Epidemiology and predictors of a poor outcome in elderly patients with candidemia

Epidemiology

and

predictors

of

a

poor

outcome

in

elderly

patients

with

candidemia

Thaı´s

Guimara˜es

*

,

Ma´rcio

Nucci

,

Joa˜o

S.

Mendonc

¸

a

,

Roberto

Martinez

,

Ligia

R.

Brito

,

Nivia

Silva

,

Maria

Luiza

Moretti

,

Reinaldo

Saloma˜o

,

Arnaldo

L.

Colombo

a_{UniversidadeFederaldeSa˜oPaulo,Sa˜oPaulo,Brazil}

b_{HospitaldoServidorPu´blicoEstadualdeSa˜oPaulo,Sa˜oPaulo,Brazil} c_{UniversidadeFederaldoRiodeJaneiro,RiodeJaneiro,Brazil}

d_{UniversidadedeSa˜oPaulo,CampusRibeira˜oPreto,Ribeira˜oPreto,Brazil} e_{HospitalBeneficeˆnciaPortuguesa,Sa˜oPaulo,Brazil}

f_{UniversidadeEstadualdeCampinas,Campinas,Brazil} g_{CasadeSau´deSantaMarcelina,Sa˜oPaulo,Brazil}

1. Introduction

Theincidenceofcandidemiaintertiarycarehospitalsworldwide has increased substantially over recent decades.1 _Candidemia representsasignificantcauseofmorbidityandmortality, particu-larlyamongcriticallyillpatients.Inaddition,candidemiaprolongs hospital stays and increases the costs associated with patient management.2,3_{Theepidemiologyofcandidemiahasbeenstudied} extensivelyworldwide,anddataareavailablefromalargeseriesof laboratory-basedandpopulation-basedsurveillancestudies,aswell asstudiesfocusingonspecificpatientpopulationssuchasneonates, cancer,surgical,andintensivecareunit(ICU)patients.4–8_Although elderlypatientsrepresentasignificantproportionofpatientswith

candidemia (24–57% in a majority of published series), few investigators have specifically addressed the epidemiological aspectsofcandidemiainthispopulation.9,10_{Becausebloodstream} infectionsinthesepatientshavedifferentclinicalpresentationsand outcomes when comparedto those in younger individuals, we hypothesizedthatcandidemia inelderly patientswouldpresent several peculiarities for patient care.11,12 _{To characterize these} putativepeculiaritiesinelderlypatients,weevaluatedadatabaseof patientcandidemiafromthreemulticenter,prospective, laboratory-basedsurveillancestudiescoordinatedbyourgroup,andcompared the clinical and epidemiological aspectsof candidemia in older versusyoungerpatients.

2. Patientsandmethods

Thiswasaretrospectiveanalysisofadatabaseofcandidemia generated by combining the databases from three prospective, ARTICLE INFO

Articlehistory:

Received7September2011 Accepted2February2012

CorrespondingEditor:WilliamCameron,

Ottawa,Canada

Keywords:

Candidemia Elderly Epidemiology Bloodstreaminfections

SUMMARY

Background:Candidemiaaffectspatientpopulationsfromneonatestotheelderly.Despitethis,little informationisavailableabouttheepidemiologyofcandidemiainelderlypatients.

Methods:Weperformedaretrospectiveanalysisof987episodesofcandidemiainadults(>14yearsof age)fromthedatabasesofthreelaboratory-basedsurveysofcandidemiaperformedat14tertiarycare hospitals.Patientsaged60yearswereconsideredelderly(group1,n=455,46%)andwerecomparedto youngerpatients(group2,n=532,54%)regardingdemographics,underlyingdiseases,comorbidities, exposuretomedicalprocedures,species,treatment,andoutcome.

Results:ThemedianAPACHEIIscorewassignificantlyhigherintheelderlypatients(19vs.15,p=0.03). Variablesthatwereobservedsignificantlymorefrequentlyinelderlypatientsincludedadmissiontoan intensivecareunit,diabetesmellitus,renalfailure,cardiacdisease,lungdisease,receiptofantibioticsor H2blockers,insertionofacentralvenouscatheter,mechanicalventilation,andcandidemiadueto Candidatropicalis.The30-daymortalityofelderlypatientswassignificantlyhigherthanthatofyounger patients(70%vs.45%,p<0.001).Factorsassociatedwithhighermortality bymultivariateanalysis includedAPACHEIIscoreandbeingingroup1(elderly).Factorsassociatedwithmortalityinelderly patientswerelungdiseaseandthereceiptofmechanicalventilation.

