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This article is a CME certified activity. To earn credit for this activity visit:

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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 ef fectively prescribe antibiotics to critically ill patients with AKI.

Learning Objectives

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

Analyze alterations in pharmacokinetics among critically ill patients1.

Distinguish the most important variable of renal replacement therapy in altering antibiotic concentrations2.

Evaluate effective strategies for antibiotic prescribing among critically ill patients with AKI3.

Specify how to prescribe certain antibiotics among critically ill patients4.

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Kidney Injury: Antibiotic Dosing in Critically Ill Patients (printer-fr... http://www.medscape.org/viewarticle/737

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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 disc losed 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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From Nature Reviews Nephrology

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 f luid 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 dec isions 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.

Editor(s)

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.

CME Reviewer(s)

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.

Antibiotic Dosing in Critically Ill Patients WithAcute Kidney Injury CMERachel F. Eyler, PharmD; Bruce A. Mueller, PharmD, FCCP

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


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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 dif ficult to

quantify, their volume status also f luctuates, and drug doses need to be frequently reassessed. Pharmacokinetic studies to guide

the clinician through the complexities of drug dosing in patients with AKI have only been conducted for a limited number of

antibiotics.[2,3]

Furthermore, the results of these trials might only be applicable to institutions with similar populations of patients and

those using comparable renal replacement therapy (RRT) techniques.

Antibiotic dosing decisions should take into account the individual patient's characteristics, the choice of RRT, and drug-related

factors. Critically ill patients with AKI exhibit altered pharmacokinetic parameters in response to antibiotic therapy, and interpatient

variability is high.[4]

RRTs remove drugs f rom 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 eff icacy. 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 of ten 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 o ral 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 f low 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 ciprof loxacin by 72%.[10]

Critically ill patients also of ten 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 f rom 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% f luid-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 d istribution of hydrophilic antibiotics, such as aminoglycosides, -lactams, and glycopeptides.

[16]

This increased volume ofdistribution 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 pos toperative 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 candecline dramatically within days, and drug dosages should be adjusted to account for this change. Trigineret 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 f luid 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

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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 p lasma 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 f ill 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 d istribution 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 diff icult 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 -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 f low decreases. In patients with hyper-dynamic sepsis, however, hepatic metabolism may be preserved as b lood 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 specif ic 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/minconsiderably 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. -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 f iltration 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 (

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

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 diff icult 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 g/ml have been associated with an increased risk of elevations in creatine phosphokinase levels, a

Table 2. Pharmacodynamic Measures Linked to Antibacterial Activity*

Table 2. Pharmacodynamic Measures Linked to Antibacterial Activity*


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serum marker of myopathy.[59]

In critically ill patients with AKI who were receiving continuous RRT at a mean eff luent 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 g/ml versus 53.0 g/ml), but also produced lower troughs (7.2 g/ml versus 12.3 g/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 ef fects

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 (def ined 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 halthough in their study clotting and other factors limited the typical treatment duration toapproximately 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 d ialysis, drug clearance will be decreased and the risk of toxic effects increased.

Time-dependent Antibiotics

For time-dependent antibiotics, such as -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 -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

-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 -lactam antibiotics for which continuous infusions have been tested in patients on continuous RRT include

meropenem and ceftazidime. Langgartneret 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 -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 -lactams are not available, an unadjusted loading dose,

followed by small, frequent maintenance doses is thought to maintain serum concentrations above the MIC more ef fectively than

large doses given at extended intervals. The development and implementation of clinically useful assays for therapeutic drug

monitoring could alleviate some of the dif ficulties with dosing of -lactams. Roberts et al.[69]

performed twice-weekly therapeutic

drug monitoring for -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 -lactams is currently unavailable to most clinicians.

Individual Drug-dosing Strategies

Individual patient-specific (body weight and volume status), RRT-specific (ef fluent 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 fo r 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]

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

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


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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

eff luent rates that are similar to those being utilized. Our institution, for example, often employs dialyzate flow rates of at least 2 l/h

and, consequently, we tend to use higher antibiotic doses than are recommended in some of these published sources.

Dosage Adaptations

A review of the dosing techniques aimed at 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 specif ied 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

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


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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 decis ions 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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Disclaimer

The material presented here does not necessarily reflect the views of Medscape, LLC, or companies that support educational programming on

www.medscape.org. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-labeluses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all

information and data before treating patients or employing any therapies described in this educational activity.

Acknowledgments

C. P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of

the Medscape, LLC-accredited continuing medical education activity associated with this article.

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 [email protected]

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



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Gilbert, D. N. (Ed.) The Sanford Guide to Antimicrobial Therapy40th

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