1 A randomized, placebo-controlled trial of pre-emptive antifungal therapy for the prevention of ...

22 Pages·2015·0.73 MB·English

by  Lisa Thomas

MAJOR ARTICLE
A Randomized, Placebo-controlled Trial of
Preemptive Antifungal Therapy for the Prevention
of Invasive Candidiasis Following Gastrointestinal
Surgery for Intra-abdominal Infections
D
o
w
WolfgangKnitsch,1Jean-LouisVincent,4StefanUtzolino,2BrunoFrançois,5TamásDinya,7GeorgeDimopoulos,8 nlo
Il̇hanÖzgünes,̧9JuanCarlosValía,10PhilippeEggimann,12CristóbalLeón,11PhilippeMontravers,6StephenPhillips,13 ad
e
LorraineTweddle,14AndreasKaras,14MalcolmBrown,15andOliverA.Cornely3 d fro
1DepartmentofGeneral,VisceralandTransplantationSurgery,HanoverMedicalSchool,2DepartmentofGeneralandVisceralSurgery,Universityof m
EFrxecieblulergn,cFereCiubsutregrimonBCreeilsluglaaur,Satnredss3DReepsaprotmnseenstiInofAIgnitnegr-nAaslsMoceidaitceidneD,iCsleinaisceasl,TUrinailvseCrseintytreofCColoolgongen,eG,GeremrmananCye;n4tDreefpoarrtInmfeencttioonfRInetseenasrivceh,CaanrdeCEorlaosgmnee https
Hospital,UniversitéLibredeBruxelles,Brussels,Belgium;5InsermCIC1435/Medical-SurgicalIntensiveCareUnit,CentreHospitalierUniversitaire ://a
Dupuytren,Limoges,and6Départementd’AnesthésieRéanimationChirurgicale,CentreHospitalierUniversitaireBichatClaudeBernardandUniversity ca
d
DenisDiderotSorbonneCité,Paris,France;7InstituteofSurgery,UniversityofDebrecen,Hungary;82ndIntensiveCareDepartment,UniversityHospital e
m
Attikon,Athens,Greece;9DepartmentofClinicalMicrobiologyandInfectiousDiseases,EskisehirOsmangaziUniversityFacultyofMedicine,Turkey; ic
10ServiciodeAnestesiayReanimación,HospitalGeneralUniversitario,Valencia,and11IntensiveCareUnit,ValmeUniversityHospital,Universityof .ou
Seville,Spain;12AdultIntensiveCareService,DepartmentofInterdisciplinaryCentersandLogistics,CentreHospitalierUniversitaireVaudoisand p.c
UniversityofLausanne,Switzerland;13ChilternInternational,Leiden,TheNetherlands;14AstellasPharmaEMEAMedicalAffairs,Chertsey,United om
Kingdom;and15AstellasPharmaGlobalMedicalAffairs,Northbrook,Illinois /c
id
Background. Patientsundergoingemergencygastrointestinalsurgeryforintra-abdominalinfectionareatriskof /artic
invasivecandidiasis(IC)andcandidatesforpreemptiveantifungaltherapy. le
Methods. Thisexploratory,randomized,double-blind,placebo-controlledtrialassessedapreemptiveantifungal -ab
s
approachwithmicafungin(100mg/d)inintensivecareunitpatientsrequiringsurgeryforintra-abdominalinfection. tra
c
CoprimaryefficacyvariablesweretheincidenceofICandthetimefrombaselinetofirstICinthefullanalysisset; t/6
an independent data review board confirmed IC.An exploratory biomarkeranalysis was performed using logistic 1/1
1
regression. /1
6
Results. Thefullanalysissetcomprised124placebo-and117micafungin-treatedpatients.TheincidenceofIC 71
was8.9%forplaceboand11.1%formicafungin(difference,2.24%;[95%confidenceinterval,−5.52to10.20]).There /33
4
was no difference between the arms in median time to IC. The estimated odds ratio showed that patients with a 12
positive (1,3)-β-D-glucan (ßDG) result were 3.66 (95% confidence interval, 1.01–13.29) times more likely to have 9 b
y
confirmedICthanthosewithanegativeresult. g
u
Conclusions. Thisstudywasunabletoprovideevidencethatpreemptiveadministrationofanechinocandinwas es
effectiveinpreventingICinhigh-risksurgicalintensivecareunitpatientswithintra-abdominalinfections.Thismay t on
havebeenbecausethedrugwasadministeredtoolatetopreventICcoupledwithanoveralllownumberofICevents. 04
A
ItdoesprovidesomesupportforusingßDGtoidentifypatientsathighriskofIC. p
ClinicalTrialsRegistration. NCT01122368. ril 2
0
1
Keywords. Preemptiveantifungaltherapy;invasivecandidiasis;micafungin;intensivecare;gastrointestinalsurgery. 9
Received15April2015;accepted7August2015;electronicallypublished13 DiseasesSocietyofAmerica.ThisisanOpenAccessarticledistributedundertheterms
August2015. oftheCreativeCommonsAttribution-NonCommercial-NoDerivslicence(http://
Correspondence:OliverA.Cornely,MD,DepartmentIofInternalMedicine,Clin- creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial
icalTrialsCentreCologne(ZKSCologne,BMBF01KN1106),GermanCentreforIn- reproductionanddistributionofthework,inanymedium,providedtheoriginalwork
fection Research (DZIF), and Cologne Excellence Custer on Cellular Stress isnotalteredortransformedinanyway,andthattheworkisproperlycited.For
ResponsesinAging-AssociatedDiseases(CECAD),UniversityofCologne,Kerpener commercialre-use,[email protected].
