Analytic Review

Journal of Intensive Care Medicine

2016, Vol. 31(3) 164-176
Antibiotic Dosing in Patients With Acute ª The Author(s) 2014
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Kidney Injury: ‘‘Enough But Not Too Much’’ DOI: 10.1177/0885066614555490
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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 The Surviving Sepsis Guidelines emphasize the significance

of ‘‘appropriate antimicrobial therapy,’’ which is defined as
A 68-year-old female (height 5 ft 2 in, weight 95 kg) was
‘‘initial empiric anti-infective therapy of one or more drugs that
admitted for complaint of increasing abdominal pain and have activity against all likely pathogens and that penetrate in
altered mental status. Her past medical history is extensive
adequate concentrations into tissue presumed to be the source
including recurrent urosepsis caused by b-lactamase-positive
of sepsis.’’1 However, even in the straightforward case men-
Escherichia coli. In the intensive care unit (ICU), she has not
tioned earlier, numerous barriers exist to achieve ‘‘adequate
yet received empiric antibiotic therapy but did get aggressive
concentrations’’ at the infection site. Recent evidence suggests
fluid resuscitation in the emergency department. The patient’s
that clinicians prescribe antibiotics with doses that are higher
oxygen saturation dropped rapidly and she developed respira-
than what is recommended for the patients’ glomerular filtra-
tory failure and septic shock, requiring mechanical ventilation
tion rate in elderly patients with chronic kidney disease stages
with oxygen and vasopressor support. The laboratory results IV and V,7,8 increasing the risk of antibiotic toxicity. However,
include serum creatinine (SCr) 2.2 mg/dL and blood urea nitro-
in critically ill patients with AKI, higher doses may be war-
gen (BUN) 45 mg/dL (baseline SCr 1.1 mg/dL, BUN 23 mg/dL
ranted. Appropriate antibiotic therapy requires a balance
1 month ago). The patient’s weight in the nursing home chart 1
between a need for doses high enough to account for pharma-
week ago was 80 kg. Susceptibility results are pending. The
cokinetic alterations in these patients, pathogen resistance that
ICU team needs to prescribe antibiotic therapy.
is common in the ICU,9 and extracorporeal drug clearance ver-
This complicated scenario is not unlike those faced regu-
sus concerns of antibiotic toxicity in these vulnerable patients
larly by clinicians. The Surviving Sepsis Guidelines provide
with impaired drug clearance (Figure 1). The purpose of this
very straightforward guidance on how to treat patients with article is to explore the challenges of providing appropriate
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 1
Department of Clinical, Social, and Administrative Sciences, University of
injury (AKI), which is a common complication of sepsis in the Michigan College of Pharmacy, Ann Arbor, MI, USA
ICU2 and is associated with high morbidity and mortality Received March 13, 2014, and in revised form August 4, 2014. Accepted
(60%-77%).3-5 About 70% of patients with AKI in the ICU for publication August 25, 2014.
require some type of renal replacement therapy (RRT),6 and
with the degree of fluid overload manifested by this patient, Corresponding Author:
Bruce A. Mueller, Department of Clinical, Social and Administrative Sciences,
it is likely that RRT will be necessary as diuretics and conser-
University of Michigan College of Pharmacy, 428 Church St, Ann Arbor, MI
vative management are unlikely to be able to remove 15 L of 48109, USA.
extra volume in a timely manner. Email: muellerb@med.umich.edu
Lewis and Mueller
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.
antibiotic doses to attain adequate concentrations at the site of
infection and to suggest alternative strategies balancing neces-
sity and risk of antibiotic higher doses to maximize antibiotic
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
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.
165
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 espe-
cially prominent with hydrophilic drugs such as aminoglycosides,
b-lactams, glycopeptides, and daptomycin. Many researchers
have demonstrated decreased serum levels of antibiotics in criti-
cally ill patients secondary to increased volume of distribution,
suggesting the need for higher doses than standard dosing recom-
mendations to maintain suitable serum concentrations.22,36-44 The
increased volume of distribution is more pronounced in severe
sepsis and in the early stages of sepsis. Patients with hyperdy-
namic sepsis have a significantly larger volume of distribution
of gentamicin (0.48 L/kg), compared with those who have hypo-
dynamic sepsis (0.32 L/kg) and nonseptic patients receiving post-
surgical prophylactic doses of gentamicin (0.29 L/kg).38 Taccone
et al noted that the first conventional 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 distri-
bution is also observed in critically ill patients with AKI receiving
continuous 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.
