In Vitro Antifungal Activity of Ibrexafungerp (SCY-078) Against Contemporary Blood Isolates From Medically Relevant Species of Candida: A European Study

In Vi o An i ungal Ac i i y o
Ib exa unge p (SCY-078) Agains
Con empo a y Blood Isola es F om
Medically Rele an Species o
Candida: A Eu opean S udy
Guille mo Quindo
´s
1
*
§
, Ka he ine Mi anda-Cadena
1§
,Rosa ioSan-Milla
´n
1†§
,
Ka yna Bo o o-Esoda
2
,EmiliaCan o
´n
3
,Ma ı
´
aJose
´Lina es-Sicilia
4
, Axel Hamp ech
5
,
Isabel Mon esinos
6‡
, Anna Ma ia To o ano
7
, Anna P igi ano
7
, Ma xalen Vidal-Ga cı
´
a
8‡
,
C is ina Ma cos-A ias
1
, And ea Gu idi
1
, Fe an Sanchez-Reus
9
,Jesu
´s Machuca-Ba
´ cena
10
,
Manuel An onio Rod ı
´
guez-Iglesias
10
,Es ellaMa ı
´
n-Mazuelos
11
, Ca men Cas o-Me
´ndez
11
,
Ley e Lo
´pez-So ia
12
, Alba Ruiz-Gai a
´n
3
, Ma celo Fe nandez-Ri e o
3
, Dama is Lo enzo
13
,
Ja ie Capilla
13
,An onioRezus a
8
, Ja ie Pema
´n
3
, Josep Gua o
13
,JoanaPe ei a
14
,
Ce
´lia Pais
14
,O azioRomeo
15
, Guille mo Ezpele a
16
, Ne ea Jau egiza
17
, Da id Angulo
2
and Elena E aso
1
1
Labo a o io de Micologı
´aMe
´dica, UFI 11/25, Depa amen o de Inmunologı
´a, Mic obiologı
´a y Pa asi ologı
´a, Facul ad de
Medicina y En e me ı
´a, Uni e sidad del Paı
´s Vasco/Euskal He iko Unibe si a ea (UPV/EHU), Bilbao, Spain,
2
SCYNEXIS, Inc., Je sey Ci y, NJ, Uni ed S a es,
3
Ins i u o de In es igacio
´n Sani a ia, Hospi al Uni e si a io y Poli e
´cnico La
Fe, Valencia, Spain,
4
Resea ch G oup GC24, Maimonides Biomedical Resea ch Ins i u e o Co doba (IMIBIC), Depa men o
Mic obiology, Facul ad de Medicina y En e me ı
´a, Uni e sidad de Co
´ doba, Co
´ doba, Spain,
5
Uni e si y Hospi al Cologne,
Cologne and Ins i u e o Medical Mic obiology and Vi ology, Uni e si y o Oldenbu g, Oldenbu g, Ge many,
6
Mic obiology Depa men , LHUB-ULB, Ho
ˆpi al E asme, B ussels, Belgium,
7
Dipa imen o di Scienze Biomediche pe la
Salu e, Uni e si à degli S udi di Milano, Milan, I aly,
8
Se icio de Mic obiologı
´a, Hospi al Uni e si a io Miguel Se e ,
Za agoza, Spain,
9
Se ei de Mic obiologia, Hospi al de la San a C eu i San Pau, Ba celona, Spain,
10
A
´
ea de Mic obiologı
´a,
Depa amen o de Biomedicina, Bio ecnologı
´a y Salud Pu
´blica, Facul ad de Medicina, Uni e sidad de Ca
´diz, Ca
´diz, Spain,
11
Se icio de Mic obiologı
´a, Hospi al Uni e si a io de Valme, Se illa, Spain,
12
Se icio de Mic obiologı
´a, Hospi al
Uni e si a io de C uces and BioC uces Bizkaia, Ba akaldo, Spain,
13
Mic obiology Uni , Medical School, Uni e si a Ro i a i
Vi gili, Reus, Spain,
14
Cen e o Molecula and En i onmen al Biology (CBMA), Depa men o Biology, Uni e si y o Minho,
B aga, Po ugal,
15
Depa men o Chemical, Biological, Pha maceu ical and En i onmen al Sciences, Uni e si y o Messina,
Messina, I aly,
16
Se icio de Mic obiologı
´a, Complejo Hospi ala io de Na a a, Pamplona and Depa amen o de Medicina
P e en i a y Salud Pu
´blica, Facul ad de Medicina y En e me ı
´a, Uni e sidad del Paı
´s Vasco/Euskal He iko Unibe si a ea
(UPV/EHU), Bilbao, Spain,
17
Depa amen o de Fa macologı
´a, Facul ad de Medicina y En e me ı
´a, Uni e sidad del Paı
´s
Vasco/Euskal He iko Unibe si a ea (UPV/EHU), Bilbao, Spain
Backg ound: Ib exa unge p (SCY-078) is he newes o al and in a enous an i ungal
d ug wi h b oad ac i i y, cu en ly unde going clinical ials o in asi e candidiasis.
Objec i e: The aim o his s udy was o assess he in i o ac i i y o ib exa unge p and
compa a o s agains a collec ion o 434 Eu opean blood isola es o Candida.
Me hods: Ib exa unge p, caspo ungin, fluconazole, and mica ungin minimum inhibi o y
concen a ions (MICs) we e collec ed om 12 Eu opean labo a o ies o 434 blood
isola es, including 163 Candida albicans, 108 Candida pa apsilosis,60Candida
glab a a,40Candida opicalis,29Candida k usei,20Candida o hopsilosis,6
Candida guillie mondii,2Candida ama a,2Candida lusi aniae, and 1 isola e each o
F on ie s in Cellula and In ec ion Mic obiology | www. on ie sin.o g May 2022 | Volume 12 | A icle 9065631
Edi ed by:
Jose L. Lopez-Ribo ,
Uni e si y o Texas a San An onio,
Uni ed S a es
Re iewed by:
Hamid Badali,
The Uni e si y o Texas Heal h Science
Cen e a San An onio, Uni ed S a es
Ma ı
´a Guembe,
G ego io Ma año
´n Hospi al, Spain
*Co espondence:
Guille mo Quindo
´s
[email p o ec ed]
†
Deceased
‡
P esen add esses:
Isabel Mon esinos,
Labo a oi e/Biologie Clinique, CHU
UCL Namu , Uni e si e
´ca holique de
Lou ain, Godinne, Belgium
Ma xalen Vidal-Ga cı
´a,
Se icio de Mic obiologı
´aClı
´nica y
Con ol de In eccio
´n, Hospi al
Uni e si a io Basu o & BioC uces
Bizkaia, Bilbao, Spain
§
These au ho s ha e con ibu ed
equally o his wo k and sha e
fi s au ho ship
Special y sec ion:
This a icle was submi ed o
Fungal Pa hogenesis,
a sec ion o he jou nal
F on ie s in Cellula and
In ec ion Mic obiology
Recei ed: 28 Ma ch 2022
Accep ed: 19 Ap il 2022
Published: 16 May 2022
ORIGINAL RESEARCH
published: 16 May 2022
doi: 10.3389/ cimb.2022.906563
Candida b aca ensis, Candida ca enula a,Candida dubliniensis, and Candida
ke y . MICs we e de e mined by he EUCAST b o h mic odilu ion me hod, and
isola es we e classified acco ding o ecommended clinical b eakpoin s and
epidemiological cu o s. Addi ionally, 22 Candida au is om di e en clinical
specimens we e e alua ed.
