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Antibiotic dosing in critically ill patients with acute kidney injury

Article  in  Nature Reviews Nephrology · February 2011

DOI: 10.1038/nrneph.2011.12 · Source: PubMed

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REVIEWS

Antibiotic dosing in critically ill patients

with acute kidney injury
Rachel F. Eyler and Bruce A. Mueller
Abstract | A common cause of acute kidney injury (AKI) is sepsis, which makes appropriate dosing of
antibiotics in these patients essential. Drug dosing in critically ill patients with AKI, however, can be
complicated. Critical illness and AKI can both substantially alter pharmacokinetic parameters as compared
with healthy individuals or patients with end-stage renal disease. Furthermore, drug pharmacokinetic
parameters are highly variable within the critically ill population. The volume of distribution of hydrophilic
agents can increase as a result of fluid overload and decreased binding of the drug to serum proteins, and
antibiotic loading doses must be adjusted upwards to account for these changes. Although renal elimination of
drugs is decreased in patients with AKI, residual renal function in conjunction with renal replacement therapies
(RRTs) result in enhanced drug clearance, and maintenance doses must reflect this situation. Antibiotic dosing
decisions should be individualized to take into account patient-related, RRT-related, and drug-related factors.
Efforts must also be made to optimize the attainment of antibiotic pharmacodynamic goals in this population.
Eyler, R. F. & Mueller, B. A. Nat. Rev. Nephrol. 7, 226–235 (2011); published online 22 February 2011; doi:10.1038/nrneph.2011.12

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Learning objectives
Upon completion of this activity, participants should be able to:
1 Analyze alterations in pharmacokinetics among critically ill
patients.
2 Distinguish the most important variable of renal
replacement therapy in altering antibiotic concentrations.
3 Evaluate effective strategies for antibiotic prescribing among
critically ill patients with AKI.
4 Specify how to prescribe certain antibiotics among critically
ill patients.
Department of Clinical,
Social, and
Administrative
Sciences, College of
Pharmacy, University of
Michigan, 428 Church
Street, Ann Arbor, Competing interests
MI 48109-1065, USA
R. F. Eyler declares associations with the following companies:
(R. F. Eyler,
B. A. Mueller).
Merck, Roche. B. A. Mueller declares associations with the
following companies: Amgen, Cubist Pharmaceuticals, Gambro,
Correspondence to: Merck, Roche. See the article online for full details of the
B. A. Mueller relationships. The locum journal Chief Editor R. Ireland and the
muellerb@umich.edu CME questions author C. P. Vega declare no competing interests.
Introduction
Sepsis is a common cause of acute kidney injury (AKI);1
consequently, the proper dosing of antibiotics in these
patients is crucial. Drug dosing in critically ill patients
with AKI, however, can be complex as a patient’s renal
function is dynamic and difficult to quantify, their
volume status also fluctuates, and drug doses need to be
frequently reassessed. Pharmacokinetic studies to guide
the clinician through the complexities of drug dosing in
patients with AKI have only been conducted for a limited
number of antibiotics.2,3 Furthermore, the results of these
trials might only be applicable to institutions with similar
populations of patients and those using comparable renal
replacement therapy (RRT) techniques.
Antibiotic dosing decisions should take into account
the individual patient’s characteristics, the choice of RRT,
and drug-related factors. Critically ill patients with AKI
exhibit altered pharmacokinetic parameters in response
to antibiotic therapy, and interpatient variability is high.4
RRTs remove drugs from the circulation, and the extent
of removal is dependent not only on drug-related prop-
erties, but also on the RRT technique employed. For
each individual patient, antibiotic drug regimens must
be adjusted to optimize pharmacodynamics and maxi-
mize treatment efficacy. In this Review, we describe
the character­istics that should guide initial antibiotic
dosing decisions in critically ill patients with AKI. We
also discuss the need for dose adjustment to ensure that
adequate serum concentrations of antibiotics are consis-
tently achieved despite changes in the patient’s clinical
status, particularly when difficult-to-treat pathogens are
implicated. We focus on the role of evidence-based anti-
biotic dosing in attaining pharmacodynamic targets in
patients requiring RRT for AKI.

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© 2011 Macmillan Publishers Limited. All rights reserved

