Pharmacokinetics and pharmacodynamics in critically ill patients

Julie M. Varghesea, Jason A. Robertsa,b,c and Jeffrey Lipmana,b

a
Burns, Trauma and Critical Care Research Centre,
The University of Queensland, bDepartment of
Intensive Care Medicine and cPharmacy Department,
Royal Brisbane and Women’s Hospital, Herston,
Brisbane, Australia
Correspondence to Jeffrey Lipman, Burns, Trauma and
Critical Care Research Centre, The University of
Queensland, Brisbane, Australia
Tel: +617 3636 1852; fax: +617 3636 3542;
e-mail: j.lipman@uq.edu.au
Current Opinion in Anaesthesiology 2010,
23:472–478
Purpose of review
The purpose of this review is to highlight the recently published studies in the area of
pharmacokinetics and pharmacodynamics in critically ill patients and ascertain the
relevance to clinical practice.
Recent findings
The majority of the published studies in this area were related to antibiotics and this will
form the main focus of this review. A number of studies have focused on antibiotic
concentrations at various target sites of infection or other tissue sites including
cerebrospinal fluid, peritoneal fluid and burns tissues. The administration of time-
dependent antibiotics using continuous infusion has also been the subject of recently
published studies which support the superior achievement of pharmacodynamic targets
using continuous infusion compared with bolus dosing. Antibiotic dosing during renal
replacement therapies, mainly during extended daily dialysis (EDD) and during other
forms of extracorporeal techniques including extracorporeal membrane oxygenation
(ECMO), have also been described in a few recent studies and case reports.
Summary
Studies have shown that critically ill patients display large variations in pharmacokinetics
mainly due to altered pathophysiology. An understanding of the pathophysiological
changes that occur in critically ill patients is essential to optimize dosing particularly to
achieve the pharmacodynamic targets for antibiotics.

Keywords
antibiotics, continuous infusion, dosing, renal replacement therapy, target site

Curr Opin Anaesthesiol 23:472–478

ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
0952-7907

pharmacodynamics in critically ill patients and ascertain

Introduction
Pharmacokinetics describes the relationship between the
dose administered and the changes in drug concentration
in the body over time. Pharmacodynamics, on the con-
trary, describes the relationship between drug con-
centration and its pharmacological effect at the target
site. Pharmacokinetics/pharmacodynamics refers to the
dose–effect relationship of a drug. Figure 1 describes the
inter-relationship between pharmacokinetics and phar-
macodynamics. The altered pathophysiology in critically
ill patients can have a major impact on pharmacokinetic
parameters which in turn results in changes in achieve-
ment of pharmacodynamic targets and potentially drug
efficacy. A poor understanding of the inter-relationship
between drug dosing and pathophysiology persists in
contemporary medicine and as such pharmacokinetic
studies are essential to enable improved pharmacother-
apy of critically ill patients. Importantly, recent studies
have attempted to provide more data in this area, parti-
cularly for antibiotics.
The purpose of this review is to highlight the recently
published studies in the area of pharmacokinetics and
0952-7907 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
the relevance to clinical practice.
Pharmacokinetics/pharmacodynamics
The two most important pharmacokinetic parameters
that determine drug dosing are the apparent volume of
distribution and clearance. Table 1 describes the phar-
macokinetic parameters relevant to drug pharmaco-
kinetics and pharmacodynamics. Volume of distribution
is important in determining the initial or loading dose of a
drug, whereas maintenance dosing is dependent on clear-
ance. In critically ill patients, the major pathophysio-
logical changes that occur can alter clearance and volume
of distribution, and thus a knowledge of how altered
physiology impacts on these parameters can be used to
optimize drug dosing to meet pharmacodynamic targets
and achieve better clinical outcomes [1]. A recent review
article by Roberts and Lipman [1] covers in detail the
pharmacokinetic issues related to antibiotic use in the
critically ill, specifically the relevance of increased
volume of distribution in critically ill patients compared
with noncritically ill patients and the elevated clearance
that may occur in the presence of augmented renal
DOI:10.1097/ACO.0b013e328339ef0a

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Figure 1 The relationship between pharmacokinetics and
pharmacodynamics
clearance (ARC) [2] or decreased clearance in acute
kidney injury (AKI), both of which appear to be common
in this patient population.
