Table Of ContentLillyetal.BMCInfectiousDiseases2013,13:14
http://www.biomedcentral.com/1471-2334/13/14
RESEARCH ARTICLE Open Access
Evaluation of intravenous voriconazole in patients
with compromised renal function
Craig M Lilly1, Verna L Welch2, Thomas Mayer1, Paul Ranauro1, Joanne Meisner1 and David R Luke2*
Abstract
Background: Incorporation of the solubilizing excipient, sulfobutylether-β-cyclodextrin (SBECD), in theintravenous
(IV) formulation ofvoriconazole has resulted in therecommendation that this formulation be used withcautionin
patients withcreatinine clearances (Cl )<50 mL/min. This study evaluatedthe safety of IV voriconazolecompared
cr
withtwo other IV antifungals not containing SBECD inpatientswith compromisedrenal function.
Methods: A total of128 patients aged 11–93 years who had a baseline Cl <50 mL/min between January 1, 2007
cr
and December 31,2010 were identified from a database of a university-affiliated inpatient healthcare system; of
these, 55 patients received caspofungin, 54 patients received fluconazole,and 19 patientsreceivedvoriconazole.
Changes in serum creatinine (S ) and Cl levels whileon therapy were compared with baseline values and
cr cr
between groups.
Results: The groups had similar characteristics apart from the larger proportion of females that received
fluconazole. Baseline S was higher inthose receiving caspofungin, but maximal increases of S and decreases in
cr cr
Cl were greatest for the fluconazole group. Acutekidney injury (AKI), assessed by RIFLEcriteria, was more frequent
cr
inthe fluconazole vs. thecaspofungin group (p<0.01); incidence ofAKI inthe voriconazole group was not
significantly different than found in theothertwo groups. The infecting organism was a predictorof AKI and
formulation with SBECD was not.
Conclusions: Treatment offungal infections inpatientswith compromisedrenal function with an
SBECD-containing antifungal agent was not associated with AKI in clinical practice.Since the infecting organism
was associated with AKI, decisionon which antifungalto use should be determined bysusceptibilities to the
organism and not the incorporation ofSBECD inthe IV formulation.
Keywords: Voriconazole, Caspofungin, Fluconazole, Renal dysfunction, Sulfobutylether-β-cyclodextrin,SBECD,
Acute kidney injury
Background introduction and wide spread use of fluconazole and
The incidence of serious fungal infections has increased lipid-based amphotericin-B formulations. Further,
over the last two decades [1], coincident with increased there has been a shift in the frequency of isolates from
prevalence of immunocompromised patients, including C. albicans to non-albicans species, most notably C.
those treated for cancer, acquired immune deficiency glabrata and C. parapsilosis [2,3]. This decline in
syndrome (AIDS), and those treated with immunosup- Candidalinfectionswasassociatedwithariseinmould
pressants in the setting of organ transplantation and infections including aspergillosis [4]. More recently,
autoimmunedisease.Historically,yeastswerethemost the incidence of Aspergillus infections has been stable,
prevalent cause of fungal infections with Candida [5,6]. However, a rising incidence of nosocomial infec-
albicans being the most frequently identified. More tions by other filamentous fungi has been observed.
recently, yeast infections have declined following the These previously ultra-rare fungal diseases, such as
Scedosporium spp., Fusarium spp., and Zygomycetes
spp., are becoming more prevalent, particularly in
*Correspondence:[email protected]
2MedicalAffairs,PfizerInc,Collegeville,Pennsylvania,USA
Fulllistofauthorinformationisavailableattheendofthearticle
©2013Lillyetal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative
CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and
reproductioninanymedium,providedtheoriginalworkisproperlycited.
