Salvage combination antifungal therapy for acute invasive aspergillosis may improve outcomes

15 Pages·2014·1.92 MB·English

by  Anil A. Panackal

InternationalJournalofInfectiousDiseases28(2014)80–94

ContentslistsavailableatScienceDirect

International Journal of Infectious Diseases

journal homepage: www.elsevier.com/locate/ijid

Review
Salvage combination antifungal therapy for acute invasive

aspergillosis may improve outcomes: a systematic review

§
and meta-analysis

Anil A. Panackala,b,*, Emilio Parisinic, Michael Proschand

aLaboratoryofClinicalInfectiousDiseases,NationalInstituteofAllergyandInfectiousDiseases,NationalInstitutesofHealth,ClinicalResearchCenter,

Building10,Room11N222,10CenterDrive,Bethesda,MD20892,MSC1888,USA
bDivision of Infect iousDise ase s,Depa rtment ofMedici ne,F .He`ber tSch oolof Medicine,UniformedServicesUniversityoftheHealthSciences(USUHS),

Bethesda,Maryland,USA
cCenterfo rNanoSci enceandTechnology,PolitecnicodiMilano,IstitutoItalianodiTecnologia,Milan,Italy
dBiostat isti csRes earchBr anch ,NationalIn stituteofA lle rgyand Infectiou sDiseas es ,NationalIn stitute sofHealth,Bethesda,Maryland,USA

A RTI CLE IN FO S UM MAR Y

Articlehistory: Objective: Ameta-analysiswasperformedtocomparemold-activetriazolesorlipidamphotericinBplus
Receiv ed2April2014 anechino ca ndintonon-ec hino candinmo no therapyf oracuteinv asiveasp erg illos is(IA).
Received in revise d form 2 July 2014 Me thods: We sea rc hed PubMed, EMB ASE, and othe r d ataba ses throu gh May 201 3 unrestricted by
Accepted4July2014
language. We included observational and experimental studies wherein patients with proven or
CorrespondingEditor:TimothyBarkham, probable IA b y EORTC/M SG criteria u nderw ent our com parative interven tion. PRIS MA a nd MOO SE
Singapore guideline s w ere followed an d qualit y was asses sed using the Jad ad and Newc astle–Ott awa criteria.

Meta-regressionwithfixedandrandomeffectsandsensitivityanalyseswereperformed.Theprimary

Keywords: studyoutcomemeasurewas12-weekoverallmortality.Thesecondaryoutcomeassessedwascomplete
Invasiveaspergillosis andp artialresp onse.
COoumtcboimnae tsion antifungal therapy Resu lts: On ly observational studies of primary 12-week survival showed heterogeneity (I2= 48.96%,
p=0.05).ForsalvageIAtherapy,fixedeffectsmodelsdemonstratedimproved12-weeksurvival(Peto
Salvagetherapy
oddsratio(OR)1.80,95%confidenceinterval(CI)1.08–3.01)andsuccess(PetoOR2.17,95%CI1.21–3.91)

ofcombinationtherapy.Significanceremainedafterapplyingrandomeffectsasasensitivityanalysis

(12-weeksurvival:PetoOR1.90,95%CI1.04–3.46,andunchangedvalueforsuccess).Restrictiontohigh

qualitystudiesandincludingechinocandinsasthecomparatorforrefractoryIArevealedanadjustedOR

of1.72(95%CI0.96–3.09;p=0.07)forglobalsuccess,whilethesurvivalendpointremainedunaltered.

Conclusions: CombinationantifungalsforIAdemonstrateimprovedoutcomesovermonotherapyinthe

salvagesetting.Cliniciansshouldconsiderthisapproachincertainsituations.

PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.Thisisanopenaccess

articleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/3.0/).

causinginvasivediseaseindecreasingfrequencytobeA.fumigatus,
1. Introduction A. flavu s, A. nige r, A. te rre us, and A. versicolor .1 Ac ute invasive

aspergillosis (IA) leads to high morbidity and mortality in the
Aspergillusspeciesareubiquitousfungithatcanbeinhaledand immunocom prom isedh ost .Fori nstance,da tafro mtheTran sp lant
developintoa ngioinv asiv eforms.Th eresu ltso fast ud yusingd ata AssociatedInfectionsS urvei llan ceNetwo rk(T RANS NET )revealed
fromthe Pro spectiveAntifu ngalT hera pyAllia nc e (PATH Allia nce) 1-yearsurv ivalfromI Aof59%amo ngsolido rgantranspla nt(SOT)
regist ry reported in 2012, sho wed the most c ommon species recipie nts and 25.4% a mo ng h emato poieti c stem cell trans plant
(HSCT)rec ipien ts,from 2001t o2006.2,3Desp iteim prov edcare,IA-

associated hospitalization costs remain exorbitant. According to
§ Systematic Review Registration: http://www.crd.york.ac.uk/prospero/; datafrom theHealthcare Utiliza tionPro ject(HCUP ),theavera ge
CRD42013004006.
length of hospitalization due to IA in 1996 was 17.3(cid:2)0.6 days,
* Correspondingauthor.
correspondingtoacostof$62426(cid:2)$4977;thisdroppedin2004only
(A.AE.-Pmanaial cakdadl)r.esses: [email protected], [email protected] to 16.4(cid:2)0.5 da ys wi th a r educ ti on in c ost to $41 8 91 (cid:2)$1 842

http://dx.doi.org/10.1016/j.ijid.2014.07.007
1201-9712/PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://

creativecommons.org/licenses/by-nc-nd/3.0/).
A.A.Panackaletal./InternationalJournalofInfectiousDiseases28(2014)80–94 81

(p=0.09),whichisstillhigh.4,5Whilesinopulmonaryinvolvementis echinocandin compared to non-echinocandin monotherapy in

most common, dissemination to the central nervous system, ordertodeterminetheoptimumtreatmentstrategyforIA.