Resul s: Ib exa unge p MICs anged om 0.016 o ≥8 mg/L. The lowes
ib exa unge p MICs we e obse ed o C. albicans (geome ic MIC 0.062 mg/L,
MIC ange 0.016–0.5 mg/L) and he highes ib exa unge p MICs we e obse ed o
C. opicalis (geome ic MIC 0.517 mg/L, MIC ange 0.06–≥8 mg/L). Modal MICs/
MIC
50
s (mg/L) agains Candida spp. we e 0.125/0.06 o C. albicans, 0.5/0.5 o
C. pa apsilosis, 0.25/0.25 o C. glab a a, 0.5/0.5 o C. opicalis, 1/1 o C. k usei,
4/2 o C. o hopsilosis, and 0.5/0.5 o C. au is. Ib exa unge p showed ac i i y
agains fluconazole- and echinocandin- esis an isola es. I adop ing wild- ype
uppe limi s, a non-wild- ype pheno ype o ib exa unge p was only obse ed o
16/434 (3.7%) isola es: 11 (4.6%) C. pa apsilosis, 4 (5%) C. glab a a, and 1 (2.5%)
C. opicalis.
Conclusion: Ib exa unge p showed a po en in i o ac i i y agains Candida.
Keywo ds: an i ungal es ing, an i ungal esis ance, Candida,ib exa unge p,SCY-078,EUCAST,
caspo ungin, mica ungin
INTRODUCTION
In asi e candidiasis (IC) is he mos common heal hca e-
associa ed in asi e mycosis, being a majo cause o human
mo bidi y and mo ali y. Candida albicans is he mos
p e alen e iology, bu o he species, such as Candida glab a a,
Candida pa apsilosis,Candida k usei (Pichia kud ia ze ii), and,
mo e ecen ly, Candida au is, a e inc easing causes o IC. These
eme gen species a e usually less suscep ible o cu en an i ungal
d ugs. Al hough Candida isola es displaying an i ungal
esis ance a e s ill uncommon, hey a e inc easingly epo ed
wo ldwide. The apy o IC is an unsol ed clinical challenge and,
o his eason, moni o ing an i ungal suscep ibili y pa e ns and
esis ance mechanisms is o u mos impo ance. Mo eo e , new
an i ungal d ugs a e needed as he numbe o a ailable an i ungal
d ug classes, and pa icula ly hose o o al adminis a ion, is
limi ed (A end up and Pa e son, 2017;Quindos e al., 2018;
Fulle e al., 2019;P alle e al., 2019).
Ib exa unge p ( o me ly SCY-078) is a semisyn he ic
i e penoid glycoside de i ed om en uma ungin, which is
s uc u ally di e en om echinocandins and o m a new class
o an i ungal d ugs called “ unge ps” ha s ongly inhibi ungal
1,3-b-glucan syn hase (Da is e al., 2020). E en ib exa unge p
and echinocandins sha e simila mechanisms o ac ion, and hei
binding si es o he a ge enzyme is no he same, esul ing in
e y limi ed c oss- esis ance (Jimenez-O igosa e al., 2017;
P alle e al., 2017). Ib exa unge p displays significan in i o
and in i o ac i i ies agains azole- and echinocandin- esis an
isola es o Candida species, including biofilm- o ming s ains
(Jimenez-O igosa e al., 2014;P alle e al., 2017;Schell e al.,
2017;Gamal e al., 2021).
Ib exa unge p aims o be he fi s o ally and in a enously
a ailable glucan syn hase inhibi o use ul in he ea men o li e-
h ea ening ungal in ec ions (Da is e al., 2020) as well as
supe ficial ones, such as ul o aginal candidiasis (Schwebke
e al., 2021;Sobel e al., 2022). Cu en ly, he e a e 13 lis ed
clinical ials o ib exa unge p, eigh o which ha e been
comple ed (h ps://ClinicalT ials.go /; accessed on Ma ch
8, 2022).
In he cu en s udy, we ha e de e mined he an i-Candida in
i o ac i i y o ib exa unge p, caspo ungin, fluconazole, and
mica ungin agains 434 Eu opean Candida blood isola es
analyzed in 12 Eu opean labo a o ies.
MATERIALS AND METHODS
Mic oo ganisms
In i o suscep ibili y o a collec ion o 434 Candida blood
isola es (2016–2018) om 434 pa ien s was de e mined a 12
labo a o ies om Belgium, Ge many, I aly, Po ugal, and Spain.
Abb e ia ions: ATCC,Ame icanTypeCul u eCollec ion;CBP,clinicalb eakpoin s;
DMSO,dime hylsul oxide;ECV,epidemiologicalcu o alues;EUCAST,Eu opean
Commi ee on An imic obial Suscep ibili y Tes ing; GM, geome ic mean; IC, in asi e
candidiasis; ITS, in e nal ansc ibed space ; MALDI-TOF, ma ix-assis ed lase
deso p ion/ioniza ion– ime-o -fligh ; MM, modal MIC; MIC, minimum inhibi o y
concen a ion; MOPS, mo pholinop opane sulpha e; NWT, non-wild ype; PK/PD,
pha macokine ics and pha macodynamics; QC, quali y con ol; UPV/EHU,
Uni e sidad del Paı

s Vasco/Euskal He iko Unibe si a ea; WT, wild ype; WTUL,
wild- ype uppe limi s.
Quindo
´s e al. An i-Candida Ac i i y o Ib exa unge p
F on ie s in Cellula and In ec ion Mic obiology | www. on ie sin.o g May 2022 | Volume 12 | A icle 9065632
Each labo a o y s udied i s own clinical isola es. The collec ion
included 163 C. albicans, 108 C. pa apsilosis,60C. glab a a,40
C. opicalis,29C. k usei,20Candida o hopsilosis,6Candida
guillie mondii (Meye ozyma guillie mondii), 2 Candida ama a
(Deba yomyces hansenii), 2 Candida lusi aniae (Cla ispo a
lusi aniae), and 1 isola e each o Candida b aca ensis, Candida
ca enula a (Diu ina ca enula a), Candida dubliniensis,and
Candida ke y (Kluy e omyces ma xianus). Addi ionally, 22 C.
au is om di e en clinical specimens we e e alua ed: Eigh
isola es we e om blood, se en om o al specimens, and 7 om
u ine (Ruiz-Gai an e al., 2017;Ruiz-Gai an e al., 2018). Isola es
we e iden ified by pheno ypic me hods, MALDI-TOF
(p o eomic me hod), and, when needed, in e nal ansc ibed
space (ITS) sequencing (geno ypic me hod) (Mi anda-Zapico
e al., 2011). C. pa apsilosis ATCC 22019 and C. k usei ATCC
6258 we e included as quali y con ol (QC) s ains. Re e ence
s ain C. albicans ATCC 64550 was also included as
ecommended by EUCAST o de ec ing a ia ion in
echinocandin ac i i ies. P io o es ing, each isola e was
cul u ed on o Sabou aud dex ose aga and/o CHROMaga
Candida medium (Bec on Dickinson, Spa ks, MD, USA) o
ensu e pu i y and iabili y. QC and e e ence s ain we e
included e e y es ing day and all hei esul s we e wi hin
published anges.
