Clin Pharmacokinet 2005; 44 (10): 1009-1034REVIEW ARTICLE 0312-5963/05/0010-1009/$34.95/0

2005 Adis Data Information BV. All rights reserved.

Antimicrobial Therapy in CriticallyIll PatientsA Review of Pathophysiological Conditions Responsible forAltered Disposition and Pharmacokinetic Variability

Federico Pea,1 Pierluigi Viale2 and Mario Furlanut1

1 Department of Experimental and Clinical Pathology and Medicine, Medical School, Instituteof Clinical Pharmacology and Toxicology, University of Udine, Udine, Italy

2 Department of Medical and Morphological Research, Medical School, Clinic of InfectiousDiseases, University of Udine, Udine, Italy

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10091. General Principles for Appropriate Prescription of Antimicrobials in Critically Ill Patients . . . . . . . . . 10102. General Intrinsic Characteristics of Antimicrobials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10133. Influence of Different Pathophysiological Mechanisms in Altering Disposition of Antimicrobials in

Critically Ill Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10144. Pathophysiological Conditions Altering Pharmacokinetics of Antimicrobials in Critically Ill

Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10154.1 Causes of Increased Volume of Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1015

4.1.1 Oedema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10154.1.2 Fluid Therapy or Parenteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10194.1.3 Pleural Effusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10204.1.4 Ascites and Peritoneal Exudate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10204.1.5 Mediastinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10214.1.6 Indwelling Post-surgical Drainages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10214.1.7 Hypoalbuminaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1021

4.2 Causes of Enhanced Renal Clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10224.2.1 Burns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10224.2.2 Hyperdynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10234.2.3 Haemodynamically Active Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10244.2.4 Acute Leukaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10254.2.5 Drug Abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1026

4.3 Causes of Reduced Renal Clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10264.3.1 Renal Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10264.3.2 Muscle Wastage and Long-Term Bedridden Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1027

5. The Importance of a Multidisciplinary Team in Tailoring Antimicrobial Therapy in Critically IllPatients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1027

6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1029

Antimicrobials are among the most important and commonly prescribed drugsAbstractin the management of critically ill patients. Selecting the appropriate antimicrobialat the commencement of therapy, both in terms of spectrum of activity and dose

1010 Pea et al.

and frequency of administration according to concentration or time dependency, ismandatory in this setting. Despite appropriate standard dosage regimens, failureof the antimicrobial treatment may occur because of the inability of the antimicro-bial to achieve adequate concentrations at the infection site through alterations inits pharmacokinetics due to underlying pathophysiological conditions.

According to the intrinsic chemicophysical properties of antimicrobials,hydrophilic antimicrobials (β-lactams, aminoglycosides, glycopeptides) have tobe considered at much higher risk of inter- and intraindividual pharmacokineticvariations than lipophilic antimicrobials (macrolides, fluoroquinolones, tetracy-clines, chloramphenicol, rifampicin [rifampin]) in critically ill patients, withsignificant frequent fluctuations of plasma concentrations that may require signifi-cant dosage adjustments. For example, underexposure may occur because ofincreased volume of distribution (as a result of oedema in sepsis and trauma,pleural effusion, ascites, mediastinitis, fluid therapy or indwelling post-surgicaldrainage) and/or enhanced renal clearance (as a result of burns, drug abuse,hyperdynamic conditions during sepsis, acute leukaemia or use of haemodynami-cally active drugs). On the other hand, overexposure may occur because of a dropin renal clearance caused by renal impairment. Care with all these factorswhenever choosing an antimicrobial may substantially improve the outcome ofantimicrobial therapy in critically ill patients. However, since these situations mayoften coexist in the same patient and pharmacokinetic variability may be unpre-dictable, the antimicrobial policy may further benefit from real-time application oftherapeutic drug monitoring, since this practice, by tailoring exposure to theindividual patient, may consequently be helpful both in improving the outcome ofantimicrobial therapy and in containing the spread of resistance in the hospitalsetting.

1. General Principles for Appropriate icies for their wise use should be accurately definedPrescription of Antimicrobials in in these settings.[5]

Critically Ill Patients It is worth noting that the inappropriate use ofantimicrobials may cause therapeutic failure orCritically ill patients, especially when admitteddelayed clinical response in the individual patient,to intensive care units (ICUs), are at very high riskand at the same time antimicrobial exposure mayof developing severe nosocomial infections, withcontribute towards promoting the colonisation andincidence rates about 5- to 10-fold higher than inspread of resistant pathogens in the ICU.[6]

general medical wards.[1,2] In the EPIC (EuropeanLooking at the recent past, it should not be over-Prevalence of Infection in Intensive Care) study,

looked that the selective antimicrobial pressureVincent et al.[1] reported a prevalence for nosocomi-caused by the extensive use of a given class ofal infections in ICUs of 20.6%, about half of whichantimicrobials was often chronologically correlated(46.9%) were pneumonia, while other studies have

quoted incidence rates ranging between 9% and with the proliferation of resistant strains. Historical-37%, these differences being mainly related to dif- ly, this occurred in the 1960s with methicillin-ferent inclusion criteria of the studied populations.[3] resistant Staphylococcus aureus, in the 1980s with

β-lactamase-producing Gram-negative bacteria,[7] inAntimicrobials are consistently among the mostthe early 1990s with vancomycin-resistant entero-important and commonly prescribed drugs in the

management of ICU patients,[4] and appropriate pol- cocci, in the late 1990s with glycopeptide intermedi-

2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (10)

Disposition of Antimicrobials in Critically Ill Patients 1011

ate sensitive S. aureus[8] and fluoroquinolone-resis- each class of antimicrobial. This recommendation istant Pseudomonas aeruginosa,[9] concluding with drawn on the basis of the integration between the inthe recent isolation of a totally vancomycin-resistant vitro susceptibility of the involved aetiological or-strain of S. aureus.[10,11] ganism (minimum inhibitory concentration [MIC])

and the in vivo pharmacokinetic indicators of quanti-Among the putative causes of failure of antimi-tative and qualitative drug exposure (area under thecrobial therapy, inadequate spectrum of activity ofplasma concentration-time curve [AUC], peak plas-the selected antimicrobials, presence of host immu-ma concentration [Cmax] and minimum plasma con-nosuppression, severity of underlying diseases,centration [Cmin]). Such strategy helps in preventingwithdrawal due to adverse effects, inappropriatethe colonisation and spread of resistant strains.length of therapy, emergence of breakthrough resis-

tance or development of superinfections may be Three major pharmacodynamic determinants ofrelevant. antimicrobial efficacy have been identified: the du-

ration of time the concentration exceeds the MICSelecting the appropriate antimicrobial at the(t>MIC), Cmax/MIC ratio and the AUC/MIC ratio.commencement of therapy is certainly mandatory,According to the different relative importance ofsince an inappropriate initial choice may be respon-these determinants, antimicrobial activity may besible for higher therapeutic failure and higher mor-

tality rates in the ICU setting, as definitely demon- defined as time-dependent or concentration-depen-strated in several studies.[12-15] Therefore, with the dent. Time-dependent antimicrobials whose effica-intent of ensuring broad-spectrum empirical antimi- cy is mainly related to t>MIC are β-lactams,crobial therapies, several guidelines have been de- glycopeptides and oxazolidinones. Particularly, itveloped according to pathophysiological and epide- has been shown that t>MIC must be at least 50% ofmiological features.[16-19] However, it has not to be the dosage interval to ensure standard efficacy withoverlooked that, once culture results become availa- these antimicrobials,[37,38] whereas t>MIC of 100%ble, anti-infective therapies must be narrowed in of the dosage interval should be ensured for optimalorder to preserve the most effective drugs (i.e. exposure in immunocompromised patients. Indeed,carbapenems, fluoroquinolones) and, at the same a further improvement in efficacy of time-dependenttime, avoid adverse effects and contain pharmaceu- antimicrobials has been observed when concentra-tical expenditure.[20,21] Moreover, different methods tions 4- to 5-fold greater than the MIC arefor implementing antimicrobial control (e.g. period- achieved,[39] whereas no further benefit will be ob-ic cycling of the empirically used antimicrobi- tained with higher levels. Additionally, all of theseals,[22-28] restriction of formulary,[29] antimicrobial antimicrobials (with the notable exception of theorder forms or stop order forms,[30] computerised carbapenems) exhibit valid post-antimicrobial effectsystems,[31]) have been advocated, even if conflict- (PAE) against only Gram-positive microorga-ing opinions still exist in the literature. nisms.[40] Therefore, very low trough levels should

be avoided since bacteria rapidly recover and startAlthough selecting the appropriate antimicrobialregrowing as soon as concentrations fall below thein terms of spectrum of activity is certainly theMIC. As a consequence, in order to avoid drug-freemainstay of antimicrobial therapy in critically illintervals, the shorter the terminal elimination half-patients, the consistent choice of correct dosagelife (t1/2β) of the drug, the more frequent the doseregimen (in terms of both dose and frequency offractioning (from two to six times per day) must be,administration) has definitely been shown in the lastand in some situations even the application of con-10 years to be at least of the same importance intinuous intravenous infusion may be beneficial inensuring successful clinical cure and microbiologi-improving efficacy. In fact, under the same totalcal eradication.[32-37] The dose and length of dosingdaily dosage, continuous intravenous infusioninterval should be chosen by taking into account themay represent the best mode of administering time-pharmacokinetic/pharmacodynamic relationships of

2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (10)

1012 Pea et al.

dependent antimicrobials by ensuring the highest this being a frequently neglected concern in thesteady-state concentration.[39,41,42] recent past.[33] It is well known that underexposure

in difficult-to-access sites (i.e. CNS or eye) mayConcentration-dependent antimicrobials whoseoccur because of poor tissue penetration during sys-efficacy is mainly related to the Cmax/MIC andtemic administration of standard dosages of antimi-AUC/MIC ratios are fluoroquinolones and aminog-crobial. However, more importantly, in critically illlycosides. Forrest et al.[43] were among the first topatients underexposure may also occur in un-demonstrate the usefulness of these pharmacoki-restricted accessible sites because of high inoculum,netic/pharmacodynamic parameters for fluoroqui-for example, as sometimes occur in pneumonia ornolone efficacy, showing that in patients treatedalways in endocarditis, and/or because of alteredwith ciprofloxacin for lower respiratory tract infec-pharmacokinetics of antimicrobials due to underly-tions the probability of both clinical cure and bacte-ing pathophysiological conditions.rial eradication achieved good levels when the

AUC/MIC ratio was at least 100–125. More recent- It should not be overlooked, with the exception ofly, it has been postulated that whereas this bloodstream infections in which microorganisms arethreshold has to be considered mandatory against located in the plasma compartment, that the actualGram-negative pathogens,[33,44] an AUC/MIC ratio compartment of bacterial infection is, in most pa-of 30–40 might be sufficient against Gram-positive tients, the extracellular fluid space. Therefore, topathogens.[45,46] Moreover, several studies showed effectively treat these infections, physicians must bethat a Cmax/MIC ratio of 10–12 may ensure clinical aware of ensuring adequate concentrations not onlycure and may prevent the spreading of resistance in plasma, but also in the extracellular tissue com-with these antimicrobials.[47-50] Additionally, most

partment. Indeed, Craig[37] stated that plasma con-aminoglycosides and fluoroquinolones show valid

centrations of a drug may be predictive of interstitialPAE against both Gram-positive and Gram-negative

tissue fluid concentrations, since an equilibrium be-microorganisms,[40,51] so that sub-MIC trough levels

tween the two environments is usually achieved.at the end of the dosage interval may be allowed.[52]

Drug concentrations in plasma (or serum) are muchOn this basis, the best dosage regimen for concentra-

better predictors of interstitial fluid levels than aretion-dependent antimicrobials has to be consideredtissue homogenate concentrations in which the in-the less fractioned one according to the toxicityterstitial, intracellular and vascular compartmentspattern and length of t1/2β of each antimicrobial.are mixed together.[37]

Once-daily dosing should be preferred wheneverpossible,[53] but if this is inapplicable due to either However, a discrepancy between plasma and in-toxicity or short t1/2β, twice-daily dosing may be terstitial fluid levels of unbound drug may occur inhelpful in enabling sufficiently high plasma peaks critically ill patients, since distribution of antimicro-while ensuring the same total daily exposure. bials in tissue may be substantially impaired.[54] On

this basis, several methods have been proposed withIn applying these pharmacokinetic/pharmacody-the intent of studying target site drug distribu-namic concepts, it is important that only the un-tion in antimicrobial chemotherapy,[54] amongbound fraction of the drug should be considered as itwhich microdialysis may be considered one of theis the only one microbiologically active and able tomost promising techniques in detecting interstitialpass capillary endothelium and diffuse in tissues.fluid levels of antimicrobials, especially in soft tis-

Despite the application of appropriate standardsues, in many different clinical settings.[54]

dosage regimens, failure of the antimicrobial treat-Therefore, whenever available, data concerningment in critically ill patients may further occur be-

interstitial fluid concentrations may perhaps because of impairment of immunological function ormore informative, but if these are lacking, plasmabecause of the inability of the antimicrobial to

achieve adequate concentrations at the infection site, concentration data should be considered helpful.

2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (10)

Disposition of Antimicrobials in Critically Ill Patients 1013

• Limited volume of distribution

• Unable to passively diffuse through plasmaticmembrane of eukaryotic cells

• Inactive against intracellular pathogens

• Eliminated renally as unchanged drug

Hydrophilic antimicrobials Lipophilic antimicrobials

• β-lactams• penicillins• cephalosporins• carbapenems• monobactams

• Glycopeptides

• Aminoglycosides

• Macrolides

• Fluoroquinolones

• Tetracyclines

• Chloramphenicol

• Rifampicin (ripampin)

• Large volume of distribution

• Freely diffuse through plasmatic membrane of eukaryotic cells

• Active against intracellular pathogens

• Eliminated by hepatic metabolism

Fig. 1. Classification of antimicrobials according to their solubility and pharmacokinetic/pharmacodynamic properties.

