Candida infections: a post hoc analysis Efﬁcacy and safety of anidulafungin in elderly, critically ill patients with invasive International Journal of Antimicrobial Agents

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ContentslistsavailableatSciVerseScienceDirect

International Journal of Antimicrobial Agents

j o ur na l ho me p ag e :ht t p : / / w w w . e l s e v i e r . c o m / l o c a t e / i j a n t i m i c a g

Efﬁcacy and safety of anidulafungin in elderly, critically ill patients with invasive Candida infections: a post hoc analysis

^夽

George Dimopoulos

^a,∗

, José-Artur Paiva

^b

, Wouter Meersseman

^c

, Jan Pachl

^d

, Ioana Grigoras

^e

, Gabriele Sganga

^f

, Philippe Montravers

^g

, Georg Auzinger

^h

, Marcio Borges Sá

ⁱ

, Paul J. Miller

^j

, Tomas Marˇcek

^k

, Michal Kantecki

^k

, Markus Ruhnke

^l

aUniversityHospital‘Attikon’,Athens,Greece

bHospitaldeSãoJoão,Porto,Portugal

cUniversityHospitalLeuven,Leuven,Belgium

dUniversityHospitalKrálovskéVinohrady,Prague,CzechRepublic

eUniversityofMedicineandPharmacy,Ias¸i,Romania

fCatholicUniversityHospitalAgostinoGemelli,Rome,Italy

gHôpitalBichat-ClaudeBernard,Paris,France

hKing’sCollegeHospital,London,UK

iHospitalSonLlatzer,PalmadeMallorca,Spain

jPﬁzerGlobalResearchandDevelopment,Sandwich,UK

kPﬁzerInternationalOperations,SpecialtyCare,Paris,France

lCharitéUniversityHospital,Berlin,Germany

a r t i c l e i n f o

Articlehistory:

Received28March2012 Accepted30July2012

Keywords:

Azole Candidaemia Echinocandin Elderly Globalsuccess Posthocanalysis

a b s t r a c t

Posthocanalysisofanon-comparative,prospective,multicentre,phaseIIIbstudywasperformedtocom- pareefﬁcacyandsafetyofanidulafungininelderly(≥65years)versusnon-elderly(<65years)Intensive CareUnit(ICU)patientswithcandidaemia/invasivecandidiasis(C/IC).AdultICUpatientswithcon- ﬁrmedC/ICmeeting≥1ofthefollowingcriteriawereenrolled:post-abdominalsurgery;solidtumour;

renal/hepaticinsufficiency;solidorgantransplantation;neutropenia;age≥65years.Patientsreceived anidulafungin(200mgonDay1,100mg/daythereafter)for≥10daysfollowedbyoptionalazolestep- downtherapyforatotaltreatmentdurationof14–56days.Theprimaryefficacyendpointwasglobal (clinicalandmicrobiological)responseattheendofalltherapy(EOT).Primaryefficacyanalysiswas performedinthemodifiedintent-to-treat(mITT)population(n=170),excludingunknownandmissing responses.Intotal,80patients(47.1%)wereaged≥65yearsand90(52.9%)wereaged<65years;the meanagedifferencebetweenthetwogroupswas21.9years.GlobalsuccessatEOTinmITTpatients wassimilarinelderly(68.1%)andnon-elderly(70.7%)patients(P=0.719).However,globalsuccessrates weresignificantlylowerinelderlyversusnon-elderlypatientsat2and6weeksafterEOT(P=0.045and P=0.016,respectively).Ninety-daysurvivalwassignificantlylower(P=0.006)forelderly(42.8%)versus non-elderlypatients(63.3%).Theincidenceandprofileofadverseeventsweresimilarinelderlyand non-elderlypatients.AnidulafunginwaseffectiveandsafefortreatmentofC/ICinelderlyICUpatients, despitehigherbaselineseverityofillnessscores.

1. Introduction

Candidaemiaandotherformsofinvasivecandidiasisremaina signiﬁcantclinicalprobleminIntensiveCareUnit(ICU) patients andareassociatedwithconsiderablemorbidityandmortality[1,2].

夽 Thesedatawerepresentedinpartatthe5thCongressonTrendsinMedical Mycology(TIMM-5),2–5October2011,Valencia,Spain.

∗ Correspondingauthor.Presentaddress:CriticalCareMedicine,Departmentof CriticalCare,UniversityHospital‘ATTIKON’MedicalSchool,UniversityofAthens, Athens,Greece.Tel.:+302105832182;fax:+302105832182.

E-mailaddress:[email protected](G.Dimopoulos).

A recent report from theinternational Extended Prevalence of InfectionintheICU(EPIC)IIstudyshowedthatpatientswithcan- didaemiahadhighercrudeICUmortalityratesandlongerICUstays thanpatientswithbacterialbloodstreaminfections[1].

Prompt initiation of antifungal therapy is essential for the effectivemanagementofcandidaemia/invasivecandidiasis(C/IC).

Treatmentguidelinesrecommendthatinitialantifungaltherapy shouldbeselectedonthebasisoftheinfectingorganismandlocal susceptibilitypatterns[3].Whilstﬂuconazoleisgenerallyeffective forC/IC,itsusemaybelimitedbytheincreasingprevalenceofCan- didaspp.withacquiredorintrinsicresistancetoﬂuconazole[4].

