomycin
Aztreonam
Ceftriaxone
Teicoplanin
Clindamycin
Fig. 5. Plasma protein binding of some antimicrobial agents.
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Disposition of Antimicrobials during CRRT 1005
0.0 0.2 0.4 0.6
Sieving coefficient
0.8 1.0 1.2
Oxacillin
Teicoplanin
Ceftriaxone
Clindamycin
Ciprofloxacin
Penicillin
Ampicillin
Vancomycin
Gentamicin
Piperacillin
Metronidazole
Ceftazidime
Imipenem
Tobramycin
Netilmicin
Amikacin
Cefotaxime
Fig. 6. Sieving coefficients of some antimicrobial agents.
more useful to extend the dosing interval while sible in the presence of multiple references, somemaintaining a fixed dosage. suggestions on how to interpret the data and how to
proceed with dosage adjustments are provided. ForBearing these principles in mind will almost cer-clarity, it should be considered that in the descrip-tainly aid the management of antimicrobial therapytion of the different studies, the various flow ratesin critically ill patients undergoing CRRT, thus con-(QUF and/or the dialysate flow rate [QD]) in condi-taining the risk of inappropriate exposure.tioning CLCRRT have been qualitatively defined asFinally, it is worth noting that in critically illfollows: low when <0.5 L/h, moderate when approx-patients, it is mandatory to consider the severity ofimately 1.0 L/h, high when approximately 1.5–2 L/hthe infection and the susceptibility pattern of patho-and very high when >2.5–3.0 L/h.gens involved in the infections in order to contain
the mortality risk of infection. Accordingly, in the3.1 Hydrophilic Antimicrobialspresence of a severe life-threatening infection po-
tentially caused by less susceptible pathogens with Generally speaking, most hydrophilic antimicro-higher MICs (e.g. Pseudomonas aeruginosa), a bials exhibit a low Vd and high CLR in healthyhigher starting dose would probably be prudent. volunteers, and so they are expected to be highly
CRRT removable. Interestingly, given their low Vd,3. Pharmacokinetics of Antimicrobials the application of high CRRT flow rates may mark-during CRRT edly increase the extent of elimination since the drug
is essentially confined in the plasma and in the tissueThe most recent and relevant studies on the
interstitium.pharmacokinetics of antimicrobials during the appli-
3.1.1 Carbapenemscation of CVVH or CVVHDF since 1996 are listedin table IV. In this review, the studies have been The carbapenems imipenem/cilastatin and mer-summarised for each compound and, whenever fea- openem exhibit low Vd, low plasma protein binding
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
1006 Pea et al.
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Tab
le I
V.
Ove
rvie
w o
f th
e ph
arm
acok
inet
ics
(PK
) of
som
e an
timic
robi
al a
gent
s du
ring
cont
inuo
us r
enal
rep
lace
men
t th
erap
y (C
RR
T)
and
dosa
ge r
ecom
men
datio
ns
Dru
g;R
esid
ual
CR
RT
RF
aM
embr
ane/
QB
FQ
UF
QD
CL
Sca
CL C
RR
TC
L CR
RT
t1 /2
Com
men
t an
d do
sage
dosa
gea
CL C
Rsu
rfac
e(m
L/(m
L/h)
a(m
L/h)
a(m
L/(m
L/m
in)a
(% o
f(h
)are
com
men
datio
n(m
L/m
in)
area
am
in)a
min
)aC
L)a
An
tib
acte
rial
s
Car
bape
nem
s
mer
open
em;
NS
CV
VH
Pos
tP
S/
150
2748
143.
7N
S49
.734
.62.
331g
q8h
app
ropr
iate
for
1g S
D (
9)[4
0](A
RF
)0.
43m
2in
fect
ions
cau
sed
bysu
scep
tible
bac
teria
(pla
sma
conc
entr
atio
n4.
3 m
g/L
afte
r 6h
)
mer
open
em;
1.3
CV
VH
NS
AN
6916
011
0052
.01.
1722
.042
.38.
7O
bser
ved
Cm
in 7
.3 m
g/L;
0.5g
q8h
0.5g
q12
h ap
prop
riate
or q
12h
(9)[4
1]
mer
open
em;
NS
CV
VH
NS
AN
6920
016
5076
.20.
6317
.222
.56.
370.
5g q
12h
appr
opria
te0.
5g q
12h
(5)[4
2](A
RF
)fo
r in
fect
ions
cau
sed
by s
usce
ptib
le b
acte
ria(C
min
3.0
mg/
L)
mer
open
em;
NS
CV
VH
Pre
(1)
,A
N69
/10
1600
82.9
NS
24.4
29.4
3.63
Obs
erve
d T
>4
mg/
L0.
5g q
12h
(8)[4
3](A
RF
)po
st (
7)0.
9m2
= 8
.22h
Obs
erve
d T
>8
mg/
L=
4.7
2h0.
5g q
12h
appr
opria
tefo
r in
fect
ions
cau
sed
bysu
scep
tible
bac
teria
mer
open
em;
NS
CV
VH
Pos
tA
N69
/15
017
0060
.50.
9525
.041
.35.
891.
0g q
12h
appr
opria
te1.
0g q
12h
(10)
[44]
(AR
F)
(5)
0.9m
2fo
r in
fect
ions
cau
sed
by s
usce
ptib
le b
acte
ria(T
>4
mg/
L =
8h)
NS
CV
VH
DF
Pos
tA
N69
/15
012
0012
0074
.90.
9238
.949
.44.
441.
0g q
12h
appr
opria
te(A
RF
)(5
)0.
9m2
for
infe
ctio
ns c
ause
dby
sus
cept
ible
bac
teria
(T>
4 m
g/L
= 8
h)
mer
open
em;
NS
CV
VH
DF
Pre
AN
69/
119
500
600
74.7
0.65
27.0
36.2
5.13
Pre
dict
ed C
min
>4
mg/
L1.
0g q
12h
(9),
(AR
F)
0.9m
2fo
r >
8h w
ith 0
.75g
q8h
;0.
5g q
12h
(4),
for
>12
h w
ith 1
.5g
q12h
1.0g
q8h
(1)
,0.
5g q
8h (
1)[4
5]
mer
open
em;
NS
CV
VH
NS
PS
/10
040
054
.5N
SN
SN
S7.
5C
VV
H a
ccou
nted
for
1g (
6)[4
6](A
RF
)(6
)0.
7m2
13%
of
elim
inat
ion
in 1
2h;
0.5g
q8h
app
ropr
iate
Con
tinue
d ne
xt p
age
Disposition of Antimicrobials during CRRT 1007
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Tab
le I
V.
Con
td
Dru
g;R
esid
ual
CR
RT
RF
aM
embr
ane/
QB
FQ
UF
QD
CL
Sca
CL C
RR
TC
L CR
RT
t1 /2
Com
men
t an
d do
sage
dosa
gea
CL C
Rsu
rfac
e(m
L/(m
L/h)
a(m
L/h)
a(m
L/(m
L/m
in)a
(% o
f(h
)are
com
men
datio
n(m
L/m
in)
area
am
in)a
min
)aC
L)a
NS
CV
VH
DF
NS
PS
/10
040
010
0078
.7N
SN
SN
S5.
6C
VV
HD
F 1
L/h
(AR
F)
(6)
0.7m
2ac
coun
ted
for
33%
of
elim
inat
ion
in 1
2h;
1.0g
q12
h ap
prop
riate
NS
CV
VH
DF
NS
PS
/10
040
020
0095
.2N
SN
SN
S4.
8C
VV
HD
F 2
L/h
(AR
F)
(6)
0.7m
2ac
coun
ted
for
40%
of
elim
inat
ion
in 1
2h;
1.0g
q12
h ap
prop
riate
mer
open
em;
1.1
CV
VH
DF
Pre
AN
69/
150
1057
928.
615
0.3
0.76
27.0
22.7
3.72
Obs
erve
d C
min
>4
mg/
L0.
5 q6
h (5
),1.
4m2
(4),
exce
pt f
or 0
.5g
q8h
0.5
q8h
(1),
PS
/1.
0g q
8h (
1)[4
7]0.
9m2
(3)
mer
open
em;
23.5
CV
VH
Pre
AN
69/
182.
118
430
134.
40.
8532
.229
.32.
73O
bser
ved
Cm
in >
2 m
g/L
0.5g
q6h
(6)
,(4
),1.
4m2
(5),
(4),
exce
pt f
or 1
.0g
q8h
1.0g
q8h
(1)
[47]
CV
VH
DF
PS
/10
00(3
)0.
9m2
(2)
(3)
mer
open
em;
95.9
CV
VH
Pre
AN
69/
140
1250
1064
.80.
7216
.43.
61.
512g
q8h
did
not
ens
ure
2.0g
q8h
(5)
,1.
4m2
(6)
adeq
uate
T>
MIC
1.0g
q6h
(1)
[47]
(Cm
in 0
.98
mg/
L)
imip
enem
;0
(10)
,C
VV
HN
SA
N69
/16
011
1512
2.2
1.20
22.9
19.7
2.87
Obs
erve
d C
min
0.5g
q6h
(N
S),
61 (
2)N
S4.
1 m
g/L
for
0.5g
q6h
;0.
5g q
8h (
NS
)[48]
2.34
mg/
L fo
r 0.
5g q
8h;
0.5g
q6h
nee
ded
imip
enem
;N
SC
VV
HP
ost
AN
69/
150
1130
145.
01.
2136
.024
.82.
71O
bser
ved
Cm
in 1
.4 m
g/L;
0.5g
q12
h (4
),(A
RF
)0.
6m2
0.5g
q8–
12h
appr
opria
te0.
5g q
8h (
2)[4
9]on
ly if
MIC
≤2
mg/
L;0.
5g q
6h n
eede
d in
mos
tcr
itica
lly il
l pts
imip
enem
;N
SC
VV
HD
FP
ost
AN
69/
158.
311
6097
317
8.0
1.28
57.0
32.0
2.56
Obs
erve
d C
min
1.1
mg/
L;0.
5g q
12h
(3),
(AR
F)
0.6m
20.
5g q
8–12
h ap
prop
riate
0.5g
q8h
(3)
[49]
only
if M
IC ≤
2 m
g/L;
0.5g
q6h
nee
ded
in m
ost
criti
cally
ill p
ts
Pen
icill
ins
flucl
oxac
illin
;N
SC
VV
HP
ost
PA
M/
169
3420
117.
20.
2110
.38.
84.
94.
0g q
8h a
dequ
ate
for
MS
4g q
8h (
10)[5
0](A
RF
)0.
7m2
stap
hylo
cocc
al in
fect
ions
Con
tinue
d ne
xt p
age
1008 Pea et al.
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Tab
le I
V.
Con
td
Dru
g;R
esid
ual
CR
RT
RF
aM
embr
ane/
QB
FQ
UF
QD
CL
Sca
CL C
RR
TC
L CR
RT
t1 /2
Com
men
t an
d do
sage
dosa
gea
CL C
Rsu
rfac
e(m
L/(m
L/h)
a(m
L/h)
a(m
L/(m
L/m
in)a
(% o
f(h
)are
com
men
datio
n(m
L/m
in)
area
am
in)a
min
)aC
L)a
pipe
raci
llin;
NS
CV
VH
NS
PS
/15
081
679
.2N
SN
SN
S5.
1V
ery
smal
l am
ount
4.0g
firs
t(A
RF
)0.
5m2
of p
iper
acill
in in
dose
(6)
[51]
ultr
afilt
rate
(0–
8 m
g/L)
;4.
0g q
12h
reco
mm
ende
d
pipe
raci
llin;
NS
CV
VH
NS
PS
/15
061
224
.8N
SN
SN
S4.
84.
0g q
8h (
4)[5
1](A
RF
)0.
5m2
pipe
raci
llin/
NS
CV
VH
Pre
NS
NS
1554
42.0
/N
SN
SN
S5.
9/R
isk
of a
ccum
ulat
ion
ofta
zoba
ctam
;(A
RF
)74
.08.
1ta
zoba
ctam
; pi
pera
cilli
n4.
0g/0
.5g
alon
e sh
ould
be
give
nq8
h (9
)[52]
inte
rmitt
ently
with
the
pipe
raci
llin/
tazo
bact
amco
mbi
natio
n
pipe
raci
llin/
NS
CV
VH
Pos
tP
S/
100
800
64.8
/N
SN
SN
S7.
7/M
ean
elim
inat
ion
inta
zoba
ctam
;(A
RF
)0.
7m2
40.3
13.9
12h
= 2
9%/3
7%;
4.0g
/0.5
g (6
)[53]
4.0g
/0.5
g q8
hre
com
men
ded
NS
CV
VH
DF
Pos
tP
S/
100
800
1000
84.3
/N
SN
SN
S6.
7/M
ean
elim
inat
ion
in(A
RF
)0.
7m2
52.2
11.6
12h
= 4
2%/5
7%;
4.0g
/0.5
g q8
hre
com
men
ded
NS
CV
VH
DF
Pos
tP
S/
100
800
2000
91.3
/N
SN
SN
S6.
1/M
ean
elim
inat
ion
in(A
RF
)0.
7m2
62.5
9.4
12h
= 4
6%/6
9%;
4.0g
/0.5
g q8
hre
com
men
ded
pipe
raci
llin/
NS
CV
VH
DN
SA
N69
150
140
1500
72.0
/0.
84/
22.0
/43
.1/
4.3/
4.0g
/0.5
g q1
2h s
houl
dta
zoba
ctam
;(A
RF
)38
.00.
6417
.047
.55.
6re
sult
in T
>M
IC o
f 50
%4.
0g/0
.5g
vs s
usce
ptib
le p
atho
gens
q8h
(3),
with
MIC
≤16
mg/
L;4.
0g/0
.5g
TD
M s
houl
d be
use
d to
q12h
(4)
,in
divi
dual
ise
trea
tmen
t4.
0g/0
.5g
q24h
(1)
[54]
pipe
raci
llin/
8.67
(4)
CV
VH
Pre
AN
69/
185
1626
50.0
/0.
42/
11.5
/37
.0/
7.8/
100%
T>
MIC
vs
all
tazo
bact
am;
0.9m
250
.40.
7620
.962
.57.
9su
scep
tible
pat
hoge
ns4.
0g/0
.5g
q6h
(7),
4.0g
/0.5
gq8
h (7
)[39]
Con
tinue
d ne
xt p
age
Disposition of Antimicrobials during CRRT 1009
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Tab
le I
V.
Con
td
Dru
g;R
esid
ual
CR
RT
RF
aM
embr
ane/
QB
FQ
UF
QD
CL
Sca
CL C
RR
TC
L CR
RT
t1 /2
Com
men
t an
d do
sage
dosa
gea
CL C
Rsu
rfac
e(m
L/(m
L/h)
a(m
L/h)
a(m
L/(m
L/m
in)a
(% o
f(h
)are
com
men
datio
n(m
L/m
in)
area
am
in)a
min
)aC
L)a
25.2
0 (5
)C
VV
HP
reA
N69
/18
518
1890
.6/
0.38
/12
.2/
12.7
/4.
2/10
0% T
>M
IC v
s0.
9m2
68.2
0.73
21.9
35.4
4.1
path
ogen
s w
ith M
IC≤3
2 m
g/L;
55%
T>
MIC
vs p
atho
gens
with
MIC
64
mg/
L
82.4
0 (5
)C
VV
HP
reA
N69
/18
512
0026
5.2/
0.23
/4.
8/2.
8/4.
2/55
% T
>M
IC v
s pa
thog
ens
0.9m
218
0.1
0.86
19.6
13.1
4.1
with
MIC
32
mg/
L; 1
7%T
>M
IC v
s pa
thog
ens
with
MIC
64
mg/
L; 4
.0g/
0.5g
q4h
need
ed in
pts
with
CL C
R >
50 m
L/m
in
Cep
halo
spor
ins
cefe
pim
e;N
SC
VV
HD
FP
ost
AN
69/
150
576
1000
23.8
0.72
60.9
825
813
.92g
q12
h ap
prop
riate
for
2g q
12h
(6)[5
5](A
RF
)0.
