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CME Information
CME Released: 02/22/2011; Valid for credit through 02/22/2012

Target Audience

This activity is intended for primary care physicians, nephrologists, critical care specialists, infectious disease specialists, and other
physicians who care for critically ill patients with AKI.

Goal

The goal of this activity is to effectively prescribe antibiotics to critically ill patients with AKI.

Learning Objectives

Upon completion of this activity, participants will be able to:

1. Analyze alterations in pharmacokinetics among critically ill patients

2. Distinguish the most important variable of renal replacement therapy in altering antibiotic concentrations
3. Evaluate effective strategies for antibiotic prescribing among critically ill patients with AKI
4. Specify how to prescribe certain antibiotics among critically ill patients

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Author(s)

Rachel F. Eyler, PharmD

Critical Care and Nephrology Research Fellow, College of Pharmacy, University of Michigan, Ann Arbor, Michigan

Disclosure: Rachel F. Eyler, PharmD, has disclosed the following relevant financial relationships:
Received research funding from: Merck & Co., Inc.; Roche.

Bruce A. Mueller, PharmD, FCCP

Professor of Pharmacy; Chair, Department of Clinical, Social and Administrative Sciences, College of Pharmacy, University of
Michigan, Ann Arbor, Michigan

Disclosure: Bruce A. Mueller, PharmD, FCCP, has disclosed the following relevant financial relationships:
Received research funding from: Cubist Pharmaceuticals; Merck & Co., Inc.; Roche
Member of the speakers' bureaus for: Amgen, Gambro, Cubist Pharmaceuticals

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Rebecca Ireland

Locum Chief Editor, Nature Reviews Nephrology

Disclosure: Rebecca Ireland has disclosed no relevant financial relationships.

CME Author(s)

Charles P. Vega, MD

Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine

Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

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Nafeez Zawahir, MD

CME Clinical Director, Medscape, LLC

Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

Sarah Fleischman

CME Program Manager, Medscape, LLC

Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

From Nature Reviews Nephrology

Antibiotic Dosing in Critically Ill Patients With
Acute Kidney Injury CME
Rachel F. Eyler, PharmD; Bruce A. Mueller, PharmD, FCCP
CME Released: 02/22/2011; Valid for credit through 02/22/2012

Abstract and Introduction

Abstract

A common cause of acute kidney injury (AKI) is sepsis, which makes appropriate dosing of antibiotics in these patients essential.
Drug dosing in critically ill patients with AKI, however, can be complicated. Critical illness and AKI can both substantially alter
pharmacokinetic parameters as compared with healthy individuals or patients with end-stage renal disease. Furthermore, drug
pharmacokinetic parameters are highly variable within the critically ill population. The volume of distribution of hydrophilic agents
can increase as a result of fluid overload and decreased binding of the drug to serum proteins, and antibiotic loading doses must
be adjusted upwards to account for these changes. Although renal elimination of drugs is decreased in patients with AKI, residual
renal function in conjunction with renal replacement therapies (RRTs) result in enhanced drug clearance, and maintenance doses
must reflect this situation. Antibiotic dosing decisions should be individualized to take into account patient-related, RRT-related, and
drug-related factors. Efforts must also be made to optimize the attainment of antibiotic pharmacodynamic goals in this population.

Introduction

Sepsis is a common cause of acute kidney injury (AKI);[1] consequently, the proper dosing of antibiotics in these patients is crucial.

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Drug dosing in critically ill patients with AKI, however, can be complex as a patient's renal function is dynamic and difficult to
quantify, their volume status also fluctuates, and drug doses need to be frequently reassessed. Pharmacokinetic studies to guide
the clinician through the complexities of drug dosing in patients with AKI have only been conducted for a limited number of
antibiotics.[2,3] Furthermore, the results of these trials might only be applicable to institutions with similar populations of patients and
those using comparable renal replacement therapy (RRT) techniques.

Antibiotic dosing decisions should take into account the individual patient's characteristics, the choice of RRT, and drug-related
factors. Critically ill patients with AKI exhibit altered pharmacokinetic parameters in response to antibiotic therapy, and interpatient
[4]
variability is high. RRTs remove drugs from the circulation, and the extent of removal is dependent not only on drug-related
properties, but also on the RRT technique employed. For each individual patient, antibiotic drug regimens must be adjusted to
optimize pharmacodynamics and maximize treatment efficacy. In this Review, we describe the characteristics that should guide
initial antibiotic dosing decisions in critically ill patients with AKI. We also discuss the need for dose adjustment to ensure that
adequate serum concentrations of antibiotics are consistently achieved despite changes in the patient's clinical status, particularly
when difficult-to-treat pathogens are implicated. We focus on the role of evidence-based antibiotic dosing in attaining
pharmacodynamic targets in patients requiring RRT for AKI.