Strasse62,50937Cologne,Germany([email protected]). DOI:10.1093/cid/civ707
ClinicalInfectiousDiseases® 2015;61(11):1671–8
©TheAuthor2015.PublishedbyOxfordUniversityPressonbehalfoftheInfectious
PreemptiveAntifungalTherapyinICUs (cid:129) CID 2015:61 (1December) (cid:129) 1671
Candidaspeciesarethemostcommonfungalpathogensinthe METHODS
intensive care unit (ICU) [1],and invasive candidiasis (IC) is
associated with considerable morbidity and mortality in criti- PatientsandStudyDesign
callyillpatients[2,3].Earlyantifungaltreatmentreducesmor- INTENSE (Clinicaltrials.gov identifier NCT01122368) was an
tality rates in patients with documented IC [4,5],but a swift exploratory, multicenter, randomized, double-blind, placebo-
definitive diagnosis is difficult [6,7].Although prophylaxis or controlled trial of preemptive antifungal therapy in adults
preemptive treatment strategies should be used in patients at (aged≥18years),whopresentedwithageneralizedorlocalized
highriskforIC[6,8],theiridentificationisclinicallychalleng- intra-abdominal infection requiring surgery and an ICU stay.
ing, because preemptive intervention markers have not been Patients were included if they had a community-acquired
fullydefined. (CAI) or nosocomially acquired (NAI) intra-abdominal
Risk factors for IC in critically ill patients include broad- infection. Patients with CAI were those who presented with
spectrum antibiotic exposure, cancer chemotherapy, fungal intra-abdominal infection before or within 48 hours after
colonization, indwelling vascular catheters, total parenteral hospital admission. Patients with NAI were those who devel- D
nutrition,surgery,renalfailure,hemodialysis,andprolonged opedintra-abdominalinfection>48hoursafterhospitaladmis- ow
n
ICU stay [9, 10]. Although these factors can be present sionandwerehospitalizedforreasonsotherthaninfection.Key lo
a
in patients who do not have IC and individuallyare not suf- exclusioncriteriawereacutepancreatitis,infectedintra-perito- de
d
ficiently discriminatory, together they can still be used nealdialysis,solidorgantransplantation,severeliverdisease,or fro
m
to identify high-risk patients. Risk identification strategies, neutropenia at randomization. Exclusion criteria included re- h
such as Candida colonization index [11],clinical predictive ceipt of a systemic antifungal within 14 days before study ttp
s
rules [12, 13] and a Candida score [14, 15] have been drug, documented IC at randomization, or expected survival ://a
c
proposed to aid in deciding when to initiate earlyantifungal <48 hours. The study was conducted from 13 July 2010 to 15 ad
e
therapy [7]. December2011. m
ic
Antifungal prophylaxis in patients at high risk for IC has Eligiblepatientswererandomized1:1tointravenousmicafun- .ou
p
beeninvestigatedinseveralrandomized,controlledtrials.Trials gin(100mg/d)orsalinesolutionasaplacebo.Patientswerein- .c
o
in homogenous populations, such as surgical patients with re- cluded within 48 hours (NAI) or 72–120 hours (CAI) after m/c
current gastrointestinal perforations or anastomotic leakages surgeryprovidingtheyhadanexpectedminimumICUstayof id/a
[16]and severe acute pancreatitis [17],showed prophylaxisto 48hours.Patientsweretreatedfor6weeksunlesstheyexperienced rtic
be an effective strategy, because infection rates were high with anendoftreatment(EOT)event:confirmedIC,improvementin le-a
b
placebo and significantly lower with active antifungal therapy. surgicalcondition(asindicatedbyrecoveryofgastrointestinal stra
StudieswithheterogeneousICUpatients,howeverhadlowin- functionallowingenteralfeedingofupto50%ofdailycaloriere- ct/6
cidencesofinfectionsintheplaceboarms,andtreatmentdiffer- quirement),alternativeantifungaltreatment,ordeath.IfICwas 1
/1
encesbetweenplaceboandactivetherapywerenotshown[18– confirmed,studymedicationwasdiscontinuedandalternativean- 1/1
6
24].Therefore, antifungal prophylaxis should be used only in tifungalmedicationwasgiven.Thetypeofsurgeryandantibiotic 7
1
specific subgroups where there is clearevidence of benefit [7, requiredforthetreatmentoftheintra-abdominalinfectionwere /33
4
8,25].For the majorityof ICU patients at high IC risk, a pre- prescribedaccordingtocenterpolicy.Thestudywasconducted 12
9
emptive antifungal strategy, based on clinical risk factors and inaccordancewiththeethicalprinciplesoriginatingintheDecla- b
y
microbiologicevidenceofsubstantialcolonization,isproposed rationofHelsinki.Writtenorwitnessedinformedconsentwasob- gu
e
[7,8,25]. tainedforallpatients. st o
PatientsrequiringICUmanagementafteremergencysurgery n 0
4
for intra-abdominal infection have a high IC risk [26]. As OutcomeMeasuresandAssessments A
acommensal ofthe digestivetract, Candida may leak into the EvaluationforIC pril 2
peritonealcavityafterperforationorduringsurgicalresectionof Patientswereevaluated(SupplementaryAppendix1)forICat 0
1
9
the intestine. Peritoneal seeding can result in intra-abdominal baseline,duringtreatment,atEOTassessment,andattheendof
Candidainfectionwithriskofdisseminationtothebloodstream study (EOS). The EOT assessment visit occurred within 1–3
and extra-abdominal tissue and organs [27]. The INTENSE days after thelastdose ofstudymedication,and theEOS visit
(Invasive Candidiasis – Pre-emptive Treatment in High Risk occurred 28 days after the last dose. Blinded assessments and
SurgicalSubjects)studyassessedthestrategyofpreemptivean- confirmation of IC were made byan independent data review
tifungaltherapyversusplaceboinhospitalizedpatientsrequir- board(IDRB)(P.E.,C.L.,andP.M.),aswellastheinvestiga-
ingsurgeryforintra-abdominalinfection.Micafunginwasused tors, based onhistologic evidenceat biopsyor positive culture
astheactivetherapy,andtheefficacyandsafetyofitsuseinthat from blood, from a freshly placed peritoneal drain or biliary
settingwasassessed. catheterorintra-abdominalabscess.