gastrointestinaltract,skin,orcontiguouslymayoccuramongstthe

severelyimmunosuppressed. 2. Methods

Effective therapeutic options are limited once infection is

established, relying on the host’s immune status to improve The Preferred Reporting Items for Systematic Reviews and

outcomes.Historically,amphotericinBdeoxycholate(AmB-d)–a Meta-Analyses (PRISMA) and Meta-analysis Of Observational

polyene that forms pores in the fungal ergosterol-laden cell Studies in Epidemiology (MOOSE) guidelines were followed in
membra ne– wasde emedt he ‘gold standa rd’fortreatingIA ,but describi ng ourfindingsan dstandar dmethodo logy.20 –22
dose-relate d neph rotoxicit ylim ited itswidesp read use.6To les sen

thenephrotoxicity,lipidformulationsweredeveloped:liposomal 2.1. Eligibilitycriteria

amphotericinB(L-AmB),amphotericinBlipidcomplex(ABLC),and

amphotericin B colloid dispersion (ABCD). However, infusion- 2.1.1. Inclusioncriteria

related toxicity was not eliminated by such modifications and Inclusion criteria encompassed any experimental or observa-

renaltoxicitywasfoundtopersistathighercumulativedoses. tionalstudyinwhichmold-activetriazolesoralipidamphotericin

In May 2002, voriconazole – a triazole with high oral B product was used in combination with an echinocandin for

bioavailability that inhibits a step in fungal cell membrane primaryand/orsalvagetreatmentofIA.Studiesthatinvestigated

ergosterol biosynthesis by blocking 14a-demethylase – received sequentialmonoordualtherapiesinacomparativemannerwere

approval for the primary therapy of IA as a consequence of the permitted, given the prolonged antifungal drug half-life in the
clinical t rial by H erbrech t et al.7 Vo rico na zo le was found to be setting of hepati c an d/or renal failure tha t is p revalent in the

superior to AmB-d, given its 52.8% vs. 31.6% 12-week global affectedpopulation.Salvagetherapywasdefinedasthereceiptof
response rat eand22 %redu ctio ninov erall morta lity(p=0. 02).7In antifung al(s)dueto prioran tifungal into lerance (e.g .,to xicity) or

a subsequent analysis, Patterson et al. foundthat fewer patients refractorydisease(e.g.,clinicalormicrobiologicalprogression).In

receivingvoriconazoleswitchedtootherantifungalsduetodisease somestudies,‘otherlicensedantifungaltherapies’(OLAT)wasused

progressionorintolerancethanpatientsintheAmB-darm(24%vs. asanaggregatetermtoencompassamixtureofsuchtriazolesand

70%,p<0.001),and,despitetheswitch,successat12weekswas amphotericin B products. To enhance uniformity, we selected

lesscommoninthelatterthanintheformergroup(32%vs.55%, studiesonimmunocompromisedhumancasesthatcomparedthis
p< 0.001).8 combin ed interventionto‘monoth erapy’ –asin glea ntifungald rug

Since IA treatment responses were found to remain poor in withsimilarIAsurvivalrates(i.e.,mold-activetriazolesoralipid

certain populations (e.g., allogeneic HSCT) and in cases of amphotericinBproductintheprimaryandsalvagesettings)–to

extrapulmonary involvement, with a positive response rate of permitanalysisofourpooledstudypopulation.Furthermore,only

32–42%, alternative strategies were considered. In 2001, an provenandprobableIAcaseswereincluded,inaccordancewith

echinocandin – caspofungin – was approved as salvage therapy the original and revised European Organization for the Research

for IA; the favorable response rate was 45–56%, with better and Treatment of Cancer/Mycoses Study Group (EORTC/MSG)
out com esam ongthose receiving itdu etod rugintole rance rather guid elinedefini tion s.23,24Studiesne ededto enable calculationof
thandisea seprog ression .9,10Asim il arsu cc essfu lresponsera tebut 12-week survivalasourprimary endpoin t.A lthoug hmostdeat hs

lower12-weeksurvival(50%)wasobtainedwhencaspofunginwas attributabletoIAoccurwithin6weeksaftertherapy,wefounda
used a s primar y therap y.11 O f p articular intere st is the un ique lackofconsi ste nc yacros sstudi es inmea surin gthisas ano utcom e
targe tof thisclas s–b-1,3-gluca nsynthase ,anenzy me tha tmakes and so we chose 1 2-week surviv al as our maj or e nd poi nt.25 The

animportantcomponentofsomefungalcellwalls. secondary endpoint was composite clinical, microbiological, and

Subsequently, several investigators noted further improve- radiographicsuccess(‘complete’or‘partial’response)ascertained

ments in outcome based upon in vitro and animal studies that attheendoftreatment(EOT),accordingtopreviouslypublished
demon str ated syne rgistic or ad dit ive ef fects when combini ng a de finit ions .26 Tominimi zepubl icationbia s,w eincluded studiesin

mold-activetriazole(itraconazole,voriconazole,orposaconazole) languagesotherthanEnglish.

or an amphotericin B with an echinocandin (caspofungin,
mi cafu ngin, or anidu laf ungin) .12,13 These transla tional studies 2.1.2. Exclusioncriteria

ledpractitionerstousesuchcombinationtherapyroutinely,with Exclusion criteria encompassed any case reports, case series,

thehopeofimprovingIAoutcomes. reviews, guidelines, and non-human studies that dealt with our

However, few human observational studies and small-scale researchquestion.Anystudythatfailedtohaveacomparator,did

clinicaltrialshavebeenpublishedtosupportthispractice.Infact, not include the desired combination, or did not include data to

logistical issues made recent completion of a randomized derive an effect measure of our endpoint was removed. In cases

controlled trial to investigate this approach for primary IA wheremultiplestudiesincludedthesamestudysubjects,onlyone
challengin g.14,15 Sin ce investiga tors h ave found com parable 12- studyw asselec tedtoa voiddup lica tion.