Conclusions: Elderlypatientsaccountforasubstantialproportionofpatientswithcandidemiaandhave ahighermortalitycomparedtoyoungerpatients.

ß_{2012InternationalSocietyforInfectiousDiseases.PublishedbyElsevierLtd.Allrightsreserved.}

*Correspondingauthor.Av.dosEucaliptos155Apto.121ZipCode:04517-050 Sa˜oPauloBrazil.Tel.:+551150932218;fax:+551155491565.

E-mailaddress:tguimaraes@terra.com.br(T.Guimara˜es).

ContentslistsavailableatSciVerseScienceDirect

International

Journal

of

Infectious

Diseases

j o urn a l hom e pa ge : ww w. e l s e v i e r. c om/ l o ca t e / i j i d

laboratory-basedsurveillancestudiesperformedat14tertiarycare medical centers in Brazil between June 1994 and December 2004.13–15_{Thethreestudiesenrolledsolelytertiarycarehospitals} withautomatedbloodculturesystems(BACTECorBacT-ALERT), providingmedicalcaretoadultsandchildrenindifferentmedical specialties. The case report form and the strategy for data collectionwere thesame acrossthe three surveillance studies. For each center, an investigator was specifically trained to maintaindailycontactwiththehospitalmicrobiologylaboratory and tocollectclinical and epidemiologicaldata for allincident casesofcandidemia.Investigatorswereequippedwithastandard case report form and a dictionary of terms that included all definitions of underlying conditions and medical exposures collectedduringthestudy.In addition,allCandidabloodstream isolatesweresenttoacentrallaboratoryforspeciesidentification. Isolateswereidentifiedaccordingtotheirmicroscopicmorphology oncornealTween80agarandbybiochemicalanalysisusingtheID 32Csystem(bioMe´rieux,Marcyl’Etoile,France).

Thefollowingvariableswerecollectedforeachpatientatthe time of enrollment: age, gender, date of admission, date of candidemia, duration of hospitalization, APACHE II score (for criticallyill patients), medical ward, underlyingmedical condi-tions,exposuretoinvasivemedicalprocedures,useofantibiotics orcorticosteroids,managementofcandidemia(antifungal treat-mentandcatheterremoval),andoutcome.Acaseofcandidemia wasdefinedbytheinitialisolation ofCandidasppfromablood culture.Candidemiaoccurring>30daysaftertheinitialisolation

wasdefinedasanewcase.Patientswerefollowedfor30daysafter thediagnosisofcandidemia.

Neutropeniawasdefined asanabsoluteneutrophilcountof

<0.5109_{/l. We considered as conditions associated with} candidemiathosepresent30daysbeforethedateoftheincident candidemia.Underlyingdiseases wereconsidered if thepatient presentedanyconditionrequiringactivetreatmentintheprevious 3 months. Cardiac disease was considered if the patient had congestiveheartfailure,coronaryarterialdisease,hypertension,or cardiac arrhythmias; pulmonary disease was considered if the patient had chronic obstructive pulmonary disease, asthma, bronchiectasis, granulomatous lung disease, or any restrictive pulmonary disease; neurological disease was considered if the patient had a stroke, or had Parkinson’s disease, any type of dementia,orconvulsions;andliverdiseasewasconsideredifthe patienthadchronicviralordrughepatitis,anytypeofcirrhosis,or biliary diseases that required surgery. Diabetes mellitus was consideredifthepatientrequiredspecificmedicationtomaintain normal glucose levels.Renal failure was defined as any docu-mentedserumcreatininevalue>1.5g/dl.

Patients60yearsoldwereconsideredelderly(group1)and those<60yearsoldwereconsideredyounger(group2).Patients

aged<14years wereexcludedfromtheanalysis.Wecompared

elderly patients (group 1) with younger patients (group 2) regardingbaselinecharacteristics,clinicalmanifestations,species distribution, treatment, and outcome. Categorical data were analyzedusingChi-squareorFisher’sexacttests,asappropriate, andcontinuousvariableswerecomparedusingtheWilcoxontest. A p-value of <0.05 was considered statistically significant.

Variables significant at p<0.1 by univariate analysis were

included in a multivariate model (backward and forward). StatisticalanalyseswereperformedusingSPSSversion15.0(SPSS, Inc.,USA).

3. Results

Among the987 patients >14 years of age,455 (46%) were

elderly(group1)and532(54%)wereyounger(group2).Elderly

patientsaccountedfor29–69%ofpatientsinthe14participating hospitals.