Lillyetal.BMCInfectiousDiseases2013,13:14 Page2of8
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immunocompromised patients in tertiary care cancer 20%receiving2,3,and4nephrotoxicagents,respectively);
centers[7,8]. and6(11%)fluconazolepatients(50%ofpatientseachre-
Theincreaseintheavailabilityofagentsthatareavail- ceiving2or3concomitantnephrotoxicagents).
able to treat fungal infections allows individual agents The underlying conditions are also listed in Table 1.
to be selected based on the sensitivity of the organism More than half of the patients were being treated in the
and thepotentialtoxicityprofileoftheantifungalagent. intensive care unit. Seventy-five percent of all patients
The high incidence of renal failure associated with had presumed or confirmed fungal disease, as deter-
the administration of polyenes has led to sensitivity mined by an Infectious Diseases consultant (9 [47%], 46
regarding adverse renal effects of antifungal agents. [84%], and 42 [78%] patients administered voriconazole,
Nephrotoxicity associated with the administration of caspofungin,andfluconazole,respectively,NS;Table1).
first generation β-cyclodextrins [9] led to warnings Baseline renal functional indices are listed in Table 2.
and restrictions that have made it difficult to study the Significant differences in baseline S and blood urea
cr
nephrotoxicityoflatergenerationcyclodextrins.SBECDis nitrogen (BUN) levels by treatment group were present;
a second-generation cyclodextrin chemically-engineered the caspofungin group had higher levels than both of
not to accumulate in renal epithelial cells and thus avoid the other treatment groups. However, the differences in
acute kidney injury. Despite limited evidence that SBECD baseline estimated Cl values were not significant
cr
has not been associated with renal impairment [10,11], among the groups. Cl values, as calculated by the
cr
restrictionsinitsuseinpatientswithestimatedcreatinine Cockcroft-Gault method or the MDRD equation, were
clearances (Cl ) less than or equal to 50 mL/min have not significantly different; hence, all comparisons were
cr
beendocumented[12]. madeusingtheCockcroft-Gaultmethod.
Ourstudyisdesignedtotestthehypothesisthattreat- The changes in renal function as a function of time and
ment of a known or suspected fungal infection that is antifungal agent or formulations containing SBECD and
serious enough to warrant the use of an intravenous notcontainingSBECDarepresentedinFigures1Aand1B,
agent in patients with impaired renal function at the respectively. Non-SBECD containing agents had signifi-
start of therapy with an SBECD-containing antifungal is cantlylowernadirCl valuesthanthoseobservedwiththe
cr
associated with a higher frequency of renal dysfunction SBECD containingantifungal,asreflectedbychangeinthe
than treatment with a non-SBECD containing anti- RIFLEcriteriaaswellasabsolutevalues(Table3).Similarly,
fungal. To date, there have been no comprehensive eva- thereweresignificantdifferencesofmaximalincreasefrom
luations incorporating large population sizes of clinical baseline S levels among the groups with the non-SBECD
cr
populationsintheliterature.Wefoundinourstudythat containingagentshavinggreaterincreasesthantheSBECD
the inclusion of SBECD was not associated with containing agent. There were no significant differences
drug-associatedkidneyinjuryinacutely-illpatientswith among the groups in the incidence of renal dysfunction at
systemicfungalinfections. the time of antifungal agent completion of therapy, as
stratified by baseline renal function of Cl <30 mL/min or
cr
Results Cl 30–50mL/min(EOT;Table3).
cr
Atotalof128patientswithbaselineCl <50mL/minand The differences in 28-day mortality among the three
cr
meeting all inclusion and exclusion criteria wereanalyzed treatment groups were not statistically significant.
from the aforementioned database. Fifty-five patients Mortality of patients in the voriconazole, caspofungin,
received caspofungin, 54 patients received fluconazole, andfluconazoletreatmentgroupswas42.1%,29.1%,and
and19patientsreceivedIVvoriconazole.Thegroupswere 25.9%respectively(p=0.44).
well matched with regard to age, race, comorbidities, and Stepwise logistic regression analyses were performed
the concomitant administration of a known nephrotoxic using the following 7 independent variables: age, race,
agent (Table 1). There were significantly more women in comorbidities, concomitant treatment with a nephrotoxic
the fluconazole group and this difference could not be agent, the presence or absence of SBECD, and site of in-
attributed to treatment of a mucosal infection. Further, a fection which was recoded into 3 groups (abdominal+
disproportionate number of patients with diagnosed as- lung, systemic, and urine+wound). The coefficient for
pergillosis were treated with voriconazole. Approximately infecting organism had a Wald statistic equal to 3.90 and
three-quarters of the voriconazole patients were treated a p-value of 0.048. Thus, this model identified the infect-
with a concomitant nephrotoxic agent, as compared with ingorganismastheonlysignificantpredictorofrenaldys-
56%and50%ofthosetreatedwithcaspofunginandfluco- functionbytheRIFLEcriteria.