Antibiotic pharmacokinetics/
pharmacodynamics
The pharmacological effects of many drugs (e.g. seda-
tives, vasopressors and antihypertensives) commonly
used in critically ill patients can be easily monitored
and the dose titrated according to response. However,
for antibiotics, the drug effect cannot be directly or
immediately observed and therefore dose titration is
not possible for these compounds. Hence, most of the
pharmacokinetic studies in critically ill patients are
focused on antibiotics due to their ‘silent’ pharmacody-
namic profile. Importantly, antibiotics also make up one
of the most common prescriptions in ICUs. Data from the
EPIC II study – a prospective, multicentre point preva-
lence study of ICU infection – found that 71% of all
Table 1 Relevant pharmacokinetic parameters for drug dosing
PK parameter Definition
Clearance (CL) The volume of blood cleared of drug per
unit time
Volume of Apparent volume of fluid that contains the total
distribution (Vd) drug dose administered at the same
concentration as in the plasma
Half-life (t1/2) Time required for the plasma drug concentration
to fall by half
Cmax Peak drug concentration during a dosing period
Cmin Minimum drug concentration during a dosing period
AUC0–24 Area under the concentration–time curve from 0 to 24 h
PK, pharmacokinetic.
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Pharmacokinetics and pharmacodynamics Varghese et al. 473
patients were receiving antibiotics and 51% of patients
were classified as being infected on the day of the study
[3].
Different antibiotic classes have different pharmaco-
dynamic parameters associated with optimal activity
and these have been summarized in Table 2. Beta-lactam
antibiotics, for example, are time-dependent antibiotics
when the time that the serum levels exceed the mini-
mum inhibitory concentration (MIC) is the major phar-
macodynamic index associated with efficacy and, as such,
the goal of dosing would be to optimize the duration
of exposure [4]. Concentration-dependent killing anti-
biotics such as aminoglycosides, on the contrary, require
high peak drug concentrations for maximal bacterial
killing [4]. Drug dosing should take into consideration
the pharmacokinetic/pharmacodynamic characteristics of
the antibiotic as well as the susceptibility of the particular
organism(s) targeted.
Recent pharmacokinetic/pharmacodynamic studies of
antibiotics
The following subsections describe the relevant pharmaco-
kinetic/pharmacodynamic studies recently published on
antibiotics.
Ciprofloxacin
Previous studies for ciprofloxacin have suggested that an
area under the concentration–time curve (AUC)0–24/
MIC ratio of 125 should be targeted for maximal clinical
and microbiological success against Gram-negative
pathogens [5]. A recent prospective cohort study by
van Zanten et al. [6] reported achievement of this ratio
in 100% of critically ill patients only if MIC is 0.125 mg/l
or less with moderate dosing (400 mg 12 hourly). Hence
for many infections in critically ill patients caused by
pathogens with MIC values of at least 0.5 mg/l, the
400 mg 12-hourly dosing of i.v. ciprofloxacin would be
inadequate. The authors suggest a total dose of 1200 mg
daily not only to achieve optimal bacterial killing but
also to minimize the development of resistance [6].
This study reinforces data from other pharmacokinetic
studies over the last decade [7,8] and supports our
Description
CL measures the irreversible elimination of a drug from
the body by excretion and/or metabolism
Vd is the parameter that relates the total amount of
drug in the body to the plasma concentration
Half-life is dependent on CL and Vd, when half-life is
increased with a decrease in CL or an increase in Vd
 474 Drugs in anesthesia
Table 2 Pharmacodynamic indices of significance for antibiotics
PD parameter Definition
T > MIC Time for which the concentration of a drug remains above the
minimum inhibitory concentration (MIC) during a dosing interval
Cmax/MIC Ratio of the peak drug concentration to the MIC of the pathogen
AUC0– 24/MIC Ratio of the area under the concentration–time curve (AUC) during
a 24 h period to the MIC of the pathogen
PD, pharmacodynamic.
recommendation that high doses of up to 400 mg 8 hourly
should be used particularly for empiric therapy in criti-
cally ill patients with sepsis and without organ dysfunc-
tion. Subsequent dose adjustment can occur once the
susceptibility of the causative organism is known.