Pharmacokinetic alterations
Critically ill patients with AKI often exhibit different
pharmaco­kinetic profiles in response to drug treatment
compared with healthy individuals or patients with end-
stage renal disease (ESRD).2,4 The AKI popula­tion is hetero­
geneous, and, consequently, pharmaco­kinetic parameters
can be quite variable. Generally, the pharmaco­kinetic
changes can be categorized as alterations in absorption,
distribution, metabolism, and elimination.
Altered absorption
Oral drug absorption may be altered by gastro­intestinal
dysmotility in critically ill patients. Dysmotility can
develop as a result of decreased perfusion of the gut,
particularly if the patient is taking vasoconstrictive
drugs.4,5 To ensure adequate drug exposure, intravenous
anti­biotics should be used whenever possible, although
medica­tions are sometimes switched from intravenous to
oral administra­tion for economic reasons. Interestingly,
intestinal absorption of certain drugs is increased during
renal failure; findings from animal models indicate that
this effect might relate to an accumulation of uremic mol-
ecules, which cause deterioration of the integrity of the
intestinal mucosa.6 For example, the bioavailability of a
37.5 mg/kg intraintestinal dose of propranolol increased
from 54.7% in healthy control rats to 81.4% in rats with
cisplatin-­induced acute renal failure.6 Although interesting,
this concept has yet to be studied in humans.
The enteral feeding status of a patient is tied to some
important considerations that affect oral drug absorp-
tion. A critically ill individual who does not receive
enteral feeding will develop intestinal atrophy in as
little as 3 days, 7 and their gut mass may decrease by
50% within 7 days.5 These intestinal changes could alter
drug absorption, although this hypothesis has not been
fully investigated. Enteral feeding improves blood flow
to the digestive tract, and should be used wherever fea-
sible to maintain the integrity and viability of the gut.5
Enteral feeding itself, however, can affect drug absorp-
tion. Commercial enteral feeds decrease the absorption
of many fluoroquinolone and tetracycline anti­biotics.8–10
For example, in a study of 13 healthy volunteers,
coadministra­tion of one such enteral feed decreased the
average bioavailability of a 750 mg oral dose of cipro­
floxacin by 72%.10 Critically ill patients also often receive
H2-receptor antagonists or proton pump inhibitors,
which raise the pH of the stomach and can interfere with
the absorption of weak bases that require a strongly acidic
environment for absorption.4 When 200 mg of itracon-
azole (a weak base) was orally administered to 12 healthy
patients with famotidine-induced hypochlorhydria, peak
drug concentrations were decreased by 52.9% compared
with values obtained in the absence of famotidine.11
Altered distribution
The volume of distribution is an estimate of the extent to
which a drug will migrate into extravascular tissues, and
is one of the most striking sources of pharmaco­kinetic
variability in critically ill patients with AKI. Sepsis can
lead to the development of endothelial damage and
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© 2011 Macmillan Publishers Limited. All rights reserved
FOCUS ON AKI IN CRITICAL CARE
Key points
■■ Altered drug pharmacokinetics in critically ill patients with acute kidney injury
(AKI) and heterogeneous renal replacement therapy (RRT) techniques in
intensive care units preclude standardized antibiotic dosing
■■ Most critically ill patients with AKI exhibit altered antibiotic pharmacokinetics
that necessitate increased doses in spite of decreased renal clearance,
particularly when serious infections are implicated
■■ Drug dosing decisions must take into account pharmacodynamic as well as
pharmacokinetic considerations
■■ Clinicians should compare their RRT protocols to those in published guidelines
and ensure that their recommendations are applicable to the individual
patient’s clinical situation
■■ Hybrid RRTs require the same antibiotic dosing alterations as do continuous
RRTs, but for hybrid therapies the dose timing must also be considered
Table 1 | Volume of distribution data from pharmacokinetic studies in adults
Antibiotic Healthy volunteers (l/kg) Patients with AKI
receiving RRT (l/kg)
Lipophilic drugs
Ciprofloxacin 1.9876 1.60,77 1.6578
Levofloxacin 0.96, 79
1.1380
1.02,81 1.5182
Hydrophilic drugs
Amikacin 0.1883 0.4484
Daptomycin 0.10 85
0.2326
Meropenem 0.17,86 0.18,87 0.2788 0.26,89 0.35,28 0.3729
Piperacillin 0.15 90
0.14,91 0.1892
Vancomycin 0.39,93 0.59,94 0.6395 0.57,96 0.6597
Abbreviations: AKI, acute kidney injury; RRT, renal replacement therapy.
increased capillary permeability, which cause displace-
ment of fluids from the vasculature into the interstitium.4
Consequently, the volume of distribution of hydrophilic
drugs in critically ill patients with AKI can differ sub-
stantially from that reported in pharmacokinetic studies
of healthy individuals (Table 1).
These fluid shifts into the interstitial space can be
substantial, owing to the large fluid volumes frequently
given to patients with sepsis as part of resuscitation,
medication, and delivery of nutrition. Extravascular fluid
gains can be even more marked in patients who have a
decreased urine output secondary to AKI. In a review
of data on 81 critically ill adults receiving continuous
RRTs, 38 patients (47%) had ≥10% fluid-related gains
of body weight and 13 patients (16%) gained ≥20% of their
body weight at the time of starting RRT.12 These fluid-
related weight gains correlated closely with increased
mortality. Fluid overload can lead to hypoxia and the
need for mechanical ventilation, as well as impaired
cardiac function.13 Furthermore, an increase in fluid
volume can dilute serum creatinine concentration, result-
ing in inappropriately low measurements, and thus delay
the diagnosis of AKI and initiation of RRT.12,14
Another possible contributor to the poor outcomes
associated with fluid overload could be under­treatment
with antibiotics. Just as the capillary leakage associ-
ated with sepsis can increase the volume of distribu-
tion of creati­nine,15 it can also increase the volume of
REVIEWS
distribution of hydrophilic antibiotics, such as amino­
glycosides, β-lactams, and glycopeptides.16 This increased
volume of distribution could lead to subtherapeutic
plasma concentrations of these agents. The volume of
distribution of gentamicin is 0.48 l/kg in patients with
hyperdynamic sepsis, compared with 0.29 l/kg in a
control group of nonseptic postoperative patients.17
Factors associated with an increased volume of distribu-
tion were identified as increased severity of illness, as cal-
culated by the Acute Physiology Score, and a high cardiac
index. Another study of gentamicin pharmacokinetics
in 14 critically ill patients with AKI receiving extended
daily dialysis (mean APACHE [Acute Physiology and
Chronic Health Evaluation] III score of 98) reported an
even larger volume of distribution of 0.55 l/kg.18 These
increased volumes of distribution must be ‘filled’ with
drug if therapeutic serum concentrations are to be
achieved. Consequently, initial gentamicin doses must
be adjusted upwards to account for the increased volumes
of distribution associated with sepsis, fluid overload, and
AKI. The results of these studies17,18 indicate that, for
some critically ill patients with AKI and fluid overload,
gentamicin loading doses might need to be doubled to
attain therapeutic serum concentrations simply because
of their altered volume of distribution.
As the patient’s clinical status improves and the degree
of tissue edema decreases, the volume of distribution of
gentamicin can decline dramatically within days,
and drug dosages should be adjusted to account for
this change. Triginer et al.19 measured the gentamicin
volume of distribution in 40 critically ill patients with
suspected or confirmed sepsis owing to a Gram-negative
bacterial infection on day 2 of therapy (after aggressive
fluid resuscitation), and then again on day 7 of therapy.
The volume of distribution decreased from 0.43 l/kg to
0.29 l/kg (P <0.001) and the required gentamicin dosage
decreased from 5.14 mg/kg per 24 h to 3.98 mg/kg per 24 h
(P <0.001), despite the patients’ renal function remain-
ing fairly stable.19 These ongoing changes should also be
expected in patients with AKI: not only will a patient’s
capillary leakage status change, but after the initia­
tion of RRT, fluid overload will be gradually corrected,
and drug doses need to be reduced accordingly.
The increased incidence of obesity has presented
another noteworthy source of pharmacokinetic vari­
ability, because volumes of distribution can be vastly
different for a patient weighing 70 kg compared with
a patient who is twice that weight. In obese patients
(BMI ≥30 kg/m2), lipophilic antibiotics (such as fluoro­
quinolones) tend to have a larger total volume of distri-
bution, although when the totals are corrected to take
body weight into account, the volume of distribution per
kg is lower than that in patients who are not obese.20 As
plasma volume correlates with body weight, obese
patients usually also have higher total volumes of dis-
tribution for hydrophilic drugs, although the increases
might be less pronounced than those seen with lipophilic
drugs.21 To account for the pharmacodynamic changes
associated with obesity, drugs should always be adjusted
for body weight, rather than administering a standard
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© 2011 Macmillan Publishers Limited. All rights reserved
dose to all patients.21 This consideration is especially true
for loading doses, which must be able to fill the volume
of distribution.
Pharmacokinetic studies in obese individuals often
focus on identifying a surrogate marker (such as total,
adjusted, or lean body weight) that will most accurately
predict the volumes of distribution seen in the study
popula­tion. The surrogate marker of choice seems to
be total weight for vancomycin and daptomycin, and
adjusted body weight for aminoglycosides.20 When pos-
sible, drug monitoring should be used to guide subse-
quent doses.20 For drugs that do not have weight-based
dosing recommendations, obese patients should usually
receive doses toward the top end of the dosing range.
Finally, critically ill patients with AKI often have
increased antibiotic volumes of distribution owing to
decreased binding of the drug to serum proteins. This
reduction in protein binding could be due to decreased
serum albumin synthesis or increased extracellular shifts
of serum proteins.22 In addition, studies conducted in
patients with ESRD have indicated that decreased protein
binding could result from the accumulation of certain
uremic molecules that can bind to these proteins and
displace the drug from its binding site.23 In patients with
advanced stages of AKI, uremic molecules could also
contribute to decreased protein binding. The extent of
the decrease in protein binding in critically ill patients
with AKI is difficult to quantify, however, as therapeutic
drug monitoring in the hospital setting usually involves
measurement of total rather than free drug concentra-
tions. Furthermore, the amount of protein-bound drug
may be dependent on its concentration in serum, and not
remain constant throughout the dosing interval.24
Altered metabolism
Although they have rarely been studied directly, altera-
tions in the metabolism and nonrenal clearance of
antibiotics have been observed in patients with AKI.
The metabolism of drugs that are largely extracted by the
liver, such as β‑blockers and midazolam, is highly influ-
enced by hepatic blood flow.4 In patients with advanced
sepsis, the clearance of these drugs can be reduced as
hepatic blood flow decreases. In patients with hyper-
dynamic sepsis, however, hepatic metabolism may be
preserved as blood is shunted to the liver and other vital
organs.4 Vasoconstrictive drugs, such as phenyl­ephrine,
norepinephrine, epinephrine, and dopamine, can also
decrease hepatic blood flow, although the extent of this
effect varies according to the specific agent used. 4,25
Metabolic enzyme activity in the liver also seems to be
decreased in patients with AKI.26 Although some animal
models of AKI demonstrate variability in the expression
of a number of cytochrome P450 isoenzymes, human
data are currently lacking.26 Several drugs that are non-
renally eliminated have recognized alterations in their
hepatic clearance, including imipenem, meropenem, and
vancomycin. In anuric patients with AKI, the total clear-
ance rate of imipenem is 90–95 ml/min—considerably
lower than that reported in patients with normal renal
function (130 ml/min), but higher than that reported in