6m2
(4),
Cm
in >
5×
MIC
(20
mg/
L)57
.8(2
)
cefe
pim
e;C
VV
HP
ost
AN
69/
150
960
360.
8613
4012
.92g
q24
h or
1g
q12h
2g 1
2h (
1),
(5)
0.6m
2ap
prop
riate
for
pat
hoge
ns2g
q24
h (3
),w
ith M
IC ≤
8 m
g/L
1g q
12h
(1)[5
6]
cefe
pim
e;C
VV
HD
FP
ost
AN
69/
150
1020
957
470.
7826
598.
62g
q24
h or
1g
q12h
2g q
24h
(4),
(7)
0.6m
2ap
prop
riate
for
pat
hoge
ns1g
q12
h (1
),w
ith M
IC ≤
8 m
g/L
1g q
24h
(2)[5
6]
cefe
pim
e;24
.7 (
3)C
VV
UP
reA
N69
/19
515
600
121.
30.
6218
.515
.34.
12g
q8h
app
ropr
iate
for
2g q
8h (
4)[5
7](2
),0.
9m2
(3),
(4)
(2),
(2),
(2),
(2),
(2),
(2),
Cm
in >
10 m
g/L
CV
VH
DF
PS
(1)
750
101.
80.
9035
.935
.35.
2(2
)(2
)(2
)(2
)(2
)(2
)(2
)
cefp
irom
e;N
SC
VV
HP
ost?
PA
M/
150–
1620
–32
0.64
1753
.18.
82g
LD
the
n 1g
q12
h of
fers
1g q
12h
(6)[5
8](A
RF
)0.
6m2
200
2040
appr
opria
te c
over
age
cefp
irom
e;N
SC
VV
HP
ost
PS
/15
028
2058
9.1
0.78
43.3
7.4
2.36
2g q
8h a
ppro
pria
te f
or2g
q8h
(8)
[59]
(AR
F)
0.7m
2su
scep
tible
pat
hoge
ns
cefta
zidi
me;
NS
CV
VH
DF
NS
PA
N/
100
1050
500
NS
NS
NS
NS
6.8
CL
19.0
mg/
L at
6h
and
1g (
3)[6
0](A
RF
)0.
6m2
11.9
mg/
L at
12h
; 1g
q24
hap
prop
riate
Con
tinue
d ne
xt p
age
1010 Pea et al.
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Tab
le I
V.
Con
td
Dru
g;R
esid
ual
CR
RT
RF
aM
embr
ane/
QB
FQ
UF
QD
CL
Sca
CL C
RR
TC
L CR
RT
t1 /2
Com
men
t an
d do
sage
dosa
gea
CL C
Rsu
rfac
e(m
L/(m
L/h)
a(m
L/h)
a(m
L/(m
L/m
in)a
(% o
f(h
)are
com
men
datio
n(m
L/m
in)
area
am
in)a
min
)aC
L)a
cefta
zidi
me;
NS
CV
VH
No
AN
69/
100
500/
0N
S0.
917.
5/C
L in
crea
sed
with
QU
F;
no1g
(8)
[61]
(ES
RD
)0.
6m2
1000
15.3
bsi
gnifi
cant
diff
eren
ce in
CL
was
attr
ibut
ed t
o th
e ty
peof
mem
bran
e ut
ilise
d;di
ffere
nt d
osag
esac
cord
ing
to Q
UF a
ndre
sidu
al r
enal
fun
ctio
n
CV
VH
No
PM
MA
/10
050
0/0
NS
0.91
6.3/
2.1m
210
0012
.5b
CV
VH
No
PS
/10
050
0/0
NS
0.91
9.0/
0.65
m2
1000
16.5
b
cefta
zidi
me;
NS
CV
VH
DN
oA
N69
/10
00
500/
NS
8.4/
CL
incr
ease
d w
ith Q
D;
no1g
(8)
[61]
(ES
RD
)0.
6m2
1000
/13
.5/
sign
ifica
nt d
iffer
ence
in C
L15
00/
18.3
/w
as a
ttrib
uted
to
the
type
2000
21.6
of m
embr
ane
utili
sed;
diffe
rent
dos
ages
acco
rdin
g to
QD
and
resi
dual
ren
al f
unct
ion
CV
VH
DN
oP
MM
A/
100
050
0/N
S7.
3/2.
1m2
1000
/14
.5/
1500
/20
.1/
2000
24.2
CV
VH
DN
oP
S/
100
050
0/N
S8.
6/0.
65m
210
00/
16.6
/15
00/
23.2
/20
0027
.5
cefta
zidi
me;
NS
CV
VH
Pos
tP
S/
143
2820
98.7
0.69
32.1
32.5
4.3
Cm
in 1
4.0
mg/
L –
i.e.
2g q
8h (
12)[6
2](A
RF
)0.
7m2
>M
IC o
f su
scep
tible
path
ogen
s (4
mg/
L);
2g q
8h a
ppro
pria
te;
3g q
8h s
ugge
sted
for
inte
rmed
iate
ly r
esis
tant
path
ogen
with
MIC
8 m
g/L
cefta
zidi
me;
<1
(6),
CV
VH
DF
Pre
AN
69/
150
1500
1000
62.4
0.81
33.6
53.8
3.6
Css
33.
5 m
g/L
– i.e
.3g
q24
h C
I (7
)[63]
5 (1
)0.
6m2
4×
MIC
of
susc
eptib
lepa
thog
ens;
3g q
24 C
I af
ter
2g L
Dap
prop
riate
Con
tinue
d ne
xt p
age
Disposition of Antimicrobials during CRRT 1011
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Tab
le I
V.
Con
td
Dru
g;R
esid
ual
CR
RT
RF
aM
embr
ane/
QB
FQ
UF
QD
CL
Sca
CL C
RR
TC
L CR
RT
t1 /2
Com
men
t an
d do
sage
dosa
gea
CL C
Rsu
rfac
e(m
L/(m
L/h)
a(m
L/h)
a(m
L/(m
L/m
in)a
(% o
f(h
)are
com
men
datio
n(m
L/m
in)
area
am
in)a
min
)aC
L)a
ceftr
iaxo
ne;
2C
VV
HP
ost
PA
M12
515
0039
.30.
6916
.642
.210
.8N
o do
sage
red
uctio
n2g
q24
h (5
),ne
eded
; 2g
q24
h4g
q24
h (1
)[64]
appr
opria
te
ceftr
iaxo
ne;
NS
CV
VH
No
AN
69/
100
500/
0N
S0.
483.
9/C
L in
crea
sed
with
QU
F1g
(8)
[65]
(ES
RD
)0.
6m2
1000
7.2b
and
was
sig
nific
antly
low
er w
ith A
N69
tha
nw
ith P
MM
A a
nd P
S f
ilter
s;di
ffere
nt d
osag
esac
cord
ing
to Q
UF a
ndre
sidu
al r
enal
fun
ctio
n
CV
VH
No
PM
MA
/10
050
0/0
NS
0.86
6/2.
1m2
1000
11.8
b
CV
VH
No
PS
/10
050
0/0
NS
0.82
5.8/
0.65
m2
1000
11.0
b
ceftr
iaxo
ne;
NS
CV
VH
DN
oA
N69
/10
00
500/
NS
1.5/
CL
incr
ease
d w
ith Q
D a
nd1g
(8)
[65]
(ES
RD
)0.
6m2
1000
/2.
3/w
as s
igni
fican
tly lo
wer
1500
/3.
1/w
ith A
N69
tha
n w
ith20
003.
3P
MM
A a
nd P
S f
ilter
s;di
ffere
nt d
osag
esac
cord
ing
to Q
D a
ndre
sidu
al r
enal
fun
ctio
n
CV
VH
DN
oP
MM
A/
100
050
0/N
S1.
5/2.
1m2
1000
/2.
7/15
00/
3.8/
2000
4.4
CV
VH
DN
oP
S/
100
050
0/N
S2.
2/0.
65m
210
00/
4.0/
1500
/5.
6/20
006.
1
Am
inog
lyco
side
s
netil
mic
in;
22.3
CV
VH
DF
NS
AN
69/
130
150
875
44.0
36.
8315
0mg
q12h
doe
s no
t15
0mg
q12h
0.6m
2pr
ovid
e ef
fect
ive
peak
(6)[6
6]co
ncen
trat
ions
Gly
cope
ptid
es
teic
opla
nin;
35C
VV
HP
reA
N69
/15
020
000.
17D
rug
rem
oval
dep
ende
nt5.
71–1
1.42
0.9m
2on
QU
F a
nd f
u;m
g/kg
/day
(1)
[38]
TD
M r
ecom
men
ded
Con
tinue
d ne
xt p
age
1012 Pea et al.
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Tab
le I
V.
Con
td
Dru
g;R
esid
ual
CR
RT
RF
aM
embr
ane/
QB
FQ
UF
QD
CL
Sca
CL C
RR
TC
L CR
RT
t1 /2
Com
men
t an
d do
sage
dosa
gea
CL C
Rsu
rfac
e(m
L/(m
L/h)
a(m
L/h)
a(m
L/(m
L/m
in)a
(% o
f(h
)are
com
men
datio
n(m
L/m
in)
area
am
in)a
min
)aC
L)a
teic
opla
nin;
3.9
CV
VH
Pos
tP
AM
/20
344
2856
.64.
6F
ixed
dos
age
12 m
g/kg
q24
h0.
7m2
reco
mm
enda
tion
for
2 do
ses
(3)[6
7]un
suita
ble;
TD
Mre
com
men
ded
teic
opla
nin;
2.41
CV
VH
DF
Pos
tC
ellu
lose
105
2250
1250
11.3
NS
3.46
30.6
78.6
Effe
ctiv
e dr
ug r
emov
al40
0mg
q24h
tria
ceta
te/
whe
n us
ing
high
-flu
x(3
)[68]
1.5m
2m
embr
ane;
TD
Mre
com
men
ded
vanc
omyc
in;
NS
CV
VH
No
AN
69/
100
500/
0N
S0.
704.
6bC
L in
crea
sed
with
QU
F;
500m
g (5
)[69]
(ES
RD
)0.
6m2
1000
no s
igni
fican
t di
ffere
nce
in C
L w
as a
ttrib
uted
to
the
type
of
mem
bran
eus
ed;
diffe
rent
dos
ages
acco
rdin
g to
QU
F a
ndre
sidu
al r
enal
fun
ctio
n;T
DM
rec
omm
ende
d
NS
CV
VH
No
PM
MA
/10
050
0/0
NS
0.86
6.0b
(ES
RD
)2.
1m2
1000
NS
CV
VH
No
PS
/10
050
0/0
NS
0.68
5.4b
(ES
RD
)0.
65m
210
00
vanc
omyc
in;
NS
CV
VH
DN
oA
N69
/10
00
500/
NS
5.8/
CL
incr
ease
d w
ith Q
D a
nd50
0mg
(5)[6
9](E
SR
D)
0.6m
210
00/
10.0
/at
QD
of
1500
/200
0 m
L/h
1500
/13
.7/
was
sig
nific
antly
hig
her
2000
13.4
with
PM
MA
tha
n w
ithA
N69
and
PS
filt
ers;
diffe
rent
dos
ages
acco
rdin
g to
QD
,fil
ter
mem
bran
e an
dre
sidu
al r
enal
fun
ctio
n;T
DM
rec
omm
ende
d
NS
CV
VH
DN
oP
MM
A/
100
050
0/N
S7.
5/(E
SR
D)
2.1m
210
00/
14.7
/15
00/
22.8
/20
0027
.0
NS
CV
VH
DN
oP
S/
100
050
0/N
S5.
2/(E
SR
D)
0.65
m2
1000
/11
.4/
1500
/16
.0/
2000
22.1
Con
tinue
d ne
xt p
age
Disposition of Antimicrobials during CRRT 1013
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Tab
le I
V.
Con
td
Dru
g;R
esid
ual
CR
RT
RF
aM
embr
ane/
QB
FQ
UF
QD
CL
Sca
CL C
RR
TC
L CR
RT
t1 /2
Com
men
t an
d do
sage
dosa
gea
CL C
Rsu
rfac
e(m
L/(m
L/h)
a(m
L/h)
a(m
L/(m
L/m
in)a
(% o
f(h
)are
com
men
datio
n(m
L/m
in)
area
am
in)a
min
)aC
L)a
vanc
omyc
in;
NS
CV
VH
Pos
tP
AN
/20
016
00–
32.5
0.88
23.3
71.7
17.9
LD 1
5–20
mg/
kg t
hen
1000
mg
(1),
(AR
F)
0.6m
225
0–50
0mg
q12h
sho
uld
250m
g q1
2hbe
app
ropr
iate
(1)[7
0]
vanc
omyc
in;
NS
CV
VH
Pos
tA
N69
/30
060
0053
.9–
0.57
–N
SN
SN
S50
0mg
q6h
shou
ld b
e10
00m
g (7
)[71]
(AR
F)
± pr
e1.
6m2
67.2
0.76
give
n to
sep
tic s
hock
pts
durin
g hi
gh-v
olum
eul
traf
iltra
tion
vanc
omyc
in;
NS
CV
VH
DF
Pre
AN
6920
020
0010
0041
.70.
7030
7615
.645
0mg
q12h
wou
ld p
rovi
de75
0mg
(AR
F)
aver
age
Css
of
15 m
g/L
q12h
(10
)[72]
Flu
oroq
uino
lone
s
cipr
oflo
xaci
n;N
SC
VV
HP
ost
AN
69/
150
996
84.4
0.72
12.4
14.7
18.5
Hig
hly
varia
ble
elim
inat
ion;
400m
g q2
4h(A
RF
)0.
6m2
400m
g q2
4h is
nec
essa
ry(5
)[73]
cipr
oflo
xaci
n;N
SC
VV
HD
FP
ost
AN
69/
150
1044
960
146.
20.
6321
14.4
8.3
Hig
hly
varia
ble
elim
inat
ion;
400m
g q2
4h (
3),
(AR
F)
0.6m
240
0mg
q24h
is n
eces
sary
400m
g q1
2h(2
)[73]
levo
floxa
cin;
NS
CV
VH
Pos
tA
N69
/15
011
5542
.30.
6211
.527
.226
.925
0mg
q24h
or
500m
g50
0mg
q48h
(3)
,(A
RF
)0.
6m2
q48h
are
app
ropr
iate
250m
g q2
4h(1
)[73]
levo
floxa
cin;
NS
CV
VH
DF
Pos
tA
N69
/15
011
1010
3051
.20.
6121
.742
.418
.625
0mg
q24h
or
500m
g50
0mg
q48h
(3)
,(A
RF
)0.
6m2
q48h
are
app
ropr
iate
250m
g q2
4h(3
)[73]
levo
floxa
cin;
<10
CV
VH
Pre
AN
69/
9010
0047
.94
0.79
15.7
132
.845
.9A
t le
ast
197
mg/
day
500m
g q2
4h (
5),
0.9m
2re
com
men
ded
125m
g q2
4h(1
)[74]
<10
CV
VH
DF
Pre
AN
69/
9010
0010
0054
.04
26.0
548
.228
.8A
t le
ast
250
mg/
day
0.9m
2re
com
men
ded
levo
floxa
cin;
NS
CV
VH
Pos
tA
N69
/15
013
0041
.90.
9420
.148
21.8
500m
g LD
day
1 t
hen
500m
g LD
day
1(A
RF
)0.
9m2
250m
g q2
4h s
eem
sth
en 2
50m
gap
prop
riate
q24h
(6)
[75]
Con
tinue
d ne
xt p
age
1014 Pea et al.
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Tab
le I
V.
