l','

Hanagement and diagnostic guidelines for farngal diseases in infectious

diseases and clinical nnicrobiology: critical appraisal
S" Lentux and A.
J.
Ul l maan
Depdrtnent ofinterndl Medicinx ll, Urivenilotskiinikum,Juiirs lfraximilian's Universty. Wurzburg,6*rmany
&,lxxt,r:';e.t.
lflyasiye f**gai infections
{lFlsi
are life-rhreatcning conditions that reqaire rapid diagnostic and optimal management to miligate their high
marbid,ity and mortality rate. They are also associated wlth a high economic burden, owing to prolonged hc:g,ir*lizatron, the need for
i nren:i ve:uppor-ti ve care, and the consumpri a* ofcostl y new anti fungal agents. To adci ress these i ssues. several l nternati onal organi zati ons
have proposed gui del i nes for che managernenr of l Fl s, The consi stency and rel i abi l i ty r:f these gui del i nes have r-arel y been assessed. Thi s
areicle is a review of tha differences berween the recommendations of the Infeccious Diseases Society of America, rhe Fur.opean Conierence
on Infection in L ukaernia. and the luropean Sorlery a{ Cliniml Mie robioiogy and lnfecttous Diseases, and will focus on tergeted :rarmena
and di agncsti c procedures. ,{l though the concl usi ons of the three groups of experts are i n n:any poi nts si mi far we outl i ned $ome i mportanr
di fferences i n the methodal ogy and concl usi ons of SCl ' tl D- Ti re use of these gui del i nes has the porenti al to enhance the management of
fungal i nfecti ons but i s probabfy ctrr*ndy subopti rnal .
Keywor ds: Tr er i mcnt , Asper gi l i : : , C; r ndi da. Mucel nr ycosi s
Arti cl e publ l shed onl i ne: i i Ocrui rer 2013
{! i n f l 4i <r al t i ol l nf ect T0l 3: l 9r l l l S- i i 2i
Correspcndi ng ai rthpr: A.
J-
*i i ri a' rr )et:i , i nrnt *i i rl crral
I' l *di ci qr; l l ,3:ttzi ort ci l t{ec:rer: D;l errt:. U:l ' v;r5i gi l i kl ;ni (-rrr
Jrl i u:
l"1a(;rnitriajl's Uir i vr r: ity
$ixrdrirrbacier \tr . &
-
? / B8I
,dy'erri:rrg.
Cezary
E-rnail; andrew.ullman*@ani.w**rabr*rg.dr
in recent years, invasive fungal infecrion* (lFls) have enetged as
dn impomant cause of liG$iEiGiing inf.Iion. especialiy in the
con rexr ?t I m rnunos{rppresllfrTlFdi**
lreq*en tly in n oi -nEG*
tiop enTE-plEEi6lilli nffi th Gc-e q u i ri nd tie-at6-' o'it
i n 1 6
imensi\rF<art-vnirDespi?6thegibiit-rg-bodyo+evideni:eTn?--t
kiloFlEdge-m-tnii'tiel*)lna"mag;;,:sis
ry115rnunre.'*
"f
ltius e
--
: - -
- a- - . - ' - ' '
conrolex infecriSnJ remain challenging.
lnternaricnal guidelines
__--
4
6ISd on evidence-based
medrci;tc criceria that Lrave becn
p@qlFeq6"J@E-
..fu
ry1o-aeres.f
*ilt-u*-n-rc;3ii,r-ris.'rticle:tiriEuropeirn
Society of Clinical l"{icrobio}ogy
and iniectious Diseases
{ESCl"llD} [l*I,
the lnfecriaus Di;eases Society o{ Amtrica
{lDsA} t8,9i,
and the Europeai.'
Confcrence on lnfectien in
Leukaemi a
{FCI L} l l 0*13] '
The p' ese"' revi ew' ri rrs t o {i nd and
analyse the rjiscrepancies ijr dlii :'nEii6doloF.y ffib.l-elfcrrti
conclusions of these difelgggg$giine{or inva:ive candidiasis.
dspergifl63lI*and Gucormycosis. \A'e wili b?lEdlf-ffiii--*-
ffi_il;;cudu'ffi;l;;;t*un,
.86;.'*;;Axi;;;*;-
"dxcl ude
copi cs on combi nat i on t he, ' api cs anC orophyl axrs.
Children and rreonates were also considered in guidelines
provided by alre ESCMND and rhe IDSA
{par:iy
sur*r*arized l*
Table 3), but not in rhose provided by the ECIL, but review of
these would lead to this article xcedlng the spe*ified worei
Imic- There{fe, rhe pcopg of this co:roarison was vclungrily
, /
- _! aS: +4
restric' ,ed"lnd k is
fo;
an dxiy' usrive assessnlgrp-6f each
,#o*,o",/d"*on thrJugh out theith ree g,i deitrr{
<'
il..i:",l l.t;:rl1r
The d*veiopnent of guicielines shculd be a sranCrrrjrzed
Prscess, and rhe meihodoiogies u:ed by rhe three groups
to develop these recomrne ndations arll quire sinrii*i.
i ' l *i l The Arrl rom
CiitiGi lqicrob;clelv *itc hiqction 4,r-0,: European Str*ry *i Li,iri{a1 11,{tli}oic6y anii lrlcili61r$ }i-{crs*r
f llS Qinical Microbiology ond lnfeaion, Volume 19 Number 12. December 2013 l ' r i
T.+*:."$: i . Comparison of the methodologt and experts ovarlap
EC|L ESCr.ttD
IDSA
Populariar
5<oge
xgerr selcacn
EYiden* ,*ard
La3t
Isr
covered in seardh
l4eth6d6lsgt sd ich;rfint
of exgera is5e*tus
Expe ove.hp
Flliancal srppon
Adulr haem:rcioscl fralagnecter parieas ard
aduh l'l-5Cl recpins. aduit oon-nenropenic
peienF
{lcl.-Jt
Oiagnc$r pra(edu*
An.riu[al prophtlixls
lilvsiee a$pergillosit
lnvarivc Ca*didii5i!