Dependingonwhichguidelinesarereferredto,echinocandinsare

http://dx.doi.org/10.1016/j.ijantimicag.2012.07.018

Open access under CC BY-NC-ND license.

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nowrecommendedasﬁrst-linetreatmentforC/ICinallpatients[5]

or,morespeciﬁcally,inhaemodynamicallyunstablepatients(mod- eratelyseveretoseverelyill),thosewithpriorazoleexposureand forinvasiveinfectionscausedbyCandidakruseiorCandidaglabrata [3]owingtotheirexcellentactivityagainstinvasiveCandidaspp., includingazole-resistantstrains[6].

Dueto more frequent and prolongedtreatment in hospital, especiallyintheICU,elderlypatientsareatagreaterriskforoppor- tunisticCandidainfections[7,8].Overthepasttwo decades,the numberofelderlypatientsadmittedtoICUshasincreased[9].A recent,relevantlongitudinalstudyreportedthatamongmiddle- agedandolderadults,patientsaged≥65yearsaccountedforalmost 60%ofICUadmissions[10].Inaddition,elderlyICUpatientsare morelikelythanyoungerpatientstohaveco-morbidconditions [11,12], particularlyrenal dysfunction [13], which is associated withincreasedmortalityintheICU[14].Co-morbidities,together with age-associated physiological changes and immunosenes- cence,maketheelderlyvulnerabletoinfection[15].

Althoughthenumber ofelderlypatientsadmittedtoICUsis increasing[9],ourunderstandingoftheirtreatmentneedsremains limited.Toourknowledge,nostudieshavespecificallyevaluated theefficacyofanantifungalagentinelderlyICUpatientscompared withpatients<65yearsold.ArecentphaseIIIbtrialshowedthat anidulafunginwasbothsafeandeffectiveforthetreatmentofC/IC inselectedpopulationsofICUpatients[16].Giventhepaucityof dataintheelderly,aposthocanalysisofthistrialwasconducted toevaluatetheefficacyandsafetyofanidulafungininelderly(aged

≥65years)versusnon-elderly(aged<65years)ICUpatientswith C/IC.Thetwoagegroupswerealsocomparedwithrespecttobase- linedemographics,clinicalcharacteristicsandinfectingpathogens inordertobettercharacteriseelderlypatientswithC/IC.

2. Materialsandmethods 2.1. Trialdesign

This was a prospective, phase IIIb, exploratory, open-label, non-comparative,multinational trial. The studywas conducted in accordance withthe Declaration of Helsinki and Good Clin- ical Practice guidelines and was approved by all appropriate institutional review boards and ethics committees.Allpatients wererequiredtoprovidewritteninformedconsentpriortostudy inclusion.ThetrialwasregisteredonClinicalTrials.gov(identiﬁer NCT00689338).

2.2. Patientpopulation

Adult ICU patients were eligible if they met the following criteria:conﬁrmedC/ICwithin96hbeforeto48hafterinitiation ofstudytreatment;signsandsymptomsofacutefungalinfection within 48h prior to initiating study treatment; and an Acute Physiologyand Chronic Health Evaluation (APACHE) IIscore of

<25.Patientswerealsorequiredtobelongtoatleastoneofthe followingsubpopulations:post-abdominalsurgery;solidtumour;

renalinsufficiency; hepaticinsufficiency; solidorgantransplantation; neutropenia; and/or aged ≥65 years. Patients who had receivedantifungalsfor ≤48hprior to studyentry(with upto oneechinocandindose)wereeligible,butonlyifnoimprovement had been recorded. As part of the pre-specified study design, the presence of renal/hepatic insufficiency was determined by the investigator according to local guidelines; there were no pre-specifiedprotocoldefinitions.

The key study exclusion criteria were: suspected Candida osteomyelitis, endocarditis, meningitis and/or endophthalmitis;

poorvenousaccess;orknownhypersensitivityorcontraindications

toanidulafungin,ﬂuconazoleorvoriconazole.TheCandidascore wascalculatedaccordingtopreviouslypublishedmethods[17], bothatstudyentryoratthetimewhentheﬁrstbloodsamplewas withdrawnforbloodcultureandattheendofalltherapy(EOT).

Inshort,theCandidascorewasobtainedbyassessingspeciﬁcrisk factorsandassigningatotalpointvalueaccordingtothefollowing scoring system: clinical sepsis (2 points); surgery (i.e. recent surgery requiring post-operative management; 1 point); total parenteralnutrition(1point);andmultifocalcolonisation(1point).

2.3. Treatment

Patientsreceivedintravenous (i.v.)anidulafungin(200mg on Day1,100mg/daythereafter)for10–42days.Aftercompletinga minimumof10daysoftreatment,patientscouldbeswitchedto oralvoriconazoleorﬂuconazoleprovidedtheyhadtwoconsecutive negativebloodculturesandresolutionofsignsandsymptomsof acuteinvasivefungalinfection(IFI).Theazoledosagewaschosenby theinvestigatoraccordingtolocalpractice.Treatment(withanidu- lafungin orstep-downazole)wascontinuedfor ≥14 daysafter the last positive blood/tissue culture and resolution/signiﬁcant improvementofIFIsignsandsymptoms.Thetotalmaximumtreat- mentdurationwas56days.Allpatients,includingthosewhofailed therapy,wererequiredtoreturnforfollow-upvisitsat2weeksand 6weeksafterEOT.

