antibiotic dosing in msof.full

DOI 10.1378/chest.10-2371 2011;139;1210-1220Chest

Marta Ulldemolins, Jason A. Roberts, Jeffrey Lipman and Jordi Rello Dysfunction SyndromeAntibiotic Dosing in Multiple Organ

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Postgraduate Education CornerCONTEMPORARY REVIEWS IN CRITICAL CARE MEDICINE

CHEST

1210 Postgraduate Education Corner

Despite decades of clinical experience with anti-biotic use, treatment of severe infections remains

a challenge for clinicians. Over the past years, two important phenomena have made even more essen-tial the need to improve the use of presently available antibiotics and to extend the effective life of a drug: (1) the escalation in the incidence of bacteria resis-tant to the available antibiotics 1 and (2) the dearth of antimicrobial drugs with new mechanisms of action in development. 2 One mechanism to improve optimi-zation of antibiotic use may be improvement of anti-biotic dosing because a causal relationship is thought to exist among inappropriate dosing, clinical out-come, and the development of bacterial resistance. 3 From a clinical perspective, optimization of antibiotic use is particularly important for critically ill patients in whom early and appropriate antibiotic prescription has been shown to reduce mortality. 4 - 10 The physio-logic and pharmacokinetic derangements in antibiotics have been reviewed previously for patients with sepsis 11 ;

however, there is an absence of guidance on rational approaches to antibiotic dosing in patients with mul-tiple organ dysfunction syndrome (MODS) who have higher levels of sickness severity and whereby effec-tive antibiotic therapy may be even more important to clinical outcome. The purpose of this article is to review, using examples from the literature, the key con-cepts likely to affect antibiotic pharmacokinetics and pharmacodynamics and to provide dose recommen-dations for the treatment of critically ill patients with MODS.

Search Strategy and Selection Criteria

Data were identifi ed by a systematic search in PubMed (1966-October 2010) for original articles that evaluated the variations in antibiotic pharmaco-kinetics and pharmacokinetics/pharmacodynamics (PK/PD) in MODS. Key words used were “sepsis” or “systemic infl ammation response syndrome” or “septic

Antibiotic Dosing in Multiple Organ Dysfunction Syndrome

Marta Ulldemolins , PharmD ; Jason A. Roberts , PhD, BPharm(Hons) ; Jeffrey Lipman , MD ; and Jordi Rello , MD, PhD

Although early and appropriate antibiotic therapy remains the cornerstone of success for the treatment of septic shock, few data exist to guide antibiotic dose optimization in critically ill patients, particularly those with multiple organ dysfunction syndrome (MODS). It is well known that MODS signifi cantly alters the patient’s physiology, but the effects of these variations on phar-macokinetics have not been reviewed concisely. Therefore, the aims of this article are to sum-marize the disease-driven variations in pharmacokinetics and pharmacodynamics and to provide antibiotic dosing recommendations for critically ill patients with MODS. The main fi ndings of this review are that the two parameters that vary with greatest signifi cance in critically ill patients with MODS are drug volume of distribution and clearance. Disease- and clinician-driven changes lead to an increased volume of distribution and lower-than-expected plasma drug concentrations during the fi rst day of therapy at least. Decreased antibiotic clearance is common and can lead to drug toxicity. In summary, “front-loaded” doses of antibiotic during the fi rst 24 h of therapy should account for the likely increases in the antibiotic volume of distribution. Thereafter, main-tenance dosing must be guided by drug clearance and adjusted to the degree of organ dysfunction. CHEST 2011; 139( 5 ): 1210 – 1220

Abbreviations : AKI 5 acute kidney injury ; AUC 0-24 5 area under the concentration curve over 0 to 24 h ; CL 5 clearance ; Cmax 5 peak concentration ; CrCL 5 creatinine clearance ; ƒ T . MIC 5 time over minimum inhibitory concentration ; GFR 5 glomerular fi ltration rate ; MDRD 5 modifi ed diet in renal disease ; MIC 5 minimum inhibitory concentration ; MODS 5 multiple organ dysfunction syndrome ; PK/PD 5 pharmacokinetic/pharmacodynamic ; RRT 5 renal replacement therapy ; TDM 5 therapeutic drug monitoring ; Vd 5 volume of distribution



CHEST / 139 / 5 / MAY, 2011 1211www.chestpubs.org

shock” or “multiple organ failure” and “antibacterial agents” or “antibiotics” and “pharmacokinetics” or “pharmacodynamics” and “critically ill patient” or “intensive care unit” or “critical care.” A total of 167 articles were returned, of which only 48 were deemed relevant for critically ill patients with MODS or some level of organ dysfunction. Numerous articles also were identifi ed through searches of the exten-sive fi les of the authors.