Pharmacokinetic Alterations

Critically ill patients with AKI often exhibit different pharmacokinetic profiles in response to drug treatment compared with healthy
individuals or patients with end-stage renal disease (ESRD).[2,4] The AKI population is heterogeneous, and, consequently,
pharmacokinetic parameters can be quite variable. Generally, the pharmacokinetic changes can be categorized as alterations in
absorption, distribution, metabolism, and elimination.

Altered Absorption

Oral drug absorption may be altered by gastrointestinal dysmotility in critically ill patients. Dysmotility can develop as a result of
decreased perfusion of the gut, particularly if the patient is taking vasoconstrictive drugs.[4,5] To ensure adequate drug exposure,
intravenous antibiotics should be used whenever possible, although medications are sometimes switched from intravenous to oral
administration for economic reasons. Interestingly, intestinal absorption of certain drugs is increased during renal failure; findings
from animal models indicate that this effect might relate to an accumulation of uremic molecules, which cause deterioration of the
integrity of the intestinal mucosa.[6] For example, the bioavailability of a 37.5 mg/kg intraintestinal dose of propranolol increased
from 54.7% in healthy control rats to 81.4% in rats with cisplatin-induced acute renal failure.[6] Although interesting, this concept has
yet to be studied in humans.

The enteral feeding status of a patient is tied to some important considerations that affect oral drug absorption. A critically ill
individual who does not receive enteral feeding will develop intestinal atrophy in as little as 3 days,[7] and their gut mass may
decrease by 50% within 7 days.[5] These intestinal changes could alter drug absorption, although this hypothesis has not been fully
investigated. Enteral feeding improves blood flow to the digestive tract, and should be used wherever feasible to maintain the
integrity and viability of the gut.[5] Enteral feeding itself, however, can affect drug absorption. Commercial enteral feeds decrease
the absorption of many fluoroquinolone and tetracycline antibiotics.[8-10] For example, in a study of 13 healthy volunteers,
coadministration of one such enteral feed decreased the average bioavailability of a 750 mg oral dose of ciprofloxacin by 72%.[10]
Critically ill patients also often receive H2-receptor antagonists or proton pump inhibitors, which raise the pH of the stomach and
can interfere with the absorption of weak bases that require a strongly acidic environment for absorption.[4] When 200 mg of
itraconazole (a weak base) was orally administered to 12 healthy patients with famotidine-induced hypochlorhydria, peak drug
concentrations were decreased by 52.9% compared with values obtained in the absence of famotidine.[11]

Altered Distribution

The volume of distribution is an estimate of the extent to which a drug will migrate into extravascular tissues, and is one of the most
striking sources of pharmacokinetic variability in critically ill patients with AKI. Sepsis can lead to the development of endothelial
damage and increased capillary permeability, which cause displacement of fluids from the vasculature into the interstitium.[4]
Consequently, the volume of distribution of hydrophilic drugs in critically ill patients with AKI can differ substantially from that
reported in pharmacokinetic studies of healthy individuals ( Table 1 ).

Table 1. Volume of Distribution Data From Pharmacokinetic Studies in Adults

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These fluid shifts into the interstitial space can be substantial, owing to the large fluid volumes frequently given to patients with
sepsis as part of resuscitation, medication, and delivery of nutrition. Extravascular fluid gains can be even more marked in patients
who have a decreased urine output secondary to AKI. In a review of data on 81 critically ill adults receiving continuous RRTs, 38
patients (47%) had ≥10% fluid-related gains of body weight and 13 patients (16%) gained ≥20% of their body weight at the time of
starting RRT.[12] These fluid-related weight gains correlated closely with increased mortality. Fluid overload can lead to hypoxia and
the need for mechanical ventilation, as well as impaired cardiac function.[13] Furthermore, an increase in fluid volume can dilute
serum creatinine concentration, resulting in inappropriately low measurements, and thus delay the diagnosis of AKI and initiation of
RRT.[12,14]