l'1scarfi/fcri$
All guideli*s
ORTC, tBi,l?. LN, iCHS
l'ledhne. Pvb}4eC. CocF*re i-ibnry. Abstrac:
oi ASH, ICAAC, A5O, SCMID :nC 68l'47
ilinrr$d to i,'le 4 prer'leus
).Fa6i
?009
Oagi{iin$ort co*Binee dedner rtp}t aid
ffi!tr qlfir
Woddng goup$ {l-6 exp**l r*s rh
lic6tu.e md prapare :cemr*ndarion*upciat8
l'{*riog in ECll- wi{h g.wp cr*5rn5{r
Wi* SCl'llD : 15
Wirh lDi,q : ?
Experu ne*rgs i*plortd dYodgl:
eCs(ational gesE f'os Uooedical a.d
?hnrucettial sonparE5
Paed6ri
9f,risis.
HIV patiEnls. non-neesapeni<
ad!|. p{iieryB
{lCU}, adulr b#ftarolo6;at r.alittrencis
arrd crncrr patiens and adult i-ilifT aftd t0T:r?c,Fieni.:
DiaErciia predurst
Anti-candidi
a.dphfl3xii
Inqiye,candidiari!
Pl0cormycosir
C'rndidiaii:
EFISG, EBT,IT, ECCII4. EORTC. ESICI'
l'1uroffi).csir
Errsc. Ecct'l
Pub*ed
2Ci l
FISG deiiner clini(al queraon:" intenrioo e{
qh
r?co6msdrrio*! *d interyendot
Wor*io6 gro*p: reris. ihe lia.aavie and prerlare
vecofrmgtdraon$
inot:
likdture dambare
amilab, tg rhe wi:ole pael via FTP"lpvgri
2 MfttinEs rn the ESCf,llD C*fers66s qa
1
(ofttqcurve
/trg
wi{lt gro*p cils*arus
Note: Gadrng o{ dre SoR and QoE In Mo
teparac ei#tign
Pieiem$en in wcr*shop sessir, in ESCl"tlD, and
iocorporaEon of peins of dircu::ro
lxt*rnal p*r rexew
wi r& ECI L : i 5
\lJith IDSA : I
EsC''alD
Pae,Jialri( tateaB. Hlv
pqtls:e!. mn-ts!ryopqnic
adulr pais"*
ilCUl, adutr
hnemaralog;ci ma9gnarurcl
pN6,enB md aduh HSCT
and SOT-recipienn
ArriiunEal prophylaxt
ln%rive, chronic $d .ll ic
lorms of arpergillcis
lFsYe trbd;di$it
Cardidirdr
|DSA, SPCC
Asplgr!;ori!
lrhodollgl nEt driiled
Plbfied
20w
Candidrdrs
wrdiH
Expcr pand defines diriatj
q$ion5
Ail sperB reviry rne
lltntsrq dd r9ntrib0a{
ag * prpararrtn of
t}le rKammsd&ion
OelibmrfFi dsring
t I teleconierences
I taeto-{"rc fr*ring
ExterFl per rsview
Approved iry* IDSA S?GC
ud Boar<i of drwsr
Aspergitloss guldehntl
Metirodolcay sat dailled
'fr'{h ECIL; ?
With ESCMID: ?
IDSA
F&l'lT; Europs Group fw
glrcd
llarrow Trasphnrrtsl. CCt'l: rropm Csidsa*on ot l'led'sni iJyc?L"iy, Ell56: ESClllO Furyal lnlEs:1o:r Srrdy G.o*p- ELN; iurcpan
! e! . ' f ! aNe! , of TC: 8, ; r l g*ae0r gan413g6{or R*t l r ci and7r gr ment af l l <er "E5| c| . l : El r ooel n3cci er 7' f l 5i 9r r 9i veCar ei "! edi ct l e. }CH! ; | omwconpr cmi ' f $
:aiie*. O6E.
qurlr;y c! *iier,ce, SPGC StncarCs aild Pr'ri'i{{ Gcidelres tpmryitee, SoR rt.s?ab *f r*lor6?Fr?:rer.
i.t:. r1. .i. Fresentation of th diFernt grading eyrtems for the ctrengtft of rscommendation
Strergtt ot
rc6ffisndiddil EC,L until 1009 ESCI'tlD IDSAIECIL rince 2009
e
5ren6 eridsce lor {d;G{y .nd ribssiini
djtliei b*stia :rrongiy reammxded
Stro*g qr moCsate *ldere fr elficacl.