week survival for voriconazole (70.8%) and lipid amphotericin B

(e.g., 72% using L-AmB 3mg/kg) and comparable response rates 2.2. Literaturesearch

(50.8% compared to 50%, respectively) in the treatment of IA

amongHSCT, SOT, and hematological malignancypatientswhen WeconductedasystematicsearchofMEDLINEviaPubMed(http:

used as primary therapy for IA, and because these classes have //www.ncbi.nlm.nih.gov/PubMed), EMBASE (http://www.embase.

largely similar salvage efficacy, it is cogent to combine these to com),BIOSIS/WebofKnowledge(http://apps.webofknowledge.com.
minimi ze hete rogeneit y.7,16–18 In de ed, in a r etrospect ive no n- ezpro xy.nihlibrary .n ih.gov/WOS _GeneralSearch_input.do?product=

comparative salvage study, Maertens et al. found no significant WOS&search_mode=GeneralSearch&SID=4CMPf38K95Aj2alO2bo&

difference in the favorable response rate at 84 days when preferencesSaved=),theCochraneControlledTrialsRegister(http://

caspofungin was combined with either an amphotericin B or www.cochrane.org/cochrane/hbook.htm),theNationalInstitutesof
triazole.19W ethe reforecond ucted asyste mat icreviewandm e ta- Health (http://www.clinicaltrials.gov), a nd a meta -register of

analysisofstudiesthatevaluatedtheefficacyofcombiningmold- controlled trials (http://www.controlled-trials.com) using the fol-

active triazoles or a lipid amphotericin B product with an lowingsearchterms:antifungal,combination,and/oraspergillosis.
82 A.A.Panackaletal./InternationalJournalofInfectiousDiseases28(2014)80–94

Thesemedicalsubjectheadingsweredeemedmostexpansive,but asrefractoryorintoleranttotreatmentIArequiringanewregimen

werecross-checkedwithmorespecifictermssuchasaspergillosis, including a different antifungal class), antifungal combination

echinocandin,triazole,oramphotericinB.Unpublishedstudieswere intervention and monotherapy comparator, drug duration, and

discoveredusingtheBritishLibraryIndextoConferenceProceedings number of participants in each group, as well as the duration of

(http://www.bl.uk) and other sources (e.g., Google Scholar and follow-up,infectionsite,12-weeksurvival,andcompositeresponse.

nationalandinternationalmeetings/abstracts). Data quality assessment with respect to the risk of bias was

performedamongexperimentalstudiesusingallocationmethodol-

2.3. Dataextraction ogy, therapyconcealmentdetermination, outcome ascertainment
(reli abilityan dvalidity),an dattritionbased ontheJa dadmethod.27

Usingadevelopedabstractiontemplate,twoinvestigators(AP Similarcomponent sources of biasweredetermined forobserva-
and EP) in dependentl y extracted data from stu dies meeting our tionals tudiesusing theNew ca stle– Ottaw ascale.28

eligibilitycriteria.Theseinvestigatorswereblindedtotheauthors’

affiliated institutions, funding sources, and acknowledgments to 2.4. Dataanalysis

minimizeascertainmentbias.Anydiscrepancieswereresolvedvia

referencingtheoriginalsourceandgroupdiscussions.Pilotingand We stratified by therapeutic indication (primary vs. salvage)

revision ofthe instrumentwas doneasneeded.Weacquiredthe and presented studies by design via forest plots. We assessed
followin gin form ation:jour nala rticlec ita tion,stu dyty pe,mean age hete rogeneity of the s tud ies usin g I2 – a q uantifi catio n of the
ofparticip ants,sexrat io,sourc epopu lation( e.g.,H SCT), predo mi- degreeofvaria tio nor inconsis tency acros ss tudies.29Fixed eff ects

nantIAtreatmentindication(primaryorsalvage–thelatterdefined resultswerereportedforallanalyseswiththePetooddsratio(OR)

Records iden(cid:2)fied through Addi(cid:2)onal records iden(cid:2)fied

database searching (PubMed, through other sources (conference

n EMBASE, BIOSIS, CCT) proceedings, Google Scholar)
o
(cid:2) (n = 1756) (n= 2575)
ca
(cid:2)fi
n
e
d
I
Records a(cid:3)er duplicates removed

(n = 1351)

g
n
ni
ee Records screened Records excluded
Scr ( n = 9 0) (n = 1261)

Excluded for Full-text ar(cid:2)cles assessed Full-text ar(cid:2)cles excluded,

other reasons for eligibility (n = 32) due to incorrect or

y (n = 25) (n=55) no comparator group, or
bilit reports with overlapping
gi
Eli cases t o included studies
Stufdui ertsh reerv dieewtae idl in with o ri nwfoi t rhmoua(cid:2)t osunffi cient
(n=33)

Records with echinocandin
d as comparator for sensi(cid:2)vity
ude Studi es included in Sensi(cid:2)vity analysis
Incl qua( nm(cid:2)et(atna(cid:2) -=vae n2 as4yl)ynstish)e sis analysis soa(blnvs ae =gr8ev; aI2A(cid:2) c oolnirna bilc o asttlh ut drpiiarelissm ,f a6o r ry
and salvage indica(cid:2)ons)

Primary analysis
Completed clinical trials (n = 2): Observa(cid:2)onal studies (n = 14):

Primary IA (n = 2); Primary IA (n = 9);

Salvage IA (n = 0) Salvage IA (n = 4);