2.4. Endpoints

TheprimaryefficacyendpointwasglobalresponseatEOTin themodifiedintent-to-treat(mITT)population.Globalsuccesswas defined asclinical (i.e.cure or significantimprovement of C/IC signsandsymptoms)andmicrobiologicalsuccess(i.e.eradication orpresumederadicationofCandidaspp.).ThemITTpopulationwas definedasallpatientswithaconfirmeddiagnosisofC/ICwhohad receivedatleastonedoseofanidulafungin.Globalresponsewas reportedas‘unknown’or‘missing’inpatientswithanunknown ormissingclinicalresponse,respectively,andanymicrobiological responseexceptfailure.Clinicalresponsewasdefinedas‘unknown’

innon-evaluablepatients[i.e.death(notcausedbyC/IC),lossto follow-uporreceivedlessthanthreeanidulafungindoses].Unless otherwisestated,unknownandmissingresponseswereexcluded fromtheanalysisofglobalresponse.

Secondaryendpoints included:globalresponseattheendof i.v.therapy(EOIVT)andat2weeksand6weekspostEOT;sur- vivalatDay90;andtheincidenceofadverseevents(AEs)inthe safetypopulation(i.e.patientswhoreceivedatleastonedoseof anidulafungin).

Antifungalsusceptibilitytestingforbaselineisolateswascon- ducted accordingtostandard Clinicaland LaboratoryStandards Institute(CLSI)methodsandbreakpoints[18](i.e.anidulafungin non-susceptibility,>2␮g/mL;ﬂuconazoleresistance,≥64␮g/mL;

andvoriconazoleresistance,≥4␮g/mL).

2.5. Dataanalysis

Forthis posthocanalysis,patientsweredividedintoelderly (aged≥65 years)and non-elderly (aged<65 years)cohorts.An exact two-sided95%confidence interval (CI)wascalculated for thesuccessrateateachtimepointineachagegroup.Atwo-sided Z-testwasusedtodeterminewhethertheproportionofsuccesses differedsignificantlybetweenagegroups.Thesametestwasused tocompareboththeincidenceofdeep-tissueCandidainfectionat baselineandtheincidenceofrenalinsufficiency/failure/dialysisat baselinebetweengroups.Agegroupcomparisonsofcontinuous variables were mostly performed using the two-sample t-test.

The Wilcoxon rank-sum test was used to compare the use of

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Table1

Baselinedemographicsandclinicalcharacteristicsinelderlyandnon-elderlypatients(modiﬁedintent-to-treatpopulation).

Characteristic Elderlypatients(≥65years)(N=80) Non-elderlypatients(<65years)(N=90)

Demographiccharacteristics

Male[n(%)] 49(61.3) 52(57.8)

Meanage(range)(years) 73.8(65−89) 51.9(25−64)

Race[n(%)]

White 76(95.0) 84(93.3)

Black 1(1.3) 0(0)

Other(includingunspeciﬁed) 3 (3.8) 6 (6.7)

MeanBMI(range)(kg/m²)^a 25.8(17.7−37.4) 25.5(15.4−83.0)

Clinicalcharacteristics Patientsubgroup[n(%)]

Post-abdominalsurgery 44(55.0) 46(51.1)

Renalinsufﬁciency/failure/dialysis 41(51.3) 26(28.9)

Solidtumour 18 (22.5) 27 (30.0)

Hepaticinsufﬁciency 7 (8.8) 20 (22.2)

Neutropenic 3(3.8) 10(11.1)

Solidorgantransplantrecipient 1(1.3) 9(10.0)

Infectionsite[n(%)]^b

Bloodonly 46 (57.5) 68(75.6)

Bloodandothernormallysterilesite 6(7.5) 1(1.1)

Othernormallysterilesiteonly 28(35.0) 21(23.3)

Peritonealﬂuid 16(20.0) 13(14.4)

Bile 2(2.5) 2(2.2)

Pleuralﬂuid 2 (2.5) 1 (1.1)

Multiplesites 3(3.8) 0(0.0)

Other 5(6.3) 5(5.6)

Candidascore[mean(95%CI)]^c 3.7(3.5−4.0) 3.1(2.8–3.3)

SOFAscore[mean(95%CI)]^d 8.0(7.1–8.9) 6.5(5.6–7.5)

APACHEIIscore

Mean(95%CI) 17.8(16.8–18.8) 14.9(13.8–16.0)

≤20[n(%)] 55 (68.8) 73(81.1)

>20[n(%)] 25(31.3) 17(18.9)

BMI,bodymassindex;CI,conﬁdenceinterval;SOFA,SequentialOrganFailureAssessment;APACHE,AcutePhysiologyandChronicHealthEvaluation.

aAssessedin78elderlyand87non-elderlypatients.

b‘Withcandidaemia’wasdeﬁnedasanypatientwhohadeitheraCandidabloodstreaminfectiononlyoraCandidabloodstreaminfectionandaCandidadeep-tissue infection;‘withoutcandidaemia’wasdeﬁnedasanypatientwhohadCandidadeep-tissueinfectiononly.

c UsingthemethoddescribedbyLeónetal.[17];assessedin78elderlyand89non-elderlypatients.

d Assessedin79elderlyand87non-elderlypatients.

concomitant medications between groups. A ² test of homo- geneity of distributions was employed to contrast the overall distributionof baselinepathogens. Survival datawere analysed using the Kaplan–Meier method, and the difference between groupswasassessedusingthelog-ranktest.

