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Antibiotic Dosing in Patients With Acute Kidney Injury: "Enough But Not Too
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DOI: 10.1177/0885066614555490 · Source: PubMed

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Antibiotic Dosing in Patients With Acute Kidney Injury: ''Enough But Not Too Much''
Susan J. Lewis and Bruce A. Mueller
J Intensive Care Med published online 16 October 2014
DOI: 10.1177/0885066614555490

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 Journal of Intensive Care Medicine
1-14
Antibiotic Dosing in Patients With ª The Author(s) 2014
Reprints and permission:
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Acute Kidney Injury: ‘‘Enough But DOI: 10.1177/0885066614555490
jic.sagepub.com
Not Too Much’’

Susan J. Lewis, PharmD1 and Bruce A. Mueller, PharmD, FCCP, FASN, FNKF1

Abstract
Increasing evidence suggests that antibiotic dosing in critically ill patients with acute kidney injury (AKI) often does not achieve
pharmacodynamic goals, and the continued high mortality rate due to infectious causes appears to confirm these findings.
Although there are compelling reasons why clinicians should use more aggressive antibiotic dosing, particularly in patients
receiving aggressive renal replacement therapies, concerns for toxicity associated with higher doses are real. The presence of
multisystem organ failure and polypharmacy predispose these patients to drug toxicity. This article examines the pharmacokinetic
and pharmacodynamic consequences of critical illness, AKI, and renal replacement therapy and describes potential solutions to
help clinicians give ‘‘enough but not too much’’ in these very complicated patients.

Keywords
antibiotics, pharmacokinetics, pharmacodynamics, acute kidney injury, renal replacement therapy

Introduction conservative management are unlikely to be able to remove

A 68-year-old female (height 5 ft 2 in, weight 95 kg) was
admitted for complaint of increasing abdominal pain and
altered mental status. Her past medical history is extensive
including recurrent urosepsis caused by b-lactamase-positive
Escherichia coli. In the intensive care unit (ICU), she has not
yet received empiric antibiotic therapy but did get aggressive
fluid resuscitation in the emergency department. The patient’s
oxygen saturation dropped rapidly and she developed respira-
tory failure and septic shock, requiring mechanical ventilation
with oxygen and vasopressor support. The laboratory results
include serum creatinine (SCr) 2.2 mg/dL and blood urea nitro-
gen (BUN) 45 mg/dL (baseline SCr 1.1 mg/dL, BUN 23 mg/dL
1 month ago). The patient’s weight in the nursing home chart 1
week ago was 80 kg. Susceptibility results are pending. The
ICU team needs to prescribe antibiotic therapy.
This complicated scenario is not unlike those faced regu-
larly by clinicians. The Surviving Sepsis Guidelines provide
very straightforward guidance on how to treat patients with
sepsis,1 yet the patient in the previous case comes with some
challenges that are not readily apparent. Much of the dosing
of her antibiotics is predicated on knowledge of her renal func-
tion, and it is apparent in this case that she has acute kidney
injury (AKI), which is a common complication of sepsis in the
ICU2 and is associated with high morbidity and mortality
(60%-77%).3-5 About 70% of patients with AKI in the ICU
require some type of renal replacement therapy (RRT),6 and
with the degree of fluid overload manifested by this patient,
it is likely that RRT will be necessary as diuretics and
15 L of extra volume in a timely manner.
The Surviving Sepsis Guidelines emphasize the significance
of ‘‘appropriate antimicrobial therapy,’’ which is defined as
‘‘initial empiric anti-infective therapy of one or more drugs that
have activity against all likely pathogens and that penetrate in
adequate concentrations into tissue presumed to be the source
of sepsis.’’1 However, even in the straightforward case men-
tioned earlier, numerous barriers exist to achieve ‘‘adequate
concentrations’’ at the infection site. Recent evidence suggests
that clinicians prescribe antibiotics with doses that are higher
than what is recommended for the patients’ glomerular filtra-
tion rate in elderly patients with chronic kidney disease stages
IV and V,7,8 increasing the risk of antibiotic toxicity. However,
in critically ill patients with AKI, higher doses may be war-
ranted. Appropriate antibiotic therapy requires a balance
between a need for doses high enough to account for pharma-
cokinetic alterations in these patients, pathogen resistance that
1
Department of Clinical, Social, and Administrative Sciences, University of
Michigan College of Pharmacy, Ann Arbor, MI, USA
Received March 13, 2014, and in revised form August 4, 2014. Accepted
for publication August 25, 2014.
Corresponding Author:
Bruce A. Mueller, Department of Clinical, Social and Administrative Sciences,
University of Michigan College of Pharmacy, 428 Church St, Ann Arbor, MI
48109, USA.
Email: muellerb@med.umich.edu

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2 Journal of Intensive Care Medicine
Figure 1. Enough but not too much. The clinician’s decision to
choose higher versus lower antibiotic doses in critically ill patients
with acute kidney disease requires balancing often conflicting factors.
is common in the ICU,9 and extracorporeal drug clearance ver-
sus concerns of antibiotic toxicity in these vulnerable patients
with impaired drug clearance (Figure 1). The purpose of this
article is to explore the challenges of providing appropriate
antibiotic doses to attain adequate concentrations at the site
of infection and to suggest alternative strategies balancing
necessity and risk of antibiotic higher doses to maximize anti-
biotic efficacy while minimizing toxicity.
Mortality Related to Inappropriate Antibiotic
Dosing
Mortality rates in critically ill patients with sepsis reported
from various regions around the world range from 20% to
60%.10-14 In the United States, severe sepsis and septic shock
account for approximately 10% of all mortality, representing
a substantial health care burden.10 Consequently, appropriate
antibiotic therapy is essential for both humanistic and eco-
nomic reasons. However, available data suggest that inap-
propriate antibiotic therapy in patients with sepsis in the ICU
is prevalent and is the most important independent risk factor
for hospital mortality.15-18 The primary reasons for inap-
propriate antibiotic therapy have been identified as antibiotic
resistance and absence of efficacious therapy in most
studies.15 However, attention should be paid to the other evi-
dence showing that even in the case where pathogens are sus-
ceptible to the prescribed antibiotics, hospital mortality still
remains high.9 It is not enough to select the appropriate anti-
biotic, but one must also prescribe doses sufficient to deliver suf-
ficient antibiotic concentrations at the site of infection.
Conventional antibiotic dosing may not yield pharmacodynamic
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target attainment for the infecting pathogens in this patient pop-
ulation.19-22 Many factors influence antibiotic concentrations at
the infection site, beginning with the numerous pharmacokinetic
changes seen in critically ill patients.
Pharmacokinetic Alterations in Critically Ill
Patients With AKI
Absorption
With the occasional exception of oral fluoroquinolones and line-
zolid, critically ill patients with AKI do not generally receive oral
antibiotics. It is well documented that oral drug absorption is
decreased in the critically ill patients.23-26 Although not com-
pletely understood, underlying causes of gastrointestinal dysmo-
tility may include postoperative ileus, opioid use, mechanical
ventilation, trauma, head injury, and sepsis.25,26 In a retrospective
study, gastrointestinal dysmotility was observed in 60% of ICU
patients, which can have profound effects on drug absorption
from gastrointestinal tract.27 Antibiotics may adhere to the feed-
ing tubes or interact with coadministered nutritional products and
other drugs, resulting in reduced bioavailability.28,29 Elevated
gastric pH by histamine 2 receptor antagonists or proton pump
inhibitors is associated with the absorption of weak bases such
as ketoconazole.30-32 Absorption from intravenous drugs is not
usually altered, but absorption of subcutaneous drugs may be
affected by impaired peripheral circulation by sepsis and use of
vasopressors and peripheral edema during intravenous fluid
resuscitation, reducing their bioavailabilities.33,34 Fortunately,
antibiotics are not administered by this route obviating this con-
cern, although many other drugs in the ICU are administered sub-
cutaneously (heparins, insulin, etc).
Distribution
The pathogenesis of sepsis involves endothelial abnormalities,
increase in capillary permeability, and the fluid accumulation
in interstitial spaces, resulting in increased antibiotic volume
of distribution.35 Expanded volume of distribution may be
especially prominent with hydrophilic drugs such as aminogly-
cosides, b-lactams, glycopeptides, and daptomycin. Many
researchers have demonstrated decreased serum levels of anti-
biotics in critically ill patients secondary to increased volume
of distribution, suggesting the need for higher doses than stan-
dard dosing recommendations to maintain suitable serum con-
centrations.22,36-44 The increased volume of distribution is
more pronounced in severe sepsis and in the early stages of sep-
sis. Patients with hyperdynamic sepsis have a significantly
larger volume of distribution of gentamicin (0.48 L/kg), com-
pared with those who have hypodynamic sepsis (0.32 L/kg) and
nonseptic patients receiving postsurgical prophylactic doses of
gentamicin (0.29 L/kg).38 Taccone et al noted that the first con-
ventional dose of broad-spectrum b-lactams administered in
the early stage of severe sepsis and septic shock failed to
achieve adequate concentrations due to increased volume of
distribution.19 Significantly elevated volume of distribution is
Lewis and Mueller
also observed in critically ill patients with AKI receiving con-
tinuous RRT (CRRT) after the administration of the first dose
of daptomycin which possesses both hydrophilic and lipophilic
properties (0.23 L/kg42,45 vs 0.08-0.15 L/kg in healthy volun-
teers46). However, the initially elevated volume of distribution
tends to decline over the treatment course36,45 possibly due to
physiologic changes or correction of fluid overload by RRTs.
Taken together, the increased volume of distribution of hydro-
philic antibiotics in the early stage of sepsis or severe sepsis
necessitates a higher dose or a loading dose to rapidly achieve
adequate concentrations to meet Surviving Sepsis Guidelines.