Another possible contributor to the poor outcomes associated with fluid overload could be undertreatment with antibiotics. Just as
the capillary leakage associated with sepsis can increase the volume of distribution of creatinine,[15] it can also increase the volume
of distribution of hydrophilic antibiotics, such as aminoglycosides, β-lactams, and glycopeptides.[16] This increased volume of
distribution could lead to subtherapeutic plasma concentrations of these agents. The volume of distribution of gentamicin is 0.48
l/kg in patients with hyperdynamic sepsis, compared with 0.29 l/kg in a control group of nonseptic postoperative patients.[17]
Factors associated with an increased volume of distribution were identified as increased severity of illness, as calculated by the
Acute Physiology Score, and a high cardiac index. Another study of gentamicin pharmacokinetics in 14 critically ill patients with AKI
receiving extended daily dialysis (mean APACHE [Acute Physiology and Chronic Health Evaluation] III score of 98) reported an
even larger volume of distribution of 0.55 l/kg.[18] These increased volumes of distribution must be 'filled' with drug if therapeutic
serum concentrations are to be achieved. Consequently, initial gentamicin doses must be adjusted upwards to account for the
increased volumes of distribution associated with sepsis, fluid overload, and AKI. The results of these studies [17,18] indicate that,
for some critically ill patients with AKI and fluid overload, gentamicin loading doses might need to be doubled to attain therapeutic
serum concentrations simply because of their altered volume of distribution.

As the patient's clinical status improves and the degree of tissue edema decreases, the volume of distribution of gentamicin can
decline dramatically within days, and drug dosages should be adjusted to account for this change. Triginer et al.[19] measured the
gentamicin volume of distribution in 40 critically ill patients with suspected or confirmed sepsis owing to a Gram-negative bacterial
infection on day 2 of therapy (after aggressive fluid resuscitation), and then again on day 7 of therapy. The volume of distribution
decreased from 0.43 l/kg to 0.29 l/kg (P <0.001) and the required gentamicin dosage decreased from 5.14 mg/kg per 24 h to 3.98
mg/kg per 24 h (P <0.001), despite the patients' renal function remaining fairly stable.[19] These ongoing changes should also be
expected in patients with AKI: not only will a patient's capillary leakage status change, but after the initiation of RRT, fluid overload
will be gradually corrected, and drug doses need to be reduced accordingly.

The increased incidence of obesity has presented another noteworthy source of pharmacokinetic variability, because volumes of
distribution can be vastly different for a patient weighing 70 kg compared with a patient who is twice that weight. In obese patients
(BMI ≥30 kg/m 2), lipophilic antibiotics (such as fluoroquinolones) tend to have a larger total volume of distribution, although when

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the totals are corrected to take body weight into account, the volume of distribution per kg is lower than that in patients who are not
obese.[20] As plasma volume correlates with body weight, obese patients usually also have higher total volumes of distribution for
hydrophilic drugs, although the increases might be less pronounced than those seen with lipophilic drugs.[21] To account for the
pharmacodynamic changes associated with obesity, drugs should always be adjusted for body weight, rather than administering a
standard dose to all patients.[21] This consideration is especially true for loading doses, which must be able to fill the volume of
distribution.

Pharmacokinetic studies in obese individuals often focus on identifying a surrogate marker (such as total, adjusted, or lean body
weight) that will most accurately predict the volumes of distribution seen in the study population. The surrogate marker of choice
seems to be total weight for vancomycin and daptomycin, and adjusted body weight for aminoglycosides.[20] When possible, drug
monitoring should be used to guide subsequent doses.[20] For drugs that do not have weight-based dosing recommendations,
obese patients should usually receive doses toward the top end of the dosing range.

Finally, critically ill patients with AKI often have increased antibiotic volumes of distribution owing to decreased binding of the drug
to serum proteins. This reduction in protein binding could be due to decreased serum albumin synthesis or increased extracellular
shifts of serum proteins.[22] In addition, studies conducted in patients with ESRD have indicated that decreased protein binding
could result from the accumulation of certain uremic molecules that can bind to these proteins and displace the drug from its
binding site.[23] In patients with advanced stages of AKI, uremic molecules could also contribute to decreased protein binding. The
extent of the decrease in protein binding in critically ill patients with AKI is difficult to quantify, however, as therapeutic drug
monitoring in the hospital setting usually involves measurement of total rather than free drug concentrations. Furthermore, the
amount of protein-bound drug may be dependent on its concentration in serum, and not remain constant throughout the dosing
interval.[24]