Vancomycin
A retrospective review of vancomycin in critically ill
trauma patients compared initial vancomycin doses of
1 g every 12 h (q12h) versus 1 g every 8 h (q8h) [9]. The
results showed that none of the patients who received 1 g
q12h dosing achieved trough levels above 15 mg/l and
only 23.5% of patients who received a 1 g q8h dose
achieved target trough concentrations of between 15
and 20 mg/l for the treatment of meticillin-resistant Sta-
phylococcus aureus (MRSA) pneumonia [9]. This is prob-
ably due to the generally younger age, higher estimated
creatinine clearance and larger volume of distribution of
critically ill trauma patients. Hence larger doses and/or
increased frequency of administration is required to
achieve target trough concentrations. To maximize the
pharmacodynamics of vancomycin while minimizing the
risk of nephrotoxicity, vancomycin can be administered
by continuous infusion. Pea et al. [10] have developed a
prospectively validated dosing nomogram for vancomy-
cin administered by continuous infusion. The authors
recommend an initial loading dose of 15 mg/kg over 2 h
regardless of the patient’s renal function to be followed
by continuous infusion with dosing based on the nomo-
gram that uses creatinine clearance estimates to calculate
the vancomycin daily dosage [10]. The authors recom-
mend the use of the Cockroft–Gault determined glo-
merular filtration rate, although this may be inaccurate in
some critically ill patients [11].
Aminoglycosides
Aminoglycosides are concentration-dependent anti-
biotics and a Cmax/MIC of at least 10 is the pharmaco-
dynamic target associated with clinical success [12].
Pharmacokinetic modelling and dosing simulation based
on data from a retrospective review of medical ICU
patients found that approximately 20% of patients pre-
scribed gentamicin and 40% of patients prescribed tobra-
mycin both dosed at 7 mg/kg would not achieve this
pharmacodynamic target [13]. Possible explanations
include larger volume of distribution for critically ill
patients, which would result in a lower Cmax than in
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Antibiotic classification Examples of antibiotics
Time-dependent Beta-lactams
Carbapenems
Concentration-dependent Aminoglycosides
Concentration-dependent Fluoroquinolones
with time dependence Glycopeptides
the healthy population. It is recommended that an initial
dose of 7 mg/kg of either gentamicin or tobramycin
should be used and therapeutic drug monitoring per-
formed after the first dose to guide dose adjustment.
The MIC for the pathogen(s) should also be determined
to allow further dose adjustments to achieve pharmaco-
dynamic targets.
Polymyxin B
The first pharmacokinetic study of intravenous poly-
myxin B in critically ill patients was conducted in eight
patients [14]. Urinary recovery of unchanged polymyxin
B was found to be less than 1% as polymyxin is eliminated
mainly by nonrenal pathways. This study found that, in
critically ill patients, polymyxin B displayed significantly
higher protein binding than that reported for healthy
individuals. This may be due to the drug binding to
a1-acid glycoprotein, an acute-phase reactant that is
generally elevated in critically ill patients [15]. Owing
to high plasma protein binding (78.5–92.4%) found in
this study, the unbound plasma concentrations in the
patients studied were lower than anticipated. The
authors concluded that unbound antibiotic concen-
trations in these patients were suboptimal given the
MIC90 of Pseudomonas aeruginosa and Acinetobacter spp.
(2 mg/l) [14]. Further pharmacokinetic/pharmacody-
namic studies are required to determine the precise
pharmacodynamic index for polymyxin B and to optimize
clinical dosing that will maximize antibiotic activity and
minimize the development of resistance. Toxicity of
polymyxin B also needs to be studied further before
higher doses can be recommended to treat resistant
organisms.
Colistin
Colistin methanesulfonate (CMS), the pro-drug of colis-
tin, was administered to 18 critically ill patients as part of
a population pharmacokinetic study [16]. The CMS dose
was 3 million units (equivalent to 240 mg) and was
administered 8 hourly. The results showed that, for initial
doses of this dosing regimen, colistin concentrations were
below the MIC breakpoint for P. aeruginosa and Acineto-
bacter spp. (2 mg/l). This indicates a delay in achieving
therapeutic antibiotic concentrations early in the treat-
ment. Pharmacokinetic modelling predicted that an
alternative dosing regimen when a loading dose of
9 million units (720 mg) then followed by a maintenance

dose of 4.5 million units (360 mg) of CMS would achieve
target concentration faster and yet maintain the same
average steady-state concentration of colistin.