However, increased volume of distribution will normalize after
a few days of treatment, therefore, clinicians may need to move
to more conventional dosing over the course of therapy to avoid
toxicity. Not only can pathophysiologic changes related to sep-
sis influence volume of distribution in critically ill patients, but
fluid therapy to resuscitate patients with sepsis can alter it as
well. Volume of distribution of amikacin has been shown to
range widely in a patient receiving aggressive fluid support
(0.27 to 0.61 L/kg), compared to that of healthy individuals
(0.27 + 0.06 L/kg).47 Other sources of fluid administration
in these patients, parenteral nutrition and intravenous drug
administration, add even more volume in this population,
although their impact may not be readily appreciated. The vol-
ume of distribution of aminoglycosides is increased substan-
tially in critically ill patients receiving both total parenteral
nutrition and fluid therapy, compared with those receiving only
fluid therapy.48,49 Clinicians must recognize the influence of all
the prescribed volume via fluid, blood products, parenteral
nutrition, and drug infusions on antibiotic volume of distribu-
tion and may need to use higher antibiotic doses to compensate.
The influence of fluid overload on antibiotic concentrations
and outcomes in critically ill patients has not been demon-
strated definitively. Several observational studies have high-
lighted that fluid overload is associated with an increased
mortality rate in critically ill patients with AKI.50-53 The Fluids
And Catheters Treatment Trial (FACTT) study found that the
risk of mortality was increased 1.6-fold per L/d of accumulated
fluid.52 In a post hoc analysis from The Program to Improve
Care in Acute Renal Disease (PICARD) trial among nondia-
lyzed patients, the percentage of fluid overload at the time of
AKI diagnosis was twice as high in nonsurvivors compared
with survivors, and the adjusted odds ratio for mortality related
to fluid overload at AKI diagnosis was 3.14.51 Theoretically,
fluid overload could dilute the serum concentrations of antibio-
tics resulting in decreased efficacy and contribute to the
increased mortality rate. Further studies need to explore the
impact of hemodilution of antibiotics mediated by fluid over-
load on mortality and the necessity of higher antibiotic doses
to account for excessive fluid.
Drug serum protein binding changes observed in critical ill-
ness can have a profound effect on pharmacokinetics. Hypoal-
buminemia is reported in 40% to 50% of critically ill
patients.54 As serum protein concentrations decrease, the
amount of drug binding to protein will decrease, resulting in
an increased ‘‘free’’ or unbound fraction of drug. Because only
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3
free drug is responsible for pharmacologic effects, protein bind-
ing changes strongly influence efficacy and toxicity.55 Unbound
drugs will distribute into tissues, thus increasing volume of dis-
tribution. Further, unbound drugs will be cleared by kidneys and/
or RRT, thereby increasing drug clearance. Consequently,
protein-binding changes in critical illness can have a significant
effect on highly protein-bound antibiotics. For example, ertape-
nem, a highly protein-bound (85%-95%) carbapenem, yielded
markedly larger volume of distribution (0.21-0.4 L/kg vs 0.07
L/kg) and higher total clearance (43 mL/min vs 20 mL/min) in
patients with hypoalbuminemia and sepsis, compared with
healthy individuals.56,57 Pharmacokinetic changes in this magni-
tude should result in dosing increases to maintain therapeutic
ertapenem plasma concentrations. However, as renal function
improves, gradual normalization of protein-binding capacity is
observed in patients with AKI.58,59
Metabolism
Hepatic metabolism depends on primarily hepatic blood flow,
enzymatic activity, and protein binding.60,61 Alteration in one
or more of these physiologic processes will translate into
changes in hepatic drug metabolism. The effect of AKI on
hepatic blood flow is uncertain, but different stages of sep-
sis and fluid status can affect hepatic blood flow.24 Use
of vasoconstrictors can decrease total hepatic blood flow,
while inotropes like dobutamine and dopamine have been
shown to increase hepatic perfusion by enhancing cardiac
output.24 Acute kidney injury may also affect Cytochrome
P450 (CYP) enzyme activity. Animal studies indicate that
effects of AKI on hepatic metabolism are drug specific, but one
human study demonstrated AKI reduces the activity of CYP 3A
enzymes,62 which play a significant metabolic role for more than
50% of all drugs. Drugs metabolized by the liver may exert pro-
longed therapeutic efficacy by sustaining elevated drug serum
concentrations. On the other hand, delayed pharmacologic
response may be seen with prodrugs requiring activation via
hepatic enzymes. The mechanisms of altered hepatic metabo-
lism in AKI is complicated and poorly understood,60 but clin-
icians should recognize these potential changes and monitor
drug serum concentrations to make appropriate dosage modifi-
cation and to avoid toxicity whenever feasible.
Elimination
Renal drug clearance is a dynamic process involving glomeru-
lar filtration, tubular secretion, and reabsorption. In AKI,
diminished glomerular filtration and impaired tubular secretion
secondary to decreased drug transporter activity can cause
accumulation of renally eliminated antibiotics.63 Antibiotic
dosages and dosing frequency may need to be reduced to avoid
accumulation and toxicity. This is particularly important with
antibiotics with a narrow therapeutic index, such as aminogly-
cosides and vancomycin. These drugs require frequent drug
level monitoring and subsequent adjustment of dosing
schemes. However, it should be noted that compensation of
4 Journal of Intensive Care Medicine
decreased renal clearance by increasing other elimination path-
ways may occur during AKI. For these drugs, dosage adjust-
ment on a basis of SCr alone may potentially lead to
subtherapeutic concentrations. Jones et al found that unmodi-
fied ciprofloxacin dosage (400 mg intravenously twice daily)
did not result in significantly different serum concentrations
in patients with severe sepsis with renal impairment (creatinine
clearance < 20 mL/min), compared to those with creatinine
clearance > 20 mL/min.64 Enhanced transintestinal and biliary
elimination to compensate for reduced renal clearance may
account for these findings.
Alteration in nonrenal clearances of several antibiotics such
as imipenem and vancomycin are also noted in patients with
AKI. Overall, estimated nonrenal clearances of these antibiotics
decline in patients in AKI compared to that seen in patients with
normal renal function but tend to be higher than those observed
in patients with end-stage renal disease (ESRD).65-68 However,
as AKI persists, vancomycin nonrenal clearance rates progres-
sively decline and approach that of patients with ESRD.65
The addition of RRT can markedly increase drug clearance,
adding another layer to the complexity of antibiotic dosing in cri-
tically ill patients. Physicochemical properties of drugs such as
molecular weight, protein binding, and volume of distribution
will all influence on drug clearance via RRT. Determining drug
clearance can be complicated, given the heterogeneity in modal-
ities of RRT.69,70 Duration and intensity of RRT can increase
solute clearance,71 and different modes of fluid replacement
(predilution or postdilution) will affect solute clearance.69 The
details of pharmacokinetic studies of antibiotics in different RRT
settings are evaluated in several recent reviews.72-77
With the benefits of hemodynamic stability and fluid con-
trol, CRRT is often preferred in critically ill patients with AKI,
but many antibiotic dosing recommendations in patients
receiving CRRT are based on in vitro and very small pharma-
cokinetic studies using obsolete techniques or are extrapolated
from pharmacokinetic data in noncritically ill patients or
patients with ESRD receiving intermittent hemodialysis
(IHD).78 In CRRT, the effluent rate (Qf) and the extraction
coefficient (sieving coefficient [Sc] or saturation coefficient
[Sd]) are 2 primary parameters used to calculate dialytic drug
clearance (CLcrrt ¼ Qf  Sc or Sd). The extraction coefficient
approximates the percentage of unbound drug and the Qf is
determined from dialysate rate (Qd) and ultrafiltration rate
(Quf; Qf ¼ Qd þ Quf). Higher extraction coefficients and Qfs
will result in greater drug clearance. Although several large
randomized trials indicated that high Qfs do not reduce mortal-
ity rate among critically ill patients,79-81 compared with low Qf,
these trials did not take the impact of high Qfs on increased
antibiotic clearance into account.82,83 Because high Qfs yield
lower antibiotic concentrations, these studies may be con-
founded by reduced pharmacodynamic target attainment rates
in patients receiving high Qfs.
Clinicians employing prolonged intermittent RRT (PIRRT)
will find that <1% of drugs have validated dosing recommen-
dations available to them.76,84 Recent reviews suggest that,
despite the ‘‘slower than IHD’’ blood and dialysate flow rates,
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the extended duration of PIRRT (8-12 hours) contributes to
substantial antibiotic clearance, increasing the risk of pro-
longed subtherapeutic antibiotic concentrations.76,77 In addi-
tion, the extended duration of PIRRT may result in some
doses administered while dialysis is running, which will affect
delivered drug dose. This can further complicate efficacy of
antibiotic therapy.
Appropriate antibiotic dosing in critically ill patients with
RRT requires understanding of the influences of RRT variables
and non-RRT clearance on antibiotic therapy to determine opti-
mal dosing regimens. As evidenced in numerous reports, cur-
rent antibiotic dosing recommendations in RRT often fail to
reach pharmacodynamic goals.20,44,67,85-90 These findings have
prompted several clinicians to consider antibiotic doses higher
than what are traditionally recommended to attain pharmaco-
dynamic target.20,44,67,85-90
Pharmacodynamic Target Attainment
Although pharmacokinetics predicts how patient physiology
affects antibiotic concentrations, pharmacodynamics integrates
pharmacokinetic characteristics with antibacterial effect. In
order to optimize antibiotic therapy, pharmacokinetic para-
meters must be accounted for if pharmacodynamic targets are
to be met. This complex pharmacokinetic/pharmacodynamic
relationship has been explained by characterizing antibiotics
into 2 different categories, concentration-dependent activity
or time-dependent activity. For concentration-dependent anti-
biotics (aminoglycosides, daptomycin, and fluoroquinolones),
therapeutic outcome will be maximized when a high peak
serum concentration (Cmax) relative to the organism’s mini-
mum inhibitory concentration (MIC) is achieved. With time-
dependent activity antibiotics (b-lactams, carbapenems), the
time of the serum concentration above the MIC (T > MIC) is
the most important determinant of their efficacy. For several
antibiotics (vancomycin, linezolid) displaying both characteris-
tics, the high ratio of area under the serum concentration–time
curve (AUC) to the bacterial MIC has been associated with
antibacterial success. Besides bacterial killing characteristics,
the postantibiotic effect, the persistent suppression of bacterial
growth after concentrations fall below the MIC for a particular
organism,91 can influence antibacterial effect and help to deter-
mine optimal antibiotic dosing and frequency of administra-
tion. Table 1 suggests several alternative antibiotic dosing
strategies to maximize the efficacy of antibiotic therapy in cri-
tically ill patients with AKI receiving various RRTs, based on
available data and consideration of antibiotic profile and extra-
corporeal antibiotic clearance.
