atb en dialisis[1]

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)


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.



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.


1002 Pea et al.


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.


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)


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.



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


1006 Pea et al.


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



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.


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



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.


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



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.


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



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.


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

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rugi

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4h

150m

gaf

ter

dosi

ng;

2–3

mg/

kg(2

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kg)

q12h

sho

uld

be m

ore

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(1)

[86]

appr

opria

te

Con

tinue

d ne

xt p

age



Tab

le I

V.

Con

td

Dru

g;R

esid

ual

CR

RT

RF

aM

embr

ane/

QB

FQ

UF

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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

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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

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293.

330.

0335

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Elim

inat

ion

only

lipid

com

plex

;(A

RF

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7m2

(7);

slig

htly

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ance

d;2.

82 m

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(7)

[87]

0.07

3–4m

g/kg

q24

h(7

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com

men

ded

amph

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BN

SC

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HP

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1980

787.

480.

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n un

affe

cted

lipid

com

plex

;(A

RF

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7m2

by C

VV

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4.94

mg/

kg5

mg/

kg q

24h

q24h

(2)

[88]

reco

mm

ende

d

Tria

zole

s

fluco

nazo

le;

NS

CV

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Pre

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d 15

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at Q

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)[89]

2000

37.5

18.9

50.5

24.7

1000

and

200

0 m

L/h,

(9)

(9)

(9)

(9)

(9)

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ectiv

ely;

800

mg

q24h

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ende

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reat

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g C

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fect

ions

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(3),

CV

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Pos

tC

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105

2250

1225

59.7

NS

NS

NS

8.08

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ged

6.8

and

400m

g q1

2h (

3),

5.5

(4)

tria

ceta

te/

(4)

(4)

(4)

(3),

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L af

ter

400m

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252

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12q1

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ded

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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-



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.


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



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


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.



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


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).



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


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



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


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-



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


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



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


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



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


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



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


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




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-

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atb en dialisis[1]

Education

crrt characteristics

antimicrobial therapy

application of crrt

renal replacement therapies

cvvhdf cvvh ihd

principles of drug removal

antifungal agents

efficiency of drug removal