Expert Opinion on Pharmacotherapy

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ieop20

An overview of current and emerging antifungal

pharmacotherapy for invasive fungal infections

Scott W. Mueller, Sonya K. Kedzior, Matthew A. Miller, Paul M. Reynolds,

Tyree H. Kiser, Martin Krsak & Kyle C. Molina

To cite this article: Scott W. Mueller, Sonya K. Kedzior, Matthew A. Miller, Paul M. Reynolds,
Tyree H. Kiser, Martin Krsak & Kyle C. Molina (2021): An overview of current and emerging
antifungal pharmacotherapy for invasive fungal infections, Expert Opinion on Pharmacotherapy,
DOI: 10.1080/14656566.2021.1892075

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Published online: 21 Apr 2021.

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EXPERT OPINION ON PHARMACOTHERAPY
https://doi.org/10.1080/14656566.2021.1892075

REVIEW

An overview of current and emerging antifungal pharmacotherapy for invasive

fungal infections
Scott W. Mueller a,b, Sonya K. Kedziora,b, Matthew A. Millerb, Paul M. Reynoldsa,b, Tyree H. Kisera,b, Martin Krsakc
and Kyle C. Molinab
a
Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA; bDepartment
of Pharmacy, University of Colorado Hospital, Aurora, CO, USA; cDepartment of Medicine, Division of Infectious Diseases, University of Colorado
School of Medicine, Aurora, CO, USA

ABSTRACT ARTICLE HISTORY

Introduction: Invasive fungal infections (IFIs) remain a significant cause of morbidity and mortality Received 16 December 2020
despite significant advancements in currently available therapy. With a flush pipeline of investigational Accepted 15 February 2021
antifungals, the clinician must identify appropriate roles of currently available therapies, potential KEYWORDS
advantages of emerging antifungals, and shortcomings in the evolving clinical evidence. Antifungals; aspergillosis;
Areas covered: Standard and developing treatment approaches for IFIs with currently available anti­ candidiasis; invasive fungal
fungals are summarized with a focus on invasive candidiasis and invasive aspergillosis. Emerging infections; novel antifungal
investigational antifungals are discussed in depth, including mechanisms of action, fungal activity, therapies; pipeline; review
clinical evidence, and ongoing research. An opinion on the impact and potential role of therapy for
emerging antifungals of interest is also provided.
Expert opinion: Despite advances and clinical studies optimizing antifungal use, current therapies
fall short in preventing IFI morbidity and mortality. Further optimization of currently available
antifungals may improve outcomes; however, novel agents are required for historically difficult-to-
treat infections, transitions to oral treatment, minimizing adverse drug effects, decreasing drug
interactions, and ultimately improving patient quality of life. Emerging antifungals may positively
revolutionize the treatment of IFIs.

1. Introduction – invasive fungal infections

Invasive fungal infections (IFIs) are deep-seated or blood­
stream-disseminated infections affecting both immunocom­
promised and immunocompetent patients [1]. In the
intensive care unit (ICU), IFIs make up nearly 20% of micro­
biologically documented infections and primarily consist of
Candida spp. (~80%), followed by Aspergillus spp. (~10%) [2].
Although IFIs include Cryptococcus spp., dimorphic fungi,
Mucorales group, Pneumocystis jiroveci, and other hyaline
and dematiaceous molds, the majority of this discussion will
focus on invasive candidiasis (IC) and invasive aspergillosis (IA),
noting niche roles for new therapies in other IFIs. Additionally,
this review of therapeutic approaches will not address current
or novel approaches to diagnostics. For a recent publication
on diagnostics, we refer the readers to an excellent publica­
tion by the Mycoses Study Group and European Organization
for Research and Treatment of Cancer [3].
Associated mortality rates for IC (specifically candide­
mia) are approximately 25%, but can reach as high as
40–60% in the ICU population [4–6]. Although IA is often
associated with neutropenic and hematologic malignan­
cies, it has been increasingly recognized as a pathogen in
non-neutropenic hosts [7]. In some populations, where
triazole resistance exists, the associated mortality rate of
IA can exceed 80% [8–10]. Management of IFIs in these
complex patient populations is challenging with currently
available agents due to associated toxicities, drug–drug
interactions (DDIs), and the development of resistance [11].
Three drug classes (triazoles, echinocandins, polyenes)
account for the majority of guideline recommended back­
bone antifungal therapies for IFIs (Table 1) [12–20].
Amphotericin B (AmB), a polyene antifungal, is typically
used as an intravenous (IV) lipid formulation and demon­
strates a wide spectrum of activity, but is associated with
significant toxicities including nephrotoxicity, hepatotoxi­
city, and infusion-related reactions. In comparison to AmB,
triazoles are better tolerated and collectively provide
a broad spectrum of activity with oral formulations avail­
able. However, triazoles are associated with significant
DDIs and hepatotoxicity. Echinocandins offer fungicidal
activity against yeast and are well tolerated but are nar­
row-spectrum and lack oral formulations. We refer the
reader to an in depth review of current antifungal activity,
labeled and off-labeled use, and clinical pearls published
elsewhere [19]. To reduce the high mortality rates seen
with IFIs, novel antifungals which circumvent these