An i ungal D ugs and Suscep ibili y
Tes ing
All isola es we e es ed o in i o suscep ibili y o ib exa unge p,
caspo ungin, fluconazole, and mica ungin using he EUCAST
b o h mic odilu ion me hod (A end up e al., 2020a;A end up
e al., 2020b;EUCAST, 2020;EUCAST, 2021). The e e ence
powde o ib exa unge p was ob ained om he manu ac u e
(SCYNEXIS Inc., Je sey Ci y, NJ, USA). S ock solu ions we e
p epa ed in dime hyl sul oxide (DMSO), and he final ange o
ib exa unge p, caspo ungin, and mica ungin concen a ions es ed
was 0.008 o 8 mg/L excep o fluconazole, which anged om
0.125 o 128 mg/L. The EUCAST me hod was pe o med by using
RPMI 1640 wi h 2% glucose and bu e ed o pH 7.0 wi h 0.165 M
mo pholinop opane sulpha e (MOPS). Panels we e inocula ed
wi h a final s anda dized cell concen a ion o 0.5–2.5 × 10
5
cells/ml. Panels we e ead spec opho ome ically a 450 nm
a e 24 h o incuba ion a 36 ± 1°C. Al hough caspo ungin
p esen s excessi e in e -labo a o y a ia ion in minimum
inhibi o y concen a ion (MIC) esul s by he EUCAST b o h
mic odilu ion me hod (Espinel-Ing o e al., 2013), MICs we e
calcula ed o compa ison pu poses.
Da a Analysis
MIC alues we e de e mined as he lowes concen a ion o
an i ungal d ug ha inhibi ed 50% o g ow h compa ed o ha o
he g ow h con ol. Fo indi idual species o Candida o which
en o mo e isola es we e es ed, summa y desc ip i e s a is ics,
including MIC anges, modal MIC (MM) ( he mos epo ed
MIC), geome ic mean MIC (GM), MIC a which 50% o he
isola es was inhibi ed (MIC
50
), and MIC a which 90% o he
isola es was inhibi ed (MIC
90
), we e calcula ed o each species
and d ug. High o -scale MIC esul s we e con e ed o he nex
highes concen a ion, and low o -scale MIC esul s we e le
unchanged. Epidemiological cu o alues (ECVs) we e used o
di e en ia e wild- ype (WT) (wi hou acqui ed esis ance
mechanisms) om non-wild- ype (NWT) (may ha bo
acqui ed esis ance mechanisms) isola es. Fo an i ungal d ugs,
such as ib exa unge p and caspo ungin, o /and species, such as
C. au is and C. o hopsilosis, wi hou EUCAST ECVs, WT uppe
limi s (WTUL) we e used as he suscep ibili y cu o alues and
MICs > 2 dilu ion s eps abo e he MM we e ega ded as NWT
(Table 1). Compa ison o e ficacy among an i ungal d ugs was
based on MIC
90
di e ences: Those an i ungal d ugs wi h a
di e ence o one double dilu ion we e conside ed o ha e a
simila ac i i y (Wiede hold, 2021). This compa ison should no
be conside ed absolu e, as o he pha macokine ics and
pha macodynamics (PK/PD) pa ame e s should be aken
in o accoun . The s udy was app o ed by he E hics
Commi ee o he Uni e sidad del Paı

s Vasco/Euskal He iko
Unibe si a ea (UPV/EHU, Bilbao, Spain, CEIAB E hics
e e ence numbe M30_2015_248).
RESULTS
MICs o ib exa unge p agains all species we e es ed in i o
anging om 0.016 o ≥8mg/L(MIC
90
2 mg/L). These alues
we e compa able o hose o caspo ungin and mica ungin (MIC
90
2
mg/L). The lowes ib exa unge p MICs we e obse ed o C.
albicans (GM 0.062 mg/L, MIC ange 0.016–0.5 mg/L, MIC
90
0.125 mg/L) and he highes ib exa unge p MICs we e obse ed
o C. opicalis (GM 0.517 mg/L, MIC ange 0.06–≥8mg/L,MIC
90
2mg/L)(Table 2). Echinocandins MIC alues o C. albicans
anged om ≤0.008 mg/L o 2 mg/L o mica ungin (MM 0.008
mg/L, GM 0.001 mg/L, MIC
90
0.016 mg/L) and om 0.016 mg/L o
2 mg/L o caspo ungin (MM 0.125 mg/L, GM 0.104 mg/L, MIC
90
0.125 mg/L). Fo he h ee isola es wi h ele a ed caspo ungin o /and
mica ungin MICs, ib exa unge p MIC ange was 0.06 mg/L o 0.25
mg/L. In he cu en epo , ib exa unge p MICs anged om 0.016
mg/L o8mg/L o 108C. pa apsilosis isola es (MM 0.5 mg/L, GM
0.660 mg/L, MIC
90
4mg/L)(Table 2). I we conside ib exa unge p
WTULs(>2mg/L)ob ainedin hiss udy,11C. pa apsilosis isola es
we e NWT (4.6%). These NWT isola es we e inhibi ed by ≤1mg/L
o fluconazole and by ≤4 mg/L o caspo ungin o mica ungin. We
also obse ed ha o six C. pa apsilosis NWT (5.6%) and wo
esis an isola es o fluconazole (0.9%), he MIC ange o
ib exa unge p was 0.5–2 mg/L. Acco ding o MIC90s,
ib exa unge p showed compa able alues wi h caspo ungin (MM
1 mg/L, GM 0.846 mg/L, MIC
90
2 mg/L) and mica ungin (MM 2
mg/L, GM 0.933 mg/L, MIC
90
2 mg/L). Mo eo e , wo isola es
esis an o mica ungin we e inhibi ed by 2 mg/L o ib exa unge p.
Ib exa unge p also displayed po en in i o ac i i y agains
60 C. glab a a isola es (MIC ange 0.016–8 mg/L, MM 0.25 mg/
L, GM 0.322 mg/L, MIC
90
1 mg/L) (Table 2). Six een C. glab a a
isola es esis an o fluconazole we e inhibi ed by ≤1 mg/L o
ib exa unge p. Among 9 C. glab a a isola es wi h ele a ed MICs
o caspo ungin o /and mica ungin, he MIC ange o
Quindo
´s e al. An i-Candida Ac i i y o Ib exa unge p
F on ie s in Cellula and In ec ion Mic obiology | www. on ie sin.o g May 2022 | Volume 12 | A icle 9065633
ib exa unge p was 0.25 mg/L o 4 mg/L wi h a MIC
50
o 1 mg/L.