Table 1 shows the comparison of baseline characteristics betweenthetwogroups.Themedianageofgroup1was72years (range60–99years)andof group2was41years (range14–59 years).ElderlypatientsweremorelikelytobeinanICUatthetime ofdiagnosisofcandidemiaandlesslikely tobeina medicalor hematologywardcomparedtoyoungerpatients.Inaddition,the mediandurationofhospitalizationbeforetheonsetofcandidemia wassignificantlyhigheramongelderlypatients(24vs.19 days, p<0.001).Likewise,thepresenceofcertaincomorbidities,suchas

diabetes,renalfailure,cardiacdisease,andlungdiseaseweremore likelytobepresentinelderlypatients.Incontrast,liverdiseasewas more frequent among younger patients. Elderly patients were sicker, asshown by the significantly highermedian APACHE II scoreonthedayoftheincidentcandidemia(19vs.15,p=0.03). Othervariablesmorefrequentlyobservedinelderlypatientswere thereceiptofantibioticsandH2blockers,thepresenceofacentral venous catheter (CVC), and receipt of mechanical ventilation. Neutropenia, organ transplantation, and the receipt of cancer chemotherapyweremorefrequentlyobservedinyoungerpatients. AsshowninTable2,non-albicansspeciesaccountedfor61%of candidemias. Candida tropicalis (24%) and Candida parapsilosis (21%) were the most frequent non-albicans species. Of note, Candidaglabrataaccountedforonly7%ofcases.Candidemiadueto C.tropicalis wasmore commonamongelderlypatients (28%vs. 21%,p=0.02),whereasC.parapsilosiswasmorefrequentamong youngerpatients(24%vs.18%,p=0.02).Wefurtherexploredthe associationbetweenelderlypatientsandC.tropicaliscandidemia by stratifying patients by cancer diagnosis. Among patients withoutcancer,candidemiaduetoC.tropicaliswasobservedin 21%ofyoungerand24%ofelderlypatients(p=0.23).Incontrast, amongpatientswithcancer,C.tropicaliscandidemiaoccurredin 23%ofyoungerand35%ofelderlypatients(p=0.02).

Overall,68%ofpatientsreceivedantifungal therapy–70%of youngerpatientsand66%ofelderlypatients(p=0.12).Themedian time from the diagnosis of candidemia to the initiation of antifungal therapywas3days (range 10 to39 days)andwas similarinthetwogroups(p=0.46).DeoxycholateamphotericinB wasthemostfrequentagentusedasprimarytherapy(394ofthe 673patientswhoreceivedtreatment,59%),followedby flucona-zole (37%). Other treatments included a lipid formulation of amphotericin B (three episodes), caspofungin (three episodes), voriconazole (twoepisodes),and a blinddrugin a randomized clinicaltrial(20episodes).DeoxycholateamphotericinBwasmore likelytohavebeenusedinyoungerpatients(239of374younger patients, 64%, vs. 155 of 299 elderly patients, 52%, p=0.001), whereasfluconazolewasmorefrequentlyusedinelderlypatients (136of299,45%,vs.115of374,31%,p<0.001).

Onday30afterthediagnosisofcandidemia,57%ofpatientshad died – 71% of elderly patients and 45% of younger patients (p<0.001).AsshowninTable3,variablesassociatedwithhigher

30-day mortality by univariate analysis included age group (elderly), hospitalization in an ICU, certain underlying medical conditionssuchasdiabetesmellitus,renalfailure,cardiacdisease, andlungdisease,higherAPACHEIIscoreonthedayofdiagnosisof candidemia, presence of a CVC, abdominal surgery, receipt of mechanical ventilation, total parenteral nutrition, dialysis, and corticosteroids, and candidemia due to Candida albicans, C. tropicalis,andC.glabrata.Factorsassociatedwithbettersurvival atday30wereneutropenia,receiptofcancerchemotherapy,and candidemiaduetoC.parapsilosis.

the APACHE II score was available for only 220 patients, we performedasecondmultivariateanalysisexcludingthisvariablein ordertoanalyzethewholepatientpopulation (987episodesof candidemia).AsshowninTable4,agegroupwasanindependent variableassociatedwith30-daymortality(OR3.38,95%CI2.34– 4.87).Theothersignificantvariableswerelungdisease, candide-miaduetoC.glabrata,andthereceiptofmechanicalventilation, dialysis,and totalparenteral nutrition. Among elderlypatients, factorsassociatedwith30-daymortalitywerelungdiseaseandthe receiptof mechanical ventilation. In contrast,variables signifi-cantlyassociatedwith30-daymortalityinyoungerpatientswere

candidemiaduetoC.glabrata,lungdisease,receiptofmechanical ventilation,parenteralnutrition,anddialysis,andneutropenia.