3. Results

3.1. Patientpopulation

ThemITTpopulationcomprisedatotalof170patientswhowere includedinthepresent posthocanalysis.Ofthesepatients, 80 (47.1%)wereaged≥65yearsand90(52.9%)wereaged<65years;

thedifferenceinmeanagebetweenthetwogroupswas21.9years.

Baselinedemographicswereverysimilarbetweenthetwoage groups(Table1).However,atstudyentry,elderlypatientsappeared tobeinworsehealththannon-elderlypatients(meanAPACHEII scoresof17.8vs.14.9;P=0.0002)andtohavehighermeanorgan failurescores[meanSequentialOrganFailureAssessment(SOFA) scoresof8.0 vs.6.5;P=0.033].Elderly patientsalsohad higher mean Candidascores(3.7 vs. 3.1;P=0.001),a higher incidence ofdeep-tissueinfections(42.5%vs.24.4%;P=0.012)andahigher incidenceof renal insufﬁciency/failure/dialysisthannon-elderly patients(51.3%vs.28.9%;P=0.003).

Elderlypatientswerereceivingamedianof12(range3–36)con- comitantmedicationsatbaseline,whichwassimilartonon-elderly patients(median13,range2–34;P=0.649).

Intermsofoveralldistributionofbaselinepathogens,Candida albicanswasthemostcommonsinglepathogeninbothagegroups (Fig.1).Candidaglabratawasmorecommonin elderlypatients

(17.5%vs.12.2%innon-elderlypatients)andCandidaparapsilosis wasmorecommoninnon-elderlypatients(13.3%vs.6.3%inelderly patients).However,therewasnosigniﬁcantdifferenceintheover- alldistributionsofCandidaspp.betweenagegroups(P=0.599).

3.2. Susceptibilitytesting

Atotalof167baselineisolatesunderwentsusceptibilitytest- ing and most (n=153) were fully susceptible to anidulafungin, ﬂuconazoleandvoriconazole.Twoof96C.albicansisolateswere notsusceptible toboth ﬂuconazoleand voriconazole,4of27C.

glabratawerenotsusceptibletoﬂuconazole,5of21C.parapsilosis

Fig.1.Distributionofpathogensatbaselineinelderlyandnon-elderlypatients (modiﬁedintent-to-treatpopulation).*Ifapatienthadmorethanonebaseline Candidaspp.,theyonlycontributedtothegroup‘multiple’pathogens.Theoverall distributionofbaselinepathogensdidnotdiffersigniﬁcantlybetweenelderlyand non-elderlypatients(P=0.599).

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werenotsusceptibletofluconazoleand1ofthese21wasnotsus- ceptibletoanidulafungin,butallC.kruseiwerenotsusceptibleto fluconazole.Overall,minimuminhibitoryconcentrationsrequired toinhibit50%and90%ofisolates(MIC₅₀/MIC₉₀values)foranidu- lafungin,fluconazole and voriconazolewere 0.03/0.5,0.5/8 and

≤0.015/0.5␮g/mL,respectively.

3.3. Treatment

Themeanoveralltreatmentduration inelderlypatientswas 18.4days(median17.5days,range1–49days)andinnon-elderly patientsitwas21.3days(median19.5days,range1–67days),with ameandurationofanidulafungintherapy of15.6days(median 14.0days,range1–42days)and16.3days(median14.5days,range 1–42days),respectively.Oftheelderlypatients,57(71.3%)received anidulafunginonly,whilst20(25.0%)wereswitchedtooralﬂu- conazoleand3(3.8%)wereswitchedtooralvoriconazole.Ofthe non-elderlypatients,55(61.1%)receivedanidulafunginonly,whilst 24(26.7%)wereswitchedtooralﬂuconazoleand11(12.2%)were switchedtooralvoriconazole.

3.4. Efﬁcacy

Globalandmicrobiologicalsuccessratesateachtimepointby ageare shownin Table 2.Global successrates atEOT in mITT patientsweresimilarinelderly(68.1%)and non-elderly(70.7%) patients(P=0.719).Whenunknownandmissingresponseswere includedastreatmentfailures,thesuccessrateswere61.3%and 64.4%,respectively(P=0.667).Globalsuccessrateswerealsosimi- laratEOIVT.However,globalsuccessratesweresigniﬁcantlylower inelderlypatientscomparedwithnon-elderlypatientsatthe2- weekand 6-week post-EOTfollow-ups (P=0.045 and P=0.016, respectively).Thisislargelybecausemorepatientsachievingglobal treatmentsuccessatEOTintheelderlypatientpopulation(n=13;

26.5%)diedbetweenEOTandthe2-weekfollow-upthanthosein thenon-elderlypopulation(n=5;8.6%)(P=0.014fordifference).

Thesedeathswereallduetonon-Candida-relatedcauses.Thesame trendwasnotobservedbetweenWeek2andWeek6offollow-up [n=3(11.1%)vs.n=5(10.0%);P=0.879].