Altered Metabolism

Although they have rarely been studied directly, alterations in the metabolism and nonrenal clearance of antibiotics have been
observed in patients with AKI. The metabolism of drugs that are largely extracted by the liver, such as β-blockers and midazolam,
is highly influenced by hepatic blood flow.[4] In patients with advanced sepsis, the clearance of these drugs can be reduced as
hepatic blood flow decreases. In patients with hyper-dynamic sepsis, however, hepatic metabolism may be preserved as blood is
shunted to the liver and other vital organs.[4] Vasoconstrictive drugs, such as phenylephrine, norepinephrine, epinephrine, and
dopamine, can also decrease hepatic blood flow, although the extent of this effect varies according to the specific agent used.[4,25]
Metabolic enzyme activity in the liver also seems to be decreased in patients with AKI.[26] Although some animal models of AKI
demonstrate variability in the expression of a number of cytochrome P450 isoenzymes, human data are currently lacking.[26]
Several drugs that are non-renally eliminated have recognized alterations in their hepatic clearance, including imipenem,
meropenem, and vancomycin. In anuric patients with AKI, the total clearance rate of imipenem is 90-95 ml/min—considerably lower
than that reported in patients with normal renal function (130 ml/min), but higher than that reported in patients with ESRD (50
ml/min). These results indicate that hepatic metabolism of imipenem is relatively preserved in patients with AKI compared with
those with ESRD.[26,27] Similarly, the rate of clearance of meropenem is greater in patients with AKI than in those with ESRD
(40-60 ml/min versus 30-35 ml/min).[26,28,29] The same pattern of comparatively preserved nonrenal clearance in patients with AKI
is found with vancomycin; the clearance rate of this drug in patients with normal renal function is 40 ml/min, compared with 15
ml/min in patients with AKI, and 5 ml/min in patients with ESRD. However, as AKI persists, clearance of vancomycin may decline to
the rate seen in ESRD.[26,30] Nonhepatic elimination pathways can also account for increased drug clearance. Ciprofloxacin
undergoes transintestinal excretion, which, in patients with renal failure, may represent a compensatory clearance mechanism that
prevents accumulation of this drug.[31,32]

Altered renal Elimination

Sepsis-induced AKI is not only associated with decreased glomerular filtration by the kidney, but also with impairment of tubular
secretion and reabsorption.[33-35] These changes can influence drug dosing in ways that are not always recognized. β-lactams, for
example, are thought to be excreted by the organic anionic transporter type 1 and, at least in theory, dosing methods that take into
account the decrease in glomerular filtration but not decreased transport could produce a larger than anticipated drug exposure.[35]
The reabsorption of fluconazole, which can be substantial in patients with normal renal function, is decreased in critically ill patients
with AKI. In many cases, these patients might require unadjusted doses of fluconazole, or even higher doses than are required for
patients with normal renal function.[36,37]

A critically ill patient with AKI usually has some residual renal function, which may change dynamically along with the patient's

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clinical status. For some renally eliminated drugs, patients with residual renal function will require higher antibiotic doses than their
anuric counter-parts.[38] The patient's urine output should, therefore, be monitored closely, and drug doses adjusted upwards as
renal function returns. If a patient is taking renally eliminated antibiotics that permit therapeutic drug monitoring, such as
aminoglycosides or vancomycin, an increase in the clearance of these drugs can also signal the return of renal function and the
possible need for upward adjustment of other renally eliminated drugs for which monitoring might not be available.

Elimination by RRT

In general, drugs that are primarily renally eliminated, with a small molecular weight,[39] small volume of distribution (<1 l/kg), and
low degree of protein binding, are likely to be removed by RRTs.[40] Although decreased protein binding (which is often exhibited
by critically ill individuals) increases the volume of distribution of a drug, elimination is also increased, because more free drug is
available to be removed by the kidney or RRTs. Although exceptions exist to this general rule,[41] the percentage of unbound drug
can be used as a rough estimate of the RRT extraction coefficient.[42] However, when calculating the extraction coefficient,
clinicians should use protein binding values reported in critically ill individuals rather than those from healthy persons.