Of note, according to the intrinsic characteristics Conversely, by freely crossing the plasmaticof antimicrobials, drug disposition in the body may membrane of eukaryotic cells, lipophilic antimicro-be affected, to a variable extent, by the different bials (e.g. macrolides, most fluoroquinolones, tetra-underlying diseases. cyclines, chloramphenicol and rifampicin [ri-

fampin]) are characterised, from a pharmacody-namic point of view, by their activity against2. General Intrinsic Characteristicsintracellular pathogens and, from a pharmacokineticof Antimicrobialspoint of view, by intracellular penetration with widedistribution and, whenever presenting low enough

Chemicophysical properties, molecular weight molecular weight, with extensive diffusion throughand degree of plasma protein binding are among the anatomical barriers (for example the blood-brainmost important intrinsic characteristics conditioning barrier).[55] On the other hand, due to their lipophilicdisposition of a given drug in the body. nature they often have to be metabolised through

Antimicrobials may be divided into two major different pathways, mainly by the liver, to eliminategroups according to their solubility: hydrophilic and them from the body. Obviously, there are somelipophilic (figure 1). Because of their inability to notable exceptions to these rules. For example,passively diffuse through the plasmatic membrane levofloxacin and gatifloxacin, two moderately lipo-of eukaryotic cells, hydrophilic antimicrobials (e.g. philic fluoroquinolones, are mainly renally ex-β-lactams, glycopeptides and aminoglycosides) are creted as antimicrobially active unchanged drugscharacterised, from a pharmacodynamic point of

(>75%),[56,57] while azithromycin, a highly lipophil-view, by their inactivity against intracellular patho-

ic macrolide, is not metabolised but almost com-gens (i.e. Legionella pneumophila, Chlamydia

pletely eliminated unchanged in the faeces throughpneumoniae) and, from a pharmacokinetic point of

biliary excretion.[58]view, either by volume of distribution (Vd) limited

According to hydrophilicity or lipophilicity, theat the extracellular space or by major renal elimina-tion as unchanged drug. pharmacokinetics of antimicrobials may be affected,

2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (10)

1014 Pea et al.

to a different extent, by the various underlying dis- als may occur because of dynamic changes in renaleases occurring in critically ill patients. function, an event frequently occurring in critically

ill patients.3. Influence of Different Conversely, the disposition of most lipophilicPathophysiological Mechanisms in antimicrobials, although only minimally or moder-Altering Disposition of Antimicrobials in ately affected by changes in renal function, mayCritically Ill Patients vary significantly according to the degree of hepatic

function.[61] However, significant reduction in theVariations occurring in the extracellular fluid

elimination of most lipophilic antimicrobials shouldcontent and/or in renal or liver function may be

occur only in the presence of advanced liver diseas-considered the most relevant and frequent

es (i.e. severe cirrhosis, acute hepatitis) conspicu-pathophysiological mechanisms possibly affecting

ously impairing hepatic blood flow and/or metabolicdrug disposition in critically ill patients. Comparedactivity.[61] On the other hand, daily fluctuations ofwith healthy volunteers or non-critically ill patients,liver function are uncommon even in critically illsome of these situations may promote significantpatients and therefore they should not be consideredchanges of drug disposition in individual patientsa major cause of daily fluctuations of concentrationseven in a brief period of hours by altering distribu-during therapy with lipophilic antimicrobials. Livertion and/or elimination processes.transplant patients during the first 2 or 3 weeks post-

Of note, hydrophilic and renally excreted moder-transplantation may obviously represent a notable

ately lipophilic antimicrobials must be considered atexception to this rule.[62]

much higher risk of presenting substantial dailyIn summary, generally speaking this means thatfluctuations of plasma concentrations that may re-

in critically ill patients hydrophilic and moderatelyquire repeated subsequent dosage adjustments inlipophilic antimicrobials, being at higher risk ofindividual patients. For example, regarding Vd, it isdaily pharmacokinetic variations, should be morewell known that the presence of extensive fluidclosely monitored and their dosages should beextravasation, i.e. ascites or pleural effusions, bystreamlined according to the underlying diseases incausing dilution in the extracellular compartment –order to prevent under- or overexposure. Consistentthe most frequent location site of infection – maywith this, when searching PubMed for data to reviewlower antimicrobial concentrations in the body.the modifications in pharmacokinetics of antimicro-However, according to hydrophilicity or lipophilici-bials occurring in critically ill patients we found thatty, the net effect of dilution might be substantial ormost findings referred to these groups of antimicro-negligible, respectively. In fact, since hydrophilicbials, whereas data regarding highly lipophilicantimicrobials exhibit Vd limited at the extracellularantimicrobials were generally lacking.space (<0.3–0.4 L/kg for most aminoglycosides, β-

lactams and glycopeptides), their plasma and inter- Accordingly, most of the information on pharma-stitial concentrations may dramatically drop because cokinetic changes of antimicrobials in critically illof substantial fluid extravasation (3L).[59,60] On the patients reported in this review concern third- orother hand, for lipophilic antimicrobials presenting fourth-generation cephalosporins, carbapenems,larger volumes of distribution (>1 L/kg for most penicillins, monobactams, glycopeptides, aminogly-fluoroquinolones or macrolides), the dilution of in- cosides, ciprofloxacin and levofloxacin, whereasterstitial fluids caused by the presence of such extra very few data, if any, concerning macrolides, tetra-volume will be less relevant as a consequence of cyclines, chloramphenicol, rifampicin are reported.higher intra-/extracellular concentration ratios.[60] Data on this topic concerning new antimicrobials

such as ertapenem, linezolid, gemifloxacin, ga-Likewise, significant daily fluctuations of plasmatifloxacin and moxifloxacin are also presentlyand extracellular concentrations of hydrophilic andlacking.moderately lipophilic renally excreted antimicrobi-

2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (10)

Disposition of Antimicrobials in Critically Ill Patients 1015

Variations inextracellular fluid

Variations inrenal clearance

Critically ill patients

Antimicrobial dilutionor loss

Considerdosage increase

Reduced antimicrobialrenal excretion

Considerdosage decrease

Enhanced antimicrobialrenal excretion

Considerdosage increase

drug abuse

haemodynamically active drugs

burns

leukaemia

hyperdynamics

Increased if:

hypoalbuminaemia

renal impairment

Decreased if:

dialysis

ascites

oedema

mediastinitis

post-surgicaldrainages

Increased if:

hypoalbuminaemia

pleural effusion

fluid therapy

Fig. 2. Pathophysiological or iatrogenic conditions affecting the distribution and elimination of antimicrobials, and clinical recommendationsin such conditions.

4. Pathophysiological Conditions (especially aminoglycosides), which require loadingAltering Pharmacokinetics of doses (LDs) to be administered at the commence-Antimicrobials in Critically Ill Patients ment of therapy, since LD is directly proportional to

the drug Vd (LD = Ctarget × Vd), where Ctarget is theCritically ill patients often present with several target concentration,[99] and a low peak level due to

peculiar pathophysiological or iatrogenic condi- high Vd might result in more frequent developmenttions, which may substantially affect both distribu- of resistance. However, it should not be overlookedtion and elimination of antimicrobials (figure 2, that for antimicrobials with a low Vd the presence oftable I); taking this into account may be critical in such extra volume in the interstitial fluid compart-ensuring a successful outcome of antimicrobial ther- ment may substantially increase total bodyweightapy. (‘weight gain’) thus potentially also resulting in the

For further clarification of pharmacokinetic need for higher maintenance dosages.drug-drug interactions in the ICU setting, readers

4.1.1 Oedemaare referred to our previously published review.[98]

The per se influence of oedema on the pharma-cokinetics of drugs has rarely been accurately as-4.1 Causes of Increased Volumesessed.[59] However, the oedematous status, regard-of Distributionless of the underlying pathogenetic mechanism, may

Several pathophysiological situations through in- certainly play a major role in altering distribution ofcreasing the Vd may cause antimicrobial dilution drugs, especially of those antimicrobials showing(especially for hydrophilic antimicrobials) in plasma limited extracellular distribution, namely hydrophil-and extracellular fluids, so that an increase in dosage ic antimicrobials. Among the multiple causes ofshould be considered with the intent of ensuring oedema, sepsis and trauma are the two that mostoptimal care. This may be especially true for con- frequently expand the extracellular fluids of critical-centration-dependent antimicrobials with a small Vd ly ill patients. Both the endothelial damage leading

2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (10)

1016P

ea et al.

2005 A

dis D

ata

Info

rma

tion

BV. A

ll righ

ts rese

rved

.C

lin P

ha

rma

co

kine

t 2005; 44 (10)

Table I. Factors affecting pharmacokinetics of antimicrobials in critically ill patients

Study Pathophysiological or Study population Antimicrobial Mechanism(s) Pharmacokinetic Comment/clinicaliatrogenic situation effect significance

Dorman et al.[63]a Oedema 52 septic surgical patients Gentamicin or Capillary leakage; ↑ Vd; ↓ Cmax ↑ Loading doses neededtobramycin hypoalbuminaemia

Brunner et al.[66] Oedema 6 postsurgical patients Piperacillin/tazobactam Capillary leakage ↓ AUC in muscle Inadequate t>MIC forvs 6 controls and subcutis high-MIC strains

Joukhadar et Oedema 6 septic patients vs Piperacillin Capillary leakage ↓ AUC in muscle ↑ Doses neededal.[67] 6 controls and subcutis

Joukhadar et Oedema 12 septic patients vs Piperacillin Capillary leakage ↓ Cmax and AUC in ↑ Doses neededal.[68] 6 controls muscle

Gomez et al.[69] Oedema 15 critically ill patients Ceftazidime Capillary leakage ↓ Cmin Standard dosesinsufficient

Hanes et al.[70] Oedema 31 trauma patients Ceftazidime – Capillary leakage ↑ Vd Continuous IV infusionintermittent IV or regimen suggestedcontinuous IV infusion

McKindley et Oedema 20 trauma patients Aztreonam or imipenem Capillary leakage ↑ Vd Standard initial dosesal.[71] insufficient

Botha et al.[72] Fluid therapy 1 trauma patient Amikacin Extracellular ↑ Vd Frequent TDM requiredcompartmentexpansion

Gous et al.[73] Fluid therapy Critically ill infants Vancomycin Extracellular ↑ Vd Frequent TDM requiredcompartmentexpansion

Ronchera-Oms Parenteral nutrition 86 critically ill patients Gentamicin Extracellular ↑ Vd; ↓ Cmax ↑ Doses neededet al.[74] compartment

expansion

Etzel et al.[75] Pleural effusion 260 patients with pleural Gentamicin or Extracellular ↑ Vd; ↓ Cmax ↑ Doses neededeffusion vs 1049 patients tobramycin compartmentwithout pleural effusion expansion

Aldaz et al.[76] Ascites 154 cancer patients Vancomycin Extracellular ↑ Vd Dosage adjustmentcompartment neededexpansion

Buijk et al.[77] Peritoneal exudate 18 patients with intra- Ceftazidime – Extracellular ↑ Vd ↑ Doses neededand/or drainages abdominal infection intermittent IV or compartment

continuous IV infusion expansion

Romano et al.[78] Hypoalbuminaemia 121 oncohaematological Amikacin ↓ Plasma oncotic ↑ Vd ↑ Doses neededpatients pressure

Pea et al.[79] Hypoalbuminaemia 1 transplant patient Teicoplanin ↓ Plasma oncotic ↑ Vd; ↑ CL ↑ Doses neededpressure; ↑ free drug

Sanchez et al.[80] Hypoalbuminaemia 21 critically ill children Teicoplanin ↓ Plasma oncotic ↓ Cmin ↑ Doses neededplus fluid therapy pressure; ↑ free drug

Continued next page

Disposition of A

ntimicrobials in C

ritically Ill Patients1017

2005 A

dis D

ata

Info

rma

tion

BV. A

ll righ

ts rese

rved

.C

lin P

ha

rma

co

kine

t 2005; 44 (10)

Table I. Contd

Study Pathophysiological or Study population Antimicrobial Mechanism(s) Pharmacokinetic Comment/clinicaliatrogenic situation effect significance

Joynt et al.[81] Hypoalbuminaemia 10 septic patients Ceftriaxone ↓ Plasma oncotic ↑ Vd; ↑ CL; ↓ Cmin ↑ Doses or continuousplus pressure; ↑ free drug infusion neededhaemodynamicallyactive drugs

Mimoz et al.[82] Hypoalbuminaemia 11 postsurgical patients Ceftriaxone ↓ Plasma oncotic ↑ Vd Enhanced efficacyvs 11 controls pressure; ↑ free drug

Bonapace et Burns 12 burn patients Cefepime Weeping in exudates; ↑ Vd; ↑ CL ↑ Doses might beal.[83] ↑ in cardiac output needed

Sampol et al.[84] Burns 6 burn patients Cefepime Weeping in exudates ↑ Vd; ↔CL Use standard dosage

Tang et al.[65] Hyperdynamics 77 critically ill patients Gentamicin ↑ Cardiac output ↑ CL Correlation with CLCRvs 27 controls

Hanes et al.[70] Hyperdynamics 31 trauma patients Ceftazidime – ↑ Cardiac output ↑ CL Continuous IV infusionintermittent IV or regimen suggestedcontinuous IV infusion

Pea et al.[85] Hyperdynamics plus 10 ventilator-associated Levofloxacin ↑ Cardiac output; ↑ CL ↑ Doses neededhaemodynamically pneumonia patients ↑ in glomerularactive drugs filtration rate

Lipman et al.[86] Hyperdynamics 10 septic patients Cefepime ↑ Glomerular filtration ↑ CL ↑ Doses neededrate

Lipman et al.[87] Hyperdynamics 25 critically ill patients Cefepime or cefpirome ↑ Glomerular filtration ↑ CL ↑ Doses needed or applyrate continuous IV infusion

Pea et al.[88] Haemodynamically 18 cardiosurgical patients Vancomycin ↑ Glomerular filtration ↑ CL TDM stronglyactive drugs rate and tubular recommended

secretion

Fernandez de Leukaemia 31 oncohaematological Vancomycin ↑ Glomerular filtration ↑ CL ↑ Doses neededGatta et al.[89]b patients vs 9 controls rate and/or tubular

secretion

Pea et al.[92] Leukaemia 33 leukaemic patients Teicoplanin Hypoalbuminaemia, ↑ Vd; ↑ CL ↑ Doses needed↑ in renal blood flow

King et al.[93]c Drug abuse 18 drug abusers Gentamicin ↑ Glomerular filtration ↑ CL ↑ Doses neededrate

Lugo and Renal failure 30 critically ill patients Amikacin ↓ Glomerular filtration ↓ CL ↓ Doses neededCastaneda- rateHernandez[96]

Pea et al.[97] Muscle wastage 1 spinal cord injury patient Vancomycin Overestimation of Overestimation of Measurement of CLCRglomerular filtration CL and TDM stronglyrate recommended

a Other studies include Zaske et al.[64] and Tang et al.[65].

b Other studies include Le Normand et al.[90] and Chang.[91].

c Other studies include Rybak et al.[94,95].