1672 (cid:129) CID 2015:61 (1December) (cid:129) Knitschetal
ThecoprimaryefficacyvariablesweretheincidenceofIDRB- calculations. It was considered that randomization of 125 pa-
confirmedICdiagnosedbetweenbaselineandEOTassessment tients perarm might allow observation of clinically important
and the time from baseline to first IDRB-confirmed IC. The differencesintheincidenceofIC,evenwitha20%dropoutrate.
start date of aconfirmed casewas provided by the IDRB, and
the time to IC was calculated relative to the date of first dose AnalysisSets
ofstudydrug.TheincidenceofICaccordingtotheinvestigator Baselinecharacteristics,incidenceandtimetoIDRB-confirmed
wasalsocalculated.PosthocanalysisoftheincidenceofICcon- IC, and biomarker data are reported for the full analysis set
firmed by the IDRB or an investigator (hereafter “any- (FAS), which comprised all randomized patients who received
confirmed” IC) was conducted forall patients and subgroups, ≥1 dose of study medication and did not have an IDRB-
asdescribedinSupplementaryAppendix2. confirmed IC at baseline. For the investigator-confirmed IC, a
modified FAS was used, which took into account investigator-
Biomarkers confirmed IC at baseline. Similarly for any-confirmed IC
Thefungalbiomarkers(1,3)-β-D-glucan(ßDG),Candidaanti- (confirmed by the IDRB or investigator), a modified FAS was D
body, mannan antigen, and Candidawere measured in blood used,whichtookintoaccounttheany-confirmedICatbaseline. ow
n
samples at baseline, during treatment and at the EOTassess- TheincidenceandtimetoIDRB-confirmedICwerefurtheras- lo
a
ment; Candida antibodyand mannan antigen were measured sessedintheper-protocolset (PPS),definedasallFASpatients de
d
with enzyme-linked immunosorbent assay, and Candida was (1)whohadanassessmentofIC,asconfirmedbytheIDRBat fro
detectedbypolymerasechainreaction. EOT;(2)received≥3daysofstudymedication;(3)hadnocon- m h
firmedICbeforebaseline,accordingtotheIDRB;and(4)hadno ttp
s
Safety majorprotocolviolations.Priorandconcomitantmedicationuse ://a
c
a
Treatment-emergentadverseevents(AEs)andseriousAEs,in- and safetyassessments are described forthesafetyanalysisset, d
e
cludingdeath,wererecordedupto90daysafterEOT.Routine whichincludedallrandomizedpatientswhoreceivedstudymed- m
ic
laboratory assessments, including biochemistry, hematology, icationatleastonce. .o
u
p
andurinalysis,wereperformedatbaselineanduptotheEOS. .c
o
StatisticalAnalysis m
/c
StatisticalMethods Unlessotherwisestated,dataaresummarizedusingdescriptive id
/a
PowerCalculation statisticsofmean(standarddeviation[SD])andmedian(where rtic
le
Aformalpowercalculationwasnotperformedforthisexplor- not normally distributed) values forcontinuous variables, and -a
b
atorystudy,owingtoalackofsuitabledataonpreventivether- frequencyand percentage forcategorical data. The differences s
tra
apy studies at time of study design and therefore the use of in IC incidence between micafungin- and placebo-treated pa- c
potentially poor estimates of parameters for sample size tients and the corresponding 95% confidence intervals (CIs) t/61
/1
1
/1
6
7
1
/3
3
4
1
2
9
b
y
g
u
e
s
t o
n
0
4
A
p
ril 2
0
1
9
Figure1. Patientflowthroughthestudy.Inthefullanalysisset(FAS),30.7%ofpatientshadeitherviolatedtheprotocol(10.4%hadreceivedconcurrent
antifungalagentsand12.9%wereoutsidethedrugstudywindow)orhadreceivedtreatmentfor<3days(11.6%).Abbreviations:IC,invasivecandidiasis;
IDRB,independentdatareviewboard;PPS,per-protocolset.