Linezolid
The best predictor of antibiotic efficacy for linezolid is the
time that the free drug concentration is above the MIC (T
> MIC) and AUC0–24/MIC [17]. A pharmacokinetic study
of linezolid was conducted in 18 critically ill patients to
compare administration by intermittent dosing (600 mg 12
hourly) versus continuous infusion (300 mg loading dose
then 900 mg continuous infusion on day 1, followed by
1200 mg daily by continuous infusion thereafter) [18]. The
results showed that the pharmacodynamic targets for line-
zolid of T > MIC of above 85% and AUC0–24/MIC of 80–
120 mg h/l were more frequently achieved with adminis-
tration by continuous infusion than by intermittent dosing.
On the basis of these data, administration of linezolid by
continuous infusion in critically ill patients would
appear advantageous.
Beta-lactams
Prolonged or continuous infusion has also been employed
to optimize the time-dependent characteristics of beta-
lactam antibiotics. The results of a population pharmaco-
kinetic study of cefepime 2 g q8h administered as a pro-
longed infusion over 3 h for the treatment of ventilator-
associated pneumonia describe how this regimen will
improve the probability of achieving pharmacodynamic
targets against organisms with high MICs [19]. A study of
bolus versus continuous dosing of meropenem in critically
ill patients with sepsis observed that continuous infusion
maintains higher concentrations in plasma and subcu-
taneous tissue [20]. Pharmacokinetic modelling and
dosing simulations further showed that pharmacodynamic
targets were better achieved by extended or continuous
infusion of meropenem especially against less susceptible
organisms such as P. aeruginosa and Acinetobacter spp.
Similar results were observed when piperacillin penetra-
tion into tissues during continuous and intermittent dosing
was studied [21] and the authors concluded that the
pharmacodynamic advantages of continuous infusion are
greatest when treating organisms with high MICs. A recent
meta-analysis and systemic review of studies of beta-
lactam administration by continuous infusion versus bolus
dosing compared data on mortality and clinical outcomes
[22]. The authors concluded that continuous infusion of
beta-lactam antibiotics leads to similar clinical results to
bolus dosing in hospitalized patients [22]. Emerging retro-
spective data evaluations suggest advantages for patients
with greater levels of sickness severity, such as critically ill
patients, to be administered beta-lactams by continuous
infusion. Administration by continuous infusion would
prolong drug exposure above the MIC, particularly when
targeting organisms with high MIC values and/or in
patients with ARC.
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Pharmacokinetics and pharmacodynamics Varghese et al. 475
Antibiotic pharmacokinetics/pharmacodynamics during
renal replacement therapy
Drug dosing during renal replacement therapies (RRTs)
is a challenging area as there are different forms of RRTs
and multiple factors that can influence the pharmaco-
kinetics of drugs in critically ill patients undergoing RRT.
The principles of antibiotic dosing in critically ill patients
during continuous renal replacement therapies (CRRTs)
have recently been reviewed [23]. Another review has
commented that insufficient data are reported in pub-
lished pharmacokinetic studies on CRRT to allow the
implementation of rational dosing regimens [24]. Studies
on CRRT modalities are lacking, and recent publications
have focused on extended daily dialysis (EDD). EDD is a
hybrid form of dialysis that typically runs for 8–12 h a day
and combines the advantages of intermittent haemodia-
lysis (IHD) and CRRT. This form of dialysis is increas-
ingly being used in critically ill patients and some recent
studies have examined the pharmacokinetics of anti-
biotics during EDD in a small number of patients
[25,26,27].
Ertapenem, a carbapenem antibiotic with a long half-
life, was studied in critically ill patients undergoing 8 h
EDD treatment. In this study, EDD was started 8 h
post-ertapenem dosing and the clearance while on
dialysis was comparable to patients with normal renal
function. Although the unbound drug concentrations
were not actually measured as part of this study but
were instead estimated using an equation, the data
proved useful for assessment of pharmacodynamic
effects of the drug. The authors suggested the standard
dose of 1 g/day to maintain adequate unbound drug
concentrations [25].