Overview of Antibiotic Physicochemistry, Pharmacokinetics, and Pharmacodynamics

The term “antibiotic” includes a variety of chemical compounds that exhibit great differences among them in terms of mechanism of action and physicochemical, pharmacokinetic, and pharmacodynamic characteris-tics. The uniqueness of each class makes independent study essential to provide accurate characterization of antibiotic behavior.

Physicochemistry

A simple, but useful chemical classifi cation for antibiotics is by their affi nity for water. Hydrophilic drugs predominantly distribute into intravascular and interstitial water but are unable to passively cross the lipid cellular membrane and, therefore, do not penetrate intracellularly in meaningful concentrations. Hence, their volume of distribution (Vd) is equiva-

lent to the extracellular water and usually corresponds to a value between 0.1 L/kg and 0.3 L /kg. 11 On the con-trary, lipophilic drugs can cross lipid membranes and, therefore, distribute intracellularly and into adipose tissues. Hence, the Vd of lipophilic drugs depends on the amount of adipose tissue, which generally is proportional to total body weight. 11 There are a few exceptions where this approach cannot be extrapo-lated, for example, in patients with increased muscle mass, as muscle tissue is highly hydrophilic and affects the Vd of lipophilic drugs to a lesser extent.

Pharmacokinetics

Pharmacokinetics is the study of the interrela-tionship between drug dose and variations in con-centrations in plasma and tissue over time. The most relevant pharmacokinetic parameters include the following 12 :

peak concentration achieved after a single • dose (Cmax) Vd: the apparent volume of fl uid that contains • the total drug dose administered at the same concentration as in plasma clearance (CL): quantifi cation of the irrevers-• ible loss of drug from the body by metabo-lism and excretion elimination half-life: time required for the • plasma concentration to fall by one-half protein binding: proportion of drug binding • to plasma proteins AUC • 0-24 : total area under the concentration curve over 0 to 24 h

Pharmacodynamics and PK/PD

Pharmacodynamics is the study of the relationship between drug concentrations and effect. 12 The PK/PD approach seeks to establish a relationship between dosage and pharmacological effect. 12 Figure 1 repre-sents the relationship among pharmacokinetics, phar-macodynamics, and PK/PD. Antibiotics can be cate-gorized in three different classes depending on the PK/PD indices associated with their optimal killing activity. 13

Time-Dependent Antibiotics: Optimal activity is achieved when unbound plasma concentrations are maintained above the minimum inhibitory concen tration (MIC) of the bacteria ( ƒ T . MIC) for a defi ned fraction of the dosing interval.

Concentration-Dependent Antibiotics: Optimal activity correlates with Cmax, quantifi ed by its ratio with the MIC of the bacteria (Cmax/MIC).

Manuscript received September 13 , 2010 ; revision accepted January 3 , 2011 . Affi liations: From the Burns, Trauma and Critical Care Research Centre (Drs Ulldemolins, Roberts, and Lipman), The University of Queensland, Brisbane, QLD, Australia; Critical Care Depart-ment (Drs Ulldemolins and Rello), Vall d’Hebron University Hospital, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica En Red de Enfermedades Respiratorias (CIBERES) (Drs Ulldemolins and Rello), Barcelona, Spain ; and Department of Intensive Care Medicine (Drs Roberts and Lipman) and Phar-macy Department (Dr Roberts), Royal Brisbane and Women’s Hospital, Herston, Brisbane, QLD, Australia. Funding/Support: Funded by the National Health and Medical Research Council of Australia [Project Grant 519702; Australian Based Health Professional Research Fellowship 569917 (to Dr Roberts)]; Australia and New Zealand College of Anaes-thetists [ANZCA 06/037 and 09/032]; Queensland Health-Health Practitioner Research Scheme; Royal Brisbane and Women’s Hospital Research Foundation (to Drs Roberts and Lipman); and CIBERES [0606036], Agència de Gestió d’Ajuts Universitaris i de Recerca [09/SGR/1226], and Fondo de Investigación Sanitaria [07/90960] (to Drs Ulldemolins and Rello) . Correspondence to: Jordi Rello, MD, PhD, Critical Care Depart-ment, Vall d’Hebron University Hospital, Institut de Recerca Vall d’Hebron-UAB, Passeig de la Vall d’Hebron 119-129, 08035 Barcelona, Spain; e-mail: [email protected] © 2011 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( http :// www . chestpubs . org / site / misc / reprints . xhtml ). DOI: 10.1378/chest.10-2371


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Concentration-Dependent Antibiotics With Time Dependence: A defi ned ratio between the unbound AUC 0-24 and the MIC of the bacteria (ƒAUC 0-24 /MIC) corre lates with optimal activity.