CONTACT Scott W. Mueller scott.mueller@cuanschutz.edu Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and
Pharmaceutical Sciences, Aurora, CO, USADepartment of Pharmacy, University of Colorado Hospital, Aurora, CO, USA
*
Co-first/lead author SWM and SKK
© 2021 Informa UK Limited, trading as Taylor & Francis Group
2 S. W. MUELLER ET AL.
Article highlights
● There is an unmet clinical need to address emerging antifungal
resistance among invasive fungal infections (IFIs).
● Significant advancements in the antifungal pipeline have resulted in
promising agents with unique mechanisms of action, improved for­
mulations, fewer toxicities, and drug–drug interactions compared to
many current antifungal therapies.
● Tetrazoles, specifically oral oteseconazole, VT-1129, and VT-1598,
have increased specificity for fungal CYP51 and the potential to
replace triazoles in many fungal infections (e.g., vulvovaginal candi­
diasis) as they are associated with minimal drug–drug interactions
and fewer adverse effects. Tetrazoles can preserve excellent activity
against some resistant IFIs and boast a broad spectrum of activity,
particularly with VT-1598.
● Rezafungin is a new echinocandin with an extended half-life allowing
for once weekly intravenous dosing while maintaining a satisfactory
pharmacokinetic/pharmacodynamic and safety profile against
Candida, Aspergillus and Pneumocystis spp.
● Ibrexafungerp is a novel oral and intravenous triterpenoid with
a broad spectrum and has shown promising efficacy in triazole and
echinocandin-resistant infections. In vivo and in vitro activity has been
demonstrated for the treatment of invasive candidiasis, invasive
aspergillosis and other fungal infections refractory to current stan­
dards of care.
● Encochleated amphotericin B, pending clinical efficacy studies, is en
route to be the first oral amphotericin maintaining a broad range of
activity against yeasts and molds with reduced toxicity compared to
intravenous formulations.
● Fosmanogepix is formulated for both oral and intravenous adminis­
tration against multidrug-resistant and difficult-to-treat infections
including Candida spp., Aspergillus spp., and rare molds. It has
a favorable safety profile and attains wide tissue distribution, making
it a viable future option for empiric treatment and continuation as
oral step-down therapy.
● Olorofim offers a unique mechanism by inhibiting fungal growth via
inhibition of dihydroorotate dehydrogenase. It has shown efficacy in
targeting Aspergillus spp. and rare molds, but is limited in its yeast
coverage. This agent has great promise as a targeted mold agent or
for salvage therapy in refractory or difficult-to-treat IFIs.
This box summarizes key points contained in the article.
limitations are urgently needed. This review provides an
update on antifungal treatment, focusing on new and
emerging agents and their place in therapy for IFIs.
2. Overview of current antifungal approaches
2.1. Invasive Candidiasis (IC)
In selected hospitalized populations, Candida spp. remains the
fourth most common cause of bloodstream infections [12
,21–23]. Current therapeutic strategies have been reviewed
in depth within the Infectious Disease Society of American
(IDSA) guidelines [12]. Echinocandins are recommended for
initial treatment in critically ill and neutropenic patients with
candidemia, and are effective for various IC infections with the
exception of central nervous system (CNS) and urinary infec­
tions. Lipid formulations of AmB are an option for echinocan­
din-resistant or refractory IC, or for deep-seated infection sites
where echinocandins lack adequate penetration. Stepdown
therapy to a triazole is possible once candidemia has cleared,
susceptibilities are confirmed, and clinical improvement is
observed (Figure 1).
Candida spp. have become increasingly resistant with
approximately 7% of bloodstream isolates demonstrating flu­
conazole resistance, the majority being Candida glabrata and
Candida krusei [6]. Voriconazole is an acceptable alternative for
voriconazole-susceptible isolates. However, its non-linear
pharmacokinetic (PK) profile is characterized by extensive
interindividual variability subject to CYP-2C19 polymorphisms
and coupled with significant toxicities (e.g., CNS, hepatotoxi­
city, periostitis, squamous cell carcinoma) can limit use [24].
Echinocandin resistance has also been rising within
C. glabrata, often leaving only toxic and poorly tolerated
alternatives [6,12,23].
The greatest concern among Candida spp. is the increasing
rate of resistant non-albicans infections [25,26]. Candida auris
is rapidly emerging globally as a multidrug-resistant (MDR)
yeast that has demonstrated an increase in United States
(U.S.) cases by over 300% in 2018 compared to 2015–2017
[22]. The Centers for Diseases Control and Prevention reported
that 90% of the isolates were resistant to at least one anti­
fungal, 30% were resistant to at least two, and approximately
4% of the isolates have been resistant to the three aforemen­
tioned drug classes [22,27]. Echinocandins remain a preferred
empiric therapy with antifungal combinations being required
in cases of MDR, unresponsive infections, or difficult-to-treat
sites [12,28]. Additional therapies for this increasingly resistant
pathogen with associated mortality rates of 30–78% in IC are
urgently needed [22,29].
2.2. Invasive Aspergillosis (IA)
Patient outcomes following IA remain poor despite clear
expert guidance for antifungal therapies targeting Aspergillus
spp. The IDSA Aspergillosis Guidelines recommend voricona­
zole for IA as a preferred therapy, with liposomal AmB or
isavuconazole as alternatives [14,30]. European guidelines
recommend either voriconazole or isavuconazole as initial
treatment for IA, but advocate for switching to liposomal
AmB if voriconazole resistance is suspected or confirmed in
Aspergillus fumigatus or in those unresponsive to initial mold-
active triazoles (Figure 2) [15].
Combinations of echinocandins and triazoles have
demonstrated synergy in vitro against many Aspergillus
spp. For difficult-to-treat IA, voriconazole in combination
with an echinocandin could be considered [14,15].
However, clinical trials with combination therapies have
not shown consistent clinical superiority over appropriate
triazole monotherapy [28,31]. In patients with hematologic
malignancies with IA, 6-week mortality was non-
significantly lower with voriconazole–anidulafungin combi­
nation compared to voriconazole alone (19.3% vs. 27.5%,
p= 0.087) [31]. Combination therapy may be useful for
patients with high fungal burden, suboptimal response to
monotherapy, or as salvage therapy, since high failure
rates have been reported in the treatment of IA with
echinocandin monotherapy [28].
Azole-resistance has also been increasing worldwide
[26,32]. Azole-resistant A. fumigatus (ARAF) threatens the
effectiveness of mold-active triazoles, which are currently
Table 1. Selected currently available anti-fungal drug classes [12,14,15].
Strategies for
Class Target Agents TDM (mg/L) Advantages Current limitations improvement
Triazoles Inhibit 14α-lanosterol ● Fluconazole Trough Levels ● Oral formulations ● DDIs ● Improved fungal
demethylase ● Itraconazole ● Well tolerated compared to polyenes ● Toxicities (hallucinations, hepatotoxicity, enzyme selectivity
● Voriconazole:
● Voriconazole ● Agent specific extended spectrum QT prolongationb) (CYP51)
● Posaconazole 1–5.5 ● Favorable pharmacokinetics, tissue, and ● Erratic absorption of some oral ● Optimize formulations
● Itraconazole:
● Isavuconazole CNS distribution (for many triazoles) formulations to improve absorption
1–4 ● Non-linear PK (TDM recommended for
● Posaconazole: itraconazole, voriconazole, posaconazole)
1–3.75
● Isavuconazole:
2–3a
Glucan Inhibit 1,3-βD-glucan ● Anidulafungin N/A ● Excellent activity against Candida spp. ● IV formulations only ● Oral formulation
Synthesis synthesis ● Caspofungin ● Fungicidal ● Once daily dosing ● Longer t1/2
Inhibitors ● Micafungin ● Wide spectrum ● Minimal distribution to CNS, urine ● Improved CNS distribu­
● Optimal safety profile tion
● Minimal DDIs
Polyenes Inhibit ergosterol binding ● Amphotericin B (deoxycholate, N/A ● Broad spectrum ● Toxicities (infusion reactions, ● Decreased systemic
to fungal membrane lipid, and liposomal formulations) ● Fungicidal nephrotoxicity, hepatotoxicity) toxicities
● CNS tissue distribution for most formu­ ● IV formulation only ● Oral formulation
lations