Both (n = 1)
Figure1.Flowdiagramoftheselectionprocessforstudyinclusioninthemeta-analysisofcombinationantifungaltherapyforthetreatmentofacuteinvasiveaspergillosis.
Table1
Observationalandexperimentalstudiesofcombinationantifungaltherapycomparedwithmonotherapyforthetreatmentofinvasiveaspergillosis,meetingtheinclusioncriteria
Citation Typeof Study Study Predominant Combination Combination Monotherapy Monotherapy Follow-up Age(median Maleto
study location population indication treatment treatmentduration treatment treatmentduration [range]or female
regimen (median[range] regimen (median[range]or Mean(cid:2) ratio
orMean(cid:2)SD Mean(cid:2)SDdays,or SDyears)
days,or approximation)
approximation)
Munoz Retrospective Boston,MA Hematological Primary Voriconazole+ N/A Voriconazole (cid:3)14 >100days NR NR
etal.34 cohort malignancy caspofungin
Steinbach Retrospective USA HSCT,SOT, Primary OLAT+caspofungin (cid:3)7 Voriconazole 14–28 12weeks NR 2.1
etal.35 cohort (multicenter) hematological
malignancy
Marr Retrospective Seattle,WA HSCT Salvage Voriconazole+ 68[3–248] Voriconazole 33[2–205] 3months 47[17–66] 0.62
etal.36 cohort caspofungin
A
Trullas Retrospective Spain HSCT,SOT Primary AmB-d+ NR L-AmBorABLC NR NR 51.7(cid:2)14.1 1.81 .A
etal.37 cohort caspofungin .P
a
Dı´az Retrospective Spain SOT, Salvage Voriconazole+ NR Voriconazole NR 30days 51.5[4.5–75.5] 1.29 n
a
Pedroche cohort hematological caspofungin ck
etal.38 malignancy ale
Singh Prospective International SOT Primary Voriconazole+ NR L-AmB <90 90days 50[19–68] mono:0.9; ta
Caeeilttloaatll..3498 cColihnoicratltrial F(mraunlcteicenter) HheSmCTa,tological Primary Lccaa-AssppmooBffuu+nnggiinn 18[10–35] L(1-A0mmBg/kg/day) 17[4–24] 12weeks 53.6[16–75] 2co.3m3bo:2.1 l./Intern
malignancy atio
Waala Retrospective Seattle,WA HSCT, Primary Voriconazole+ 16.2(cid:2)10 Voriconazole 28.1(cid:2)28.2 3months NR 0.8 n
a
etal.40 cohort hematological echinocandin lJo
malignancy u
Pagano Prospective Italy AML Primary L-AmBor 20[2–90] L-AmBorvoriconazole 20[2–90] 120days 57[14–79] 1.8 rna
etal.41 cohort (multicenter) voriconazoleor orposaconazole lo
posaconazole+ fIn
Mihu Retrospective Houston,TX Hematological Salvage Lca-AspmoBfu+ngin 14[2–112] L-AmB 8[1–170] 12weeks 50[9–79] 1.6 fectio
etal.42 cohort malignancy echinocandin usD
Secthawl.4a3rtz Rcoehtroorstpective I(nmteurltniacteinotnearl) HheSmCTa,toSlOoTg,ical Salvage Vcaosrpicoofunnazgoinle+ NR Voriconazole 48[1–1128] 12months 44[0.75–81] 1.35 isea
malignancy ses2
Lortholary Prospective France HSCT,SOT, Primary Voriconazole+ NR Voriconazole NR 12weeks 56[18–84] 1.64 8
etal.44 cohort hematological OLAT (2
0
malignancy 14
Jacobs Prospective Belgium HSCT,SOT, Primary Voriconazole+ 49.5[1–183] Voriconazole 32[1–183] 183days 55.6[14–85] 1.46 )8
etal.45 cohort (multicenter) hematological OLAT 0–
9
malignancy 4

Marr Clinicaltrial International HSCT, Primary Voriconazole+ 14–28 Voriconazole (cid:3)42 12weeks 52[18–83] 1.25
etal.14 (multicenter) hematological anidulafungin
malignancy
Racil Retrospective CzechRepublic HSCT, Primary+ Voriconazole+ 19[5–159] Voriconazoleor 15[5–139] 12months 56[3–77] 1.44
etal.46 cohort (multicenter) hematological salvage caspofungin L-AmB
malignancy
Baddley Retrospective USA HSCT,SOT Primary VoriconazoleorL- Mean115 Voriconazoleor Mean115 12weeks 49(cid:2)14.7 1.55
etal.47 cohort (multicenter) AmB+caspofungin L-AmB
Citation Organinvolvement Number in combina- Numberinmonother- Dataqualityassessmentpoints: Dataqualityassessmentpoints:
tiongroup apygroup Experimentalstudies*(max.5points) Observationalstudiesz(max.9points)
Pulmonary Extrapulmonary Primary Salvage Primary Salvage Randomized Concealment Attrition Selection Comparability Outcome
Munozetal.34 NR NR 10 N/A 24 N/A N/A N/A N/A 2 1 0
Steinbachetal.35 74 9 17 N/A 34 N/A N/A N/A N/A 4 1 2
Marretal.36 40 7 N/A 16 N/A 31 N/A N/A N/A 4 2 3
Trullasetal.37 25 6 8 N/A 13 N/A N/A N/A N/A 2 0 0 83
84 A.A.Panackaletal./InternationalJournalofInfectiousDiseases28(2014)80–94