bnt ont limiled {!tnica, banifig gener*lly reccnnrenrjad
l$d$ddt *tde"e for effmy. or efirocy dcs m
auryejgb p#3lbte rdveria cnseq{cncs
ie,g-
dtug
to{i{itt dr hrtrectinsS! or c6r of clErcpropat/iaril
fir aldnailve approldps; sDaiaffii
l4e&Gi-*idilrc agei*t eitarcT cr lry adqsroq
d$tsffi: grefttlf 1 recotrfitr'ded
kro*g eidence agai*f effscy cr irr ldverte
ovtcffi: f)ffgr recqmnendgd
Erideoce lrsm at ist w
qell-qacgled
rundonirEd
yi{l
Evrdsce trom ai la+t orc
qell.dm8ned
ci;nie{ trai;
*itflout nndgmi?*m: colsn tr adGeorltrciiad
analy*cal s$dt$
{prefurably
fron :ncre thar
ore .entre : muir4Je sm6.sse! tudie$ tr
d.aftarit rtr!& fror uarontroiled expqsenln
Evid*<e
t*w gpiE
sr o{ rewceed aud}oriar:
b#d +ii t i6iet expefleilcs. deirr$tiye s*drer,
qr
tsFftg irffi
gxtn
conmilttrs
!3Cfi|fr ;ro*giy rlpponr n
lecontwdatre lcr uge
ESCfllO mpdearely rlpF c6
a rectnmgndagon ior use
ESC f'{lD *urginrlly *r99ac:
B retwandaaon igr u5e
i3Cf1l0;agpccr I
r<osBsrilr* aCa;f sr use
li.A
6rsj sidexe 6 lcgoorr a
caBfttrditrtr for or :gaire ure
rJodarae *ideace luppoE a
recffi|dttcn lor or ;tainsr l;e
Fcor widen<e rc lupfsi r
f6aqmmsn6ltoi
p.
t
Qu$ir7 ol rvid*<e
t
tl
!l
FlA
XA
lell EorcAeen Caoltrsrce cr tnlsrricr ir leskrmiij EgCf{lD. Edr*pe!.n Sastt it Ctjn(q} Mjc:ebiclcgr arrd h&<.ow! tbfi1 lD5A, Infe{ties 9be**: !*dey o{ Aner,:a
NA @t apelcal,le
' Addcdl c4ezproposedbyth,eE5Ctl l Pcol y*orl e;ci l l ItFi d${a;
r-se*-anttl ri ror:t*rmati crsrso:rodgni zed*rtr6l l Mtri ai 3i Lrrefme{i ri <1exz.z-e.r{*!l Btron
di f{e.e.' i padf!co| }0r3,o!-si ml | al i mf!F5farU55Jtl sti cc:i ]-{orF*qrl 8fc!pi :ah;' taf'
stfiFs$i}il cr f,Eertngl.
E2Ol3 The Agthort
Cltnktl Hicrcbiolop and lnf*tion '.4?O jl
Europss Society of Cliniml Plictobrolo$r and In{xtiouu O uu**. C}rtl, 19" I I 15- l l? l
x:'
'1.,
5, Leroux and A,
J"
Ullrnann l4anagement and diagnostic guidelines for fungal disea:es I i l7
Nevertheiess, there are some differences in term o{ob.}ectives,
scope. and editoriai choices" In particular, ii is irnportant to
note thar the ECIL group r'estricted its recommendations to
the group of patients with haematological diseases and io
,
__<- - _r . r _- - f f ' - _- __-
haematopoietic stem cell traFSlanr
{HSCT) .recipients.
There
ar<i ali6-Tofr'-e-imperani?lTcrepa$res-in-the- methodology
regarding the presentation of the srrength of the recornmen-
ditions-
lSatfrfabte n.
T#lOSa uss -a dtfee-category
s ystem ro. ra n k rts recomrybilaricfislTif ry*"*G *"p* o
by the ECIL group in its 2009 updae of its guidelines, replacing
the previous five-c*tegory slstem in
"_Se.-tgl1
;
different internationalguidelbes. The ESCMID proposed a
=-
four-category systern in--iG-Tefor"nmendations oR invasive
candidiasis in 20t2
{a
further rhree ESCXID guidelines, which
incorporate this ESCMID system of four categories, are in
development or have been submttted for publication). Tlereit-..-.*
a difference in the paradigm underlying this system in cDmpar-
_%_. _, _- - - *<- - - _ ___
iroq_v4ith the iDSA, The la*er mainly :erves the purpase of
- , _- . ' . ". _
ranking dre quality of evidence
{QoE},
which leads co the
recoTilgldgglsn3-8ede' The ESCMID systm, on th other
hand, aims at ranking che strength of the recommendations by
the interpretadon ef an international exprt group. brsed on
their analysis of che lirerarure, This diflerence seerls nrinimal,
but leads co very different conclusions in the case ol some much
debated issues
{e.g.
the application cf arnphoeericin S deoxy-
cholate). To further enhance the use of irs guidelines in daily
practlce, the ESCMID group defines
' inrention' for
each af its
recomrnendations
ithe
intervention). .According to the GRADE
working gfoLlp: ' Recommendations to administer, or not
adrninister, an inrervendon,' should be
' based
on the trade-offs
between benefits
pn
the one hand, and rtsks, burden and,
porentially, costs on the other.' lf benefits outweigh rishs and
burden, experts will recommend that clinicians offer a sreat-
rnefir ro rypical patienx. The uncerrainty associtted with rhe
trade-off beeween the benefits and risks and burdens will
determine the SoR
fi41"
The ESCI*ID tandida guidelines
follorryed slis
pdvice
for grading a recommendation, as the
QoE
by i*elf is usually not sufficient All three groups differentiate
oniy tirree instead of the four categories proposed by GFADF
to classify rhe QoE {high"
moderare, low, or very low}. The
authors of this articie think that lhree cacegories are sufficient
to provide evidence, es a. treast the ESMID
Qof
prcvides a
more detailed subcategorization
for level ll
Il].
eandidaemiadinvasive candidiasis l}1 hntaatetoglcal patients
r"i HSCT recipierts
The rnoss updated guideliner lar {cndida infectisns were
released by the IDSA in ?009
[8]"
the ECIL in 20il
liOl'
and
the ESCMID in }?tVtt--63{Tabie
3}. Fo..ggljgbslLixillg@5
with hleyratq,b&Sal.-salien.lincie$
o19., HSCT
:.,pi.":,:'
thu
recommendations for first.line antifungai therapy are relatively
consistenr in the three guicielines, with ec"hingg1fiy bsing the
drugs of choice. The ECIL group gives a more moderare
reiJmm"nAidon ior the uss olrhese agents, bygraclingthem Bll.
l-iposomal amphotericin B (LAmB' } is recommended as *
firstJine rherapy alternatiye wirh rhe same s{reng[h as echino-
candins by the !D5A and rhe ECIL
{respectively"
All and Bll}.