CNS: central nervous system; DDI: drug–drug interactions; IV: intravenous; N/A: not applicable; PK: pharmacokinetic; TDM: therapeutic drug monitoring; t1/2: half-life
a
Provisional target, TDM not universally recommended and may be unavailable
b
Isavuconazole is QT shortening
EXPERT OPINION ON PHARMACOTHERAPY
3
4 S. W. MUELLER ET AL.

Figure 1. Working framework of antifungal therapy for disseminated candidiasis with currently available agents as empiric therapy and possible roles for future
agents.
a) Clinically stable non-neutropenic patients. Preferred for C. parapsilosis, C. krusei is fluconazole resistant, and C. glabrata may have higher MICs or resistance to triazoles.
b) Echinocandins preferred empiric therapy for most including clinically unstable and/or neutropenic patients. C. parapsilosis has higher echinocandin MICs.
c) Lipid or liposomal AmB formulation is an alternative agent to those with first-line intolerance or suspected or proven resistance to other agents but is limited by toxicities. Liposomal
products are preferred in some scenarios. C. lusitaniae may be AmB resistant.
d) Clinical response good: Partial to complete resolution of clinical symptoms, clearance of cultures, decrease in fungal biomarkers (e.g., 1, 3 Beta-D-glucan) and improvement in radiological
data (>25–50% decrease in lesion size if available).
e) Clinical response poor: Minimal to no improvement on current therapy based on clinical, radiological, and microbiological data.
f) Clinically appropriate: Patient is clinically stable and tolerating oral.
g) Potential causes of poor response: Source control, PK/PD, inadequate dose/penetration to site of infection, failure to meet TDM targets, etc.
h) Often retains activity against triazole-resistant organisms, however, elevated MICs may occur.
i) APX001: No activity against C. krusei, higher MIC C. kefyr.
j) CAmB if AmB susceptible. AmB: Amphotericin-b; APX001: Fosmanogepix; CAmB: Encochleated amphotericin B; IBX: Ibrexafungerp; L-AmB: Lipid or liposomal Amphotericin-b product; PD:
Pharmacodynamic; PK: Pharmacokinetic; RZA: Rezafungin.

the preferred initial and only oral therapeutic options. The
Netherlands has documented increasing prevalence in ARAF
isolates from 2013 to 2018 (7.6% to 14.7%, p= 0.0001), and
although reports of ARAF are increasing in the U.S., they
remain relatively uncommon [22,33,34]. Importantly, mortal­
ity rates increase from 40% with susceptible strains to
a staggering 90% with resistant strains [35]. Triazole resis­
tance epidemiology, mechanisms, and detection in
Aspergillus spp. have been reviewed in detail elsewhere
[1,14,36].
2.3. Optimizing current triazoles
The increasing rates of ARAF and limited second-line
options for IA emphasize the importance of triazole use
optimization. This goal is complicated by extensive intra-
and inter-patient PK and pharmacodynamic (PD) variability;
therefore, therapeutic drug monitoring (TDM) to meet tar­
gets safely is paramount (Table 1) [37]. In clinical practice,
triazole trough concentrations are used as surrogate mar­
kers for area under the curve (AUC), the PD parameter
associated with improvements in clinical effectiveness
[38]. In situations of variable triazole susceptibility, choos­
ing an azole that can meet PK/PD targets through opti­
mized dose-escalation, without undue toxicity, may help
overcome elevations in minimum inhibitory concentrations
(MICs). Such approaches require close TDM and subse­
quent dose adjustments, which may be burdensome or
not available in all settings [39].
Posaconazole retains the most in vitro activity against
ARAF, and in vivo studies suggest that it may achieve PD
targets in isolates with MICs of 0.5 mg/L (European
Committee on Antimicrobial Susceptibility Testing
[EUCAST] breakpoint of 0.125 mg/L) [40,41]. There is inter­
est in augmenting posaconazole exposure to overcome
elevated MICs, which is supported by PK modeling
[23,41,42]. Ninety-percent target attainment (AUC0-24/MIC
≥167) was obtained with standard IV and delayed-release
posaconazole dosing at an MIC of 0.125 mg/L, but
a cumulative fractional response of <80% was predicted
for all simulated Aspergillus spp., except for Aspergillus
terreus. High-dose steady state regimens (200 mg twice
daily) may be needed to meet cumulative fractional
response PD efficacy targets for Aspergillus flavus,
Aspergillus fumigatus, and Aspergillus nidulans.
Additionally, a clinical case series suggests that troughs
>3 mg/L may be a reasonable target to overcome ARAF
infections [42]. More clinical data are needed, but TDM-
guided higher posaconazole exposures as a step-down
therapy (with or without an echinocandin) could improve
 EXPERT OPINION ON PHARMACOTHERAPY 5