Table1(Continued) CitationOrganinvolvementNumberincombina-Numberinmonother-Dataqualityassessmentpoints:Dataqualityassessmentpoints:*ztiongroupapygroupExperimentalstudies(max.5points)Observationalstudies(max.9points) PulmonaryExtrapulmonaryPrimarySalvagePrimarySalvageRandomizedConcealmentAttritionSelectionComparabilityOutcome 38´153N/A12N/A12N/AN/AN/A311DıazPedrocheetal.39Singhetal.783040N/A47N/AN/AN/AN/A32248Caillotetal.30015N/A15N/A201N/AN/AN/A40Waalaetal.NRNR19N/A38N/AN/AN/AN/A31241Paganoetal.12614143774N/AN/AN/A42242Mihuetal.11526N/A71N/A70N/AN/AN/A42343Schwartzetal.0120NR18NR102N/AN/AN/A42244Lortholaryetal.3652873N/A294N/AN/AN/AN/A42245Jacobsetal.NRNR27N/A72N/AN/AN/AN/A32214Marretal.2770135N/A142N/A221N/AN/AN/A46Raciletal.165114177612N/AN/AN/A40247Baddleyetal.33472103NR141NRN/AN/AN/A322 *zJadadqualityassessmentscale;Newcastle-Ottawaqualityassessmentscale;HSCT=hematopoieticstemcelltransplant;SOT=solidorgantransplant;EOT=endoftreatment;N/A=notapplicable;NR=notreported;OLAT=otherlicensedantifungaltherapy;Antifungaldrugdoseswereasfollowsunlessotherwiseindicated:itraconazole200mgIVorpoTID;voriconazole6mg/kgIVorpoq12h1dayfollowedby4mg/kgIVq12h;posaconazole200mgpoTID;(cid:4)liposomalamphotericinB(L-AmB)3–5mg/kgIVqd;amphotericinBlipidcomplex(ABLC)5mg/kgIVqd;amphotericinBcolloiddispersion(ABCD)3–4mg/kgIVqd;amphotericinBdeoxycholate(AmB-d)0.7mg/kgIVqd;caspofungin70mgIV1dthen50mgIVqd;Micafungin100mgIVqd;Anidulafungin200mgIV1then100mgIVqd;Dosagesareasmentionedunlessotherwisestatedintabletext.(cid:4)(cid:4) wsfaaaM1t(gesClcemqc5s3ib(LRrpAbcpvhftmprs(aa(satocf2sbmcaalaniooehT1h5hTeepoettiooaooanmffndss reb7u5.yy4iaaroesePomtquu ffmearcffvaoaooia50ely aeeniunammmtrtdtrddsg te0m eea)boeen raRruusfpddsoIAFFjlbise inuartrcm.h9ne drfiacd dcinc a uMoinre0ceaerac eeiiipbbisanretrmciilgw9iaporp eo tentroimcotrdggsw l onrteerb–el nioioi msvenn wssii awapngndei wkl5tanuouiu imiintmenuueecwossnn otaaty5eg- vteou tadhrtn i a ertniSaed%nchtd strogsntaea1 yrrfrclesntaai eaan5netnhwibpoeecaltdibdaronrev e cttit eeae na temtlsisci )ntttntscirc 3d.gesoa nie)rerfeoesoaolgx iiraf tcr1 6ot iitsloo e>am,g h (i.ovai(nygertd2n1 t 8oomle yhv iisus tnp 4hngytgapnitemnTs) 6rs–sifwelniownpsaei:i qn,a p2 ,i nna.t6in oe vderiuar)a 1t i iotrafiio3 iswp d0eHvs eg n t(hyfitgncy iusryo eyl ino5i eam,littd3yitortlrtne 11entili cr%ei m( im tcv a3gd h,heaaeta,rodcu afti rno utu n3hga iiero >isdtt26plsostsuliie),eyienswttaee.aeasten4 egq srnlebo 1sei dsbc p0eaAnne uaiei n t iwr owrr vt–p1r n n ul nttertotdulrsc tiir5rurvyrt.tl:Iasucr a irgtmlws4aihterfeio1m(ln vrshvdnanbtayn/sacaritlnah avaiuhoifis 6ri 8ttaa tkdun(ob s/uznsiteiusat afltaentp-ne isc teoec lhnma ieowansni nt eh ou( ei1oyihdsauiae 0tl d g e=pwc.arslud yrledante ztralisc2gns1l)edjyfsianluodn ld 2ndauehitsne–mhqeawni yefu sin s sean ee o ynodeef01g6 e lei aotnu o(prs .i- ra 4cms t u efaclydonns3gmadsa.wmnee np bt1tsa6mrwrwi5eoyervewt srcelyf rt 0lbeihso(rnh1 eccf nesm)s y shwo–yiis3 c)fy rin oaspsioe ,ao eeip.0c fint3et.ye)wgnetuaae o ei e.meveats r,cs e era-sgamnm5oo giwt,ipar1t bS nr–a e Msy htrrcri ( n i-lnoal,a0gwemwfirnoes tie stseti0oigleydtmaceoigeapokvf3 latnlRhsnae,lhsopy5nsehm,ur,it aice:ct rchetPe ps .,rdn ea aai treme (p g1ehsai c no evh eo-theirent lsT(cmtith)aaaC)ottsrwieswatiatd isis1hclseyy6ac1s iiee,buutlnwnrte.mac ehsedcn clnel ua )juoIsnm ss hiio sa6al6 alt dm4p.e uaoic)i ta(r eraahs ardet suii3eyddnna,t tmegtc.pnc kHrev2a;ncoc tl4e listnafnltlo as ihtudiEea 2rnM t i roao aeoo op dcatp iy fi,Jn9mhucan enmagdtptS=t eh1Ties 1n vg aaN.–w.r)tmatm ltcsahluso hfianyon rcesfC,nau ig.or hsw2 yi alga1ada(doo l1Od8.p eptnmtese niswlt erseoisd let y5 iTbrp lr0peneeelnIiuao rfp nhrryh.wa) giuitwaheedeA f fensecr5 ,s 0m sjn rbirt ae4dudheed gf odaerseee/osrfe Itree3ea nwiinapR a e 2te2cwpc)rfArafogdi tcsdu eiiuemuirt le( wd c(slh‘2efie sGpustfcaomla hroipe)eb hfaws ait mh9nre.eddnrncsawtfgsbp ieFtt mehocne6 (tpshumxn roneueetapt ieaid cr i hy7e Ay iToiudourtoar lt oigri ift mahrcos) eireglsbnsndi)ltei t neoreliueino3oemearsbteubm niot.hnmwtge; mln eem nhrsnree irwgndine,t dnraemnuay rrbldo orarlpe eenn e dr’s–rpmtdToatmv esr e q aisdbti ator ot p detfvltw ehiatrn istersttdt Oitdirfhts sehe,e>swsd ndn evpuiae t honayti ao spahtriiordoriaiedaewutwca ,eraasi eanteh.ta sum dnryori aoasetnc.n1ehanro l axioinis2ustttoal st( pwse irr tugnrett,ere