I was no able ha whe eas he inc ease in MM be ween C.
glab a a WT and NWT isola es was 4- old o caspo ungin and
63- old o mica ungin, MM alues o ib exa unge p did no
inc ease (Table 3).
In i o ac i i y o ib exa unge p was also obse ed agains 40
C. opicalis blood isola es and MICs anged om 0.06 mg/L o ≥8
mg/L (MM 0.5 mg/L, GM 0.517 mg/L, MIC
90
2 mg/L) (Table 2).
Agains 14 C. opicalis esis an o fluconazole, ib exa unge p
MIC ange was 0.25–2 mg/L (MIC
90
1mg/L).
Mo eo e , ib exa unge p showed high in i o ac i i y agains
29 C. k usei (MIC ange 0.125–1 mg/L, MM 1 mg/L, GM 0.666
mg/L, MIC
90
we e 1 mg/L). MIC alues o mica ungin anged
om 0.03 mg/L o 0.25 mg/L (MM 0.125 mg/L, GM 0.122 mg/L,
MIC
90
0.125 mg/L) and om 0.25 mg/L o 1 mg/L o
caspo ungin (MM 0.5 mg/L, GM 0.465 mg/L, MIC
90
1 mg/L).
Addi ionally, all C. au is isola es we e esis an in i o o
fluconazole (MIC ≥128 mg/L) while ib exa unge p showed
ac i i y (MIC ange 0.5 mg/L o 8 mg/L, MM 0.5 mg/L, GM
0.753 mg/L, MIC
90
2 mg/L) (Table 4). C. au is u ina y isola es
showed highe MICs (da a no shown). Agains his species, he
ac i i y o ib exa unge p was simila o he ac i i y o mica ungin
(MIC ange 0.125–>8 mg/L, MM 0.125 mg/L, GM 0.377 mg/L,
MIC
90
4 mg/L) and 8- old mo e ac i e han caspo ungin (MIC
ange 0.25–>8 mg/L, MM 0.25 mg/L, GM 0.585 mg/L, MIC
90
>8
mg/L). Among six isola es wi h ele a ed caspo ungin o /and
mica ungin MICs, ib exa unge p MICs anged om 0.5 mg/L o
8 mg/L (MIC
50
0.5 mg/L).
MICs o ib exa unge p we e ≤1 mg/L o he 2 C. ama a
isola es and 1 isola e each o C. b aca ensis,C. ca enula a,C.
dubliniensis, and C. ke y (Table 5). Ib exa unge p MIC
50
was 2
mg/L o he 6 C. guillie mondii blood isola es wi h a MIC ange
om 2 o 4 mg/L, being wo old less ac i e han caspo ungin
o mica ungin.
DISCUSSION
The p esen s udy aimed o e alua e he in i o ac i i y o
ib exa unge p agains a collec ion o 434 Eu opean blood isola es
TABLE 1 | EUCAST clinical b eakpoin s (CBPs) and epidemiological cu o alues (ECVs).
Species An i ungal d ug CBPs (mg/L) ECVs (mg/L)
Suscep ible Resis an Wild- ype Non Wild- ype
Candida albicans
(n= 163) Ib exa unge p ––≤0.5 >0.5
Caspo ungin ––≤0.5 >0.5
Mica ungin ≤0.016 >0.016 ≤0.016 >0.016
Fluconazole ≤2>4≤0.5 >0.5
Candida au is
(n= 22) Ib exa unge p ––≤2>2
Caspo ungin ––≤1>1
Mica ungin ––≤0.5 >0.5
Fluconazole ≤2>4≤64 >64
Candida glab a a
(n= 60) Ib exa unge p ––≤1>1
Caspo ungin ––≤1>1
Mica ungin ≤0.03 >0.03 ≤0.03 >0.03
Fluconazole ≤0.001 >16 ≤16 >16
Candida k usei
(n= 29) Ib exa unge p ––≤4>4
Caspo ungin ––≤2>2
Mica ungin ––≤0.25 >0.25
Fluconazole ––≤128 >128
Candida pa apsilosis
(n= 108) Ib exa unge p ––≤2>2
Caspo ungin ––≤8>8
Mica ungin ≤2>2≤2>2
Fluconazole ≤2>4≤2>2
Candida o hopsilosis
(n= 20) Ib exa unge p ––≤8>8
Caspo ungin ––≤8>8
Mica ungin ––≤4>4
Fluconazole ≤2>4≤2>2
Candida opicalis
(n= 40) Ib exa unge p ––≤2>2
Caspo ungin ––≤1>1
Mica ungin ––≤0.06 >0.06
Fluconazole ≤2>4≤1>1
G ay shaded a ea: Po en ially non-wild- ype MICs > 2 dilu ion s eps abo e he modal MIC.
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´s e al. An i-Candida Ac i i y o Ib exa unge p
F on ie s in Cellula and In ec ion Mic obiology | www. on ie sin.o g May 2022 | Volume 12 | A icle 9065634
TABLE 2 | Summa y o ib exa unge p and compa a o s’in i o an i ungal ac i i ies agains blood isola es om medically ele an species o Candida.