Inelderlypatients,globalsuccessratesatEOTweresimilarin thosewithand withoutcandidaemia (66.7%and 70.4%, respectively;P=0.744)andinthosewithC.albicansandnon-C.albicans C/IC,excludingpatientswithmultiplebaselineCandidapathogens (68.3%and72.0%,respectively;P=0.751).Microbiologicalsuccess atEOTinmITTpatientswassimilar(P=0.833)inelderly(72.0%) andnon-elderlypatients(73.5%)(Table2);microbiologicalsuccess rateswerealsosimilaratEOIVT.However,atbothpost-EOTfollow- upvisits,microbiologicalsuccessratesweresigniﬁcantlylowerin

Fig.2.Kaplan–MeierestimatesofsurvivaltoDay90inelderlyandnon-elderly patients(modiﬁedintent-to-treatpopulation).Day1representstheﬁrstdayof anidulafungintherapy.

elderlypatientscomparedwithnon-elderlypatients(P=0.045and P=0.016at2-weekand6-weekpost-EOTfollow-ups,respectively).

3.5. Survival

Kaplan–Meier curveswere producedto illustratesurvivalto Day 90in elderlyand non-elderly patients(Fig.2).The90-day Kaplan–Meiersurvivalestimatewassigniﬁcantlylower(P=0.006) forelderlypatients(42.8%,95%CI 31.8–53.8%)thannon-elderly patients(63.3%,95%CI53.4–73.3%).Deathcausalitywasadjudi- catedbytheinvestigators.Alleventsofdeathamongpatientswho achievedglobaltreatmentsuccessatEOTandwhodiedbetween EOTandthe2-weekfollow-upwereduetonon-Candida-related causes.

3.6. Safety

Among the216patients in thesafety population, 100were elderlyand116werenon-elderly.Atotalof42and38treatment- related AEs occurred in 12/100 (12.0%) and 21/116 (18.1%) elderlyandnon-elderlypatients,respectively.Althoughnoserious treatment-relatedAEswerereportedamongelderlypatients,four seriouseventswerereportedinthenon-elderlypatientsubpopu- lation.Amongtheelderly,nosingletreatment-relatedAEoccurred inmorethantwopatients(Table3).Innon-elderlypatients,the mostcommonlyreportedtreatment-relatedAEwasanincreasein bloodalkalinephosphataselevels(n=3).

4. Discussion

Theﬁndingsofthepresentanalysissuggestthatanidulafungin iseffectiveforthetreatmentofC/ICinICUpatientsaged≥65years.

AhighglobalsuccessrateatEOT,theprimarystudyendpoint,was

Table2

Globalandmicrobiologicalsuccessratesinelderlyandnon-elderlypatients(modiﬁedintent-to-treatpopulation).^a

Response No.(%)ofpatients[95%CI] P-value

Elderlypatients(≥65years) Non-elderlypatients(<65years) Globalsuccess

EOT 49/72(68.1%)[56.0–78.6%] 58/82(70.7%)[59.6–80.3%] 0.719

EOIVT 51/73(69.9%)[58.0–80.1%] 60/84(71.4%)[60.5–80.8%] 0.830

2weeksafterEOT 27/54(50.0%)[36.1–63.9%] 50/74(67.6%)[55.7–78.0%] 0.045

6weeksafterEOT 16/44(36.4%)[22.4–52.2%] 39/65(60.0%)[47.1–72.0%] 0.016

Microbiologicalresponse

EOT 54/75(72.0%)[60.4–81.8%] 61/83(73.5%)[62.7–82.6%] 0.833

EOIVT 56/76(73.7%)[62.3–83.1%] 63/85(74.1%)[63.5–83.0%] 0.950

2weeksafterEOT 27/54(50.0%)[36.1–63.9%] 50/74(67.6%)[55.7–78.0%] 0.045

6weeksafterEOT 16/44(36.4%)[22.4–52.2%] 39/65(60.0%)[47.1–72.0%] 0.016

CI,conﬁdenceinterval;EOT,endofalltherapy;EOIVT,endofintravenoustherapy.

aPatientswithmissingandunknownglobalormicrobiologicalresponseswereexcludedfromtheseanalyses.

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Table3

Mostfrequentlyreported(>1%)treatment-related(duetoanidulafunginand/or azoles)adverseeventsinelderlyandnon-elderlypatients(safetypopulation).

Adverseevent n(%)

Elderlypatients(≥65 years)(N=100)

Non-elderlypatients (<65years)(N=116)

≥1adverseevent 12 (12.0) 21(18.1)

Abdominalpain 2(2.0) 0(0.0)

ALTincreased 2(2.0) 0(0.0)

ASTincreased 2(2.0) 1(0.9)

Atrialﬁbrillation 1(1.0) 2(1.7)

BloodALPincreased 0(0.0) 3(2.6)

Cholestasis 0 (0.0) 2 (1.7)

Convulsion 0 (0.0) 2 (1.7)

Cytolytichepatitis 0(0.0) 2(1.7)

Diarrhoea 2(2.0) 1(0.9)

Erythema 2(2.0) 2(1.7)

Hyperbilirubinaemia 2(2.0) 0(0.0)

Hyperglycaemia 2(2.0) 0(0.0)

Hypotension 2(2.0) 1(0.9)

ALT,alanineaminotransferase;AST,aspartateaminotransferase;ALP,alkalinephos- phatase.