dkT chOft wriueia s rev1gctr u AoiosaI eyrnaece sanDtosmrip1 (ye dridaothaei Awe tl dhea ien(cid:3)f1aigsesoforfnrc .od eps )aeeunishll2 lgt c3d episni i ( texy.ptl.i(titoy vneeuemvnsrfnsge.d ar r14t24wodt esecieer7s(ah1iui3ita f Oht,ate tet heosit9fba o e cS ioo,eth e23asn1n aepnr h2sd3ymce poeebat‘9ntecas–asusnbl.tectn)ij,ramr fsrccd 3 iatru edm l-3osme0d5tnetrehdl thi as0 da(P ha cdtwps rypacaooeimnetiinw0 t1e 6rdZ acdno19l rdeeeonc heegovluhiiolin Semttusavaoracd– stef-srneiiiimfa t t ltr aaamegTa ubsmstrrrocdttstnfepc uas odclnt ueuem2a svatmoaao-itflho eoytmspaea iceichlosgrgtu rnsera sn dyioffsirhat noian ctpeerl) mleheboao )eicimnofiieafeiSt csaesbircaf)viool rit no man,mensarn dashenunfrsenlaa n ca.anir )-gwitmgcalflargft fsen nrtnl e i5nogt n’ Peiarersrigd ttep Siegl roeuyaaa aaonT uagoii n( ettttdrottacigiei n 1i l leee nccOcil ivnnnsr2rnoaodpnbnahehhhhhheeeecununaeorottrtemiosdd.aaat yits RBnn)hnnddddd–dd7)Tooyyyyyggeeeeeeeessssssr---ttt:flll..,,.,
Table2
Studiesinwhichanechinocandinwasusedasacomparatortocombinationtherapywithanechinocandinandamold-activetriazoleorlipidamphotericinBproductforthetreatmentofinvasiveaspergillosis.SeetextandFigure2e
forthesensitivityanalysis
(A)
Citation Typeof Study Study Predominant Combination Combination Monotherapy Monotherapy Follow-up Age Maleto
study location population indication treatment treatment treatment treatmentduration (median female
regimen duration regimen (median[range] [range]or ratio
(median orMean(cid:2)SDdays, Mean(cid:2)SD
[range]orMean orapproximation) years)
(cid:2)SDdays,or
approximation)
Denning Clinicaltrial International HSCT,SOT, Primary+salvage Micafungin+OLAT 35[7–284] Micafungin <90 6weeksafterRx 36[0.2–84] 1.73
etal.55 (multicenter) hematological
malignancy,others
Izumikawa Retrospective Japan non-HSCT,non- Primary OLAT+micafungin 59.2[29–96] Micafungin 59.2[29–96] EOT 61.9[20–83] 3.5 A
etal.49 cohort hematological .A
malignancy .Pa
Kontoyiannis Prospective International HSCT Primary+salvage OLAT+micafungin NR Micafungin NR (cid:5)90days NR NR na
etal.50 cohort (multicenter) cka
Lichtenstern Retrospective Multinational SOT Primary OLAT+caspofungin56[22–228] Caspofungin 59[9–398] 7daysafterEOT 56 1.92 le
etal.51 cohort (Germanyand ta
otherEuropean l./In
countries) te
Maertens Prospective International HSCT, Primary+salvage OLAT+caspofunginNR Caspofungin NR 7daysafterEOT 50.4(cid:2)16.09 1.64 rn
a
etal.52 cohort (multicenter) hematological tio
malignancy na
Winkler Retrospective International SOT Primary OLAT+caspofunginNR Caspofungin NR 7daysafterEOT NR NR lJo
etal.53 cohort (multicenter) urn
Egeetrearl.54 Rcoehtroorstpective I(nmteurltniacteinotnearl) HhmeSamCliTag,tnoalnocgyic,aolther Primary+salvage OLAT+caspofunginNR Caspofungin 13.7[5–38] 7daysafterEOT 57[17–75] 1.33 alofInfe
Jareqtuael.56 Clinicaltrial Spain Hmeamligantoalnocgyical Salvage VAmorBico+ncaazsoploefourngLi-n19[2–52] Caspofungin 19[2–52] 28days 52[23–78] 1.5 ctiou
(B) sD
Citation Pulmonary Extrapulmonary Primarycombo Salvagecombo Primarymono Salvagemono Randomized* Concealment* Attrition* Selectionz Comparabilityz Outcomez isea
se
Denningetal.55 61 19 17 173 12 22 0 1 1 N/A N/A N/A s2
IKzounmtoikyaiawnaniesteatl.a49l.50 981 017 57 N83/A 42 4N/A NN//AA NN//AA NN//AA 24 11 12 8(20
1
LMicahetretennstseerntaelt.5a2l.51 N87R N16R 45 N11/A 415 N70/A NN//AA NN//AA NN//AA 44 12 22 4)80
Winkleretal.53 NR NR 10 N/A 9 N/A N/A N/A N/A 3 1 2 –9
Egereretal.54 NR NR 1 5 10 26 N/A N/A N/A 4 1 1 4
Jarqueetal.56 34 0 N/A 20 N/A 14 0 0 1 N/A N/A N/A
*Jadadqualityassessmentscale;zNewcastle-Ottawaqualityassessmentscale;HSCT=hematopoieticstemcelltransplant;SOT=solidorgantransplant;EOT= endoftreatment;N/A=notapplicable;NR=notreported;
OLAT=otherlicensedantifungaltherapy;Antifungaldrugdoseswereasfollowsunlessotherwiseindicated:itraconazole200mgIVorpoTID;voriconazole6mg/kgIVorpoq12h(cid:4)1dayfollowedby4mg/kgIVq12h;
posaconazole200mgpoTID;liposomalamphotericinB(L-AmB)3–5mg/kgIVqd;amphotericinBlipidcomplex(ABLC)5mg/kgIVqd;amphotericinBcolloiddispersion(ABCD)3–4mg/kgIVqd;amphotericinBdeoxycholate
(AmB-d)0.7mg/kgIVqd;caspofungin70mgIV(cid:4)1dthen50mgIVqd;Micafungin100mgIVqd;Anidulafungin200mgIV(cid:4)1then100mgIVqd;Dosagesareasmentionedunlessotherwisestatedintabletext.
8
5
86 A.A.Panackaletal./InternationalJournalofInfectiousDiseases28(2014)80–94