AUC = area under the plasma concentration-time curve; CL = total body clearance; CLCR = creatinine clearance; Cmax = peak plasma concentration; Cmin = minimum plasmaconcentration; IV = intravenous; TDM = therapeutic drug monitoring; t>MIC = duration of time the concentration exceeds minimum inhibitory concentration; Vd = volume ofdistribution; ↑ indicates increase; ↓ indicates decrease; ↔ indicates no change.

1018 Pea et al.

to increased capillary permeability[100,101] and the bution of piperacillin in six patients undergoingconspicuous reduction of oncotic pressure due to aortic valve replacement. After a single dose admin-severe hypoalbuminaemia (<1.5 mg/dL)[59] may istration of piperacillin/tazobactam 4/0.5g, intersti-promote substantial fluid extravasation responsible tial fluid concentrations of free piperacillin in skele-for the so-called ‘third spacing’ phenomenon. tal muscle and subcutaneous adipose tissue were

significantly lower in patients than in healthy volun-Several studies documented that oedematous sta-teers, with AUCinterstitium/AUCserum ratios averag-tus, by increasing Vd and lowering antimicrobialing 0.27 and 1.22 in muscle and 0.25 and 0.43 inconcentrations, could cause clinical failure of anti-subcutis, respectively. The investigators concludedmicrobial therapy in sepsis and/or trauma. Interest-that these lower antimicrobial concentrations at tar-ingly, aminoglycosides were among the most stud-get sites in patients were at least partially due toied drugs,[64,102-114] consistently showing a drop inincreased capillary permeability and subsequent ac-peak plasma concentrations, possibly causing im-cumulation of fluid in the interstitial space of softpairment of their concentration-dependent bacterici-tissues as a response to the trauma of surgery, anddal efficacy. Two examples are outlined here; for anthat this may have resulted in inadequate t>MIC forexhaustive review on increased Vd of aminoglyco-

sides in patients with sepsis the readers are referred high-MIC strains, leading to therapeutic failure into the work of De Paepe et al.[115] some patients. Using the same technique, Joukhadar

et al.[67] assessed piperacillin penetration in softDorman et al.[63] assessed the initial peak plasmatissues of six septic patients compared with a groupconcentrations achievable after a 3 mg/kg loadingof correctly matched healthy volunteers. They ob-dose (based on an adjusted bodyweight defined asserved that interstitial fluid concentrations of piper-the sum of ideal bodyweight plus half the differenceacillin in soft tissues of septic patients, due to capil-between actual and ideal bodyweight) of aminog-lary leakage, were 5- to 10-fold lower than in plasmalycosides (gentamicin or tobramycin) in 52 criticallyand that AUCinterstitium/AUCplasma ratios were 3- toill surgical patients with life-threatening Gram-4-fold lower than in the control group of healthynegative infections. Based on previously publishedvolunteers (with concentration ratios beingdata, this initial loading dose was estimated to pro-0.08–0.27 in patients and ≤0.94 in healthy volun-duce a peak level of 8.3 mg/L. Indeed, due to a 1.34-teers), concluding that higher than currently admin-fold increase in Vd, the target peak plasma concen-istered dosages of piperacillin (4g three times daily)tration of ≥8.3 mg/L was not achieved in about halfshould be considered for patients with septic shock,of the patients, and in 15.3% of patients the peakpreferably by shortening the dosage interval.plasma concentration was even lower than 5 mg/L.

These findings lead the investigators to conclude The penetration of cefpirome in the interstitialthat greater loading doses (at least 3.7 mg/kg) are space fluid of skeletal muscle was measured byrequired to achieve valid peak plasma concentra- microdialysis in 12 patients with septic shock and intions in critically ill surgical patients. Likewise, a six age-matched healthy volunteers.[68] After1.66-fold increase of Vd of gentamicin due to cefpirome 2g single dose, both peak plasma concen-hyperdynamic conditions causing increased cardiac tration and muscle interstitial AUC from 0 to 6 hoursoutput and low systemic vascular resistance oc- (AUC6) of cefpirome were found to be significantlycurred in critically ill septic surgical patients.[65]

lower in septic patients compared with healthy vol-Also, the Vd of several β-lactams was shown to unteers (Cmax 62 ± 4 vs 127 ± 15 mg/L; AUC6 9.80

increase because of oedema in critically ill pa- ± 0.72 vs 15.52 ± 1.44 mg • min/mL) because oftients.[60]

interstitial oedema resulting from capillary leakagein response to the infection, suggesting that in orderBrunner et al.[66] examined, by means of microdi-to ensure effective concentrations at the infectionalysis, the influences of cardiac surgery and ex-

tracorporeal circulation on the postoperative distri- site even in the presence of less susceptible bacteria

2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (10)

Disposition of Antimicrobials in Critically Ill Patients 1019

such as P. aeruginosa (MIC that inhibits the growth Score ≥10. After 2–3 days of treatment, as a conse-quence of trauma, the resulting Vd of both drugs wasof 90% bacteria [MIC90] >16 mg/L) the dosagesignificantly increased in the patients comparedinterval for cefpirome 2g should be shortened fromwith historical controls (aztreonam 0.42 ± 0.19 vs12 hours to 8 hours in patients with sepsis.0.21 ± 0.06L; p < 0.05; imipenem 0.35 ± 0.13 vsIn 15 critically ill adult patients with a median0.23 ± 0.03L; p < 0.05), suggesting that standardAcute Physiology and Chronic Health Evaluationinitial dosages of aztreonam and imipenem may(APACHE) II score of 12 and a mean creatinineresult in lower concentrations in these critically illclearance of 61 mL/min receiving ceftazidime 2gpatients.every 8 hours, the Vd of ceftazidime at steady-state

In summary, all of these studies suggest thatwas more than 4-fold greater than in historical con-higher dosages for most hydrophilic antimicrobialstrols (56.91 ± 25.93 vs 13.9 ± 1.9L; p < 0.001) due to(either aminoglycosides or β-lactams) should beincreased extracellular volume as a result of capilla-considered to ensure therapeutic concentrations inry leak.[69] Interestingly, despite no significant dif-critically ill patients with oedema.ferences in ceftazidime clearance compared with

control (9.06 ± 4.79 vs 6.64 ± 0.67 L/h), serum 4.1.2 Fluid Therapy or Parenteral Nutritionceftazidime concentration dropped below the MIC90 Aggressive intravenous fluid therapy may con-for P. aeruginosa (8 mg/L) just after 6 hours in one tribute to expanding extracellular water and causingpatient and after 8 hours in another four patients, dilution of hydrophilic antimicrobials in the extra-suggesting that in the presence of less susceptible cellular compartment in critically ill patients.pathogens, standard ceftazidime dosages (2g three In a case report concerning a 19-year-old critical-times daily) may be insufficient for optimal drug ly ill post-trauma male patient receiving a standardexposure in some septic patients. Hanes et al.,[70]

dosage of amikacin 1g once daily for 35 consecutiveassessing disposition of ceftazidime 2g three times days because of a Gram-negative respiratory infec-daily in critically ill trauma patients with Gram- tion, Botha et al.[72] clearly showed that, as a resultnegative nosocomial pneumonia, showed that both of copious administered fluid supplements (rangeVd (0.32 ± 0.14 vs 0.21 ± 0.03 L/kg; p = 0.003) and 2.94–5.62 L/day), the Vd of amikacin was substan-total body clearance (2.33 ± 1.06 vs 1.58 ± 0.23 mL/ tially increased with significant daily fluctuationsmin/kg; p = 0.003) of ceftazidime were substantially occurring throughout therapy (from 16.23L on day 4increased in comparison with healthy volunteers. to 39.66L on day 30). They concluded that amikacinSince this dosage regimen was estimated enabling peak plasma concentrations should be frequentlyt>MIC only for 74% of the dosage interval for monitored in critically ill patients receiving fluidcausative pathogens with an MIC of 8 mg/L, they supplements. Likewise, the Vd of vancomycin wasconcluded that caution should be taken in using the found to be almost doubled on day 2 versus day 8 of2g three times daily dosage regimen of ceftazidime therapy (0.81 L/kg vs 0.44 L/kg) in critically illfor the treatment of pneumonia caused by P. aerugi- infants treated with a standard vancomycin dosagenosa or Acinetobacter species in critically ill trauma of 10 mg/kg every 6 hours, probably because ofpatients, suggesting that continuous intravenous in- initial aggressive fluid resuscitation.[73] This led thefusion by maintaining serum concentrations above investigators to conclude that monitoring vanco-the MIC for the entire day may circumvent this mycin serum levels may be beneficial in this popula-problem. tion. In addition, fluid load was also considered to be

a possible co-factor in increasing the Vd of cef-McKindley et al.[71] assessed the pharmacokinet-pirome in septic patients.[68,116]ics of aztreonam (2g every 8 hours) and imipenem

(500mg every 6 hours) in two parallel groups of Total parenteral nutrition may also contribute topost-trauma critically ill patients affected by expanding the Vd of hydrophilic antimicrobials innosocomial pneumonia with an Injury Severity critically ill patients.

2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (10)

1020 Pea et al.

Ronchera-Oms et al.[74] assessed the influence of fotaxime,[141] piperacillin,[142] aztreonam[143]), andtotal parenteral nutrition on the pharmacokinetics of has been confirmed more recently in a populationgentamicin in critically ill adult patients with severe pharmacokinetic study assessing the effects of asci-Gram-negative infections. They showed a signifi- tes and hepatic function on vancomycin dispositioncantly higher Vd of gentamicin in patients receiving in patients with cancer.[76] Interestingly, whereas nototal parenteral nutrition compared with those re- major changes in clearance related to liver functionceiving only fluid therapy (0.43 ± 0.12 vs 0.34 ± was observed, the Vd of vancomycin was found to0.08 L/kg), and suggested that higher dosages of be significantly increased in patients presenting withgentamicin should be administered to attain thera- hepatic failure and ascites (1.02 ± 0.25 L/kg) com-peutic peak concentrations of gentamicin in paren- pared with those presenting with hepatic failure butterally fed critically ill patients. without ascites (0.75 ± 0.17 L/kg) or those without

In summary, substantial fluid load and parenteral hepatic failure (0.64 ± 0.15 L/kg).[76] On this basis,nutrition should be considered major causes of anti- the investigators suggested that dosage adjustmentsmicrobial dilution, possibly leading to undertreat- during vancomycin treatment may be needed inment. patients with hepatic failure only in the presence of

ascites.4.1.3 Pleural EffusionAlso, the formation of exudative fluid in theAlthough pleural effusion may be related to in-

peritoneal cavity as a result of intra-abdominal in-fection, it should not be overlooked that sometimesfections may, in turn, be responsible for a larger Vdfluid extravasation in the pleural cavity may also

occur because of hypoalbuminaemia[117] or other for hydrophilic antimicrobials. Interestingly, thisconditions. Despite only a few studies in the litera- site of pathological increase of Vd may behave like ature specifically addressing the issue of increased Vd deep compartment with long elimination half-life,of antimicrobials in patients with pleural effusions and hence the pharmacokinetics may be very differ-(for example Etzel et al.[75] for gentamicin and ent in this compartment than in others. In a pharma-tobramycin), undoubtedly the penetration in pleural cokinetic study assessing ceftazidime disposition inexudate shown by several hydrophilic antimicrobi- patients with severe intra-abdominal infectionsals[118-131] and the resulting dilution may justify the treated with ceftazidime 4.5 g/day administered ei-need for higher dosages in the presence of signifi- ther as continuous (n = 12) or intermittent (n = 6)cant pleural effusion. Consistent with the variable intravenous infusion, the Vd of ceftazidime waspharmacokinetics of the different drugs in animal found to be significantly higher than in healthymodels,[132] the required dosage adjustments could volunteers (0.28 vs 0.18 L/kg), probably owing tobe unpredictable, and therefore should be based the presence of peritoneal exudate (volume of exu-whenever possible on the measurements of serum date 200–3200mL).[77] Continuous intravenous infu-levels of drugs in these circumstances. sion resulted in more favourable concentrations in

both plasma and peritoneal exudate, but since the4.1.4 Ascites and Peritoneal Exudateexudate to plasma AUC ratio was about 0.6, theIn patients with advanced liver diseases, plasmainvestigators concluded that higher dosages ofand blood volume expansion,[133] ascites related toceftazidime may be necessary when treating patientsportal hypertension and decrease in albumin synthe-with severe intra-abdominal infections caused bysis, by causing an increase in the extracellular com-less susceptible pathogens such as P. aeruginosa.partment fluid,[61] may lead to significant increases

in Vd of hydrophilic antimicrobials. Whatever the mechanism responsible for fluidextravasation, as a consequence of drug dilution inThis was documented in early studies con-the extra volume, in patients with severe liver dis-cerning both aminoglycosides (gentamicin,[134]

eases and ascites, as well as in patients with perito-amikacin,[135] tobramycin[136]) and β-lactams (ampi-cillin,[137] ceftazidime,[138,139] ceftriaxone,[140,141] ce- neal exudate, often the dosages of hydrophilic or

2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (10)