documentedintheelderlypatientcohort(68.1%),whichdidnot differsignificantlyfromtherateobservedinnon-elderlypatients (70.7%). A similar outcome was observed when unknown and missing responses were included in the analysis as treatment failures,indicatingthattheprimaryobservationwasrobust.This resultwasachieveddespitethefactthatelderlypatientshadhigher scoresforseverityofillnessatbaselinecomparedwithnon-elderly patients,asreflectedbytheirsignificantlyhigherSOFA,APACHE IIandCandidascoresaswellasagreaterlikelihoodtohaverenal insufficiency/failure/dialysis. Similar outcomes were observed in elderly patients regardless of whether or not candidaemia waspresent and in patientswith C.albicans ornon-C. albicans C/IC.Themicrobiologicalsuccessrateinelderlypatientswasalso high(72.0%)andsupportiveoftheprimaryefficacyfindings.The observationsfromthisanalysisareofclinicalrelevancegiventhat, toourknowledge,nostudiesspecificallyfocusingonthetreatment ofC/ICinICUelderlypatientshavebeenperformedtodate.

Anotablefindingfromthisanalysiswasthatthesuccessrate amongelderlypatientsdeclinedovertime.At2weeksand6weeks postEOT,theglobalsuccessrates amongelderlypatientswere significantly lower than the rates observed among non-elderly patients.Thesedifferencescanbelargelyexplainedbythefactthat significantlymoreelderly(26.5%)thannon-elderly(8.6%)patients whoachievedglobaltreatmentsuccessatEOTdiedbetweenEOT andthe2-weekfollow-up,allduetonon-Candida-relatedcauses.

Thisobservationisconsistentwithpreviousreportssuggestingthat olderageisasignificantandindependentriskfactorformortal- ityinICUpatientswithcandidaemia[19,20].Althoughtheprecise reasonsforthis areunknown,reducedage-relatedphysiological reserveanddiminishedhostresistancemaybecontributingfac- tors.Thispossibleexplanationissupportedbytheobservationthat elderlypatientshadsignificantlyhighermeanAPACHEIIscores, meanSOFAscoresandmeanCandidascoresaswellasahigher incidenceof renal insufficiency/failure/dialysisthannon-elderly patients.

Thisanalysisrevealedsomesubtledifferencesintheepidemi- ologyofC/ICbetweenelderlyandyoungerpatients.Candidaemia wasless commonin elderlypatients(65%) thanin non-elderly patients(77%),whichisconsistentwithapreviousstudyindicat- ingthatage<65yearsisariskfactorforcandidaemia[21],anda retrospectivecohortstudyreportedthatelderlyICUpatientswere lesslikelytohavebloodstreaminfectionsthanyoungerpatients [10]. Data from a recent pooled analysis of clinical trial data withanotherechinocandin(micafungin)suggestedthatpatients

withcandidaemiahavea higherlikelihood oftreatmentsuccess withantifungaltherapythanthosewithinvasivecandidiasis[22].

Thismay,inturn,havebeenacontributingfactortothepoorer outcomesobservedinolderpatients(≥70years)inthesamestudy [22].Incontrast,inthepresentstudy,theratesofglobalsuccess weresimilarinpatientswith(67%)andwithoutcandidaemia(70%) andaresupportiveoftheefﬁcacyofanidulafunginindeep-seated infectionaswellasincandidaemia.

Althoughthereweresomenumericaldifferencesinthebase- linedistributionofCandidaspp.betweenelderlyandnon-elderly patients, the overall distribution did not differ signiﬁcantly betweenagegroups.Candidaalbicanswasthepredominantsingle pathogenin bothpatientcohorts,accountingfor ≥55%of base- linepathogensbothinelderlyandnon-elderlypatients.Candida glabratawasthesecondmostcommonsingleaetiologicalagent inelderlypatients(17.5%) butwaslesscommoninnon-elderly patients(12.2%).AnincreasedprevalenceofC.glabratainfections appearstobeassociatedwitholderage,ashasbeendocumented inseverallarge-scalesurveillancestudies[23].Furthermore,inat- riskpatients, C.glabratahasahighmortalityrate[24,25].Since currenttreatmentguidelinesrecommendtheuseofechinocandins forpatientswithC.glabratainfectionsbecauseofemergingazole resistance[3,5],thecurrentobservationssuggestthatechinocan- dinsmayprovidebettercoverageofpotentialpathogensinthisage group.Amongthe167baselineisolatesthatunderwentsuscepti- bilitytesting,anunusuallyhighrateofﬂuconazoleresistancewas observedamongC.parapsilosis.

Anidulafunginwaswelltoleratedbyelderlypatientsdespitethe factthattheywerereceivingmultipleconcomitantmedicationsin additiontostudytreatment.Therewerenomarkeddifferencesin theincidenceofAEsinelderlypatientscomparedwithnon-elderly patients.NoseriousAEswereobservedintheelderlypatientcohort.

Anidulafunginiscurrentlytheonlyavailableechinocandinfor which no doseadjustments are required for renal and hepatic impairmentandithasnoknowndrug–druginteractions[26,27].

Thesepropertiesmayhavecontributedtotheexcellenttolerability proﬁledocumentedinthepresentanalysisandshouldbeconsid- eredwhenselectingtreatmentfor elderlyICU patientswhoare oftenreceivingmultiplemedicationsandwhocommonlypresent withmultipleorganfailure.