Pathophysiology of MODS and Effect on Drug Vd and CL

Sepsis-related MODS has been defi ned as the worsening of organ function due to a severe infection such that homeostasis cannot be maintained without intervention, usually involving two or more organ systems. 14 Endotoxins have a cascade effect on the production of endogenous molecules that act on the vascular endothelium, leading to vasodilatation and transcapillary leakage of fl uid and proteins into the extracellular space. 15 Moreover, sepsis is known to produce myocardial dysfunction. 16 These hemody-namic alterations lead to sepsis-induced tissue hypop-erfusion, which can affect pharmacokinetics. Because antibiotics are a group of drugs with “silent” pharma-codynamics (ie, the pharmacologic effect is not per-ceivable immediately after administration), it is almost impossible to assess whether therapeutic concentra-tions are being achieved during the early phase of therapy. Therefore, consideration of the scenarios likely to alter antibiotic pharmacokinetics and necessitate dosage adjustment are necessary to enable individu-alization of antibiotic therapy.

Tissue Hypoperfusion

In the fi rst stage of septic shock (warm shock), arteries dilate, decreasing peripheral arterial resis-tance and causing a refl ex increase in cardiac output.

Later, typical features of septic shock may appear, including a decrease in cardiac output and BP. 17 This sepsis-mediated altered blood fl ow may have impor-tant effects on drug delivery to tissues.

During the warm shock phase, hypoperfusion of vital organs (eg, brain or lung) occurs, whereas peripheral tissues and nonvital organs still receive high blood fl ow as a consequence of peripheral vaso-dilation and increased cardiac work. 17 Vital organs hypoperfusion can lead to suboptimal delivery of antibiotic and subtherapeutic levels at the target site during the initial stages of the infection in vital organ infections (eg, respiratory tract infections). However, a challenge for interpretation is the absence of phar-macokinetic data specifi cally targeting the effects of warm shock on drug distribution, and more research is required in this area.

Peripheral tissue hypoperfusion can occur during the second phase of septic shock as a result of the body’s attempt to increase perfusion of the vital organs. 18 Because peripheral tissues frequently are the source of infection, 19 hypoperfusion can lead to a failure to attain therapeutic concentrations at the site of infec-tion. 20 A similar scenario may be observed in patients with fl uid shifts, capillary leak, and edema. 21 In this case, despite increased movement of plasma and solutes (eg, hydrophilic antibiotics) to the extravas-cular compartment, drug concentrations at the tar-get site could decrease because of a dilution effect. 21 Alternative approaches to drug administration, such as continuous or extended infusion, have been shown to reach more consistent antibiotic concentrations in tissue for time-dependent antibiotics in these scenarios and should be considered when treating infections by poorly susceptible bacteria. 22 , 23 Monte Carlo simulations can be used to this end to compare

Figure 1. Interrelationship among pharmacokinetics, pharmacodynamics, and pharmacokinetics/pharmacodynamics.




the relative PK/PD target attainments for different dosing approaches for antibiotics, particularly for time-dependent antibiotics. These analyses have shown consistently that extended infusions ( . 3 h) or contin-uous infusions of time-dependent antibiotics achieve PK/PD targets more successfully than intermittent infusions ( � 30 min). 24 - 26 Monte Carlo simulations also can be used to show the effect of renal dysfunc-tion on the achievement of PK/PD targets. Figure 2 has been adapted from Roberts et al 22 and describes how administering the same dose of meropenem in different levels of renal dysfunction will provide dif-ferent levels of achievement of PK/PD targets. Use of extended or continuous infusions in this context could serve to further increase the achievement of PK/PD targets.

Renal Dysfunction

Several factors can precipitate acute kidney injury (AKI) in critically ill patients. 27 Early identifi cation of AKI and accurate assessment of renal function are essential for daily dose adjustment of hydrophilic antibiotics. The estimations of creatinine clearance (CrCL) as a surrogate for glomerular fi ltration rate (GFR) using formulas such as Cockroft-Gault and modifi ed diet in renal disease (MDRD) must be interpreted carefully in critically ill patients because despite having well-documented clinical value in spe-cifi c patient populations (eg, patients with chronic kid-ney disease), they are yet to be validated in critically ill patients. Because plasma creatinine concentrations can vary for many reasons other than renal function in these patients (eg, decreases due to immobility-

related cachexia) and are rarely at steady state, these formulas may lead to inaccurate estimations of GFR and lead to inappropriate dose adjustments. 28 , 29 Where possible, it is preferable to use either 8-, 12-, or 24-h urinary CrCL to estimate GFR in critically ill patients. 30 - 32

When using urinary CrCL, dose recommendations in the product information for estimated GFR by MDRD or Cockroft-Gault also apply. The main issue here is not the change in drug CL relative to GFR that is problematic; rather, it is how GFR is calcu-lated. If GFR is not accurately estimated, then any dose adjustment is likely to be suboptimal.