166
Taken together, the increased volume of distribution of hydrophi-
lic antibiotics in the early stage of sepsis or severe sepsis necessi-
tates 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 con-
ventional dosing over the course of therapy to avoid toxicity. Not
only can pathophysiologic changes related to sepsis influence vol-
ume of distribution in critically ill patients, but fluid therapy to
resuscitate patients with sepsis can alter it as well. Volume of dis-
tribution 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 volume of distribution of aminoglycosides is increased sub-
stantially 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 nutri-
tion, and drug infusions on antibiotic volume of distribution and
may need to use higher antibiotic doses to compensate. The influ-
ence of fluid overload on antibiotic concentrations and outcomes
in critically ill patients has not been demonstrated definitively.
Several observational studies have highlighted 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 nondialyzed 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 Theoreti-
cally, fluid overload could dilute the serum concentrations of anti-
biotics 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 overload
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. Hypo-
albuminemia 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
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
Journal of Intensive Care Medicine 31(3)
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
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
Lewis and Mueller
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 control,
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 pharmacokinetic
studies using obsolete techniques or are extrapolated from phar-
macokinetic 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 coef-
ficient [Sc] or saturation coefficient [Sd]) are 2 primary para-
meters used to calculate dialytic drug clearance (CLcrrt ¼ Qf
 Sc or Sd). The extraction coefficient approximates the per-
centage 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 clear-
ance. Although several large randomized trials indicated that
high Qfs do not reduce mortality 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 concentra-
tions, these studies may be confounded by reduced pharmacody-
namic target attainment rates in patients receiving high Qfs.
Clinicians employing prolonged intermittent RRT (PIRRT)
will find that <1% of drugs have validated dosing recommenda-
tions available to them.76,84 Recent reviews suggest that, despite
the ‘‘slower than IHD’’ blood and dialysate flow rates, the
extended duration of PIRRT (8-12 hours) contributes to substan-
tial antibiotic clearance, increasing the risk of prolonged subther-
apeutic antibiotic concentrations.76,77 In addition, 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,
167
current 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 phar-
macodynamic 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 parameters 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 cate-
gories, concentration-dependent activity or time-dependent activ-
ity. For concentration-dependent antibiotics (aminoglycosides,
daptomycin, and fluoroquinolones), therapeutic outcome will
be maximized when a high peak serum concentration (Cmax)
relative to the organism’s minimum 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 effi-
cacy. For several antibiotics (vancomycin, linezolid) displaying
both characteristics, the high ratio of area under the serum con-
centration–time curve (AUC) to the bacterial MIC has been asso-
ciated with antibacterial success. Besides bacterial killing
characteristics, the postantibiotic effect, the persistent suppres-
sion of bacterial growth after concentrations fall below the MIC
for a particular organism,91 can influence antibacterial effect and
help to determine optimal antibiotic dosing and frequency of
administration. Table 1 suggests several alternative antibiotic
dosing strategies to maximize the efficacy of antibiotic therapy
in critically 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
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/
168
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.
tazobactam was reported to be nearly equivalent to patients
with normal renal function.108 Seyler and colleagues report that
recommended 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 aerugi-
nosa within 48 hours of antibiotic therapy in 34% to 100% of
modeled cases.20 Therefore, initiation of CRRT should be fol-
lowed 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
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
Journal of Intensive Care Medicine 31(3)
hemofiltration 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 significantly higher in those with higher daily doses.
Potential drug accumulation and higher risk of toxicity man-
dates routine monitoring of vancomycin serum concentration
and subsequent 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 valu-
able in a case with reduced susceptibility, high CRRT Qf,
increased antibiotic volume of distribution, and/or in immuno-
compromised patients where prolonged serum concentration
above the MIC may be critical. Compared to shorter conven-
tional infusion times, extended antibiotic infusions can be diffi-
cult 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 organism’s MIC. Further stud-
ies are warranted to investigate the efficacy 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
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.
Lewis and Mueller
25
1g q12h Intermittent infusion
Serum Concentration (mg/L)
20 2g q24h Continuous infusion
15
10
MIC of 8mg/L
5
0
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.