patients with ESRD (50 ml/min). These results indicate
that hepatic metabolism of imipenem is relatively pre-
served in patients with AKI compared with those with
ESRD.26,27 Similarly, the rate of clearance of meropenem
is greater in patients with AKI than in those with ESRD
(40–60 ml/min versus 30–35 ml/min). 26,28,29 The same
pattern of comparatively preserved nonrenal clearance
in patients with AKI is found with vancomycin; the clear-
ance rate of this drug in patients with normal renal func-
tion is 40 ml/min, compared with 15 ml/min in patients
with AKI, and 5 ml/min in patients with ESRD. However,
as AKI persists, clearance of vancomycin may decline
to the rate seen in ESRD.26,30 Nonhepatic elimination
pathways can also account for increased drug clearance.
Ciprofloxacin undergoes transintestinal excretion, which,
in patients with renal failure, may represent a compensa-
tory clearance mechanism that prevents accumulation
of this drug.31,32
Altered renal elimination
Sepsis-induced AKI is not only associated with decreased
glomerular filtration by the kidney, but also with impair-
ment of tubular secretion and reabsorption.33–35 These
changes can influence drug dosing in ways that are not
always recognized. β‑lactams, for example, are thought to
be excreted by the organic anionic transporter type 1 and,
at least in theory, dosing methods that take into account
the decrease in glomerular filtration but not decreased
transport could produce a larger than anticipated drug
exposure.35 The reabsorption of fluconazole, which can
be substantial in patients with normal renal function,
is decreased in critically ill patients with AKI. In many
cases, these patients might require unadjusted doses of
fluconazole, or even higher doses than are required for
patients with normal renal function.36,37
A critically ill patient with AKI usually has some resid-
ual renal function, which may change dynamically along
with the patient’s clinical status. For some renally elimi-
nated drugs, patients with residual renal function will
require higher antibiotic doses than their anuric counter­
parts.38 The patient’s urine output should, therefore, be
monitored closely, and drug doses adjusted upwards as
renal function returns. If a patient is taking renally elimi-
nated antibiotics that permit therapeutic drug monitor-
ing, such as aminoglycosides or vanco­mycin, an increase
in the clearance of these drugs can also signal the return
of renal function and the possible need for upward
adjustment of other renally eliminated drugs for which
monitoring might not be available.
Elimination by RRT
In general, drugs that are primarily renally eliminated,
with a small molecular weight,39 small volume of dis-
tribution (<1 l/kg), and low degree of protein binding,
are likely to be removed by RRTs.40 Although decreased
protein binding (which is often exhibited by critically
ill individuals) increases the volume of distribution
of a drug, elimination is also increased, because more
free drug is available to be removed by the kidney or
RRTs. Although exceptions exist to this general rule,41
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FOCUS ON AKI IN CRITICAL CARE
the percent­age of unbound drug can be used as a rough
estimate of the RRT extraction coefficient.42 However,
when calculating the extraction coefficient, clinicians
should use protein binding values reported in critically ill
indivi­duals rather than those from healthy persons.
RRT techniques vary widely,43 and each variation can
also affect drug clearance. Diffusive therapies (such as
intermittent hemodialysis and continuous venovenous
hemodialysis) and convective therapies (such as continu-
ous venovenous hemofiltration) both efficiently remove
small solutes, but convective therapies are superior with
regard to the removal of solutes with large molecular
weights.44,45 Furthermore, hemofilters themselves vary
by material, surface area, pore size, water permeability,
and the efficiency of removal of low-molecular-weight and
mid-molecular-weight solutes. High-flux hemofilters
have increased permeability to mid-molecular-weight
molecules and remove considerably more drug than
low-flux filters do.46–48 Almost all currently used con-
tinuous RRTs utilize high-flux hemofilters; however, the
hybrid RRTs used to treat AKI (which typically involve
slow, low-efficiency daily dialysis or extended daily
dialysis) sometimes utilize low-flux hemofilters.49,50
When low-flux filters are used, drug clearances may
differ (sometimes dramatically) from those achieved
with high-flux membranes. An additional issue related
to antibiotic clearance is drug adsorption to the filter.
Polyacrylonitrile filters are particularly associated with
this phenomenon, although the extent of adsorption is
difficult to quantify.51,52
Another technical consideration that affects drug
clearance occurs with continuous RRTs that utilize a high
convective component, such as continuous venovenous
hemofiltration. The point at which fluid replacement
occurs in these techniques alters drug clearance, because
dilution before filtration decreases the concentration of
drug available for removal by the filter.53,54 The differ-
ences between predilution and postdilution modes of
fluid replacement are predictable, and can be easily cal-
culated from the rates of blood flow, fluid replacement,
and clearance.2
In general, the most important RRT-related factor
affecting drug removal is effluent volume, which is deter-
mined by both flow rate and therapy duration.2 Effluent
rates vary between institutions, and contemporary efflu-
ent flow rates are often much higher than those used even
10 years ago.55 Consequently, drug-dosing recommenda­
tions for use with continuous RRT published in the past
might not apply today. Clinicians prescribing RRTs at
high effluent rates should use higher antibiotic doses
than those recommended in guidelines developed for
low flow rates. For example, the 2007 edition of Drug
Prescribing in Renal Failure assumes a continuous RRT
effluent rate of 2 l/h.56 Thus, these dosing recommenda-
tions may not be applicable if the patient is being treated
with substantially lower or higher effluent rates.
Pharmacodynamic considerations
Successful antibiotic treatment of a patient with AKI
requires not only consideration of pharmacokinetic
REVIEWS
Table 2 | Pharmacodynamic measures linked to antibacterial activity*
Antibiotic Pharmacodynamic measure
Time-dependent pharmacodynamic profile
β-Lactams: penicillins, cephalosporins, carbapenems %T>MIC
Glycopeptides: vancomycin AUC/MIC
Oxazolidinones: linezolid AUC/MIC
Concentration-dependent pharmacodynamic profile
Aminoglycosides AUC/MIC, ratio of peak to MIC
Colistin AUC/MIC
Lipopeptides: daptomycin, telavancin AUC/MIC, ratio of peak to MIC‡
Fluoroquinolones AUC/MIC, ratio of peak to MIC
*Selected antibiotics commonly used in the intensive care unit. ‡Telavancin only. Abbreviations: AUC, area
under the serum concentration–time curve; MIC, minimum inhibitory concentration; %T>MIC, the % of the
dosing interval above MIC.
profiles, but also careful attention to pharmaco­dynamics.
The study of pharmacodynamics, as it applies to anti­
biotics, seeks to link measures of drug exposure (such
as peak and trough serum concentrations, and area
under the serum concentration–time curve [AUC])
to bactericidal activity. For example, most anti­biotics
fall into one of two pharmacodynamic categories:
concentration-­dependent or time-dependent. In general,
for concentration-­dependent antibiotics, a favorable high
ratio of the peak serum concentration to the minimum
inhibitory concentra­tion (MIC, the minimum concentra-
tion required to inhibit bacterial growth) is best associ-
ated with clinical success, whereas for time-dependent
antibiotics, the percentage of the dosing interval spent
above the MIC is the most important parameter to
maximize (Table 2).57,58 A third parameter, AUC/MIC, is
closely related to the other two parameters, and is some-
times most predictive of clinical success for antibiotics of
either type (Table 2). However, an antibiotic’s pattern
of bactericidal activity (concentration-dependent or
time-dependent) is not the sole determinant of which
pharmaco­dynamic parameter is most predictive of effi-
cacy. The presence and duration of any postantibiotic
effect—defined as the period between antibiotic exposure
and the point at which the surviving microbes begin to
multiply—is also important.57 Decreased drug elimina­
tion as a result of AKI, increased volume of distribution
from fluid overload and decreased protein binding, and
increased clearance owing to RRTs not only affect anti-
biotic pharmacokinetics, but also influence whether
optimal pharmacodynamic targets can be met.
Concentration-dependent antibiotics
Desirable pharmacodynamic characteristics for
concentration-­d ependent antibiotics are high peak
concentra­tions that optimize bactericidal activity, fol-
lowed by low troughs that minimize toxic effects. This
knowledge can help guide dosing decisions. However,
owing to the increased volume of distribution in critically
ill patients with AKI, the high peaks and low troughs that
are desirable for concentration-dependent antibiotics can
be difficult to attain with usual doses, as illustrated by the
following examples.
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© 2011 Macmillan Publishers Limited. All rights reserved
Daptomycin is a concentration-dependent lipopeptide
antibiotic primarily eliminated by the kidneys. Trough
plasma concentrations of daptomycin above 24.3 μg/ml
have been associated with an increased risk of eleva-
tions in creatine phosphokinase levels, a serum marker
of myopathy.59 In critically ill patients with AKI who
were receiving continuous RRT at a mean effluent rate of
33 ml/kg/h, the pharmacokinetics of a single daptomycin
dose of 8 mg/kg was studied during the subsequent 48 h.60
This dose was selected based on the results of an in vitro
investigation carried out by the same group.61 The team
used the serum concentration–time data collected from
each patient to generate a pharmacodynamic model, in
which they simulated the effects of daptomycin dosing
regimens of 8 mg/kg every 48 h and 4 mg/kg every 24 h.60
The 8 mg/kg dose every 48 h not only achieved higher
peaks at steady state (88.8 μg/ml versus 53.0 μg/ml),
but also produced lower troughs (7.2 μg/ml versus
12.3 μg/ml). These findings indicate that the 8 mg/kg
every 48 h regimen not only optimizes pharmaco­dynamic
goal attainment, but could, furthermore, reduce the risk
of myopathy.
Aminoglycoside antibiotics also have concentration-
dependent activity, and peak:MIC ratios of 10–12 are
associated with the greatest bacterial killing effect.58
Prolonged courses of treatment and elevated trough
levels of these agents are associated with nephrotoxic
and ototoxic effects.62 However, to fully optimize the
concentration-­dependent pharmacodynamic profile of
amikacin in patients with sepsis who have an increased
volume of distribution, initial doses that are higher than
the conventional 15 mg/kg might be required. Amikacin
doses of 15 mg/kg and 20 mg/kg have produced sub­
optimal mean peak concentrations of 33.5 mg/l and
33.8 mg/l, respectively, in critically ill patients with
preserved renal function.63,64 Use of a loading dose of
aminoglycosides, to ensure an adequate initial concentra­
tion peak in these often fluid-overloaded patients, fol-
lowed with close drug therapeutic monitoring of serum
concentra­tions, will help with pharmacodynamic goal
attainment. Aggressive treatment to optimize pharmaco­
dynamic parameters is particularly warranted in the
presence of pathogens that have a high MIC to the anti-
biotic, or in patients with sepsis and large accumulations
of extravascular volume.
The use of RRTs may aid pharmacodynamic goal
attainment for concentration-dependent antibiotics
by preventing toxic effects associated with prolonged
high levels of antibiotic. For example, the drug clearance
produced by continuous RRTs could help to prevent
the persistence of high levels of aminoglycosides after
a loading dose. In patients managed with intermittent
hybrid RRTs, some researchers have suggested that the
antibiotic dose should be scheduled before dialysis,
so that drug removal by the RRT can be used to avoid
toxic effects. Roberts et al. 18 prospectively collected
pharmaco­kinetic data and then used population mod-
eling to evaluate several gentamicin dosing regimens
in patients receiving extended daily hemodiafiltration,
and concluded that 6 mg/kg of gentamicin administered