Extended Antibiotic Infusion
Optimal efficacy of time-dependent killing antibiotics is best
correlated with the T > MIC for susceptible organisms. The
T > MIC of at least 40% to 60% of the dosing interval has
known to be desirable to yield appropriate antibacterial effect
of b-lactams,105,106 but maintaining a longer T > MIC has shown
Lewis and Mueller
Table 1. Antibiotic Dosing Strategies in Critically Ill Patients With AKI
to Improve Pharmacodynamic Target Attainment Rates.
Antibacterial
Profile Potential Dosing Strategies
Time dependent
b-lactams (1) Continuous or prolonged infusions in
Carbapenems CRRT,83,92-96 but not IHD or PIRRT
Vancomycin (2) More frequent administration of smaller doses
(3) Supplemental dose during PIRRT97,98 and post-
IHD
(4) Weight-based dosing
Concentration dependent
Aminoglycosides (1) Loading dose to achieve target
Colistin pharmacodynamic goals (peaks) early92-94,99,100
Daptomycin (2) Extended dosing interval for aminoglycosides99
Fluoroquinolones (3) Predialytic administration of aminoglycosides in
Linezolid IHD or PIRRT101-104
Macrolides (4) Weight-based dosing
Metronidazole
Vancomycin
Abbreviations: AKI, acute kidney injury; CRRT, continuous renal replacement
therapy; IHD, intermittent hemodialysis; PIRRT, prolonged intermittent renal
replacement therapy.
to further maximize the time-dependent killing effect. McKin-
non et al indicated that achievement of T > MIC of 100% for
b-lactams resulted in much higher clinical cure than T > MIC
of less than 100% in patients with sepsis (82% vs 33%).107
Serendipitously, patients with AKI may be able to take an
advantage of reduced renal clearance to prolong T > MIC.
However, RRT drug removal, particularly CRRT, may inter-
fere with this advantage and even cause the drug concentration
to fall below the MIC for a susceptible organism unless a dos-
ing change is made to account for CRRT clearance. In patients
with AKI receiving continuous venovenous hemodiafiltration
at an Qf of 1 to 2 L/h, the mean elimination of piperacillin/tazo-
bactam was reported to be nearly equivalent to patients with
normal renal function.108 Seyler and colleagues report that rec-
ommended b-lactam dosing for critically ill patients under-
going CRRT with the mean Qf of 45 mL/kg/h failed to
achieve stated pharmacodynamic goals against Pseudomonas
aeruginosa within 48 hours of antibiotic therapy in 34% to
100% of modeled cases.20 Therefore, initiation of CRRT
should be followed by the consideration of increased antibiotic
doses or alternative administration strategies to prolong T >
MIC with b-lactams.
Extended antibiotic infusion time can increase T > MIC;
however, clinically improved outcomes of longer infusions
continues to be debated.109,110 A few studies show the effec-
tiveness of antibiotic continuous infusion in maintaining steady
state target serum concentrations in critically ill patients receiv-
ing CRRT.92,93,111 A small randomized study involving 6 ICU
patients compared meropenem 500 mg loading dose followed
by 2 g given as continuous infusion over 24 hours versus 1 g
every 12 hours as intermittent bolus (10-20 minutes) in patients
with continuous venovenous hemodialysis (HD) with an Qf of
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5
25 mL/kg/h.93 The continuous infusion regimen generated a
constant serum concentration above the MIC (Cmedian 19.1
mg/L) for 100% of the treatment period, while the intermittent
bolus maintained serum concentration above the MIC of
8 mg/L for only 45% of the dosing interval. This 45% T >
MIC is thought to be a minimally required T > MIC goal but
might not be sufficient to cover intermediately resistant P
aeruginosa, a common pathogen in critically ill patients
(Figure 2). The benefit of continuous infusion has also been
proposed for vancomycin which predominantly has a time-
dependent killing activity and will be effectively removed
by conventional CRRT.65,83,94,95,112,113 A retrospective eva-
luation in patients receiving continuous venovenous hemofil-
tration or continuous venovenous hemodiafiltration reports
that continuous infusion of vancomycin (16-35 mg/kg/d) after
a loading dose of 15 mg/kg could be employed to achieve
adequate serum concentrations (20-30 mg/mL) on the first day
of therapy.83 However, drug accumulation was noticeable on
day 3 of therapy, and the proportion of patients with excessive
vancomycin trough concentrations (> 30 mg/mL) was signifi-
cantly higher in those with higher daily doses. Potential drug
accumulation and higher risk of toxicity mandates routine
monitoring of vancomycin serum concentration and subse-
quent dosage adjustment for this strategy.85
Prolonged infusion is a compromise between a typical
30-minute antibiotic infusion and continuous infusion. Pro-
longed infusion duration can vary but is often as long as half
the dosing interval and does extend T > MIC. An advantage
of this practice is that an intravenous line does not have to be
dedicated solely to continuous antibiotic infusion. Use of pro-
longed infusion antibiotics has not been published in patients
with CRRT. With higher peaks and lower troughs, intermittent
infusion will produce the same AUC as prolonged infusion, but
a higher proportion of T > MIC with prolonged infusion theo-
retically should result in better efficacy.
This strategy of extended infusions may be particularly
valuable in a case with reduced susceptibility, high CRRT
Qf, increased antibiotic volume of distribution, and/or in
immunocompromised patients where prolonged serum concen-
tration above the MIC may be critical. Compared to shorter
conventional infusion times, extended antibiotic infusions can
be difficult to employ because of limited vascular access in the
ICU and drug compatibility/stability issues. More frequent
administration of smaller doses may be able to mimic the T
> MIC of extended infusion without a drop below the organ-
ism’s MIC. Further studies are warranted to investigate the effi-
cacy and safety of extended antibiotic infusion strategies in the
patients with AKI.
Loading or Postdialysis Supplemental Dose
Loading doses have been traditionally used to achieve early
adequate antibiotic concentrations or initial high-peak concen-
trations which are strongly related to clinical response to anti-
biotics with concentration-dependent activity including
aminoglycosides.114 The importance of a loading dose is
6 Journal of Intensive Care Medicine
25
Serum Concentration (mg/L)
20
15
10
5
0 Altered Antibiotic Administration Time
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (h)
Figure 2. Modeled meropenem steady state concentrations with
continuous infusion versus intermittent infusion in a patient on con-
tinuous renal replacement therapy (CRRT).93 A hypothetical 70-kg
patient with anuria having AKI receiving CRRT with an effluent rate of
35 mL/kg/h is modeled. The percentage of time of the serum con-
centration above the minimum inhibitory concentration (MIC; T >
MIC) at 8 mg/L for intermediately resistant Pseudomonas aeruginosa is
58% with meropenem 1 g every 12 hours intermittent infusion over 30
minutes and 100% with 2 g every 24 hours continuous infusion.
reinforced by the growing findings that initial suboptimal anti-
biotic exposure can reduce the susceptibility of pathogens and
facilitate the amplification of resistant strains in a large
inoculum.115,116 Considering the increased volume of distribu-
tion and constant extracorporeal drug removal, patients receiv-
ing CRRT may require a loading dose of all types of antibiotics.
A subgroup analysis by Taccone et al indicated that patients
with severe sepsis treated with CRRT with the mean Qf of
33 mL/kg/h required a loading dose of at least 25 mg/kg of ami-
kacin, substantially higher than the usual loading dose,117 to
attain adequate peak concentrations.99 However, while the
25mg/kg loading dose yielded target peak concentrations, the
serum concentrations 24 hours later were persistently high.
Consequently, if this regimen is to be used, the dosing interval
should be longer than 24 hours for these CRRT Qfs.99
Use of loading doses should not be limited to concentration-
dependent antibiotics. A loading dose can be effective to
achieve early therapeutic concentration of all antibiotics
including those with time-dependent activity.94,95,100 A loading
dose is needed when continuous infusion b-lactams are used
because continuous infusion initially results in subtherapeutic
drug levels until the serum concentration slowly reaches the
equilibration with the tissues.92,93 Early attainment of thera-
peutic drug concentrations at the infection site should improve
increased mortality associated with a delay in appropriate anti-
biotic therapy.1 Consequently, continuous infusion b-lactams
should follow a loading dose.96 Other RRTs offer different
antibiotic administration challenges. The PIRRT removes a
significant amount of antibiotics because of prolonged dialysis
duration. It may require a higher dose during the duration of
PIRRT and less when PIRRT is off. Supplemental doses may
be guided by therapeutic drug monitoring to ensure adequate
1g q12h Intermittent infusion
2g q24h Continuous infusion
MIC of 8mg/L
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maintenance of therapeutic serum concentrations.97 The con-
ventional daptomycin dose of 6 mg/kg recommended for IHD
did not produce targeted AUC values when it was infused
within 8 hours before an 8-hour PIRRT session (Qb and
Qd of 160 mL/min) due to increased PIRRT drug
clearance.97 Clinicians may use additional postdialytic antibio-
tic doses to accelerate the achievement of pharmacodynamic
goals or to prevent unwanted drop in antibiotic level caused
by the extended duration of PIRRT.98
Changing antibiotic administration time with relation to RRT
can be a strategy to meet pharmacodynamic goals while
accounting for RRT drug clearance. Predialysis administration
of higher dosage has been suggested to be more efficacious
than conventional postdialysis aminoglycoside administration
because it can allow a higher peak concentration to maximize
antibacterial pharmacodynamic goals (peak/MIC) while subse-
quently rapid dialytic clearance can minimize toxicity from
prolonged drug exposure (Figure 3).101,102,118,119 A simulated
gentamicin 6 mg/kg dose given 1 hour prior to a 4-hour HD
treatment achieved predetermined pharmacodynamic targets
with a mean peak concentration of 31 mg/mL. However, a
simulated post-HD infusion of 1.7 mg/kg dose, the maximum
dose recommended by the package insert, failed to meet any
pharmacodynamic targets (Cmax 8.8 + 3.1 mg/L).103 Use of
a high predialytic antibiotic dose is also proposed for PIRRT,
where ‘‘when to dose’’ matters more than ‘‘how much to
dose’’ due to unpredictable drug clearance with the prolonged
duration of dialysis.77 Roberts et al showed that gentamicin
6 mg/kg every 48 hours given 30 minutes to 1 hour before a
10-hour PIRRT session can be an effective dosing strategy to
maximize pharmacodynamic target attainment while minimiz-
ing sustained elevated serum concentrations responsible for
toxicity.104 However, caution should be followed when this
novel strategy is instituted. Delay in dialysis schedule or unex-
pected dialysis discontinuation secondary to clotting or intoler-
ance can put a patient at risk of antibiotic toxicity due to
inadequate dialytic drug clearance. Thus, when the benefit of
maximized pharmacokinetic/pharmacodynamic goal is critical
and a subsequent full dialysis session is ensured, clinicians may
consider predialytic administration of a higher aminoglycoside
dose.