Species/An i-
ungal d ugs
No. o isola es a MIC (mg/L) (Cumula i e %) To al MIC (mg/L)
≤0.008 0.016 0.03 0.06 0.125 0.25 0.5 1 2 4 8 16 32 64 ≥128 Range Mode GM 50 90
Candida albicans (n= 163)
Ib exa unge p 0 7 (4.3) 50
(35)
48
(64.4)
50
(95.1)
6
(98.8)
2 (100) 0 0 0 0 0 –– –163 0.016-0.5 0.125 0.062 0.06 0.125
Caspo ungin 0 3 (1.9) 7 (6.1) 38
(29.4)
100
(90.8)
8
(95.7)
4 (98.2) 1 (98.7) 1 (100) 0 0 0 –– –163 0.016-2 0.125 0.104 0.125 0.125
Mica ungin 82 (50.3) 79
(98.8)
1
(99.4)
0 0 0 0 0 1 (100) 0 0 0 –– –163 ≤0.008–2 0.008 0.001 0.008 0.016
Fluconazole – ––– 56
(34.4)
90
(89.6)
14
(98.2)
1 (98.8) 0 0 01
(99.4)
0 0 1 (100) 163 0.125-
≥128
0.25 0.226 0.25 0.5
Candida pa apsilosis (n= 108)
Ib exa unge p 0 6 (5.6) 0 1 (6.5) 3 (9.3) 10
(18.5)
38
(53.7)
24
(75.9)
15
(89.8)
6
(95.4)
5
(100)
0–– –108 0.016-8 0.5 0.660 0.5 4
Caspo ungin 0 0 0 1 (0.9) 5 (5.6) 3 (8.3) 26
(32.4)
51
(79.6)
19
(97.2)
3 (100) 0 0 –– –108 0.06–4 1 0.846 1 2
Mica ungin 3 (3.3) 2 (4.6) 1 (5.6) 0 0 5
(10.2)
15
(24.1)
32
(53.7)
48
(98.1)
2
(100)
00 –– –108 ≤0.008–4 2 0.933 1 2
Fluconazole – ––– 0 7 (6.5) 68
(69.4)
21
(88.9)
6 (94.4) 4
(98.1)
00 1
(99.1)
0 1 (100) 108 0.25-
≥128
0.5 0.698 0.5 2
Candida glab a a (n= 60)
Ib exa unge p 0 2 (3.3) 0 1 (5) 10
(21.7)
22
(58.3)
16 (85) 5 (93.3) 1 (95) 2
(98.3)
1
(100)
0–– –60 0.016-8 0.25 0.322 0.25 1
Caspo ungin 0 0 0 3 (5) 17
(33.3)
19 (65) 15 (90) 4 (96.7) 0 1
(98.3)
01
(100)
–– –60 0.06->8 0.25 0.280 0.25 0.5
Mica ungin 18 (30) 30 (80) 3 (85) 1
(86.7)
1 (86.7) 0 1 (90) 4
(96.7)
2 (100) 0 0 0 –– –60 ≤0.008-2 0.016 0.023 0.016 0.5
Fluconazole – ––– 0 2 (3.3) 4 (10) 1 (11.7) 11 (30) 6 (40) 12
(60)
5
(68.3)
2
(71.7)
6
(81.7)
11
(100)
60 0.25-
≥128
8 9.514 8 ≥128
Candida opicalis (n= 40)
Ib exa unge p 0 0 0 2 (5) 3 (12.5) 9 (35) 12 (65) 8 (85) 5 (97.5) 0 0 1
(100)
–––40 0.06->8 0.5 0.517 0.5 2
Caspo ungin 0 0 0 1 (2.5) 15 (40) 19
(87.5)
4 (97.5) 0 0 0 0 1
(100)
–––40 0.06->8 0.25 0.221 0.25 0.5
Mica ungin 1 (2.5) 7 (20) 24
(80)
7 (97.5) 0 0 0 1 (100) 0 0 0 0 –––40 ≤0.008-1 0.03 0.032 0.03 0.06
Fluconazole – –––1 (2.5) 8
(22.5)
9 (45) 6 (60) 1 (62.5) 1 (65) 0 0 2 (70) 12
(100)
040 0.125-64 64 3.364 2 64
Candida k usei (n= 29)
Ib exa unge p 0 0 0 0 1 (3.4) 2
(10.3)
10
(44.8)
16 100) 0 0 0 0 –––29 0.125-1 1 0.666 1 1
Caspo ungin 0 0 0 0 0 7
(24.1)
18
(86.2)
4 (100) 0 0 0 0 –––29 0.25 –1 0.5 0.465 0.5 1
Mica ungin 0 0 1 (3.4) 1 (6.9) 25
(93.1)
2 (100) 0 0 0 0 0 0 –––29 0.03-0.25 0.125 0.122 0.125 0.125
Fluconazole – ––– 0 0000004
(13.8)
18 (75.9) 5
(93.1)
2 (100) 29 16-≥128 32 37.828 32 64
Candida o hopsilosis (n= 20)
(Con inued)
Quindo
´s e al. An i-Candida Ac i i y o Ib exa unge p
F on ie s in Cellula and In ec ion Mic obiology | www. on ie sin.o g May 2022 | Volume 12 | A icle 9065635

o Candida. Ib exa unge p showed a po en in i o ac i i y
agains Candida, wi h MICs anging om 0.016 o 16 mg/L.
The lowes ib exa unge p MICs we e obse ed agains C.
albicans and he highes ib exa unge p MICs we e obse ed
agains C. opicalis Mo eo e , ib exa unge p also displayed
ema kable ac i i y agains fluconazole- and echinocandin-
esis an isola es.
Fi e species o Candida (C. albicans,C. pa apsilosis,C. glab a a,
C. opicalis,andC. k usei) cause mo e han 90% o IC (Quindos,
2014;A end up and Pa e son, 2017;Quindose al.,2018). C.
albicans emains he p edominan cause, bu he e is an e iden
shi in he e iology, and IC caused by o he species less suscep ible
o cu en an i ungal d ugs is becoming mo e equen (Fulle e al.,
2019;P alle e al., 2019). Echinocandins, such as anidula ungin,
caspo ungin, and mica ungin, a e conside ed fi s -line he apy o
IC because hey possess ungicidal ac i i y agains Candida (Gil-
Alonso e al., 2015a;Gil-Alonso e al., 2015b). Howe e , eme gence
o azole- and echinocandin- esis an [mul id ug- esis an (MDR)]
isola es has been epo ed o C. au is,C. glab a a,C.
guillie mondii,C. lusi aniae,andC. pa apsilosis (Lo hola y e al.,
2011;Peman e al., 2012;P alle e al., 2012;Alexande e al., 2013;
Pham e al., 2014;Dudiuk e al., 2017;Ruiz-Gai an e al., 2019;
To o ano e al., 2021). MDR Candida isola es complica e clinical
decision-making and a e associa ed wi h ea men ailu e and high
mo ali y a es (Lo hola y e al., 2011;Alexande e al., 2013;
Shields e al., 2013;Quindos e al., 2018;To o ano e al., 2021).
Ib exa unge p is a no el o ally bioa ailable semi-syn he ic
de i a i e o he e penoid en uma ungin ha inhibi s glucan
syn hase, dec easing 1,3-b-D-glucan polyme s and weakening
ungal cell wall (Jimenez-O igosa e al., 2014;P alle e al., 2017;
Schell e al., 2017;Da is e al., 2020). The cu en s udy ha has
e alua ed Eu opean blood isola es confi ms and ex ends he
obse a ions published in p e ious s udies (P alle e al., 2013;
Jimenez-O igosa e al., 2014;Be kow e al., 2017;La kin e al.,
2017;Ma cos-Zamb ano e al., 2017;P alle e al., 2017;Schell
e al., 2017;Nunnally e al., 2019;Gamal e al., 2021). Howe e ,
hese p e ious s udies ha e mos ly es ed Ame ican isola es. Ou
s udy wi h Eu opean isola es is in line wi h he conclusion ha
ib exa unge p displays po en in i o ac i i y agains he mos
clinically ele an species o Candida.
Ib exa unge p showed an excellen ac i i y agains he C.
albicans isola es included in he p esen s udy (MICs ange
0.016–0.5 mg/L). These esul s confi m p e ious findings by
o he au ho s, such as Jimenez-O igosa e al. (2014);Schell e al.
(2017),andMesquida e al. (2021), demons a ing ha
ib exa unge p showed ac i i y agains mos FKS-media ed
echinocandin- esis an C. albicans and agains azole- esis an
C. albicans.
Al hough he e a e no clinical b eakpoin s (CBPs) o ECVs
a ailable o ib exa unge p, he s udy by Mesquida e al. (2022)
as well as he p esen wo k ha e p oposed WTULs. The e a e no
di e ences in he p oposed limi s o C. glab a a (1 mg/L).
Howe e , ou s udy sugges s highe WTUL o C. albicans (0.5
mg/L s. 0.25 mg/L by Mesquida e al.), o C. pa apsilosis and C.
opicalis (2 mg/L s. 1 mg/L by Mesquida e al.), and o C.
k usei (4 mg/L s. 2 mg/L by Mesquida e al.).