PreemptiveAntifungalTherapyinICUs (cid:129) CID 2015:61 (1December) (cid:129) 1673
Table1. BaselineDemographicandClinicalCharacteristics(Full antibody(5.0–10.0or>10.0antibodyunits[AU]/mLforinterme-
AnalysisSet) diate or positive, respectively, vs 5.0AU/mL for negative), and
mannan antigen (62.5–125 or >125pg/mL for intermediate or
Patients,No.(%)a positivevs<62.5pg/mLfornegative).Othercovariates(continu-
Placebo Micafungin Total ous andcategorical)includedin the modelwereage, sex, study
Characteristic (n=124) (n=117)b (n=241) drug,CAI orNAI,andtime from ICUadmissiontofirst study
Sex drugdose.DataanalyseswereperformedusingSASsoftwarefor
Male 41(33.1) 50(42.7) 91(37.8) Windows(version9.2[2011];SASInstitute).
Female 83(66.9) 67(57.3) 150(62.2)
Age,mean(SD),y 63.0(15.8) 61.6(14.8) 62.3(15.3)
RESULTS
Agegroup
18–65y 63(50.8) 66(56.4) 129(53.5)
StudyPopulation
>65y 61(49.2) 51(43.6) 112(46.5)
The study was conducted at 53 centers across 17 countries. D
Typeofintra-abdominalinfection o
CAI 45(36.3) 41(35.0) 86(35.7) Participant flow is shown in Figure 1. The FAS comprised wn
lo
NAI 79(63.7) 76(65.0) 155(64.3) 241patients,124randomizedtoplaceboand117tomicafungin ad
e
(100mg/d);baselinecharacteristicsareprovidedinTable1. d
Abbreviations:CAI,community-acquiredinfection;NAI,nosocomiallyacquired fro
infection;SD,standarddeviation. m
aDatarepresentNo.(%)exceptwhereotherwiseindicated. StudyDrugExposure h
bMicafungin100mg/d. Themean(SD)durationofstudydrugexposurewas8.3(6.9)days ttps
forplaceboand7.7(6.8)daysformicafungin(median,6daysfor ://ac
a
botharms).Intheplaceboandmicafunginarms,thepercentages de
m
were derived using the Newcombe–Wilson method without ofpatientswhoreceivedthestudydrugfor<3days(protocolde- ic
continuity correction. The time to IDRB-confirmed IC was viations)were9.7%and13.7%,respectively;for3–14days,79.0% .ou
p
modeled using the accelerated failure time model, a general and75.2%;andfor>14days,11.2%and11.1%. .co
m
model for time-to-event data. The time to IDRB-confirmed /c
IC was presentedgraphically by nonparametric Kaplan–Meier Efficacy id/a
curves, with patients without IDRB-confirmed IC during the IntheFAS,theIDRB-confirmedICincidenceatEOTwas8.9% rtic
le
treatment period censored eitheron the dayof the EOTevent (n=11) for placebo and 11.1% (n=13) for micafungin, for -a
b
or at the EOT assessment. Statistical comparisons were per- anestimateddifferenceof2.24%(95%CI,−5.52to10.20)(Table2). stra
formedusinglog-ranktests. TheCandidaspeciesarelistedinTable3.Mostinfectionsoccurred ct/6
1
Logisticregressionwasusedtoevaluatetheimpactofbiomark- inNAIpatients;9of11intheplaceboarmand11of13inthe /1
1
ersonthebinaryresponseforIDRB-confirmedIC.All4biomark- micafungin arm. There was no difference between treatment /1
6
erswereincludedinthemodel:ßDG(≥62.5pg/mLforpositive groupsinthemediantimetoIDRB-confirmedIC;thetimeratio 71
response vs <62.5pg/mL for negative), Candida polymerase ofmicafunginrelativetoplacebowas0.69(95%CI,.34–1.38).The /33
4
chain reaction (positive vs negative after >30 cycles), Candida Kaplan–MeierfailurecurvesaredisplayedinFigure2.Forpatients 12
9
b
y
g
u
e
s
Table2. IncidenceofInvasiveCandidiasisintheFullAnalysisSetandPer-ProtocolSetforAllPatients t o
n
0
4
PatientWithIC/TotalPatients,No.(%) A
p
TreatmentDifference ril 2
ICIncidence Placebo Micafunginb (Micafungin−Placebo),%(95%CI) 01
9
Allpatients(FAS)
IDRB-confirmedIC 11/124(8.9) 13/117(11.1) 2.24(−5.52to10.20)
Investigator-confirmedICa 20/121(16.5) 16/116(13.8) −2.74(−11.92to6.56)
Any-confirmedICa 20/120(16.7) 17/115(14.8) −1.88(−11.24to7.58)
Allpatients(PPS)
IDRB-confirmedIC 5/88(5.7) 5/79(6.3) 0.65(−7.17to8.95)
Abbreviations:CI,confidenceinterval;FAS,fullanalysisset;IC,invasivecandidiasis;IDRB,independentdatareviewboard;PPS,per-protocolset.
aFASwasmodifiedaccordingtowhoassessedforICatbaseline.Any-confirmedICincludesICconfirmedbyIDRBand/orinvestigator.
bMicafungin100mg/d.