Weight-Based Dosing
The ‘‘one-size-fit-all’’ dosing strategy (eg 500 mg regardless of
body mass) ignores the variability in body size and body fluid
composition of critically ill patients, possibly leading to an
inappropriately low serum concentration. For example, in the
case described at the beginning of this article, we present a
patient with *15 L fluid overloaded, sepsis, possibly hypoal-
buminemia, and in need of RRT. Most penicillin, cephalos-
porin, and carbapenem antibiotics have recommended dosing
in adults who are ‘‘flat dosed’’ with a dosing interval adjusted
Lewis and Mueller
30
Pre-dialytic 6mg/kg dose
Serum Concentration (mg/L)
25
Post-dialytic 1.7mg/kg dose
20
15
10
5 spective cohort, a significantly higher risk of hospital mortality
0 tant gram-negative bacteria (63.4% vs 40.0%).9 Further logistic
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (h)
Figure 3. Modeled gentamicin predialytic high dose versus postdia-
lytic lower dose.103,120 A hypothetical 70-kg patient with anuria having
AKI receiving a 4-hour intermittent hemodialysis (IHD) session is
modeled. Gentamicin predialytic 6 mg/kg dose yielded a high-peak
serum concentration (Cmax) of 26.8 mg/L which is higher than pro-
posed pharmacodynamic target of Cmax  8 mg/L, while postdialytic
1.7 mg/kg dose yielded Cmax of 7.6 mg/L.
for AKI. The use of a 500-mg carbapenem/cephalosporin dose
in a patient with volume of distribution that is likely 50% to
100% larger than that of the ‘‘normal volunteer’’ in whom this
dose was derived will have a substantially lower chance to
attain pharmacodynamic targets. Use of mg/kg or mg/m2 dos-
ing regimens, like our colleagues who treat pediatric patients
usually use, is much more likely to meet these targets.
Inadequate Concentration at the Target Sites
The emphasis of the Surviving Sepsis Guidelines on antibiotics
that ‘‘penetrate in adequate concentrations into tissue presumed
to be the source of sepsis’’ is often overlooked because of our
limited ability to measure drug concentrations at the actual sites
of infection which mostly occur in tissue. Serum concentrations
are routinely monitored to predict therapeutic efficacy, with a
theoretical assumption of equilibration between free drug in
plasma and tissue. However, tissue penetration might be
impaired in critically ill patients due to altered pathophysiology
and transporter activity.121-123 In a small prospective study,
interstitial concentrations of piperacillin in soft tissues were
7-fold lower than free plasma concentrations in patients with
septic shock.123 Results from animal and human studies
demonstrate that plasma concentrations do not always repre-
sent equivalent concentration in the sites of infection,124-
126
suggesting that poor tissue penetration may result in sub-
therapeutic antibiotic concentrations at infection sites and con-
sequent treatment failure, which is not uncommon in patients
with sepsis. Accordingly, modifying antibiotic doses based
on the measured plasma concentration may not guarantee to
achieve the desired concentration at the sites of infection.
Therefore, in the absence to measure adequacy of antibiotic
concentration at the infection sites, higher antibiotic dosage
Downloaded from jic.sagepub.com at UNIV OF MICHIGAN on December 2, 2014
7
may be warranted to ensure adequate local antibiotic concen-
trations in these patients.
Rising Bacterial Resistance Rates
Finally, the increasing prevalence of antibiotic resistance high-
lights the significance of ‘‘appropriate’’ antibiotic therapy.
Antibiotic resistance in critically ill patients has been related
to increased mortality rates in several studies.9,127,128 In a retro-
was noted in patients with sepsis who were infected with resis-
regression analysis determined resistance to the initial antibio-
tics as an independent risk factor, associated with a doubling of
hospital mortality.9 A prospective study also demonstrated that
patients infected with high vancomycin MIC ( 2 mg/mL) of
methicillin-resistant Staphylococcus aureus (MRSA) strains
had 20% lower clinical response to vancomycin therapy, com-
pared to those infected with low MIC (MIC < 2 mg/mL) MRSA
strains, despite targeted vancomycin trough concentrations of
15 to 20 mg/mL.129 For a pathogen with an elevated MIC,
higher doses of antibiotic therapy will be required to achieve
targets.130 However, higher antibiotic doses may cause antibio-
tic toxicity in this vulnerable patient population, as high vanco-
mycin trough levels (15-20 mg/mL) were found to be a
significant predictor of nephrotoxicity development in the lat-
ter study.129 Alternative antibiotic agents may be considered
in a case with high MIC strains and increased predisposition
to drug toxicity.131 Treatment of infection in the ICU becomes
more challenging with the emerging incidence of multidrug
resistant and even panantibiotic-resistant pathogens among Aci-
netobacter species, P aeruginosa, carbapenem-resistant Kleb-
siella species and E coli.132-134 The effectiveness of available
antibiotics and efforts to develop novel antibiotics have been
declining as well.134 All these circumstances mandate clinicians
to aim toward higher pharmacodynamic targets and higher anti-
biotic doses to ensure bacterial eradication and to reduce the risk
of further development of antibiotic resistance.127,128 As dis-
cussed, clinicians should endeavor to maximize antibacterial
killing effect by using aggressive antibiotic dosing and/or alter-
native dosing strategies.19,20,41,92,93,102,111,136
Toxicity
Although there are many compelling reasons to consider more
aggressive antibiotic dosing in critically ill patients with AKI,
toxicity from antibiotic doses that are too high is a genuine con-
cern. These dynamic yet vulnerable patients often have multi-
ple organ dysfunction but often receive many toxic
medications. Nephrotoxic drugs account for 22% of the total
medication orders in the adult ICU patients.137 With the pres-
ence of numerous risk factors, these patients would be more
prone to drug accumulation and toxicity due to AKI. In their
7.5-year retrospective study, Kane-Gill and colleagues identi-
fied that critically ill patients with AKI were 16 times more
prone to manifest drug-induced toxicity compared to those
8 Journal of Intensive Care Medicine
without AKI.138 Antibiotics were the most common drug class
causing toxicity in the ICU.138
Despite the concern for their well-known nephrotoxicity,
aminoglycosides and vancomycin remain as mainstays of anti-
biotic therapy in the ICU. Another renowned nephrotoxin,
colistin, has been reintroduced as a last treatment option
for multidrug resistant gram-negative bacterial infections,
despite its exceedingly high rate of nephrotoxicity
(~50%).139,140 Treatment with these nephrotoxic agents requires
the clinician to make difficult choices when it is apparent that
antibiotic toxicity is likely to develop. A study with 201 criti-
cally ill patients treated with aminoglycosides reported up to
30% of incidence of nephrotoxicity.141 Moreover, fever, endo-
toxemia, and renal hypoperfusion associated with sepsis and
AKI can aggravate preexisting renal impairment with the use
of aminoglycosides.142
Although the guidelines suggest raising goal trough serum
concentrations for vancomycin, a recent meta-analysis suggests
that patients with higher trough serum concentrations (>15 mg/
dL) had a 2- to 3-time greater risk of nephrotoxicity than those
who had lower troughs (<15 mg/dL).143 High dose, longer
duration of therapy, concomitant use of other nephrotoxins, and
renal impairment are common risk factors to precipitate
nephrotoxicity with these antibiotics.139,140,143-149 Ensuring
pharmacodynamic target attainment with high doses can
improve patient outcome, but such benefit has definite but
unpredictable toxicity trade-offs.150-152 Thus, the risk–benefit
analysis should be performed when clinicians consider these
antibiotics, and close monitoring must occur during the
therapy.
Beyond nephrotoxicity, other toxicities associated with
antibiotic accumulation can occur. For example, b-lactam anti-
biotics have been associated with neurotoxicity. Carbapenem-
induced seizures have been well documented in the literature
in patients with renal insufficiency receiving high doses
(eg imipenem > 4 g/day).153-157 Neurotoxicity associated
with cefepime in the ICU setting has been increasingly
described.158-161 In a prospective study, reduced renal function
(creatinine clearance < 30 mL/min) was a strong predictor for
nonconvulsive epilepsy (eg altered mental status, myoclonus)
in patients receiving cefepime.160 Intriguingly, the doses used
in these incidents were appropriately adjusted for renal
function and were not initially linked to the drug accumula-
tion until the trough level confirmed toxicity. These authors
postulated that other individual pathophysiological variables
such as plasma albumin and hemoglobin concentrations may
influence pharmacokinetic properties, increasing the serum
cefepime trough levels.160 The authors suggested that unno-
ticed toxicity may contribute to the increased mortality rate
associated with cefepime therapy versus other b-lactam
therapy.160 Alternative administration techniques such as
continuous or prolonged infusion might yield lower peaks
and have an added benefit of reducing the toxicity risk of
b-lactams.