nazole, respectively. A total of 21 (16%) patients received
multiple concomitantnephrotoxicagents: 5(26%) vorico- Discussion
nazole patients (all receiving 2 concomitant nephrotoxic This study found no evidence of renal toxicity that was
agents); 10 (18%) caspofungin patients (70%, 10%, and attributable to the solubilizing agent, sulfobutylether-β-
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Table1Patientcharacteristics
Parameter Voriconazole Caspofungin Fluconazole p-value
n(%) 19(14.8) 55(43.0) 54(42.2) for
overall
difference
Age,Mean(SD) 61.7(13.9) 63.9(13.9) 63.7(14.7) 0.83
Male,n(%) 10(52.6) 34(61.8) 20(37.0) 0.03
White,n(%) 17(89.5) 43(78.2) 49(90.7) 0.63
Lengthoftreatment(days)
Mean(SD) 8.1(6.3) 8.6(5.3) 9.8(9.8) 0.62
Median(IQR) 6.0(4–12) 7.0(5–11) 8.0(5–11) 0.53
Min,Max 2,29 2,27 2,74 NS
Comorbidities:Diabetesmellitus,hypertensionornephropathy,n(%) 11(57.9) 46(83.6) 43(79.6) 0.06
Underlyingcondition,n(%) 0.001
Cancer 12(63)* 7(13) 13(24)
HIV 0 0 1
ICU 15(79) 31(56) 26(48)
Immunosuppression** 12(63) 3(5) 12(22)
Morethan1underlyingcondition 12(63) 9(16) 16(30)
Concomitantnephrotoxicagent,n(%) 14(73.7) 31(56.4) 27(50.0) 0.20
Underlyingfungaldisease,n(%)* 0.002
Candidaspp. 5(55.6) 43(93.5) 39(92.9)
Aspergillusspp. 4(44.4) 3(6.5) 3(7.1)
Indicationforantifungaltherapy,n(%)† NS
Prophylaxis 10(53) 8(15) 5(9)
Empiric 0 1(2) 5(9)
PresumedorConfirmed 9(47) 46(84) 42(78)
*10patientswithAMLweretreatedwithvoriconazoleprophylaxis.
**Chemotherapy,transplantrejectionpreventionortreatment,≥1mg/kgprednisone.
†CaseswereincludedonlywhenanInfectiousDiseasesconsultantdeterminedthattheisolaterepresentedaninfectionratherthancolonization.
cyclodextrin (SBECD), in patients with impaired renal
function (Cl <50 mL/min) who were treated with an
cr
intravenousantifungalagentinclinicalpractice.Themax-
imal increase in S levels was less and calculated nadir
cr
Cl was higher for the SBECD-containing voriconazole
cr
Table2Renalfunctionatthestartoftherapy group than those of fluconazole and caspofungin groups
thatdidnotcontainSBECD.Importantly,SBECDwasnot
Parameter Voriconazole Caspofungin Fluconazole p-valuefor
overall associated with increased renal dysfunction during or at
difference theendoftherapy.