Owingto its increased toxiciry, the E5Cf'llD propores a weaker
recommendar.ion
{Bl
l}, despite no*-infericrity in comparison
with.glcal1tg9. The other lipid formutations of amphotericin B
are not considered in the IDSA guidelines, but the ECIL
recommends eheir use with ch same strngth as for iiposcmai
amgl"ro.g:_r-!cin B
{Btfi"
Owing to their toxicir/ profile and weaker
daabase, the fSCl"llD proposes these agen?s far second-line
treatment. with a C{l recommendation
{marginally
suppor$ a
recommendation for use) for amphorericin B lipid complex
iABLC)
and a Cill recornmendation forarnphotericin B colloidal
dispersion (ABCD). Fluconazole is no lojger considged to be a
first-line therapy optipn, The IDSA considers its use to be
possible in patients with mild to modei-ate disease and no prior
exposure co azoles
{Blll},
whereas the ESCMID advises thar it
should be reserved as a step-down rherapy opdon in case of
infecrion wirh susceptlble Candfdo species
{Cll}.
One of the rnain
differei' ices ccncerns ihe recornmendation on the use of
amphot' .lricin B deoxycholate: the ECIL considers irs use a: rn
option (Clil), unless there ig concomitant nephroroxic rnedica'
tion
{Dlll)
or renal impairment
{Elll);
the IDSA does not srate a
recornmendarion; anci the ESCMTD strongly recomnrends
against its use in adults. because o{ ics increased toxicity rn
comparison wirh rhe *ther, cleariy becter, therapy oprions
{Dll).
There is also a difference in recommendatiofls between
rhe ESCP4ID and the tlyo other grcups concerning the
follow-up str"tegy. The CSCHID recommends a s'nitch to an
The management of cenral venous catheters in the context
of ca*didaernia is iess scraight{orward in this population of
patiene thnn in non-neuropenic patients, owing to the
increased morbidiiy associared with carheter replacement.
The IDSA guideiines only srate that remov*l rhould be
considered for parients who have pei-sisent candidaemja
{Blll}:
the ECIL gives a similar recommendation
iBlil},
uniess
Candidc pordpsilosis is lnvolved, in which ca$e rhe authors
consider remoyal to be rnandatory
{All},
this species being
more frequently associaced with ca*reter*assoclated infec-
tions. Tha ESCI' {ID suppcr$ more clearly early carheler
removal
{All}
:f feasible, and the use oi echinocaldins
{or
iipo:omal arnphctericin BJ in cases of clinically recessary
9?Ci l ' fhe Asthaq
Clilifr! f'ltcrobtoi+gl and iriectior '$lfl !3 furopean SDrirry ol C,,ei(n, l"r,crabt3iDe, ;i
j
hkuous b,seses. (f,,ll,
19, , t I !- I 12 |
i ! {i
l l t S ctinicol Microbiolagy ond lnfeaion volume 19 Number 12, December 2013
Tt-S;-t i, ComParison
of the recommendations on the management of <andidaemia/invasive candidiasis
ct1-
ESCMTD IDSA
A*dung;l sscePcibili:t
tes;int
Theiapeuli( drsg
moii!oring
DiagFotis Prscedures
lnir!3l brgerEi rea!ftnt tn
tld hacmatoloticil
rotign*cie5 Padeq5
a{d
HSCT-rcipien6
lnillal h?Fred iGtftr- In
non-nettto9ecic Peitef,
15
bjid [argete]j :.eirj.!st n
4g:!Es
Cortb;f,qrioii rherdpY
to:raverut ctn.ler
rerwi
-; iilnirji dsnJcl
Follw'.9
Recmmended
h/
kk of
clinical relponse A ll
Recoreddd 10 suPPoft a
.han8e I inirial tlreaPY B ll
Recomm&d bfore a sirh
to onl n?ol A ll
NR
Blood cultures: thtrYi
reonrmendcd {no soR.l
t"lantiafi^nci-run3i;
For aod;daemia: C ll
for hcpamspleni: candiditsir: B lll
S-luor
For haeroiologicit Parienis
I ll
Caspofi.ngln I ll
l'4icatungio B ll
AnidllatutEin B ll
L-AnB B It
ABLC B tI
ASCD B II
Vorico$iole B ll
Flucomrle C lll
Am&d C [f
lwonarele NR
PolaconaPte NR
Caspolurgin I t
Anidultiungin A I
Mi(afungir A I
L.Am8 A I
An8-d A I
Flronaoll A It
Vskomzole A l'
ASLC A F
F*CD A Ii
1'66ep.11,i6 I'iR
Po5f,coiuoie NR
NR
Recommmd,:d {or rll Cr'dida
;(.ais isolrred Fon blooC
rnd oths oeP si6
{no
SoRl
Rccmruded t6t tvFe.ficial isohls in
ms of no-relgonle !o irslmeni
or relaF3es {no SoRi
Recqmeoded lor
(/a1tdc
Eidb.dta
{N SoRl
Reccmnre*ded bt Aiirire !9 rtFcnd E hriial
afirilcnsal *lsaPy lno 9oR)
Recori nmded i i azqi c
' et rt 8l ' e' 5
sson&l y
suspeaed inc soR,
Not recmmencjcd iel Cgnddo o/flffi
{f,o SoRt
gsaq66snfu lor vorrconaoie lnd Recommeoed ,cr vor:collzol and
poieooude and S-R.t (rc SoRt iv*rcnrzole ior
Patiss
wifi Ptelangac
F."io-*e"a"a for shiffiltdin; lor
Falionti
coursal {or deeP-selea! or rets'tory
with urc-corPorzl mombrane *ygeunon rat*iens
{no
SoRl
tECl'lOi
ino SoRi
Bl@d .!l!: asaadal iove:rigat s irc SoR) NR
H*naruamiqanna'
For ffdidaenit HofiNndcd ll
Fs rnvatrye onords$r: rct remmlwded
{na daai
Fgr heprtblPlenic @d;dinJit: recoatmended ll
j -Gl ucan:
For erdidaem;a: reffimetde4 ll
F*r irvu*e Gnddii$t!: recomended ll
Carpo{uogrn
A llr
ilicafungrn A llr
Aniduhfungt B ll(
L.AmB B ll:
V'oriconlzoie C llt
Fiuconarole C iltr
AELC C Ih
A"BCD c lll
Asgd D lii
lm<o$lola D ll!