Con
td
Dru
g;R
esid
ual
CR
RT
RF
aM
embr
ane/
QB
FQ
UF
QD
CL
Sca
CL C
RR
TC
L CR
RT
t1 /2
Com
men
t an
d do
sage
dosa
gea
CL C
Rsu
rfac
e(m
L/(m
L/h)
a(m
L/h)
a(m
L/(m
L/m
in)a
(% o
f(h
)are
com
men
datio
n(m
L/m
in)
area
am
in)a
min
)aC
L)a
levo
floxa
cin;
NS
CV
VH
NS
PA
M/
180
3240
0.47
27.6
8.3
Sig
nific
ant
and
rapi
d50
0mg
(12)
[76]
(AR
F)
0.7m
2el
imin
atio
n
levo
floxa
cin;
27C
VV
HP
reP
S/
156
1464
213.
528
.7N
o do
sage
500m
g q2
4h0.
71m
2re
com
men
datio
n;(4
)[77]
TD
M s
ugge
sted
mox
iflox
acin
;N
SC
VV
HD
FP
reA
N69
150
1000
1000
318.
20.
8427
.28.
59.
87P
K c
ompa
rabl
e to
pts
400m
g q2
4h(A
RF
)w
ithou
t re
nal i
mpa
irmen
t;(9
)[78]
400m
g q2
4h a
ppro
pria
te
oflo
xaci
n;N
SC
VV
HP
ost
PS
/20
030
0027
8.4
0.24
89.9
32.3
2.8
Sig
nific
ant
and
rapi
d40
0mg
q24h
(AR
F)
0.7m
2el
imin
atio
n; 4
00m
g q8
h(8
)[79]
sugg
este
d
Oxa
zolid
inon
es
linez
olid
;N
SC
VV
HP
reP
S/
125
2000
–60
.20.
8423
.438
.915
.5S
igni
fican
t el
imin
atio
n;60
0mg
q12h
(AR
F)
1.2m
260
0mg
q12h
ade
quat
e(2
)[80]
in p
ts w
ith n
o im
pairm
ent
of e
xtra
RR
T-r
elat
ed C
L;T
DM
cou
ld b
e us
eful
linez
olid
;N
SC
VV
HP
reA
N69
/15
022
40N
S0.
5720
.4N
S4.
54S
igni
fican
t el
imin
atio
n;60
0mg
(2)[8
1](A
RF
)1.
65m
2no
spe
cific
dos
age
reco
mm
enda
tion;
TD
M c
ould
be
usef
ul
linez
olid
;N
SC
VV
HP
ost
PS
/18
6.5
2382
172.
50.
7739
22.6
4.63
Sig
nific
ant
elim
inat
ion;
600m
g(A
RF
)1.
2m2
(7),
(7),
(7),
(7),
(7),
(7),
600m
g q1
2h a
dequ
ate
but
q12h
(20
)[82]
PS
/14
5.7
0.69
27.2
18.7
4.14
600m
g q8
h so
met
imes
0.9m
2 (1
3)(1
3)(1
3)(1
3)(1
3)(1
3)ne
eded
[83]
linez
olid
;N
SC
VV
HD
FP
reP
AN
/20
018
0012
0018
9N
S21
.611
.4N
SN
o si
gnifi
cant
elim
inat
ion;
600m
g q1
2h(A
RF
-CR
F)
1.0m
260
0mg
q12h
ade
quat
e; n
o(1
)[84]
addi
tiona
l dos
es n
eede
d
linez
olid
;A
RF
CV
VH
DF
NS
PS
/20
077
420
0084
.70.
7936
.543
.17.
560
0mg
q12h
ach
ieve
d;60
0mg
q12h
1.6m
2ap
prop
riate
Cm
in(1
)[85]
(6.2
–7.2
mg/
L);
noad
ditio
nal d
oses
nee
ded
Oth
ers
colis
tinN
SC
VV
HD
FP
ost
AN
69/
200
2000
1000
48.7
NS
11.2
23.0
6.83
Pla
sma
conc
entr
atio
nsm
etha
nesu
lfona
te;
(AR
F)
NS
<M
IC o
f P
. ae
rugi
nosa
4h
150m
gaf
ter
dosi
ng;
2–3
mg/
kg(2
.46
mg/
kg)
q12h
sho
uld
be m
ore
q48h
(1)
[86]
appr
opria
te
Con
tinue
d ne
xt p
age
Disposition of Antimicrobials during CRRT 1015
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Tab
le I
V.
Con
td
Dru
g;R
esid
ual
CR
RT
RF
aM
embr
ane/
QB
FQ
UF
QD
CL
Sca
CL C
RR
TC
L CR
RT
t1 /2
Com
men
t an
d do
sage
dosa
gea
CL C
Rsu
rfac
e(m
L/(m
L/h)
a(m
L/h)
a(m
L/(m
L/m
in)a
(% o
f(h
)are
com
men
datio
n(m
L/m
in)
area
am
in)a
min
)aC
L)a
An
tifu
ng
als
Pol
iene
s
amph
oter
icin
B;
NS
CV
VH
Pre
PS
/20
018
0041
2.5
0.29
78.
19.
35E
limin
atio
n on
ly1.
06 m
g/kg
(2)
[87]
(AR
F)
0.7m
2(1
)sl
ight
ly e
nhan
ced
lipos
omal
NS
CV
VH
Pre
PS
/17
818
7822
4.4
0.16
10.
411
.78
Elim
inat
ion
only
amph
oter
icin
B;[8
7](A
RF
)0.
7m2
(3);
slig
htly
enh
ance
d;4.
09 m
g/kg
(5)
[87]
0.04
3–4m
g/kg
q24
h(3
)re
com
men
ded
amph
oter
icin
BN
SC
VV
HP
reP
S/
168
2172
3709
.80.
293.
330.
0335
.53
Elim
inat
ion
only
lipid
com
plex
;(A
RF
)0.
7m2
(7);
slig
htly
enh
ance
d;2.
82 m
g/kg
(7)
[87]
0.07
3–4m
g/kg
q24
h(7
)re
com
men
ded
amph
oter
icin
BN
SC
VV
HP
reP
S/
NS
1980
787.
480.
2514
017
.813
.2E
limin
atio
n un
affe
cted
lipid
com
plex
;(A
RF
)0.
7m2
by C
VV
H;
4.94
mg/
kg5
mg/
kg q
24h
q24h
(2)
[88]
reco
mm
ende
d
Tria
zole
s
fluco
nazo
le;
NS
CV
VH
Pre
PS
/18
0–10
0030
.2N
S11
.839
.133
.3C
min
ave
rage
d 15
.4 a
nd80
0mg
q24h
1.3m
220
0(7
),(7
),(7
),(7
),(7
),12
.1 m
g/L
at Q
UF o
f(9
)[89]
2000
37.5
18.9
50.5
24.7
1000
and
200
0 m
L/h,
(9)
(9)
(9)
(9)
(9)
resp
ectiv
ely;
800
mg
q24h
rec
omm
ende
d fo
rlif
e-th
reat
enin
g C
andi
dain
fect
ions
fluco
nazo
le;
7.3
(3),
CV
VH
DF
Pos
tC
ellu
lose
105
2250
1225
59.7
NS
NS
NS
8.08
Cm
in a
vera
ged
6.8
and
400m
g q1
2h (
3),
5.5
(4)
tria
ceta
te/
(4)
(4)
(4)
(3),
(3),
4.2
mg/
L af
ter
400m
g80
0mg
q24h
1.5m
252
.99.
12q1
2h a
nd 8
00m
g q2
4h,
(4)[9
0](4
)(4
)re
spec
tivel
y; 5
00–6
00m
gq1
2h r
ecom
men
ded
aT
he v
alue
s in
par
enth
eses
indi
cate
the
no.
of
patie
nts.
bV
isua
l ins
pect
ion.
AN
69 =
acr
ylon
itrile
; A
RF
= a
cute
ren
al f
ailu
re;
CI
= c
ontin
uous
inf
usio
n; C
LC
R =
cre
atin
ine
clea
ranc
e; C
LC
RR
T =
ext
raco
rpor
eal
clea
ranc
e; C
L =
tot
al b
ody
clea
ranc
e; C
min
=m
inim
um p
lasm
a co
ncen
trat
ion;
Css
= s
tead
y-st
ate
plas
ma
conc
entr
atio
n; C
VV
H =
con
tinuo
us v
enov
enou
s ha
emof
iltra
tion;
CV
VH
DF
= c
ontin
uous
ven
oven
ous
haem
odia
filtr
atio
n;E
SR
D =
end
-sta
ge r
enal
dis
ease
; f u
= u
nbou
nd f
ract
ion
LD
= l
oadi
ng d
ose;
MIC
= m
inim
um i
nhib
itory
con
cent
ratio
n; M
S =
met
hici
llin
susc
eptib
le;
NS
= n
ot s
peci
fied;
PA
M =
poly
amid
e; P
AN
= p
olya
cryl
onitr
ile; P
MM
A =
pol
ymet
hylm
etha
cryl
ate;
po
st =
pos
tdilu
tion;
pre
= p
redi
lutio
n; P
S =
pol
ysul
fone
; pts
= p
atie
nts;
qxh
= e
very
x h
ours
; QB
F =
blo
od fl
owra
te; Q
D =
dia
lysa
te f
low
rat
e; Q
UF =
ultr
afilt
ratio
n flo
w r
ate;
RF
= r
epla
cem
ent
fluid
; R
RT
= r
enal
rep
lace
men
t th
erap
y; S
c =
sie
ving
coe
ffici
ent;
SD
= s
ingl
e do
se;
t1 /2 =
elim
inat
ion
half-
life;
TD
M =
the
rape
utic
dru
g m
onito
ring.
1016 Pea et al.
and high CLR in healthy volunteers, and so they are averaging 1.60–1.65 L/h[42,43] confirmed that a mer-expected to be highly CRRT removable. According- openem dosing regimen of 0.5g every 8–12 hoursly, since CLCRRT is a significant part of total body may ensure appropriate pharmacodynamic expo-clearance (CL), additional doses in comparison with sure, in terms of the T>MIC, against susceptibleanephric patients will usually be needed in these pathogens.circumstances. The different influence that CVVHDF and CV-
VH, applied in postdilution mode and at a relativelyhigh flow rate, may have on meropenem pharma-Meropenemcokinetics was comparatively assessed in twoMeropenem represents one of the most exten-groups of critically ill patients with acute renal fail-sively investigated antimicrobial agents during theure receiving a dosing regimen of 1.0g every 12application of CRRT in critically ill patients, consid-hours.[44] Although during CVVHDF higherering that in the last decade, several investigatorsCLCRRT (38.9 vs 25.0 mL/min) and a shorter t1/2have assessed its pharmacokinetic behaviour during(4.44 vs 5.89 hours) were documented, in bothboth CVVH and CVVHDF.groups the plasma concentrations of meropenemThalhammer et al.[40] first studied the pharma-remained at >4 mg/L for most of the dosing intervalcokinetic properties of meropenem during CVVH(8 hours). This led the investigators to conclude thatafter a single intravenous dose of 1g in nine critical-in patients undergoing both of these CRRT tech-ly ill patients with acute renal failure. Of note, bothniques in the aforementioned operating conditions, aCL and the elimination half-life (t1/2) of meropenemdosing regimen of 1g every 12 hours may be appro-were comparable to those observed in subjects with-priate for treating infections caused by susceptibleout renal failure, suggesting that in anephric patientsbacteria.the elimination of meropenem may be significantly
Interestingly, when CVVHDF was applied inenhanced by the application of CVVH. On the basispredilution mode and at relatively low flow ratesof these results and the finding of plasma drug(QUF of 0.5 L/h, QD of 0.6 L/h) to 15 critically illconcentrations higher than the MIC90 of most of thepatients with acute renal failure receiving four dif-susceptible pathogens at 6 hours after dosingferent dosing regimens, meropenem CLCRRT was(4.3 mg/L), the investigators concluded that a dosingfound to be lower (27.0 mL/min).[45] Accordingly,regimen of 1g every 8 hours should be consideredthe investigators predicted that under these operat-adequate in these circumstances. Interestingly, theing conditions, optimal pharmacodynamic exposureneed for such a dosing regimen, which is similar to(Cmin >4 mg/L) may be ensured with a dosingthat indicated for patients with normal renal func-regimen of 0.75g every 8 hours or 1.5g everytion, may be explained considering that in this study,12 hours.a high QUF (2.75 L/h) in the postdilution mode was
applied, this leading to high CLCRRT of meropenem The relevance that different dialysate flow rates(49.7 mL/min). (1 L/h and 2 L/h) may have in increasing mer-
Consistent with this hypothesis, in a subsequent openem removal by CVVHDF in comparison withstudy carried out in critically ill patients with acute CVVH alone applied at a low QUF (0.4 L/h) wasrenal failure receiving multiple doses of meropenem tested over three subsequent periods of 12 hours in(0.5g every 8 hours or 0.5g every 12 hours) and six patients with acute renal failure.[46] Whereas overundergoing CVVH under similar operating condi- 12 hours CVVH alone accounted for the eliminationtions, the application of a lower QUF (1.1 L/h) led to of 13% of a 1g dose of meropenem, CVVHDF atproportionally reduced CLCRRT (22.0 mL/min).[41] dialysate flow rates of 1 and 2 L/h accounted forIn this case, the meropenem Cmin averaged 7.3 mg/ 33% and 40%, respectively. Consistently, the mer-L, and so a dosing regimen of 0.5g every 12 hours openem t1/2 decreased from 7.5 hours to 5.6 andwas considered appropriate under these operating 4.8 hours, respectively. These findings led the inves-conditions. tigators to conclude that in order to ensure adequate
Likewise, two other studies assessing the phar- pharmacodynamic exposure (Cmin >8 mg/L), amacokinetics of meropenem during CVVH at QUF higher dosing regimen may be needed during CV-
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Disposition of Antimicrobials during CRRT 1017
VHDF (1.0g every 12 hours) than during CVVH served renal function, a subtherapeutic Cmin of(0.5g every 8 hours). <1 mg/L was frequently documented even when
administering 2g every 8 hours – that is, the maxi-In the most recent study, Isla et al.[47] assessedmum daily dosage usually suggested for treatingthe influence that different degrees of residual re-severe infections in patients with normal renal func-nal function may have in affecting clearance oftion.meropenem during both CVVH and CVVHDF
In summary, when comparing the results of theseequipped with acrylonitrile or polysulfone mem-different studies, as a consequence of very differentbranes. Different operating conditions were testeddevice operating conditions and patients’ patho-while administering various dosing regimens rang-physiological status, it may be noted that in ordering between 0.5g every 8 hours and 2.0g everyto ensure appropriate pharmacodynamic exposure6 hours. As expected, meropenem was significantly(Cmin >4 mg/L), very different daily dosages ofremoved by both CVVH and CVVHDF but, inter-meropenem may be needed (ranging from 0.5g eve-estingly, the relative influence of CRRT on CLry 12 hours to >2g every 8 hours). This obviouslyvaried according to the extent of the patients’ residu-poses some doubts about the possibility of generalis-al renal function. In patients with total renal failureing these results, suggesting the need for therapeutic(mean CLCR 1.1 mL/min) undergoing CVVHDFdrug monitoring (TDM) whenever possible. Be-and in those with moderately impaired renal func-sides, considering the high interstudy variability ob-tion (mean CLCR 23.5 mL/min) undergoing eitherserved for various pharmacokinetic parameters ofCVVHDF or CVVH, the mean CLCRRT was of ameropenem (CLCRRT ranging between 16.4 andsimilar extent and accounted for as much as 22%49.7 mL/min; t1/2 ranging between 1.51 and 8.7and 29% of meropenem CL, respectively; converse-hours; Sc ranging between 0.63 and 1.17) and thely, in those patients with preserved renal functionfact that the optimal pharmacodynamic target for(mean CLCR 95.9 mL/min) undergoing CVVH,treating infections due to susceptible pathogens withCLCRRT was lower and accounted for only 3.6%.meropenem should be a Cmin of 4–8 mg/L, theseThis fact may be explained considering that in pa-data confirm the opportunity of considering a regi-tients undergoing CRRT and presenting with signif-men based on multiple fractioning of the total dailyicant residual renal function, drugs with dominantdosage of meropenem in critically ill patients under-renal clearance are removed by both the renal andgoing CVVH or CVVHDF. Starting with 0.5g everythe extracorporeal pathways, but generally to a6–8 hours may be a good choice in various in-greater extent by the kidney than by RRT. Accord-stances, especially when applying high ultrafiltra-ingly, a significant shortening of the mean mer-tion and dialysate flow rates. However, in patientsopenem t1/2 (from 3.72 hours in patients with totalpresenting with significant residual renal function orrenal failure to 2.73 hours in those with moderateeven in very critically ill patients presenting withrenal failure and 1.51 hours in those with preservedmore severe infections, presumably due to border-renal function) was observed. These findings high-line susceptible pathogens, a higher dosing regimenlight that patients’ residual renal function may sig-of up to 1g every 4–6 hours may be needed.nificantly enhance meropenem elimination during
CRRT. Consistently, when pharmacodynamics ofImipenem/Cilastatinmeropenem, in terms of an appropriate Cmin>MIC,
were assessed in relation to the different dosing Tegeder et al.[48] first investigated the influenceregimens used, optimal exposure was not always of CVVH on the pharmacokinetic behaviour of imi-found. In anephric patients undergoing CVVHDF, a penem administered in a dosing regimen of 0.5gmeropenem Cmin of >4 mg/L was obtained with every 6–8 hours in 12 critically ill patients with0.5g every 6 hours or 1g every 8 hours, but not with acute renal failure. During the application of a rela-0.5g every 8 hours. In those presenting with moder- tively high QUF, the CLCRRT accounted for aboutate residual renal function, a Cmin of >2 mg/L was 20% of CL, and so the imipenem t1/2 was found to beachieved with 0.5g every 6 hours, but not with 1.0g significantly shorter than had been previously re-every 8 hours. More importantly, in those with pre- ported in patients with severe renal insufficiency.