Figure 2. Working framework of antifungal therapy for invasive aspergillosis with currently available agents as empiric therapy and possible roles for future agents.
a) Triazoles (voriconazole or isavuconazole) are preferred first-line therapy for most invasive aspergillus infections.
b) Combination triazole-echinocandin preferred empiric therapy if regional A. fumigatus triazole resistance >10% (some experts recommend if >5%). Synergistic combination trended
toward improved outcomes in some populations. Two weeks of combination therapy trended toward improved outcomes vs. triazole monotherapy among those with hematologic
malignancy and invasive aspergillosis, though some situations may require longer combination therapy (e.g., resistance).
c) Liposomal Amphotericin-b an alternative preferred empiric therapy if regional A. fumigatus triazole resistance >10% but is limited by toxicities. Not effective for A. terreus.
d) Clinical response good: Partial to complete resolution of clinical symptoms, clearance of cultures, decrease in fungal biomarkers (e.g., galactomanin) and improvement in radiological
data (>25–50% decrease in lesion size if available).
e) Clinical response poor: Minimal to no improvement on current therapy based on clinical, fungal biomarkers, radiological, and microbiological data.
f) ISA TDM controversial, target trough not set.
g) Clinically appropriate: Patient is clinically stable and tolerating oral.
h) Potential causes of poor response: Source control, PK/PD, inadequate dose/penetration to site of infection, failure to meet TDM targets, and so on.
i) VT-1598 as the tetrazole active against Aspergillus spp. Elevated VT-1598 MIC and resistance are reported for triazole resistant A. fumigatus.
j) CAmB if AmB susceptible. AmB: Amphotericin-b; CAmB: Encochleated amphotericin B; APX001: Fosmanogepix; IBX: Ibrexafungerp; ISA: Isavuconazole; LAmB: Liposomal amphotericin-b;
OLO: Olorofim; PD: Pharmacodynamic; PK: Pharmacokinetic; POS: Posaconazole; RZA: Rezafungin; TDM: Therapeutic drug monitoring.