30 min before RRT with dosing repeated every 48 h
was the optimal regimen for achieving the pharmaco­
dynamic goals (defined as a peak serum concentration
of 10 mg/l, and trough below 1.5 mg/l).
The use of RRT to meet pharmacodynamic goals of
concentration-dependent antibiotics is not without
limita­tions. A major problem is the variability of RRT
treatments, which can be interrupted for a variety of
reasons in the intensive care setting. When Roberts
et al. 18 investigated the effect of RRT on gentamicin
pharmacodynamic goal attainment, the assumption was
made that extended daily hemodiafiltration would last
10 h—although in their study clotting and other factors
limited the typical treatment duration to approximately
6 h. If the timing of antibiotic doses is intended to be
coordinated with that of RRT, dialysis must be per-
formed at the same time every day. The investigators
of a pharmaco­kinetic study of daptomycin in patients
undergoing hybrid RRT (blood and dialyzate flows of
160 ml/min; 8 h treatment) recommended a daily dose
of 6 mg/kg, but emphasized that daptomycin must be
given 8 h before the hemodialysis session.65 In institutions
that employ similar hybrid dialysis techniques, if dapto­
mycin is given less than 8 h before dialysis, increased
drug removal will lower the AUC and the drug might be
underdosed. If daptomycin is administered more than
8 h before dialysis, drug clearance will be decreased and
the risk of toxic effects increased.
Time-dependent antibiotics
For time-dependent antibiotics, such as β‑lactams, main-
taining serum concentrations above the MIC optimizes
therapeutic efficacy and prevents the develop­ment of
microbial drug resistance.57 Unlike the disadvantages
experienced with having to attain both high peaks and
low troughs for concentration-dependent antibiotics,
the reduced renal function in patients with AKI helps
to prevent inadequate serum concentrations of time-
­d ependent antibiotics. RRTs that run at high efflu-
ent rates, however, can remove substantial amounts of
β‑lactams.32 Several modified methods of administra­
tion, which include prolonged intermittent infusions,
low-dose with short-interval regimens, and continuous
infusions, have been developed to optimize the bacteri-
cidal activity of β‑lactams.66 Continuous infusions are
of particular interest for use in patients on RRTs, as they
could theoretically be adjusted to administer the drug at
a similar rate to that at which it is removed by dialysis.
Examples of β‑lactam antibiotics for which continuous
infusions have been tested in patients on continuous RRT
include meropenem and ceftazidime. Langgartner et al.67
compared an intermittent meropenem regimen (1 g
infused every 12 h) with a continuous regimen (500 mg
loading dose followed by an infusion of meropenem 2 g
over 24 h) in 12 critically ill patients receiving continu-
ous hemodiafiltration at an effluent rate of 25 ml/kg/h.
The continuous infusion maintained steady state
serum concentrations of 18.6 mg/l, and produced an
AUC similar to that of the intermittent dosing regimen.
Continuous infusions of ceftazidime have also been
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© 2011 Macmillan Publishers Limited. All rights reserved
FOCUS ON AKI IN CRITICAL CARE
investigated in patients undergoing continuous RRT; a
2 g loading dose and 3 g infusion over 24 h produced
mean steady state concentrations of 33.5 mg/l, effectively
maintaining the level of antibiotic at ≥4 times the MIC
(4 mg/l) required to eliminate susceptible pathogens for
100% of the dosing interval.68 Continuous infusions of
β‑lactams have not been investigated with hybrid RRT.
Such continuous infusions, with an administration rate
adjustment depending on whether the hybrid RRT is
running or not, might prove useful. When continuous
infusions of β‑lactams are not available, an unadjusted
loading dose, followed by small, frequent maintenance
doses is thought to maintain serum concentrations
above the MIC more effectively than large doses given at
extended intervals. The development and implementa­
tion of clinically useful assays for therapeutic drug
monitoring could alleviate some of the difficulties with
dosing of β‑lactams. Roberts et al.69 performed twice-
weekly therapeutic drug monitoring for β‑lactams in
236 critically ill patients who were prescribed this agent.
Of the 36 (15.3%) patients in the study who were receiv-
ing continuous venovenous hemodiafiltration (blood
flow 200 ml/min, dialyzate flow rate 1 l/h, and ultra-
filtration rate of 2 l/h), 25 required dose adjustments,
among whom seven required dose increases after their
first monitoring session.69 Unfortunately, therapeutic
drug monitoring for β‑lactams is currently unavailable
to most clinicians.
Individual drug-dosing strategies
Individual patient-specific (body weight and volume
status), RRT-specific (effluent rate, dialyzer flux,
and mode of fluid replacement), and drug-specific
(pharmaco­kinetic and pharmacodynamic) character-
istics should guide initial dosing decisions, and doses
should be adjusted continually as a patient’s clinical
status changes. Drug dosing in patients with AKI can,
therefore, be quite complex.
Practical approaches to drug dosing
In nearly all situations, a loading dose that will achieve
the target serum concentrations based on the expected
volume of distribution should be given.70 No adjustments
need to be made for residual renal function or RRT for
this initial dose. Therapeutic drug monitoring should
subsequently be used whenever possible, but is not
available for many drugs. Among the antibiotics com-
monly used in the intensive care unit setting (Table 3),
thera­peutic drug monitoring is available only for amino­
glycosides and vancomycin in most hospitals, and in these
two cases monitoring should, therefore, be used to guide
dosing. For hybrid RRTs, additional attention should be
paid to the timing of drug administration relative to that
of the dialysis treatment. Monitoring should also take
into account that some drugs exhibit rebound, that is,
an increase in drug concentrations in the blood that
can occur when RRT ends and drug sequestered in the
tissues redistributes back into the blood.70
Consulting the literature would be the most
evidence-­b ased method of dose adjustment, as long
REVIEWS