[43]
RRT techniques vary widely, and each variation can also affect drug clearance. Diffusive therapies (such as intermittent
hemodialysis and continuous venovenous hemodialysis) and convective therapies (such as continuous venovenous hemofiltration)
both efficiently remove small solutes, but convective therapies are superior with regard to the removal of solutes with large
molecular weights.[44,45] Furthermore, hemofilters themselves vary by material, surface area, pore size, water permeability, and the
efficiency of removal of low-molecular-weight and mid-molecular-weight solutes. High-flux hemofilters have increased permeability
to mid-molecular-weight molecules and remove considerably more drug than low-flux filters do.[46-48] Almost all currently used
continuous RRTs utilize high-flux hemofilters; however, the hybrid RRTs used to treat AKI (which typically involve slow,
low-efficiency daily dialysis or extended daily dialysis) sometimes utilize low-flux hemofilters.[49,50] When low-flux filters are used,
drug clearances may differ (sometimes dramatically) from those achieved with high-flux membranes. An additional issue related to
antibiotic clearance is drug adsorption to the filter. Polyacrylonitrile filters are particularly associated with this phenomenon, although
the extent of adsorption is difficult to quantify.[51,52]

Another technical consideration that affects drug clearance occurs with continuous RRTs that utilize a high convective component,
such as continuous venovenous hemofiltration. The point at which fluid replacement occurs in these techniques alters drug
clearance, because dilution before filtration decreases the concentration of drug available for removal by the filter.[53,54] The
differences between predilution and postdilution modes of fluid replacement are predictable, and can be easily calculated from the
rates of blood flow, fluid replacement, and clearance.[2]

In general, the most important RRT-related factor affecting drug removal is effluent volume, which is determined by both flow rate
and therapy duration.[2] Effluent rates vary between institutions, and contemporary effluent flow rates are often much higher than
those used even 10 years ago.[55] Consequently, drug-dosing recommendations for use with continuous RRT published in the
past might not apply today. Clinicians prescribing RRTs at high effluent rates should use higher antibiotic doses than those
recommended in guidelines developed for low flow rates. For example, the 2007 edition of Drug Prescribing in Renal Failure
assumes a continuous RRT effluent rate of 2 l/h.[56] Thus, these dosing recommendations may not be applicable if the patient is
being treated with substantially lower or higher effluent rates.

Pharmacodynamic Considerations

Successful antibiotic treatment of a patient with AKI requires not only consideration of pharmacokinetic profiles, but also careful
attention to pharmacodynamics. The study of pharmacodynamics, as it applies to antibiotics, seeks to link measures of drug
exposure (such as peak and trough serum concentrations, and area under the serum concentration-time curve [AUC]) to
bactericidal activity. For example, most antibiotics fall into one of two pharmacodynamic categories: concentration-dependent or
time-dependent. In general, for concentration-dependent antibiotics, a favorable high ratio of the peak serum concentration to the
minimum inhibitory concentration (MIC, the minimum concentration required to inhibit bacterial growth) is best associated with
clinical success, whereas for time-dependent antibiotics, the percentage of the dosing interval spent above the MIC is the most
important parameter to maximize ( Table 2 ).[57,58] A third parameter, AUC/MIC, is closely related to the other two parameters, and
is sometimes most predictive of clinical success for antibiotics of either type ( Table 2 ). However, an antibiotic's pattern of
bactericidal activity (concentration-dependent or time-dependent) is not the sole determinant of which pharmacodynamic parameter
is most predictive of efficacy. The presence and duration of any postantibiotic effect—defined as the period between antibiotic
exposure and the point at which the surviving microbes begin to multiply—is also important.[57] Decreased drug elimination as a
result of AKI, increased volume of distribution from fluid overload and decreased protein binding, and increased clearance owing

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to RRTs not only affect antibiotic pharmacokinetics, but also influence whether optimal pharmacodynamic targets can be met.

Table 2. Pharmacodynamic Measures Linked to Antibacterial Activity*

Table 2. Pharmacodynamic Measures Linked to Antibacterial Activity*

Concentration-dependent Antibiotics

Desirable pharmacodynamic characteristics for concentration-dependent antibiotics are high peak concentrations that optimize
bactericidal activity, followed by low troughs that minimize toxic effects. This knowledge can help guide dosing decisions. However,
owing to the increased volume of distribution in critically ill patients with AKI, the high peaks and low troughs that are desirable for
concentration-dependent antibiotics can be difficult to attain with usual doses, as illustrated by the following examples.