outcomes in patients with ARAF with posaconazole MICs of
0.5 mg/L; however, aggressive dosing may incur additional
toxicities [39,43]. Similar PK simulations suggest that dou­
bling the standard dose of isavuconazole could achieve
90% target attainment for ARAF with MICs of 2 mg/L,
although more data are needed confirming safety at
higher dosages [44].
3. Emerging antifungals
Fortunately, promising novel antifungal agents and classes to
overcome drug resistance achieve adequate concentrations
at the site of infection and provide oral options for prolonged
treatment courses while minimizing toxicity and potential
DDIs, are in the pipeline. Ideal agents have high selectivity
for fungal cells, minimal off-target effects, and potent activity
against IFIs to decrease morbidity and mortality (Tables 2 and
3; Figures 1 and 2) [1].
3.1. Tetrazoles
Tetrazoles, like the triazoles, inhibit fungal cell wall synthesis
by preventing the conversion of lanosterol to ergosterol cata­
lyzed by 14α-demethylase. In contrast, tetrazoles bind fungal
CYP51 with much higher selectivity (>2,200-fold), largely
sparing mammalian CYP450 enzymes [45]. Such selectivity
could minimize CYP450-mediated DDIs and hepatotoxicity,
which limits current triazole use. Three tetrazoles under inves­
tigation will be discussed: oteseconazole, VT-1129, and VT-
1598.
3.1.1. Oteseconazole
Oteseconazole (previously VT-1161), is an oral tetrazole anti­
fungal currently in Phase 2 and Phase 3 clinical development
for the treatment of onychomycosis and recurrent vulvova­
ginal candidiasis (RVVC), respectively [46–49]. Oteseconazole
has potent in vitro activity against Candida spp. with geo­
metric mean MICs lower than that of compared triazoles [50].
It retains activity in many fluconazole-resistant C. glabrata
strains; however, experimental MICs increase with ABC-
transporter overexpression, suggesting that azole cross resis­
tance is possible [51].
Compared to fluconazole, oteseconazole showed non-
statistical improved efficacy for the treatment of VVC with
low mycological recurrence rates at 3 and 6 months [52].
The median reported half-life was on the order of months.
A Phase 2b placebo-controlled dose-ranging study sup­
ported low rates of 48-week recurrences when given weekly
for 11 weeks [53]. Active Phase 3 studies will provide more
definitive clinical data regarding oteseconazole 150 mg
6 S. W. MUELLER ET AL.
weekly for RVVC [47–49]. Oteseconazole has been granted
Qualified Infectious Disease Product and fast track designa­
tions by the Food and Drug Administration (FDA) and may
be the first tetrazole to receive FDA-approval (Table 4) [1].
3.1.2. VT-1129
VT-1129 showed in vitro activity against 31 Candida spp.,
including azole-resistant strains, in patients with chronic
mucocutaneous candidiasis [54]. An in vitro study tested VT-
1129 and oteseconazole activity against azole and echinocan­
din-resistant C. krusei (n = 50) and C. glabrata (n = 34) isolates
[55]. The MIC50 for VT-1129 and oteseconazole against C. krusei
were 0.5 and 0.25 mg/L, respectively, and 0.12 mg/L for both
agents against C. glabrata. Although clinical breakpoints are
not defined, all isolates were inhibited at concentrations
≤2 mg/L of VT-1129 and oteseconazole, again demonstrating
potency even in the setting of resistance.
VT-1129 may be especially useful against Cryptococcus
spp. It retained great activity against investigator labeled
“fluconazole dose-dependent susceptible” (n = 27) and
“resistant” (n = 6) Cryptococcus neoformans isolates with
MIC50 ranges of 0.05 and 0.25 mg/L, respectively [56]. This
is in comparison to fluconazole’s dose-dependent MICs
16–32 mg/L, and resistant MICs ≥ 64 mg/L. A murine model
demonstrated successful fungal burden reduction and survi­
val with VT-1129 compared to fluconazole and placebo
against C. neoformans [57]. VT-1129 showed 100% survival
with undetectable fungal burden more than 20 days after
regimen completion, whereas rebound fungal burden was
observed in the fluconazole arm.
3.1.3. VT-1598
VT-1598 is an oral agent with the broadest antifungal activ­
ity among the three investigational tetrazoles. It is active
against yeasts, molds, endemic fungi, and retains in vitro
activity against many resistant isolates, such as a variety of
Candida spp. (n = 175) and Aspergillus spp. (n = 134) [58].
The MIC50 for all Candida spp. were lower than that of
fluconazole. Specifically for C. glabrata, the MIC50/100 was
0.248/6.04 mg/L and it retained activity against many azole-
resistant strains, MIC50/100 1.19/>8 mg/L. VT-1589 has also
shown compelling in vitro activity for Aspergillus spp. with
geometric mean MIC ranges similar to posaconazole and
voriconazole for A. flavus (0.685 mg/L), Aspergillus niger
(1.78 mg/L), and A. terreus (0.533 mg/L). In wild-type isolates
of A. fumigatus, geometric mean MIC ranges of VT-1598
(0.25–2 mg/L) tended to be similar to that of posaconazole
and voriconazole. However, in ARAF isolates containing
CYP51A mutations, the MIC of VT-1598 significantly
increased (MIC100 = 13.3 mg/L) suggesting cross-resistance.
For C. auris (n = 100), VT-1598 had MIC ranges between
0.03 and 8 mg/L (mode 0.25 mg/L) with activity in fluconazole-
resistant strains and improvements in fungal burden similar to
caspofungin [59]. Future clinical and PK/PD studies will help
define the role of VT-1598 in the treatment of C. auris; how­
ever, current data suggests it retains activity in isolates with
reduced susceptibilities to currently available regimens.
Overall, the potency and activity against a broad array of
fungal species, including resistant organisms, and decreased
probability of DDIs, position tetrazoles as a promising new
antifungal class.
3.2. Glucan synthase inhibitors
Echinocandins are glucan synthase inhibitors which prevent
the biosynthesis of β-1,3-glucan, a key component of the
fungal cell wall structure [60,61]. There are currently three
FDA approved echinocandins for the treatment of candidemia
and IC: caspofungin, micafungin, and anidulafungin. Two glu­
can synthesis inhibitors are under investigation that offer
improved PK and PD profiles; rezafungin, a novel once-
weekly echinocandin, and ibrexafungerp a triterpenoid, glucan
synthase inhibitor with a differentiated structure and enzyme-
inhibition properties.
3.2.1. Rezafungin
Rezafungin (CD101, previously SP3025), is an IV echinocandin
under Phase 3 investigation for the treatment of IC including
candidemia and prophylaxis of invasive fungal disease in
patients undergoing allogeneic blood and marrow transplan­
tation [62,63]. Rezafungin has received Qualified Infectious
Disease Product and fast track status by the FDA for these
indications [1].
Rezafungin has enhanced stability, solubility, and pene­
trates difficult-to-treat sites, such as infected abscesses, but
like other echinocandins, it has limited CNS and urine
penetration [64,65]. Promisingly, rezafungin has
a prolonged half-life (~133 hours) allowing for once-
weekly dosing [64,66]. This offers an improved PD profile
through front loading, where rapid fungal killing is
achieved with high initial concentrations, especially in
hard-to-penetrate infectious sites, and may decrease the
potential for resistance development.
Rezafungin provides potent in vitro activity against
Candida spp. including azole-resistant and MDR strains
[67]. The in vitro activity of rezafungin was evaluated in
the SENTRY surveillance program, which included 1,904
Candida isolates collected worldwide between 2016 and
2018 [68]. Rezafungin had comparable activity to anidula­
fungin against Candida albicans (n = 835; MIC90 0.06 vs.
0.03 mg/L), C. glabrata (n = 374; MIC90 0.12 vs. 0.12 mg/L),
Candida tropicalis (n = 196; MIC90 0.06 vs. 0.06 mg/L) and
C. krusei (n = 77; MIC90 0.06 vs. 0.125 mg/L). Rezafungin
had greater in vitro activity against C. auris isolates (n = 16)
compared to caspofungin and micafungin, but equivocal
potency to anidulafungin [25,69]. Rezafungin demonstrated
similar activity to anidulafungin against A. fumigatus
(n = 183; MIC90 0.03 mg/L) and A. flavus (n = 45; MIC90
0.015 mg/L) [68].
A Phase 2, randomized, double-blinded, multicenter
study (STRIVE), compared IV rezafungin 400 mg once weekly
(400 mg; n = 81), rezafungin 400 mg on week 1 followed by
200 mg weekly (400/200 mg; n = 57), and caspofungin
70 mg once, followed by 50 mg daily (70/50 mg; n = 69)
for the treatment of candidemia and IC [70]. The overall
cure rate at day 14 was non-statistically higher in the reza­
fungin 400/200 mg weekly regimen (76.1%) compared to
400 mg weekly (60.5%) and caspofungin (67.2%). All-cause