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
1018 Pea et al.
Accordingly, whereas adequate pharmacodynamic the low Vd and the very high Sc (about 1.2), aexposure, in terms of a Cmin of >4 mg/L, was subtherapeutic Cmin may be expected if longer dos-observed with the standard 0.5g 6-hourly dosing ing intervals are chosen. This may be especially theregimen (averaging 4.1 mg/L), potentially subther- case in the presence of pathogens potentially exhib-apeutic concentrations (2.34 mg/L) were found iting borderline susceptibility, as may frequentlywhen administering the reduced 0.5g 8-hourly dos- occur in the ICU setting for Acinetobacter bauman-age. On the basis of these findings, the investigators nii and P. aeruginosa.concluded that CVVH contributed substantially to Finally, it should be mentioned that in earlierimipenem elimination and so, under these operating studies that also assessed the pharmacokinetic beha-conditions, a dosing regimen much higher than that viour during CRRT of the renal dehydropeptidase-Isuggested in patients with total renal failure, namely (DHP-I) inhibitor cilastatin which is always coad-0.5g every 6 hours, must be administered to ensure a ministered to preserve imipenem from rapid elimi-Cmin of >4 mg/L. nation, it was shown that in patients with renal
failure, accumulation of cilastatin occurred.[91] Al-These conclusions were recently confirmed inthough no adverse effect was specifically attributeda comparative study assessing the influence ofto this, it may theoretically represent a potentialboth CVVHDF and CVVH on imipenem pharma-disadvantage compared with carbapenems not meta-cokinetics in two groups of critically ill patients withbolised by renal DHP-I.acute renal failure receiving a dosing regimen rang-
ing between 0.5g every 8 hours and 0.5g every3.1.2 Penicillins
12 hours.[49] CVVH was applied in postdilutionMost penicillins exhibit pharmacokinetic charac-mode and at a high QUF approaching that of the
teristics (a low Vd, moderate plasma protein bind-previous study of Tegeder et al. Interestingly, highering, high CLR) which makes them theoreticallyimipenem CLCRRT was documented during thehighly removable by CRRT. In fact, CLCRRT isapplication of CVVHDF (57.0 and 36.0 mL/minfrequently a significant part of CL of the drug, andduring CVVHDF and CVVH, respectively), sug-so in these circumstances, additional doses are usu-gesting that this technique may be more efficient inally necessary in comparison with anephric patients.removing imipenem, even if the small size of theThe most recent literature data concern flucloxacil-study did not allow definite conclusions to be drawn.lin and piperacillin alone or in combination withHowever, both administered dosages were consid-tazobactam.ered inappropriate, since in both groups they result-
ed in subtherapeutic Cmin values of imipenem (1.1 Flucloxacillinand 1.4 mg/L during CVVHDF and CVVH, respec- The pharmacokinetics of flucloxacillin 4g everytively). This led the investigators to confirm that an 8 hours was recently assessed in 10 anuric, criticallyimipenem dosing regimen of 0.5g every 6 hours ill patients during high-volume postdilution CVVHmust be administered to treat infections caused by equipped with a polyamide haemofilter.[50] Surpris-susceptible bacteria in patients undergoing either of ingly, the investigators demonstrated a great dis-these CRRT techniques. crepancy between the minor relevance of CLCRRT
In summary, the findings suggest that for this (accounting for only 8.8% of CL) and the drugcarbapenem (as with meropenem), although fewer concentration in the haemofiltrate (12.3 mg/L) and,data are available in the literature and they are on the opposite side, the high CL and the significantessentially limited to devices equipped with ac- drug removal (56.9%). As a possible explanation, itrylonitrile membranes, the most important factor for was suggested that significant drug adsorption to theensuring appropriate pharmacodynamic exposure haemofilter might have occurred in this particularfor the entire dosing interval (in terms of the case. As an adjunctive mechanism to explain this, itCmin>MIC) during the application of both CVVH may be speculated that due to hypoalbuminaemia, aand CVVHDF may be the frequency of dosing every frequently occurring condition in critically ill pa-6 hours. In fact, given that imipenem is rapidly and tients, the unbound moiety of flucloxacillin mightextensively removed by these CRRTs, according to have been significantly higher than expected. In
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Disposition of Antimicrobials during CRRT 1019
fact, although no mention was made about the al- lin/tazobactam removal by CVVHDF in compari-buminaemic status of the patients, the observed Sc son with CVVH alone applied at a moderate QUFwas indeed four times higher than expected (0.21 (0.8 L/h) was tested over three subsequent periods ofinstead of 0.05) on the basis of normally very high 12 hours in six patients with acute renal failure.[53]
protein binding of flucloxacillin (96%). This might Whereas over 12 hours CVVH alone accounted forobviously have made drug removal easier. Besides, elimination of 29%/37% of a 4.0g/0.5g dose ofthe pharmacodynamic analysis suggested that in piperacillin/tazobactam, CVVHDF at dialysate flowmost cases, a flucloxacillin dosage of 4g every 8 rates of 1 and 2 L/h accounted for elimination ofhours might ensure an appropriate T>MIC against 42%/57% and 46%/69%, respectively. However,methicillin-susceptible staphylococcal bacteria with the piperacillin/tazobactam t1/2 decreased only slight-a breakpoint MIC of 4 mg/L. ly from 7.7/13.9 hours to 6.7/11.6 hours and to 6.1/
9.4 hours, respectively. CVVHDF at high QDcaused the highest removal of piperacillin/tazobac-Piperacillin and Piperacillin/Tazobactamtam, but, on the basis of the pharmacodynamic ana-The pharmacokinetic behaviour of piperacillinlysis, it was concluded that during the application ofalone at a dosage of 4g every 8 hours was assessedboth CRRT techniques, a daily dosage of 4.0/0.5gduring the application of CVVH in ten critically illevery 8 hours should be recommended in orderpatients with acute renal failure.[51] Neither CLCRRTto ensure appropriate exposure (in terms of thenor the Sc were estimated, but very small amounts ofCmin>MIC) against both enterobacteriaceae andpiperacillin were recovered in the ultrafiltrate (rangeP. aeruginosa.0–8 mg/L). These findings suggested that piperacil-
Mueller et al.[54] assessed the influence of contin-lin was only slightly removed by CVVH even if,uous venovenous haemodialysis (CVVHD)indeed, a relatively low QUF was used. Accordingly,equipped with a acrylonitrile haemofilter on theconsidering the high Cmin observed (48 mg/L), thepharmacokinetic profile of piperacillin/tazobac-investigators concluded that to avoid the risk of drugtam administered at three different dosages to anu-accumulation under these operating conditions, aric, critically ill patients. The relatively high QDdaily dosage of 4g every 12 hours might be suffi-(1.5 L/h) with a low QUF (0.14 L/h) accounted forcient for piperacillin.about one half of the CL of both piperacillin andLikewise, a potential risk of drug accumulationtazobactam, suggesting high extracorporeal drug re-was also documented when piperacillin/tazobactammoval under these operating conditions. Interesting-was administered at a dosage of 4.0g/0.5g every 8ly, the CL of piperacillin/tazobactam was onlyhours during the application of predilution CVVH toslightly lower than that observed during CVVHDFnine critically ill patients with acute renal failure.[52]
in the previous study by Valtonen et al.[53] On theOf note, although a direct relationship betweenbasis of the pharmacodynamic analysis, it was esti-piperacillin/tazobactam CL and the QUF was ob-mated that a dosage of 4.0g/0.5g every 12 hoursserved during the application of a relatively highshould result in a T>MIC of 50% against susceptibleQUF, the t1/2 values of both compounds were signifi-pathogens with an MIC for piperacillin/tazobactamcantly longer than in normal subjects, especially forof ≤16 mg/L. However, due to the very wide inter-tazobactam. This may be related to the fact thatindividual pharmacokinetic variability, the use oftazobactam may accumulate relative to piperacillinTDM was advocated to individualise treatment.because of its larger Vd. Accordingly, the investiga-
tors suggested that the drug dosage should be re- In the most recent study, Arzuaga et al.[39] as-duced as in patients with slightly impaired renal sessed the influence that different degrees of residu-function, but in order to prevent tazobactam ac- al renal function may have in affecting clearance ofcumulation, piperacillin alone should be given inter- piperacillin/tazobactam during predilution CVVHmittently with the piperacillin/tazobactam combina- equipped with acrylonitrile membranes. Moderatelytion. high ultrafiltration rates (averaging between 1.2 and
The relevance that different dialysate flow rates 1.8 L/h) were applied during administration of two(1 L/h and 2 L/h) may have in increasing piperacil- different dosing regimens (4.0g/0.5g every 6 hours
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
1020 Pea et al.
and 4.0g/0.5g every 8 hours). Interestingly, the rela- choosing dosing adjustments for piperacillin duringthe application of CVVH, it may be inappropriate totive influence of CRRT on piperacillin/tazobactamassume equivalence between the Sc and the unboundCL varied according to the extent of the patients’fraction.residual renal function. In patients with total renal
This concept has been recently confirmed by thefailure (mean CLCR 8.67 mL/min) the meansame investigators in a further in vitro study assess-CLCRRT accounted for as much as 37% and 62.5%ing the different influence that acrylonitrile andof the CL of piperacillin and tazobactam, respective-polysulfone haemofilters may have on removal ofly; in those with moderately impaired renal functionpiperacillin and tazobactam from human plasma(mean CLCR 25.20 mL/min), it decreased to 12.7%during predilution CVVH.[92] In fact, when using theand 35.4%, respectively; in those with preservedacrylonitrile haemofilter, the Sc was similar to therenal function (mean CLCR 82.4 mL/min), it ac-unbound fraction only for tazobactam (0.78 vs 0.80)counted for only 2.8% and 13.1%, respectively.while for piperacillin it was much lower (0.70 vsAccordingly, a significant shortening of the mean0.92). It was also noted that during CVVH,piperacillin/tazobactam t1/2 (from 7.8/7.9 hours inpolysulfone was found to have a significantly higherpatients with total renal failure to 4.2/4.1 hours inpermeability than acrylonitrile for both piperacillinthose with moderate renal failure and 2.6/5.0 hours(Sc 0.92 and 0.70, respectively) and tazobactam (Scin those with preserved renal function) was ob-1.04 and 0.78, respectively), thus obviously condi-served. These findings highlight the relevance thattioning the need for different approaches in dosagepatients’ residual renal function may have in signifi-adjustments.cantly enhancing the elimination of piperacillin/
From all of these studies, considering the verytazobactam during CVVH. Indeed, optimal pharma-wide pharmacokinetic variability documented undercodynamic exposure (in terms of an appropriatethe different operating conditions, it seems quiteCmin>MIC) against susceptible pathogens wasdifficult to identify the optimal dosage for piperacil-not always ensured by the two administered dos-lin/tazobactam during CRRT. As a general rule, iting regimens of piperacillin/tazobactam. Whereas inmay be suggested that in most cases, a dosing regi-anephric patients a T>MIC of 100% was alwaysmen of 4.0g/0.5g every 8 hours seems to be appro-ensured against all of the susceptible pathogenspriate for ensuring optimal pharmacodynamic expo-(MIC ≤64 mg/L), in those presenting with moderatesure in terms of the Cmin>MIC when applying bothresidual renal function this goal was achieved onlyCVVH and CVVHDF at moderately high QUF and/against pathogens with an MIC of ≤32 mg/L, where-or QD. However, it should not be overlooked thatas it dropped to only 55% against pathogens with anearlier studies suggested a potential for accumula-MIC of 64 mg/L. More importantly, in those withtion when using this dosage regimen. Conversely,preserved renal function, a subtherapeutic T>MICthe most recent studies have highlighted higher drugwas frequently documented even when administer-removal when using polysulfone rather than ac-ing 4.0g/0.5g every 6 hours (T>MIC 55% with anrylonitrile haemofilters and the need for intensifiedMIC of 32 mg/L; T>MIC 17% with an MIC offrequency of administration from every 8 hours to64 mg/L). This led the investigators to suggest thatevery 4 hours in patients with a significant residualan increase in the frequency of administration of therenal function, especially in settings at high risk of4.0g/0.5g dose from every 8 hours to every 4 hourspathogens with borderline susceptibility (MICshould be considered when applying CVVH to pa-32–64 mg/L).tients with normal renal function. Another interest-
ing aspect of this study was the observation that,irrespective of the patient’s residual renal function, 3.1.3 Cephalosporinsthe Sc of tazobactam was similar to the unbound Similarly to the other classes of β-lactams, mostfraction, with no patient presenting tazobactam ac- cephalosporins are frequently characterised by lowcumulation; conversely, that of piperacillin was al- Vd, poor or moderate plasma protein binding andways less than one-half of the unbound fraction. high CLR (table III), and these pharmacokineticThis led the investigators to conclude that when parameters make them highly CRRT removable.