Table 3 | Dosing recommendations for selected intravenous antibiotics in patients on continuous RRT
Drug *Aronoff et al.56 ‡
Trotman et al.98 §
Heintz et al.99 ||
Sanford Guide100
Amikacin 7.5 mg/kg every 10 mg/kg LD, then 7.5 mg/kg 10 mg/kg LD then 7.5 mg/kg 7.5 mg/kg every 24 h
24–72 h every 24–48 h every 24–48 h
Ciprofloxacin 400 mg every 24 h 200–400 mg every 12 h 400 mg every 12–24 h 200–400 mg every 24 h
Daptomycin 8 mg/kg every 48 h 4 mg/kg or 6 mg/kg every 48 h 4 mg/kg or 6 mg/kg every 48 h No recommendation
Levofloxacin 500 mg every 48 h 500 mg LD, then 250 mg every 500–750 mg LD, then 750 mg LD, then
24 h 250–500 mg every 24 h 500 mg every 48 h
Meropenem 1–2 g every 12 h 1 g every 12 h 1 g LD then 0.5–1 g every 1 g every 12 h
8–12 h
Piperacillin– 4.5 g every 8 h 2.25–3.375 g every 6 h 2.25–3.375 g every 6 h 2.25 g every 6 h
tazobactam
Vancomycin 1 g every 24–96 h 15–20 mg/kg LD, then 1 g every 15–25 mg/kg LD, then 500 mg every 24–48 h
24 h 10–15 mg/kg every 24 h
*Recommendations based on dialyzate/ultrafiltrate/effluent rate of 2 l/h. ‡Recommendations for patients on continuous venovenous hemodialysis with a
dialyzate flow rate of 1 l/h. §Recommendations for patients on continuous venovenous hemodialysis with a dialyzate flow rate of 1–2 l/h. ||Flow rates not
specified. Abbreviations: LD, loading dose; RRT, renal replacement therapy.

as the clinician ensures that their patient’s clini-
cal situation is comparable to that of the population
of patients and the RRT modalities studied. Drug-
dosing recommenda­t ions for continuous RRT are
available, although the conclusions vary according to
which source is consulted (Table 3). Before using these
recom­mendations, it is crucial to verify that they are up
to date and based on dialyzate, ultrafiltrate, and efflu-
ent rates that are similar to those being utilized. Our
institution, for example, often employs dialyzate flow
rates of at least 2 l/h and, consequently, we tend to use
higher antibiotic doses than are recommended in some
of these published sources.
Dosage adaptations
A review of the dosing techniques aimed at individual-
izing antibiotic therapy in patients on continuous RRT
has been published.71 One commonly used drug-dosing
technique involves calculating the total creatinine clear-
ance rate by adding any estimated residual renal creati-
nine clearance to the expected extracorporeal creatinine
clearance. The extracorporeal creatinine clearance rate
can be assumed to be approximately equivalent to the
dialyzate, ultrafiltrate, or effluent rate, and medication
dosing guidelines specified for the total creatinine clear-
ance can be used to guide dose selection. In most patients
receiving conventional continuous RRT, most drugs
will fall within the 25–50 ml/min creatinine clearance
range. This method is useful, although it assumes that
drugs only undergo glomerular filtration, not tubular
secretion or reabsorption.70 For drugs that do undergo
tubular secretion, this method could lead to increased
drug exposures, and in patients with impaired reabsorp­
tion, underdosing can potentially occur. Several equa-
tions have been developed to adjust drug doses,
although they do not take a drug’s pharmacodynamics
into account.72,73
approach is not appropriate for all situations. Taking
every one of the factors discussed in this Review into
account may, however, be time consuming and imprac-
tical for the intensive care unit clinician. Further
compli­cating the issue is the variability of how RRT is
delivered, and the lack of sufficient pharmacokinetic
and pharmacodynamic data provided in the drug man-
ufacturer’s prescribing information.74 Hybrid therapies
carry the added difficulty of ensuring that medications
are given with an optimal timing in relation to RRT.
Owing to the variation in intermittent, hybrid, and
continuous RRT techniques, published pharmaco­
kinetic trials may lack generalizability. Furthermore,
published trials are often missing information that is
vital to making appropriate clinical interpretations.
Less than 90% of pharmacokinetic studies in patients
undergoing continuous RRT actually specified the
continuous RRT dose used in their respective popula­
tions, and only 58% of studies in patients on continu-
ous venovenous hemodialysis specified whether fluid
replacement was given before or after filtration. 75
Without such essential informa­t ion, the translation
of published continuous RRT studies to the clinical
setting is very difficult.
The review by Li et al.75 establishes an ideal data set
that should published in all pharmacokinetic studies
conducted in patients receiving RRTs. Efforts to con-
vince drug manufacturers to conduct trials in critically
ill patients receiving RRTs, as well as to update drug-
dosing recommendations in package inserts that were
developed using outdated RRT techniques, will also
improve the quality of the pharmacokinetic data avail-
able. Population modeling could be a useful tool to
improve the interpretability of the results of pharmaco­
kinetic trials. Pharmacodynamic targets should also
be tied to the pharmacokinetic data in a way that is
easily interpretable.