Hepatic Dysfunction

The most common causes of liver failure in criti-cally ill patients are infection-related cholestasis and hepatocellular injury, which occur in response to bac-terial toxins and to the toxins themselves. 33 In the fi rst case, bacterial toxins and released cytokines can affect the uptake and excretion of bile by hepatocytes, leading to jaundice. In the second case, endotoxins and bacteria are phagocytized by Kupffer cells that release several hepatotoxic molecules, leading to cel-lular damage . 33 Hepatic dysfunction also may result from organ hypoperfusion, hemolysis, or concomi-tant administration of hepatotoxic drugs (eg, rifam-picin). 33 , 34 Assessment of the degree of hepatic dys-function in acute liver failure is mainly clinical and may include signs and symptoms such as elevations in liver enzymes, bilirubin, or ammonia and decreases in the concentration of liver-produced proteins (eg, albu-min, a 1 -acid glycoprotein, coagulation factors). Hepatic dysfunction may impair metabolism and, therefore, lead to accumulation of hepatically cleared antibi-otics. 35 , 36 A decrease in the hepatic production of albumin and a 1 -acid glycoprotein also can alter phar-macokinetics of highly protein-bound antibi otics. 25 , 37 , 38

Albumin is the most frequent drug carrier in the bloodstream. The drug-protein interaction is rapid and dynamic, and an equilibrium depends on the concentration of both drug and protein. 39 In the presence of hypoalbuminemia, a larger number of unbound drug molecules are able to distribute from the bloodstream into tissues to a larger extent than when there is normal protein binding; pharmacoki-netically, this is translated into a larger Vd. 39

Furthermore, clinical management of severe hepatic failure may include renal replacement therapy (RRT) and the use of adsorbent columns for removing excess ammonia and other waste products in the blood. 40 The additive effect of these interventions and endog-enous renal function on the excretion of renally cleared antibiotics has to be considered when dosing with hydrophilic antibiotics.

Figure 2. The effect of varying levels of renal dysfunction on the achievement of pharmacokinetics/pharmacodynamics targets for the same dose of meropenem. This example describes the prob-ability of target attainment ( f T . MIC) for meropenem administered by intermittent bolus (infused over 5 min), in a man aged 50 years and weighing 70 kg with Cr of 50, 100, 200, and 300 mmol/L. Cr 5 plasma creatinine concentration; f T . MIC 5 time over the minimum inhibitory concentration; MIC 5 minimum inhibitory concentration. Adapted with permission of Oxford University Press from Roberts et al. 22


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Optimizing Initial Dosing of Antibiotics in MODS

Pharmacokinetic alterations mediated by MODS should be considered during antibiotic prescription in critically ill patients. During the initial phase of sepsis, increased Vd and CL are common, and dosing must be adjusted, 11 , 41 , 42 which has been confi rmed by two recent studies. The fi rst study, by Roberts et al, 43 was a b -lactam therapeutic drug monitoring (TDM) evaluation in critically ill patients, including patients with MODS, that found that � 70% of patients did not achieve appropriate antibiotic concentrations, with requirement of 50.4% and 23.7% dose increases and decreases, respectively, on the initial phase of therapy. The second was a multicenter study by Taccone et al 44 that showed that conventional initial dosing for many b -lactams frequently used in criti-cally ill patients was insuffi cient for achieving PK/PD targets on the fi rst day of therapy. In this study, only 28% of the patients on ceftazidime, 16% on cefepime, and 44% on piperacillin/tazobactam achieved the PK/PD targets on the fi rst day of therapy. The authors found that 40% of patients receiving piperacillin/tazobactam had plasma concentrations of less than four times MIC within 90 min after administration.