1674 (cid:129) CID 2015:61 (1December) (cid:129) Knitschetal
Table3. TypeandFrequencyofCandidaSpeciesConfirmedby Table4. EndofTreatmentEvents(FullAnalysisSet)
IndependentDataReviewBoardattheEndofTreatment
EOTEvents,No.(%)
CulturesPositiveforCandidaSpecies,No.a
Placebo Micafungin
Placebo Micafungin ReasonforEOT (n=124) (n=117)b
IDRB-confirmedIC 11(8.9) 13(11.1)
Blood Other Blood Other
CandidaSpecies Culture Cultureb Culture Cultureb NoIDRB-confirmedIC, 113(91.1) 104(88.9)
Sufficientimprovement 78(62.9) 75(64.1)
C.albicans 1 6 2 7
Alternativeantifungaltherapy 8(6.5) 5(4.3)
C.glabrata 1 3 1 0
Death 1(0.8) 5(4.3)
C.parapsilosis 1 1 0 1
OtherreasonsforEOTa 25(20.2) 18(15.4)
C.tropicalis 0 2 0 0
Maximum6-wktreatment 1(0.8) 1(0.9)
C.dubliniensis 0 2 0 0
Notidentifiedto 2 2 2 3 Abbreviations: EOT, end of treatment; IC, invasive candidiasis; IDRB, D
specieslevel independentdatareviewboard. ow
aSomepatientswereinfectedwith>1Candidaspecies. aefOficthaceyr,raenadsopnrostoinccolluvdieolaintivoens.tigator-confirmedIC,adverseevents,lackof nloa
d
bOtherculturesitesincludedfreshlyplacedperitonealdrainorbiliarycatheter bMicafungin100mg/d. ed
andintra-abdominalabscess. fro
m
h
ttp
s
without an IDRB-confirmed IC, the most common EOTevent change from baseline at the EOT assessment for ßDG was ://ac
was sufficientimprovementin surgical condition(Table4). The +53 (356) pg/mL in the placebo arm (n=54) and −35 (207) ade
m
results obtainedin thePPSfor incidence(Table 2) andtime to pg/mL in the micafungin arm (n=44). Logistic regression ic
IDRB-confirmedIC(timeratioofmicafunginrelativetoplacebo, modelingusedtoevaluatetheimpactofbiomarkersonthebi- .ou
p
0.80,95%CI,.26–2.50)wereconsistentwiththoseintheFAS. naryresponseforIDRB-confirmedICshowedonlyßDGtobe .co
m
In the FAS, the investigators diagnosed IC in 20 patients related to the response, with an odds ratio of 3.66 (95% CI, /c
(16.5%) in the placebo arm and 16 (13.8%) in the micafungin 1.01–13.29). id/a
arm (Table 2). The incidence of any-confirmed IC was also rtic
le
lowerformicafunginthanforplaceboforallpatients(Table2), Safety -ab
s
aswellasforallposthocsubgroupsconsideredtohaveahigher AEs and deaths are reported in Supplementary Appendix 3. tra
riskofIC,althoughtheCIsincluded0(Figure3). Therewere no clinicallysignificant differences between study ct/6
1
armsinthemeanbiochemical,hematologic,andurinalysispa- /1
1
Biomarkers rametersanalyzedbetweenbaselineandeitherEOTorEOS.Al- /1
6
7
Biomarker results are reported for ßDG data, which were anine aminotransferase levels were similar between treatment 1
/3
available for 41% of the FAS population. The mean (SD) groups(SupplementaryAppendix3;Figure1). 34
1
2
9
b
y
g
u
e
s
t o
n
0
4
A
p
ril 2
0
1
9
Figure2. Kaplan–Meierfailurecurvesoftimetoindependentdatareviewboard(IDRB)-confirmedinvasivecandidiasis(IC)(fullanalysisset).
PreemptiveAntifungalTherapyinICUs (cid:129) CID 2015:61 (1December) (cid:129) 1675
D
o
w
n
lo
a
d
e
d
Figure3. Incidenceofconfirmedcasesofinvasivecandidiasis(IC)byhigher-risksubgroups(fullanalysisset,modifiedaccordingtowhoassessedforICat from
baseline;caseswereconfirmedbyindependentdatareviewboardand/orinvestigator).Abbreviations:CI,confidenceinterval;NAI,nosocomiallyacquired http
infection. s
://a
c
a
d
e
m
ic
DISCUSSION ThechallengeofearlyICidentificationinthesurgicalsetting .ou
p
is widely recognized [26],and for this reason we used blinded .c
o
The INTENSE study did not provide evidence to support the assessment and confirmation of IC by an independent panel m/c
useofapreemptiveantifungalstrategyinhigh-risksurgicalpa- of experts. The incidence was higher with investigator- id/a
tients with intra-abdominal infections. In the FAS, the patient diagnosed IC (16.5% for placebo in the FAS), and onlysome rtic
selectioncriteriasuccessfullyidentifiedanIDRB-confirmedin- diagnosed infections overlapped with those assessed by the le-a
b
cidencerateof8.9%intheplaceboarm.However,theincidence IDRB. The disparity between the IDRB and investigators in stra
of11.1%inthemicafunginarmwasunexpected.Becausemica- the incidence of confirmed IC, a phenomenon observed in ct/6
funginisaneffectivetreatmentforcandidemiaandIC,thissug- other studies [30,31], again illustrates the difficulty in early 1
/1
geststhatICmighthavebeenestablishedinthesepatientsand identificationofIC. 1/1
6
preemptivetherapywasadministeredtoolate.Thissupposition PreliminarystudiesinvestigatingßDGinICUpatientsfound 7
1
issupportedbytherelativelyhighnumberofbaselineICcases higherßDGlevelsinthosewithICthaninthosewithoutIC[24, /33
4
(Figure 1), with the majorityof emergent IC cases within the 28,32],anditsdetectionhasbeenshowntoprecedeamicrobi- 12
firstfewstudydays(Figure2). ologicdiagnosisbyseveraldays[33,34].Inourstudy,ßDGwas 9 b
y
Asimilarlackofevidenceforaprophylaxisantifungalstrat- the only biomarker correlating with confirmed IC, although gu
e
egyinat-riskICUpatientswasfoundinarandomized,placebo- ßDGmeasurementswerenotavailableforallpatients. st o
controlledstudyofcaspofungin[24].Alower-than-expectedIC Micafunginwaswelltoleratedinthesepatients,withone-half n 0
incidence resulted in a lack of difference between placebo theincidenceofpyrexia,woundinfection,vomiting,andpleural 4 A
(e1m6p.7t%iv)eaannddceamsppoifruicngainnti(f9u.n8%ga)l.tAhecroampypawriitshonanbiedtwuleaefnunpgrien- eslfifguhstiolynhciogmheprairnedmwiciathfunplgaicne-btroe.aTtehdepiantciiednetnsctehaonfainnetmhoisaewraes- pril 20
1
alsoshowednodifferencebetweenstrategiesintheincidenceof ceivingplacebo.NohepatobiliaryAEswererelatedtomicafun- 9
IC in ICU patients [28].Antifungal treatment administered in gin.Therewasnoclinicallyrelevantdifferenceinmortalityrates
theabsenceofaprovenICdiagnosiswasfoundtohavenoeffect betweenmicafunginandplacebo.