Barriers to effective dosing Conclusions

With a variety of factors influencing drug removal in a With the large variability in pharmacokinetic para­
particularly vulnerable population, a ‘one dose fits all’ meters reported in critically ill patients, increased

232  |  APRIL 2011  |  VOLUME 7  www.nature.com/nrneph

© 2011 Macmillan Publishers Limited. All rights reserved

antibiotic dosing is essential to ensure that adequate
serum concentra­tions are achieved, particularly when
difficult-to-treat pathogens are implicated. Until thera-
peutic monitoring for a wider selection of antibiotics is
more readily available, much of antibiotic dosing will
continue to be based on estimates. Nonetheless, edu-
cated, evidence-based dosing can make a large differ-
ence in attaining pharmaco­dynamic targets, preventing
resistance, and optimizing patient outcomes.
1. Uchino, S. et al. Acute renal failure in critically ill
patients: a multinational, multicenter study. JAMA
294, 813–818 (2005).
2. Choi, G. et al. Principles of antibacterial dosing in
continuous renal replacement therapy. Crit. Care
Med. 37, 2268–2282 (2009).
3. Li, A. M. 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. 64, 929–937 (2009).
4. Boucher, B. A., Wood, G. C. & Swanson, J. M.
Pharmacokinetic changes in critical illness. Crit.
Care Clin. 22, 255–271 (2006).
5. Stechmiller, J. K., Treloar, D. & Allen, N. Gut
dysfunction in critically ill patients: a review of the
literature. Am. J. Crit. Care 6, 204–209 (1997).
6. Okabe, H. et al. The increased intestinal
absorption rate is responsible for the reduced
hepatic first-pass extraction of propranolol in rats
with cisplatin-induced renal dysfunction. J. Pharm.
Pharmacol. 55, 479–486 (2003).
7. Hughes, C. A. & Dowling, R. H. Speed of onset of
adaptive mucosal hypoplasia and hypofunction in
the intestine of parenterally fed rats. Clin. Sci.
(Lond.) 5, 317–327 (1980).
8. Fagerman, K. E., McGuigan, D. & Pixley, B.
Potential interaction between enteral feeding
solutions and oral tetracycline. Nutr. Clin. Pract. 1,
257–258 (1986).
9. Wright, D. H., Pietz, S. L., Konstantinides, F. N. &
Rotschafer, J. C. Decreased in vitro
fluoroquinolone concentrations after admixture
with an enteral feeding formulation. J. Parenter.
Enteral Nutr. 24, 42–48 (2000).
10. Mueller, B. A., Brierton, D. G., Abel, S. R. &
Bowman, L. Effect of enteral feeding with ensure
on oral bioavailabilities of ofloxacin and
ciprofloxacin. Antimicrob. Agents Chemother. 38,
2101–2105 (1994).
11. Lim, S. G., Sawyerr, A. M., Hudson, M.,
Sercombe, J. & Pounder, E. Short report:
the absorption of fluconazole and itraconazole
under conditions of low intragastric acidity.
Aliment. Pharmacol. Ther. 7, 317–321 (1993).
12. Fülöp, T. et al. Volume-related weight gain and
subsequent mortality in acute renal failure
patients treated with continuous renal
replacement therapy. ASAIO J. 56, 333–337
(2010).
13. Schrier, R. W. AKI: fluid overload and mortality.
Nat. Rev. Nephrol. 5, 485 (2009).
14. Mehta, R. L. et al. Nephrology consultation in
acute renal failure: does timing matter? Am. J.
Med. 113, 527–528 (2002).
15. Edwards, K. D. Creatinine space as a measure of
total body water in anuric subjects, estimated
after single injection and haemodialysis. Clin. Sci.
18, 455–464 (1959).
16. Roberts, J. A. & Lipman, J. Pharmacokinetic
issues for antibiotics in the critically ill patient.
Crit. Care Med. 37, 840–850 (2009).
17. Tang, G. J., Tang, J. J., Lin, B. S., Kong, C. W. &
Lee, T. Y. Factors affecting gentamicin
NATURE REVIEWS | NEPHROLOGY VOLUME 7  |  APRIL 2011  |  233
FOCUS ON AKI IN CRITICAL CARE
Review criteria
Studies for inclusion in this article were identified from a
search of the PubMed database using combinations of
the following terms: “drug dosing”, “renal replacement
therapy”, “pharmacokinetics”, “critical illness”, and
“acute kidney injury”. The reference lists of published
articles and the personal records of the authors were
also searched for further relevant papers.
pharmacokinetics in septic patients. Acta
Anaesthesiol. Scand. 43, 726–730 (1999).
18. Roberts, J. A. et al. Using population
pharmacokinetics to determine gentamicin
dosing during extended daily diafiltration in
critically ill patients with acute kidney injury.
Antimicrob. Agents Chemother. 54, 3635–3640
(2010).
19. Triginer, C. et al. Gentamicin volume of
distribution in critically ill septic patients.
Intensive Care Med. 16, 303–306 (1990).
20. Pai, M. P. & Bearden, D. T. Antimicrobial dosing
considerations in obese adult patients.
Pharmacotherapy 27, 1081–1091 (2007).
21. Falagas, M. E. & Karageorgopoulos, D. E.
Adjustment of dosing of antimicrobial agents for
bodyweight in adults. Lancet 375, 248–251
(2010).
22. Fry, D. The importance of antibiotic
pharmacokinetics in critical illness. Am. J. Surg.
172, 20S–25S (1996).
23. Vanholder, R., Van Landschoot, N., De Smet, R.,
Schoots, A. & Ringoir, S. Drug protein binding in
chronic renal failure: evaluation of nine drugs.
Kidney Int. 33, 996–1004 (1988).
24. Crandon, J. L., Banevicius, M. A. & Nicolau, D. P.
Pharmacodynamics of tigecycline against
phenotypically diverse Staphylococcus aureus
isolates in a murine thigh model. Antimicrob.
Agents Chemother. 53, 1165–1169 (2009).
25. Meier-Hellman, A. et al. Epinephrine impairs
splanchnic perfusion in septic shock. Crit. Care
Med. 25, 399–404 (1997).
26. Vilay, A. M., Churchwell, M. D. & Mueller, B. A.
Clinical review: drug metabolism and nonrenal
clearance in acute kidney injury. Crit. Care 12,
235 (2008).
27. Mueller, B. A., Scarim, S. K. & Macias, W. L.
Comparison of imipenem pharmacokinetics in
patients with acute or chronic renal failure
treated with continuous hemofiltration. Am. J.
Kidney Dis. 21, 172–179 (1993).
28. Giles, L. J. et al. Pharmacokinetics of
meropenem in intensive care unit patients
receiving continuous veno-venous hemofiltration
or hemodiafiltration. Crit. Care Med. 28,
632–637 (2000).
29. Ververs, T. F. et al. Pharmacokinetics and dosing
regimen of meropenem in critically ill patients
receiving continuous venovenous hemofiltration.
Crit. Care Med. 28, 3412–3416 (2000).
30. Macias, W. L., Mueller, B. A. & Scarim, S. K.
Vancomycin pharmacokinetics in acute renal
failure: preservation of nonrenal clearance. Clin.
Pharmacol. Ther. 50, 688–694 (1991).
31. Pea, F., Poz, D., Viale, P., Pavan, F. & Furlanut, M.
Which reliable pharmacodynamic breakpoint
should be advised for ciprofloxacin monotherapy
in the hospital setting? A TDM-based
retrospective perspective. J. Antimicrob.
Chemother. 58, 380–386 (2006).
32. Pea, F., Viale, P., Pavan, F. & Furlanut, M.
Pharmacokinetic considerations for
antimicrobial therapy in patients receiving renal
© 2011 Macmillan Publishers Limited. All rights reserved
replacement therapy. Clin. Pharmacokinet. 46,
997–1038 (2007).
33. Schmidt, C., Höcherl, K., Schweda, F. &
Bucher, M. Proinflammatory cytokines cause
down-regulation of renal chloride entry pathways
during sepsis. Crit. Care Med. 35, 2110–2119
(2007).
34. Sun, H., Frassetto, L. & Benet, L. Z. Effects of
renal failure on drug transport and metabolism.
Pharmacol. Ther. 109, 1–11 (2006).
35. Miyazaki, H., Sekine, T. & Endou, H. The
multispecific organic anion transporter family:
properties and pharmacological significance.
Trends Pharmacol. Sci. 25, 654–662 (2004).
36. Bergner, R. et al. Fluconazole dosing in
continuous veno-venous haemofiltration
(CVVHF): need for a high daily dose of 800 mg.
Nephrol. Dial. Transplant. 21, 1019–1023
(2006).
37. Schetz, M. Drug dosing in continuous renal
replacement therapy: general rules. Curr. Opin.
Crit. Care 13, 645–651 (2007).
38. Joy, M. S., Matzke, G. R., Frye, R. F. &
Palevsky, P. M. Determinants of vancomycin
clearance by continuous venovenous
hemofiltration and continuous venovenous
hemodialysis. Am. J. Kidney Dis. 31, 1019–1027
(1998).
39. Clark, W. R. & Ronco, C. CRRT efficiency and
efficacy in relation to solute size. Kidney Int.
Suppl. 72, S3–S7 (1999).
40. Churchwell, M. D. & Mueller, B. A. Drug dosing
during continuous renal replacement therapy.
Semin. Dial. 22, 185–188 (2009).
41. Bouman, C. S. et al. Discrepancies between
observed and predicted continuous venovenous
hemofiltration removal of antimicrobial agents in
critically ill patients and the effects on dosing.
Intensive Care Med. 32, 2013–2019 (2006).
42. Golper, T. A. Drug removal during continuous
hemofiltration or hemodialysis. Contrib. Nephrol.
93, 110–116 (1991).
43. Uchino, S. et al. Continuous renal replacement
therapy: a worldwide practice survey. The
beginning and ending supportive therapy for the
kidney (BEST kidney) investigators. Intensive
Care Med. 33, 1563–1570 (2007).
44. Jeffrey, R. F. et al. A comparison of molecular
clearance rates during continuous hemofiltration
and hemodialysis with a novel volumetric
continuous renal replacement system. Artif.
Organs 18, 425–428 (1994).
45. Huang, Z., Letteri, J. J., Clark, W. R., Ronco, C. &
Gao, D. Operational characteristics of
continuous renal replacement modalities used
for critically ill patients with acute kidney injury.
Int. J. Artif. Organs 31, 525–534 (2008).
46. DeSoi, C. A., Sahm, D. F. & Umans, J. G.
Vancomycin elimination during high-flux
hemodialysis: kinetic model and comparison of
four membranes. Am. J. Kidney Dis. 20, 354–360
(1992).
47. Agarwal, R. & Toto, R. D. Gentamicin clearance
during hemodialysis: a comparison of high-
REVIEWS
efficiency cuprammonium rayon and
conventional cellulose ester hemodialyzers. Am.
J. Kidney Dis. 22, 296–299 (1993).