The results of both studies are likely to be due to an increased Vd for these patients. 15 , 45 It is important to note that in the study by Taccone et al, 44 27% of the patients had AKI, and despite having been prescribed with standard non-AKI initial doses, most of them had suboptimal concentrations after the fi rst dose. In contrast, in the study by Roberts et al, 43 19% of patients had AKI (with or without dialysis require-ments), and on days 2 through 5, 72% of these patients required a dose decrease. The data from both studies suggest that initial antibiotic dosing needs to account for the increased Vd that occurs in critically ill patients with MODS 15 ; therefore, higher-than-standard doses should be considered in the initial phase of therapy. This concept will be referred throughout this review as “front-loaded” dosing and especially applies to hydrophilic drugs whose Vd dramatically increases in this scenario. 22 , 23 , 46 , 47 This concept was demonstrated by Marik 46 who showed a twofold increase in the Vd of amikacin in critically ill patients with gram-negative infections. This pharmacokinetic alteration will signifi cantly affect the achievement of therapeutic peak concentrations (Cmax/MIC � 10). 46 Recent research also supports administration of front-loaded doses for aminoglycosides (eg, 25 mg/kg for amikacin) on the fi rst day of therapy for severe sepsis and septic shock. 48

For lipophilic drugs, front-loaded doses based on total body weight should be considered for patients with a higher proportion of adipose tissue to achieve

therapeutic concentrations. 49 This is the same prin-ciple by which loading doses of drugs such as amio-darone and phenytoin are required. 50 , 51 Further, evidence supports that even the Vd of hydrophilic antibiotics is increased in obese patients due to the increased interstitial fl uid, connective tissue, and muscle mass also present in obesity. 52 , 53 Therefore, obesity must be a factor to consider for initial dosing. In this context, use of an equation that assists cal-culation of lean body weight should be used. 54

Table 1 provides broad recommendations for opti-mizing initial dosing in patients with increased Vd. Table 2 provides guidance for specifi c drugs in this scenario.

Optimizing Maintenance Dosing of Antibiotics in MODS

Maintenance dosing must be guided by drug CL. Depending on the organ systems impaired by MODS, the effect on antibiotic CL can vary widely. The most relevant organ systems that may affect pharmacoki-netics (mainly renal and hepatic systems) will be con-sidered individually.

Table 1 provides general principles for mainte-nance dosing in renal failure, hepatic failure, and RRT. Table 2 provides guidance for specifi c drugs in these scenarios. Figure 3 summarizes the scenarios likely to alter pharmacokinetics in MODS.

Renal Dysfunction

Hydrophilic antibiotics are mostly renally cleared by glomerular fi ltration and tubular secretion. Decreased CL of these drugs is well described in renal dysfunc-tion, and as such, dose reductions or extended dosing intervals are required to prevent drug accumulation and toxicity. 55 Dose adjustments to prevent toxicity are especially relevant for antibiotics with a narrow therapeutic window, such as glycopeptides and amin-oglycosides, that can produce nephrotoxicity, and, hence, its accumulation may lead to a vicious circle of injury in the damaged kidney that may lead to greater antibiotic accumulation.

When dose reducing, it is essential to consider anti-biotic pharmacodynamics to ensure that targets are still attained where possible. For instance, a more appro-priate dose reduction of time-dependent antibiotics would be to reduce the dose rather than the fre-quency of administration as a strategy to preserve the ƒ T . MIC (eg, recommended dosing of meropenem for an estimated GFR , 15 mL/min would be a front-loaded dose of 1,000 mg to provide therapeutic con-centrations followed by a maintenance dose of 500 mg every 12 h to enable continued optimization of ƒ T . MIC without toxicity). For concentration-dependent drugs,




Tabl

e 1 —

Bro

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Ant

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Tabl

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h

Ert

apen

em1

g q1

2h1

g q1

2h50

0 m

g q1

2h50

0 m

g q8

-12h

Peni

cilli

nsPi

pera

cilli

n/ta

zoba

ctam

4.5

g q4

-6h

4.5

g q6

h4.

5 g

q8h

or 2

.25

g q6

h4.

5 g

q8h

Ti

carc

illin

/cla

vula

nate

3.1

g q4

-6h

3.1

g q6

h2

g q4

-6h

2 g

q4-6

h

Isox

azol

yl p

enic

illin

s (c

loxa

cilli

n,

fl ucl

oxac

illin

, di

clox

acill

in)