Disposition of Antimicrobials in Critically Ill Patients 1021

moderately lipophilic antimicrobials should not be found to be as high as 4900mL in one instance, thisreduced (unless simultaneously impaired renal func- loss might be even larger in some patients. Like-tion may decrease plasma clearance), and therapeu- wise, substantial concentrations of cefamandoletic drug monitoring (TDM) may be helpful with the were found in the haematoma fluid draining fromintent of optimising drug exposure in this sub- the operation sites after hip replacement, averagingpopulation.[61,144] Of note, Lugo and Castaneda- 7.2 mg/L 6–8 hours after administration of the firstHernandez[145] showed that in patients with sepsis pre-anaesthesia dose of 1g, and 15.0 mg/L and 10.4and cirrhosis the Vd of amikacin was significantly mg/L, 10–12 hours and 14–16 hours, respectively,increased (0.67 L/kg) not only in comparison with with a further dose given after 8 hours.[149]

healthy volunteers (0.25 L/kg) but also with respect Therefore, considering that drainages may re-to the general septic population without cirrhosis present a pathway of antimicrobial loss and may(0.47 L/kg). Subsequently, the population pharma- thereby contribute to lower antimicrobial levels,cokinetic parameters estimated in this study were larger dosages of hydrophilic antimicrobials maysuccessfully used as a priori distribution in a Baye- sometimes be necessary for optimal treatment of thissian forecasting method with the intent of improving subpopulation, especially when other co-factors re-prediction of plasma concentrations with acceptable sponsible for dilution may be simultaneously pre-precision.[145] sent. TDM may therefore be of great value in such

patients for clinicians with the intent of tailoring4.1.5 Mediastinitisdrug exposure in the individual patient.A special issue possibly affecting antimicrobial

disposition in post cardiac surgery patients is repre- 4.1.7 Hypoalbuminaemiasented by mediastinitis. Although haematoma or Hypoalbuminaemia is a frequently occurringfluid collection occurring in the mediastinum after condition in critically ill patients as a consequencesternotomy for cardiac operation is usually of mod- of increased albumin capillary escape rate througherate extent,[146] in the presence of mediastinitis third leaky endothelium, or fluid overload or malnutri-space problems due to the sequestration of protein- tion. By reducing plasma oncotic pressure, hypoal-rich fluids that may require albumin administra- buminaemia may contribute to fluid extravasationtion[147] may occur.[148] It should not be overlooked and antimicrobial dilution, whereas the increase inthat significant dilution of hydrophilic antimicrobi- the free fraction of drugs may increase their Vd.als as a consequence of third space sequestration in In a recent population pharmacokinetic study onthe mediastinum may require higher dosages in or- amikacin disposition in patients with haematologi-der to achieve therapeutic concentrations. cal malignancies, despite the negligible plasma pro-

tein binding of this aminoglycoside, hypoalbu-4.1.6 Indwelling Post-surgical Drainagesminaemia was proven to be one of the mostA frequently underestimated cause of antimicro-important covariates in explaining interindividualbial loss (‘false increase in Vd’) in surgical patientspharmacokinetic variability of amikacin in this pop-may be the presence of indwelling drainages posi-ulation.[78] Particularly, due to the significant contri-tioned after major thoracic and abdominal opera-bution in increasing amikacin Vd, the investigatorstions. Buijk et al.[77] found that after a loading bolusrecommended that the initial dosage of amikacin indose of ceftazidime 1g and a daily maintenancepatients with haematological malignancies withdosage of 4.5g as continuous intravenous infusion,hypoalbuminaemia and normal renal functionon day 4 the mean ceftazidime concentration inshould be about 1.6-fold higher than in the standardperitoneal exudate in patients with intra-abdominalpatient.[78]infections was 26.6 mg/L, with a total 24-hour vol-

ume of drained exudate of 1600mL. Although aver- When considering renally excreted highly albu-age drainages-related loss of ceftazidime was about min-bound antimicrobials (i.e. teicoplanin and cef-50mg daily, since daily volume of exudate was triaxone) it should not be overlooked that by in-

2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (10)

1022 Pea et al.

creasing the unbound fraction, hypoalbuminaemia Interestingly, iatrogenic hypoalbuminaemia in-duced by hydroxyethyl starch in postsurgical adultmay promote not only more extensive distribution,patients was found, on the contrary, to alter mainlybut also higher renal clearance.[98,150]

the Vd of ceftriaxone.[82] As expected, the signifi-In a renal transplant patient treated with te-cantly higher free fraction of ceftriaxone observed inicoplanin at a daily dose of 8.57–11.42 mg/kg be-patients versus correctly matched normoalbu-cause of sepsis resulting from coagulase-negativeminaemic healthy volunteers (14% and 46% in pa-staphylococci, Pea et al.[79] recently showed thattients vs 10% and 18% in volunteers at 0 hours andsevere hypoalbuminaemia (1.73–2.58 g/L) may sig-24 hours after dosage, respectively) caused an in-nificantly enhance both distribution and eliminationcrease in Vd, but not a greater total clearance, proba-of teicoplanin during renal replacement therapy withbly due to saturation of the biliary excretion of thecontinuous veno-venous haemofiltration (CVVH).free fraction of ceftriaxone. On the basis of theseOf note, the increased free moiety of teicoplaninfindings, the investigators concluded that the in-resulted in an almost doubled sieving coefficientcreased free concentrations of ceftriaxone might(0.17 vs <0.10), suggesting that teicoplanin clear-have even enhanced effectiveness on this particularance may be enhanced in patients with sepsis under-occasion.[82]

going CVVH and presenting with major hypoalbu-In summary, higher dosages of hydrophilicminaemia. TDM is thus strongly advisable consider-

antimicrobials may frequently be necessary to ade-ing that unexpectedly high doses could be needed toquately treat critically ill patients presenting withensure optimal therapeutic concentrations.[79]

severe hypoalbuminaemia, and TDM may be help-Likewise, hypoalbuminaemia, together with mul- ful to streamline therapy for these patients.

tiple drug infusions and volume expansion treat-ments, was considered one of the most important co- 4.2 Causes of Enhanced Renal Clearancefactors in contributing to low steady-state trough

Enhanced renal clearance of hydrophilic andlevels (<10 mg/L in 89% of patients) observed dur-moderately lipophilic antimicrobials may be ex-ing teicoplanin treatment at a dosage of 10 mg/kg/pected whenever pathophysiological or iatrogenicday in 21 critically ill children aged between 7 daysconditions increasing renal blood flow – and therebyand 12 years. The investigators concluded thatglomerular filtration and tubular secretion rates –higher dosages should be administered to ensuremay occur.optimal treatment in these conditions.[80]

4.2.1 BurnsIn ten critically ill patients with severe sepsisSeveral factors may substantially alter the phar-treated with intravenous ceftriaxone 2g once daily,

macokinetics of antimicrobials in patients with ex-the severe hypoalbuminaemia (22 ± 6.1 g/L) result-tensive third degree burns (>30–40% body surfaceed in a substantial increase in Vd and an almostarea).doubling of drug clearance (41.3 ± 11.7 vs 19.8 ±

According to the elapsed time from the event2.5 mL/min) in patients with normal renal function(less than or more than 48 hours), differentcompared with healthy volunteers, thereby loweringpathophysiological changes may occur in burn pa-trough concentrations below the desired thresholdtients.[151,152](<8 mg/L) with possible suboptimal exposure in five

of ten patients.[81] Based on these findings, the in- In the first 2 days, namely the acute or resuscita-vestigators suggested either shortening the dosage tion phase of thermal injury, hypovolaemia possiblyinterval or administering the same dose as continu- leading to a drop in renal blood flow and glomerularous intravenous infusion to ensure optimal ceftriax- filtration rate may occur as a result of protein-richone concentrations over the entire dosage interval in fluid loss due to altered capillary permeability.critically ill patients with severe hypoalbuminaemia However, during this phase the resultant partial im-and normal renal function.[81] pairment of renal clearance may be counteracted by

2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (10)

Disposition of Antimicrobials in Critically Ill Patients 1023

nonrenal/hepatic clearance via the weeping of the for at least 50% of the dosage interval, both 2g twicedaily and 1g three times daily of cefepime should beantimicrobial out of the body in abundant exudatesenough, but to ensure a t>MIC for the entire dosagefrom the burns, so that the net pharmacokineticinterval, higher dosages (2g three times daily)effect could be that there is no need for major dosageshould be considered appropriate. Sampol et al.[84]adjustments of antimicrobials to ensure therapeuticassessed the disposition of cefepime 2g after the firstconcentrations in the first 48 hours.and fifth dose in a small population of burn patientsIndeed, from a pharmacokinetic point of view(n = 6), with mean burn surface area of 31.5%.perhaps more relevant pathophysiological changesDifferent to the previous study,[83] only an increasemay occur beyond 48 hours when, after providingin Vd (0.36 L/kg vs 0.18–0.24 L/kg) without anyappropriate fluid replacement, the hypermetabolicmajor changes in clearance and t1/2β of cefepimephase usually begins. This period is frequentlycompared with healthy volunteers was found,[84]

characterised by an increase in cardiac output lead-leading the investigators to conclude that no changesing to enhanced renal blood flow and in turn glomer-in the standard dosage of cefepime (2g every 12ular filtration rate, which may become significantlyhours) are needed in burn patients. However, in aincreased compared with healthy controls, as sug-commentary on this latter study, Weinbren[171] ap-gested by creatinine clearance values being some-propriately highlighted that pharmacokinetic studies

times as high as 240 mL/min.[152,153] This phaseof antimicrobials in burn patients should also be

usually lasts several days, with the intensity progres-conducted in the late post-injury period and in a

sively decreasing according to the elapsed time fromlarge number of patients and heterogeneous popula-

thermal injury. As a consequence, the renal clear-tions, in order to define appropriate dosages applica-

ance of most hydrophilic and moderately lipo-ble throughout the entire post-injury period.

philic antimicrobials is expected to increase sig-In any case, given the complex pathophysiologi-nificantly during the hypermetabolic phase,[151] as

cal changes, the frequent need for more aggressiveobserved in several pharmacokinetic studies con-dosages and the wide interindividual pharmacoki-cerning aminoglycosides (gentamicin,[154,155]

netic variabilities, several investigators have advo-amikacin,[156] tobramycin[157]), β-lactams (ticarcil-cated a major role for TDM in optimising antimicro-lin/clavulanic acid,[158] cefepime,[83] ceftazidime,[159]

bial therapy in severely burnt patients, not only formeropenem,[160] aztreonam[161]), glycopeptides

drugs with a narrow therapeutic index (i.e. aminog-(vancomycin,[162-164] teicoplanin[165,166]) and even

lycosides[155,172] or glycopeptides[153,164-166,173]) but,partially renally eliminated fluoroquinolones

whenever possible, also for other hydrophilic(ciprofloxacin[167]), although other studies of

antimicrobials, such as β-lactams.[151,152,174]

imipenem,[168] piperacillin[169] and ciprofloxacin[170]

For a comprehensive review of antimicrobial dis-failed to show this.position in burn patients, readers are referred to the

The pharmacokinetics of cefepime in burn pa- works of Jaehde and Sorgel[151] and Weinbren.[152]

tients was assessed in two recently published stud-4.2.2 Hyperdynamicsies. Bonapace et al.[83] showed that in 12 burn pa-The hyperdynamic conditions frequently occur-tients presenting with extremely high creatinine

ring in the early phase of sepsis may be responsibleclearance values (104–191 mL/min) receiving a sin-for an increase in cardiac output and renal bloodgle 2g dose of cefepime, drug Vd was almostflow that may, in turn, lead to enhanced glomerulardoubled (0.43 L/kg vs 0.18–0.24 L/kg) and renalfiltration rate and tubular secretion of renally elimi-clearance increased by 10–30% compared withnated drugs in critically ill patients.[60,175]healthy volunteers. According to the plasma concen-

tration-time profiles simulated by means of patients’ Changes occurring in gentamicin pharmacokinet-pharmacokinetic estimates, the investigators ics related to the intensity of cardiac output wereshowed that, in all of the patients, to ensure a t>MIC assessed by Tang et al.[65] during treatment for

2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (10)

1024 Pea et al.

Gram-negative-related sepsis. Although, when con- ciprofloxacin clearance found in at least one patientsidering the septic population as a whole, the clear- (0.82 mL/min/kg) might have been related to theance of gentamicin was decreased compared with hyperdynamic condition during sepsis. Neverthe-controls, after splitting patients into two groups ac- less, ciprofloxacin 400mg three times daily wascording to cardiac index the clearance of gentamicin considered suitable for ensuring optimal exposurewas found to be 1.5-fold higher in hyperdynamic (in terms of either Cmax/MIC or AUC/MIC) in criti-septic patients (4.1 ± 0.59 L/min/m2) than in hypo- cally ill patients with severe sepsis.dynamic septic patients (2.7 ± 0.43 L/min/m2) or In ten critically ill patients with sepsis, troughcontrols (2.4 ± 0.2 L/min/m2). plasma concentrations of cefepime after multiple

administrations of 2g every 12 hours were particu-Similarly, in critically ill trauma patients treatedlarly low (<1 mg/L in four patients and <4 mg/L inwith ceftazidime 2g every 8 hours or 60 mg/kgfive patients) owing to increased drug renal clear-continuous intravenous infusion, drug clearance wasance.[86] On this basis, the investigators suggestedfound to be significantly higher than in healthythe daily dosage of cefepime should be increased tovolunteers (2.35 ± 0.89 vs 1.58 ± 0.23 mL/min/kg),6g in critically ill patients with normal renal func-so that in the presence of infections due to lesstion, and in order to maintain therapeutic concentra-susceptible pathogens, the application of continuoustions during the whole dosage interval a more re-intravenous infusion was advocated to circumventfracted dosage regimen (i.e. 1g every 4 hours orthe problem.[70]

continuous intravenous infusion) would be prefera-Pea et al.[85] evaluated levofloxacin disposition inble. Recently, the importance of increased glomeru-critically ill patients treated with a high dosagelar filtration rate in enhancing clearance and lower-regimen of 500mg every 12 hours because of early-ing trough levels of either cefepime and cefpiromeonset ventilator-associated pneumonia. Levoflox-after administration of standard dosages in criticallyacin renal clearance was significantly higher than inill patients has been further emphasised by the samehealthy volunteers (3.40 vs 2.42 mL/min/kg), proba-investigators.[87] They suggested overcoming thisbly due to the enhancement of both glomerularproblem by shortening the dosage interval or apply-filtration rate and tubular secretion as a result ofing continuous intravenous infusion, and to measurehyperdynamic conditions. The investigators con-creatinine clearance more frequently in ICU patientscluded that this improved dosage should be consid-to allow prediction of low cephalosporin levels atered appropriate for the treatment of critically illthe bedside.patients showing high estimated creatinine clear-

In summary, all these studies underline the neces-ance.sity of defining higher than presently recommended

Likewise, Lipman et al.[176] assessed the pharma- dosages for most renally excreted antimicrobials incokinetics of ciprofloxacin at very high doses the treatment of septic patients presenting with nor-(400mg three times daily) in 18 critically ill patients mal renal function.who had severe sepsis and no major impairment ofrenal function (creatinine clearance ≥30 mL/min).