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Disposition of Antimicrobials during CRRT 1021
Since CLCRRT is frequently a significant part of CL and of a similar value in the two groups (0.78of the drug, additional doses in comparison with and 0.86 in CVVHDF and CVVH, respectively).anephric patients are frequently needed in these As expected, during the application of CVVHDF,circumstances. However, a notable exception to this higher CLCRRT (26.0 vs 13.0 mL/min) and a shorterrule is represented by ceftriaxone, which is highly t1/2 (8.6 vs 12.9 hours) were documented. However,protein bound and mainly cleared by the biliary although CLCRRT accounted for a larger extent offaecal route.[15,16] The most recent literature con- CL during CVVHDF (59% vs 40%), the calculatedcerns those cephalosporins most frequently used to pharmacodynamic parameters led the investigatorstreat life-threatening infections in the ICU setting, to conclude that in patients undergoing both CRRTnamely cefepime, cefpirome, ceftazidime and cef- techniques in the aforementioned operating condi-triaxone. tions, a dosing regimen of either 2g every 24 hours
or 1g every 12 hours may be appropriate for ensur-Cefepime ing a T>MIC of 100% against susceptible pathogensCefepime is a fourth-generation cephalosporin with an MIC of ≤8 mg/L.
that is approximately 16–19% plasma protein Recently, the influence of CVVHDF and CVVHbound, has a low Vd and is primarily renally excret- on cefepime removal was comparatively reassesseded, with a t1/2 of 2.3 hours in patients with normal in four critically ill patients.[57] In this study,renal function.[12]
cefepime CL was found to be significantly higherThe pharmacokinetic behaviour of cefepime at a than in the previous study[56] during both CVVH
dosage of 2g every 12 hours was first investigated in (121.3 vs 36 mL/min) and CVVHDF (101.8 vssix anuric patients during postdilution CVVHDF 47.0 mL/min), and so a higher dosing regimen (2gequipped with a acrylonitrile haemofilter.[55] The
every 8 hours) was advocated in order to ensure anmean Sc of 0.72 coupled with the low Vd (0.71 L/kg)
appropriate Cmin of >10 mg/L. Interestingly, in thesuggested that cefepime may be highly cleared bytwo studies, the CRRT device’s operating condi-CVVHDF. However, a very surprising and unex-tions were quite similar (acrylonitrile membrane inplained finding was the fact that the CLCRRTall but one case, with relatively high ultrafiltrationwas about 2.56 times higher than CL (60.98 vsand dialysate flow rates) and the absolute values of23.80 mL/min/kg). This apparent impossibilityCLCRRT (18.5 vs 13.0 mL/min during CVVH andmight be due to potentially inappropriate handling35.9 vs 26 mL/min during CVVHDF) were notof data analysis, considering that the methods usedsufficiently different to justify these findings. Thisfor calculating drug clearances were not identifiedapparent incongruence was explained consideringby the investigators, who simply stated that estima-that the patients undergoing CRRT in this studytions were generated automatically by means ofpresented with significant residual renal functionpharmacokinetic software (P-PHARM). Although(mean CLCR 24.7 mL/min), a fact that may havethis poses some doubts about the reliability of theenhanced cefepime clearance. Consistent with this,results, on the basis of the cefepime Cmin averagingin these subjects the cefepime t1/2 was significantly17.7 mg/L at 12 hours, it was concluded that 2g ofshorter (4.1 hours vs 12.9 hours during CVVH;cefepime every 12 hours may be appropriate for5.2 hours vs 8.6 hours during CVVHDF) and theensuring optimal pharmacodynamic exposure, inCLCRRT accounted for a significantly lower percent-terms of Cmin >5 times the MIC, against susceptibleage of CL (15.3% vs 40% during CVVH, 35.3% vspathogens (MIC ≤4 mg/L).59% during CVVHDF) than in the study by MaloneThe different influence that CVVHDF and CV-et al.[56] An additional finding of this study was theVH, applied in postdilution mode and at a relativelyfact that no differences were detected in the in vitrohigh flow rate, may have on cefepime pharmacoki-permeability of the acrylonitrile and polysulfonenetics was comparatively assessed in two groups ofmembranes to cefepime in human plasma duringcritically ill patients receiving various dosing regi-both CVVH (Sc 0.95 vs 0.90) and CVVHDF (Scmens ranging between 1.0g every 24 hours and 2.0g0.82 vs 0.92).[57]every 12 hours.[56] The Sc was confirmed to be high
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
1022 Pea et al.
In summary, cefepime was found to be signifi- Consistent with the low trough concentrations thatcantly removed during both CVVH and CVVHDF, were documented (3.1 mg/L), the investigators re-but to a very different extent according to various commended a dosage of 2g every 8 hours in anuricoperating conditions and the patient’s pathophysio- patients undergoing CVVH under these operatinglogical status. As a general rule, in anuric patients conditions in order to maintain drug concentrationsundergoing CVVH and CVVHDF, a dosage of 1–2g above the MIC of most susceptible pathogens.every 12 hours may be reasonably suggested for In a subsequent commentary on the discrepanciesensuring appropriate pharmacodynamic exposure in between these two studies, Thalhammer and Sios-terms of a Cmin of >1–5 times the MIC for suscepti- trzonek[93] correctly pointed out that the differencesble pathogens. However, in patients with residual might have been due to patient-related factors andrenal function, the cefepime dosage must be in- to differences in various characteristics of thecreased to 2g every 8 hours, especially when using haemofiltration systems, such as the haemofilterhigh ultrafiltration rates. membrane, QUF and CLCRRT. However, they did
not take issue with an even more important finding.Cefpirome In fact, the CL of cefpirome during their studyCefpirome is a fourth-generation cephalosporin (589.1 mL/min) was enormously higher than those
that is approximately 10% plasma protein bound, observed not only by Van der Werf et al.[58] duringpresents a low Vd and is almost exclusively renally CVVH with a polyamide membrane (32.0 mL/min)excreted, with a t1/2 of 1.8 hours in patients with but also in healthy volunteers (142.0 mL/min). Thisnormal renal function.[13]
finding seems to suggest that significant adsorptionThe pharmacokinetic behaviour of cefpirome of cefpirome to the polysulfone haemofilter might
during the application of CVVH was assessed by have occurred in this particular case, probably cou-two groups of investigators, but both the findings pled also to compensatory clearance by other elimi-and the conclusions drawn were conflicting. Van der nation routes.Werf et al.[58] investigated cefpirome removalduring CVVH equipped with a polyamide haemofil- Ceftazidimeter. Surprisingly, despite use of a relatively high
Ceftazidime is a third-generation anti-pseu-QUF and an Sc of 0.64, suggesting valid permeabili-domonal cephalosporin that is approximately 10%ty of the membrane, a very low absolute CLCRRTplasma protein bound, presents a low Vd and iswas documented (17 mL/min). This value corre-almost exclusively renally excreted in patients withsponded to about one half of the CL of cefpirome innormal renal function, with a t1/2 of 1.6 hours.[14]
these patients, which in turn was about a quarterThe pharmacokinetics of ceftazidime during CV-of that observed in healthy volunteers (32.0 vs
VHDF equipped with a polyacrylonitrile membrane142.0 mL/min), with a correspondently longer t1/2
were first investigated by Sato et al.[60] in three(8.8 vs 1.7 hours). On the basis of these results, theanuric critically ill patients after administrationinvestigators concluded that in order to avoidof a single 1g dose. The t1/2 of ceftazidime wasoverdosing with cefpirome during CVVH, 1g everyassessed during a 12-hour application with relative-12 hours may be sufficient to offer appropriate cov-ly low ultrafiltration and dialysate flow rates. Plas-erage under these operating conditions.ma ceftazidime concentrations averaged 19.0 andConversely, in eight anuric patients undergoing11.9 mg/L at 6 hours and 12 hours, respectively,postdilution CVVH equipped with a polysulfoneafter starting ceftazidime administration. The esti-membrane during administration of cefpirome 2gmated ceftazidime t1/2 was significantly longer thanevery 8 hours, much higher CLCRRT than previouslyin healthy volunteers (6.8 hours),[14] but unfortunate-observed (43.3 vs 17 mL/min) was documented.[59]
ly neither the CLCRRT nor the Sc were determined.This result may be partially explained by the higherOn the basis of these few data, the investigatorsQUF applied, but suggests also that the permeabilityestimated that a dosing regimen of 1g every 24 hoursof the polysulfone membrane to cefpirome may bewould have been appropriate.higher than that of polyamide (Sc 0.78 vs 0.64).
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Disposition of Antimicrobials during CRRT 1023
The relative influence that convective and diffu- Of note, much higher dosages were subsequentlyproposed by Traunmuller et al.[62] when investigat-sive clearance may have on extracorporeal removaling the clearance of ceftazidime during the applica-of ceftazidime by means of three different typestion of high-volume postdilution CVVH equippedof RRT membranes (acrylonitrile, polymethyl-with a polysulfone membrane to 12 patients withmethacrylate [PMMA] and polysulfone) was sepa-acute renal failure. On the basis of a pharmacody-rately investigated during subsequent application ofnamic analysis, it was suggested that the correctboth CVVH and CVVHD (for periods of 1 hourdoses for maintenance of optimal exposure againsteach) in eight stable haemodialysis patients withfully susceptible pathogens (target Cmin 4 mg/L) orend-stage renal disease (ESRD) and no infection.[61]
against intermediately resistant pathogens (targetInterestingly, during the application of CVVH,Cmin 8 mg/L) would have been 2g every 8 hours orCLCRRT of ceftazidime was found to increase lin-3g every 8 hours, respectively. Indeed, when look-early with the QUF that was applied (0.5 and 1 L/h),ing at extracorporeal drug removal, it may be ob-but it was not influenced by the type of haemofilterserved that in this study, CLCRRT was proportionalused. The high Sc, averaging 0.91 in all cases,to that observed by Matzke et al.[61] using a lower
suggested that ceftazidime may be highly removedQUF with a device equipped with a similar mem-
by means of this technique, irrespective of the brane (32.1 mL/min at a QUF of 2.82 L/h vstype of membrane. Likewise, during the application 16.5 mL/min at a QUF of 1.0 L/h) and that the Sc wasof CVVHD, CLCRRT of ceftazidime increased pro- even lower (0.69 vs 0.91). This suggests that, theo-portionally with the QD applied (0.5, 1.0, 1.5 and retically, the dosage adjustments proposed on the2.0 L/h) in a manner unaffected by the membrane basis of extracorporeal drug removal should havetype. Consistent with these findings, it was suggest- been more or less of a similar extent. Conversely,ed that the most important factor for choosing the the very different dosages may be explained by thecorrect adjustment of the ceftazidime dosage during fact that the investigators did not take issue with anCRRT may be represented by the applied QUF or QD important aspect, namely that CLCRRT accountedfor CVVH and CVVHD, respectively. Interestingly, for about only one-third of ceftazidime CL (32.1 vsalthough the CL of ceftazidime was not directly 98.7 mL/min). This means that in these critically illassessed in this study, it may be noted that the patients, ceftazidime should have been significantlyminimum and maximum values of CLCRRT corre- cleared (other than by means of CRRT) by othersponded to about 5% and 21%, respectively, of compensatory routes and/or may even have beenthe CL found in historical healthy volunteers adsorbed to the haemofilters. This may explain why(131.83 mL/min).[14] Accordingly, proportional dos- its t1/2 was only moderately prolonged in comparison
with healthy volunteers (4.3 vs 1.7 hours).age adjustments were proposed. As an example, inanuric patients the proposed dosages ranged from Very recently, in an attempt to maximise the0.25g every 12 hours to 0.5g every 12 hours during time-dependent pharmacodynamic activity of cef-CVVH with ultrafiltration rates of 0.3 and 3.0 L/h, tazidime, drug removal was assessed during intrave-from 0.5g every 12 hours to 0.75g every 12 hours nous continuous infusion of 3g every 24 hours induring CVVHDF with dialysate flow rates of 1.0 seven critically ill patients undergoing predilutionand 2.0 L/h, and concomitant ultrafiltration rates CVVHDF equipped with a acrylonitrile mem-ranging from 0.5 to 2.0 L/h. Obviously, the eventual brane.[63] The application of relatively high CRRTpresence of residual renal function must be taken flow rates (QUF 1.5 L/h and QD 1.0 L/h) caused ainto account in order to avoid underdosing with both CLCRRT of a similar extent to that observed duringof these techniques. Although interesting, the com- high-volume postdilution CVVH by Traunmuller etplicated design of the study and the different patho- al.[62] (33.6 vs 32.1 mL/min). However, in this study,physiological status of the population studied the relative influence of CLCRRT – by accounting(ESRD without an infection) mean that these results for a much higher percentage of ceftazidime CLare not fully applicable to critically ill patients with (53.8% vs 33%) – was found to be significantlyacute renal failure. higher. On the basis of the most recent literature