2 g

q4h

2 g

q4h

2 g

q6h-

1g q

4h2

g q6

h-1g

q4h

C

epha

losp

orin

sC

eftr

iaxo

ne1-

2 g

q12h

1 g

q12h

1 g

q12h

1-2g

q12

h

Cef

tazi

dim

e2

g q8

h2

g q8

h1

g q8

h1

g q8

h

Cef

epim

e1-

2 g

q8-1

2h1-

2 g

q8-1

2h50

0 m

g-1

g q1

2h1-

2 g

q12h

Mon

obac

tam

sA

ztre

onam

1-2

g q8

h1

g q6

-8h

500

mg

q6-8

h50

0 m

g q6

-8h

Am

inog

lyco

side

sA

mik

acin

25 m

g/kg

q24

h to

ach

ieve

a

Cm

ax/M

IC 5

10

15 m

g/kg

q24

h; m

onito

r C

min

aft

er 2

4 h,

aim

ing

for

leve

ls ,

5 m

g/L

Mon

itor

Cm

in a

fter

24

h, a

imin

g fo

r le

vels

, 5

mg/

L. D

osin

g q4

8h m

ay b

e re

quir

ed fo

r se

vere

ren

al d

ysfu

nctio

n

Mon

itor

Cm

in a

fter

24

h,

aim

ing

for

leve

ls ,

5 m

g/L

an

d tit

rate

dos

ing

acco

rdin

g to

res

ults

Gen

tam

ycin

, to

bram

ycin

7 m

g/kg

as

a L

D o

n da

y 1

to

achi

eve

a C

max

/MIC

5 1

05

mg/

kg q

24h;

mon

itor

Cm

in a

fter

24

h, a

imin

g fo

r le

vels

, 0

.5 m

g/L

Mon

itor

Cm

in a

fter

24

h, a

imin

g fo

r le

vels

, 0

.5 m

g/L

. Dos

ing

q48h

may

be

requ

ired

for

seve

re r

enal

dys

func

tion

Mon

itor

Cm

in a

fter

24

h,

aim

ing

for

leve

ls ,

0.5

mg/

L

and

titra

te d

osin

g ac

cord

ing

to r

esul

ts

Gly

cope

ptid

esVa

ncom

ycin

20-3

0 m

g/kg

LD

c 15

-20

mg/

kg q

12h

Use

TD

M (C

min

) on

day

3,

aim

ing

for

rang

e 15

-20

mg/

L

(20-

25 m

g/L

if C

I). D

osin

g m

ust b

e tit

rate

d to

fi t i

n th

is r

ange

Use

TD

M (C

min

) on

day

3,

aim

ing

for

rang

e 15

-20

mg/

L

(20-

25 m

g/L

if C

I). D

osin

g sh

ould

be

titra

ted

to th

is

rang

e

Teic

opla

nin

12 m

g/kg

q12

h fo

r th

ree

dose

s3-

6 m

g/kg

q12

h, ti

trat

e do

sing

on

day

4 gu

ided

by

TD

M, a

imin

g fo

r C

min

. 1

0 m

g/L

Pres

crib

e 3

mg/

kg q

12h

from

the

four

th d

ose

and

titra

te d

osin

g on

day

4 g

uide

d by

TD

M, a

imin

g fo

r C

min

. 1

0 m

g/L

Pres

crib

e 3

mg/

kg q

12h

from

the

four

th d

ose

and

titra

te d

osin

g on

day

4 g

uide

d by

TD

M,

aim

ing

for

Cm

in .

10

mg/

L

Flu

oroq

uino

lone

sC

ipro

fl oxa

cin

400

mg

q8h

400

mg

q12-

24h

400

mg

q12-

24h

400

mg

q12-

24h

L

evofl

oxa

cin

500-

750

mg

q24h

500-

750

mg

q24h

250

mg

q24-

48h

500

mg

q48h

or

250

mg

q24h

Mox

ifl ox

acin

400

mg

q24h

400

mg

q24h

400

mg

q24h

400

mg

q24h

L

inco

sam

ides

Lin

com

ycin

Adm

inis

ter

600

mg

q6-8

h as

an

LD

on

day

160

0 m

g q1

2h60

0 m

g q1

2h60

0 m

g q8

h

C

linda

myc

inA

dmin

iste

r 60

0 m

g q6

-8h

as a

n L

D o

n da

y 1

600

mg

q12-

24h

600

mg

q8h

600

mg

q8h

Mac

rolid

esC

lari

thro

myc

in50

0 m

g q1

2h50

0 m

g q1

2hIn

sev

ere

rena

l fai

lure

, 25

0 m

g q1

2h50

0 m

g q1

2h

A

zith

rom

ycin

500

mg

q24h

500

mg

q24h

500

mg

q24h

500

mg

q24h

(Con

tinu

ed)




Ant

ibio

tic C

lass

Ant

ibio

tic N

ame

Rec

omm

ende

d L

D fo

r Pa

tient

s W

ith -

Vd

(Day

1)