Baseline 2.1(0.9) 2.8(1.5) 2.2(1.3) 0.04 Voriconazole, a second-generation triazole, is a steric
Scr inhibitor of fungal cytochrome P450-dependent 14α-sterol
(mg/dL)
demethylase,whichisessentialfortheconversionoflanos-
Baseline 33.3(31.9) 56.5(39.8) 48.7(28.7) 0.04
BUN terol to ergosterol required for building the cell mem-
(mg/dL) branes of fungal organisms [13]. Like other triazoles,
Baseline voriconazolehasactivityforthisenzymeforbothyeastand
Clcr moulds, whereas fluconazole, the backbone structure of
(mL/min)
voriconazole, is only active against yeast. The early devel-
Cockcroft- 33.9(9.0) 28.2(12.0) 30.4(10.3) 0.14
opment plan for voriconazole incorporated the medical
Gault
method need for an intravenous formulation [written communica-
MDRD1 33.3(14.0) 28.4(17.1) 32.1(15.5) 0.36 tion,ChrisHitchcock,PhD,PfizerInc].Since voriconazole
calculation hasalowaqueoussolubility(0.7mg/mL)[14],itsintraven-
1ModificationofDietinRenalDisease. ousformulationincludesSBECDasasolubilizingagent.
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Figure1A:Kaplan-MeierplotofpatientswhomeettheRIFLEcriteriabytreatmentwithintravenousvoriconazole(____),
caspofungin(____),andfluconazole(.....).B:Kaplan-MeierplotofpatientswhomeettheRIFLEcriteriabyformulationscontainingSBECD
(____)andthosewithformulationswhichdonotcontainSBECD(____).
Table3Differencesinrenalfunctionduringtherapy
Parameter Voriconazole Caspofungin Fluconazole
BaselineCl (mL/min) <30 30–50 p-value <30 30–50 p-value <30 30–50 p-value
cr
n(%) 6(31.6) 13(68.4) – 33(60.0) 22(40.0) – 27(50.0) 27(50.0) –
Maximum↑S ,mg/dL(SD) 0.68(1.01) 0.62(0.54) 0.88 1.17(1.9) 0.15(0.78) 0.02 2.6(2.7) 2.0(2.0) 0.33
cr
LowestCl duringtreatment,mL/min(SD) 16.8(3.7) 31.7(7.3) 0.0002 15.8(6.0) 34.6(7.7) <0.0001 13.9(5.1) 24.3(8.2) <0.0001
cr
Cl atEOT,mL/min(SD) 28.7(18.1) 50.3(27.8) 0.11 46.4(43.1) 59.5(28.4) 0.21 30.6(19.2) 49.0(22.6) 0.0025
cr
%ChangeCl (Lowest-SOT)/SOT(SD) −24.6(12.6) −19.6(13.4) 0.45 −19.4(17.7) −15.6(15.1) 0.41 −35.3(18.4) −37.5(20.7) 0.68
cr
Renaldysfunction,n(%) 3(50.0) 4(30.8) 0.42 12(36.4) 3(13.6) 0.06 17(63.0) 15(55.6) 0.58
Scr:serumcreatinine;Clcr:creatinineclearance;EOT:endoftherapy,SOT:startoftherapy.
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Naturally occurring cyclodextrins, notably α- and β- those with systemic fungal infections, many of whom
cyclodextrins, are reabsorbed and concentrated in the were treated with fluconazole for sensitive isolates of
renal tubule, resulting in acute kidney injury at clinically- Candida albicans. It is important to note that all cases
translatable doses in animal models [9]. SBECD is a ofrenalimpairmentwereclassifiedasmild-to-moderate
rationally-designed cyclodextrin which does not undergo according to the RIFLE criteria [23]. We did not find
significant tubular reabsorption,thusit wasformulatedto evidenceforotherpossiblemechanismsofrenaltoxicity
prevent injury to renal tubular cells. Animal studies with such as obstructive hydronephrosis [24-31] or microan-
SBECD havenot shown discrete changes in renal morph- giopathy such as that which occurs with hemolytic
ology at doses used clinically [11]; moreover, SBECD is uremicsyndrome[32,33].