on mortality rates or IC occurrence compared with no treat- Statistical powering of prophylaxis and preemptive trials in
ment in critically ill patients receiving mechanical ventilation, ICU patients is difficult, and for this reason INTENSE was
possiblyowingtotheabsenceofactualIC[29].Thesestudies, designed to be an exploratory study and was not formally
togetherwithours,highlightthechallengeofdemonstratingthe powered. We recognize this as a limitation of our study. Any
benefitofantifungalsintheabsenceofprovenIC,eveninICU Pvaluesareconsiderednominalandonlyhypothesisgenerating
patientpopulationswithmultipleriskfactorsforIC. rather than conclusive. Other limitations include the possible
1676 (cid:129) CID 2015:61 (1December) (cid:129) Knitschetal
inclusionofpatientswhoalreadyhadestablishedICanddiffi- MedicineCompanyandtoreceivinglectureandhonorariafromBasileaand
cultyonthepartoftheinvestigatorsindecidingwhichpatients Gilead.S.P.isaconsultantstatisticianatChilternInternationalworkingon
behalfofAstellasEuropeGlobalDataScience.L.T.,A.K.,andM.B.arefull-
shouldbeenrolledinthisstudy,ashighlightedbythefactthat
timeemployeesofAstellasPharma.O.A.C.hasreceivedsupportfromthe
31%ofpatientsintheFASwereexcludedfromthePPS. German Federal Ministry of Research and Education (BMBF grant
SeveralkeyfindingsfromtheINTENSEstudyshouldbecon- 01KN1106);hasreceivedresearchgrantsfrom3M,Actelion,AstellasPhar-
ma,AstraZeneca,Basilea,Bayer,Celgene,Cubist/Optimer,Genzyme,Gile-
sidered in future studies of preventive antifungal strategies in
ad,GlaskoSmithKline,Merck/MerckSharp&Dohme,Miltenyi,Pfizer,
critically ill patients. The type of treatment strategy needs to Quintiles,Shionogi,andViropharma;isaconsultantto3M,AstellasPhar-
beclassifiedbycurrentdefinitionsasprophylactic,preemptive, ma,AstraZeneca,Basilea,Cidara,Cubist/Optimer,DaVolterra,Daiichi
orempiric[7],becausethisclassificationdeterminesthetiming Sankyo,F2G,Genentech,Gilead,GlaskoSmithKline,Merck/MerckSharp
&Dohme,MerckSerono,Pfizer,Rempex,SanofiPasteur,Summit;and
oftreatment.ThesedefinitionshaveevolvedfromwhentheIN-
Vifor; and received lecture honoraria from Astellas Pharma, Gilead,
TENSEstudywasdesigned,andwithhindsightitcouldbecon- Merck/MerckSharp&Dohme,andPfizer.Allotherauthorsreportnopo-
sidered a prophylaxis study. Identification of ICU patients at tentialconflicts.