Daptomycin is a concentration-dependent lipopeptide antibiotic primarily eliminated by the kidneys. Trough plasma concentrations
of daptomycin above 24.3 µg/ml have been associated with an increased risk of elevations in creatine phosphokinase levels, a

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serum marker of myopathy.[59] In critically ill patients with AKI who were receiving continuous RRT at a mean effluent rate of 33
ml/kg/h, the pharmacokinetics of a single daptomycin dose of 8 mg/kg was studied during the subsequent 48 h.[60] This dose was
selected based on the results of an in vitro investigation carried out by the same group.[61] The team used the serum
concentration-time data collected from each patient to generate a pharmacodynamic model, in which they simulated the effects of
daptomycin dosing regimens of 8 mg/kg every 48 h and 4 mg/kg every 24 h.[60] The 8 mg/kg dose every 48 h not only achieved
higher peaks at steady state (88.8 µg/ml versus 53.0 µg/ml), but also produced lower troughs (7.2 µg/ml versus 12.3 µg/ml). These
findings indicate that the 8 mg/kg every 48 h regimen not only optimizes pharmacodynamic goal attainment, but could, furthermore,
reduce the risk of myopathy.

Aminoglycoside antibiotics also have concentration-dependent activity, and peak:MIC ratios of 10-12 are associated with the
greatest bacterial killing effect.[58] Prolonged courses of treatment and elevated trough levels of these agents are associated with
nephrotoxic and ototoxic effects.[62] However, to fully optimize the concentration-dependent pharmacodynamic profile of amikacin
in patients with sepsis who have an increased volume of distribution, initial doses that are higher than the conventional 15 mg/kg
might be required. Amikacin doses of 15 mg/kg and 20 mg/kg have produced sub-optimal mean peak concentrations of 33.5 mg/l
and 33.8 mg/l, respectively, in critically ill patients with preserved renal function.[63,64] Use of a loading dose of aminoglycosides, to
ensure an adequate initial concentration peak in these often fluid-overloaded patients, followed with close drug therapeutic
monitoring of serum concentrations, will help with pharmacodynamic goal attainment. Aggressive treatment to optimize
pharmacodynamic parameters is particularly warranted in the presence of pathogens that have a high MIC to the antibiotic, or in
patients with sepsis and large accumulations of extravascular volume.

The use of RRTs may aid pharmacodynamic goal attainment for concentration-dependent antibiotics by preventing toxic effects
associated with prolonged high levels of antibiotic. For example, the drug clearance produced by continuous RRTs could help to
prevent the persistence of high levels of aminoglycosides after a loading dose. In patients managed with intermittent hybrid RRTs,
some researchers have suggested that the antibiotic dose should be scheduled before dialysis, so that drug removal by the RRT
can be used to avoid toxic effects. Roberts et al.[18] prospectively collected pharmacokinetic data and then used population
modeling to evaluate several gentamicin dosing regimens in patients receiving extended daily hemodiafiltration, and concluded that
6 mg/kg of gentamicin administered 30 min before RRT with dosing repeated every 48 h was the optimal regimen for achieving the
pharmacodynamic goals (defined as a peak serum concentration of 10 mg/l, and trough below 1.5 mg/l).

The use of RRT to meet pharmacodynamic goals of concentration-dependent antibiotics is not without limitations. A major problem
is the variability of RRT treatments, which can be interrupted for a variety of reasons in the intensive care setting. When Roberts et
al.[18] investigated the effect of RRT on gentamicin pharmacodynamic goal attainment, the assumption was made that extended
daily hemodiafiltration would last 10 h—although in their study clotting and other factors limited the typical treatment duration to
approximately 6 h. If the timing of antibiotic doses is intended to be coordinated with that of RRT, dialysis must be performed at the
same time every day. The investigators of a pharmacokinetic study of daptomycin in patients undergoing hybrid RRT (blood and
dialyzate flows of 160 ml/min; 8 h treatment) recommended a daily dose of 6 mg/kg, but emphasized that daptomycin must be
given 8 h before the hemodialysis session.[65] In institutions that employ similar hybrid dialysis techniques, if daptomycin is given
less than 8 h before dialysis, increased drug removal will lower the AUC and the drug might be underdosed. If daptomycin is
administered more than 8 h before dialysis, drug clearance will be decreased and the risk of toxic effects increased.

Time-dependent Antibiotics

For time-dependent antibiotics, such as β-lactams, maintaining serum concentrations above the MIC optimizes therapeutic efficacy
and prevents the development of microbial drug resistance.[57] Unlike the disadvantages experienced with having to attain both
high peaks and low troughs for concentration-dependent antibiotics, the reduced renal function in patients with AKI helps to prevent
inadequate serum concentrations of time-dependent antibiotics. RRTs that run at high effluent rates, however, can remove
substantial amounts of β-lactams.[32] Several modified methods of administration, which include prolonged intermittent infusions,
low-dose with short-interval regimens, and continuous infusions, have been developed to optimize the bactericidal activity of
β-lactams.[66] Continuous infusions are of particular interest for use in patients on RRTs, as they could theoretically be adjusted to
administer the drug at a similar rate to that at which it is removed by dialysis.