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
1024 Pea et al.
suggesting a steady-state value of 4–5 times the tients with acute renal failure while applying moder-MIC as the optimal pharmacodynamic goal against ately high QUF.[64] Interestingly, the study designsusceptible pathogens in the treatment of immuno- included a simultaneous comparison with the phar-compromised patients with ceftazidime,[94] the ob- macokinetic data observed in two control groups inservation of a steady-state plasma drug concentra- which patients, receiving similar drug dosages andtion (Css) averaging 33.5 mg/L led the investigators not undergoing to CRRT, were split according to theto recommend that after a loading dose of 2g, a degree of renal function (normal renal function ormaintenance dosage of 3g every 24 hours should be mild renal insufficiency). The CLCRRT of ceftriax-administered by continuous infusion in the treat- one in patients undergoing CVVH was very similarment of critically ill patients undergoing CVVHDF. to the extent of renal clearance observed in patients
with normal renal function (16.6 vs 15.8 mL/min)In summary, from the different studies assessingand accounted for the same percentage of CLpharmacokinetic behaviour during CRRT, it appears(42.2%). Considering that ceftriaxone is primarilythat ceftazidime is significantly removed duringcleared by the biliary route, these findings suggesteither CVVH or CVVHDF, always with CLCRRTthat in anuric patients, CRRT may efficiently re-being linearly proportional to the applied CRRTplace renal function in removing ceftriaxone. Ac-flow rates and with a high Sc regardless of thecordingly, no dosage reduction in comparison withhaemofilter utilised. This obviously means that thepatients with normal renal function was recommen-higher the CRRT flow rate is, the higher the dosingded in these circumstances (2g every 24 hours).regimen should be. As a general rule, a dosingDespite this fact, it should be noted that the Sc ofregimen ranging from 0.25g every 12 hours to 0.75gceftriaxone was significantly greater than expectedevery 12 hours seems to appropriately substituteon the basis of the theoretical unbound drug moietydrug removal due to CRRT. However, it should not(0.69 vs 0.10–0.15). Although this may be partiallybe overlooked that in some studies, the CL of cef-explained by the potential hypoalbuminaemia oc-tazidime in anuric patients was found to be 2 or 3curring in some patients (total plasma protein aver-times higher than CLCRRT (98.7 vs 32.1 mL/min;[62]
aging 5.7 g/dL), the investigators concluded that62.4 vs 33.6 mL/min[63]). Therefore, in these cir-factors other than protein binding may be importantcumstances, since CL in anuric patients may ap-determinants of drug removal during haemofiltra-proach the values normally observed in healthy vol-tion, among which the requirement for electroneu-unteers,[60] correspondently higher dosages shouldtrality across the haemofiltration membrane wasbe recommended, up to 2–3g every 8 hours. Per-considered the most relevant.[64]haps, in these circumstances, the most cost-effective
approach may be represented by continuous infu- Likewise, similarly higher than expected Sc val-sion of 3 g/day, which may enable maximisation of ues, which were unpredictable on the basis of thethe pharmacodynamic exposure to ceftazidime by free moiety, were subsequently documented byusing relatively low dosages. However, given the Matzke et al.[65] when assessing the relative influ-wide interindividual pharmacokinetic variability ob- ence that convective and diffusive clearance mayserved, tailoring of the dosing regimen by means of have on extracorporeal removal of ceftriaxone byTDM should be considered whenever possible. means of three different types of RRT membranes
(acrylonitrile, PMMA and polysulfone). After ad-Ceftriaxone ministration of a single 1g dose of ceftriaxone, CV-Ceftriaxone is a third-generation cephalosporin VH and CVVHD at increasing ultrafiltration rates
with a low Vd and a relatively long t1/2 due to (0.5 and 1.0 L/h) and dialysate flow rates (0.5, 1.0,extensive plasma protein binding. It is only partially 1.5, 2.0 L/h) were applied during subsequent periodsrenally cleared in patients with normal renal func- of 1 hour each to eight stable haemodialysis patientstion.[15,16] with ESRD and no infection. Although the fraction
The pharmacokinetic profile of ceftriaxone dur- of ceftriaxone bound to plasma protein was found toing postdilution CVVH equipped with a polyamide vary in a concentration-dependent manner and to behaemofilter was investigated in six critically ill pa- significantly lower in these ESRD patients than in
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Disposition of Antimicrobials during CRRT 1025
subjects with normal renal function (average 43%, route and that CLCRRT was found to almost equaterange 13–92%), the Sc of ceftriaxone was found to to CLR in healthy volunteers, it may be reasonablybe more or less proportional to the unbound moiety suggested that an unmodified dosage of 2g every 24(0.48) during application of CVVH only with the hours be used to ensure appropriate pharmacody-acrylonitrile membrane. Conversely, much higher namic exposure against susceptible pathogens.Sc values were observed with the PMMA and However, in hypoalbuminaemic patients and inpolysulfone filters (averaging 0.86 and 0.82, respec- those with residual renal function, even higher dos-tively). Accordingly, CLCRRT of ceftriaxone, al- ages could be needed, especially when using high-though increasing linearly with the QUF applied (0.5 volume ultrafiltration rates.and 1 L/h), was found to be significantly higher with
3.1.4 Aminoglycosidesthe PMMA and polysulfone membranes than withAminoglycosides are hydrophilic antibacterialsthe acrylonitrile membrane. These data suggested
characterised by low Vd, absence of plasma proteinthat CVVH may efficiently replace renal function inbinding and almost complete CLR, which may ex-removing ceftriaxone, but in a manner dependent onplain their rapid and consistent extracorporeal re-both the membrane type and the QUF applied. Formoval during CRRT. This means that in these cir-example, the mean CLCRRT rates observed with thecumstances, additional doses would usually be re-PMMA and polysulfone membranes when applyingquired in comparison with anephric patients.a QUF of 1 L/h (11.8 and 11.0 mL/min, determinedNetilmicin is the only aminoglycoside whoseby visual inspection of a figure) were even higherpharmacokinetics during CRRT have been recentlythan the CLR rates observed in historical healthyinvestigated.volunteers (8.6 mL/min), indeed approaching CL
(14.2 mL/min).[15,16] These data suggest that no dos- Netilmicinage reduction may be necessary for ceftriaxone in The pharmacokinetic profile of netilmicin duringthese circumstances. Likewise, during the applica- the application of CVVHDF equipped with an ac-tion of CVVHD, CLCRRT of ceftriaxone increased rylonitrile haemofilter was investigated in six criti-proportionally with the QD applied (0.5, 1.0, 1.5 and cally ill patients with acute renal failure.[66] During2.0 L/h) but in a manner affected by the membrane the application of moderate QD (0.87 L/h) and lowtype, being greater with the PMMA and polysulfone QUF (0,15 L/h), the estimated peak plasma concen-membranes. However, it should be noted that the trations of netilmicin following administration ofefficiency of diffusive clearance was always lower 150mg every 12 hours ranged between 4.02 andthan that of convective clearance, even when apply- 7.69 mg/L. Since the Cmax/MIC ratio estimatesing the highest QD of 2 L/h. Consistent with these against the most relevant bacterial pathogens werefindings, it was suggested that the most important frequently lower than the proposed pharmacody-factor for choosing the right adjustment of ceftriax- namic threshold of 8, it was concluded that such aone dosage during CVVH and CVVHD may be regimen did not allow optimal exposure for therepresented by the applied QUF and QD, respective- treatment of severe infections in the ICU setting.ly. Indeed, once more it must be highlighted that the Given the wide interindividual pharmacokineticcomplicated design of the study and the different variability observed, adjustment of both the drugpathophysiological status of the studied population dosage and the dosing interval by means of TDM(ESRD patients without an infection) mean that was strongly advocated. Unfortunately, neither thethese results are not fully applicable to critically ill Sc nor CLCRRT were directly assessed, and so nopatients with acute renal failure. definitive evidence regarding the extent of drug
In summary, ceftriaxone was found to be signifi- removal by means of this CRRT technique wascantly removed during both CVVH and CVVHD presented. However, it may be noted that althoughbut to a different extent according to RRT operating these patients presented with some residual renalconditions and the membranes utilised. Generally, function (mean CLCR 22.3 mL/min), the CL ofin anuric patients undergoing CVVH, considering netilmicin corresponded to about one-half that ob-that ceftriaxone is mainly cleared by the biliary served in historical volunteers with normal renal
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
1026 Pea et al.
function (44.03 vs 91 mL/min),[17] suggesting that avoid underexposure to teicoplanin in hy-the drug may be significantly removed by CRRT. poalbuminaemic patients undergoing CVVH.
The potential influence that the exhaustion of the3.1.5 Glycopeptides filter may have in reducing teicoplanin extractionThe glycopeptides teicoplanin and vancomycin during CVVH at very high ultrafiltration rates was
are hydrophilic antimicrobials frequently used for tested in three critically ill patients with acute renalthe treatment of life-threatening, multidrug resistant, failure by comparing the pharmacokinetic profileGram-positive related infections in ICU patients. after administration of 12 mg/kg every 24 hours onAlthough their very high molecular weight may two subsequent days.[67] The mean CL of teico-prevent their removal during haemodialysis, the low planin was significantly higher with the new mem-Vd and prevalent CLR (table III) make them theoret- brane than with the one previously used for 24 hoursically removable by CRRT. As with other hydro- (56.6 vs 14.5 mL/min), suggesting that the efficien-philic compounds, in these circumstances additional cy of drug extraction may be consistently reduced asdoses are frequently needed in comparison with a consequence of filter use. Since only negligibleanephric patients, but indeed their amount is diffi- drug concentrations were documented in the ultrafil-cult to predict considering that drug removal is trate, the investigators hypothesised that in this par-expected to be influenced to a variable extent by the ticular case, drug adsorption to the polyamideunderlying pathophysiological conditions. haemofilter, rather than ultrafiltration, might have
been the major drug removal mechanism. Besidesthis, it was concluded that fixed dosage recommen-Teicoplanindations for teicoplanin are unsuitable during CVVHTeicoplanin is a highly protein-bound drug. Inand that daily dosage adjustment by means of TDMhealthy volunteers, it exhibits a long t1/2 with a smallis strongly advisable. Interestingly, it should beVd and low CL, and is almost completely renallymentioned that in this study, CL of teicoplanincleared.[21]
during the application of very high ultrafiltrationThe removal of teicoplanin during CVVH wasrates in the presence of a new membrane was morefirst assessed by Pea et al.[38] in a renal trans-than three times higher than that observed in histori-plant patient with some residual renal function.cal healthy volunteers (56.6 vs 14.7 mL/min),[21] andAfter an initial loading period with dosages rang-this, although not directly addressed by the investi-ing between 8.57 and 11.42 mg/kg/day in order togators, may mean that unexpectedly high mainten-rapidly achieve a therapeutically effective Cmin ofance dosages may be needed to ensure therapeutical->20 mg/L (22.79 mg/L on day 6), it was observed only effective concentrations in these circumstances.day 9 that despite high maintenance doses, the appli-
cation of CVVH at a relatively high QUF led to a The pharmacokinetic profile of teicoplanin at ansignificant drop in the Cmin (to 18.52 mg/L). Of intravenous daily dosage of 400mg was investigatednote, when the QUF was halved the next day, the during postdilution CVVHDF in three critically illteicoplanin Cmin became 1.5 times higher (from patients with acute renal failure while applying18.52 to 27.67 mg/L), suggesting that the applica- moderately high RRT flow rates.[68] Teicoplanintion of different ultrafiltration rates might have in- was found to be significantly removed by this tech-fluenced the extent of drug removal. Interestingly, nique, considering that CLCRRT accounted foralthough CLCRRT was not directly estimated, it was about 30% of CL which, in turn, was found to benoted that the Sc was significantly higher than ex- only slightly lower than that observed in healthypected on the basis of the theoretical drug protein volunteers (11.3 vs 14.7mL/min).[21] According tobinding (0.17 vs 0.10). On the basis of these find- a pharmacokinetic simulation, it was estimatedings, it was hypothesised that by increasing the free that in order to maintain an appropriate Cmin ofmoiety, the severe hypoalbuminaemic status of the 10–20 mg/L in these situations, very different dos-patient might have accounted for higher than expec- ages may be needed (200mg every 48 hours in twoted extracorporeal drug removal. Accordingly, it cases and 400mg every 24 hours in another case),was concluded that TDM is highly recommended to and therefore routine TDM was recommended. In-
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Disposition of Antimicrobials during CRRT 1027
deed, the very large variability in drug dosing might Sc in the three filter groups was high, averagingbe explained by the different albuminaemic status of between 0.68 and 0.86, and this suggested that van-the patients. Although this hypothesis may not be comycin may be highly removed by means of CV-directly corroborated (neither serum albumin levels VH irrespective of the membrane type. Likewise,nor Sc values were reported in this study), it may be during the application of CVVHD, CLCRRT of van-supported by other investigators’ findings showing a comycin increased linearly with the applied QD (0.5,significant inverse relationship between teicoplanin 1.0, 1.5 and 2.0 L/h), but in a manner significantlyCL and serum albumin levels in 12 critically ill greater with the PMMA filter than with the acryloni-hypoalbuminaemic patients.[95] trile and polysulfone filters in the presence of high
flow rates. Consistent with these findings, it wasIn summary, teicoplanin was found to be signifi-suggested that the most important factor for choos-cantly removed during both CVVH and CVVHDF,ing the right dosage adjustment for vancomycinbut to a very different extent according to the RRTduring CVVH and CVVHD may be represented byoperating conditions and the albuminaemic status ofthe applied QUF and QD, respectively. Interestingly,the patients. Generally, in anuric patients undergo-although vancomycin CL was not directly assesseding CRRT, considering that CLCRRT was found toin this study, it may be speculated that the range ofbe similar or even higher than CL in healthy volun-CLCRRT fluctuated between 4% and 21% of the CLteers, it may be reasonably suggested that to ensureobserved in historical healthy volunteers (131.0 mL/appropriate pharmacodynamic exposure against sus-min).[19] Accordingly, proportional dosage adjust-ceptible pathogens (Cmin of 10–20 mg/L), after anments were proposed with the intent of achievinginitial loading period of 6 mg/kg every 12 hours forappropriate pharmacodynamic exposure (average3–4 doses, the maintenance dosage should be at leaststeady-state concentration 20 mg/L). For example,3–6 mg/kg every 24 hours. However, in patientsin anuric patients, the proposed 24-hour dosagewith hypoalbuminaemia and/or with residual renalranged from 500 to 1050mg during CVVH at ultra-function, even higher dosages could be needed, es-filtration rates of 0.12 and 1.8 L/h, and from 800 topecially when using high-volume ultrafiltration1350mg during CVVHDF for dialysate flow rates ofrates. Accordingly, given the very large pharma-1.0 and 2.0 L/h and concomitant ultrafiltration ratescokinetic variability of teicoplanin, TDM is stronglyof 0.12 and 0.3 L/h, depending also on the filter usedrecommended in critically ill patients undergoing(PMMA > polysulfone > acrylonitrile). Obviously,CRRT.the presence of residual renal function must be takeninto account to avoid underdosing during RRT withVancomycinboth of these techniques. Again, it should not beVancomycin is a moderately protein-bound hy-overlooked that the complicated design of the studydrophilic compound, which in healthy volunteersand the different pathophysiological status of theexhibits a relatively short t1/2 as a consequence ofstudied population (ESRD with no infection) meanextracellularly limited distribution and mainly renalthat these results are not fully applicable to criticallyclearance.[21]
ill patients with acute renal failure. Additionally,The relative influence that convective and diffu-given the marked interindividual pharmacokineticsive clearance may have on vancomycin ex-variability, dosage optimisation by means of TDMtracorporeal removal by means of three differentwas suggested.types of RRT membranes (acrylonitrile, PMMA and
polysulfone) was investigated separately during the The pharmacokinetics of vancomycin duringapplication of CVVH and CVVHD (at increasing postdilution CVVH equipped with a polyacryloni-flow rates for periods of 1 hour each) in stable trile haemofilter were assessed in two critically illhaemodialysis patients with ESRD and no infec- patients with acute renal failure under moderatelytion.[69] During the application of CVVH, CLCRRT high ultrafiltration rates.[70] The high Sc andof vancomycin was found to increase linearly with CLCRRT accounting for about 70% of drug CL sug-the QUF applied (0.5 and 1 L/h), but no differences gested that vancomycin may be significantly re-between the three haemofilters were observed. The moved by CVVH. On the basis of these findings, it
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
1028 Pea et al.
was recommended that in order to ensure adequate initial loading dose of 15 mg/kg, a maintenance doseexposure under these operating CVVH conditions ranging from 0.25 to 0.5g every 12 hours may be24 hours after an initial loading dose of 15–20 mg/ appropriate during the application of CVVH andkg, the maintenance dose should be between 250 CVVHDF at moderately high ultrafiltration and/orand 500mg every 12 hours, and that subsequent dialysate flow rates, but in the presence of very highadjustments should be based on close TDM of se- QUF (6 L/h), even full daily dosages of 0.5g every 6rum concentrations. Of note, the proposed mainten- hours may be necessary. Obviously, in these pecu-ance dosage corresponded to about 25–50% of the liar situations, frequent TDM of serum concentra-conventional starting dosage used in patients with tions may be extremely helpful in optimising day-normal renal function, and this approach is consis- by-day vancomycin exposure in critically ill pa-tent with the fact that the CL found in this study tients.corresponds to about 25–50% of that found in his-
3.2 Lipophilic Antibacterialstorical healthy volunteers (32.5 vs 84.8 mL/min).[20]
Interestingly, more recently it was shown that the Generally speaking, most lipophilic antibac-application of a very high QUF of 6 L/h during terials exhibit a high Vd and low CLR in healthyCVVH in patients with septic shock and multiple volunteers, and so they are expected to be poorly ororgan failure may significantly increase van- moderately CRRT removable. Interestingly, givencomycin CL to values approximating those ob- their wide intracellular distribution, the applicationserved in healthy volunteers. These values, averag- of high CRRT flow rates may increase eliminationing 53.9 mL/min during pure predilution and in- to a lesser extent than with hydrophilic compounds,creasing to a maximum of 67.2 mL/min during the since only a small fraction of the drug present in theapplication of 2 L/h predilution and 4 L/h postdilu- body is located in the plasma.tion, led the investigators to conclude that the
3.2.1 Fluoroquinolonesstandard full dosage (500mg every 6 hours) may beFluoroquinolones are poorly-to-moderately plas-necessary to appropriately treat septic shock patients
ma protein bound lipophilic antibacterials which inwith vancomycin during the application of CVVH athealthy volunteers have been shown to always ex-very high ultrafiltration rates.[71]
hibit high Vd (>1 L/kg), as a consequence of freeThe influence that predilution CVVHDFdiffusion through the plasmatic membrane and in-equipped with an acrylonitrile filter may have ontracellular accumulation, but whose extent of CLRextracorporeal removal of vancomycin was assessedwas shown to be significantly different according toin ten critically ill patients with acute renal failurethe physicochemical characteristics of each singlereceiving 750mg every 12 hours while applyingcompound (table III). Consistently, the entity ofmoderately high ultrafiltration and dialysate flowdrug removal by CRRT may be variable, and sorates.[72] Interestingly, both CLCRRT and CL of van-different approaches may be necessary for dosagecomycin (41.7 and 30.0 mL/min, respectively) wereadjustment: for those compounds normally at highhigher than the values observed by Boereboom etCLR, additional doses may be necessary in compari-al.[70] during the application of CVVH at similarson with anephric patients, whereas for those pre-ultrafiltration rates (32.5 and 23.3 mL/min, respec-dominantly cleared via nonrenal routes, convention-tively), suggesting that, under similar flow rates,al unmodified standard dosages, or even higher thanCVVHDF may be a more efficient technique fornormal dosages, may be required.removal of vancomycin. Accordingly, a mainten-
ance dose of 450mg every 12 hours was suggested in Ciprofloxacinorder to achieve an average steady-state concentra- Ciprofloxacin has been shown to exhibit ation of 15 mg/L. unique pharmacokinetic behaviour among fluoro-
In summary, vancomycin was shown to be signif- quinolones, in that multiple routes of clearance mayicantly removed during both CVVH and CVVHDF, explain its extreme pharmacokinetic variability inbut to a very different extent according to the CRRT critically ill patients. Whereas the renal route andoperating conditions. As a general rule, after an hepatic metabolism account for about 50–60% and
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Disposition of Antimicrobials during CRRT 1029
Levofloxacin20%, respectively, of ciprofloxacin elimination inConsistent with its frequent use in the treatmenthealthy volunteers, significant transintestinal excre-
of ICU-related infections, levofloxacin has beention may also occur. Of note, this latter eliminationthe most extensively investigated fluoroquinolonepathway may represent a compensatory mechanismduring the application of CRRT in recent years.that prevents drug accumulation in patients withSince renal function was shown to be the mostrenal failure.relevant factor accounting for its pharmacokineticThe different influence that CVVH and CV-variability, due to the fact that it is almost complete-VHDF, equipped with an acrylonitrile haemofilterly renally cleared (table III), CRRT is expected to
and applied in postdilution mode at a relatively highsignificantly contribute to its removal.