(t2=0.20(cid:2)0.22;I2=49.0%;p=0.05).Thiswasconfirmedvisuallyby
Description TrialofCombinationAntifungalTherapy(Vori+Micavs.Vori+Placebo)inInvasiveAspergillosis(http://clinicaltrials.gov/ct2/show/NCT01207128?term=aspergillosis+and+combination&rank=4)Primaryoutcome:Responseat6weekswhereresponseisdefinedasnormalizationoftheserumAspergillusgalactomannanindex(GMI)values(firstnormalGMIvalueisconsidereddayofresponse)WithdrawnpriortoenrollmentVoriconazoleAndAnidulafunginCombinationForInvasiveAspergillosisInPediatricSubjects(http://clinicaltrials.gov/ct2/show/NCT01188759?term=aspergillosis&rank=10)Primaryoutcome:Safetyandtolerabilityofvoriconazoleandanidulafunginincombinationversusvoriconazolealoneasdeterminedbyratesofadverseeventsat12weeks(EOT)Secondaryoutcomes:Rateofall-causemortalityat6weeksandatEOTGlobalresponsetotherapyat6weeksandatEOTWithdrawnpriortoenrollmentAStudytoEvaluatetheEffectivenessofVoriconazole+MicafunginVersusVoriconazoleAloneforInvasiveAspergillosis(http://clinicaltrials.gov/ct2/show/NCT00423163?term=aspergillosis&rank=12).Primaryoutcome:Globalsuccess(completeandpartialresponse)at6weeksbasedonthecombinationofclinical,mycological,andradiologicalresponseSecondaryoutcomes:Globalsuccessatweek12,favorableresponseandsurvivalatweeks6and12.Globalsuccessandfavorableresponsebyinfectionsite,overallfrequencyofemergentandrecurrentfungalinfectionsatweeks6and12,durationoffavorableresponse,andrelationshipofgalactomannantoclinicaloutcomeEstimatedenrollment350Withdrawnpriortoenrollment prc(bttp9cop(f1fec3fiecrcacmfT–noroohhPpaeloaooaffd nu5..arr oi=99ffirn rrecfoeeoinnnmmnbd%en=eetm rm 01ltr Sdlsv 0cfid icc alIue G sodfia,0)cuCfieppAeeo.ttan a rcaid nsa 2pa-a9.ss On,dIc(ooamm.irt1 l iav 2 cl8 2Fylly5vcyoo1r sbsta Reb3TsmceoiA, i0e eeh a% irn. ptgsduer ht)0 fterdt1yd sr)geea i oou atple fir h ee8f.iavsCd. t ore ir vadsrf6 orrtscxe ontesi–IFeeIvir f e oioslaeehA6 fh iner cveisd3 c1Iau 1gcaall aga ,Ad h2ti gtatms . 2tponec.ttncp90r uchsar0 p ild iths-ahflimci o lneo51ynaraetwco4farfiw)heiniem emhne n%c) ooiiodsazt–fbcoonsn nw ic ea fOea id(c smo tao3s(C2uiaefct eFeenh rlaanduF lnas Rsd.aaic Ielicwakde4pndnr it (dsscgrattcl e1o gpa soe P6 rs ut lsaeeidiut soelt.symul entuelr f ye,i,0rddigriimrr l ui aoe imgnrea1nsdi,tusam2e hn b inealrtno n tts.anm bi aos–uwrvcoa2di l2ioecdhi o in2tsticdintlt2iniw5fiiocOsarPnpri aad vhniahaac v.(,i).av lmzoce6ua rsva (le efRea,itpe ie tiHoao9ocatsritpl8elnvdrstt dr eloo pi sh,n=vnrl5eyiyoi aie) ooc 0asie gnmg da e d d% tc dsurph(n0w wn.Osahn w wdrh,9 Fito – t tay . sgndCathaRti2ai hsfeho8mf nuefi ()gehnnotaa Im1ai(na0 vmep;,i rodgcurpcP elli0oor ic2pt)dree yfibeulceare9 pr=r ,eh.fotae-=a r 7 se t aseec dnn 5 althwptgs,d h ri0o1sai4au p io0 hcdss2t%ypaeoytt hsv.enln.e–sye u .2hee 3avntb i t (Oon7laa ee(t l2 ceod re16e)6ceaCa(elyPts l6 osdkoR .l.e uFsrow2)i gg a ooh0I edt T emac,is i (me-fe ageu1mft9ocskg oh9os tte0(woo cdwvu ristmp).eunt fe5mapfn7.oredI a.ai eaor4rfieOa rAo n i i%aNa8g micvloo sinrteer4bgncwlRrB oca ths aia,gteo ka tla e–vis m Cpr2tipt m 9tmo ehdnnnb2 gudescoah2efIobsapns5b iet eo.yonld lcs pue t.ps1fir)tael 1ea%2dtescog rn l.yio e or(l7hth iloGfi .mes1f tn ivPFi0 tido hsCwof,mmncoeoenswsyc )asoiiiee2t e9lIbtuslvfitet.t tgau,lhiirt ceooit– eeot)e5b1stast nlco cn oceMt.sienn ahh1rser. %larasa.n i cFn rst:r0 iaTtacroo.m ue nOl o e, coig8aliCv l 8ePaihergtt tyocstigvtr p0oRsahhaeIhfnlec–lneuc(sh enea i fiy)vynt aakeeh1t)ee gt2ero. ngfiisB1 o eb,c drrpsr s.oein w.=t eve2aTxaaiin. aur9soolnw w8ffmOi a i 2enao1pphe cfiooo46uIertmoa0lrAldRtdd–yoyyyeeesrrr---)t;fll,,,