Rec

omm

ende

d M

D fo

r Pa

tient

s W

ith H

epat

ic F

ailu

re a

Rec

omm

ende

d M

D fo

r Pa

tient

s W

ith A

cute

Kid

ney

Inju

ry a

Rec

omm

ende

d M

D fo

r Pa

tient

s W

ith R

RT

b

Nitr

oim

idaz

oles

Met

roni

dazo

le50

0 m

g q8

h50

0 m

g q1

2-24

h in

sev

ere

hepa

tic fa

ilure

500

mg

q8h

500

mg

q8h

Cyc

lic li

pope

ptid

esD

apto

myc

in6-

8 m

g/kg

q24

h6

mg/

kg q

24h

6 m

g/kg

q48

h6

mg/

kg q

48h

Gly

cylc

yclin

esTi

gecy

clin

e10

0 m

g do

se 1

12 h

aft

er L

D, a

dmin

iste

r 25

mg

q12h

12 h

aft

er L

D, a

dmin

iste

r 50

-100

mg

q12h

12 h

aft

er L

D, a

dmin

iste

r 50

-100

mg

q12h

O

xazo

lidin

ones

Lin

ezol

id60

0 m

g q8

-12h

600

mg

q12h

600

mg

q12h

600

mg

q12h

Dat

a ar

e m

odifi

ed fr

om th

e pr

oduc

t inf

orm

atio

n of

eac

h pa

rtic

ular

dru

g. N

ote

that

the

prod

uct i

nfor

mat

ion

for

man

y of

the

hydr

ophi

lic a

ntib

iotic

s in

clud

ed in

the

tabl

e (e

xcep

t tei

copl

anin

and

the

amin

o-gl

ycos

ides

) doe

s no

t con

side

r di

ffer

ent d

osin

g sc

hedu

les

for

LD

s an

d M

Ds

and

is b

ased

on

stud

ies

of p

atie

nts

who

wer

e no

t cri

tical

ly il

l. T

he r

ecom

men

ded

LD

s ar

e ba

sed

on d

ata

from

cri

tical

ly il

l pat

ient

s to

ena

ble

rapi

d at

tain

men

t of t

hera

peut

ic c

once

ntra

tions

. Cm

in 5

trou

gh c

once

ntra

tion;

RR

T 5

rena

l rep

lace

men

t the

rapy

. See

Tab

le 1

lege

nd fo

r ex

pans

ion

of o

ther

abb

revi

atio

ns.

a Act

ual d

ose

pres

crib

ed w

ill b

e gu

ided

by

the

actu

al le

vel o

f org

an d

ysfu

nctio

n.

b Dos

e de

pend

s on

dat

a av

aila

ble

for

dial

ysis

set

tings

. c T

here

are

few

dat

a m

easu

ring

toxi

city

of v

anco

myc

in L

Ds;

ther

efor

e, w

e w

ould

sug

gest

not

adm

inis

teri

ng L

Ds

that

exc

eed

35 m

g/kg

.

Tabl

e 2—

Con

tinu

ed

like aminoglycosides, it is suggested to prolong the interval between doses rather than to decrease the dose so that the peak concentration required for opti-mal bacterial killing is still achieved. 11

However, despite these theoretical recommenda-tions, uncertainty is always present when prescribing antibiotics in patients with MODS because organ function is very likely to fl uctuate from day to day during therapy. It follows that TDM is a very useful tool to titrate antibiotic dosing in MODS. TDM is widely used with aminoglycosides and glycopeptides to ensure appro priate exposure and minimize the incidence of toxicity. 56 However, the potential and usefulness of TDM as a strategy for optimizing antibiotic doses of b -lactams (the most frequently prescribed class of anti-biotics) has not yet been confi rmed. Recent research has assessed its usefulness with a broad group of criti-cally ill patients. 43 , 44 Roberts et al 43 showed that in the maintenance phase of therapy, many patients with renal dysfunction required a dose decrease due to high con-centrations (about 10 times MIC), despite empirical dose adjustment for renal dysfunction. However, some other patients with renal failure or on RRT exhibit sub-optimal concentrations with this adjusted dosing, which evidences that concentrations do not depend exclusively on renal function but on various other factors.

Renal Replacement Therapy

As renal function deteriorates, waste products will accumulate, and commencement of RRT should be considered. The main determinants of CL during RRT are the modality and settings prescribed. Hemodial-ysis, hemofi ltration, hemodiafi ltration, and peritoneal dialysis all have different mechanisms of removing metabolic waste and have a different effect on the extent to which each drug is cleared. Other factors that determine the extraction ratio are drug molec-ular weight (drugs with a molecular weight greater than the pores of the fi lter membrane are not able to be removed), protein binding (only unbound mole-cules can be removed), drug affi nity for fi lter adsorp-tion, whether replacement fl uid is added prefi lter or postfi lter, and the ultrafi ltration rate . 57 The implica-tions of RRT on drug dosing have been reviewed recently, 57 and a further discussion is beyond the scope of this article. However, Table 1 provides some recommendations for dosing in RRT.