mortality at day 30 was lowest in the 400/200 mg group
(4.4%) versus 400 mg (15.8%) and caspofungin (13.1%). The
safety analysis showed comparable rates of adverse events
across all arms.
Rezafungin is currently under investigation in multiple
Phase 3 trials. The ReSTORE trial is a non-inferiority study
comparing rezafungin 400/200 mg weekly to caspofungin
70/50 mg daily for the treatment of IC including candidemia
[62]. The ReSPECT trial is investigating rezafungin 400/
200 mg weekly in prevention of Candida, Aspergillus and
Pneumocystis infections in patients undergoing allogeneic
blood and marrow transplant (Table 4) [63]. Further clinical
data are needed to determine the role of rezafungin for
Pneumocystis prophylaxis or treatment, but murine data
appear promising [71].
3.2.2. Ibrexafungerp
Ibrexafungerp (SCY-078, previously MK-3118) is a novel, triter­
penoid, glucan synthase inhibitor currently undergoing late-
phase clinical trials (Table 4) [67]. It is being developed as both
oral and IV formulations, allowing for flexibility in dosing regi­
mens. In vitro and in vivo data have demonstrated potent
activity against MDR Candida and Aspergillus spp., and is cur­
rently being evaluated for IC and IA [72–74].
Ibrexafungerp is a substrate of CYP3A4 and a potential
inhibitor of CYP2C8 in vitro, but no significant DDIs have
been identified to preclude clinical use [75]. Unlike echinocan­
dins, ibrexafungerp achieves tissue concentrations several-fold
higher than plasma concentrations, which may be beneficial
for IFIs where high tissue penetration is required, such as in
the lung, liver, bone, or vaginal tissue [76]. Similar to echino­
candins, ibrexafungerp is unlikely to adequately penetrate the
CNS or urine, but is expected to have minimal off-target
effects limiting potential toxicities.
The in vitro activity of ibrexafungerp against wild-type,
azole-resistant, and echinocandin-resistant Candida isolates
compared to caspofungin and fluconazole revealed the fol­
lowing respective MIC90 values: C. albicans (n = 29; 1, 2,
≥128 mg/L), C. glabrata (n = 29; 2, 16, ≥128 mg/L), Candida
parapsilosis (n = 15; 0.5, 0.5, 64 mg/L), C. tropicalis (n = 21; 1, 1,
≥128 mg/L), and C. krusei (n = 19; 2, 1, ≥128 mg/L) [73].
Ibrexafungerp MIC90 was 8-fold lower than caspofungin for
C. glabrata strains, and remained highly potent in fluconazole-
resistant strains. In vitro activity of ibrexafungerp was also
compared against AmB and caspofungin for Aspergillus spp.
revealing the following respective MIC90 values: A. flavus
(n = 23; 0.12, 2, 0.03 mg/L), A. fumigatus (n = 21; 0.25, 2,
0.06 mg/L), A. terreus (n = 18; 0.12, 2, 0.06 mg/L), and MIC50
A. niger (n = 9; 0.06, 1, 0.03 mg/L) [74]. Ibrexafungerp’s
potency was not superior to caspofungin, but displayed ade­
quate activity to make it a viable option pending further
clinical research. Preliminary studies also suggest that ibrexa­
fungerp could be utilized in Pneumocystis based on a murine
and prophylaxis model [1].
Ibrexafungerp has in vitro activity against C. auris strains
(n = 122), including echinocandin-resistant isolates [77]. The
EXPERT OPINION ON PHARMACOTHERAPY 7
MICs for ibrexafungerp (0.06 to 2 mg/L) were comparatively
narrower than ranges for anidulafungin (0.03 to >32 mg/L)
and micafungin (0.016 to >32 mg/L). Of the eight echinocan­
din-resistant isolates with FKS mutations, ibrexafungerp had
MICs of 0.25 mg/L (n = 3) or 0.5 mg/L (n = 5). Currently
assessed FKS mutations have not affected ibrexafungerp to
the same degree as echinocandins, likely due to nonidentical
binding sites of action [78,79]. Similar MIC ranges have been
seen in other in vitro studies in C. auris isolates [72,78,80,81].
A Phase 2 study evaluated the safety and efficacy of ibrex­
afungerp therapy in non-neutropenic patients (n = 21) with IC
[82]. After an initial echinocandin treatment for 3–10 days,
patients were randomized either to oral ibrexafungerp
1000 mg then 500 mg daily (1000/500 mg; n = 6) or ibrex­
afungerp 1250 mg then 750 mg daily (1250/750 mg; n = 7)
and were compared to standard of care (SOC) (n = 8). Similar
rates of global favorable responses were seen across all treat­
ment arms, 1000/500 (71%), 1250/750 (86%) and SOC (71%).
No differences in adverse events were noted between the
groups. Population PK analysis demonstrated that the 1250/
750 mg dosing regimen achieved the greatest steady-state
target exposure, supporting this dose for further clinical
evaluation.
SCYNERGIA is a Phase 2 clinical trial evaluating ibrexafun­
gerp in combination with voriconazole versus voriconazole
monotherapy for the treatment of IA [83]. Ibrexafungerp dos­
ing is 500 mg orally twice daily for 2 days, followed by 500 mg
daily for a minimum of 6 weeks. Preclinical animal models
have shown lower pulmonary infarct scores and improved
survival. This combination was proven synergistic against
Aspergillus isolates (n = 51) from lung transplant patients [84].
FURI is a Phase 3 single-arm, open-label trial of oral ibrex­
afungerp in those with refractory IFIs or intolerant to SOC [85].
The hospital-based regimen is 750 mg orally twice daily for 2
days, followed by 750 mg daily for up to 6 months. At an
interim analysis, 83% (n = 34) of patients have experienced
a clinical benefit of either a complete or partial (56%; n = 23)
or stable (27%; n = 11) response [84]. The most common
adverse events were mild to moderate gastrointestinal (GI)
disturbances, which were generally tolerated.
CANDLE is a Phase 3 multicenter, randomized, double-
blinded study evaluating the efficacy and safety of oral ibrex­
afungerp in women with RVVC compared to placebo [86].
Patients with response to fluconazole for acute treatment of
VVC will be randomized to receive ibrexafungerp 300 mg
orally twice daily for 1 day or placebo. If they fail fluconazole
treatment, they will be enrolled in an open-label sub-study
and receive ibrexafungerp 300 mg twice daily until their acute
episode has been resolved. The primary endpoint is RVVC at
24 weeks of evaluation.
CARES is a Phase 3 single-arm, open-label, emergency pro­
tocol study assessing ibrexafungerp in those with IC or candi­
demia due to C. auris [87]. Ibrexafungerp is dosed at 750 mg
orally twice daily for 2 days, then 750 mg once daily for up to
90 days. Complete response has been reported in two patients