48. Scott, M. K., Mueller, B. A. & Clark, W. R.
Vancomycin mass transfer characteristics of
high-flux cellulosic dialysers. Nephrol. Dial.
Transplant. 12, 2647–2653 (1997).
49. Ahern, J. W., Lai, C., Rebuck, J. A.,
Possidente, C. J. & Weidner, M. Experience with
vancomycin in patients receiving slow low
efficiency dialysis. Hosp. Pharm. 39, 138–143
(2004).
50. Fiaccadori, E. et al. Removal of linezolid by
conventional intermittent hemodialysis,
sustained low-efficiency dialysis, or continuous
venovenous hemofiltration in patients with acute
renal failure. Crit. Care Med. 32, 2437–2442
(2004).
51. Choi, G. et al. The effect of adsorption, filter
material and point of dilution on antibiotic
elimination by haemofiltration: an in vitro study
of levofloxacin. Int. J. Antimicrob. Agents 24,
468–472 (2004).
52. Tian, Q. et al. Effect of drug concentration on
adsorption of levofloxacin by polyacrylonitrile
haemofilters. Int. J. Antimicrob. Agents 28,
147–150 (2006).
53. Uchino, S., Cole, L., Morimatsu, H.,
Goldsmith, D. & Bellomo, R. Clearance of
vancomycin during high-volume haemofiltration:
impact of pre-dilution. Intensive Care Med. 28,
1664–1667 (2002).
54. Clark, W. R., Turk, J. E., Kraus, M. A. & Gao, D.
Dose determinants in continuous renal
replacement therapy. Artif. Organs 27, 815–820
(2003).
55. Mueller, B. A., Pasko, D. A. & Sowinski, K. M.
Higher renal replacement therapy dose delivery
influences on drug therapy. Artif. Organs 27,
808–814 (2003).
56. Aronoff, G. R. et al. Drug prescribing in renal
failure: dosing guidelines for adults and children
5th edn (American College of Physicians,
Philadelphia, 2007).
57. Ambrose, P. G. et al. Pharmacokinetics:
pharmacodynamics of antimicrobial therapy:
it’s not just for mice anymore. Clin. Infect. Dis.
44, 79–86 (2007).
58. Owens, R. C. Jr & Shorr, A. F. Rational dosing of
antimicrobial agents: pharmacokinetic and
pharmacodynamic strategies. Am. J. Health Syst.
Pharm. 66, S23–S30 (2009).
59. Bhavnani, S. M., Rubino, C. M., Ambrose, P. G. &
Drusano, G. L. Daptomycin exposure and the
probability of elevations in the creatine
phosphokinase level: data from a randomized
trial of patients with bacteremia and
endocarditis. Clin. Infect. Dis. 50, 1568–1574
(2010).
60. Vilay, A. M. et al. Daptomycin pharmacokinetics
in critically ill patients receiving continuous
venovenous hemodialysis. Crit. Care Med. 39,
19–25 (2011).
61. Churchwell, M. D., Pasko, D. A. & Mueller, B. A.
Daptomycin clearance during modeled
continuous renal replacement therapy. Blood
Purif. 24, 548–554 (2006).
62. Turnidge, J. Pharmacodynamics and dosing of
aminoglycosides. Infect. Dis. Clin. North Am. 17,
503–528 (2003).
63. Beaucaire, G. et al. Clinical and bacteriological
efficacy, and practical aspects of amikacin given
once daily for severe infections. J. Antimicrob.
Chemother. 27 (Suppl. C), 91–103 (1991).
64. Marik, P. E., Lipman, J., Kobilski, S. &
Scribante, J. A prospective randomized study
comparing once- versus twice-daily amikacin
dosing in critically ill adult and paediatric
234  |  APRIL 2011  |  VOLUME 7  www.nature.com/nrneph
patients. J. Antimicrob. Chemother. 28, 753–764
(1991).
65. Kielstein, J. T. et al. Dosing of daptomycin in
intensive care unit patients with acute kidney
injury undergoing extended dialysis—a
pharmacokinetic study. Nephrol. Dial. Transplant.
25, 1537–1541 (2010).
66. Perrott, J., Mabasa, V. H. & Ensom, M. H.
Comparing outcomes of meropenem
administration strategies based on
pharmacokinetic and pharmacodynamic
principles: a qualitative systematic review. Ann.
Pharmacother. 44, 557–564 (2010).
67. Langgartner, J., Vasold, A., Glück, T., Reng, M. &
Kees, F. Pharmacokinetics of meropenem during
intermittent and continuous intravenous
application in patients treated by continuous
renal replacement therapy. Intensive Care Med.
34, 1091–1096 (2008).
68. Mariat, C. et al. Continuous infusion of
ceftazidime in critically ill patients undergoing
continuous venovenous haemodiafiltration:
pharmacokinetic evaluation and dose
recommendation. Crit. Care 10, R26 (2006).
69. Roberts, J. A. et al. Therapeutic drug monitoring
of β-lactams in critically ill patients: proof of
concept. Int. J. Antimicrob. Agents 36, 332–339
(2010).
70. Schetz, M. Drug dosing in continuous renal
replacement therapy: general rules. Curr. Opin.
Crit. Care 13, 645–651 (2007).
71. Choi, G. et al. Principles of antibacterial dosing in
continuous renal replacement therapy. Blood
Purif. 30, 195–212 (2010).
72. Reetze-Bonorden, P., Böhler, J. & Keller, E. Drug
dosage in patients during continuous renal
replacement therapy: pharmacokinetic and
therapeutic considerations. Clin. Pharmacokinet.
24, 362–379 (1993).
73. Kroh, U. F. Drug administration in critically ill
patients with acute renal failure. New Horiz. 3,
748–759 (1995).
74. Mueller, B. A. & Smoyer, W. E. Challenges in
developing evidence-based drug dosing
guidelines for adults and children receiving renal
replacement therapy. Clin. Pharmacol. Ther. 86,
479–482 (2009).
75. Li, A. M. 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. 64, 929–937 (2009).
76. Wingender, W. et al. Pharmacokinetics of
ciprofloxacin after oral and intravenous
administration in healthy volunteers. Eur. J. Clin.
Microbiol. 3, 355–359 (1984).
77. Fish, D. N., Bainbridge, J. L. & Peloquin, C. A.
Variable disposition of ciprofloxacin in critically ill
patients undergoing continuous arteriovenous
hemodiafiltration. Pharmacotherapy 15,
236–245 (1995).
78. Wallis, S. C., Mullany, D. V., Lipman, J.,
Rickard, C. M. & Daley, P. J. Pharmacokinetics of
ciprofloxacin in ICU patients on continuous veno-
venous hemodiafiltration. Intensive Care Med.
27, 665–672 (2001).
79. Chien, S. C. et al. Pharmacokinetic profile of
levofloxacin following once-daily 500-milligram
oral or intravenous doses. Antimicrob. Agents
Chemother. 41, 2256–2260 (1997).
80. Chow, A. T. et al. Safety and pharmacokinetics of
multiple 750-milligram doses of intravenous
levofloxacin in healthy volunteers. Antimicrob.
Agents Chemother. 45, 2122–2125 (2001).
81. Malone, R. S., Fish, D. N., Abraham, E. &
Teitelbaum, I. Pharmacokinetics of levofloxacin
and ciprofloxacin during continuous renal
replacement therapy in critically ill patients.
© 2011 Macmillan Publishers Limited. All rights reserved
Antimicrob. Agents Chemother. 45, 2949–2954
(2001).
82. Guenter, S. G., Iven, H., Boos, C., Bruch, H. P. &
Muhl, E. Pharmacokinetics of levofloxacin during
continuous venovenous hemodiafiltration and
continuous venovenous hemofiltration in
critically ill patients. Pharmacotherapy 22,
175–183 (2002).
83. Lode, H., Grunert, K., Koeppe, K. P. &
Langmaack, H. Pharmacokinetic and clinical
studies with amikacin, a new aminoglycoside
antibiotic. J. Infect. Dis. 134, S316–S322
(1976).
84. Kinowski, J. M. et al. Multiple-dose
pharmacokinetics of amikacin and ceftazidime in
critically ill patients with septic multiple-organ
failure during intermittent hemofiltration.
Antimicrob. Agents Chemother. 37, 464–473
(1993).
85. Benvenuto, M., Benziger, D. P., Yankelev, S. &
Vigliani, G. Pharmacokinetics and tolerability of
daptomycin at doses up to 12 milligrams per
kilogram of body weight once daily in healthy
volunteers. Antimicrob. Agents Chemother. 50,
3245–3249 (2006).
86. Nilsson-Ehle, I., Hutchison, M., Haworth, S. J. &
Norrby, S. R. Pharmacokinetics of meropenem
compared to imipenem–cilastatin in young,
healthy males. Eur. J. Clin. Microbiol. Infect. Dis.
10, 85–88 (1991).
87. Krueger, W. A. Evaluation by Monte Carlo
simulation of the pharmacokinetics of two doses
of meropenem administered intermittently or as
a continuous infusion in healthy volunteers.
Antimicrob. Agents Chemother. 49, 1881–1889
(2005).
88. Dreetz, M. et al. Serum bactericidal activities and
comparative pharmacokinetics of meropenem
and imipenem–cilastatin. Antimicrob. Agents
Chemother. 40, 105–109 (1996).
89. Krueger, W. A. et al. Pharmacokinetics of
meropenem in critically ill patients with acute
renal failure treated by continuous
hemodiafiltration. Antimicrob. Agents Chemother.
42, 2421–2424 (1998).
90. Occhipinti, D. J. et al. Pharmacokinetics and
pharmacodynamics of two multiple-dose
piperacillin–tazobactam regimens. Antimicrob.
Agents Chemother. 41, 2511–2517 (1997).
91. Capellier, G. et al. Removal of piperacillin in
critically ill patients undergoing continuous
venovenous hemofiltration. Crit. Care Med. 26,
88–91 (1998).
92. van der Werf, T. S., Mulder, P. O., Zijlstra, J. G.,
Uges, D. R. & Stegeman, C. A. Pharmacokinetics
of piperacillin and tazobactam in critically ill
patients with renal failure, treated with
continuous veno-venous hemofiltration (CVVH).
Intensive Care Med. 23, 873–877 (1997).
93. Blouin, R. A., Bauer, L. A., Miller, D. D.,
Record, K. E. & Griffen, W. O. Jr. Vancomycin
pharmacokinetics in normal and morbidly obese
subjects. Antimicrob. Agents Chemother. 21,
575–580 (1982).
94. Healy, D. P., Polk, R. E., Garson, M. L., Rock, D. T.
& Comstock, T. J. Comparison of steady-state
pharmacokinetics of two dosage regimens of
vancomycin in normal volunteers. Antimicrob.
Agents Chemother. 31, 393–397 (1987).
95. Boeckh, M. et al. Pharmacokinetics and serum
bactericidal activity of vancomycin alone and in
combination with ceftazidime in healthy
volunteers. Antimicrob. Agents Chemother. 32,
92–95 (1988).
96. Kielstein, J. T. et al. Pharmacokinetics and total
elimination of meropenem and vancomycin in
intensive care unit patients undergoing extended
daily dialysis. Crit. Care Med. 34, 51–56 (2006).