Hepatic Dysfunction

Liver impairment may have a signifi cant impact on the CL of both lipophilic and hydrophilic drugs. Lipophilic drugs may undergo metabolism in the liver to increase the hydrophilicity of the compound. The CL of hepatically eliminated drugs depends on


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Figure 3. Clinical scenarios likely to alter antibiotic PK in MODS. MODS 5 multiple organ dysfunction syndrome; PK 5 pharmacokinetics.

the hepatic blood fl ow and intrinsic clearance (ie, degree of enzymatic activity). Therefore, two kinds of scenarios can be distinguished. CL of highly extracted drugs is mainly correlated with hepatic blood fl ow (eg, lidocaine), whereas in less-extracted drugs, CL is determined by intrinsic CL and degree of pro-tein binding (eg, nitroimidazoles, fl uoroquinolones). 12 Hepatic failure may imply modifi cation of both fac-tors, leading to decreased drug elimination, accumu-lation, and potential toxicity. For example, in liver failure, metronidazole oxidation by microsomes may be decreased because of reduced enzyme expression and enzymatic activity, 58 leading to potential toxic-ities, including seizures and peripheral neuropathy.

Other drugs may be cleared by biliary excretion, which may be substantially decreased in hepatic impairment (eg, tigecycline). A study comparing patients with different degrees of hepatic failure found that tigecycline CL was reduced by 55%, and elimination half-life was prolonged by 43% in patients with severe hepatic impairment. In this context, a dose reduction is suggested to avoid toxicity. 59

Additionally, the decreased synthesis of albumin and a 1 -acid glycoprotein in liver dysfunction, together with the transcapillary distribution of these proteins due to capillary leakage, 60 may alter the pharmacokinetics of highly protein-bound antibiotics. Hypoalbuminemia has been shown to cause signifi cant increases in the Vd and CL of drugs such as ceftriaxone (85%-95% protein bound), ertapenem (85%-95%), fl ucloxacillin (95%), and teicoplanin (90%-95%). 25 , 37 , 38 , 61 Therefore, front-loaded doses should be considered when pre-scribing these drugs in critically ill patients with MODS and hypoalbuminemia. 39 Initial dosing rec-ommendations for highly bound hydrophilic antibi-

otics ( Table 2 ) account for this scenario. Maintenance dosing should be guided by the level of organ func-tion and in the context of the main elimination path-ways for the drug and, where possible, guided by TDM. Decreased plasma concentrations of a 1 -acid glycoprotein increase substantially erythromycin Vd (73%-81% protein bound), whereas CL decreases by 60% in the presence of metabolic impairment. 62 Other antibiotics that bind substantially to this protein include trimethoprim and the lincosamides. 63

As a fi nal consideration for organ dysfunction, it is noteworthy that critically ill patients can present with underlying comorbidities, such as chronic renal or hepatic dysfunction, unrelated to sepsis. In this case, the previously mentioned dosing principles for initial and maintenance dosing also should apply. Dose adjustments should always be made according to the degree of organ function and the estimated level of drug Vd and CL present in the patient, regardless of preexisting dysfunction. Preexisting dysfunction should only be considered as a guide to the likely level of organ function in the maintenance phase of therapy.

Conclusions

Appropriate antibiotic dosing in MODS is complex and depends on several drug- and patient-related fac-tors. Consideration of antibiotic physicochemical and pharmacodynamic characteristics and disease-related alterations in pharmacokinetics is essential for design-ing dosing regimens that avoid suboptimal dosing. There are two important phases in antibiotic therapy in MODS. During the fi rst day of therapy, front-loaded dosing is required and must be guided by the




predicted Vd, which is likely to be increased in critically ill patients despite impaired organ function. From day 2 onward, maintenance dosing can be adjusted in line with the CL associated with the organ dysfunc-tion. The requirements for dose adjustment for anti-biotics should be considered individually depending on the organ system that is failing and the drug CL pathway. Because of the great variability of organ function during a septic insult, TDM should be regarded as a useful tool to individualize dosing and ensure appropriate exposure to the antibiotic. Further research on dose adjustment in MODS is required for improving patient quality of care and outcomes in this population.

Acknowledgments Financial/nonfi nancial disclosures: The authors have reported to CHEST the following confl icts of interest: Dr Roberts serves as a consultant for AstraZeneca and Janssen-Cilag. Dr Lipman serves as a consultant for AstraZeneca and Wyeth and has received grant support from AstraZeneca. Drs Ulldemolins and Rello have reported that no potential confl icts of interest exist with any com-panies/organizations whose products or services may be discussed in this article .

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DOI 10.1378/chest.10-2371 2011;139; 1210-1220Chest

Marta Ulldemolins, Jason A. Roberts, Jeffrey Lipman and Jordi RelloAntibiotic Dosing in Multiple Organ Dysfunction Syndrome

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