Daptomycin, an antibiotic with concentration-dependent
kill characteristics, was studied in 10 anuric patients
with a once-daily dose of 6 mg/kg administered 8 h
before the start of EDD [26]. Within 30 min after the
end of the EDD treatment, a 31% rebound increase in
daptomycin levels was also observed. Also worth noting
is the fact that daptomycin is 92% protein-bound and, in
critically ill patients with low plasma protein levels, this
translates to increased free (unbound) drug concen-
tration and possibly increased clearance during dialysis
as only the unbound fraction of a drug is cleared by the
dialyser. One limitation of this study is that it did not
examine pharmacodynamic targets, although the authors
suggest that a once daily dose of 6 mg/kg is considered
well tolerated as long as EDD commences 8 h after
daptomycin dosing.
The pharmacokinetics of linezolid in septic patients with,
and without, EDD was studied using the population
pharmacokinetic approach [27]. However, the average
EDD time in this study was 19.5 h, which was longer than
 476 Drugs in anesthesia
the typical 8 h used in most similar pharmacokinetic
studies. EDD has been recently reviewed by Mushatt
et al. [28]. During EDD, a range of blood and dialysate
flow rates, different types of filters and varying treatment
duration can all influence drug clearance. Other factors
that need to be considered are the timing of antibiotic
dosing in relation to EDD treatment and the possible
need for supplemental dosing after an EDD treatment
session [28]. A knowledge of the pharmacokinetic/phar-
macodynamic characteristics of the drug (e.g. whether it
is a concentration-dependent or time-dependent anti-
biotic) can be used to guide dosing regimens in patients
undergoing EDD.
Antibiotic pharmacokinetics during extracorporeal
membrane oxygenation
Extracorporeal membrane oxygenation (ECMO) can
influence drug pharmacokinetics through increased
volume of distribution as well as possible binding of
drugs by the ECMO circuit [29]. Case reports of the
pharmacokinetics of antifungal agents during ECMO
have been published [30,31]. On the basis of these
studies it appears that there is saturable binding of
voriconazole within the ECMO circuit. This binding
may be dependent on the age of the circuit with increased
drug binding to a newer circuit [30]. In practice it is
suggested that therapeutic drug monitoring be performed
when possible to monitor efficacy and minimize toxicity
of voriconazole.
Target site antibiotic concentrations
Most antibiotic pharmacokinetic studies focus on anti-
biotic concentrations in plasma; however, most infections
occur in body tissues [32]. Antibiotic concentration in
tissues is of central importance for predicting drug effec-
tiveness. A number of studies in critically ill patients have
compared plasma concentrations of antibiotics with con-
centrations in various sites or tissues of interest. Above,
we noted the studies by Roberts and colleagues [20]
with meropenem and piperacillin [21] that described
more sustained subcutaneous tissue antibiotic concen-
trations when administered by continuous infusion com-
pared with standard intermittent dosing.
A study by Markantonis et al. [33] measured plasma and
cerebrospinal fluid (CSF) concentrations of colistin.
Colistin was administered intravenously to nine patients
and the results identified a CSF penetration of only 5%.
With minimal penetration into CSF when administered
intravenously, the authors concluded that intrathecal
administration may be required to achieve adequate
antibiotic concentrations during CNS infections. In this
particular study the patients all had minimally inflamed
meninges on the day of sampling and the authors
suggested that it is possible that colistin levels in
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CSF may be higher in patients with greater meningeal
inflammation.
Continuous infusion of cefotaxime at a dose of 4 g/24 h was
administered to critically ill patients with secondary per-
itonitis as part of a pharmacokinetic study to determine
plasma and peritoneal concentrations of cefotaxime and its
metabolite [34]. The results suggest that this dosing regi-
men provides adequate peritoneal concentrations far
exceeding the MIC of 1 mg/l which was considered the
susceptibility breakpoint for Enterobacteriaceae.
For all drugs, only the unbound fraction of a drug is
pharmacologically active at its target site or receptor.