TABLE 2 | Con inued
Species/An i-
ungal d ugs
No. o isola es a MIC (mg/L) (Cumula i e %) To al MIC (mg/L)
≤0.008 0.016 0.03 0.06 0.125 0.25 0.5 1 2 4 8 16 32 64 ≥128 Range Mode GM 50 90
Ib exa unge p 0 0 0 1 (5) 1 (10) 0 3 (25) 2 (35) 3 (50) 10
(100)
00 –––20 0.06-4 4 1.566 2 4
Caspo ungin 0 0 0 0 0 1 (5) 6 (35) 1 (40) 8 (80) 4 (100) 0 0 –––20 0.25-4 2 1.320 2 4
Mica ungin 0 0 0 1 (5) 0 1 (10) 5 (35) 10 (85) 3 (100) 0 0 0 –––20 0.06-2 1 0.756 1 1
Fluconazole – –––1 (5) 0 12 (65) 3 (80) 2 (90) 1 (95) 01
(100)
00020 0.125-16 0.5 0.783 0.5 2
Resis an isola es acco ding o EUCAST c i e ia o fluconazole and mica ungin a e highligh ed in bold ype. Accep ed and po en ially non-wild- ype MIC anges a e shaded o blood isola es wi h MICs > 2 dilu ion s eps abo e he modal MIC.
Quindo
´s e al. An i-Candida Ac i i y o Ib exa unge p
F on ie s in Cellula and In ec ion Mic obiology | www. on ie sin.o g May 2022 | Volume 12 | A icle 9065636
C. pa apsilosis is he fi s o second e iology o IC in China,
Japan, La in Ame ica, and he Medi e anean coun ies o A ica,
Asia, and Eu ope, such as I aly, Po ugal, and Spain (Quindos
e al., 2018). In he cu en epo , ib exa unge p MICs anged
om 0.016 mg/L o 8 mg/L. Ou esul s a e in acco dance o
hose by Ma cos-Zamb ano e al. (2017). In bo h s udies,
ib exa unge p displayed ema kably lowe MICs han
mica ungin agains C. pa apsilosis. Al hough Mesquida e al.
(2022) did no di e en ia e among C. pa apsilosis species
complex, hey also epo ed lowe MICs o ib exa unge p han
o echinocandins. These high MIC alues epo ed o
echinocandins agains C. pa apsilosis ha e been associa ed wi h
subs i u ions in he hs1 egion o FKS1 (Ga cia-E on e al.,
2008;Dudiuk e al., 2017;Ma cos-Zamb ano e al., 2017;
Mesquida e al., 2022). Schell e al. (2017) also epo ed lowe
ib exa unge p MIC
90
alues o 19 C. pa apsilosis blood isola es
(0.25 mg/L) compa ed wi h echinocandins, sugges ing ha
changes in FKS1 may no a ec he capaci y o ib exa unge p
o inhibi glucan syn hase in his species.
C. glab a a has inc eased i s e iological impo ance in IC in
Aus alia, Canada, he USA, and coun ies in Cen al and No he n
Eu ope, such as Belgium and Ge many (Quindos, 2014;T ou e
e al., 2017;Quindos e al., 2018). In ou s udy, ib exa unge p
displayed po en ac i i y (MIC ange 0.016–8 mg/L) also agains
fluconazole- esis an isola es. No c oss- esis ance has been ound
be ween ib exa unge p and fluconazole, as p e iously no ed by
Ma cos-Zamb ano e al. (2017). The incidence o echinocandin
esis ance in C. glab a a is gene ally conside ed low, app oxima ely
3%–4%, bu can be as high as 30% in specific ins i u ions
(Alexande e al., 2013;Pham e al., 2014;A end up and
Pa e son, 2017). In he cu en s udy, ib exa unge p MIC was ≤4
mg/L agains ou C. glab a a esis an o bo h fluconazole and
mica ungin. P alle e al. (2013) ound simila esul s o ou s bu , in
hei epo , ib exa unge p was 8- old mo e ac i e han caspo ungin
agains C. glab a a. Fu he mo e, ib exa unge p showed ac i i y
agains 31 C.glab a as ains wi h mu a ions in he hs o FKS1 o
FKS2 (MIC ≤2 mg/L) and agains 14 s ains esis an o bo h
caspo ungin and fluconazole. In a la e s udy by he same au ho s
(P alle e al., 2017), 20 ou o 25 FKS mu an C. glab a a isola es
(80%) we e NWT o one o mo e echinocandins, bu only six (24%)
we e NWT o ib exa unge p. Isola es o C. glab a a o which he
ib exa unge p MIC was > 2 mg/L (NWT) all we e NWT and ei he
in e media e o esis an o anidula ungin, caspo ungin, and
mica ungin. In ou s udy, 3 ou o 4 isola es po en ially NWT o
ib exa unge p we e inhibi ed by ≤1 mg/L o caspo ungin and one by
0.03 mg/L o mica ungin. Howe e , h ee o hese ou
ib exa unge p NWT isola es we e esis an o mica ungin.
Schell e al. (2017) e alua ed 34 echinocandin- esis an C.
glab a a isola es along wi h 34 pai ed con ol C. glab a a isola es,
obse ing ha ib exa unge p MICs o indi idual C. glab a a
isola es ended o be h ee o fi e dilu ions highe han hose o
he echinocandins. Howe e , ib exa unge p MICs ended in
ag eemen wi h hose o he echinocandins. These au ho s
de ec ed ha C. glab a a isola es wi h FKS1 o FKS2 mu a ions
o echinocandin esis ance we e inhibi ed by ≤4mg/Lo
ib exa unge p. Nunnally e al. (2019) also epo ed good
ib exa unge p ac i i y agains 89 C. glab a a isola es wi h FKS1
o FKS2 mu a ions ha con e ed esis ance o a leas one
echinocandin. Ib exa unge p MIC alues anged om <0.03
mg/L o 4 mg/L while caspo ungin and mica ungin MICs
anged om 0.03 o >16 mg/L and 0.008 o >16 mg/L,
espec i ely. In he s udy by Mesquida e al. (2022), an isola e
o C. glab a a ha displayed an ib exa unge p MIC o 2 mg/L
and echinocandin NWT pheno ype ha bo ed a mu a ion a
FKS2. The spec um o esis ance mu a ions ound in C.
glab a a sugges ed a pa ially o e lapping bu independen
binding si e o ib exa unge p ela i e o echinocandins on
glucan syn hase as hese d ugs a e s uc u ally dissimila and
in e ac di e en ly wi h he a ge (Jimenez-O igosa e al., 2014).
Consequen ly, his po en in i o ac i i y o ib exa unge p has
been epo ed agains C. glab a a isola es ha bo ing FKS1 and
FKS2 poin mu a ions ha cause echinocandin esis ance
(Ma cos-Zamb ano e al., 2017;P alle e al., 2017;Schell e al.,
2017;Nunnally e al., 2019;Mesquida e al., 2022). Mo eo e ,
TABLE 3 | MICs dis ibu ion o ib exa unge p and compa a o an i ungal d ugs agains echinocandin wild- ype (WT) and non-wild- ype/ esis an (NWTR) Candida spp.