not nephrotoxic in these models when given at dose This study has important limitations that should be
equivalents of naturally occurring cyclodextrins that are taken into account when interpreting the data. It is a
associated with nephrotoxicity and/or hepatotoxicity. nonrandomized observational study of clinical practice
However, at the time of FDA approval, a lack of informa- at an academic medical center with policies that
tion regarding the safety of SBECD in patients with mandate the involvement of infectious disease experts
impairedrenalfunctionledtowarningsagainsttheuseof for cases involving the administration of intravenous
SBECD in patients with Cl <50 mL/min for products antifungals for nearly all patients. This leads to differ-
cr
including intravenous voriconazole [12]. This study is ences among the groups that are due to non-random
important to clinicians because it provides evidence that factors that may be important. On the other hand, this
SBECD-containing medications can be used to treat approach may be more informative about the effects in
patients with serious fungal infections including those clinical practice because cases are not excluded. We
with impaired renal function without increased risk of attempted to review patient cases with compromised
nephrotoxicity. renal function treated with amphotericin B but, despite
Our main finding that treatment of a serious fungal our large database, we could not find a sufficient num-
infection for patients with impaired renal function with ber of patients meeting this criteria. Similarly, the num-
SBECD-containing voriconazole is not associated with ber of patients with compromised renal function treated
worse renal outcomes than treatment with a non- with intravenous voriconazole is low and likely related
SBECD containing alternative antifungal is consistent to labeling that raises concerns about renal toxicity in
with recent smaller studies. A retrospective analysis of thisgroup.
the Candida Phase 3 trial database for nephrotoxic Mortality was higher in the voriconazole group
effects of intravenous voriconazole containing SBECD compared with the other two groups, likely as a result of
did not detect renal toxicity from voriconazole in con- the severity of the underlying fungal disease. A greater
trasttotherenaldysfunctionassociatedwithamphoter- percentage of patients in the voriconazole group was
icin B [10,15]. Despite accumulation of SBECD in the infected with Aspergillus spp. A higher mortality rate is
plasma of patients with compromised renal function expected inthis group becauseinfection with Aspergillus
[16-18], its lack of reabsorption in renal epithelial cells spp. has been associated with higher mortality rates
appears to prevent deleterious effects on renal function compared to yeast infections. In addition, a greater
inthisandotherclinicalreports[19-21]. percentage of patients in the voriconazole group were
Targeting high risk patients may have increased the treated with voriconazole prophylactically as part of a
ability of our study of modest size to detect differences treatment plan for poor prognosis malignancies includ-
among agents with regard to renal toxicity. The associ- ing acute myelogenous leukemia (AML). Importantly,
ation of fluconazole with worse renal function during differences among the indications for antifungal treat-
therapyisconsistentwithitslabeling:“Insomepatients, ment did not appear to alter the validity of the associ-
particularly those with serious underlying diseases such ation of the infecting organism that was isolated with
asAIDSand cancer, changes in renal and hematological the development of renal dysfunction. Nonetheless,
function test results and hepatic abnormalities have there was a limited number of Candida and Aspergillus
been observed during treatment with fluconazole and isolates identified in this study such that associations
comparative agents, but the clinical significance and between the subspecies of yeast or mould with more
relationship to treatment is uncertain [22].” Our find- severerenal disease couldnotbedefinitive.
ings do not identify fluconazole as a direct nephrotoxin, Another limitation of this study is the lack of dosing in-
rather they imply that the underlying disease state of formation or therapeutic drug monitoring. At the time of
which fluconazole is treating influences renal function. datacollection,therewasnoharmonizationbetweenphar-
This is consistent with our identification of the organ- macy and medical records. However, there are defined
ism as a significant predictor of renal outcome. The guidelines for the dosing of the three IVantifungals estab-
association was driven by worse renal function among lished by the Food and Drug Administration which were
Lillyetal.BMCInfectiousDiseases2013,13:14 Page6of8
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reviewed by a UMass clinical pharmacist. Antifungal agent Age is in years, ABW is actual body weight in kilo-
levels were not measured as part of this study and are not grams, and S is measured in milligrams per deciliter
cr
recommended by current therapeutic guidelines. The [37-39]. Given the controversy in the literature regard-
effects of SBECD on renal function that we observed do ing the best estimator of renal function [36], we also
notsuggestthatmeasuringdruglevelstopreventrenaltox- evaluated renal function by the Modification of Diet in
icitywouldbejustified. RealDisease(MDRD)studyequation[40]:
Conclusions Cl ¼eGFR
cr
A main finding of this studyis that the administrationof ¼186(cid:3)ðS Þ(cid:2)1:154(cid:3)ðAGEÞ(cid:2)0:203
SBECD in renally-compromised patients does not result (cid:3)ð0:742crif FemaleÞ(cid:3)ð1:212 if BlackÞ
in renal damage that is attributable to its inclusion in
the formulation of voriconazole. The finding that the
Thisstudywasperformedwiththepriorapprovalofthe
infecting organism is a significant predictor of renal
University of Massachusetts Human Subjects Committee
outcomes in this high risk population suggests that the
underawaiveroftherequirementforinformedconsent.