with candidemia following 17 and 22 days of therapy [88].
8 S. W. MUELLER ET AL.
3.3. Polyenes
AmB is an IV polyene antifungal that disrupts the integrity of the
fungal cell membrane by interacting with ergosterol, causing
cellular membrane leakage and releasing intracellular compo­
nents leading to cell death [60,61]. AmB retains broad fungicidal
activity, but tolerability remains poor despite various IV lipid
formulations. To circumvent these limitations, a novel nanopar­
ticle-based encochleated AmB has been developed as an orally
bioavailable polyene formulation [89].
3.3.1. MAT2203
Encochleated AmB (CAmB; MAT2203) utilizes a nanostructure
chelate allowing for water-insoluble or hydrophobic drugs to
be carried and delivered from the GI tract to the systemic
circulation. There it can undergo macrophagic endocytosis,
releasing the active drug to the fungal cell wall using macro­
phages for transportation [1,90]. CAmB has been granted FDA
fast track, Qualified Infectious Disease Product, and orphan
drug designations for the treatment of IC and IA, prevention
of IFIs in immunocompromised patients, and treatment of
cryptococcosis [1].
In vivo models suggest CAmB rapidly attains high con­
centrations in target organs such as the liver, spleen, and
kidneys [91,92]. Mice infected with C. albicans were treated
with oral CAmB 0.5–10 mg/kg/day or intraperitoneal AmB
1–2 mg/kg/day [92]. While all CAmB and AmB 2 mg/kg
dosing strategies resulted in 100% survival, tissue concen­
trations exceeded the MIC of 0.25 mg/L in the 10 mg/kg
CAmB group after 1–2 days versus 3–5 days for AmB. Tissue
concentrations with CAmB were maintained slightly above
the MIC, whereas AmB increased by 4 to 40-fold by day 15.
This suggests that CAmB can rapidly attain high concentra­
tions in targeted tissues, without accumulation, thereby
mitigating potential side effects or toxicities. In a murine
model of disseminated aspergillosis, CAmB at 40 mg/kg
attained 70% survival versus 20% in the intraperitoneal
AmB 4 mg/kg group [93]. Further, dose ranging studies
are warranted, but in vivo data are promising.
Phase 1 tolerability studies suggest that daily divided doses
of 1–2 g/day are tolerable, and doses of 1.5 g/day for a week
showed no renal toxicity in 9 patients [94]. A Phase 2 study of
patients with moderate to severe VVC evaluated the safety
and efficacy of CAmB (200 mg; n = 46 and 400 mg; n = 45) for
5 days compared to a single dose of fluconazole (150 mg;
n = 46) [95]. Clinical cure, mycological response, and overall
response rates were inferior with CAmB. Although GI side
effects were higher with CAmB (22–27%) compared to fluco­
nazole (9%), the lack of nephrotoxicity and hepatotoxicity after
a short course of therapy was importantly recognized.
EnACT is a Phase 2 prospective study investigating the
safety, efficacy and tolerability of CAmB for the treatment of
cryptococcal meningitis in approximately 140 HIV-infected
patients (Table 4) [96]. The study will be rolled out in four
phases and is planned to compare CAmB to SOC as stepdown
and initial therapy [1,96]. The primary efficacy endpoint at day
14 will assess the reduction in fungal cell counts measured by
cerebral spinal fluid studies, which is pivotal in providing CNS
activity data.
Although there is a high cost associated with manufactur­
ing cochleates and other potential limitations, the prospect of
safely delivering a highly active antifungal otherwise known
for toxicities orally to the site of active infection remains
attractive [90].
3.4. Glycosylphosphatidylinositol (GPI) inhibitors
In the novel class of GPI inhibitors, fosmanogepix (APX001) is
a prodrug of manogepix (E121) that inhibits the fungal
enzyme Gwt1 [97,98]. This leads to inactivation of GPI anchor
proteins thereby decreasing the integrity of the fungal cell
wall. This differentiated mechanism of action is specific to
fungal cells thereby limiting adverse effects to human cells.
3.4.1. Fosmanogepix
Fosmanogepix is a broad-spectrum antifungal with activity
against yeasts, such as Candida spp. (except C. krusei, poten­
tially Candida kefyr, but including C. auris), C. neoformans, and
Coccidioides immitis. Additionally, its activity extends to molds
such as Aspergillus, Fusarium, and Scedosporium spp. with less
potency, but in vivo activity against some of the Mucorales
group [97,99]. Fosmanogepix is currently in three Phase 2 trials
for IC, C. auris, IA, and is in pre-clinical status for
Cryptococcosis [1, 67].
Phase 1 clinical trials have shown excellent safety and
tolerability profiles along with superior bioavailability (>90%),
allowing for convenient IV to oral transitions [1,97].
Fosmanogepix has also shown adequate tissue penetration
into the brain, lung, kidney and eye, while clinically relevant
DDIs have remained low [100].
In vitro studies have shown equivocal to superior activity
of fosmanogepix compared to echinocandins and triazoles
[101]. The MIC90 values for fosmanogepix, anidulafungin and
voriconazole against Candida spp. are as follows, respec­
tively: C. albicans (n = 414; 0.008, 0.03, 0.015 mg/L),
C. glabrata (n = 321; 0.12, 0.12, 1 mg/L), and C. parapsilosis
(n = 270; 0.015, 2, 0.06 mg/L). Fosmanogepix was less active
against C. krusei (n = 43; >2, 0.12, 0.5 mg/L) and C. kefyr
(n = 12; 0.5, 0.12, ≤0.008 mg/L). Fosmanogepix activity
against Aspergillus spp. was comparable to anidulafungin
and more potent than voriconazole with these respective
MIC90 values: A. fumigatus (n = 182; 0.03, 0.03, 0.5 mg/L),
A. flavus (n = 18; 0.03, 0.03, 1 mg/L), A. niger (n = 23; 0.015,
0.015, 2 mg/L), and A. terreus (n = 10; 0.03, 0.03, 0.5 mg/L).
For C. auris isolates (n = 16), fosmanogepix MIC90 values
were 8-fold lower than anidulafungin (0.031 vs. 0.25 mg/L) and
>30-fold lower than voriconazole (0.031 vs. 1 mg/L) [102]. In
vivo data in a neutropenic mouse model (n = 5) showed that
intraperitoneal fosmanogepix 78 mg/kg three times daily had
significantly higher survival outcomes than intraperitoneal
anidulafungin 10 mg/kg twice daily (100% vs. 50%;
p= 0.034). Fosmanogepix maintained better CNS penetration
based on a 1.48 log reduction in colony-forming unit counts
after 48 hours of treatment (p= 0.005).
In a multicenter, open-label Phase 2 trial (SURGE), the safety
and efficacy of fosmanogepix were evaluated for first-line
treatment of candidemia in non-neutropenic patients