Most studies suggest that antibiotic-induced toxicities are
transient and reversible upon discontinuation of the insulting
Downloaded from jic.sagepub.com at UNIV OF MICHIGAN on December 2, 2014
agent, viewing them as acute issues. However, short-term out-
comes during a hospital stay may not reflect the full spectrum
of antibiotic toxicity. This approach may underestimate poten-
tial long-term effect on morbidity and mortality of these
patients.162 Although there is a dearth of studies on this issue,
a prospective observational study reports that after 5-year
follow-up, the mortality of survivors from severe AKI requir-
ing RRT was 47%.163 The causes of AKI in these patients
include sepsis (33%) and nephrotoxins (7%). Among those sur-
viving patients, only 57% of them had complete recovery of
renal function at hospital discharge. Patients with partial renal
function recovery showed significantly higher mortality rate,
compared to those with complete recovery after 5 years (P ¼
.001).163 Therefore, short-term toxicity caused by antibiotics
may carry the prolonged risk of deteriorating organ function
and increased probability of mortality as a long-term conse-
quence in critically ill patients.
Antibiotic toxicity is also associated with substantial
increase in health care costs, although it may be understated
compared to the cost related to antibiotic treatment failure.
Unfortunately, data quantifying both direct and indirect costs
of antibiotic toxicity are scarce. In an economic evaluation of
aminoglycoside nephrotoxicity, the total hospital costs includ-
ing pharmacokinetic and nephrologist consultations, ancillary
laboratory tests, and additional hospital stay was estimated to
be 2-fold higher in patients with nephrotoxicity compared to
those without nephrotoxicity.164
Conclusion
A multitude of factors influence the determination of ‘‘appro-
priate antibiotic dosing’’ in critically ill patients with AKI.
Many of them motivate clinicians to consider higher antibiotic
doses, but toxicity associated with higher doses may also cause
a negative patient outcome. Balancing the concerns of ‘‘too
much’’ antibiotic with the compelling pharmacokinetic, phar-
macodynamic, and antibacterial resistance evidence suggesting
that higher doses are necessary should initiate intriguing con-
versations among the interdisciplinary team caring for criti-
cally ill patients with AKI. For patients like the case
described at the beginning of this article, it is likely best that
we try to rapidly identify the appropriate antibiotics and then
use as much of those antibiotics as we can safely, particularly
early in the course of the patient’s sepsis and AKI. Patient mon-
itoring needs to be as vigilant as possible to identify antibiotic
toxicity as early as possible.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship,
and/or publication of this article.
Lewis and Mueller
References
1. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Cam-
paign: international guidelines for management of severe sepsis
and septic shock, 2012. Intensive Care Med. 2013;39(2):165-228.
2. Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in cri-
tically ill patients. JAMA. 2005;294(7):813-818.
3. Silvester W, Bellomo R, Cole L. Epidemiology, management, and
outcome of severe acute renal failure of critical illness in Austra-
lia. Crit Care Med. 2001;29(10):1910-1915.
4. Hoste EA, Clermont G, Kersten A, et al. RIFLE criteria for acute
kidney injury are associated with hospital mortality in critically ill
patients: a cohort analysis. Crit Care. 2006;10(3):R73.
5. Waikar SS, Liu KD, Chertow GM. The incidence and prognostic
significance of acute kidney injury. Curr Opin Nephrol Hyper-
tens. 2007;16(3):227-236.
6. Bagshaw SM, Uchino S, Kellum JA, et al. Association between
renal replacement therapy in critically ill patients with severe
acute kidney injury and mortality. J Crit Care. 2013;28(6):
1011-1018.
7. Aronoff GR, Aronoff JR. Drug prescribing in kidney disease:
can’t we do better? Am J Kidney Dis. 2014;63(3):382-383.
8. Farag A, Garg AX, Li L, Jain AK. Dosing errors in prescribed
antibiotics for older persons with CKD: a retrospective time series
analysis. Am J Kidney Dis. 2014;63(3):422-428.
9. Micek ST, Welch EC, Khan J, et al. Resistance to empiric
antimicrobial treatment predicts outcome in severe sepsis
associated with gram-negative bacteremia. J Hosp Med.
2011;6(7):405-410.
10. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo
J, Pinsky MR. Epidemiology of severe sepsis in the United States:
analysis of incidence, outcome, and associated costs of care. Crit
Care Med. 2001;29(7):1303-1310.
11. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of
sepsis in the United States from 1979 through 2000. N Engl J
Med. 2003;348(16):1546-1554.
12. Angus DC, Pereira CA, Silva E. Epidemiology of severe sepsis
around the world. Endocr Metab Immune Disord Drug Targets.
2006;6(2):207-212.
13. Vincent JL, Rello J, Marshall J, et al. International study of the
prevalence and outcomes of infection in intensive care units(EPIC
II study). JAMA. 2009;302(21):2323-2329.
14. Quenot JP, Binquet C, Kara O, et al. The epidemiology of septic
shock in French intensive care units: the prospective multicenter
cohort EPISS study. Crit Care. 2013;17(2):R65.
15. Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicro-
bial treatment of infections: a risk factor for hospital mortality
among critically ill patients. Chest. 1999;115(2):462-474.
16. Ibrahim EH, Sherman G, Ward S, Fraser VJ, Kollef MH. The
influence of inadequate antimicrobial treatment of bloodstream
infections on patient outcomes in the ICU setting. Chest. 2000;
118(1):146-155.
17. Harbarth S, Garbino J, Pugin J, Romand JA, Lew D, Pittet D.
Inappropriate initial antimicrobial therapy and its effect on sur-
vival in a clinical trial of immunomodulating therapy for severe
sepsis. Am J Med. 2003;115(7):529-535.
Downloaded from jic.sagepub.com at UNIV OF MICHIGAN on December 2, 2014
9
18. Shorr AF, Micek ST, Welch EC, Doherty JA, Reichley RM, Kol-
lef MH. Inappropriate antibiotic therapy in Gram-negative sepsis
increases hospital length of stay. Crit Care Med. 2011;39(1):
46-51.
19. Taccone FS, Laterre PF, Dugernier T, et al. Insufficient B-lactam
concentrations in the early phase of severe sepsis and septic
shock. Crit Care. 2010;14(4):R126.
20. Seyler L, Cotton F, Taccone FS, et al. Recommended B-lactam
regimens are inadequate in septic patients treated with continuous
renal replacement therapy. Crit Care. 2011;15(3):R137.
21. Udy AA, Varghese JM, Altukroni M, et al. Subtherapeutic initial
B-lactam concentrations in select critically ill patients. Chest.
2012;142(1):30-39.
22. Binder L, Schwörer H, Hoppe S, et al. Pharmacokinetics of mer-
openem in critically ill patients with severe infections. Ther Drug
Monit. 2013;35(1):63-70.
23. Stechmiller JK, Treloar D, Allen N. Gut dysfunction in critically
ill patients: a review of the literature. Am J Crit Care. 1997;6(3):
204-209.
24. Boucher BA, Wood GC, Swanson JM. Pharmacokinetic changes
in critically illness. Crit Care Clin. 2006;22(2):255-271.
25. Smith BS, Yogaratnam D, Levasseur-Franklin KE, Forni A, Fong
J. Introduction to drug pharmacokinetics in the critically ill
patient. Chest. 2012;141(5):1327-1336.
26. Roberts DJ. Drug absorption, distribution, metabolism and excre-
tion considerations in critically ill adults. Expert Opin Drug
Metab Toxicol. 2013;9(9):1067-1084.
27. Nguyen NQ, Ng MP, Chapman M, Fraser RJ, Holloway RH. The
impact of admission diagnosis on gastric emptying in critically ill
patients. Crit Care. 2007;11(1):R16.
28. Mueller BA, Brierton DG, Abel SR, Bowman L. Effect of enteral
feeding with Ensure on oral bioavailabilities of ofloxacin and cipro-
floxacin. Antimicrob Agents Chemother. 1994;38(9):2101-2105.
29. Mimoz O, Binter V, Jacolot A, et al. Pharmacokinetics and abso-
lute bioavailability of ciprofloxacin administered through a naso-
gastric tube with continuous enteral feeding to critically ill
patients. Intensive Care Med. 1998;24(10):1047-1051.
30. Blum RA, D’Andrea DT, Florentino BM, et al. Increased gastric
pH and the bioavailability of fluconazole and ketoconazole. Ann
Intern Med. 1991;114(9):755-757.
31. Piscitelli SC, Goss TF, Wilton J, D’Andrea DT, Goldstein H,
Schentag JJ. Effects of ranitidine and sucralfate on ketocona-
zole bioavailability. Antimicrob Agents Chemother. 1991;
35(9):1765-1771.
32. Chin TWF, Loeb M, Fong IW. Effects of an acidic beverage
(Coca-Cola) on absorption of ketoconazole. Antimicrob Agents
Chemother. 1995;39(8):1671-1675.
33. Dörffler-Melly J, de Jonge E, Pont AC, et al. Bioavailability of
subcutaneous low-molecular- weight heparin to patients on vaso-
pressors. Lancet. 2002;359(9309):849-850.
34. Haas CE, Nelsen JL, Raghavendran K, et al. Pharmacokinetics
and pharmacodynamics of enoxaparin in multiple trauma patients.
J Trauma. 2005;59(6):1336-1343.
35. Parrillo JE. Pathogenetic mechanisms of septic shock. N Engl J
Med. 1993;328(20):1471-1477.
10
36. Triginer C, Izquierdo I, Fernandez R, et al. Gentamicin volume of
distribution in critically ill septic patients. Intensive Care Med.
1990;16(5):303-306.
37. Gous AG, Dance MD, Lipman J, Luyt DK, Mathivha R, Scribante
J. Changes in vancomycin pharmacokinetics in critically ill
infants. Anaesth Intensive Care. 1995;23(6):678-682.