4. Discussion

Infectionsinelderlypatientsarecurrentlyamajorpublichealth concern,gainingincreasingrelevancebecauseoftheexpansionof theelderlypopulationworldwide.16_{Inaddition,thepopulationof} immunocompromised patients in this age grouphasincreased, withanexpandedpopulationofelderlypatientsundergoingorgan transplantation and receiving aggressive regimes of cancer

Table2

Speciesdistributionofcandidemicepisodesinelderly(group1)andyounger(group2)patients

Candidaspecies Allpatients (N=987)

Group1(60years) (n=455)

Group2(<60years) (n=532)

p-Valuea

C.albicans 386(39) 184(40) 202(38) 0.43

C.tropicalis 240(24) 126(28) 114(21) 0.02

C.parapsilosis 209(21) 82(18) 127(24) 0.02

C.glabrata 66(7) 31(7) 35(7) 0.89

C.rugosa 29(3) 11(2) 18(3) 0.37

C.krusei 18(2) 8(2) 10(2) 0.42

C.guilliermondii 16(2) 7(1.5) 9(2) 0.85

C.lusitaniae 10(1) 2(0.5) 8(1.5) 0.12

Otherb _{8(1) 4(1) 4(1.5) 1.00}

a_{p-Valueforthecomparisonbetweenthetwogroups.}

b_{OtherspeciesincludedCandidafamata(twocasesingroup1andfouringroup2)andCandidasp(twocasesingroup1).}

Table1

Baselinecharacteristicsandcoexistingexposuresofelderly(group1)andyounger(group2)patientswithcandidemia

Variable Allpatients

(N=987)

Group1(60years) (n=455)

Group2(<60years) (n=532)

p-Valuea

Gendermale/female,n 569/418 270/185 299/233 0.32

Ward,n(%)

ICU 374(38) 202(44) 172(32) <0.001

Medical 298(30) 122(27) 176(33) 0.03

Surgical 187(19) 90(20) 97(18) 0.54

Emergency 61(6) 29(6) 32(6) 0.81

Hematology 60(6) 8(2) 52(10) <0.001

Gynecology 7(1) 4(1) 3(1) 1.00

Duration(days)ofhospitalizationbefore candidemia,median(range)

21(0–611) 24(0–324) 19(0–611) <0.001

Underlyingdisease,n(%)b

Cancer 314(32) 143(31) 171(32) 0.81

Hematologicalmalignancy 167(17) 18(4) 149(28) <0.001

Solidtumor 147(15) 125(27) 22(4) <0.001

Diabetesmellitus 152(15) 109(24) 43(8) <0.001

Neurologicaldisease 143(14) 60(13) 83(16) 0.28

Renalfailure 161(16) 89(20) 72(14) 0.01

Cardiacdisease 119(12) 83(18) 36(7) <0.001

Lungdisease 80(8) 49(11) 31(6) 0.005

Liverdisease 54(5) 15(3) 39(7) 0.005

Immunologicaldisease 31(3) 10(2) 21(4) 0.12

AIDS 36(4) 2(0.4) 34(6) <0.001

APACHEIIscore,median(range)c _{17(2–42) 19(5–42) 15(2–39) 0.03}

Coexistingexposures,n(%)b

Receiptofantibiotics 903(92) 434(95) 469(88) <0.001

Centralvenouscatheter 632(64) 369(81) 263(49) <0.001

ReceiptofH2blockers 768(78) 372(82) 396(74) 0.006

Surgery 418(42) 191(42) 227(43) 0.83

Abdominalsurgery 208(21) 111(24) 97(18) 0.02

Mechanicalventilation 455(46) 242(53) 213(40) <0.001

Receiptofcorticosteroids 377(38) 179(39) 198(37) 0.49

Receiptoftotalparenteralnutrition 190(19) 83(18) 107(20) 0.46

Receiptofdialysis 169(17) 79(17) 90(17) 0.85

Neutropenia 95(10) 21(5) 74(14) <0.001

Organtransplantation 13(1) 1(0.2) 12(2) 0.005

Receiptofcancerchemotherapy 102(10) 20(4) 82(15) <0.001

ICU,intensivecareunit;AIDS,acquiredimmunodeficiencysyndrome;APACHE,AcutePhysiologyandChronicHealthEvaluation. a_{p-Valueforthecomparisonbetweenthetwogroups.}

b_{Thesumexceeds100%becausepatientsmayhavehadmorethanoneunderlyingconditionorcoexistingexposure.}

chemotherapyandimmunosuppressivetherapiesfordegenerative diseases.17 _{Finally, elderly patients are hospitalized more} fre-quentlyandhaveahighermortalityrate,longerhospitalization, and increased risk of disability when compared with younger patients.18