Examples of β-lactam antibiotics for which continuous infusions have been tested in patients on continuous RRT include
meropenem and ceftazidime. Langgartner et al.[67] compared an intermittent meropenem regimen (1 g infused every 12 h) with a
continuous regimen (500 mg loading dose followed by an infusion of meropenem 2 g over 24 h) in 12 critically ill patients receiving
continuous hemodiafiltration at an effluent rate of 25 ml/kg/h. The continuous infusion maintained steady state serum
concentrations of 18.6 mg/l, and produced an AUC similar to that of the intermittent dosing regimen. Continuous infusions of

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ceftazidime have also been investigated in patients undergoing continuous RRT; a 2 g loading dose and 3 g infusion over 24 h
produced mean steady state concentrations of 33.5 mg/l, effectively maintaining the level of antibiotic at >4 times the MIC (4 mg/l)
required to eliminate susceptible pathogens for 100% of the dosing interval.[68] Continuous infusions of β-lactams have not been
investigated with hybrid RRT. Such continuous infusions, with an administration rate adjustment depending on whether the hybrid
RRT is running or not, might prove useful. When continuous infusions of β-lactams are not available, an unadjusted loading dose,
followed by small, frequent maintenance doses is thought to maintain serum concentrations above the MIC more effectively than
large doses given at extended intervals. The development and implementation of clinically useful assays for therapeutic drug
monitoring could alleviate some of the difficulties with dosing of β-lactams. Roberts et al.[69] performed twice-weekly therapeutic
drug monitoring for β-lactams in 236 critically ill patients who were prescribed this agent. Of the 36 (15.3%) patients in the study
who were receiving continuous venovenous hemodiafiltration (blood flow 200 ml/min, dialyzate flow rate 1 l/h, and ultra-filtration rate
of 2 l/h), 25 required dose adjustments, among whom seven required dose increases after their first monitoring session.[69]
Unfortunately, therapeutic drug monitoring for β-lactams is currently unavailable to most clinicians.

Individual Drug-dosing Strategies

Individual patient-specific (body weight and volume status), RRT-specific (effluent rate, dialyzer flux, and mode of fluid
replacement), and drug-specific (pharmacokinetic and pharmacodynamic) characteristics should guide initial dosing decisions, and
doses should be adjusted continually as a patient's clinical status changes. Drug dosing in patients with AKI can, therefore, be
quite complex.

Practical Approaches to Drug Dosing

In nearly all situations, a loading dose that will achieve the target serum concentrations based on the expected volume of
distribution should be given.[70] No adjustments need to be made for residual renal function or RRT for this initial dose. Therapeutic
drug monitoring should subsequently be used whenever possible, but is not available for many drugs. Among the antibiotics
commonly used in the intensive care unit setting ( Table 3 ), therapeutic drug monitoring is available only for aminoglycosides and
vancomycin in most hospitals, and in these two cases monitoring should, therefore, be used to guide dosing. For hybrid RRTs,
additional attention should be paid to the timing of drug administration relative to that of the dialysis treatment. Monitoring should
also take into account that some drugs exhibit rebound, that is, an increase in drug concentrations in the blood that can occur when
RRT ends and drug sequestered in the tissues redistributes back into the blood.[70]

Table 3. Dosing Recommendations for Selected Intravenous Antibiotics in Patients on Continuous RRT

Consulting the literature would be the most evidence-based method of dose adjustment, as long as the clinician ensures that their
patient's clinical situation is comparable to that of the population of patients and the RRT modalities studied. Drug-dosing
recommendations for continuous RRT are available, although the conclusions vary according to which source is consulted ( Table

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3 ). Before using these recommendations, it is crucial to verify that they are up to date and based on dialyzate, ultrafiltrate, and
effluent rates that are similar to those being utilized. Our institution, for example, often employs dialyzate flow rates of at least 2 l/h
and, consequently, we tend to use higher antibiotic doses than are recommended in some of these published sources.