primaryIA(k=3),wasinfluentialontheoverallcompositesuccess

ofprimaryobservationalstudiesinanunexpecteddirection(i.e.,

nolongersignificant,withfixedeffectsPetoOR1.29,95%CI0.87–
II) III) IV) 1.9 2 com pared to F igure 2a). Surviva l wa s n ot sy stem at ically
(phase (phase (phase asseFsu snende alsp alont se nsdh poowinedt ian pthreeds eo mstiundainets .lack of p ublication bias
trial trial trial except for studie s that in cl uded primary com pos ite success a s an
design mizedcontrolled mizedcontrolled mizedcontrolled l(foeiuFnutinedtgrncpuaoeortmleui n repte3, l ()oisE.t te g iHasgar eocdsrwhyi’fs mefi arvcmneeugdrler,t te irtnswyosc, ii ldtouhprnsa i=wtos eno0 s . fit0o fr3uefm )nw,n dc oegosnrintv -uacEe dlnnmuig esilisxtio shenhbeds y .le abfnifrneegcdautidasctg ahmet i oosodntfue lda ofinuoedsrr
Study Rando Rando Rando amSoinngc es awlvea gfoe uonbds ear vsaigtinoinfiacla nstt uedfifeesc,t wofh iccohm cbainn atbieo np rtohnerea ptoy
selectionbias,andnotednosucheffectamongtheclinicaltrials,

whicharedesignedtoavoidsuchsystematicerrorsinallocation,

weperformedmeta-regressionon‘highquality’studiesaccording

am,ClinicalTrials.govnumber etal.,NCT01207128 CT01188759 NCT00423163 T1omstoehu.8e tett0ac itcs,noh ulmgie9rn e5(eiJc % Nafab odele raCwtc drIas ci amaas1llcsvse.ot0 a lfr8megae––ie la3 O<er1.dtg032t i1)ta-n.o,wwa mlepa e ( e=Oke c 0Rtos . ‘0muh12ri.pv7g),oi2h vn, ba qe9luun 5trat %eslimt .t hCyaeIT’ i mh0nc.ee9ao dr6m ka–uspd3n ioj.ncu0sh 9sittta,he enpe dg s s=eua d0elcv f.c0f(aeeO7gscR)est.
Studyteprotocol Annasie Pfizer,N Astellas, nt. 4. DOiusrcuresssuioltnsindicatethatthereismeta-evidencetosupportthat
me dual an tifunga l therap y aff ords sig nificantly impr ov ed 12-w eek
at
tre survival and composite success over monotherapy when given as
Startdate 2/2011 5/2012 2/2007 OT,endof btshayle v paarbgimese tanhrceyer aaopnfy da f posarr loIvApae.g nTeos it tchyoe nsrcatroporyle , f-ofimrn acdtoicnnhgfeo dtu hnaandtai nltyhgs ebirsye, wiwneda issc taratanito i8nfi0 ei%nd
E increased odds of 12-week survival among those who received
A.A.Panackaletal./InternationalJournalofInfectiousDiseases28(2014)80–94 87

Figure2.Forest(leftcolumn)andGalbraith(rightcolumn)plotsofstudiescontainingdataofcombinationantifungaltherapyversusmonotherapybytherapeuticindication

andprimaryandsecondaryoutcomes(asdefinedinthetext).(a)Primarysurvival.(b)Primaryclinicalresponse.(c)Salvagesurvival.(d)Salvageclinicalresponse.The
com positeef fectm easureise xpresseda sth ePetoo dds rat io.Afi xed effectsm odelwas fitt edforall analyses .Ifheterog en eitywas presentv iath eI2test andGal braithplot s(x-

axis=inversestandarderrororprecision;y-axis=Z-score;slopeisthemodelpointestimate)andthenumberofstudies(k)>8,arandomeffectsmodelusingthe

DerSimonian–Laird estimator and an approximate t-test for confidence intervals are also reported (see text). (e) When studies that included echinocandins as the

monotherapycomparatorforsalvagewereincluded,sincethisdrugclasshassimilarefficacyforrefractoryinvasiveaspergillosisastheothersingledrugclasses,combination

therapyremainedofsignificantbenefitovermonotherapyamongobservationalstudies;thesuccessendpointisonlylistedassurvivalandwasnotuniformlyassessedin

thesestudies.RCT=clinicaltrialsandnotnecessarilythemethodofallocation.
88 A.A.Panackaletal./InternationalJournalofInfectiousDiseases28(2014)80–94

Fig.2. (Continued).
A.A.Panackaletal./InternationalJournalofInfectiousDiseases28(2014)80–94 89

Fig.2. (Continued).

combinationtherapycomparedtothosewhoreceivedsingle-drug Our results also demonstrated that the meta-evidence to

therapy as salvage, and this effect remained when restricted to support the routine use of combination antifungal therapy for

high-qualityobservationalstudies.Theglobalsuccessdropped39– initial target IA treatment is less pronounced. While our fixed

45% (all vs. high quality studies) after adding similar studies in effects model showed a benefit of combination therapy for 12-

whichechinocandinswerethecomparator,butremainedsignifi- weeksurvivalinbothstudydesigns,theheterogeneityamongthe

cant.Moreover,althoughsalvagetherapyclinicaltrialsfoundno observational studies negated this when random effects were

benefit,theirqualitywaspoor. applied. Of note, when we restricted observational studies on