Althoughunderlying medical conditions typically associated with candidemia are frequent in the elderly population, the proportionofelderlypatientsindifferentstudiesofcandidemia hasnotbeenextensivelyreported. Withdifferentdefinitionsof ‘elderly’(>60or>65yearsofage),theproportionhasrangedfrom

24%to46%intheUSA,10,19_{41%to57%inEurope,}9,20_22%to48%in

Brazil,21,22_{andhasbeenreportedas39%inJapan.}23_Inthepresent study, elderly patients represented 46% of adult patients (>14

yearsold)and31%ofthe1485adultsandchildreninthiscohort (datanotshown).

Cancer was the most frequent underlying disease in both younger and older patients. However, while candidemia in younger patients with cancer occurred more frequently in the context of hematological malignancies and chemotherapy-in-ducedneutropenia,elderlycancerpatientswithcandidemiawere morelikelytohavesolidtumors.Inaddition,candidemiaoccurred inthesettingofcomplicationsofabdominalsurgeryratherthan

Table3

Univariateanalysisoffactorsassociatedwith30-daymortalityamong987adultpatientswithcandidemia

Variable Died(n=561) Survived(n=426) p-Value

Agegroupelderly,n(%) 321(57) 134(31) <0.001

Gendermale/female,n 325/236 244/182 0.84

Hospitalizationintheintensivecareunit,n(%) 262(47) 112(26) <0.001

Underlyingdisease,n(%)

Cancer 188(34) 126(30) 0.19

Diabetesmellitus 100(18) 52(12) 0.01

Neurologicaldisease 79(14) 64(15) 0.68

Renalfailure 105(19) 56(13) 0.02

Cardiacdisease 81(14) 38(9) 0.008

Lungdisease 70(12) 10(2) <0.001

Liverdisease 35(6) 19(4) 0.22

APACHEIIscore,median(range)a _{20.5(7–42) 13(2–34) <0.001}

Coexistingexposures,n(%)

Centralvenouscatheter 401(71) 231(54) <0.001

Surgery 242(43) 176(41) 0.57

Abdominalsurgery 136(24) 72(17) 0.005

Mechanicalventilation 331(59) 124(29) <0.001

Receiptofcorticosteroids 238(42) 139(33) 0.002

Receiptoftotalparenteralnutrition 128(23) 62(15) 0.001

Receiptofdialysis 119(21) 50(12) <0.001

Neutropenia 45(8) 50(12) 0.05

Organtransplantation 7(1) 6(1) 0.83

Receiptofcancerchemotherapy 46(8) 56(13) 0.01

Candidaspecies

C.albicans 235(42) 151(35) 0.04

C.tropicalis 150(27) 90(21) 0.04

C.parapsilosis 84(15) 125(29) <0.001

C.glabrata 49(9) 17(4) 0.003

Treatment,n(%)

DeoxycholateamphotericinB 203(36) 191(45) 0.006

Fluconazole 131(23) 120(28) 0.08

Time(days)fromdiagnosisofcandidemiato treatmentinitiation,median(range)

2( 10to23) 3( 10to39) 0.04

a_{Dataavailableforonly220patients.}

Table4

Multivariateanalysisoffactorsassociatedwith30-daymortalityamong987adultpatientswithcandidemia

Variablea _{OR 95%CI p-Value}

Allpatients

Lungdisease 4.35 1.97–9.59 <0.001

CandidemiaduetoC.glabrata 3.58 1.49–8.58 0.004

Agegroupelderly 3.38 2.34–4.87 <0.001

Receiptofmechanicalventilation 2.61 1.81–3.78 <0.001

Receiptofdialysis 2.18 1.29–3.69 0.004

Receiptoftotalparenteralnutrition 2.06 1.30–3.24 0.002

Elderlypatients

Lungdisease 4.76 1.39–16.29 0.01

Receiptofmechanicalventilation 2.35 1.40–3.96 0.001

Youngerpatients

CandidemiaduetoC.glabrata 6.32 1.90–20.99 0.003

Lungdisease 3.61 1.25–10.41 0.02

Receiptofmechanicalventilation 2.62 1.58–4.34 <0.001

Receiptoftotalparenteralnutrition 2.53 1.41–4.54 0.002

Receiptofdialysis 2.40 1.19–4.84 0.01

Neutropenia 2.37 1.19–4.73 0.01

OR,oddsratio;95%CI,95%confidenceinterval.

chemotherapy and neutropenia. This is reflected in the wards where patients were located when the candidemia developed: younger patients in medical or hematology wards and elderly patientsintheICU.