Perioperative cefalotin concentrations in burn and non-
burn subcutaneous tissue sites were the subject of a
recent study that utilized microdialysis [35]. A 1 g dose
of cefalotin was administered preoperatively before burn
debridement surgery and achieved equivalent pharma-
cokinetics in subcutaneous tissues of burn sites as well as
nonburn sites in burns patients. This study also compared
burns patients with healthy volunteers and found that
interstitial cefalotin concentrations were maintained
longer in burns patients than in healthy volunteers with
higher antibiotic concentration in burn tissue than tissue
concentrations in healthy volunteers.
Pharmacokinetics/pharmacodynamics of
other drugs (nonantibiotics)
A small number of studies have examined the pharmaco-
kinetics of nonantibiotic agents. The effect of acute
inflammatory brain injury on the accumulation of mor-
phine and its metabolites in the human brain was studied
by Roberts et al. [36]. The authors found markedly
elevated levels of the pro-inflammatory marker interleu-
kin-6 (IL-6) in CSF and that CSF IL-6 levels were a
significant predictor of the accumulation of morphine-3-
glucuronide (M3G) and morphine-6-glucuronide (M6G)
in CSF. The results from this study suggest that CNS
inflammation post acute brain injury may inhibit M3G
and M6G-specific drug efflux transporters in the blood–
brain barrier. This finding may have an impact on patients
with inflammatory brain injury administered centrally
acting drugs that are usually eliminated from the brain
by these transporters [36].
The role of atorvastatin as a therapeutic agent in sepsis is
currently being investigated in randomized controlled
trials [37,38]. A preliminary pharmacokinetic study of a
single 20 mg dose of atorvastatin administered orally
found that critically ill patients with sepsis had signifi-
cantly higher Cmax and AUC than healthy volunteers
[39]. A possible reason for these pharmacokinetic differ-
ences may be decreased CYP3A4 metabolism of atorvas-
tatin which was not able to be explained by prescription

of CYP3A4 inhibitors, but may be due to reduced meta-
bolic functionality. Until further pharmacokinetic and
pharmacodynamic studies become available, the authors
advise clinicians to be cautious in prescribing high-dose
atorvastatin regimens in patients with sepsis [39].
Conclusion
Critically ill patients make up a group of patients when
altered pathophysiology results in significant variation in
pharmacokinetic parameters which then also impacts on
the pharmacodynamics. Poor clinical outcomes in some
patients have been attributed to a failure to achieve
pharmacodynamic targets for some drugs, particularly
antibiotics. Therefore it is important to have an under-
standing of these alterations in the critically ill and to use
the knowledge of pharmacokinetic/pharmacodynamic
properties of antibiotics to optimize dosing regimens
not only to maximize antibiotic activity but also minimize
toxicity and reduce the development of antibiotic resist-
ance.
Acknowledgements
Financial support: National Health and Medical Research Council of
Australia (project grant 519702; Australian Based Health Professional
Research Fellowship 569917), Australia and New Zealand College of
Anaesthetists (ANZCA 06/037 and 09/032), The University of
Queensland New Staff Research Start-Up Fund (2009003100), the
Viertel Charitable Foundation, Clive and Vera Ramaciotti Foundation,
Royal Brisbane and Women’s Hospital Research Foundation, Society
of Hospital Pharmacists of Australia-DBL Professional Development
Fund-Research Grant.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
 of special interest
 of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 535–536).
1 Roberts JA, Lipman J. Pharmacokinetic issues for antibiotics in the critically ill
patient. Crit Care Med 2009; 37:840–851.
2 Udy AA, Roberts JA, Boots RJ, et al. Augmented renal clearance: implications
for antibacterial dosing in the critically ill. Clin Pharmacokinet 2010; 49:1–16.
3 Vincent J-L, Rello J, Marshall J, et al. International study of the prevalence and
outcomes of infection in intensive care units. J Am Med Assoc 2009;
302:2323–2329.
4 Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for anti-
bacterial dosing of mice and men. Clin Infect Dis 1998; 26:1–10.
5 Forrest A, Nix DE, Ballow CH, et al. Pharmacodynamics of intravenous
ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother 1993;
37:1073–1081.
6 van Zanten ARH, Polderman KH, van Geijlswijk IM, et al. Ciprofloxacin
pharmacokinetics in critically ill patients: a prospective cohort study. J Crit
Care 2008; 23:422–430.
7 Lipman J, Scribante J, Gous AGS, et al. Pharmacokinetic profiles of high-dose
intravenous ciprofloxacin in severe sepsis. Antimicrob Agents Chemother
1998; 42:2235–2239.