Isola es.
Species Pheno ype (no. o isola es) Modal MIC (MIC ange) [mg/L]
Ib exa unge p Caspo ungin Mica ungin Fluconazole
Candida albicans WT (160) 0.125 (0.016–2) 0.125 (0.016–0.5) 0.016 (≤0.008–0.016) 0.25 (0.125–≥128)
NWTR (3) −(0.03–0.25) −(0.125–2) −(0.03–>8) 0.25 (0.25)
Candida pa apsilosis WT (106) 0.5 (0.016–8) 1 (0.06–4) 2 (≤0.008–2) 0.25 (0.25–≥128)
NWTR (2) 2 (2) −(1–2) 4 (4) −(0.25–4)
Candida glab a a WT (51) 0.25 (0.016–8) 0.25 (0.06–0.5) 0.016 (≤0.008–0.03) 8 (0.25–≥128)
NWTR (9) 0.25 (0.25–4) 1 (0.5–>8) 1 (0.06–2) 128 (0.5–128)
Candida opicalis WT (39) 0.25 (0.03–>8) 0.25 (0.03–>8) 0.5 (0.03–>8) 0.25 (0.03–16)
NWTR (1) >8 (>8) >8 (>8) 0.5 (0.5) 0.25 (0.25)
Candida o hopsilosis WT (16) 4 (0.06–4) 2 (0.25–2) 1 (0.06–2) 0.5 (0.125–16)
NWTR (4) 4 (2–4) 4 (4) 1 (1–2) 0.5 (0.5–1)
Candida au is WT (16) 0.5 (0.5–4) 0.25 (0.25–2) 0.25 (0.25–1) ≥128 (≥128)
NWTR (6) 0.5 (0.5–8) >8 (2–>8) 1 (1–>8) ≥128 (≥128)
Candida guillie mondii WT (5) 2 (2–4) 0.5 (0.5–1) 0.5 (0.5–1) 0.5 (0.5–64)
NWTR (1) 4 (4) 8 (8) 0.008 (0.008) 8 (8)
Fo an i ungals wi hou es ablished epidemiological cu o poin s, he poin s es ablished in Table 1 (shaded a ea) ha e been aken in o accoun .
Quindo
´s e al. An i-Candida Ac i i y o Ib exa unge p
F on ie s in Cellula and In ec ion Mic obiology | www. on ie sin.o g May 2022 | Volume 12 | A icle 9065637
he in i o e ficacy o ib exa unge p has been suppo ed by
success ul ea men s in mu ine IC caused by C. glab a a
esis an o echinocandins (Lepak e al., 2015;Wiede hold
e al., 2018). In a mu ine model o IC caused by C. albicans,C.
pa apsilosis,o C. glab a a using an o al he apy wi h
ib exa unge p, Lepak e al. (2015) demons a ed ha he AUC/
MIC was he bes pha macodynamics pa ame e p edic ing
clinical esponse. A MIC ≤1 mg/L ob ained by CLSI would
p edic a clinical esponse using o al ib exa unge p (Ma cos-
Zamb ano e al., 2017).
In Asia, C. opicalis was he second e iological agen o IC in
many hospi als om China, India, Singapo e, Thailand, and
Taiwan (Quindos e al., 2018). We obse ed ha ib exa unge p
MICs anged om 0.06 mg/L o ≥8 mg/L o 40 C. opicalis
blood isola es, which confi ms he consis en ly low
ib exa unge p MICs o azole- esis an C. opicalis epo ed by
Schell e al. (2017).Mesquida e al. (2022) ound mu a ions in he
FKS1 gene o wo NWT isola es o C. opicalis ha esul ed, in
bo h cases, in ib exa unge p MICs be ween 0.5 and 1 mg/L.
We obse ed high ac i i y o ib exa unge p agains 29 C.
k usei (MIC ange 0.125–1 mg/L). Schell e al. (2017) epo ed
ib exa unge p MICs o six isola es o C. k usei (MIC ange om
0.5 mg/L o 4 mg/L), which we e highe han hose o he o he
Candida species. These au ho s sugges ed ha a na u ally
occu ing uniden ified subs i u ion may be esponsible o he
educed ac i i y o ib exa unge p on glucan syn hase in C. k usei.
Howe e , i is unknown i his ansla es in o clinical ailu e.
In a ecen Spanish na ionwide s udy on candidemia, C.
o hopsilosis was he fi h mos equen ly isola ed species,
p eceding C. k usei (Peman e al., 2012). In he p esen s udy,
ib exa unge p showed good ac i i y agains 20 C. o hopsilosis
(MIC ange 0.06–4 mg/L). To ou knowledge, his is he fi s
s udy on in i o ac i i y o ib exa unge p agains C. o hopsilosis.
The lack o p e ious epo s in his ega d p ecludes compa ison.
Di e ences in ib exa unge p ac i i y agains he closely ela ed
species C. o hopsilosis and C. pa apsilosis highligh s he
impo ance o a co ec iden ifica ion o he Candida species
in ol ed in in asi e in ec ions.
C. au is is an eme ging pa hogen ha has been iden ified in
many coun ies associa ed wi h high mo ali y and a ma ked
abili y o de elop esis ance o mul iple commonly used
an i ungal agen s and o wi hs and s anda d in ec ion con ol
p ac ices (La kin e al., 2017;Ruiz-Gai an e al., 2017;Ruiz-
Gai an e al., 2018;Ruiz-Gai an e al., 2019). Da a om La kin
e al. (2017) show ha he C. au is isola es exhibi ed mul id ug
esis ance agains fluconazole and ampho e icin B. Mo eo e ,
some isola es also exhibi ed high MIC alues o o iconazole
and i aconazole. In he p esen epo , all C. au is isola es we e
esis an o fluconazole while ib exa unge p showed no able
ac i i y (MIC ange 0.5 mg/L o 8 mg/L). The in i o ac i i y
o ib exa unge p agains Eu opean C. au is isola es om ou
s udy was simila o ha desc ibed by Be kow e al. (2017) who
s udied 100 isola es o his species om Asia, A ica, and
Ame ica. O no e, in he cu en s udy, MM alues be ween C.
au is WT and NWT isola es inc eased 64- old o caspo ungin
and 4- old o mica ungin, whe eas MM alues o ib exa unge p
did no change. In e es ingly, ib exa unge p has been shown o
TABLE 4 | Summa y o ib exa unge p and compa a o s’in i o an i ungal ac i i ies agains 22 clinical isola es o Candida au is.