Elderly patientswithcandidemiahada higherprevalenceof diabetesmellitusandcardiacandpulmonarydiseases, comorbid-itiesfrequentlyfoundinthispopulation.Ahigherprevalenceinthe elderlyof degenerative diseases, suchas diabetes mellitus and heart and lung diseases, has also been observed in other studies.24,25 _{In contrast, young adults with candidemia had a} higherprevalenceofliverdisease,AIDS,andorgantransplantation. These data are consistent with the higher prevalence of these conditionsin individualsyounger than 60 years of age. In this context, the prevalence of candidemia in different underlying diseasesreflectsthefrequencydistributionintheagegroups.

Ofnote,despitethefactthatelderlypatientsweresickerand had multiple comorbidities at the time that candidemia was diagnosed, the duration of hospitalization before developing candidemiawassignificantlyshorterforyoungadults.Thisfinding may reflect the higher proportion of younger patients with neutropenia and cancer chemotherapy. These patients usually haverepeated periodsof hospitalization andaremore likely to haveanepisodeofcandidemiaearlierinthehospitalization.

Thespeciesdistributioninthepresentseriesistypicalofthe epidemiologyintheregion,withapredominanceofC.albicans,C. tropicalis,andC.parapsilosisandlowproportionofcasescausedby C. glabrata.26 _{Of note, we did not observe an increase in the} proportionofcasescausedbyC.glabratainelderlypatients,unlike otherreportsinwhichthisrelationshiphasbeenobserved.19,27,28 ItisworthmentioningthattheoccurrenceofC.glabratainBrazilis muchlowerthanintheNorthernHemisphere.

In contrast, candidemiadue toC. tropicalis wassignificantly morefrequentintheelderlypopulation.InBrazil,C.tropicalisisthe firstorsecondmostfrequentnon-albicansspecies.26_Asfoundin thepresentstudy,anassociationbetweenC.tropicaliscandidemia andelderlypatients hasalsobeenreported inprevious studies conductedinBrazil,SaudiArabia,Taiwan,andSingapore.29–32_In thepresent study,we observedthattheassociationbetweenC. tropicalis candidemia and elderly patients occurred in patients withcancerbutnotinthosewithoutcancer.Abetter characteri-zationof this epidemiologyandthefactorsrelated tothis high proportionofC.tropicalisdeservesfurtherexamination.

Amajorfindingofthepresentstudyisthehighmortalityrate forcandidemiainpatients60yearsofage.Notonlydidelderly patientshaveasignificantlyhigherdeathrate,buttheeffectofage groupalsoremainedsignificantbymultivariateanalysisevenafter controlling for APACHE II score. Most infections have poorer outcomes in the elderly when compared with young adults. Therefore,whileitisreasonabletoassumethisdifferenceinthe outcome just because of comorbidities and higher scores for severityofillness,factorspotentiallypronetointerventionshould beexploredinfuturestudies.Currentguidelinesforthe manage-mentofcandidemiaandinvasivecandidiasisrecommendthata fungicidaldrugshouldbeusedasprimarytreatmentifpatientsare sick.30,32,33_{Consideringthatinourstudymortalitywasaffectedby} age group even after controlling for the APACHE II score and comorbidities,shouldallpatients60yearsreceiveafungicidal drugasprimarytreatment?Otherfactorsthatshouldbetakeninto account in selecting a primary drug include the potential for concomitant toxicity (especially for the kidneys) and drug interactions, particularly with the growing incidence of poly-pharmacyinelderlypatients.34_{Inaddition,somestudiessuggest} thatcomorbiditiesandfunctionalstatusthatarealteredbyageare significantriskfactorsfortreatmentfailure.35,36

Intheanalysisofprognosticfactors,excludingtheAPACHEII score,significantvariables werelungdiseaseandthereceiptof

mechanicalventilationamongelderlypatients,andlungdisease and candidemiadue toC.glabratain youngerpatients. A more preciseinterpretationoftheassociationbetweenlungdiseaseand higher mortality is hampered because our definition of lung disease in this study was broad. The correlation between mechanical ventilation and a higher risk of death is probably secondarytotheseverityoftheillness.