AllauthorshavesubmittedtheICMJEFormforDisclosureofPotential
high risk for IC is challenging and requires careful selection ConflictsofInterest.Conflictsthattheeditorsconsiderrelevanttothecon- D
o
of patients. In our study forexample, the overall incidence of tentofthemanuscripthavebeendisclosed. w
n
IC(any-confirmed cases) intheNAI subgroup was21%, con- lo
firming that this might be a population worth focusing on in References ade
d
future studies, whereas the infection rate in the CAI group 1. VincentJL,RelloJ,MarshallJ,etal.Internationalstudyofthepreva- fro
wasverylow.WeechoapointmadebyMontraversetal[27], lenceandoutcomesofinfectioninintensivecareunits.JAMA2009; m h
that additional tools and prediction rules to identify patient 302:2323–9. ttp
populations with the highest risk are required. Our data add 2. aCmaloanngdrpaatTie,nMtsaurncdheertgtoiiOng. sCulrigneircya.lCtrliinalsInofefcatnDtiisfu2n0g0a4l;p3r9o(spuhpyplalx4i)s: s://a
c
to the evidence that, in conjunction with risk factors, ßDG S185–92. ad
e
3. Schelenz S. Management of candidiasis in the intensive care unit. m
has potential use as a marker to help physicians select high-
JAntimicrobChemother2008;61(suppl1):i31–4. ic
riskpatientswhomightbenefitfromearlyantifungaltreatment. 4. MorrellM,FraserVJ,KollefMH.Delayingtheempirictreatmentof .ou
p
Our findings support the need for further investigations on Candidabloodstreaminfectionuntilpositivebloodcultureresultsare .c
o
thesemeasuresascriteriainpredictionrules. oAbgteanintseCd:haempoottheenrti2a0l0r5is;k49fa:3c6to4r0–f5o.rhospitalmortality.Antimicrob m/cid
5. GareyKW,RegeM,PaiMP,etal.Timetoinitiationoffluconazolether- /a
SupplementaryData apyimpactsmortalityinpatientswithcandidemia:amulti-institutional rtic
study.ClinInfectDis2006;43:25–31. le-a
6. EggimannP,Ostrosky-ZeichnerL.Earlyantifungalinterventionstrate- b
SupplementarymaterialsareavailableatClinicalInfectiousDiseasesonline giesinICUpatients.CurrOpinCritCare2010;16:465–9. stra
(http://cid.oxfordjournals.org).Supplementarymaterialsconsistofdata c
providedbytheauthorthatarepublishedtobenefitthereader.Theposted 7. EthgegiImCUan.nAPn,nBIinllteenJ,siMvearCcahreett2i0O1.1D;1ia:3g7n.osisofinvasivecandidiasisin t/61
materialsarenotcopyedited.Thecontentsofallsupplementarydataarethe /1
8. CornelyOA,BassettiM,CalandraT,etal.ESCMID*guidelineforthe 1
soleresponsibilityoftheauthors.Questionsormessagesregardingerrors diagnosisandmanagementofCandidadiseases2012:non-neutropenic /16
shouldbeaddressedtotheauthor. adultpatients.ClinMicrobiolInfect2012;18(suppl7):19–37. 71
9. WeySB,MoriM,PfallerMA,WoolsonRF,WenzelRP.Riskfactorsfor /33
Notes hospital-acquiredcandidemia:amatchedcase-controlstudy.ArchIn- 41
ternMed1989;149:2349–53. 29
Acknowledgments. MedicalwritingassistancewasprovidedbyLisa 10. EggimannP,GarbinoJ,PittetD.EpidemiologyofCandidaspeciesin- by
Thomas,PhD,Connect2CMELtd,Westerham,UnitedKingdom. fectionsincriticallyillnon-immunosuppressedpatients.LancetInfect gu
Authorcontributions. Allauthorshadaccesstothedata,participated Dis2003;3:685–702. es
inthepreparationofthemanuscript,agreedtosubmitthemanuscript, 11. PittetD,MonodM,SuterPM,FrenkE,AuckenthalerR.Candidacol- t o
n
andvouchfortheaccuracyofthedataandanalyses. onizationandsubsequentinfectionsincriticallyillsurgicalpatients. 0
4
Financialsupport. TheINTENSE(InvasiveCandidiasis–Pre-emptive AnnSurg1994;220:751–8. A
p
TPhreaartmmaenEtMinEAH,iwghhiRchiskcoSlluarbgoircaatledSuwbijtehcttsh)estpurdinycwipaaslifnuvnedsetidgabtyorAssinteltlhaes 12. PtiaenpthsitaotuinNcrIe,aOsesdtrorisskky-foZreiccahnndeirdaLl,iRnfeexctJiHon.sRiunletshefosruirdgeicnatlifiynitnegnspivae- ril 2
0
designofthestudyandconductedallstatisticalanalyses. careunit:approachtodevelopingpracticalcriteriaforsystematicusein 19
Potentialconflictsofinterest. W.K.reportsservingasaconsultantfor antifungalprophylaxistrials.MedMycol2005;43:235–43.
AstellasPharma,Gilead,MerckSharp&Dohme,Novartis,andPfizer.B.F. 13. Ostrosky-ZeichnerL,SableC,SobelJ,etal.Multicenterretrospective
reportsbeingamemberofadvisoryboardsforCubist,KentaBiotech,and developmentandvalidationofaclinicalpredictionrulefornosocomial
MedimmuneandservingasaconsultantforAsahi-Kasei,GlaxoSmithKline, invasivecandidiasisintheintensivecaresetting.EurJClinMicrobiol
Lascco,Sanofi,andTigenix.J.C.V.isamemberofthespeakers’bureausfor InfectDis2007;26:271–6.
AstellasPharma,MerckSharp&Dohme,Novartis,Orion,andPfizer.P.E. 14. LeonC,Ruiz-SantanaS,SaavedraP,etal.Abedsidescoringsystem
hasreceivedresearchgrants,educationalgrants,speakerhonoraria,and/or (“Candidascore”)forearlyantifungaltreatmentinnonneutropenic
consultant honoraria from Astellas Pharma, Merck Sharp & Dohme- criticallyillpatientswithCandidacolonization.CritCareMed2006;
Chibret,andPfizer.C.L.hasreceivedresearchgrantsand/orconsultant 34:730–7.
honorariafromAstellasPharma.P.M.reportsactingasaconsultantforAs- 15. LeonC,Ruiz-SantanaS,SaavedraP,etal.Usefulnessofthe“Candida
tellasPharma,AstraZeneca,Cubist,MerckSharp&Dohme,Pfizer,andThe score”fordiscriminatingbetweenCandidacolonizationandinvasive
PreemptiveAntifungalTherapyinICUs (cid:129) CID 2015:61 (1December) (cid:129) 1677
candidiasisinnon-neutropeniccriticallyillpatients:aprospectivemul- risk adults in the critical care setting. Clin Infect Dis 2014; 58:
ticenterstudy.CritCareMed2009;37:1624–33. 1219–26.