4.2.3 Haemodynamically Active DrugsInterestingly, although in this population meanciprofloxacin clearance was similar to that observed Although the role of haemodynamically activein healthy volunteers (0.4 mL/min/kg), the coeffi- drugs (HADs), i.e. dopamine, dobutamine andcient of variation was as high as 50% in critically ill furosemide (frusemide), aimed at improving haemo-patients versus only 11% in historical controls, sug- dynamics and renal blood flow,[177-179] is generallygesting that very high interindividual pharmacoki- recognised in the ICU setting,[180,181] their impor-netic variability may occur in this setting. Addition- tance in affecting the disposition of antimicrobials inally, although not directly addressed by the investi- critically ill patients has often been neglected in thegators, it may be hypothesised that the very high past.[98]

2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (10)

Disposition of Antimicrobials in Critically Ill Patients 1025

Pea et al.[88] first assessed the potential role of In summary, given the frequent simultaneous useof antimicrobials and HAD in ICU patients, clini-dopamine, dobutamine and furosemide in alteringcians must be aware of possible drug-drug interac-the disposition of vancomycin in cardiac surgicaltions altering the pharmacokinetics of antimicrobi-patients. Serum trough levels of vancomycin wereals. TDM is strongly recommended for optimisationsignificantly decreased in 8 of 18 patients during co-of exposure in these circumstances.treatment with at least two of these HADs

(dobutamine + furosemide in four patients and4.2.4 Acute Leukaemiadopamine + dobutamine + furosemide in anotherMost hydrophilic antimicrobials have beenfour patients), so that dosages 1.25- to 1.90-fold

shown to exhibit altered pharmacokinetics in pa-higher than recommended by Moellering’s nomo-tients with haematological malignancies,[78,89,184-188]gram[182] had to be administered to maintain thera-and several investigators documented that enhance-peutic concentrations. Interestingly, withdrawal ofment of renal function may partially account for this.coadministered HAD in four of these eight patientsFor example, higher than normally expected dos-occurred during vancomycin treatment and was fol-ages of vancomycin (38 mg/kg/day) as a result oflowed by a subsequent marked increase of vanco-enhanced renal clearance were shown to be necessa-mycin trough levels. This suggested that during co-ry to ensure therapeutic concentrations in patientstreatment, renal clearance of vancomycin was sig-with haematological malignancies.[89] Similar find-nificantly increased as a result of enhanced glomeru-ings were also observed with other drugs (namelylar filtration rate and tubular secretion due to theamikacin[78,186] and teicoplanin[187]) and further con-synergistic effect of HAD on cardiac output and/orfirmed with vancomycin.[90,91]

renal blood flow.[88] The investigators concludedRecently, Pea et al.[92] assessed plasma te-that TDM for the pharmacokinetic optimisation of

icoplanin trough levels achievable in patients withvancomycin is strongly recommended in these situa-acute leukaemia empirically treated with teicoplanintions.at standard (n = 11) or high (n = 22) dosage regi-

Likewise, dopamine and furosemide were con- mens. It was observed that standard teicoplanin dos-sidered by the same investigators to contribute to the ages (an average loading dose of 6.2 mg/kg every 12enhancement of renal clearance of levofloxacin ob- hours for three doses followed by 6.2 mg/kg everyserved in some ICU neurosurgical patients during 24 hours) in patients with acute leukaemia mighttreatment with levofloxacin 500mg twice daily for achieve only much lower concentrations thanventilator-associated pneumonia.[85] In the same achievable in healthy volunteers (none of 11 patientsstudy, co-treatment with mannitol administered to achieved the recommended trough level of 10 mg/Llower intracranial pressure was, in turn, considered in the first 72 hours), whereas a more aggressiveto increasing levofloxacin clearance in some other dosage regimen (an average loading dose of 12.2patients, taking into account that this osmotic diuret- mg/kg + 6.1 mg/kg 12 hours apart on day 1 and 9.2ic may improve renal blood flow.[183]

mg/kg + 6.1 mg/kg 12 hours apart on day 2, fol-In critically ill patients with severe sepsis, the lowed by a daily maintenance dose of 6.1 mg/kg

clearance of ceftriaxone at a dosage of 2g every 24 every 12 hours) may enable, in most patients withhours was found to be almost doubled in comparison normal renal function, trough concentrations of te-with healthy volunteers.[81] Among the possible fac- icoplanin exceeding 10 mg/L at 24 hours (13 of 22tors responsible for this, the use of inotropes was patients) and approaching 20 mg/L at 72 hours (10considered to significantly contribute in three of ten of 22 patients). Some investigators believe that en-patients, therefore the investigators recommended a hancement in renal clearance of hydrophilic antimi-more aggressive dosage regimen of ceftriaxone in crobials in febrile neutropenic patients may be thethis setting by decreasing dosage interval or apply- consequence of fever and/or acute infectious dis-ing continuous intravenous infusion. ease.[189] However, our contention is that, consistent

2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (10)

1026 Pea et al.

with an acute protein load increasing renal blood moderately lipophilic antimicrobials. Appropriateflow,[190] an increased glomerular filtration rate oc- studies are advisable to confirm this hypothesis, butcurring as a consequence of huge renal load of physicians should meanwhile be aware that higherproteic cellular catabolites deriving from massive dosage regimens of most β-lactams should be appro-lysis of circulating cells may be a co-factor, at least priate whenever very high values of creatinine clear-in the early post-chemotherapy period.[92] ance are estimated in intravenous drug abusers, and

that even in this circumstance TDM may be helpfulBesides enhancement of renal function, it shouldin tailoring antimicrobial therapy to individual pa-not be overlooked that patients with acute leukaemiatients.may frequently present other underlying situations

that may also increase the Vd of drugs (i.e. hypoal-4.3 Causes of Reduced Renal Clearancebuminaemia, fluid overload and parenteral nutri-

tion). Therefore, higher than currently suggested4.3.1 Renal Failuredosages may probably be necessary for most hydro-In critically ill patients, renal failure may occurphilic antimicrobials, and TDM with the intent of

because of several different underlying diseases (i.e.ensuring optimal exposure in this special populationtrauma, multiple organ failure, extensive burns,should be performed wherever available. It is wor-cardiogenic or hypovolaemic shock) or it may bethy to note that we have recently shown that the useiatrogenically induced by nephrotoxic therapies (i.e.of continuous intravenous infusion may be a helpfulaminoglycosides, vancomycin, ciclosporin, metho-tool for maximising pharmacodynamic exposuretrexate). Moreover, it should not be overlooked thatwith ceftazidime in this special population.[191]

the simultaneous use of cathecholamines, by de-4.2.5 Drug Abuse creasing renal blood flow, may be associated with a

reduced clearance of renally eliminated drugs. LugoThere are only very few studies in the literatureand Castaneda-Hernandez[96] showed that the use ofassessing the possible role of drug abuse in alteringcathecholamines or even very high-dose dopaminethe disposition of antimicrobials. In 1985, King et(15 mg/kg/min) was significantly associated with aal.[93] evaluated the pharmacokinetics of gentamicindecrease of amikacin renal clearance in 30 criticallyand tobramycin in 18 drug abusers, observing that inill patients with severe Gram-negative sepsis.most patients (66%) a faster elimination of these

aminoglycosides occurred. Similar findings in intra- In these situations a reduction in the averagevenous drug abusers were also observed with two daily dosage of most hydrophilic and moderatelyglycopeptides (teicoplanin and vancomycin) in sub- lipophilic antimicrobials may be required to avoidsequent studies conducted by Rybak et al.[94,95] Inter- overexposure. In reality, the choice of appropriateestingly, in all three studies the investigators agreed dosage may be particularly difficult when applica-that the frequently increased glomerular filtration tion of renal replacement therapies (RRTs) is re-rate observed in drug abusers was the pathophysio- quired in ICU patients.logical mechanism responsible for the enhanced An in-depth analysis of the role of RRTs inclearance of these antimicrobials, and concluded modifying antimicrobial disposition is beyond thethat frequently more aggressive dosages may be aims of this review and readers are referred to othernecessary to ensure therapeutic concentrations in more comprehensive reviews,[192,193] however, itthis subpopulation. must be mentioned that extraction ratios of different

To the best of our knowledge no other major antimicrobials may vary greatly according to bothstudy evaluating the pharmacokinetics of antimicro- the intrinsic properties of the antimicrobials (physi-bials in this kind of patient population has been cochemical characteristics, molecular weight, plas-published recently; however, it seems extremely ma protein binding, elimination route) and the char-reasonable that similar enhanced elimination may acteristics of the applied RRT. Generally, intermit-occur for most renally eliminated hydrophilic and tent dialysis (usually 4 hours every 2 days) removes,

2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (10)

Disposition of Antimicrobials in Critically Ill Patients 1027

by means of diffusion, only renally eliminated an- 5. The Importance of a MultidisciplinaryTeam in Tailoring Antimicrobial Therapytimicrobials that have sufficiently low molecularin Critically Ill Patientsweight (<700) and negligible protein binding (most

β-lactams, aminoglycosides, some fluoroqui- Considering all the aforementioned factorsnolones). On the other hand, CVVH or continuous should be helpful for clinicians in appropriatelyvenovenous haemodiafiltration by means of convec- handling antimicrobials in critically ill patients.tion or convection plus diffusion, respectively, may However, specifically regarding antimicrobial use, a

decisional approach involving both the infectiousalso remove bulky antimicrobials (i.e. vancomycin);disease specialist and the clinical pharmacologistand through continuous application 24 hours a daymay surely be beneficial to streamline antimicrobialthey are often very efficacious techniques in drugtherapy in an attempt to maximise the outcome inremoval, especially when very high replacementthese difficult-to-treat patients.

flows are selected.[194]

The valuable role of the infectious disease spe-As a consequence, TDM may be especially im- cialist in appropriate management of antimicrobial

portant in tailoring antimicrobial therapy in patients use has been efficaciously debated by Petrak etundergoing RRT. al.[198] who emphasised, among others, the impor-

tance of instituting programmes of antimicrobial4.3.2 Muscle Wastage and Long-Term stewardship.Bedridden Patients In addition, considering that in critically ill pa-

tients several of the previously outlined underlyingAlthough kidney function is frequently assessedpathophysiological or iatrogenic situations may oft-on the basis of serum creatinine and estimated creat-en coexist in the same individual and that theinine clearance, in the presence of prolonged im-pharmacokinetic variability may be partially unpre-

mobilisation and/or extensive muscle trauma thesedictable, the antimicrobial policy may further bene-

parameters may often fail to estimate renal function fit from the application of TDM.appropriately in critically ill patients.[115] In a patient Several studies support the major role of TDM inwith spinal cord injury affected by staphylococcal tailoring antimicrobial therapy in critically ill pa-sepsis and Clostridium difficile colitis, the inappro- tients,[197,199] and many clinical trials have demon-

strated a positive impact of TDM on clinical out-priate estimation of creatinine clearance on the basiscome[114,200,201] and cost of hospitalisation,[202] andof serum creatinine and the Cockcroft and Gaultalso emphasised the importance of the consultantformula[195] was responsible for vancomycin over-clinical pharmacologist. Hansen et al.[114] evaluateddosage.[97] Subsequent measurement of 24-hour cre-the influence of the clinical pharmacologist in op-

atinine clearance revealed the actual value was 61%timising gentamicin dosage in critically ill patients

lower than predicted as a result of reduced creatinine by comparing conventional TDM versus so-calledproduction due to muscle atrophy.[196]

intensified TDM, which differed by including anassociated clinical pharmacologist who was respon-Likewise, dosage adjustments of antimicrobialssible for the dosage recommendations. Intensifiedbased on estimated renal function may cause antimi-TDM was significantly more efficacious in ensuringcrobial overdosage whenever ICU patients are bed-optimal peak plasma exposure to gentamicin, reduc-ridden for a long time (i.e. >3–4 weeks).[197]

ing time of hospitalisation, and preventing drug-Therefore, in these situations direct measurement related nephrotoxicity.[114] Likewise, at the Medical

of creatinine clearance is strongly advisable in order School, University of Udine, Italy, we have recentlyto avoid overestimation of renal clearance of antimi- assessed the role of TDM in optimising vancomycincrobials, and thereby overtreatment. exposure in critically ill patients by comparing dos-

2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (10)

1028 Pea et al.

Institute of Clinical Pharmacology & Toxicology - University of Udine - Italy

Patient's data collection formfor TDM of antimicrobial agents

Hospital department Physician sending enquiry

Patient's data

Birth date Weight (kg) Height (cm)

Male Female

sGOT sGPT Albuminaemia sCr CLCR

Underlying pathophysiological conditions infection site

fluid extravasation (pleuritis − mediastinitis − ascites − pericarditis − others..................) drainages

dialysis CVVH CVVHDF obesity (BMI..................)

burns (%)....... from days.......

hydration status sepsis haematological malignancies VAP

Aetiological agent MIC (mg/L)

Drug therapy Haemodynamically active drugs/diuretics:

furosemidemannitol

Antibacterial agent dopamine dobutamine

Reasons for TDM enquiry

PK interactionspossible undertreatment

possible overtreatmentimpairment of renal function

others

Data for TDM

Date Samplingtime

Drug Dosage Time of adms Time ofprevious adms

Comments:

Fig. 3. Patient data collection form for therapeutic drug monitoring (TDM) of antimicrobials. adms = administration; BMI = body mass index;CLCR = creatinine clearance; CVVH = continuous veno-venous haemofiltration; CVVHDF = continuous venovenous haemodiafiltration; MIC= minimum inhibitory concentration; PK = pharmacokinetics; sCr = serum creatinine; sGOT = serum glutamic-oxaloacetic transaminase;sGPT = serum glutamic-pyruvic transaminase; VAP = ventilator-associated pneumonia.