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
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
Altered Antibiotic Administration Time
Changing antibiotic administration time with relation to RRT
can be a strategy to meet pharmacodynamic goals while
169
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 pro-
longed 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 simu-
lated post-HD infusion of 1.7 mg/kg dose, the maximum dose
recommended by the package insert, failed to meet any pharma-
codynamic targets (Cmax 8.8 + 3.1 mg/L).103 Use of a high pre-
dialytic 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 ses-
sion can be an effective dosing strategy to maximize pharmaco-
dynamic target attainment while minimizing sustained elevated
serum concentrations responsible for toxicity.104 However, cau-
tion should be followed when this novel strategy is instituted.
Delay in dialysis schedule or unexpected dialysis discontinua-
tion secondary to clotting or intolerance can put a patient at risk
of antibiotic toxicity due to inadequate dialytic drug clearance.
Thus, when the benefit of maximized pharmacokinetic/pharma-
codynamic 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 hypo-
albuminemia, and in need of RRT. Most penicillin, cephalo-
sporin, and carbapenem antibiotics have recommended dosing
in adults who are ‘‘flat dosed’’ with a dosing interval adjusted
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
170
30
Pre-dialytic 6mg/kg dose
Serum Concentration (mg/L)
25
Post-dialytic 1.7mg/kg dose
20
15
10
5 study.129 Alternative antibiotic agents may be considered in a
0 toxicity.131 Treatment of infection in the ICU becomes more
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.
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 represent equivalent
concentration in the sites of infection,124-126 suggesting that poor
tissue penetration may result in subtherapeutic antibiotic concen-
trations at infection sites and consequent treatment failure, which
is not uncommon in patients with sepsis. Accordingly, modify-
ing 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 may be warranted to ensure adequate local antibiotic
concentrations in these patients.
Rising Bacterial Resistance Rates
Finally, the increasing prevalence of antibiotic resistance high-
lights the significance of ‘‘appropriate’’ antibiotic therapy. Anti-
biotic resistance in critically ill patients has been related to
increased mortality rates in several studies.9,127,128 In a retro-
spective cohort, a significantly higher risk of hospital mortality
was noted in patients with sepsis who were infected with resis-
tant gram-negative bacteria (63.4% vs 40.0%).9 Further logistic
regression analysis determined resistance to the initial antibiotics
as an independent risk factor, associated with a doubling of hos-
pital 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
Journal of Intensive Care Medicine 31(3)
20% lower clinical response to vancomycin therapy, compared
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 antibiotic
toxicity in this vulnerable patient population, as high vancomy-
cin trough levels (15-20 mg/mL) were found to be a significant
predictor of nephrotoxicity development in the latter
case with high MIC strains and increased predisposition to drug
challenging with the emerging incidence of multidrug resistant
and even panantibiotic-resistant pathogens among Acinetobacter
species, P aeruginosa, carbapenem-resistant Klebsiella species
and E coli.132-134 The effectiveness of available antibiotics and
efforts to develop novel antibiotics have been declining as
well.135 All these circumstances mandate clinicians to aim
toward higher pharmacodynamic targets and higher antibiotic
doses to ensure bacterial eradication and to reduce the risk of fur-
ther development of antibiotic resistance.127,128 As discussed,
clinicians should endeavor to maximize antibacterial killing
effect by using aggressive antibiotic dosing and/or alternative
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
concern. These dynamic yet vulnerable patients often have
multiple 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
without AKI.138 Antibiotics were the most common drug class
causing toxicity in the ICU.138
Despite the concern for their well-known nephrotoxicity, ami-
noglycosides and vancomycin remain as mainstays of antibiotic
therapy in the ICU. Another renowned nephrotoxin, colistin, has
been reintroduced as a last treatment option for multidrug resis-
tant 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 critically ill patients treated with aminoglycosides
reported up to 30% of incidence of nephrotoxicity.141 Moreover,
fever, endotoxemia, and renal hypoperfusion associated with sep-
sis 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
Lewis and Mueller
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 dura-
tion of therapy, concomitant use of other nephrotoxins, and renal
impairment are common risk factors to precipitate nephrotoxi-
city with these antibiotics.139,140,143-149 Ensuring pharmacody-
namic 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 per-
formed when clinicians consider these antibiotics, and close
monitoring must occur during the therapy.
Beyond nephrotoxicity, other toxicities associated with anti-
biotic accumulation can occur. For example, b-lactam antibio-
tics 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
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
171
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.
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