97. DelDot, M. E., Lipman, J. & Tett, S. E.
Vancomycin pharmacokinetics in critically ill
patients receiving continuous venovenous
haemodiafiltration. Br. J. Clin. Pharmacol. 58,
259–268 (2004).
98. Trotman, R. L., Williamson, J. C.,
Shoemaker, D. M. & Salzer, W. L. Antibiotic
dosing in critically ill adult patients receiving
continuous renal replacement therapy. Clin.
Infect. Dis. 41, 1159–1166 (2005).
NATURE REVIEWS | NEPHROLOGY VOLUME 7  |  APRIL 2011  |  235
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FOCUS ON AKI IN CRITICAL CARE
99. Heintz, B. H., Matzke, G. R. & Dager, W. E.
Antimicrobial dosing concepts and
recommendations for critically ill adult
patients receiving continuous renal
replacement therapy or intermittent
hemodialysis. Pharmacotherapy 29, 562–577
(2009).
100. Gilbert, D. N. (Ed.) The Sanford Guide to
Antimicrobial Therapy 40th edn (Sanford,
Sperryville, 2010).
© 2011 Macmillan Publishers Limited. All rights reserved
Acknowledgments
C. P. Vega, University of California, Irvine, CA, is the
author of and is solely responsible for the content of
the learning objectives, questions and answers of the
Medscape, LLC-accredited continuing medical
education activity associated with this article.
Author contributions
R. F. Eyler and B. A. Mueller contributed equally to all
aspects of the manuscript.