2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (10)

Disposition of Antimicrobials in Critically Ill Patients 1029

Sanofi-Aventis, and has also received grant support fromage adjustment suggested by the clinical pharmacol-and been on the speakers’ bureau for GlaxoSmithKline.ogist on the basis of TDM and Bayesian forecastingHe has also been on the speakers bureau for Abbott and

with that based on Moellering’s nomogram.[197]Wyeth. Mario Furlanut has received grant support from

Dosage adjustment based on the Bayesian method GlaxoSmithKline and Sanofi-Aventis.enabled more frequent achievement of the desiredtarget steady-state trough level of vancomycin (10 References

1. Vincent JL, Bihari DJ, Suter PM, et al. The prevalence ofmg/L); several underlying pathophysiological con-nosocomial infection in intensive care units in Europe. Resultsditions at least partially responsible for the unrelia-of the European Prevalence of Infection in Intensive Care

bility of Moellering’s nomogram in this population (EPIC) Study. EPIC International Advisory Committee.JAMA 1995; 274 (8): 639-44were also highlighted.[197]

2. Weber DJ, Raasch R, Rutala WA. Nosocomial infections in theAccordingly, at our institute several of the ICU: the growing importance of antibiotic-resistant pathogens.

Chest 1999; 115 (3 Suppl.): 34-41Santimicrobials most frequently used in the critical3. Vincent JL. Nosocomial infections in adult intensive-care units.care setting, namely meropenem, ceftazidime,

Lancet 2003; 361 (9374): 2068-77levofloxacin and ciprofloxacin, and not only narrow 4. Paterson DL. Restrictive antibiotic policies are appropriate in

intensive care units. Crit Care Med 2003; 31 (1 Suppl.): S25-8therapeutic index antimicrobials such as aminog-5. Emmerson M. Antibiotic usage and prescribing policies in thelycosides and glycopeptides, are routinely moni- intensive care unit. Intensive Care Med 2000; 26 Suppl. 1:

tored in real time with the intent of improving judi- S26-306. Eggimann P, Pittet D. Infection control in the ICU. Chest 2001;cious use of antimicrobials. To facilitate clinicians’

120 (6): 2059-93work and improve our consultation competence, a 7. Cohen ML. Epidemiology of drug resistance: implications for a

post-antimicrobial era. Science 1992; 257 (5073): 1050-5comprehensive data sheet (figure 3) with marked8. Marchese A, Schito GC, Debbia EA. Evolution of antibioticboxes including the most important variables that

resistance in gram-positive pathogens. J Chemother 2000; 12may affect drug disposition in critically ill patients (6): 459-62

9. Hooper DC. Emerging mechanisms of fluoroquinolone resis-has been developed.tance. Emerg Infect Dis 2001; 7 (2): 337-41

10. Bartley J. First case of VRSA identified in Michigan. Infect6. Conclusion Control Hosp Epidemiol 2002; 23 (8): 480

11. Vancomycin-resistant Staphylococcus aureus: Pennsylvania,2002. MMWR Morb Mortal Wkly Rep 2002; 51 (40): 902The data reviewed herein support the opportunity

12. Alvarez-Lerma F. Modification of empiric antibiotic treatmentof accurately assessing the particular underlying in patients with pneumonia acquired in the intensive care unit.ICU-Acquired Pneumonia Study Group. Intensive Care Medcircumstances of each critically ill patient to op-1996; 22 (5): 387-94timise their antimicrobial therapy, considering the

13. Luna CM, Vujacich P, Niederman MS, et al. Impact of BALpharmacokinetics of each drug, so that the useful- data on the therapy and outcome of ventilator-associated pneu-

monia. Chest 1997; 111 (3): 676-85ness of a multidisciplinary team involving several14. Leibovici L, Shraga I, Drucker M, et al. The benefit of appropri-pivotal skills – the clinical microbiologist, the infec- ate empirical antibiotic treatment in patients with bloodstream

tious disease specialist and the clinical pharmacolo- infection. J Intern Med 1998; 244 (5): 379-8615. Kollef MH, Ward S. The influence of mini-BAL cultures ongist – may be advocated with the intent of support-

patient outcomes: implications for the antibiotic managementing the intensivists and other specialists in the man- of ventilator-associated pneumonia. Chest 1998; 113 (2): 412-

20agement of hospital antimicrobial policy.16. Barcenilla F, Gasco E, Rello J, et al. Antibacterial treatment of

invasive mechanical ventilation-associated pneumonia. DrugsAcknowledgements Aging 2001; 18 (3): 189-200

17. Bergogne-Berezin E. Guidelines on antimicrobial chemothera-No sources of funding were used to assist in the prepara- py for prevention and treatment of infections in the intensive

care unit. J Chemother 2001; 13 Spec. No. 1 (1): 134-49tion of this review. Federico Pea has been a consultant for,18. Carter AB, Hornick DB. Therapy for ventilator-associatedand has been on the speakers’ bureau for Sanofi-Aventis,

pneumonia. Clin Chest Med 1999; 20 (3): 681-91and has also been on the speakers’ bureau for Abbott,19. Singh N, Yu VL. Rational empiric antibiotic prescription in theGlaxoSmithKline, Merck Sharp & Dohme and Pfizer- ICU. Chest 2000; 117 (5): 1496-9

Pharmacia. Pierluigi Viale has been a consultant for, has 20. Antonelli M, Mercurio G, Di Nunno S, et al. De-escalationreceived grant support from, and has been on the speakers’ antimicrobial chemotherapy in critically ill patients: pros andbureau for Merck Sharp & Dohme, Pfizer-Pharmacia and cons. J Chemother 2001; 13 Spec. No. 1 (1): 218-23

2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (10)

1030 Pea et al.

21. Hoffken G, Niederman MS. Nosocomial pneumonia: the impor- 42. Craig WA. Basic pharmacodynamics of antibacterials withtance of a de-escalating strategy for antibiotic treatment of clinical applications to the use of beta-lactams, glycopeptides,pneumonia in the ICU. Chest 2002; 122 (6): 2183-96 and linezolid. Infect Dis Clin North Am 2003; 17 (3): 479-501

22. Niederman MS. Appropriate use of antimicrobial agents: chal- 43. Forrest A, Nix DE, Ballow CH, et al. Pharmacodynamics oflenges and strategies for improvement. Crit Care Med 2003; 31 intravenous ciprofloxacin in seriously ill patients. Antimicrob(2): 608-16 Agents Chemother 1993; 37 (5): 1073-81

23. Houghton D. Antimicrobial resistance in the intensive care unit: 44. Schentag JJ. Clinical pharmacology of the fluoroquinolones:understanding the problem. AACN Clin Issues 2002; 13 (3): studies in human dynamic/kinetic models. Clin Infect Dis410-20 2000; 31 Suppl. 2: S40-4

24. Pujol M, Gudiol F. Evidence for antibiotic cycling in control of 45. Ambrose PG, Grasela DM, Grasela TH, et al. Pharmacodynam-resistance. Curr Opin Infect Dis 2001; 14 (6): 711-5 ics of fluoroquinolones against Streptococcus pneumoniae in

25. McGowan Jr JE. Strategies for study of the role of cycling on patients with community-acquired respiratory tract infections.antimicrobial use and resistance. Infect Control Hosp Epidemi- Antimicrob Agents Chemother 2001; 45 (10): 2793-7ol 2000; 21 (1 Suppl.): S36-43 46. Nightingale CH, Grant EM, Quintiliani R. Pharmacodynamics

26. Gerding DN. Antimicrobial cycling: lessons learned from the and pharmacokinetics of levofloxacin. Chemotherapy 2000;aminoglycoside experience. Infect Control Hosp Epidemiol 46 Suppl. 1: 6-142000; 21 (1 Suppl.): S12-7 47. Preston SL, Drusano GL, Berman AL, et al. Pharmacodynamics

27. Kollef MH. Is there a role for antibiotic cycling in the intensive of levofloxacin: a new paradigm for early clinical trials. JAMAcare unit? Crit Care Med 2001; 29 (4 Suppl.): N135-42 1998; 279 (2): 125-9

28. Gruson D, Hilbert G, Vargas F, et al. Strategy of antibiotic 48. Rodvold KA, Neuhauser M. Pharmacokinetics and pharmaco-rotation: long-term effect on incidence and susceptibilities of dynamics of fluoroquinolones. Pharmacotherapy 2001; 21 (10Gram-negative bacilli responsible for ventilator-associated Pt 2): 233-52Spneumonia. Crit Care Med 2003; 31 (7): 1908-14

49. Aminimanizani A, Beringer P, Jelliffe R. Comparative29. Himmelberg CJ, Pleasants RA, Weber DJ, et al. Use of antimi- pharmacokinetics and pharmacodynamics of the newer fluoro-

crobial drugs in adults before and after removal of a restriction quinolone antibacterials. Clin Pharmacokinet 2001; 40 (3):policy. Am J Hosp Pharm 1991; 48 (6): 1220-7 169-87

30. John Jr JF, Fishman NO. Programmatic role of the infectious 50. Turnidge J. Pharmacokinetics and pharmacodynamics of fluoro-diseases physician in controlling antimicrobial costs in the quinolones. Drugs 1999; 58 Suppl. 2: 29-36hospital. Clin Infect Dis 1997; 24 (3): 471-85

51. Burgess DS. Pharmacodynamic principles of antimicrobial ther-31. Evans RS, Pestotnik SL, Classen DC, et al. A computer-assisted apy in the prevention of resistance. Chest 1999; 115 (3 Suppl.):

management program for antibiotics and other antiinfective 19-23Sagents. N Engl J Med 1998; 338 (4): 232-8

52. Odenholt I. Pharmacodynamic effects of subinhibitory antibiot-32. Hyatt JM, McKinnon PS, Zimmer GS, et al. The importance ofic concentrations. Int J Antimicrob Agents 2001; 17 (1): 1-8pharmacokinetic/pharmacodynamic surrogate markers to out-

53. Olsen KM, Rudis MI, Rebuck JA, et al. Effect of once-dailycome: focus on antibacterial agents. Clin Pharmacokinet 1995;dosing vs multiple daily dosing of tobramycin on enzyme28 (2): 143-60markers of nephrotoxicity. Crit Care Med 2004; 32 (8): 1678-33. Hyatt JM, Schentag JJ. Potential role of pharmacokinetics,82pharmacodynamics, and computerized databases in controlling

54. Muller M, dela Pena A, Derendorf H. Issues in pharmacokinet-bacterial resistance. Infect Control Hosp Epidemiol 2000; 21ics and pharmacodynamics of anti-infective agents: distribu-(1 Suppl.): S18-21tion in tissue. Antimicrob Agents Chemother 2004; 48 (5):34. Schentag JJ. Antimicrobial action and pharmacokinetics/phar-1441-53macodynamics: the use of AUIC to improve efficacy and avoid

55. Pea F, Pavan F, Nascimben E, et al. Levofloxacin disposition inresistance. J Chemother 1999; 11 (6): 426-39cerebrospinal fluid in patients with external ventriculostomy.35. Thomas JK, Forrest A, Bhavnani SM, et al. PharmacodynamicAntimicrob Agents Chemother 2003; 47 (10): 3104-8evaluation of factors associated with the development of bacte-

rial resistance in acutely ill patients during therapy. Antimi- 56. Pea F, Pavan F, Di Qual E, et al. Urinary pharmacokinetics andcrob Agents Chemother 1998; 42 (3): 521-7 theoretical pharmacodynamics of intravenous levofloxacin in

intensive care unit patients treated with 500mg bid for ventila-36. Schentag JJ. Antimicrobial management strategies for Gram-tor-associated pneumonia. J Chemother 2003; 15 (6): 563-7positive bacterial resistance in the intensive care unit. Crit Care

Med 2001; 29 (4 Suppl.): N100-7 57. Boy D, Well M, Kinzig-Schippers M, et al. Urinary bactericidalactivity, urinary excretion and plasma concentrations of ga-37. Craig WA. Pharmacokinetic/pharmacodynamic parameters: ra-tifloxacin (400mg) versus ciprofloxacin (500mg) in healthytionale for antibacterial dosing of mice and men. Clin Infectvolunteers after a single oral dose. Int J Antimicrob AgentsDis 1998; 26 (1): 1-102004; 23 Suppl. 1: S6-1638. Craig WA. Choosing an antibiotic on the basis of pharmacody-

namics. Ear Nose Throat J 1998; 77 (6 Suppl.): 7-11 58. Garey KW, Amsden GW. Intravenous azithromycin. AnnPharmacother 1999; 33 (2): 218-2839. Mouton JW, Vinks AA. Is continuous infusion of beta-lactam

antibiotics worthwhile? Efficacy and pharmacokinetic consid- 59. Vrhovac B, Sarapa N, Bakran I, et al. Pharmacokinetic changeserations. J Antimicrob Chemother 1996; 38 (1): 5-15 in patients with oedema. Clin Pharmacokinet 1995; 28 (5):

405-1840. MacKenzie FM, Gould IM. The post-antibiotic effect. J Antimi-crob Chemother 1993; 32 (4): 519-37 60. Pinder M, Bellomo R, Lipman J. Pharmacological principles of

41. MacGowan AP, Bowker KE. Continuous infusion of beta- antibiotic prescription in the critically ill. Anaesth Intensivelactam antibiotics. Clin Pharmacokinet 1998; 35 (5): 391-402 Care 2002; 30 (2): 134-44

2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (10)

Disposition of Antimicrobials in Critically Ill Patients 1031

61. Westphal JF, Brogard JM. Clinical pharmacokinetics of newer 79. Pea F, Brollo L, Lugano M, et al. Therapeutic drug monitoring-antibacterial agents in liver disease. Clin Pharmacokinet 1993; guided high teicoplanin dosage regimen required to treat a24 (1): 46-58 hypoalbuminemic renal transplant patient undergoing continu-

ous venovenous hemofiltration. Ther Drug Monit 2001; 23 (5):62. Park JM, Lin YS, Calamia JC, et al. Transiently altered acetami-587-8nophen metabolism after liver transplantation. Clin Pharmacol