8 Conil J-M, Georges B, de Lussy A, et al. Ciprofloxacin use in critically ill
patients: pharmacokinetic and pharmacodynamic approaches. Int J Antimi-
crob Agents 2008; 32:505–510.
9 Patanwala AE, Norris CJ, Nix DE, et al. Vancomycin dosing for pneumonia in
critically ill trauma patients. J Trauma 2009; 67:802–804.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pharmacokinetics and pharmacodynamics Varghese et al. 477
10 Pea F, Furlanut M, Negri C, et al. Prospectively validated dosing nomograms
 for maximizing the pharmacodynamics of vancomycin administered by con-
tinuous infusion in critically ill patients. Antimicrob Agents Chemother 2009;
53:1863–1867.
This study utilized retrospective data from critically ill patients to develop a
prospectively validated dosing nomogram for continuous infusion of vancomycin
to optimize the achievement of target concentrations.
11 Martin JH, Fay MF, Udy A, et al. Pitfalls of using estimations of glomerular
filtration rate in an intensive care population. Intern Med J (in press). doi:
10.1111/j.1445-5994.2009.02160.x.
12 Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside
therapy: importance of the ratio of peak concentration to minimal inhibitory
concentration. J Infect Dis 1987; 149:443–448.
13 Rea RS, Capitano B, Bies R, et al. Suboptimal aminoglycoside dosing in
critically ill patients. Ther Drug Monit 2008; 30:674–681.
14 Zavascki AP, Goldani LZ, Cao G, et al. Pharmacokinetics of intra-
 venous polymyxin B in critically ill patients. Clin Infect Dis 2008; 47:1298–
1304.
The first pharmacokinetic study of polymyxin B conducted in critically ill
patients.
15 Israili ZH, Dayton PG. Human alpha-1-glycoprotein and its interactions with
drugs. Drug Metab Rev 2001; 33:161–235.
16 Plachouras D, Karvanen M, Friberg LE, et al. Population pharmacokinetic
analysis of colistin methanesulfonate and colistin after intravenous adminis-
tration in critically ill patients with infections caused by gram-negative bacteria.
Antimicrob Agents Chemother 2009; 53:3430–3436.
17 Rayner CR, Forrest A, Meagher AK, et al. Clinical pharmacodynamics of
linezolid in seriously ill patients treated in a compassionate use programme.
Clin Pharmacokinet 2003; 42:1411–1423.
18 Adembri C, Fallani S, Cassetta MI, et al. Linezolid pharmacokinetic/pharma-
codynamic profile in critically ill septic patients: intermittent versus continuous
infusion. Int J Antimicrob Agents 2008; 31:122–129.
19 Nicasio AM, Ariano RE, Zelenitsky SA, et al. Population pharmacokinetics of
high-dose, prolonged-infusion cefepime in adult critically ill patients with
ventilator-associated pneumonia. Antimicrob Agents Chemother 2009;
53:1476–1481.
20 Roberts JA, Kirkpatrick CMJ, Roberts MS, et al. Meropenem dosing in
 critically ill patients with sepsis and without renal dysfunction: intermittent
bolus versus continuous administration? Monte Carlo dosing simulations and
subcutaneous tissue distribution. J Antimicrob Chemother 2009; 64:142–
150.
The first study to compare pharmacokinetic profiles for bolus versus continuous
infusion of meropenem in subcutaneous tissue and plasma. Continuous infusion
maintains higher concentrations in plasma and subcutaneous tissue.
21 Roberts JA, Roberts MS, Robertson TA, et al. Piperacillin penetration into
 tissue of critically ill patients with sepsis: bolus versus continuous adminis-
tration? Crit Care Med 2009; 37:926–933.
This study compared subcutaneous tissue concentrations and plasma concentra-
tions in patients administered piperacillin either by bolus dosing or by continuous
infusion. Pharmacodynamic advantages of continuous dosing was demonstrated
most likely to be the greatest when treating pathogens with high MICs.
22 Roberts JA, Webb S, Paterson D, et al. A systematic review on clinical
benefits of continuous administration of [beta]-lactam antibiotics. Crit Care
Med 2009; 37:2071–2078.