Thepresentanalysiswasposthocandwasnotpartoftheorig- inalstudyprotocol;thefindingsreportedhereinshouldtherefore beviewedasexploratoryonly.Afurtherlimitationofthepresent analysis wasthat nomultivariate analyseswere performed on factorsdeterminingtreatmentresponseandpatientsurvival.How- ever,a formal multivariateanalysisof this studyis inprogress and willbereported infull ata later date.It would alsobeof interest toanalyseefficacyoutcomesaccording totheunderly- ingdisease(i.e.renalorhepaticinsufficiency,solidtumour,etc.);

however,patientscommonlybelongedtooneormoresubpopu- lations,whichwouldlimittheabilitytointerprettheseresults.A particularstrengthofthepresentanalysiswasthatalmostone- halfofthestudypopulationwaselderly,whichpresentedaunique opportunitytocomparedemographic differencesandtreatment efﬁcacybetweenagegroupsinthesettingofaprospectiveclinical trial.

5. Conclusions

Inconclusion,anidulafunginwaseffectiveandsafeforthetreat- mentofC/ICinelderlyICUpatients(aged≥65years),despitethese patientshavinghigherscoresforseverityofillness(i.e.APACHEII, SOFA),higher Candidascores,greaterlikelihoodoforganfailure and greater likelihood of invasive candidiasis at baseline. Fur- thermore,thehigherincidenceofC.glabrata,whichisassociated

(6)

withhighmortalityratesandincreasingresistancetoﬂuconazole, underscorestheimportanceofeffectiveﬁrst-linetherapy,suchas echinocandins,intheelderlycriticallyillpopulation.

Funding:ThisstudywassponsoredbyPfizer.Editorialsupport wasprovidedbyLeighPrevostatPAREXELandwasfundedbyPfizer InternationalOperations.Therewerenorestrictionsfromthestudy sponsorintermsoftheanalysespresentedinthispaper.Whilst allstatisticalanalyseswereconductedbyemployeesofthestudy sponsor,thiswasdoneaccordingtodefinitionsandspecifications jointlyagreedonbytheauthors.Noothersourceprovidedfunding fortheactualclinicalstudyortheanalysespresentedinthispaper.

Competinginterests:GDhasreceivedresearchfunding,fundsfor speakingandfundsforadvisoryboardmembershipfromPﬁzer;J- APhasreceivedresearchfunding,fundsfor speakingand funds foradvisoryboard membershipfrom MSD,Novartisand Pﬁzer;

WMhasreceivedresearchfundingfromMSDand Pfizer,funds forspeakingfromMSD,andfundsforadvisoryboardmembership fromPfizer;IGhasreceivedfundsforspeakingfromAbbott,Astra- Zeneca,Bayer,EliLilly,Fresenius,MerckandPfizer,andfundsfor advisoryboardmembershipfromPfizer;GShasreceivedfundsfor speakingandfundsforadvisoryboardmembershipfromPfizer;PM hasreceivedfundsforspeakingandfundsforadvisoryboardmem- bershipfromAstellas,MSDandPfizer;GAhasreceivedfundsfor speakingandfundsforadvisoryboardmembershipfromPfizer;

MBShasreceivedfundsforspeakingfromAstellas,Astra-Zeneca and Pfizer; PJM, TMand MK are employees of Pfizer; MR has receivedresearchfundingfromMSD,PfizerandStifterverbandfür dieDeutscheWissenschaftaswellasfundsforspeakingandfunds foradvisoryboardmembershipfromAstellas,Essex,Gilead,MSD andPfizer.JPdeclaresnocompetinginterests.

Ethicalapproval:Theﬁnalprotocol,amendmentsandinformed consentdocumentationwerereviewedandapprovedbytheInde- pendentEthicsCommitteesateachoftheinvestigationalcentres participatinginthestudy.Therewereatotalof61sitesacross19 countries.Theauthorsarehappytoprovidefulldetailsifrequested.

References

[1] KettDH,AzoulayE,EcheverriaPM,VincentJL.Candidabloodstreaminfections inintensivecareunits:analysisoftheExtendedPrevalenceofInfectionin IntensiveCareUnitStudy.CritCareMed2011;39:665–70.

[2]VazquezJA.Invasivefungalinfectionsintheintensivecareunit.SeminRespir CritCareMed2010;31:79–86.

[3]PappasPG,KauffmanCA,AndesD,BenjaminJrDK,CalandraTF,Edwards JrJE,etal.Clinicalpracticeguidelinesforthemanagementofcandidiasis:

2009updatebytheInfectiousDiseasesSocietyofAmerica.ClinInfectDis 2009;48:503–35.

[4]LeroyO,GangneuxJP,MontraversP,MiraJP,GouinF,SolletJP,etal.Epidemi- ology,management,andriskfactorsfordeathofinvasiveCandidainfections in criticalcare:a multicenter,prospective,observational studyin France (2005–2006).CritCareMed2009;37:1612–18.

[5]RuhnkeM,RickertsV,CornelyOA,BuchheidtD,GlocknerA,HeinzW,etal.Diag- nosisandtherapyofCandidainfections:jointrecommendationsoftheGerman

SpeakingMycologicalSocietyandthePaul-Ehrlich-SocietyforChemotherapy.

Mycoses2011;54:279–310.