38. Tang GJ, Tang JJ, Lin BS, Kong CW, Lee TY. Factors affecting
gentamicin pharmacokinetics in septic patients. Acta Anaesthesiol
Scand. 1999;43(7):726-730.
39. Buijk SE, Mouton JW, Gyssens IC, Verbrugh HA, Bruining HA.
Experience with a once- daily dosing program of aminoglycosides
in critically ill patients. Intensive Care Med. 2002;28(7):936-942.
40. Del Mar Fernandez de Gatta Garcia M, Revilla N, Calvo MV,
Dominquez-Gil A, Sanchez Navarro A. Pharmacokinetic/pharma-
codynamics analysis of vancomycin in ICU patients. Intensive
Care Med. 2007;33(2):279-285.
41. Taccone FS, Hites M, Beumier M, Scolletta S, Jacobs F. Appro-
priate antibiotic dosage levels in the treatment of severe sepsis
and septic shock. Curr Infect Dis Rep. 2011;13(5):406-415.
42. Vilay AM, Grio M, DePestel DD, et al. Daptomycin pharmacoki-
netics in critically ill patients receiving continuous venovenous
hemodialysis. Crit Care Med. 2011;39(1):19-25.
43. Wenisch JM, Meyer B, Fuhrmann V, et al. Multiple-dose pharma-
cokinetics of daptomycin during continuous venovenous haemo-
diafiltration. J Antimicrob Chemother. 2012;67(4):977-983.
44. Bauer SR, Salem C, Connor MJ Jr, et al. Pharmacokinetics and
pharmacodynamics of piperacillin-tazobactam in 42 patients
treated with concomitant CRRT. Clin J Am Soc Nephrol. 2012;
7(3):452-457.
45. Khadzhynov D, Slowinski T, Lieker I, et al. Plasma pharmacoki-
netics of daptomycin in critically ill patients with renal failure and
undergoing CVVHD. Int J Clin Pharmacol Ther. 2011;49(11):
656-665.
46. Dvorchik B, Arbeit RD, Chung J, Liu S, Knebel W, Kastrissios H.
Population pharmacokinetics of daptomycin. Antimicrob Agents
Chemother. 2004;48(8):2799-2807.
47. Botha FJ, van der BIJL P, Seifart HI, Parkin DP. Fluctuation of
the volume of distribution of amikacin and its effect on once-
daily dosage and clearance in a seriously ill patient. Intensive
Care Med. 1996;22(5):443-446.
48. Tormo C, Abad FJ, Ronchera-Oms CL, Parra V, Jimenez NV.
Critically-ill patients receiving total parenteral nutrition show
altered amikacin pharmacokinetics. Clinical Nutrition. 1995;
14(4):254-259.
49. Ronchera-Oms CL, Tormo C, Ordovas JP, Abad J, Jimenez NV.
Expanded gentamicin volume of distribution in critically ill adult
patients receiving total parenteral nutrition. J Clin Pharm Ther.
1995;20(5):253-258.
50. Payen D, de Pont AC, Sakr Y, et al. A positive fluid balance is
associated with a worse outcome in patients with acute renal fail-
ure. Crit Care. 2008;12(3):R74.
51. Bouchard J, Soroko SB, Chertow GM, et al. Fluid accumulation,
survival and recovery of kidney function in critically ill patients
with acute kidney injury. Kidney Int. 2009;76(4):422-427.
52. Grams ME, Estrella MM, Coresh J, Brower RG, Liu KD; National
Heart, Lung, and Blood Institute Acute Respiratory Distress
Downloaded from jic.sagepub.com at UNIV OF MICHIGAN on December 2, 2014
Journal of Intensive Care Medicine
Syndrome Network. Fluid balance, diuretic use, and mortality in
acute kidney injury. Clin J Am Soc Nephrol. 2011;6(5):966-973.
53. Teixeira C, Garzotto F, Piccinni P, et al. Fluid balance and urine
volume are independent predictors of mortality in acute kidney
injury. Crit Care. 2013;17(1):R14.
54. SAFE Study Investigators. Finfer S, Bellomo R, McEvoy S, et al.
Effect of baseline serum albumin concentration on outcome of
resuscitation with albumin or saline in patients in intensive care
units: analysis of data from the Saline versus Albumin Fluid Eva-
luation (SAFE) study. BMJ. 2006;333(7577):1044.
55. Roberts JA, Federico P, Lipman J. The clinical relevance of
plasma protein binding changes. Clin Pharmacokinet. 2013;
52(1):1-8.
56. Burkhardt O, Kumar V, Katterwe D, et al. Ertapenem in critically
ill patients with early-onset ventilator-associated pneumonia:
pharmacokinetics with special consideration of free-drug concen-
tration. J Antimicrob Chemother. 2007;59(2):277-284.
57. Eyler RF, Vilay AM, Nader AM, et al. Pharmacokinetics of erta-
penem in critically ill patients receiving continuous venovenous
hemodialysis or hemodiafiltration. Antimicrob Agents Che-
mother. 2014;58(3):1320-1326.
58. Andreasen F. The effect of dialysis on the protein binding of drugs
in the plasma of patients with acute renal failure. Acta Pharmacol
Toxicol. 1974;34(4):284-294.
59. Mussche MM, Belpaire FM, Bogaert MG. Plasma protein binding
of phenylbutazone during recovery from acute renal failure. Eur J
Clin Pharmacol. 1975;9(1):69-71.
60. Vilay AM, Churchwell MD, Mueller BA. Clinical review: drug
metabolism and nonrenal clearance in acute kidney injury. Crit
Care. 2008;12(6):235.
61. Lalande L, Charpiat B, Leboucher G, Tod M. Consequences of
renal failure on non-renal clearance of drugs. Clin Pharmacoki-
net. 2014;53(6):521-532.
62. Kirwan CJ, MacPhee IA, Lee T, Holt DW, Philips BJ. Acute kid-
ney injury reduces the hepatic metabolism of midazolam in criti-
cally ill patients. Intensive Care Med. 2012;38(1):76-84.
63. Sun H, Frassetto L, Benet LZ. Effects of renal failure on drug
transport and metabolism. Pharmacol Ther. 2006;109(1-2):1-11.
64. Jones EM, McMullin CM, Hedges AJ, et al. The pharmacokinetics
of intravenous ciprofloxacin 400 mg 12 hourly in patients with
severe sepsis: the effect of renal function and intra-abdominal dis-
ease. J Antimicrob Chemother. 1997;40(1):121-124.
65. Macias WL, Mueller BA, Scarim SK. Vancomycin pharmacoki-
netics in acute renal failure: preservation of nonrenal clearance.
Clin Pharmacol Ther. 1991;18(4):451-458.
66. Mueller BA, Scarim SK, Macias WL. Comparison of imipenem
pharmacokinetics in patients with acute or chronic renal failure
treated with continuous hemofiltration. Am J Kidney Dis. 1993;
21(2):172-179.
67. Tegeder I, Bremer F, Oelkers R, et al. Pharmacokinetics of
imipenem-cilastatin in critically ill patients undergoing continu-
ous venovenous hemofiltration. Antimicrob Agents Chemother.
1997;41(12):2540-2545.
68. Golper TA, Noonan HM, Elzinga L, et al. Vancomycin pharma-
cokinetics, renal handling, and nonrenal clearances in normal
human patients. Clin Pharmacol Ther. 1988;43(5):565-570.
Lewis and Mueller
69. Brunet S, Leblanc M, Geadah D, Parent D, Courteau S, Cardinal J.
Diffusive and convective solute clearances during continuous
renal replacement therapy at various dialysate and ultrafiltration
flow rates. Am J Kidney Dis. 1999;34(3):886-892.
70. Churchwell MD, Mueller BA. Drug dosing during continuous
renal replacement therapy. Semin Dial. 2009;22(2):185-188.
71. Pasko DA, Churchwell MD, Salama NN, Mueller BA. Longitudi-
nal hemodiafilter performance in modeled continuous renal
replacement therapy. Blood Purif. 2011;32(2):82-88.
72. Choi G, Gomersall CD, Tian Q, Joynt GM, Freebairn R, Lipman
J. Principles of antibacterial dosing in continuous renal replace-
ment therapy. Crit Care Med. 2009;37(7):2268-2282.
73. Heintz BH, Matzke GR, Dager WE. Antimicrobial dosing con-
cepts and recommendations for critically ill adult patients receiv-
ing continuous renal replacement therapy or intermittent
hemodialysis. Pharmacotherapy. 2009;29(5):562-577.
74. Eyler RF, Mueller BA. Antibiotic dosing in critically ill patients
with acute kidney injury. Nat Rev Nephrol. 2011;7(4):226-235.
75. Kielstein JT, Burkhardt O. Dosing of antibiotics in critically ill
patients undergoing renal replacement therapy. Curr Pharm Bio-
technol. 2011;12(12):2015-2019.
76. Bogard KN, Peterson NT, Plumb TJ, Erwin MW, Fuller PD,
Olsen KM. Antibiotic dosing during sustained low-efficiency dia-
lysis: special consideration in adult critically ill patients. Crit
Care Med. 2011;39(3):560-570.
77. Scoville BA, Mueller BA. Medication dosing in critically ill
patients with acute kidney injury with renal replacement therapy.
Am J Kideny Dis. 2013;61(3):490-500.
78. Mueller BA, Smoyer WE. Challenges in developing evidence-
based drug dosing guidelines for adults and children receiving
renal replacement therapy. Clin Pharmacol Ther. 2009;86(5):
479-482.
79. Vesconi S, Cruz DN, Fumagalli R, et al. DOse REsponse Multi-
centre International collaborative Initiative (DO-RE-MI Study
Group): delivered dose of renal replacement therapy and mortality
in critically ill patients with acute kidney injury. Crit Care. 2009;
13(2):R57.
80. VA/NIH Acute Renal Failure Trial Network, Palevsky PM, Zhang
JH, O’Connor TZ, et al. Intensity of renal support in critically ill
patients with acute kidney injury. N Engl J Med. 2008;359(1):
7-20.