23 Choi G, Gomersall CD, Tian Q, et al. Principles of antibacterial dosing
in continuous renal replacement therapy. Crit Care Med 2009; 37:2268–
2282.
24 Li AMMY, Gomersall CD, Choi G, et al. A systematic review of antibiotic
dosing regimens for septic patients receiving continuous renal replacement
therapy: do current studies supply sufficient data? J Antimicrob Chemother
2009; 64:929–937.
25 Burkhardt O, Hafer C, Langhoff A, et al. Pharmacokinetics of ertapenem in
critically ill patients with acute renal failure undergoing extended daily dialysis.
Nephrol Dial Transplant 2009; 24:267–271.
26 Kielstein JT, Eugbers C, Bode-Boeger SM, et al. Dosing of daptomycin in
 intensive care unit patients with acute kidney injury undergoing extended
dialysis–a pharmacokinetic study. Nephrol Dial Transplant 2009 [Epub ahead
of print]. doi:10.1093/ndt/gfp704.
The first pharmacokinetic study of daptopmycin in critically ill patients with
AKI.
27 Swoboda S, Ober MC, Lichtenstern C, et al. Pharmacokinetics of linezolid in
septic patients with and without extended dialysis. Eur J Clin Pharmacol 2009
[Epub ahead of print]. doi: 10.1007/s00228-009-0766-9.
28 Mushatt DM, Mihm LB, Dreisbach AW, Simon EE. Antibiotic dosing in slow
extended daily dialysis. Clin Infect Dis 2009; 49:433–437.
 478 Drugs in anesthesia
29 Mehta NM, Halwick DR, Dodson BL, et al. Potential drug sequestration during
extracorporeal membrane oxygenation: results from an ex vivo experiment.
Intensive Care Med 2007; 33:1018–1024.
30 Spriet I, Annaert P, Meersseman P, et al. Pharmacokinetics of caspofungin
and voriconazole in critically ill patients during extracorporeal membrane
oxygenation. J Antimicrob Chemother 2009; 63:767–770.
31 Ruiz S, Papy E, Da Silva D, et al. Potential voriconazole and caspofungin
sequestration during extracorporeal membrane oxygenation. Intensive Care
Med 2009; 35:183–184.
32 Ryan DM. Pharmacokinetics of antibiotics in natural and experimental super-
ficial compartments in animals and humans. J Antimicrob Chemother 1993;
31 (Supp D):1–16.
33 Markantonis SL, Markou N, Fousteri M, et al. Penetration of colistin into
cerebrospinal fluid. Antimicrob Agents Chemother 2009; 53:4907–
4910.
34 Seguin P, Verdier MC, Chanavaz C, et al. Plasma and peritoneal concentra-
tion following continuous infusion of cefotaxime in patients with secondary
peritonitis. J Antimicrob Chemother 2009; 63:564–567.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
35 Dalley AJ, Lipman J, Deans R, et al. Tissue accumulation of cephalothin in
 burns: a comparative study by microdialysis of subcutaneous interstitial fluid
cephalothin concentrations in burn patients and healthy volunteers. Antimi-
crob Agents Chemother 2009; 53:210–215.
A pharmacokinetic study that measured cefalotin concentrations in burn and
nonburn tissue sites using microdialysis.
36 Roberts DJ, Goralski KB, Renton KW, et al. Effect of acute inflammatory brain
injury on accumulation of morphine and morphine 3- and 6-glucuronide in the
human brain. Crit Care Med 2009; 37:2767–2774.
37 The STATInS trial: Statins in Sepsis Study 2007 ACTRN 12607000028404.
[cited 1 March 2010]. Available from: http://www.anzctr.org.au/trial_view.
aspx?ID=81692.
38 The CAS trial: Continued use of Atorvastatin in sepsis 2006
ACTRN12605000756628. [cited 1 March 2010]. Available from: http://
www.anzctr.org.au/trial_view.aspx?ID=886.
39 Kruger PS, Freir NM, Venkatesh B, et al. A preliminary study of atorvastatin
 plasma concentrations in critically ill patients with sepsis. Intensive Care Med
2009; 35:717–721.
Pharmacokinetic study that found plasma concentrations of atorvastatin to be very
high in critically ill patients with sepsis.