An i ungal
d ugs
No. o blood/any o igin isola es a MIC (mg/L) (Cumula i e %) To al MIC
≤0.008 0.016 0.03 0.06 0.125 0.25 0.5 1 2 4 8 16 32 64 ≥128 Range Mode GM 50 90
Ib exa unge p 0 0 0 0 0 0 5/16 (62.5/
72.7)
½ (75/
81.8)
½ (87.5/
90.9)
0/1 (87.5/
95.5)
1/1 (100) 0 –– – 8/22 0.5-8 0.5 0.753 0.5 2
Caspo ungin 0 0 0 0 0 7/16 (87.5/
72.7)
0 0 0/1 (87.5/
77.3)
0 0 1/5
(100)
–– – 8/22 0.25-
>8
0.25 0.585 0.25 >8
Mica ungin 0 0 0 0 6/13 (75/
59.1)
0/1 (75/
63.6)
0 ¼ (87.5/
81.8)
0/1 (87.5/
86.4)
0/1 (87.5/
90.9)
0/1 (87.5/
95.5)
1/1
(100)
–– – 8/22 0.125-
>8
0.125 0.377 0.125 4
Fluconazole 0 0 0 0 0 0 0 0 0 0 0 0 0 0 8/22
(100)
8/22 ≥128 ≥128 211.905 ≥128 ≥128
Po en ially non-wild- ype MIC anges a e shaded o blood isola es wi h MICs > 2 dilu ion s eps abo e he modal MIC.
Quindo
´s e al. An i-Candida Ac i i y o Ib exa unge p
F on ie s in Cellula and In ec ion Mic obiology | www. on ie sin.o g May 2022 | Volume 12 | A icle 9065638
be e ec i e in i o in he ea men o expe imen al in ec ions
wi h C. au is (Wiede hold e al., 2021).
Ib exa unge p was wo old less ac i e han caspo ungin o
mica ungin agains six C. guillie mondii blood isola es.
Acco dingly, Mesquida e al. (2022) also ound highe
ib exa unge p MICs o 12 C.guillie mondiiisola es, om
0.125 o 8 mg/L. Na u ally occu ing high echinocandins MICs
agains C. guillie mondii ha e been ecognized since hese
an i ungal agen s we e fi s in oduced p obably in associa ion
o subs i u ions in he hs1 egion o FKS1 (Dudiuk e al., 2017;
Schell e al., 2017). In addi ion, Schell e al. (2017) epo ed ha
ib exa unge p MIC anges o h ee C. lusi aniae blood isola es
we e 1 o 2 mg/L and ib exa unge p MICs o C. lusi aniae we e
h ee o fi e dilu ions highe han hose o he o he species o
Candida. Ib exa unge p MICs o he wo isola es o C. lusi aniae
(MICs 4 and 8 mg/L) es ed in he cu en s udy we e highe han
hose obse ed o he o he Candida species.
Aside om eme ging esis ance, an impo an limi a ion o
echinocandins is ha hey mus be adminis e ed daily by
in a enous in usion, po en ially p olonging hospi al s ays o
pa ien s unde going echinocandin he apy and limi ing hem o
inpa ien se ings in mos ins ances. O no e, W ing e al. (2018)
epo ed ha he isk o in e ac ions o ib exa unge p wi h
d ugs me abolized ia he cy och ome P450 amily o enzymes is
low. Ib exa unge p exhibi ed concen a ion- and ime-
dependen ungicidal ac i i y agains C. albicans,C. glab a a,
C. k usei,C. pa apsilosis, and C. opicalis in ime-kill cu e
s udies (Sco neaux e al., 2017). Mo eo e , ib exa unge p has
demons a ed e ficacy o IC in phase 2 and 3 clinical s udies
(Spec e al., 2019).
The cu en s udy demons a es ha ib exa unge p shows
po en in i o ac i i y agains Candida blood isola es and i s
ac i i y is compa able o ha o mica ungin. Ib exa unge p e en
exhibi s good ac i i y agains fluconazole- esis an Candida
isola es. Mo eo e , echinocandin- esis an isola es exhibi
ib exa unge p MICs consis en wi h hose o echinocandin-
suscep ible isola es. Howe e , di ec compa isons o
ib exa unge p MICs wi h hose o o he an i ungal d ugs should
be in e p e ed wi h cau ion, as di e en d ugs may p oduce di e se
anges o MICs and ye ha e equi alen clinical e ficacy because o
hei di e ences in bioa ailabili y and in PK/PD p ope ies.
Al hough P alle e al. (2013) epo ed >90% essen ial ag eemen
be ween bo h me hods, CLSI and EUCAST, he compa ison
be ween ou esul s and hose o Ame ican au ho s should
conside ha he EUCAST me hod ends o yield highe MICs
han CLSI, ega dless o he s udied species. Al hough he mos
clinically ele an species o Candida ha e been included in he
cu en s udy, i would be in e es ing o assess he ac i i y o
ib exa unge p agains addi ional species as well as mo e
NWT isola es.
In conclusion, we demons a ed ha ib exa unge p, a po en
inhibi o o glucan syn hase, could be an impo an acquisi ion
o he an i ungal oolbox o he he apy o pa ien s su e ing
om IC caused by MDR species, such as C. au is,C. glab a a,o
C. k usei. Conside ing he excellen pha macokine ic p ope ies
o ib exa unge p (o al a ailabili y and excellen issue
dis ibu ion and concen a ions) as well as he po en ac i i y
obse ed agains he main species causing candidiasis,
ib exa unge p should be ega ded as a po en ial candida e o
he he apy o hese impo an diseases.
DATA AVAILABILITY STATEMENT
The aw da a suppo ing he conclusions o his a icle will be
made a ailable by he au ho s, wi hou undue ese a ion.
AUTHOR CONTRIBUTIONS
GQ,KM-C,andRS-Mdesigned he esea chandpa icipa edin
manusc ip w i ing.KB-E,EC,MJL-S,AH,IM,AT,AP,MV-G,
CM-A, AG, FS-R, JM-B, MR-I, EM-M, CC-M, LL-S, AR-G, MF-R,
DL,JC,AR,JaP,JG,JoP,CP,OR,GE,NJ,DA,andEEconduc ed
sampling and clinical measu es, ca ied ou he expe imen s,
TABLE 5 | Ac i i ies o ib exa unge p and compa a o an i ungal d ugs agains o he species o Candida blood isola es.
Species Isola e e e ence MIC (mg/L)
Ib exa unge p Caspo ungin Mica ungin Fluconazole
Candida b aca ensis 18-3133B 0.25 0.5 0.016 4
Candida ca enula a 17-011 0.5 0.5 2 1
Candida dubliniensis 18-10677-2C 0.5 0.25 0.008 0.25
Candida ama a 17-012 0.5 1 2 0.5
Candida ama a 10-10647-1C 1 1 0.125 1
Candida guillie mondii 10-606-1C 2 1 1 1
Candida guillie mondii 17-23377-2C 2 0.5 0.5 0.5
Candida guillie mondii 17-25047C 2 0.5 0.5 0.5
Candida guillie mondii 17-341 2 1 1 64
Candida guillie mondii 17-014 4 0.5 0.5 0.5
Candida guillie mondii 17-324 4 8 0.008 8
Candida ke y 18-001 0.25 0.5 0.125 0.25
Candida lusi aniae 17-018 8 0.5 0.125 0.125
Candida lusi aniae 11-423-1C 4 0.5 0.06 32
Quindo
´s e al. An i-Candida Ac i i y o Ib exa unge p
F on ie s in Cellula and In ec ion Mic obiology | www. on ie sin.o g May 2022 | Volume 12 | A icle 9065639