efficacy of the antifungal agent should be the dominant
consideration when treating a serious fungal infection.
Further studies are warranted to help us better under- Statisticalanalysis
Changes in S levels and Cl were evaluated during IV
stand the association between the underlying fungal cr cr
antifungal therapy. The highest S and lowest Cl while
infectionandacute kidneyinjury. cr cr
ontherapyandatEOTamongthegroupswerecompared
Methods with baseline Scr and Clcr, respectively, by F-test. We
compared dichotomous variables with the Fisher’s exact
Patients/samples
test, and other categorical variables with the χ2 test.
We analyzed deidentified data from a large database of
Continuous variables were compared using the F test or
hospitalized patients from the UMass Memorial
Wilcoxon rank-sum test and differences among groups
Healthcare System using the University of Massachusetts
withthelog-ranktest.Distributionsoflengthoftreatment
Biorepository database. All adults with documented or
were skewed, so these data are shown as median (IQR),
clinically suspected fungal infections that were treated
and other data are shown as mean (SD). We assessed
with an intravenous antifungal therapy, specifically,
development of renal dysfunction with RIFLE scores [23]
voriconazole, fluconazole, or caspofungin, with baseline
bylineartestoftrend.2-sidedpvalues<0.05wereconsid-
estimated Cl <50 mL/min, and who were hospitalized
cr
eredstatisticallysignificant.
between 1/1/2007 and 12/31/2010 were identified. Those
Stepwise logistic regression was conducted with a
eligible for analysis had been dosed for a minimum of
p-value to enter and stay in the model set for p≤0.20.
4 days of IVantifungal therapy and had serum creatinine
The dependent variable in the model was the presence
(S ) levels while on therapy and at the end of IVantifun-
cr
of AKI. Prespecified potential independent variables
gal therapy (EOT; ± 3 days). Patients were excluded from
included age, gender, body mass index, antifungal ther-
analyses if they had unstable renal function at baseline
apy, infecting organism, presence or absence of SBECD,
(assessed as a 50% difference in S or estimated Cl on
cr cr
site of infection, Cl at baseline, presence or absence of
two measurements within 4 days prior to start of IVanti- cr
concomitant potentially nephrotoxic agents, and comor-
fungaltherapy).Patientsundergoingchronichemodialysis,
bidities. For all analyses except the regression model,
hemofiltration, or other renal replacement therapies were
p<0.05 was considered significant. Analyses were
excluded from study. All concomitant medications which
conducted using SAS Software version 9.2 (Cary, North
could be considered nephrotoxic were evaluated in a
blinded fashion (by DRL) and subsequently tabulated by Carolina,USA).
treatment group (by VLW). The indication for treatment
Abbreviations
with an antifungal agent was classified as for prophylaxis, ABW:Actualbodyweight;AIDS:Acquiredimmunedeficiencysyndrome;
empiric treatment, or presumed/confirmed disease utiliz- AKI:Acutekidneyinjury;AML:Acutemyelogenousleukemia;BUN:Blood
ureanitrogen;Cl :Creatinineclearance;EOT:Endoftherapy;
ingtheEORTCguidelines[34]. cr
IQR:Interquartilerange;IV:Intravenous;MDRD:Modificationofdietinrenal
Scr levels below 0.7 mg/dL were rounded up to disease;RIFLEcriteria:Risk,injury,failure,lossoffunction,andend-stagerenal
0.7 mg/dL per standard protocol [35,36] Clcr was disease;SBECD:Sulfobutylether-β-cyclodextrin;Scr:Serumcreatinine;
SD:Standarddeviation;SOT:Startoftherapy.
estimatedbytheCockcroft-Gaultequation:
Competinginterests
DRLandVLWwereemployeesofPfizerPharmaceuticalsatthetimeofstudy.