[6]Pfaller MA,BoykenL, HollisRJ,KroegerJ, MesserSA,TendolkarS,etal.

InvitrosusceptibilityofinvasiveisolatesofCandidaspp.toanidulafungin, caspofungin,andmicafungin:sixyearsofglobalsurveillance.JClinMicrobiol 2008;46:150–6.

[7]HofH.Mycosesintheelderly.EurJClinMicrobiolInfectDis2010;29:5–13.

[8] KauffmanCA.Fungalinfectionsinolderadults.ClinInfectDis2001;33:550–5.

[9]NguyenYL,AngusDC,BoumendilA,GuidetB.Thechallengeofadmittingthe veryelderlytointensivecare.AnnIntensiveCare2011;1:29.

[10]BlotS,CankurtaranM,PetrovicM,VandijckD,LizyC,DecruyenaereJ,etal.

Epidemiologyandoutcomeofnosocomialbloodstreaminfectioninelderly criticallyillpatients:acomparisonbetweenmiddle-aged,old,andveryold patients.CritCareMed2009;37:1634–41.

[11] DimopoulosG,KoulentiD,SakrY,etal.Elderlypatientswithinfectionsinthe ICU:resultsoftheEPICIIstudy.In:SocietyofCriticalCareMedicine(SCCM) 40thCriticalCareCongress.2011[Abstract2966].

[12]SgangaG.Casereport4:elderlypatientwithconcomitantconditions.Mycoses 2010;53(Suppl.2):10–11.

[13] PisoniR,WilleKM,TolwaniAJ.Theepidemiologyofsevereacutekidneyinjury:

fromBESTtoPICARD,inacutekidneyinjury:newconcepts.NephronClinPract 2008;109:c188–91.

[14]RicciZ,CruzD,RoncoC.TheRIFLEcriteriaandmortalityinacutekidneyinjury:

asystematicreview.KidneyInt2008;73:538–46.

[15]GavazziG,KrauseKH.Ageingandinfection.LancetInfectDis2002;2:659–66.

[16]RuhnkeM,PaivaJ-A,MeerssemanW,PachlJ,GrigorasI,SgangaG,etal.Anidu- lafunginforthetreatmentofcandidaemia/invasivecandidiasisinselected criticallyillpatients.ClinMicrobiolInfect2012;18:680–7.

[17]LeónC,Ruiz-SantanaS,SaavedraP,AlmiranteB,Nolla-SalasJ,Alvarez-LermaF, etal.Abedsidescoringsystem(‘Candidascore’)forearlyantifungaltreatment innonneutropeniccriticallyillpatientswithCandidacolonization.CritCare Med2006;34:730–7.

[18]ClinicalandLaboratoryStandardsInstitute.Referencemethodforbrothdilu- tionantifungalsusceptibilitytestingofyeasts;approvedstandard.3rded.

DocumentM27-A3.Wayne,PA:CLSI;2008.

[19] BlotSI,VandewoudeKH,HosteEA,ColardynFA.Effectsofnosocomialcan- didemiaonoutcomesofcriticallyillpatients.AmJMed2002;113:480–5.

[20]MarriottDJ,PlayfordEG,ChenS,SlavinM,NguyenQ,EllisD,etal.Determi- nantsofmortalityinnon-neutropenicICUpatientswithcandidaemia.CritCare 2009;13:R115.

[21] ShorrAF,TabakYP,JohannesRS,SunX,SpaldingJ,KollefMH.Candidemiaon presentationtothehospital:developmentandvalidationofariskscore.Crit Care2009;13:R156.

[22] HornDL,Ostrosky-ZeichnerL,MorrisMI,UllmannAJ,WuC,BuellDN,etal.

Factorsrelatedtosurvivalandtreatmentsuccessininvasivecandidiasisor candidemia:apooledanalysisoftwolarge,prospective,micafungintrials.Eur JClinMicrobiolInfectDis2010;29:223–9.

[23] TortoranoAM,PemanJ,BernhardtH,KlingsporL,KibblerCC,FaureO,etal.

EpidemiologyofcandidaemiainEurope:resultsof28-monthEuropeanCon- federationofMedicalMycology(ECMM)hospital-basedsurveillancestudy.Eur JClinMicrobiolInfectDis2004;23:317–22.

[24] ColomboAL,NucciM,ParkBJ,NouerSA,Arthington-SkaggsB,daMattaDA, etal.EpidemiologyofcandidemiainBrazil:anationwidesentinelsurveillance ofcandidemiainelevenmedicalcenters.JClinMicrobiol2006;44:2816–23.

[25]FidelJrPL,VazquezJA,SobelJD.Candidaglabrata:reviewofepidemiology, pathogenesis,andclinicaldiseasewithcomparisontoC.albicans.ClinMicrobiol Rev1999;12:80–96.

[26]DamleBD,DowellJA,WalskyRL,WeberGL,StogniewM,InskeepPB.Invitro andinvivostudiestocharacterizetheclearancemechanismandpotential cytochromeP450interactionsofanidulafungin.AntimicrobAgentsChemother 2009;53:1149–56.

[27]DowellJA,StogniewM,KrauseD,DamleB.Anidulafungindoesnotrequire dosageadjustmentinsubjectswithvaryingdegreesofhepaticorrenalimpair- ment.JClinPharmacol2007;47:461–70.