Table 3. Dosing Recommendations for Selected Intravenous Antibiotics in Patients on Continuous RRT

Dosage Adaptations

A review of the dosing techniques aimed at individualizing antibiotic therapy in patients on continuous RRT has been published.[71]
One commonly used drug-dosing technique involves calculating the total creatinine clearance rate by adding any estimated
residual renal creatinine clearance to the expected extracorporeal creatinine clearance. The extracorporeal creatinine clearance
rate can be assumed to be approximately equivalent to the dialyzate, ultrafiltrate, or effluent rate, and medication dosing guidelines
specified for the total creatinine clearance can be used to guide dose selection. In most patients receiving conventional continuous
RRT, most drugs will fall within the 25-50 ml/min creatinine clearance range. This method is useful, although it assumes that drugs
only undergo glomerular filtration, not tubular secretion or reabsorption.[70] For drugs that do undergo tubular secretion, this method
could lead to increased drug exposures, and in patients with impaired reabsorption, underdosing can potentially occur. Several
equations have been developed to adjust drug doses, although they do not take a drug's pharmacodynamics into account.[72,73]

Barriers to Effective Dosing

With a variety of factors influencing drug removal in a particularly vulnerable population, a 'one dose fits all' approach is not
appropriate for all situations. Taking every one of the factors discussed in this Review into account may, however, be time
consuming and impractical for the intensive care unit clinician. Further complicating the issue is the variability of how RRT is
delivered, and the lack of sufficient pharmacokinetic and pharmacodynamic data provided in the drug manufacturer's prescribing
information.[74] Hybrid therapies carry the added difficulty of ensuring that medications are given with an optimal timing in relation to
RRT. Owing to the variation in intermittent, hybrid, and continuous RRT techniques, published pharmacokinetic trials may lack
generalizability. Furthermore, published trials are often missing information that is vital to making appropriate clinical interpretations.
Less than 90% of pharmacokinetic studies in patients undergoing continuous RRT actually specified the continuous RRT dose
used in their respective populations, and only 58% of studies in patients on continuous venovenous hemodialysis specified
whether fluid replacement was given before or after filtration.[75] Without such essential information, the translation of published
continuous RRT studies to the clinical setting is very difficult.

The review by Li et al.[75] establishes an ideal data set that should published in all pharmacokinetic studies conducted in patients
receiving RRTs. Efforts to convince drug manufacturers to conduct trials in critically ill patients receiving RRTs, as well as to update
drug-dosing recommendations in package inserts that were developed using outdated RRT techniques, will also improve the
quality of the pharmacokinetic data available. Population modeling could be a useful tool to improve the interpretability of the results
of pharmacokinetic trials. Pharmacodynamic targets should also be tied to the pharmacokinetic data in a way that is easily

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interpretable.

Conclusions

With the large variability in pharmacokinetic parameters reported in critically ill patients, increased antibiotic dosing is essential to
ensure that adequate serum concentrations are achieved, particularly when difficult-to-treat pathogens are implicated. Until
therapeutic monitoring for a wider selection of antibiotics is more readily available, much of antibiotic dosing will continue to be
based on estimates. Nonetheless, educated, evidence-based dosing can make a large difference in attaining pharmacodynamic
targets, preventing resistance, and optimizing patient outcomes.

Key Points

Altered drug pharmacokinetics in critically ill patients with acute kidney injury (AKI) and heterogeneous renal replacement
therapy (RRT) techniques in intensive care units preclude standardized antibiotic dosing
Most critically ill patients with AKI exhibit altered antibiotic pharmacokinetics that necessitate increased doses in spite of
decreased renal clearance, particularly when serious infections are implicated
Drug dosing decisions must take into account pharmacodynamic as well as pharmacokinetic considerations
Clinicians should compare their RRT protocols to those in published guidelines and ensure that their recommendations are
applicable to the individual patient's clinical situation
Hybrid RRTs require the same antibiotic dosing alterations as do continuous RRTs, but for hybrid therapies the dose timing
must also be considered

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C. P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of
the Medscape, LLC-accredited continuing medical education activity associated with this article.

Reprint Address
Department of Clinical, Social, and Administrative Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109-1065,
USA Bruce A. Mueller, PharmD, FCCP muellerb@umich.edu

Author contributions
R. F. Eyler and B. A. Mueller contributed equally to all aspects of the manuscript.

Nat Rev Nephrol. 2011;7(4):1-10. © 2011 Nature Publishing Group

This article is a CME certified activity. To earn credit for this activity visit:
http://www.medscape.org/viewarticle/737334

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