Cl ¼ð140(cid:2)AgeÞ(cid:3)ABW (cid:3)½0:85 if Female(cid:4) CML,TM,PR,andJMareemployeesoftheUniversityofMassachusettswith
cr
nofinancialcompetinginterests.Allanalyseswereperformedwitha
72(cid:3)S
cr databaseblindedtotreatmentallocation.
Lillyetal.BMCInfectiousDiseases2013,13:14 Page7of8
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Authors’contributions patientstreatedwithintravenousvoriconazoleunderrenalreplacement
CML,VLW,andDRLconceivedanddevelopedtheprotocol,soughtfunding therapy.BMCClinPharmacol2006,6:1–6.
fromPfizerPharmaceuticals,assessedthestatisticaloutcomes,anddrafted 17. LukeDR,WoodND,TomaszewskiKE,DamleB:Pharmacokineticsof
themanuscript.CML,TM,andPRcollectedthedataanddevelopedthe sulfobutylether-β-cyclodextrin(SBECD)insubjectsonhemodialysis.
blindeddatabase.JMassessedqualityassuranceoftheclinicaldata.VLWand NephrolDialTransplant2012,27:1207–1212.
CMLanalysedthedatabaseinablindedfashion.Allauthorsreadand 18. HafnerV,CzockD,BurhenneJ,etal:Pharmacokineticsofsulfobutylether-
approvedthefinalmanuscript. beta-cyclodextrinandvoriconazoleinpatientswithend-stagerenal
failureduringtreatmentwithtwohemodialysissystemsand
hemofiltration.AntimicrobAgentsChemother2010,54:2596–2602.
Acknowledgements 19. AbelS,AllanR,GandelmanK,TomaszewskiK,WebbDJ,WoodND:
ThisstudywasconductedbytheUniversityofMassachusettsWorcesterand Pharmacokinetics,safety,andtoleranceofvoriconazoleinrenally
fundedbyPfizer.ThomasMayer,JoanneMeisner,PaulRanauro,andCraig impairedsubjects.ClinDrugInvest2008,28:409–420.
LillyareemployeesoftheUniversityofMassachusettsWorcesterwhowere 20. PotoskiBA,SimaAP:Effectofintravenousvoriconazoleonserumcreatininein
paidconsultantstoPfizerinconnectionwiththedevelopmentofthis apopulationofpatientswithstablerenalfunction,Proceedingsofthe48th
manuscript.Thesedatawerepresentedinpartatthe49thAnnualMeeting AnnualMeetingoftheInterscienceConferenceonAntimicrobialAgents
oftheInfectiousDiseasesSocietyofAmerica,Boston,Massachusetts,USA, andChemotherapy.Washington,DC,USA:2008.
October20–23,2011. 21. NeofytosD,LombardiLR,ShieldsRK,OstranderD,WarrenL,NguyenMH,
ThompsonCB,MarrKA:Administrationofvoriconazoleinpatientswith
Authordetails renaldysfunction.ClinInfectDis2012,54:913–921.
1UniversityofMassachusettsMedicalSchool,Worcester,Massachusetts,USA.
22. PfizerInc:Diflucan(fluconazole)packageinsert.NewYork,NY:2011.
2MedicalAffairs,PfizerInc,Collegeville,Pennsylvania,USA.
23. KellumJA,LevinN,BoumanC,LamiereN:Developingaconsensus
classificationsystemforacuterenalfailure.CurrOpinCritCare2002,
Received:24March2012Accepted:8January2013 8:509–514.
Published:16January2013
24. AlouiS,GorciiM,SkhiriH,etal:Acuterenalfailureandfungusball:acase
report.NephrolTherapeut2010,6:171–172.
25. AyselK,AlevY,NurC,GonulA,SerdarS,OrhanK:Acuterenalfailure
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