Posaconaole D lll
Catpo{urgin A I
Aeidulafurgin
A. I
f4ictun6;. A I
L.AnrB B t
Vcriconazslq I I'
Flsconarolc C lid
ABLC C {a
.&nB-d D I
ASCD D ila
i i raccJi ul l e D l l a
P6.enelel {) il!
Am&d 1ml / k8l daYB! !
L-AmB 2.5 7 m6/[5ICrY B ll
FilcoFaz"lt l? fi{,ir,EldrY B li
Miriurrgin 4 i0 rr6'/kgldaY B ll
Cupofurgirr ?5 mtis:idaY C ll
ASLC C ll
A63- d' {i ur our c! *D
j
AmP- d- ! ' Fu9l t
Eiurgumab '
iipiC'asssr?ti aspibrsfti I D
l t
Nc*nadroPeric P*teil;
A llr
Haematoiog;.d PaEf,t5 A lla
Tlts r lm m S@d (rrltwa
P
day vnEr
aeedve B lll
Itin-nauuopeor sH6: lfat l4 dap aher
rin eqd o! ddidasmia B li
NeuaropeiiE piljffi; r# { learr '14 cay:
after last
Poltive
bicod cukwq if nerzopeno
penis! aPp.oPnate duqlid, aot delinei
{no
SoR)
TtrseesPtli6eal elrmdrognPhY B lla
FxCo:ccpy B ll
l! CvC. RCC or' itrff5(uttr dtri(s; *ryh
for rbmmbqr 3 ll!
Stepdovrl ro flu<on&ole aket echin@din
ala: it dayz R{ ,V, ;{ tFeci* i: ;ric*p;i9ic
pa*enl toiaE@ PO sd
Ptri.{rl
is sSle B ll
Ca?eiun8;n A ll
Hicafungio A ll
L-A$B A ll
Aaidulaiugir A l1l
Flucowole B li'
AmFd NR
ABIC NR
ABCD NR
l nconuol e NR
Pos3conarole NR
Vcrrcolazole NR
CarFofutgin A I
AnrClliiuneir A I
l4iBfuntc A I
L-A'sg A l"
Arg-d A I
Fl;.rccrsrole A I
Vorkrlaiof,e A I
l:racparzoic l-,jR
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ABLC NR
AtsCD r.lR
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L- Ar , Bl 5n8/ kgi c: vEl l
Fiv;lnazcle i? er8i!3rdry B ll
echinocaid,s B ltl
AALC NR
NR
liot-aaltrcpe.j<
Pat*
A ll
NeufoFnrc
Pidentsi
B lll
. 8i*d alures shilld be per{a'rud diily or
ryery efier dry
(no !oR)
fic'i-rcrsopenrc i'a daF rftet offi1e 9'
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Neuropsi patieo6: l 4 data ailry cl*nace
c{ Cardida from *c bloodstream rnd
resi&orr c{ the *ur*Penie i@ SoRl
Frtrde*opy (ic SoR,
Tissirioi fpq al xlinsndtn lo
tlg@md fry non'.*sPenic DrienE
t'41t
tar cclater iihel/ :c be :usceptible to
flvco{ruold A 1
r{R
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A ll
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Conddo ptzwilws int<dm A ll
;.ll# upt!@j situry f.i?
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Dt:itiY Hmd <uitrrg rnd wludd
6t 5ig:n5 and :YrPms B llt
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14 days afler
riie hrt F tiiive bload cult*re and
reolum or sitts rd !/npbrc wi
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krpoffi o{.tn acrive *arch {or
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'comr*'drrtitlt'
ib
tll ul coremiarr rephrctoxic dru8 tr{i E tll 9y renal knpaineGl
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u s?-down rnentt.
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;n r*rev ili p2tis$ ot i8
tai'-ffi
wit!:
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'lt or rn FtiqrE wtth prvsus arele prophvlaxr''
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tror' a maiority Yore
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be be$er rh?q erlr;ncaedlr5 agarnf C bofoFlcs:
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'g
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".rt;rrl.n
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palient sbbi: {A
'1i-
iCs$rdcqrron glvcf t F r tiidir-3ose ol 15 mg.rk8
rj :2013 Tbe Authcn
cliorcal f4icrob;ologt sd liferiion
.!:12013 EltoPean !dEt)/ of clinica! f'licrobioio6y and lnfcctlos! Di$eass'
(44'l' 19^ lllS-l l2l
l -t f r: 5. Leroux and A- j, Ullnr*n* l' lanagement and diag*osric guidelines for faagal diseases ,ll9
catheter retendon
{Cll}.