Thisstudyhassomeimportantlimitations,themostsignificant beingitsretrospectivenature.Whilealldatahadbeencollected prospectively,somevariables couldnot beexploredbecause of missingdata.Theseincludedclinicalmanifestationsofinfection (hypotension and hypo- and hyperthermia,among others), the dosesofcorticosteroids,theAPACHEIIscore(availableforonly220 patients), and the timing of some interventions such as CVC removal,whichhamperedananalysisoftheeffectofCVCremoval ontheoutcome.37

In conclusion, elderly patients account for a substantial proportionofpatientswithcandidemiaandhavehighermortality comparedwithyoungerpatients.Consideringthehighmortality rate in this population, measures with a potential impact on improving their outcome shouldbeexplored. These include an early start to antifungal treatment (prophylactic, empiric, or preemptive), as well as the use of fungicidal drugs with low potentialfortoxicityanddruginteractionsasprimarytreatment. Funding: There was no financial support. The data were generated as part of the routine work of the participants’ organizations.

Conflictofinterest:Nonetodeclare.

References

1.WisplinghoffH,BischoffT,TallentSM,SeifertH,WenzelRP,EdmondMB. NosocomialbloodstreaminfectionsinUShospitals:analysisof24,179cases fromaprospectivenationwidesurveillancestudy.ClinInfectDis2004;39:309– 17.

2.GudlaugssonO,GillespieS,LeeK,VandeBergJ,HuJ,MesserS,etal.Attributable mortalityofnosocomialcandidemia,revisited.ClinInfectDis2003;37:1172–7. 3.Wey SB, Mori M,Pfaller MA,Woolson RF, Wenzel RP.Hospital-acquired candidemia.Theattributablemortalityandexcesslengthofstay.ArchIntern Med1988;148:2642–5.

4.LeroyO,GangneuxJP,MontraversP,MiraJP,GouinF,SolletJP,etal. Epidemi-ology,management,andriskfactorsfordeathofinvasiveCandidainfectionsin criticalcare:amulticenter,prospective,observationalstudyinFrance(2005– 2006).CritCareMed2009;37:1612–8.

5.NeuN,MalikM,LundingA,WhittierS,AlbaL,KubinC,etal.Epidemiologyof candidemia at a children’s hospital, 2002 to 2006. Pediatr Infect Dis J

2009;28:806–9.

6.PyrgosV,RatanavanichK,DoneganN,VeisJ,WalshTJ,ShohamS.Candida bloodstreaminfectionsinhemodialysisrecipients.MedMycol2009;47:463–7. 7.SipsasNV,LewisRE,TarrandJ,HachemR,RolstonKV,RaadII,etal.Candidemia inpatientswithhematologicmalignanciesintheeraofnewantifungalagents (2001–2007):stableincidencebutchangingepidemiologyofastillfrequently lethalinfection.Cancer2009;115:4745–52.

8.BenjaminJrDK,StollBJ,FanaroffAA,McDonaldSA,OhW,HigginsRD,etal. Neonatalcandidiasisamongextremelylowbirthweightinfants:riskfactors, mortalityrates,andneurodevelopmentaloutcomesat18to22months. Pedi-atrics2006;117:84–92.

9.LuzzattiR,AmalfitanoG,LazzariniL,SoldaniF,BellinoS,SolbiatiM,etal. Nosocomialcandidemiainnon-neutropenicpatientsatanItaliantertiarycare hospital.EurJClinMicrobiolInfectDis2000;19:602–7.

10.BlumbergHM,JarvisWR,SoucieJM,EdwardsJE,PattersonJE,PfallerMA,etal. Riskfactorsforcandidalbloodstreaminfectionsinsurgicalintensivecareunit patients:theNEMISprospectivemulticenterstudy.TheNationalEpidemiology ofMycosisSurvey.ClinInfectDis2001;33:177–86.

11.McClellandRS,FowlerJrVG,SandersLL,GottliebG,KongLK,SextonDJ,etal.

Staphylococcusaureusbacteremiaamongelderlyvsyoungeradultpatients: comparisonof clinicalfeaturesand mortality. ArchInternMed 1999;159: 1244–7.

12.LeeCC,ChenSY,ChangIJ,ChenSC,WuSC.Comparisonofclinical manifesta-tionsandoutcomeofcommunity-acquiredbloodstreaminfectionsamongthe oldestold,elderly,andadultpatients.Medicine(Baltimore)2007;86:138–44. 13.ColomboAL,NucciM,Saloma˜oR,BranchiniML,RichtmannR,DerossiA,etal.

Highrateofnon-albicanscandidemiainBraziliantertiarycarehospitals.Diagn MicrobiolInfectDis1999;34:281–6.

15.ColomboAL,GuimaraesT,SilvaLR,deAlmeidaMonfardiniLP,CunhaAK,Rady P,etal.ProspectiveobservationalstudyofcandidemiainSaoPaulo,Brazil: incidencerate,epidemiology,andpredictorsofmortality.InfectControlHosp Epidemiol2007;28:570–6.