80. Sanchez A, Lopez-Herce J, Cueto E, et al. TeicoplaninTher 2003; 73 (6): 545-53pharmacokinetics in critically ill paediatric patients. J Antimi-63. Dorman T, Swoboda S, Zarfeshenfard F, et al. Impact of alteredcrob Chemother 1999; 44 (3): 407-9aminoglycoside volume of distribution on the adequacy of a

81. Joynt GM, Lipman J, Gomersall CD, et al. The pharmacokinet-three milligram per kilogram loading dose. Critical Care Re-ics of once-daily dosing of ceftriaxone in critically ill patients.search Group. Surgery 1998; 124 (1): 73-8J Antimicrob Chemother 2001; 47 (4): 421-964. Zaske DE, Cipolle RJ, Strate RJ. Gentamicin dosage require-

82. Mimoz O, Soreda S, Padoin C, et al. Ceftriaxone pharmacoki-ments: wide interpatient variations in 242 surgery patients withnetics during iatrogenic hydroxyethyl starch-induced hypoal-normal renal function. Surgery 1980; 87 (2): 164-9buminemia: a model to explore the effects of decreased protein

65. Tang GJ, Tang JJ, Lin BS, et al. Factors affecting gentamicin binding capacity on highly bound drugs. Anesthesiology 2000;pharmacokinetics in septic patients. Acta Anaesthesiol Scand 93 (3): 735-431999; 43 (7): 726-30

83. Bonapace CR, White RL, Friedrich LV, et al. Pharmacokinetics66. Brunner M, Pernerstorfer T, Mayer BX, et al. Surgery and of cefepime in patients with thermal burn injury. Antimicrob

intensive care procedures affect the target site distribution of Agents Chemother 1999; 43 (12): 2848-54piperacillin. Crit Care Med 2000; 28 (6): 1754-9 84. Sampol E, Jacquet A, Viggiano M, et al. Plasma, urine and skin

67. Joukhadar C, Frossard M, Mayer BX, et al. Impaired target site pharmacokinetics of cefepime in burns patients. J Antimicrobpenetration of beta-lactams may account for therapeutic failure Chemother 2000; 46 (2): 315-7in patients with septic shock. Crit Care Med 2001; 29 (2): 385- 85. Pea F, Di Qual E, Cusenza A, et al. Pharmacokinetics and91 pharmacodynamics of intravenous levofloxacin in patients

68. Joukhadar C, Klein N, Mayer BX, et al. Plasma and tissue with early-onset ventilator-associated pneumonia. Clin Phar-pharmacokinetics of cefpirome in patients with sepsis. Crit macokinet 2003; 42 (6): 589-98Care Med 2002; 30 (7): 1478-82 86. Lipman J, Wallis SC, Rickard C. Low plasma cefepime levels in

69. Gomez CM, Cordingly JJ, Palazzo MG. Altered pharmacokinet- critically ill septic patients: pharmacokinetic modeling indi-ics of ceftazidime in critically ill patients. Antimicrob Agents cates improved troughs with revised dosing. AntimicrobChemother 1999; 43 (7): 1798-802 Agents Chemother 1999; 43 (10): 2559-61

87. Lipman J, Wallis SC, Boots RJ. Cefepime versus cefpirome: the70. Hanes SD, Wood GC, Herring V, et al. Intermittent and continu-importance of creatinine clearance. Anesth Analg 2003; 97 (4):ous ceftazidime infusion for critically ill trauma patients. Am J1149-54Surg 2000; 179 (6): 436-40

88. Pea F, Porreca L, Baraldo M, et al. High vancomycin dosage71. McKindley DS, Boucher BA, Hess MM, et al. Pharmacokineticsregimens required by intensive care unit patients cotreatedof aztreonam and imipenem in critically ill patients with pneu-with drugs to improve haemodynamics following cardiac sur-monia. Pharmacotherapy 1996; 16 (5): 924-31gical procedures. J Antimicrob Chemother 2000; 45 (3):72. Botha FJ, van der Bijl P, Seifart HI, et al. Fluctuation of the329-35volume of distribution of amikacin and its effect on once-daily

89. Fernandez de Gatta MM, Fruns I, Hernandez JM, et al. Vanco-dosage and clearance in a seriously ill patient. Intensive Caremycin pharmacokinetics and dosage requirements in hemato-Med 1996; 22 (5): 443-6logic malignancies. Clin Pharm 1993; 12 (7): 515-20

73. Gous AG, Dance MD, Lipman J, et al. Changes in vancomycin90. Le Normand Y, Milpied N, Kergueris MF, et al. Pharmacokinet-pharmacokinetics in critically ill infants. Anaesth Intensive

ic parameters of vancomycin for therapeutic regimens in neu-Care 1995; 23 (6): 678-82tropenic adult patients. Int J Biomed Comput 1994; 36 (1-2):

74. Ronchera-Oms CL, Tormo C, Ordovas JP, et al. Expanded 121-5gentamicin volume of distribution in critically ill adult patients 91. Chang D. Influence of malignancy on the pharmacokinetics ofreceiving total parenteral nutrition. J Clin Pharm Ther 1995; 20 vancomycin in infants and children. Pediatr Infect Dis J 1995;(5): 253-8 14 (8): 667-73

75. Etzel JV, Nafziger AN, Bertino Jr JS. Variation in the 92. Pea F, Viale P, Candoni A, et al. Acute leukemic patients withpharmacokinetics of gentamicin and tobramycin in patients febrile neutropenia: a special population benefiting fromwith pleural effusions and hypoalbuminemia. Antimicrob higher dosing regimen of teicoplanin. Clin PharmacokinetAgents Chemother 1992; 36 (3): 679-81 2004; 43 (6): 405-15

76. Aldaz A, Ortega A, Idoate A, et al. Effects of hepatic function 93. King CH, Creger RJ, Ellner JJ. Pharmacokinetics of tobramycinon vancomycin pharmacokinetics in patients with cancer. Ther and gentamicin in abusers of intravenous drugs. AntimicrobDrug Monit 2000; 22 (3): 250-7 Agents Chemother 1985; 27 (3): 285-90

77. Buijk SL, Gyssens IC, Mouton JW, et al. Pharmacokinetics of 94. Rybak MJ, Lerner SA, Levine DP, et al. Teicoplaninceftazidime in serum and peritoneal exudate during continuous pharmacokinetics in intravenous drug abusers being treated forversus intermittent administration to patients with severe intra- bacterial endocarditis. Antimicrob Agents Chemother 1991;abdominal infections. J Antimicrob Chemother 2002; 49 (1): 35 (4): 696-700121-8 95. Rybak MJ, Bailey EM, Lamp KC, et al. Pharmacokinetics and

78. Romano S, Fernandez de Gatta MM, Calvo MV, et al. Popula- bactericidal rates of daptomycin and vancomycin in intrave-tion pharmacokinetics of amikacin in patients with haemato- nous drug abusers being treated for gram-positive endocarditislogical malignancies. J Antimicrob Chemother 1999; 44 (2): and bacteremia. Antimicrob Agents Chemother 1992; 36 (5):235-42 1109-14

2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (10)

1032 Pea et al.

96. Lugo G, Castaneda-Hernandez G. Relationship between hemo- pharmacokinetic modelling calls for more frequent dosing.dynamic and vital support measures and pharmacokinetic vari- Intensive Care Med 2001; 27 (2): 363-70ability of amikacin in critically ill patients with sepsis. Crit 117. Eid AA, Keddissi JI, Kinasewitz GT. Hypoalbuminemia as aCare Med 1997; 25 (5): 806-11 cause of pleural effusions. Chest 1999; 115 (4): 1066-9

97. Pea F, Furlanut M, Bianchi L. Systemic vancomycin overexpo- 118. Makino J, Yoshiyama Y, Kanke M, et al. Pharmacokinetic studysure in a patient with spinal cord injury who had Staphylococ- of penetration of meropenem into pleural effusion in patientscal sepsis and Clostridium difficile colitis. Ther Drug Monit with pleurisy. Jpn J Antibiot 2002; 55 (1): 77-882000; 22 (2): 233-4 119. Goonetilleke AK, Dev D, Aziz I, et al. A comparative analysis

98. Pea F, Furlanut M. Pharmacokinetic aspects of treating infec- of pharmacokinetics of ceftriaxone in serum and pleural fluidtions in the intensive care unit: focus on drug interactions. Clin in humans: a study of once daily administration by intramuscu-Pharmacokinet 2001; 40 (11): 833-68 lar and intravenous routes. J Antimicrob Chemother 1996; 38

(6): 969-7699. Wada DR, Drover DR, Lemmens HJ. Determination of the120. Kimura M, Matsushima T, Nakamura J, et al. Comparativedistribution volume that can be used to calculate the intrave-

study of penetration of lomefloxacin and ceftriaxone intonous loading dose. Clin Pharmacokinet 1998; 35 (1): 1-7transudative and exudative pleural effusion. Antimicrob100. Bone RC. The pathogenesis of sepsis. Ann Intern Med 1991;Agents Chemother 1992; 36 (12): 2774-7115 (6): 457-69

121. Scaglione F, Raichi M, Fraschini F. Serum protein binding and101. Glauser MP, Zanetti G, Baumgartner JD, et al. Septic shock:extravascular diffusion of methoxyimino cephalosporins: timepathogenesis. Lancet 1991; 338 (8769): 732-6courses of free and total concentrations of cefotaxime and102. Denaro CP, Ravenscroft PJ. Usefulness of estimating individualceftriaxone in serum and pleural exudate. J Antimicrobpharmacokinetic data for aminoglycoside therapy in seriouslyChemother 1990; 26 Suppl. A: 1-10ill patients. Aust N Z J Med 1987; 17 (5): 526-32

122. Miglioli PA, Pivetta P, Fantoni U, et al. Penetration of aztre-103. Summer WR, Michael JR, Lipsky JJ. Initial aminoglycosideonam into pleural exudate following rapid intravenous bolus orlevels in the critically ill. Crit Care Med 1983; 11 (12): 948-50constant infusion. Chemotherapy 1990; 36 (5): 321-4

104. Kloth DD, Tegtmeier BR, Kong C, et al. Altered gentamicin123. Limthongkul S, Charoenlap P, Nuchprayoon CJ, et al. Amikacinpharmacokinetics during the perioperative period. Clin Pharm

pharmacokinetics in plasma and pleural fluid. J Med Assoc1985; 4 (2): 182-5Thai 1989; 72 (2): 90-6

105. Chelluri L, Jastremski MS. Inadequacy of standard aminoglyco- 124. Limthongkul S, Poshyachinda M, Charoenlap P, et al. Gentam-side loading doses in acutely ill patients. Crit Care Med 1987; icin, tobramycin and netilmicin pharmacokinetics in plasma15 (12): 1143-5 and pleural fluid. J Med Assoc Thai 1988; 71 (10): 541-7

106. Fuhs DW, Mann HJ, Kubajak CA, et al. Intrapatient variation of 125. Barrueco M, Otero MJ, Garcia MJ, et al. Pleural fluid levels ofaminoglycoside pharmacokinetics in critically ill surgery pa- cefoxitin in patients with renal impairment. Int J Clintients. Clin Pharm 1988; 7 (3): 207-13 Pharmacol Ther Toxicol 1986; 24 (9): 485-9

107. Chelluri L, Warren J, Jastremski MS. Pharmacokinetics of a 3 126. Benoni G, Arosio E, Cuzzolin L, et al. Penetration of ceftriax-mg/kg body weight loading dose of gentamicin or tobramycin one into human pleural fluid. Antimicrob Agents Chemotherin critically ill patients. Chest 1989; 95 (6): 1295-7 1986; 29 (5): 906-8

108. Mann HJ, Fuhs DW, Awang R, et al. Altered aminoglycoside 127. Garcia MJ, Otero MJ, Barrueco M, et al. Pharmacokinetics ofpharmacokinetics in critically ill patients with sepsis. Clin cefoxitin in patients with pleural effusion on a multiple dosagePharm 1987; 6 (2): 148-53 regimen. Int J Clin Pharmacol Ther Toxicol 1984; 22 (6):

109. Niemiec PW, Allo MD, Miller CF. Effect of altered volume of 300-3distribution on aminoglycoside levels in patients in surgical 128. Lechi A, Arosio E, Xerri L, et al. The kinetics of cefuroxime inintensive care. Arch Surg 1987; 122 (2): 207-12 ascitic and pleural fluid. Int J Clin Pharmacol Ther Toxicol

110. Dasta JF, Armstrong DK. Variability in aminoglycoside 1982; 20 (10): 493-6pharmacokinetics in critically ill surgical patients. Crit Care 129. Barrueco M, Garcia MJ, Otero MJ, et al. Disposition of cefoxi-Med 1988; 16 (4): 327-30 tin in patients with pleural effusion. Clin Ther 1981; 3 (6): 425-

111. Beckhouse MJ, Whyte IM, Byth PL, et al. Altered aminoglyco- 35side pharmacokinetics in the critically ill. Anaesth Intensive 130. Joseph J, Vaughan LM, Basran GS. Penetration of intravenousCare 1988; 16 (4): 418-22 and oral ciprofloxacin into sterile and empyemic human pleu-

112. Townsend PL, Fink MP, Stein KL, et al. Aminoglycoside ral fluid. Ann Pharmacother 1994; 28 (3): 313-5pharmacokinetics: dosage requirements and nephrotoxicity in 131. Walstad RA, Hellum KB, Blika S, et al. Pharmacokinetics andtrauma patients. Crit Care Med 1989; 17 (2): 154-7 tissue penetration of ceftazidime: studies on lymph, aqueous

113. Triginer C, Izquierdo I, Fernandez R, et al. Gentamicin volume humour, skin blister, cerebrospinal and pleural fluid. J Antimi-of distribution in critically ill septic patients. Intensive Care crob Chemother 1983; 12 Suppl. A: 275-82Med 1990; 16 (5): 303-6 132. Teixeira LR, Sasse SA, Villarino MA, et al. Antibiotic levels in

114. Hansen M, Christrup LL, Jarlov JO, et al. Gentamicin dosing in empyemic pleural fluid. Chest 2000; 117 (6): 1734-9critically ill patients. Acta Anaesthesiol Scand 2001; 45 (6): 133. Henriksen JH, Kiszka-Kanowitz M, Bendtsen F. Review article:734-40 volume expansion in patients with cirrhosis. Aliment