Th' s is also the only group rhat
proposes recommendations for the use of colony-stirnulating
fuctors
{granulocyre
colony-stimularing faccor). with a weak
recommendation
{Clll},
and granulocpe infusion, which might
be an opdon in desperate cases
{Clfli.
Caadidaemia/invas*ve candidiasis in non-neutropenic patients
In its guideline for patients withour neueropnia, the ESCMID
provides a slrong recommendafion
{Al}
fcr rhe us of all
echinocandins in conrparison with rhe lipid formulation of
amphotericin B
{Bl}
and voriconazole
iBl}.
whereas the ECIL
and the IDSA provide a strong recommendation for the use of
these alternatives. A main difference is rfiat rhe 9SCM|D
guideline does not {onsidr fluconazole to be an agent for
first.line therapy any more
iCl),
but rather as an oral srep-down
therapy oprion in cases of good respons to featment, owing to
its limited spectrum
{concerns
r*garding resistance) and infe-
riariry in a randomized study vs. anidula{ungin
ll2,
l5]. The
ESCt' llD dccumenl suts that fluconazole might be an oprion
{or C. poropsilols infect}ons because of uncerainry abour f,llCs.
Oiagnastic procedores
Only $e tClL in its 2009 update and the ESCI' ,IiD in 2012
rnarie recomrnendations for the di:gnosir of invasive candidi-
asi s and candi daemi a
{2, 1
l , l 3] . Convendonal di agnosuc pro-
cedures, srch as nricroscopic examination, sample and blood
culture, and identification to rh species lev[. are standardized
and {crm parr of daily clinical practice, but impcrtant decails
were surnff'arized. There v/as a need for recomrnendations
concerning the new non-cuiture-based techniqus. Regarding
ics orher reccmmendalians, the ECIL group limited irs analysis
ta the se$ing of patients with haematological rnalignancies and
HSCT reeipients. Never-c.heless, their conclusio*s are very
similar. The ESC1' 4tD moderately recornmnded the use of rhe
19-r-giucan
assay in ihe diagnosis cf inv;sive {t*didiasis,
carrdidaernia, and chronic disseminated candidiasis" and the
u$e af mannanlanli-man*an assays in the diagnosis of Lhe tws
lairer conditions. but not for invasive candidiasis, fcr both
neutropenic and intensive-care unit patients" The ClL alsa
moderarely rupports chese tests, with a lower st'-ength r3f
recomnrendaiioil fcr the rnan*anlanti-mannafi assfty i;r candi-
$emia {Cll}.
fgore6\,er, ahe SCM|D s{rggests the use of seriai
determination for the
li-*-glucan
assa7, and emphasires its
urilitT {or ruiing out iniections.
inva:lve aspergillosir
Guid*lines on the rnanagement oi irl sive aspergiliosis have
profited from data frorn randorrlzed trials witl * high quality ol
evidence. Thus, rbe two lnret-nationd guideline s proposed by the
IDSA in 2000 and r.rpdateC in 2009 {9i
and those of rhe ECIL
group published in 2005 and updated three rimes up to 2009 *re
very sirnilar for neutropenic p*tienrs and HSCT recipients
[
101.
The ESCXID is in rhe proceis of developing a
6r.rideline
on rhis
roPrc.
UbiguitousNy. voriconazole 5 mglkg rwice-daily and then
4 mglt<g twice-daily is rhe trcatmenr of choice, suppo!-red by
several randomized studies, with a srong recornmendarion (A1)
in both guidelines. The ECIL specifies that cherapy should begin
with tlre ineravenous form of voriconazole, owing to insufficient
pharmacokinetic data supporting ona! rhrail/
{oral
initiaricn
graded Clll). The iDS.A recommends beginning rherapy wirh rhe
parenteral formulation for seriolsly itl patienrs
{Atll),
Neither
gives any recommendation for the cilration of rhe parenteral
adminisradon or ttre overall duration of the therapy. The
recommendacions for diagnosis strategy. indication for surgery,
adiuvant trearment wich colony-stimulating factcrs, manage-
ment of immunosuppression and coiticosteroid therapy also
appear [o be verT similar.
/ - - . - - *- r
(
Mucormvcosis I
. l . .
Despite mucormycosis being rhe third most common rype of lFl,
there has been, unril recenrly, a lack of relqqlLgnde!.g1s on
diagnosis an!
1le
be1 m?Egg1gnr:The dara on rhe manage-
ment of these infecrions are scarce, and consist mainiy of case
series and experirnental studies. On r}* basis of this lierature,
rhe ECIL made recomnnendations in 7009
[i2]
and rhe ESCMIF
in ?013
[7].