16.HighKP.Infectioninanageingworld.LancetInfectDis2002;2:655. 17.KauffmanCA.Fungalinfectionsinolderadults.ClinInfectDis2001;33:550–5. 18.GavazziG, HerrmannF, Krause KH. Agingand infectious diseasesinthe

developingworld.ClinInfectDis2004;39:83–91.

19.DiekemaDJ,MesserSA,BrueggemannAB,CoffmanSL,DoernGV,HerwaldtLA,et al. Epidemiologyofcandidemia:3-yearresultsfromtheemerginginfectionsandthe epidemiologyofIowaorganismsstudy.JClinMicrobiol2002;40:1298–302. 20.SwinneD,WatelleM,SuetensC,MertensK,FonteynePA,NolardN.Aone-year

surveyofcandidemiainBelgiumin2002.EpidemiolInfect2004;132:1175–80. 21.ChangMR,CorreiaFP,CostaLC,XavierPCN,PalharesDB,TairaDL,etal.Candida bloodstreaminfection:datafromateachinghospitalinMatoGrossodoSul, Brazil.RevInstMedTropSaoPaulo2008;50:265–8.

22.HinrichsenSL, Falca˜oE,VilellaTAS,ColomboAL,NucciM,MouraL,etal. [CandidemiainatertiaryhospitalinnortheasternBrazil].RevSocBrasMedTrop

2008;41:394–8.

23.NakamuraT,TakahashiH.Epidemiological studyofCandidainfectionsin blood:susceptibilitiesofCandidaspptoantifungalagents,andclinicalfeatures associatedwiththecandidemia.JInfectChemother2006;12:132–8. 24.ShawAB.Ageasabasisforhealthcarerationing.Supportforagistpolicies.

DrugsAging1996;9:403–5.

25.Lloyd-SherlockP.Populationageingindevelopedand developingregions: implicationsforhealthpolicy.SocSciMed2000;51:887–95.

26.NucciM,Queiroz-TellesF,TobonAM,RestrepoA,ColomboAL.Epidemiologyof opportunisticfungalinfectionsinLatinAmerica.ClinInfectDis2010;51:561–70. 27.BlotS,VandewoudeK,HosteE,PoelaertJ,ColardynF.Outcomeincriticallyill patientswithcandidalfungaemia:Candidaalbicansvs.Candidaglabrata.JHosp Infect2001;47:308–13.

28.PappasPG,RexJH,LeeJ,HamillRJ,LarsenRA,PowderlyW,etal.Aprospective observationalstudyofcandidemia:epidemiology,therapy,andinfluenceson mortality in hospitalized adult and pediatric patients. Clin Infect Dis

2003;37:634–43.

29.NucciM,ColomboAL.CandidemiaduetoCandidatropicalis:clinical, epidemio-logic,andmicrobiologiccharacteristicsof188episodesoccurringintertiary carehospitals.DiagnMicrobiolInfectDis2007;58:77–82.

30.Al-JasserAM,ElkhizziNA.DistributionofCandidaspeciesamongbloodstream isolates.SaudiMedJ2004;25:566–9.

31.ChaiYAL,WangY,KhooAL,ChanFY,ChowC,KumarasingheG,etal. Predomi-nanceofCandidatropicalisbloodstreaminfectionsinaSingapore teaching hospital.MedMycol2007;45:435–9.

32.ChengYR, LinLC, YoungTG,LiuCE, ChenCH,TsayRW.Risk factorsfor candidemia-relatedmortalityatamedicalcenterincentralTaiwan.JMicrobiol ImmunolInfect2006;39:155–61.

33.PappasPG,KauffmanCA,AndesD,BenjaminJrDK,CalandraTF,EdwardsJrJE, etal.Clinicalpracticeguidelinesforthemanagementofcandidiasis:2009 update by the Infectious Diseases Society of America. Clin Infect Dis

2009;48:503–35.

34.Varner J. Polypharmacy and elders: a deadly combination. Ala Nurse

2006;33:26–7.

35.GershwinME,BorchersAT,KeenCL.Phenotypicandfunctionalconsiderations intheevaluationofimmunityinnutritionallycompromisedhosts.JInfectDis

2000;182(Suppl1):S108–14.

36.HighKP.Nutritionalstrategiestoboostimmunityandpreventinfectionin elderlyindividuals.ClinInfectDis2001;33:1892–900.

37.NucciM,AnaissieE,BettsRF,DupontBF,WuC,BuellDN,etal.Earlyremovalof centralvenouscatheterinpatientswithcandidemiadoesnotimprove out-come:analysisof842patientsfrom2randomizedclinicaltrials.ClinInfectDis