flow rate, may have on ciprofloxacin pharmacoki-The different influence that relatively high-flownetics was comparatively assessed in two groups of
CVVH and CVVHDF equipped with acrylonitrilecritically ill patients receiving dosing regimens ofmay have on levofloxacin pharmacokinetics was400mg every 12 hours or every 24 hours.[73] Where-comparatively assessed in two groups of critically illas the Sc values were high and similar in the twopatients during two subsequent studies by different
groups (0.72 and 0.63 in CVVH and CVVHDF,investigators. In the first study, CRRT was applied
respectively), during the application of CVVHDF in postdilution mode and the levofloxacin dosingthere was almost a doubling of CL (146.2 vs regimens ranged between 250mg every 24 hours to84.4 mL/min) and CLCRRT (21.0 vs 12.4 mL/min), 500mg every 48 hours.[73] In spite of an Sc averagingand the t1/2 was halved (8.3 vs 18.5 hours). Since about 0.6 in both groups, higher drug extractionCLCRRT was found to account only for about 15% of occurred during the application of CVVHDF, withCL during both CVVH and CVVHDF, it was con- CLCRRT being almost doubled, than during CVVHcluded that CRRT did not contribute significantly to (21.7 vs 11.5 mL/min). Also, CL was found to beciprofloxacin removal. Consequently, irrespective higher during CVVHDF but to a lesser extent (51.2of the CRRT type, a dosing regimen of 400mg every vs 42.3 mL/min), thus leading to a shorter t1/2 (18.624 hours was considered adequate for the mainten- vs 26.9 hours). On the basis of these findings, it wasance of typical ciprofloxacin exposure in serum. concluded that a dosing regimen of 250mg every 24Indeed, this suggestion seems to be an excessive hours or 500mg every 48 hours may be adequatesimplification considering the highly variable inter- under these operating conditions. In another com-patient elimination (CL range 34–117 mL/min parative study with a similar design, CRRT (appliedduring CVVH and 121–208 mL/min during CV- at comparable QUF and QD) was used in predilutionVHDF) and the 2-fold higher mean CL observed mode, and the levofloxacin dosing regimen rangedduring CVVHDF. In fact, it should not be over- from 125mg to 500mg every 24 hours.[74] Interest-looked that in a recent study of critically ill patients ingly, since similar amounts of both CLCRRT and
CL were observed, it was confirmed that similarreceiving ciprofloxacin dosages ranging between24-hour dosages may be suitable during the applica-200mg and 400mg every 12 hours, drug exposure intion of CVVH (200mg every 24 hours) and CV-terms of the AUC was poorly correlated with CLCRVHDF (250mg every 24 hours).estimates, and so drug accumulation almost never
occurred in the presence of renal failure.[96] On this Similar pharmacokinetic behaviour was also doc-basis, it was suggested that lowering the ciprofloxa- umented during moderately high-flow postdilution
CVVH equipped with an acrylonitrile filter incin dosage in patients with renal failure seems un-six critically ill patients with acute renal failurenecessary in most cases, and that TDM could be(CLCRRT 20.1 mL/min; CL 41.9 mL/min),[75] andextremely helpful in these circumstances.[96] Con-this led the investigators to conclude that, after ansistently, in order to prevent underexposure withinitial loading dose of 500mg, a maintenance dose ofciprofloxacin during CRRT, it seems more prudent250mg every 24 hours seems appropriate.to consider higher dosages (i.e. 0.4g every 12
hours), especially in patients with normal hepatic In two other studies, levofloxacin removal wasfunction undergoing CVVHDF. assessed during the application of CVVH equipped
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
1030 Pea et al.
with different haemofilters and under different oper- mainly eliminated by means of hepatic phase 2ating conditions. Traunmuller et al.[76] observed that synthetic processes, namely conjugation.in 12 critically ill patients with acute renal failure The influence on moxifloxacin pharmacokineticsreceiving a single 500mg dose, the application of a of predilution CVVHDF equipped with an acryloni-high QUF (>3 L/h) in the presence of a polyamide trile haemofilter at moderately high flow rates washaemofilter led to significant and rapid drug elimi- assessed in nine critically ill patients with acutenation (CLCRRT 27.6 mL/min), the mean t1/2 value renal failure receiving 400mg every 24 hours.[78] In(8.3 hours) being similar to that in normal volun- most respects, the pharmacokinetics of moxiflox-teers; however no dosage recommendation was pro- acin were almost comparable to those in healthyvided. In another study, the application of CVVH volunteers,[26,27] and CLCRRT was found to be simi-equipped with a polysulfone haemofilter in four lar to CLR in healthy volunteers, both accounting forcritically ill patients presenting with some residual only 10–20% of CL (27.2 vs 50.5 mL/min). Indeed,renal function (mean CLCR 27 mL/min) and receiv- probably as a consequence of pathophysiologicaling 500mg every 24 hours led to enhanced drug changes in critical illness, higher CL was document-removal with greater than normal drug CL ed in these patients than in healthy volunteers (318.2(213.5 mL/min). However, because of the extreme vs 248.33 mL/min). However, considering that bothpharmacokinetic variability, a specific dosage rec- of the theoretical pharmacodynamic thresholds forommendation was not made, and TDM was suggest- moxifloxacin efficacy against Streptococcus pneu-ed with the intent of avoiding subtherapeutic plasma moniae (AUC/MIC >30 and Cmax/MIC >10) wereconcentrations.[77] achieved, it was concluded that the standard dosage
of 400mg every 24 hours may ensure appropriateIn summary, levofloxacin was shown to be sig-exposure and that no major dosage adjustment isnificantly removed during CRRT but in a mannerneeded under CRRT.dependent on the technique used (CVVHDF > CV-
VH), the flow rates applied and the patient’s residualrenal function. As a general rule, after an initial Ofloxacinloading dose of 0.5g, a maintenance dose of 0.25g Ofloxacin is the racemic mixture of levo- andevery 24 hours or 0.5g every 48 hours seems appro- dextro- isomers, which is predominantly cleared bypriate in most cases but, of note, even higher dos- the kidney.ages (0.5g every 24 hours) may be necessary in the Its pharmacokinetic behaviour during postdilu-presence of very high flow rates (>3 L/h) and/or tion CVVH equipped with polysulfone filters andresidual renal function. From a pharmacodynamic applied at a very high QUF (3 L/h) was assessedpoint of view, given the concentration-dependent during the administration of 400mg every 24 hoursantibacterial activity exhibited by fluoroquinolones, in eight critically ill patients with acute renal fail-the approach of 0.5g every 48 hours seems the most ure.[79] Interestingly, higher than normal CL wassuitable, considering that, with the same daily dose documented (278.4 mL/min), with a shorter t1/2 (2.8and therefore the same AUC, it may ensure a much hours). Despite a low Sc (0.24), CLCRRT was foundhigher peak concentration, thus increasing the likeli- to significantly contribute to drug removal, account-hood of clinical success. However, given the rele- ing for about one-third of CL (89.9 mL/min). Avant difference in plasma concentrations observed potential explanation for these unequal data is dif-in some cases, TDM must be considered helpful, ferences in membrane materials (polyamide, poly-especially when applying very high CRRT flow sulfone and acrylonitrile), blood and ultrafiltrationrates and/or in patients with significant residual re- flow rates, and probably disease severity among thenal function. patients (associated with differing serum protein
concentrations and thus modified drug protein bind-Moxifloxacin ing). Indeed, these findings are very different fromMoxifloxacin is an antipneumococcal respiratory those observed with levofloxacin (the levo-isomer
fluoroquinolone, which is increasingly used in criti- of ofloxacin) during CRRT, despite the fact that thecally ill patients with respiratory infections and is two drugs may be considered essentially the same
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Disposition of Antimicrobials during CRRT 1031
from a pharmacological standpoint. Indeed, these the time-dependent efficacy of linezolid against sus-unexpected findings were attributed by the investi- ceptible multidrug-resistant Gram-positive patho-gators to generic differences in RRT conditions gens (Cmin ≥4 mg/L), it was concluded that the(membrane materials and blood and ultrafiltration standard dosage of 600mg every 12 hours may be aflow rates), and probable differences in the disease reasonable choice during CVVH, but that attentionseverity of the patients, but this is probably not should be paid to patients in whom non-CVVH-enough to explain the huge differences. An addition- related clearance may be impaired. In fact, extremeal finding that is difficult to explain is the inconsis- interpatient variability in CL was documented (29.7tency of the low Sc with high CLCRRT, even if the and 90.75 mL/min), and so it was supposed thatinvestigators tried to justify it as a consequence of underlying pathophysiological conditions mightaltered plasma protein binding and/or substantial modify the non-CVVH-related clearance of linezol-drug adsorption to filter membranes. In any case, on id in critically ill patients. Likewise, similar ex-the basis of these findings, it was concluded that tracorporeal clearance rates (20.4 mL/min) wereofloxacin was significantly and rapidly eliminated documented by Fiaccadori et al.[81] in two patientsby CVVH, and so a minimum dosage of 400mg
receiving a single 600mg dose of linezolid duringevery 8 hours was recommended to ensure appropri-
the application of CVVH under similar operatingate exposure.conditions but equipped with a different haemofil-ter, namely acrylonitrile. However, the significantly3.2.2 Oxazolidinonesshorter t1/2 seems to suggest that in these cases, non-Oxazolidinones are a new class of antimicro-CVVH related clearance of linezolid, although notbial agents active against most multidrug resis-
tant Gram-positive bacteria, including glycopeptide- directly measured by the investigators, might haveresistant enterococci and staphylococci. been significantly higher. This fact strengthens the
hypothesis that wide variations in nonrenal clear-Linezolid
ance may represent the most relevant mechanismLinezolid, the first available member of this class of interindividual pharmacokinetic variability of
in clinical practice, is a poorly bound lipophiliclinezolid in critically ill patients. Interestingly, in 20
compound whose Vd almost equates to total bodycritically ill anuric patients, the application ofwater. In healthy volunteers, non-renal clearancepostdilution CVVH led to an almost doubled(by means of non-enzymatic metabolism via oxida-CLCRRT (39 mL/min)[82] compared with that observ-tion of the morpholine ring) accounts for most of aned by Pea et al.[80] (23.4 mL/min), although similaradministered linezolid dosage (65%), whereas theSc values were observed and the same filter typenet CLR of the unchanged drug is roughly 30%(polysulfone) and a similar QUF were applied. This(table III).suggests that much higher drug removal might occurThe influence of CVVH on linezolid pharma-when using CVVH in the postdilution mode. Incokinetics in critically ill patients with acute renaladdition, the CL of linezolid (172.5 mL/min) wasfailure was assessed in three different studies. Pea etfound to be much higher than in healthy volunteersal.[80] first reported linezolid pharmacokinetics(97.3 mL/min).[30] On the basis of these pharmaco-during predilution CVVH equipped with a polysul-kinetic findings, it was concluded that linezolid isfone filter and applied at a moderately high QUF insignificantly removed under these operating condi-two anuric, critically ill patients with severe post-tions. Accordingly, a pharmacodynamic analysissurgical intra-abdominal infections receiving asuggested that the T>MIC corresponded to 93% ofstandard dosage of 600mg every 12 hours. In boththe dosing interval for pathogens with an MIC ofpatients, a high Sc was observed and the resulting2 mg/L, but to only 57% of the dosing interval forCLCRRT (23.4 mL/min) was similar to the CLR inpathogens with an MIC of 4 mg/L,[82,83] and sohealthy volunteers (25.9 mL/min). According towhereas the standard dosage of 600mg every 12these pharmacokinetic findings, and on the basis ofhours may be adequate for fully susceptible patho-a pharmacodynamic analysis suggesting, in both
cases, appropriate pharmacodynamic exposure for gens, dose escalation up to 600mg every 8 hours