Their conclusions are very sirnilar concerning
di*gnostic procedures, first.iine and salvage therapy, and
adiuncdve trearnnr, in particular rlre recommendation against
the use of the iron ehelarorde{erasir' nx and the starciryof dau in
favcui' of hyperbaric oxygen. and both guideiines ernphasize rh*
impcnance of surgery in synergy with antifr.rngal aher:apy and
the control of anderlying conditions (e.g. neutrcpenia *nd
diabetes). lt is imporrant r$ noce here *,at rhere is sone <w*rlap
of authors between ECIL *nd ESClvtlDguideline but basically for
patient! with h;errratoiogical malignancies, Only one poinr
differs significandy between rhe rwo documenls: rhe ECIL
considers that posaconazoie cannor be recomrnended for
first-line therapy (Clll), whereas rhe ESCMID conslders posa-
conazole ?00 mg four rimes daily or 48Q rwg wrice-daily as a
therapy option, albek with a weaker srrength af |ecommenda-
t i on t han f or l i posomal amphot eri ci n B (Bl l i . Thi s di f f erence i n
the strength sf recomme*dations is explain*d mainly by two
studies assessing the use o{ posaconazolr as first-line therapy,
which were published afrer rhe EC|L guideline*
[|
6. l 7l.
finaliy, we nore lhar rhe ESCMID discourages the use of
amphoterlcin B eieoxycholate. which is conEisten! wi*h the
discussions
drat took place regarding the managernenr of
candidiasis in aduhs
[1,7].
Sorrre iterns remain unresolved in
both guidelines, in prrticulr the lack of a clear duration or
.i ;201! The As:i prs
:iit,.al l'lixrnltolog{ and intat|icri ':t20ll furel'ctn S+iea r:f
r-li::i$l yr:rob.otcty
",id
In,n.r,o$ Dicca$r. &r*1. I
g.
i I i!,,,i t? I
a' r.l :
f f 20 clinicat Microbiolagy and lnfeaion, voiume 19 Number 12. December 2013
therapeutic
endpoint, but this is not
published data on this matter is rare.
Sil*r-;i:;*r*rl
too surprisinB
The IDSA, ECIL and ESCMID aim at providing evidence-based
internasional
guidelines for the diagnosis and treatrnent of lFls'
The clinical recommendalions
from the expert panels from
these three organizations
(two scientific societies
IESCMID
and IDSAI and one working group
fEClLl)
are, in impanant
respects, consistent.
and the fact that their conclusions are
similar enhances
their reliabiliry. Although the limited number
of expents and the overlap of authors temPer this observation
for the mucormycosis
guidelines. A maior difference is the
position of the ESCMID exPerc on the use of amphotericin B
deoxycholate
in adults. Their final decision is based on a
balance beween the accrued toxicity without additional
benefits and the cost incurred by the use of alternative agents
that they feel to be acceptable, at lea$ in Europe' They further
emohasize that the cost' effectiveness
of the different thera-
peutic and diagnostic
strategies are difficult to assess, because
of the diversity
of reimbursement syslems in Europe' and that
rheir guidelines should also be easily adapted ro local clinical
practice, wirh due respect ttr the local fungal e piciemiology and
econornic considerarions'
This also applies to the strong
rcommendation
on the use of echinocandins over fluconazole
in the first-line therapy of candidaemia.
Another
important issue is that the grading systms ar not
comparable,
The ECIL chose to modify it: grading system
during the lasc update of its guideline. which is now identical to
the IDSA' s. This makes comparison between the most recent
recommendations
of the ECIL and the IDSA easier' but may
make rhem more dificulr to understand and diflicult to use in
daily clinical
Pmctice.
On the other hand" the ESCMID tries to
emphasize
this aspect in the composition of their guideline by
defining clear patient
SrouPs'
and precise intervenrions and
inrentions for each recomrnendation,
and using a more definite
grading sy$em.
The ESCMID
"strength of recomrnendation"
system is the only one proposing the need for further research
if a grade C is applied to funher irnprove the scientific grounds
for a given intervention
IlJ.
Some studies have tried to assess adherence to the interna-
rionaf recommendations
and its consequences' ln their retro'
spective ntonocenlre srudy, Nivoix et ol.
[18]
evaluated the
adherence co the recomrnendations from the ECIL and the IDSA
for 199 antifungal treatments in 133 adults, and found a low rate
of appropriace
prescription (34%). The l2' week sun' ival race
was lower in the group of padents receiving inaPProPriate or
debatable treatrnent {70%
vs. 8 | %)' but nor significantly
{p
0' 24}'
.;201 3 T,re Alrhor3
Clirica:
plicrobaotcgy
aod lofeccion i1?0 | 3 Eur*pean Socisry of Clinrcal f'{i.roblology and lofectious Diseascs' C/"11. I 9. I I I 5-l 12 I
The very low rate of adherence to the
tui{ietines
in this study
could be attribuable to rhe very stringent
criteria
defining
' appropriate'
treatment. Another study, from Patel et ol'
[19]'
assessed not only the choice and dosage of antifungal
cherapy but
also the global adequacy of the management ol | 99 patients wirh
candidaemia wirh regtrd to the recommendadons
from the
IDSA. The therapy was consistenc with she gilidlines
in 76% o{
patients, and deviation frorn these recommendations
was
associated with increased mortality (24' Avs.57%'
p 0.003). ln
a recrospective multicen$e study, Pagano et o,L
[20]
observed
55% adherence to IDSA guidelines and28% adherence ro ECIL
guidelines in 136 padents with acute leul<aemia and proven or
probable invasive aspergillosis. The firstJine therapy response
rate was sQnificantly better in rhe group with adherence to the
I DSA
(7l %) and t he ECI L (84%) gui del i nes t han i n t he remai ni ng
patients
{respectively,
59% and 62%)' although no difference
could be seen regarding the rate ofsurvival at 120 days' lt is
imporrant to note that all of these studies cook only the IDSA
and ECI L gui del i nes i nt o accounl The ESCMI D gui del i nes have
not yet been assessed.