81. RENAL Replacement Therapy Study Investigators, Bellomo R,
Cass A, Cole L, et al. Intensity of continuous renal replacement
therapy in critically ill patients. N Eng J Med. 2009;361(17):
1627-1638.
82. Kielstein JT, David S. Pro: renal replacement trauma or paracel-
sus 2.0. Nephrol Dial Transplant. 2013;28(11):2728-2733.
83. Covajes C, Scolletta S, Penaccini L, et al. Continuous infusion of
vancomycin in septic patients receiving continuous renal replace-
ment therapy. Int J Antimicrob Agents. 2013;41(3):261-266.
84. Roberts JA, Mehta RL, Lipman J. Sustained low efficiency dialy-
sis allows rational renal replacement therapy, but dose it allow
rational drug dosing? Crit Care Med. 2011;39(3):602-603.
85. Fiaccadori E, Maggiore U, Rotelli C, et al. Removal of linezolid
by conventional intermittent hemodialysis, sustained low-
efficiency dialysis, or continuous venovenous hemofiltration in
Downloaded from jic.sagepub.com at UNIV OF MICHIGAN on December 2, 2014
11
patients with acute renal failure. Crit Care Med. 2004;32(12):
2437-2442.
86. Arzuaga A, Maynar J, Gascón AR, et al. Influence of renal func-
tion on the pharmacokinetics of piperacillin/tazobactam in inten-
sive care unit patients during continuous venovenous
hemofiltration. J Clin Pharmacol. 2005;45(2):168-176.
87. Kielstein JT, Czock D, Schopke T, et al. Pharmacokinetics and
total elimination of meropenem and vancomycin in intensive
care unit patients undergoing extended daily dialysis. Crit Care
Med. 2006;34(1):51-56.
88. Burkhardt O, Joukhadar C, Traunmuller F, Hadem J, Welte T,
Kielstein JT. Elimination of daptomycin in a patient with acute
renal failure undergoing extended daily dialysis. J Antimicrob
Chemother. 2008;61(1):224-225.
89. Wilson FP, Berns JS. Vancomycin levels are frequently subther-
apeutic during continuous venovenous hemodialysis (CVVHD).
Clin Nephrol. 2012;77(4):329-331.
90. Zoller M, Maier B, Hornuss C, et al. Variability of linezolid con-
centrations after standard dosing in critically ill patients: a pro-
spective observational study. Crit Care. 2014;18(4):R148.
91. Owens RC, Shorr AF. Rational dosing of antimicrobial agents:
pharmacokinetic and pharmacodynamics strategies. Am J
Health-Sys Pharm. 2009;66(4):S23-S30.
92. Mariat C, Venet C, Jehl F, et al. Continuous infusion of ceftazi-
dime in critically ill patients undergoing continuous venovenous
haemodiafiltration: pharmacokinetic evaluation and dose recom-
mendation. Crit Care. 2006;10(1):R26.
93. Langgartner J, Vasold A, Glück T, Reng M, Kees F. Pharma-
cokinetics of meropenem during intermittent and continuous
intravenous application in patients treated by continuous
renal replacement therapy. Intensive Care Med. 2008;34(6):
1091-1096.
94. Saugel B, Nowack MC, Hapfelmeier A, et al. Continuous intra-
venous administration of vancomycin in medical intensive care
unit patients. J Crit Care. 2013;28(1):9-13.
95. Beumier M, Roberts JA, Kabtouri H, et al. A new regimen for
continuous infusion of vancomycin during continuous renal
replacement therapy. J Antimicrob Chemother. 2013;68(12):
2859-2865.
96. Lodise TP, Lomaestro B, Drusano G. Piperacillin-tazobactam
for Pseudomonas aeruginosa infection: clinical implications of
an extended infusion dosing strategy. Clin Infect Dis. 2007;
44(3):357-363.
97. Kielstein JT, Engbers C, Bode-Boeger SM, et al. Dosing of dap-
tomycin in intensive care unit patients with acute kidney injury
undergoing extended dialysis-a pharmacokinetic study. Nephrol
Dial Transplant. 2010;25(5):1537-1541.
98. Mueller BA, Scoville BA. Adding to the armamentarium: anti-
biotic dosing in extended dialysis. Clin J Am Soc Nephrol.
2012;7(3):373-375.
99. Taccone FS, de Backer D, Laterre PF, et al. Pharmacokinetics of
a loading dose of amikacin in septic patients undergoing contin-
uous renal replacement therapy. Int J Antimicrob Agents. 2011;
37(6):5.
100. Truong J, LEvkovich BJ, Padiglione AA. Simple approach to
improving vancomycin dosing in intensive care: a standardized
12
loading dose results in earlier therapeutic levels. Intern Med J.
2012;42(1):23-29.
101. Kamel Mohamed OH, Wahba IM, Watnick S, et al. Administra-
tion of tobramycin in the beginning of the hemodialysis session:
a novel intradialytic dosing regimen. Clin J Am Soc Nephrol.
2007;2(4):694-699.
102. Sowinski KM, Magner SJ, Lucksiri A, Scott MK, Hamburger
RJ, Mueller BA. Influence of hemodialysis on gentamicin phar-
macokinetics, removal during hemodialysis, and recommended
dosing. Clin J Am Soc Nephrol. 2008;3(2):355-361.
103. Veistein A, Venisse N, Badin J, Pinsard M, Robert R, Dupuis A.
Gentamicin in hemodialyzed critical care patients: early dialysis
after administration of a high dose should be considered. Antimi-
crob Agents Chemother. 2013;57(2):977-982.
104. Roberts JA, Field J, Visser A, et al. Using population phar-
macokinetics to determine gentamicin dosing during
extended daily diafiltration in critically ill patients with
acute kidney injury. Antimicrob Agents Chemother. 2010;
54(9):3635-3640.
105. Calbo E, Garau J. Application of pharmacokinetics and phar-
macodynamics to antimicrobial therapy of community
acquired respiratory tract infections. Respiration. 2005;72(6):
561-571.
106. Scaglione F, Paraboni L. Influence of pharmacokinetics/pharma-
codynamics of antibacterials in their dosing regimen selection.
Expert Rev Anti Infect Ther. 2006;4(3):479-490.
107. McKinnon PS, Paladino JA, Schentag JJ. Evaluation of area
under the inhibitory curve (AUIC) and time above the minimum
inhibitory concentration (T > MIC) as predictors of outcome for
cefepime and ceftazidime in serious bacterial infections. Int J
Antimicrob Agents. 2008;31:345-351.
108. Valtonen M, Tiula, Takkunen O, Backman JT, Neuvonen PJ.
Elimination of the piperacillin/tazobactam combination during
continuous venovenous haemofiltration and haemodiafiltration
in patients with acute renal failure. J Antimicrob Chemother.
2001;48(6):881-885.
109. Falagas ME, Tansarli GS, Ikawa K, Vardakas KZ. Clinical out-
comes with extended or continuous versus short-term intrave-
nous infusion of carbapenems and piperacillin/tazobactam: a
systematic review and meta-analysis. Clin Infec Dis. 2013;
56(2):272-282.
110. Chant C, Leung A, Friedrich JO. Optimal dosing of antibio-
tics in critically ill patients using continuous/extended infu-
sion: a systematic review and meta-analysis. Crit Care.
2013;17(6):R279.
111. Moriyama B, Henning SA, Neuhauser MM, Danner RL, Walsh TJ.
Continuous-infusion beta-lactam antibiotics during continuous
venovenous hemofiltration for the treatment of resistant gram-
negative bacteria. Ann Pharmacother. 2009;43(7):1324-1337.
112. Joy MS, Matzke GR, Frye RF, Palevsky PM. Determinants of
vancomycin clearance by continuous venovenous hemofiltration
and continuous venovenous hemodialysis. Am J Kidney Dis.
1998;31(6):1019-1027.
113. DelDot ME, Lipman J, Tett SE. Vancomycin pharmacokinetics
in critically ill patients receiving continuous venovenous haemo-
diafiltration. Br J Clin Pharmacol. 2004;58(3):259-268.
Downloaded from jic.sagepub.com at UNIV OF MICHIGAN on December 2, 2014
Journal of Intensive Care Medicine
114. Moore RD, Lietman PS, Smith CR. Clinical response to amino-
glycoside therapy: importance of the ratio of peak concentration
to minimal inhibitory concentration. J Infect Dis. 1987;155(1):
93-99.
115. Martinez MN, Papich MG, Drusano GL. Dosing regimen mat-
ters: the importance of early intervention and rapid attainment
of the pharmacokinetic/pharmacodynamic target. Antimicrob
Agents Chemother. 2012;56(6):2795-2805.
116. Jumbe N, Louie A, Leary R, et al. Application of a mathematical
model to prevent in vivo amplification of antibiotic-resistant
bacterial populations during therapy. J Clin Invest. 2003;
112(2):275-285.
117. Trotman RL, William JC, Shoemaker DM, Salzer WL. Anti-
biotic dosing in critically ill adult patients receiving continuous
renal replacement therapy. Clin Infect Dis. 2005;41(8):
1159-1166.
118. Matsuo H, Hayashi J, Ono K, et al. Administration of aminogly-
cosides to hemodialysis patients immediately before dialysis: a
new dosing modality. Antimicrob Agents Chemother. 1997;
41(12):2597-2601.
119. Teigen MM, Duffull S, Dang L, Johnson DW. Dosing
of gentamicin in patients with end-stage renal disease
receiving hemodialysis. J Clin Pharmacol. 2006;46(11):
1259-1267.
120. Gentamicin [package insert]. Lake Forest, IL: Hospira, Inc;
August 2005. http://www.hospira.com/Images/EN-1004_32-
5467_1.pdf. Accessed March 12, 2014.
121. Ryan DM, Cars O. A problem in the interpretation of beta-
lactam antibiotic levels in tissues. J Antimicrob Chemother.
1983;12(3):281-284.