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
1032 Pea et al.
may be needed in the presence of the least-suscepti- hours might be justified whenever a patient presentsble pathogens. signs and/or symptoms of drug-related toxicity. Ob-
viously, in accordance with most of these studies,The effect of CVVHDF on linezolid removal hasTDM should be considered a helpful tool for op-been assessed in only two different single case re-timising therapy with linezolid in critically ill pa-ports. In one case,[84] during the application of rela-tients undergoing CRRT.tively high ultrafiltration and dialysate flow rates in
the presence of a polyacrylonitrile haemofilter, the 3.2.3 OthersCLCRRT of linezolid (21.6 mL/min) was found to
Colistin Methanesulfonatealmost equate to the CLR in healthy volunteersColistin methanesulfonate (colistimethate) is an(25.9 mL/min),[30] and so the authors correctly stated
old antibacterial that has been increasingly used inthat CVVHDF significantly contributed to linezolidthe last years as salvage therapy for the treatment ofelimination. Conversely, in the other case[85] al-multidrug-resistant Gram-negative related infec-though during the application of moderate QUF andtions in critically ill patients. Indeed, very little ishigh QD in the presence of a polysulfone haemofilterknown about its pharmacokinetics in healthy volun-the CLCRRT was much higher (36.5 mL/min),[85] itteers and in patients with normal renal function.[97] Itwas inappropriately stated that CVVHDF did notis predominantly cleared by the renal route, but asignificantly contribute to linezolid elimination. In-fraction is converted in vivo to colistin which, interestingly, both groups concluded that no additionalturn, is mainly cleared by non-renal mechanisms. Indoses over and above the standard 600mg 12-hourlyrenal impairment, a greater fraction of the adminis-regimen were necessary. This apparent incongru-tered dose would be converted to colistin, and so theence in the interpretation of the results might bedosage must be decreased.explained by considering that because of the very
The pharmacokinetic behaviour of colistindifferent CL of linezolid (84.7 vs 189 mL/min), themethasulfonate during postdilution CVVHDFpercentage relevance of CLCRRT accounted for asequipped with an acrylonitrile haemofilter and ap-much as 43.1% of CL in the first case but for onlyplied at high flow rates was assessed in a single11.4% of CL in the second case. Indeed, similarly topatient receiving 150mg every 48 hours, corre-what was observed during CVVH, this may be thesponding to 2.46 mg/kg.[86] Both colistin methasul-consequence of the wide variability of non-CVVH-fonate and colistin were removed by CVVHDF withrelated clearance, probably as a consequence ofsimilar clearance rates (11.2 mL/min for colistime-critical illness.thate and 11.9 mL/min for colistin). Importantly,In summary, considering that linezolid is mainlyduring most of the dosing interval (approximatelycleared by non-renal routes and that both CVVH and42 hours of the 48 hours), the plasma concentrationsCVVHDF at standard flow rates were shown inof colistin were below the MICs for P. aeruginosa,anuric patients to remove a drug amount equal to theand therefore it was suggested that the dosing inter-amount removed by the kidney in healthy volun-val be shortened from 48-hourly to 12-hourly inteers, the standard 600mg 12-hourly dosage seemsorder to ensure more appropriate exposure.appropriate in most cases. However, higher CLCRRT
may be predicted whenever very high flow rates are 3.3 Antifungal Agentsapplied, and so dosage escalation to 600mg every 8hours might be necessary under these operating con- The pharmacokinetic behaviour of antifungalditions. Additionally, it should be borne in mind that agents during CRRT has been assessed only fornon-CRRT related clearance may be significantly amphotericin B and fluconazole.altered by critical illness, thus representing the most
3.3.1 Polyenessignificant factor in interpatient variability. Accord-Amphotericin Bingly, dosage escalation to 600mg every 8 hours
might also be justified whenever a patient does not Amphotericin B is considered a mainstay in theappear to be responding to linezolid therapy; con- treatment of invasive fungal infections. However, itsversely, dosage de-escalation to 600mg every 24 therapeutic use is significantly limited by the risk of
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Disposition of Antimicrobials during CRRT 1033
3.3.2 Triazolesnephrotoxicity. Accordingly, lipid formulations ofamphotericin B, namely liposomal amphotericin B Fluconazole(L-AMPB) and amphotericin B lipid complex (AM- Fluconazole is a synthetic antifungal agent of thePB-LC), have been developed to overcome this. imidazole class, which is extensively used in criti-Indeed, very little is known about the pharmaco- cally ill patients for both prophylactic and therapeu-
tic purposes against Candida-related infections. Inkinetics of amphotericin B and its lipid formulationshealthy subjects, fluconazole exhibits poor plasmain healthy subjects.[32] Amphotericin B is very high-protein binding, a Vd similar to total body water and,ly protein bound and exhibits a large Vd, and al-unlike other triazoles, predominant elimination asthough its metabolism is largely unknown, its CLRthe unchanged drug by the renal route (table III).is extremely limited. As far as lipid formulations of
The relevance that different ultrafiltration ratesamphotericin are concerned, although the pharma-(1 L/h and 2 L/h) may have to increasing flucona-cokinetics of liberated amphotericin B are similar tozole removal by predilution CVVH equipped with a
those of the parent compound, the pharmacokinetic polysulfone haemofilter was investigated in ninebehaviour of the entrapped moiety essentially re- critically ill patients with acute renal failure receiv-flects that of the lipid vehicle. L-AMPB offers much ing 800mg every 24 hours.[89] Interestingly, at a QUFhigher plasma concentrations as a consequence of a of 1 L/h, the CLCRRT (11.8 mL/min) almost equatedlimited Vd and low clearance mainly by means of to the CLR in healthy subjects (12.91 mL/min),[34]
the reticuloendothelial system; conversely, AMPB- but when the QUF was doubled, a correspondingLC, at equal dosages, achieves much lower plasma linear increase in CLCRRT was observed (18.9 mL/
min). These results suggest that fluconazole is sig-concentrations due to both wide distribution withinnificantly removed by CVVH and that when apply-cells and extensive sequestration by the reticuloen-ing high ultrafiltration rates, drug removal may bedothelial system. Even the lipid formulations ofeven greater, thus much higher dosages than thoseamphotericin B are only poorly eliminated by theconsidered standard in subjects with normal renalrenal route.function should be considered in these circum-
The pharmacokinetic behaviour of amphotericin stances. Additionally, even the CL of fluconazoleB and its lipid formulations during predilution CV- was found to be increased in this particular case.VH equipped with polysulfone haemofilters and Accordingly, when assessing plasma exposure, itapplied at high ultrafiltration rates was comparative- was observed that the dosage of 800mg every 24ly investigated in 11 critically ill patients with acute hours ensured an average Cmin of 15.4 mg/L at arenal failure receiving mean daily doses of ampho- QUF of 1 L/h but only 12.1 mg/L at a QUF of 2 L/h.
Considering that the MICs of dose-dependent Can-tericin B 1.06 mg/kg, L-AMPB 4.09 mg/kg anddida spp. may be 16–32 mg/L and that a Cmin>MICAMPB-LC 2.82 mg/kg.[87] Briefly, for all of theshould be considered the optimal goal of the time-tested formulations, very low Sc values were docu-dependent antifungal activity of fluconazole, themented because of the very high protein binding,investigators recommended a dosage of at leastand drug elimination was found to be only slightly800mg every 24 hours for appropriate treatment ofenhanced by CRRT. It was concluded that no majorlife-threatening Candida infections.dosage adjustments are needed under these operat-
The influence of postdilution CVVHDFing conditions, and so a standard mean dosage of
equipped with a cellulose triacetate haemofilter was3–4 mg/kg every 24 hours was recommended either assessed in seven critically ill patients with very lowfor L-AMPB or for AMPB-LC. In a subsequent residual renal function receiving 400mg every 12study involving two critically ill patients receiving a hours or 800mg every 24 hours.[90] The applicationmean dose of AMPB-LC 5 mg/kg every 24 hours, of a high QUF and a moderately high QD probablythe same investigators confirmed that elimination resulted in an even greater CLCRRT. In fact, al-was unaffected by CVVH even when using this though this was not directly estimated by the investi-higher dosage.[88] gators, the CL was almost double that in healthy
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
1034 Pea et al.
volunteers. Of note, the t1/2 was three times shorter, appropriate handling of renally cleared drugs duringand so the Cmin averaged 6.8 mg/L and 4.2 mg/L CRRT: the extent of drug extraction increases lin-after 400mg every 12 hours and 800mg every 24 early with the QUF and/or QD applied; under similarhours, respectively. On the basis of these findings, it operating conditions, CVVHDF is generally morewas recommended that under these operating condi- efficient than CVVH; and the postdilution mode istions, dosage escalation to 500–600mg every 12 more efficient than the predilution mode, especiallyhours should be performed in order to maximise the for hydrophilic compounds. Accordingly, nomo-pharmacodynamics of fluconazole. grams that take these key points into consideration
may represent a valid starting point for correct dos-In summary, fluconazole was shown to be veryage adjustments.[98] Conversely, those statementssignificantly removed by both CVVH and CV-suggesting that for renally cleared drugs, dosageVHDF in a manner directly related to the flow ratesadjustments might be applied considering the appli-applied. Accordingly, attention should be paid tocation of CRRT equivalent to a glomerular filtra-avoidance of underexposure in patients undergoingtion rate ranging between 10 and 30 mL/min,[36,37]CRRT, and this means that dosages significantlyseem perhaps an excessive simplification. The verygreater than those in healthy subjects must be ad-large inter- and intraindividual pharmacokineticministered. As a general rule, 0.4g every 12 hoursvariability documented in several studies suggests,may represent a suitable dosage when using CVVHin fact, that standard fixed dosages during CRRTat a QUF of up to 2 L/h, but when applying CV-may be inappropriate in several cases. Of note, whenVHDF, dosages of 0.5–0.6g every 12 hours might bevery high-volume flow rates have been used (up tonecessary with the intent of achieving a Cmin of6 L/h), dosages higher than those administered in8–10 mg/L.patients with normal renal function have been re-
4. Conclusions quired.The dosage recommendations for most of theThe results of the assessment of these studies
antimicrobials used in these patients are summarisedconfirm that correct application of pharmacokineticin table V. The suggested dosages take into accountprinciples may be useful in handling antimicrobialthe most suitable pharmacodynamic target againsttherapy during CRRT. The most suitable pharma-susceptible pathogens in order to optimise drug ex-cokinetic parameter to appropriately define the ex-posure. However, considering the very wide vari-tent of drug removal is certainly represented by theability between the various regimens proposed byCLCRRT which, however, has not always been esti-different investigators, an attempt has been made tomated in these studies. Whenever available, theinclude both the dosing regimen that may be consid-comparison of this value with the extent of CLR forered appropriate under most operating conditionseach single drug observed in healthy volunteers mayand the highest dosage that has been found to beenable better understanding of the peculiar role thatneeded under some specific conditions.CRRT may have in drug removal. Drugs that nor-
Finally, it should not be overlooked that somemally have high CLR and that exhibit high CLCRRTpeculiar pathophysiological conditions occurring induring CVVH or CVVHDF may need a significantcritical illness (i.e. hypoalbuminaemia, expansion ofdosage increase in comparison with renal failure orextracellular fluids, presence of residual renal func-even IHD. Conversely, drugs that are normallytion or oxidative stress) may significantly contributenonrenally cleared and that exhibit very lowto further alteration of the pharmacokinetic beha-CLCRRT during CVVH or CVVHDF may need un-viour of antimicrobial agents, thus potentially caus-modified dosages in comparison with normal renaling significant changes in the Vd and/or even thefunction.non-CRRT-related clearance of drugs.However, it should be noted that among the dif-
ferent studies concerning each single compound, the Bearing these pharmacokinetic principles inpercentage relevance of CLCRRT was often found to mind will almost certainly aid the management ofvary significantly. This seems to be related to some antimicrobial therapy in critically ill patients withgeneral principles, which may be considered for sepsis undergoing CRRT, thus containing the risk of
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Disposition of Antimicrobials during CRRT 1035
© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
Tab
le V
. O
verv
iew
of
dosi
ng r
ecom
men
datio
ns f
or e
nsur
ing
appr
opria
te p
harm
acod
ynam
ic (
PD
) ex
posu
re w
ith s
ome
antim
icro
bial
age
nts
durin
g co
ntin
uous
ren
al r
epla
cem
ent
ther
apy
(CR
RT
)
Ant
imic
robi
alP
ropo
sed
optim
alU
sual
dos
age
Hig
hest
dos
age
Crit
ical
fac
tors
res
pons
ible
for
hig
her
dosa
ges
PD
tar
get
vsre
com
men
datio
nsre
com
men
datio
nssu
scep
tible
pat
hoge
nsM
erop
enem
Cm
in >
4 m
g/L
0.5g
q8h
–0.5
q6h
1g q
4–6h
Ver
y hi
gh Q
UF >
2–3
L/h
and/
or Q
D >
1–2
L/h
Sig
nific
ant
resi
dual
ren
al f
unct
ion
(CL C
R >
50 m
L/m
in)
Bor
derli
ne s
usce
ptib
le is
olat
es (
MIC
s 8–
16 m
g/L)
Imip
enem
/cila
stat
inC
min
>4
mg/
L0.
5g q
8h–0
.5g
q6h
Flu
clox
acill
inC
min
>4
mg/
L4g
q8h
a
Pip
erac
illin
/C
min
>16
–64
mg/
L4.
0g/0
.5g
q8h
4.0g
/0.5
g q4
hS
igni
fican
t re
sidu
al r
enal
fun
ctio
n (C
L CR
>50
mL/
min
)ta
zoba
ctam
Cef
epim
eC
min
>8
mg/
L1–
2g q
12h
2g q
8hV
ery
high
QU
F >
2–3
L/h
and/
or Q
D >
1–2
L/h
Res
idua
l CL C
R >
50 m
L/m
in
Cef
piro
me
Cm
in >
8 m
g/L
1g q
12h
2g q
8hH
igh
non-
CR
RT
-rel
ated
com
pens
ator
y C
LA
dsor
ptio
n to
pol
ysul
fone
hae
mof
ilter
Cef
tazi
dim
eC
min
>8
mg/
L1g
q8h
or
3g/d
ay C
I2–
3 q8
hV
ery
high
CL
(2–3
tim
es h
ighe
r th
an in
hea
lthy
volu
ntee
rs)
Cef
tria
xone
Cm
in >
8 m
g/L
2g q
24h
Tei
copl
anin
Cm
in 1
0–20
mg/
LLD
6 m
g/kg
q12
hLD
6 m
g/kg
q12
hH
ypoa
lbum
inae
mia
for
4 do
ses
for
4 do
ses
Sig
nific
ant
resi
dual
ren
al f
unct
ion
(CL C
R >
50 m
L/m
in)
MD
3 m
g/kg
q24
hM
D 6
mg/
kg q
24h
Van
com
ycin
Cm
in 1
5–20
mg/
L0.
25–0
.5g
q12h
0.5g
q6h
Ver
y hi
gh C
RR
T f
low
rat
es (
QU
F±
QD
6 L
/h)
Cip
roflo
xaci
nC
max
/MIC
>8–
100.
4g q
12h
AU
C/M
IC >
100
Levo
floxa
cin
Cm
ax/M
IC >
8–10
0.5g
q48
h0.
5 q2
4hV
ery
high
QU
F >
3 L/
hA
UC
/MIC
>10
0(o
r 0.
25 q
24h)
Mox
iflox
acin
Cm
ax/M
IC >
8–10
0.4g
q24
ha
AU
C/M
IC >
100
Oflo
xaci
n0.
4g q
8ha
Line
zolid
Cm
in >
4 m
g/L
0.6g
q12
h0.
6g q
8hV
ery
high
CL C
RR
TH
igh
non-
CR
RT
-rel
ated
CL
in s
ome
criti
cally
ill p
atie
nts
Col
istin
ND
2–3
mg/
kg q
12ha
met
hane
sulfo
nate
Lipo
som
alC
max
/MIC
>10
3 m
g/kg
q24
ham
phot
eric
in B
Am
phot
eric
in B
lipi
dC
max
/MIC
>10
3 m
g/kg
q24
ha
com
plex
Flu
cona
zole
Cm
in >
8–16
mg/
L0.
4g q
12h
0.6g
q12
hC
VV
HD
F w
ith v
ery
high
flo
w r
ates
(Q
UF >
2 L/
h an
d Q
D >
1 L/
h)
aD
osag
e re
com
men
datio
n fr
om a
sin
gle
stud
y.
AU
C =
are
a un
der
the
plas
ma
conc
entr
atio
n-tim
e cu
rve;
CI
= c
ontin
uous
infu
sion
; C
L =
tot
al b
ody
clea
ranc
e; C
LC
R =
cre
atin
ine
clea
ranc
e; C
LC
RR
T =
ext
raco
rpor
eal c
lear
ance
;C
max
= m
axim
um p
lasm
a co
ncen
trat
ion;
Cm
in =
min
imum
pla
sma
conc
entr
atio
n; C
VV
HD
F =
con
tinuo
us v
eono
veno
us h
aem
odia
filtr
atio
n; C
RR
T =
con
tinuo
us r
enal
rep
lace
men
tth
erap
y; L
D =
load
ing
dose
; MD
= m
aint
enan
ce d
ose;
MIC
= m
inim
um in
hibi
tory
con
cent
ratio
n; N
D =
no
data
; qxh
= e
very
x h
our;
QD
= d
ialy
sate
flow
rat
e; Q
UF =
ultr
afilt
ratio
n flo
wra
te.
1036 Pea et al.
tions in healthy subjects. Antimicrob Agents Chemother 1992;inappropriate exposure. However, whenever avail-36: 552-7
able, the application of TDM, as correctly advocated 13. Nakayama I, Akieda Y, Yamaji E, et al. Single- and multiple-dose pharmacokinetics of intravenous cefpirome (HR810) toby several investigators, should be considered ahealthy volunteers. J Clin Pharmacol 1992; 32: 256-66mainstay, with the intent of optimising drug expo-
14. Mouton JW, Horrevorts AM, Mulder PG, et al. Pharmaco-sure in these circumstances. kinetics of ceftazidime in serum and suction blister fluid
during continuous and intermittent infusions in healthy volun-teers. Antimicrob Agents Chemother 1990; 34: 2307-11
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