These results suppoi-t the utility of international updated
guidelines for the managemetrt of fungal infections but, at rhe
same dme, emphasize the low comPliance rate and the need to
enhance their acceptanre arrd usage in daily pracdce. These
resul * suppori rhe uri l i t y of i nt ernat i onal updared gui del i nes
for the management of fungai infections but in the same time
emphasize the low compliance rate and rhe need to enhance
their acceptance and usage irr the daily
Practice'
The reasons
undertying the lack of compliance to guidelines are multi^
facorial
[21]
but the adapration of international structural
guidelines to the lccal level, with integracion of prescribers inro
the process, is likely to enhance their diffusion and accepnnce
rate. Another argumenl to the adaPation to the local setcing is
the important geographical variatiorts in the epidemiology. !n
this, the role of the speciaiist in infectious disease seems to be
pivoral and the inclusion of antifungal stewardship in the
antimicrobial stewardship
Programs
rhe keys to an oPtimisa'
tion of the manaement of fungal diseases
[22].
To this respect'
the need of several international guidelines in different areas o{
the world mithc not be ehat questionable.
In the near future further collaboracion
rnight fitl rhe gap {or
streamlined recommendations. lt could resolve the problem of
the most debated and inconsistent
Poinrs
and harmonize the
grading system for the slrength of recommendation and quality
of evidence. thar are issues in the a.dherence
due to the
difficulty of comparing rhe current guidelines. The GRADE
working group could be a possibie solution. When focussing
on those differnces a real international guideline comes wirhin
the reach of a possibiliry. The main obstacies in the
deveiopment of such a guideline rernain, as stated in rire
st nce
(li.i
i 5. Leroux and A. j" Utlmann Managemerre and di*gnostic guidelines for fungal diseases I 12 |
introduction oi ESCI' 1lD recornrnenriaqions. rhe need ro creaft
a useful and comprehensive framework
g.hat
could be utilized
in local modified operating
Frocedures
by physicians and the
difficulry af balancirg rhe economic considerations and
complexity o{ national reimbursement syscem wirh recom-
nnendations based on sound eyiden.es frorn conrrolled clin;cal
trials. While cavering all aspects and opinion$ an internadional
guideline for all will remain a challeng*.
?ranrpaa' *i?cy Se*f erati&11
5. Leroux has no potential conflicts of interest. A.
J.
Ullmann
has received research gran* trorn MSD (Schering Ffou6hi, and
islwas an advisor or received lecture honoraria {rom Astellas.
Aicurir, Basilea. Gilead, MSD, and Pfizer.
&.ef*r*ne*s
l - ul l mann AJ, Cornel y OA, Donnel l y
JP
et dL ESCf' 1l D gui del i rre for dre
di agnosi s md management o{ {cndi da di se*ses 20l l deve}opi ng
European gui del i nes i n cl i ni c.:l mi crobi ol cgr and i nf*cti our di seases.
Clin !4r:mbiot rnfe* 7At2: 18: t-.8.
2, Cuenea-s:relh M" Vemeij Pt, Arcndrup YtC et. a!. ESCMID gprdrline
tcr the diagngsis and manag*ment al tandida di:eases 20 | 2: diagnasdc
procedures. Ctin Nirrabia] lnfea. ?*17: f *: 9 .
I 8.
3. Cornei y OA, Sasseti M, CaLandra T ec aL ESCl ' l l D gui del i ne for the
diagnosis and nranagement o{ tan'liCa distases: non'neirropenic adult
pari arrcs. Ci i n hl i 3obi ol tn{ea 201?l 18: l 9*37.
4. HoB* WW. Casagnol a i , Groi l AF1 et ol SCM| D gui del i r:e for the
dirgnosis ar:d tfre managcmtnt <){
(andid{!
di:eases 2012: prevenr;on
inc! managetrent ol ln{asine inifflion:i in neonaies and childrer caused
by Condida spp- Qin lAicraliai {n{e{t 7*l2t 18; 38-52.
5. L}llmann AJ, Akcva lo1, Herbrecht R et ci, ESClllO guidciinc far the
diagnosis and rhe nan:gernent of C*ndido diseases 2012: rdults wit$
h:rqatological malignancies and aiier haelTlatopoied{ iten cell tmfls-
plarruri*rr
\tllT|
$ut llticrrsbisi In{ect 2812: lfr: 53-67.
6. Lorrholary C, Perikkcs G. Akova M et sL ESCl"llD guiCeline {or che
dirgfio$i: ar:d rhe nanagenrent of {.sndids disesse$ ?C [2: pater$ wiah
l-{tV
jn{ertign
ar AIDS. {lin .44icrcbiol hfect 201?; l8: 6S-.77.
7. Cornely OA, Arikan-Akdagti 5, Dannaoui f ei di. ESC|'4|D and !CM|{
ioint
ciinical guidel'n$ {<rr tie di:gncsis anc ftanagernent. o{ mbco-
rfiy{csis. Clin Mictobiol tn{e{t 7Qt4l:2C lSupplement 2!- ln pr55,
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ths rnaoagernent sf caadidiasis: 2009 update by the Infecclous Oiseass
Society e{ America. Clin lnfect Ots 2009: 48: 503-535.
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cl,nical pracrice guideiinec of the ln'iecrious Diseases Sociecy o{
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J,
i'larchetti O, HerbrEche R et a{ Europan guide}ines fcr
ancifungal &anagemeffr in leukenia and hematopoiedr sre* cell
tran:plant recipients: summary o{ rfre ECIL 3*2009 update 6one
l+lanow Transplont 20 | | ; 46: 7A9*7 | L
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l homepage
i n
tlre inremet].
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Aniimrefob
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I L Patel |' 4, Kunz DF. Tri vedi VM,
Jones
f16. Moser 5A, Baddl ey
JW.
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