Pharmacol Ther 2002; 16 Suppl. 5: 12-23115. De Paepe P, Belpaire FM, Buylaert WA. Pharmacokinetic andpharmacodynamic considerations when treating patients with 134. Gill MA, Kern JW. Altered gentamicin distribution in asciticsepsis and septic shock. Clin Pharmacokinet 2002; 41 (14): patients. Am J Hosp Pharm 1979; 36 (12): 1704-61135-51 135. Lanao JM, Dominguez-Gil A, Macias JG, et al. The influence of

116. Lipman J, Wallis SC, Rickard CM, et al. Low cefpirome levels ascites on the pharmacokinetics of amikacin. Int J Clinduring twice daily dosing in critically ill septic patients: Pharmacol Ther Toxicol 1980; 18 (2): 57-61

2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (10)

Disposition of Antimicrobials in Critically Ill Patients 1033

136. Sampliner R, Perrier D, Powell R, et al. Influence of ascites on 158. Adam D, Zellner PR, Koeppe P, et al. Pharmacokinetics oftobramycin pharmacokinetics. J Clin Pharmacol 1984; 24 (1): ticarcillin/clavulanate in severely burned patients. J Antimi-43-6 crob Chemother 1989; 24 Suppl. B: 121-9

159. Walstad RA, Aanderud L, Thurmann-Nielsen E. Pharmacoki-137. Lewis GP, Jusko WJ. Pharmacokinetics of ampicillin in cirrho-netics and tissue concentrations of ceftazidime in burn pa-sis. Clin Pharmacol Ther 1975; 18 (4): 475-84tients. Eur J Clin Pharmacol 1988; 35 (5): 543-9138. Benoni G, Arosio E, Raimondi MG, et al. Distribution of

160. Yoshida T, Homma K, Fujioka H, et al. Fundamental andceftazidime in ascitic fluid. Antimicrob Agents Chemotherclinical studies on meropenem in burn infections. J Chemother1984; 25 (6): 760-31993; 5 Suppl. 1: 142-3139. el Touny M, el Guinaidy MA, Abdel Barry M, et al. Pharma-

161. Friedrich LV, White RL, Kays MB, et al. Aztreonam pharma-cokinetics of ceftazidime in patients with liver cirrhosis andcokinetics in burn patients. Antimicrob Agents Chemotherascites. J Antimicrob Chemother 1991; 28 (1): 95-1001991; 35 (1): 57-61140. Stoeckel K, Koup JR. Pharmacokinetics of ceftriaxone in pa-

162. Brater DC, Bawdon RE, Anderson SA, et al. Vancomycintients with renal and liver insufficiency and correlations with aelimination in patients with burn injury. Clin Pharmacol Therphysiologic nonlinear protein binding model. Am J Med 1984;1986; 39 (6): 631-477 (4C): 26-32

163. Garrelts JC, Peterie JD. Altered vancomycin dose vs serum141. Hary L, Andrejak M, Leleu S, et al. The pharmacokinetics ofconcentration relationship in burn patients. Clin Pharmacolceftriaxone and cefotaxime in cirrhotic patients with ascites.Ther 1988; 44 (1): 9-13Eur J Clin Pharmacol 1989; 36 (6): 613-6

164. Rybak MJ, Albrecht LM, Berman JR, et al. Vancomycin142. Hary L, Smail A, Ducroix JP, et al. Pharmacokinetics and asciticpharmacokinetics in burn patients and intravenous drug abus-fluid penetration of piperacillin in cirrhosis. Fundam Cliners. Antimicrob Agents Chemother 1990; 34 (5): 792-5Pharmacol 1991; 5 (9): 789-95

165. Potel G, Moutet J, Bernareggi A, et al. Pharmacokinetics of143. el Touny M, el Guinaidy M, Abdel Barry M, et al. Pharmacoki-teicoplanin in burn patients. Scand J Infect Dis Suppl 1990; 72:netics of aztreonam in patients with liver cirrhosis and ascites.29-34J Antimicrob Chemother 1992; 30 (3): 387-95

166. Steer JA, Papini RP, Wilson AP, et al. Pharmacokinetics of a144. Montay G, Gaillot J. Pharmacokinetics of fluoroquinolones insingle dose of teicoplanin in burn patients. J Antimicrobhepatic failure. J Antimicrob Chemother 1990; 26 Suppl. B:Chemother 1996; 37 (3): 545-5361-7

167. Garrelts JC, Jost G, Kowalsky SF, et al. Ciprofloxacin145. Lugo G, Castaneda-Hernandez G. Amikacin Bayesian forecast-pharmacokinetics in burn patients. Antimicrob Agentsing in critically ill patients with sepsis and cirrhosis. Ther DrugChemother 1996; 40 (5): 1153-6Monit 1997; 19 (3): 271-6

168. Boucher BA, Hickerson WL, Kuhl DA, et al. Imipenem146. Rosenbaum GS, Klein NC, Cunha BA. Poststernotomy medias-pharmacokinetics in patients with burns. Clin Pharmacol Thertinitis. Heart Lung 1990; 19 (4): 371-21990; 48 (2): 130-7

147. Wilkes MM, Navickis RJ. Patient survival after human albumin169. Bourget P, Lesne-Hulin A, Le Reveille R, et al. Clinical phar-administration: a meta-analysis of randomized, controlled tri-

macokinetics of piperacillin-tazobactam combination in pa-als. Ann Intern Med 2001; 135 (3): 149-64tients with major burns and signs of infection. Antimicrob

148. Worman LW. The role of fluid sequestration in the pathogenesis Agents Chemother 1996; 40 (1): 139-45of mediastinitis. Am J Surg 1966; 111 (6): 813-8

170. Lesne-Hulin A, Bourget P, Ravat F, et al. Clinical149. Lovering AM, Zhang J, Bannister GC, et al. Penetration of pharmacokinetics of ciprofloxacin in patients with major

linezolid into bone, fat, muscle and haematoma of patients burns. Eur J Clin Pharmacol 1999; 55 (7): 515-9undergoing routine hip replacement. J Antimicrob Chemother 171. Weinbren MJ. Pharmacokinetics of antibiotics in burns patients.2002; 50 (1): 73-7 J Antimicrob Chemother 2001; 47 (5): 720

150. Rowland M. Clinical pharmacokinetics of teicoplanin. Clin 172. Hoey LL, Tschida SJ, Rotschafer JC, et al. Wide variation inPharmacokinet 1990; 18 (3): 184-209 single, daily-dose aminoglycoside pharmacokinetics in pa-

151. Jaehde U, Sorgel F. Clinical pharmacokinetics in patients with tients with burn injuries. J Burn Care Rehabil 1997; 18 (2):burns. Clin Pharmacokinet 1995; 29 (1): 15-28 116-24

152. Weinbren MJ. Pharmacokinetics of antibiotics in burn patients. 173. Rice TL. Simplified dosing and monitoring of vancomycin forJ Antimicrob Chemother 1999; 44 (3): 319-27 the burn care clinician. Burns 1992; 18 (5): 355-61

153. Lesne-Hulin A, Bourget P, Le Bever H, et al. Therapeutic 174. Boucher BA, Kuhl DA, Hickerson WL. Pharmacokinetics ofmonitoring of teicoplanin in a severely burned patient. Ann Fr systemically administered antibiotics in patients with thermalAnesth Reanim 1997; 16 (4): 374-7 injury. Clin Infect Dis 1992; 14 (2): 458-63

154. Zaske DE, Sawchuk RJ, Gerding DN, et al. Increased dosage 175. Fry DE. The importance of antibiotic pharmacokinetics in criti-requirements of gentamicin in burn patients. J Trauma 1976; cal illness. Am J Surg 1996; 172 (6A): 20-5S16 (10): 824-8 176. Lipman J, Scribante J, Gous AG, et al. Pharmacokinetic profiles

155. Zaske DE, Chin T, Kohls PR, et al. Initial dosage regimens of of high-dose intravenous ciprofloxacin in severe sepsis. Thegentamicin in patients with burns. J Burn Care Rehabil 1991; Baragwanath Ciprofloxacin Study Group. Antimicrob Agents12 (1): 46-50 Chemother 1998; 42 (9): 2235-9

156. Zaske DE, Sawchuk RJ, Strate RG. The necessity of increased 177. Olsen NV. Effects of dopamine on renal haemodynamics tubu-doses of amikacin in burn patients. Surgery 1978; 84 (5): 603-8 lar function and sodium excretion in normal humans. Dan Med

Bull 1998; 45 (3): 282-97157. Loirat P, Rohan J, Baillet A, et al. Increased glomerular filtra-tion rate in patients with major burns and its effect on the 178. Lass NA, Glock D, Goldberg LI. Cardiovascular and renalpharmacokinetics of tobramycin. N Engl J Med 1978; 299 hemodynamic effects of intravenous infusions of the selective(17): 915-9 DA1 agonist, fenoldopam, used alone or in combination with

2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (10)

1034 Pea et al.

dopamine and dobutamine. Circulation 1988; 78 (5 Pt 1): 192. Bohler J, Donauer J, Keller F. Pharmacokinetic principles dur-1310-5 ing continuous renal replacement therapy: drugs and dosage.

Kidney Int Suppl 1999; 72: S24-8179. Ludens JH, Hook JB, Brody MJ, et al. Enhancement of renalblood flow by furosemide. J Pharmacol Exp Ther 1968; 163 193. Bugge JF. Pharmacokinetics and drug dosing adjustments dur-(2): 456-60 ing continuous venovenous hemofiltration or hemodiafiltra-

tion in critically ill patients. Acta Anaesthesiol Scand 2001; 45180. Ichai C, Passeron C, Carles M, et al. Prolonged low-dose(8): 929-34dopamine infusion induces a transient improvement in renal

function in hemodynamically stable, critically ill patients: a 194. Mueller BA, Pasko DA, Sowinski KM. Higher renal replace-single-blind, prospective, controlled study. Crit Care Med

ment therapy dose delivery influences on drug therapy. Artif2000; 28 (5): 1329-35Organs 2003; 27 (9): 808-14

181. Ichai C, Soubielle J, Carles M, et al. Comparison of the renal195. Cockcroft DW, Gault MH. Prediction of creatinine clearanceeffects of low to high doses of dopamine and dobutamine in

from serum creatinine. Nephron 1976; 16 (1): 31-41critically ill patients: a single-blind randomized study. CritCare Med 2000; 28 (4): 921-8 196. Mohler JL, Barton SD, Blouin RA, et al. The evaluation of

creatinine clearance in spinal cord injury patients. J Urol 1986;182. Moellering Jr RC, Krogstad DJ, Greenblatt DJ. Vancomycin136 (2): 366-9therapy in patients with impaired renal function: a nomogram

for dosage. Annals of Internal Medicine 1981; 94: 343-6197. Pea F, Bertolissi M, Di Silvestre A, et al. TDM coupled with

183. Lang F. Osmotic diuresis. Ren Physiol 1987; 10 (3-4): 160-73 Bayesian forecasting should be considered an invaluable toolfor optimizing vancomycin daily exposure in unstable critical-184. Kaojarern S, Maoleekoonpairoj S, Atichartakarn V. Pharma-ly ill patients. Int J Antimicrob Agents 2002; 20 (5): 326-32cokinetics of amikacin in hematologic malignancies. Antimi-

crob Agents Chemother 1989; 33 (8): 1406-8 198. Petrak RM, Sexton DJ, Butera ML, et al. The value of aninfectious diseases specialist. Clin Infect Dis 2003; 36 (8):185. Tod M, Lortholary O, Seytre D, et al. Population pharmacoki-1013-7netic study of amikacin administered once or twice daily to

febrile, severely neutropenic adults. Antimicrob Agents 199. Buijk SE, Mouton JW, Gyssens IC, et al. Experience with aChemother 1998; 42 (4): 849-56 once-daily dosing program of aminoglycosides in critically ill

186. Zeitany RG, el Saghir NS, Santhosh-Kumar CR, et al. Increased patients. Intensive Care Med 2002; 28 (7): 936-42aminoglycoside dosage requirements in hematologic malig-

200. Bartal C, Danon A, Schlaeffer F, et al. Pharmacokinetic dosingnancy. Antimicrob Agents Chemother 1990; 34 (5): 702-8of aminoglycosides: a controlled trial. Am J Med 2003; 114

187. Lortholary O, Tod M, Rizzo N, et al. Population pharmacokinet- (3): 194-8ic study of teicoplanin in severely neutropenic patients. An-

201. Welty TE, Copa AK. Impact of vancomycin therapeutic drugtimicrob Agents Chemother 1996; 40 (5): 1242-7monitoring on patient care. Ann Pharmacother 1994; 28 (12):

188. Nyhlen A, Ljungberg B, Nilsson-Ehle I. Pharmacokinetics of 1335-9ceftazidime in febrile neutropenic patients. Scand J Infect Dis2001; 33 (3): 222-6 202. van Lent-Evers NA, Mathot RA, Geus WP, et al. Impact of goal-

oriented and model-based clinical pharmacokinetic dosing of189. Nyhlen A, Ljungberg B, Nilsson-Ehle I. Pharmacokinetics ofaminoglycosides on clinical outcome: a cost-effectivenessmeropenem in febrile neutropenic patients. Swedish Studyanalysis. Ther Drug Monit 1999; 21 (1): 63-73Group. Eur J Clin Microbiol Infect Dis 1997; 16 (11): 797-802

190. Cirillo M, Anastasio P, Spitali L, et al. Effects of a meat meal onrenal sodium handling and sodium balance. Miner Electrolyte Correspondence and offprints: Dr Federico Pea, Institute ofMetab 1998; 24 (4): 279-84

Clinical Pharmacology and Toxicology, University of191. Pea F, Viale P, Damiani D, et al. Ceftazidime in acute myeloid Udine, P.le S. Maria della Misericordia 3, DPMSC, 33100leukemia patients with febrile neutropenia: helpfulness of con-

Udine, Italy.tinuous intravenous infusion in maximizing pharmacodynamicE-mail: federico.pea@med.uniud.itexposure. Antimicrob Agents Chemother 2005; 49 (8): 3550-3

2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (10)