122. Schentag JJ, Heller AS, Hardy BG, Wels PB. Antibiotic penetra-
tion in liver infection: a case of tobramycin failure responsive to
moxalactam. Am J Gastroenterol. 1983;78(10):641-644.
123. Joukhadar C, Frossard M, Mayer BX, et al. Impaired target site
penetration of beta-lactams may account for therapeutic failure
in patients with septic shock. Crit Care Med. 2001;29(2):
385-391.
124. Zeitlinger MA, Erovic BM, Sauermann R, Georgopoulos A,
Müller M, Joukhadar C. Plasma concentrations might lead
to overestimation of target site activity of piperacillin in
patients with sepsis. J Antimicrob Chemother. 2005;56(4):
703-708.
125. Klekner A, Bagyi K, Bognar L, Gaspar A, Andrasi M, Szabo J.
Effectiveness of cephalosporins in the sputum of patients with
nosocomial bronchopneumonia. J Clin Microbiol. 2006;44(9):
3418-3421.
126. Stolle LB, Plock N, Joukhadar C, et al. Pharmacokinetics of line-
zolid in bone tissue investigated by in vivo microdialysis. Scand
J Infect Dis. 2008;40(1):24-29.
127. Tam VH, Gamez EA, Weston JS, et al. Outcomes of bacter-
emia due to Pseudomonas aeruginosa with reduced suscept-
ibility to piperacillin-tazobactam: implications on the
appropriateness of the resistance breakpoint. Clin Infect Dis.
2008;46(6):862-867.
128. Soriano A, Marco F, Martı́nez JA, et al. Influence of vancomycin
minimum inhibitory concentration on the treatment of
Lewis and Mueller
methicillin-resistant Staphylococcus aureus bacteremia. Clin
Infect Dis. 2008;46(2):193-200.
129. Hidayat LK, Hsu DI, Quist R, Shriner KA, Wong-Beringer A.
High-dose vancomycin therapy for methicillin-resistant Staphy-
lococcus aureus infections: efficacy and toxicity. Arch Intern
Med. 2006;166(19):2138-2144.
130. Rybak MJ, Lomaestro BM, Rotschafer JC, et al. Vancomycin
therapeutic guidelines: a summary of consensus recommenda-
tions from the Infectious Diseases Society of America, the
American Society of Health-System Pharmacists, and the Soci-
ety of Infectious Diseases Pharmacist. Clin Infect Dis. 2009;
49(3):325-327.
131. Kullar R, McClellan I, Geriak M, Sakoulas G. Efficacy and
safety of daptomycin in patients with renal impairment: a multi-
center retrospective analysis. Pharmacotherapy. 2014;34(6):
582-589.
132. National Nosocomial Infections Surveillance System.
National Nosocomial Infections Surveillance (NNIS) System
Report, data summary from January 1992 through June
2004, issued October 2004. Am J Infect Control. 2004;
32(6):470-485.
133. Klevens RM, Edwards JR, Gaynes RP. The impact of
antimicrobial-resistant, health care- associated infections on
mortality in the United States. Clin Infect Dis. 2008;47(7):
927-930.
134. Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no drugs:
no ESKAPE! An update from the Infectious Diseases Society of
America. Clin Infect Dis. 2009;48(1):1-12.
135. Peters NK, Dixon DM, Holland SM, Fauci AS. The research
agenda of the national institute of allergy and infectious diseases
for antimicrobial resistance. J Infect Dis. 2008;197(8):
1087-1093.
136. Barth RH, DeVincenzo N. Use of vancomycin in high-flux
hemodialysis: experience with 130 courses of therapy. Kidney
Int. 1996;50(3):929-936.
137. Taber SS, Mueller BA. Drug-associated renal dysfunction. Crit
Care Clin. 2006;22(2)357-374.
138. Kane-Gill SL, Kirisci L, Verrico MM, Rothschild JM. Analysis
of risk factors for adverse drug events in critically ill patients.
Crit Care Med. 2012;40(3):823-828.
139. Hartzell JD, Neff R, Ake J, et al. Nephrotoxicity associated with
intravenous colistin (colistin sodium) treatment at a tertiary care
medical center. Clin Infect Dis. 2009;48(12):1724-1728.
140. Kwon JA, Lee JE, Huh W, et al. Predictors of acute kidney injury
associated with intravenous colistin treatment. Int J Antimicrob
Agents. 2010;35(5):473-477.
141. Schentag JJ, Cerra FB, Plaut ME. Clinical and pharmacokinetic
characteristics of aminoglycoside nephrotoxicity in 201 criti-
cally ill patients. Antimicrob Agents Chemother. 1982;21(5):
721-726.
142. Zager RA. Endotoxemia, renal hypoperfusion, and fever: inter-
active risk factors for aminoglycoside and sepsis associated
acute renal failure. Am J Kid Dis. 1992;20(3):223-230.
143. Van Hal, Paterson DL, Lodise TP. Systematic review and meta-
analysis of vancomycin- induced nephrotoxicity associated with
Downloaded from jic.sagepub.com at UNIV OF MICHIGAN on December 2, 2014
13
dosing schedules that maintain troughs between 15 and 20 milli-
grams per liter. Antimicrob Agents Chemother. 2013;57(2):
734-744.
144. Moore RD, Smith CR, Lipsky JJ, Mellits ED, Lietman PS. Risk
factors for nephrotoxicity in patients treated with aminoglyco-
sides. Ann Intern Med. 1984;100(3):352-357.
145. Lodise TP, Lomaestro B, Graves J, Drusano GL. Larger vanco-
mycin doses (at least four grams per day) are associated with an
increased incidence of nephrotoxicity. Antimicrob Agents Che-
mother. 2008;52(4):1330-1336.
146. Lodise TP, Patel N, Lomaestro BM, Rodvold KA, Drusano
GL. Relationship between initial vancomycin concentration
time profile and nephrotoxicity. Clin Infect Dis. 2009;49(4):
507-514.
147. Pritchard L, Baker C, Leggett J, Sehdev P, Brown A, Bayley KB.
Increasing vancomycin serum trough concentrations and inci-
dence of nephrotoxicity. Am J Med. 2010;123(12):1143-1149.
148. Bosso JA, Nappi J, Rudisill C, et al. Relationship between van-
comycin trough concentrations and nephrotoxicity: a prospec-
tive multicenter trial. Antimicrob Agents Chemother. 2011;
55(12):5475-5479.
149. Cano EL, Haque NZ, Welch VL, et al. Incidence of Nephrotoxi-
city and Association With Vancomycin Use in Intensive Care
Unit Patients With Pneumonia: Retrospective Analysis of the
IMPACT-HAP Database. Clin Ther. 2012;34(1):149-157.
150. Bertino JS, Booker LA, Franck PA, Jenkins PL, Franck KR, Naf-
ziger AN. Incidence of and significant risk factors for
aminoglycoside-associated nephrotoxicity in patients dosed by
using individualized pharmacokinetic monitoring. J Infect Dis.
1993;167(1):173-179.
151. Rybak MJ, Abate BJ, Kang SL, Ruffing MJ, Lerner SA, Drusano
GL. Prospective evaluation of the effect of an aminoglycoside
dosing regimen on rates of observed nephrotoxicity and ototoxi-
city. Antimicrob Agents Chemother. 1999;43(7):1549-1555.
152. Drusano GL, Ambrose PG, Bhavnani SM, Bertino JS, Nafziger
AN, Louie A. Back to the future: using aminoglycosides again
and how to dose them optimally. Clin Infect Dis. 2007;45(15):
753-760.
153. Calandra GB, Brown KR, Grad LC, Ahonkhai VI, Wang C, Aziz
MA. Review of adverse experiences and tolerability in the first
2516 patients treated with imipenem/cilastatin. Am J Med.
1985;78(6A):73-78.
154. Hellinger WC, Brewer NS. Carbapenems and monobactams:
imipenem, meropenem and aztreonam. Mayo Clin Proc. 1999;
74(4):420-434.
155. Norrby SR. Carbapenems in serious infections: a risk benefit
assessment. Drug Saf. 2000;22(3):191-194.
156. Norrby SR, Newell PA, Faukner KL, Lesky W. Safety profile of
meropenem international clinical experience based on the first
3125 patients treated with meropenem. J Antimicrob Chemother.
2005;36(suppl A):207-223.
157. Nicolau DP. Carbapenems: a potent class of antibiotics. Expert
Opin Pharmacother. 2008;9(1):23-37.
158. Martinez-Rodriguez JE, Barriga FJ, Santamaria J, et al.
Nonconvulsive status epilepticus associated with
14
cephalosporins in patients with renal failure. Am J Med.
2001;111(2):115-119.
159. Grill MF, Maganti R. Cephalosporin-induced neurotoxicity:
clinical manifestations, potential pathogenic mechanisms, and
the role of electroencephalographic monitoring. Ann Pharmac-
other. 2008;42(12):1843-1850.
160. Chapuis TM, Giannoni E, Majcherczyk PA, et al. Prospective
monitoring of cefepime in intensive care unit adult patients. Crit
Care. 2010;14(2):R51.
161. Fugate JE, Kalimullah EA, Hocker SE, Clark SL, Wijdicks EF,
Rabinstein AA. Cefepime neurotoxicity in the intensive care
Downloaded from jic.sagepub.com at UNIV OF MICHIGAN on December 2, 2014
View publication stats
Journal of Intensive Care Medicine
unit: a cause of severe, underappreciated encephalopathy. Crit
Care. 2013;17(6):R264.
162. Bagshaw SM. Short- and long-term survival after acute
kidney injury. Nephrol Dial Transplant. 2008;23(7):
2126-2128.
163. Schiffl H, Fischer R. Five-year outcomes of severe acute kidney
injury requiring renal replacement therapy. Nephrol Dial Trans-
plant. 2008;23(7):2235-2241.
164. Eisenberg JM, Koffer H, Glick HA, et al. What is the cost of
nephrotoxicity associated with aminoglycosides? Ann Intern
Med. 1987;107(6):900-909.