16. EggimannP,FrancioliP,BilleJ,etal.Fluconazoleprophylaxisprevents 25. EggimannP,GarbinoJ,PittetD.ManagementofCandidaspeciesin-
intra-abdominalcandidiasisinhigh-risksurgicalpatients.CritCare fectionsincriticallyillpatients.LancetInfectDis2003;3:772–85.
Med1999;27:1066–72. 26. BassettiM,MarchettiM,ChakrabartiA,etal.Aresearchagendaonthe
17. HeYM,LvXS,AiZL,etal.Preventionandtherapyoffungalinfection managementofintra-abdominalcandidiasis:resultsfromaconsensus
insevereacutepancreatitis:aprospectiveclinicalstudy.WorldJGastro- ofmultinationalexperts.IntensiveCareMed2013;39:2092–106.
enterol2003;9:2619–21. 27. MontraversP,DupontH,EggimannP.Intra-abdominalcandidiasis:the
18. SlotmanGJ,BurchardKW.KetoconazolepreventsCandidasepsisin guidelines-forgottennon-candidemicinvasivecandidiasis.Intensive
criticallyillsurgicalpatients.ArchSurg1987;122:147–51. CareMed2013;39:2226–30.
19. SavinoJA,AgarwalN,WryP,PolicastroA,CerabonaT,AustriaL. 28. Hanson KE, Pfeiffer CD, Lease ED, et al. β-D-glucan surveillance
Routineprophylacticantifungalagents(clotrimazole,ketoconazole, withpreemptiveanidulafunginforinvasivecandidiasisinintensive
andnystatin)innontransplant/nonburnedcriticallyillsurgicaland careunitpatients:arandomizedpilotstudy.PLoSOne2012;7:e42282.
traumapatients.JTrauma1994;36:20–5. 29. BaillyS,BouadmaL,AzoulayE,etal.Failureofempiricalsystemic
20. Ables AZ, Blumer NA, Valainis GT, Godernick MT, Kajdasz DK, antifungaltherapyinmechanically-ventilatedcriticallyillpatients.
Palesch YY. Fluconazole prophylaxis of severe Candida infection AmJRespirCritCareMed2015;191:1139–46.
intraumaandpostsurgicalpatients:aprospecivedouble-blind,ran- 30. CornelyOA,MaertensJ,BresnikM,etal.LiposomalamphotericinBas D
o
domized, placebo-contorolled trial. Infect Dis Clin Pract 2000; initialtherapyforinvasivemoldinfection:arandomizedtrialcompar- w
n
9:169–75. ingahigh-loadingdoseregimenwithstandarddosing(AmBiLoad lo
21. Pelz RK, Hendrix CW, SwobodaSM, etal. Double-blindplacebo- trial).ClinInfectDis2007;44:1289–97. ad
e
controlledtrialoffluconazoletopreventcandidalinfectionsincritically 31. PappasPG,RotsteinCM,BettsRF,etal.Micafunginversuscaspofungin d
illsurgicalpatients.AnnSurg2001;233:542–8. fortreatmentofcandidemiaandotherformsofinvasivecandidiasis. fro
22. GarbinoJ,LewDP,RomandJA,HugonnetS,AuckenthalerR,PittetD. ClinInfectDis2007;45:883–93. m h
PreventionofsevereCandidainfectionsinnonneutropenic,high-risk, 32. MohrJF,SimsC,PaetznickV,etal.Prospectivesurveyof(1→3)-β-D- ttp
ctrriiatlicianllpyatililenptasttierenattse:dabryansedleocmtiivzeeddi,gdeostuivbeled-ebclionndt,ampliancaetbioon-c.oInntternosllievde gsilvuecacnaraenudniittssreetltaitnigo.nJshCiplintoMinicvraosbivioelc2a0n1d1id;i4a9si:5s8in–6t1h.esurgicalinten- s://ac
CareMed2002;28:1708–17. 33. PosteraroB,DePascaleG,TumbarelloM,etal.Earlydiagnosisofcan- ad
23. SchusterMG,EdwardsJEJr,SobelJD,etal.Empiricalfluconazolever- didemiainintensivecareunitpatientswithsepsis:aprospectivecom- em
susplaceboforintensivecareunitpatients:arandomizedtrial.AnnIn- parisonof(1→3)-β-D-glucanassay,Candidascore,andcolonization ic.o
ternMed2008;149:83–90. index.CritCare2011;15:R249. u
p
24. Ostrosky-ZeichnerL,ShohamS,VazquezJ,etal.MSG-01:Arandom- 34. TissotF,LamothF,HauserPM,etal.β-glucanantigenemiaanticipates .c
o
ized,double-blind,placebo-controlledtrialofcaspofunginprophylaxis diagnosisofbloodculture-negativeintraabdominalcandidiasis.AmJ m
followed by preemptive therapy for invasive candidiasis in high- RespirCritCareMed2013;188:1100–9. /cid
/a
rtic
le
-a
b
s
tra
c
t/6
1
/1
1
/1
6
7
1
/3
3
4
1
2
9
b
y
g
u
e
s
t o
n
0
4
A
p
ril 2
0
1
9
1678 (cid:129) CID 2015:61 (1December) (cid:129) Knitschetal