(n = 21) with suspected or confirmed antifungal-resistance
[103]. Patients were excluded if they were colonized with
C. krusei or had deep-seated candidal infections. Patients
were treated for up to 14 days with fosmanogepix 1000 mg
IV twice daily on day one, followed by 600 mg IV once daily,
which could transition to 700 mg orally once daily after day
two. Patients were able to stepdown to oral fluconazole ther­
apy if deemed appropriate. Preliminary data suggest an 80%
success rate with fosmanogepix with a favorable safety profile.
Several ongoing trials are evaluating fosmanogepix for
additional indications (Table 4). The APEX study is an open-
label, Phase 2 trial for IC and candidemia caused by
C. auris [104]. AEGIS is an ongoing Phase 2 study, recruit­
ing patients with IA or other invasive rare mold infections
(Scedosporium spp., Fusarium spp., and Mucorales) [105].
Fosmanogepix shows great promise for the treatment of
IFIs, especially MDR fungi including C. auris, with access to
a reliable oral option for ease of transition, good tolerabil­
ity without expected major DDIs, and penetration to diffi­
cult sites of infection where few therapeutic options exist.
3.5. Orotomides
Orotomides are a novel class of antifungals with a promising
agent in development, olorofim (F901318), which reversibly
targets the enzyme dihydroorotate dehydrogenase (DHODH).
This mechanism inhibits the biosynthesis of pyrimidine
thereby preventing fungal growth. The high degree of speci­
ficity and activity makes this a promising antifungal class for
resistant IFIs.
3.5.1. Olorofim
Olorofim’s activity is lacking against Mucorales, Candida, and
Cryptococcus spp.; however, it has great potency against
Aspergillus spp. including strains with reduced azole suscept­
ibility, and other difficult-to-treat molds such as Lomentospora
prolificans and Scedosporium spp [98,106]. Currently, both oral
and IV olorofim are in Phase 2 trials for Aspergillus and difficult
molds in patients with refractory disease, resistance, or intol­
erance to available agents. FDA breakthrough designation,
Qualified Infectious Disease Product status, and orphan drug
designation have been granted for olorofim in the manage­
ment of several invasive mold infections and coccidioidomy­
cosis refractory to or otherwise unable to be treated with
SOC [67].
Olorofim has a large volume of distribution (3 L/kg) and
a potentially therapeutic CNS distribution with repeat dosing
in mice [106]. Olorofim is >2200-fold more potent against
A. fumigatus DHODH compared to the recombinant human
enzyme, suggesting that it has reasonable fungal specific
mechanisms and an expected favorable safety profile [9]. For
healthy volunteers, multiple dosing studies showed no clini­
cally significant changes in vital signs, electrocardiograms, or
laboratory variables observed after 5 days. It has good bioa­
vailability (>45%) allowing for the development of both oral
and IV formulations with a half-life of approximately
20–30 hours [67]. Olorofim is an inhibitor of CYP3A4 and
EXPERT OPINION ON PHARMACOTHERAPY 9
a midazolam probe study concluded a weak inhibitory effect
on CYP3A4 [107].
Olorofim has excellent in vitro potency against azole-
resistant and difficult-to-treat Aspergillus isolates (n = 213).
Respective MIC90 values of olorofim, voriconazole, and anidu­
lafungin were: A. fumigatus TR34/L98H (n = 25; 0.125, >16,
0.031 mg/L), A. fumigatus TR46/Y121F/T289A (n = 25; 0.125
>16, 0.063 mg/L), A. flavus (n = 10; 0.063, >16, 0.031 mg/L),
and A. nidulans (n = 10; 0.125, 0.5, 0.063 mg/L) [108].
Olorofim’s activity was maintained in azole-resistant isolates
regardless of mechanism. Additionally, geometric mean MICs
were lowest for olorofim versus voriconazole (0.26 vs. 5.66 mg/
L) for 30 isolates of Lomentospora prolificans [109].
Investigations of inducing resistance in A. fumigatus via serial
passage and drug gradients required 40 passages before mod­
est increases in MIC were observed compared to as low as 10
with voriconazole, indicating a high barrier to resistance for
olorofim [9].
Olorofim is currently being evaluated in a Phase 2b clinical
trial (FORMULA-OLS) for patients with resistant IFIs and/or
those with limited therapeutic options (Table 4) [110]. This is
a single-arm, open-labeled trial in patients with IFIs due to
Lomentospora prolificans, Scedosporium, Aspergillus spp., and
other resistant fungi. Olorofim will be dosed according to
plasma levels to a maximum daily dose of 300 mg, possibly
indicating a role for TDM. The primary outcome will evaluate
overall clinical and mycological responses at day 42.
Outside this clinical trial, there are only case reports doc­
umenting success in disseminated lomentosporiosis and coc­
cidioidomycosis in humans [107]. Due to its niche spectrum of
activity, this agent will likely be reserved for identified or
strongly suspected mold infections, particularly those refrac­
tory to currently available options. In empiric situations, com­
bination with other therapies may be warranted to preserve
spectrum against yeasts and Mucorales until microbiological
confirmation can be obtained.
4. Conclusion
Current therapeutic options for IFIs are limited by variable PK,
toxicity, DDIs, and emerging resistance. Promising novel anti­
fungals are now being developed which offer extended spec­
trums of activity (Table 3), greater potency, more convenient
dosing formulations, and perhaps better tolerability with
fewer significant DDIs (Table 2). In cases of resistance or
difficult-to-treat IFIs, this pipeline may offer a reprieve from
clinical dilemmas currently faced by patients and providers. As
IFIs continue to impose a significant morbidity and mortality,
we must optimize our currently available agents even as
additional agents become available.
5. Expert opinion on novel antifungals
Not since the 1990s has there been a pipeline ready to change
the landscape of antifungals and the treatment of IFIs. The role
of these agents and best practices for each IFI will evolve
greatly in the years to come. We offer a framework and
potential roles in therapy for each of these agents to highlight
how transformative this age of new antifungals may be, even
10 S. W. MUELLER ET AL.

Table 2. Novel antifungals [1,61,67,69].

Class Mechanism of Action Agents Advantages Disadvantages Potential roles
Tetrazoles Inhibit lanosterol 14α- Oteseconazole ● Minimal DDIs ● Spectrum of activity ● RVVC
demethylase (CYP51) ● Oral ● Onychomycosis
● Prolonged t1/2
VT-1129 ● Minimal DDIs ● Targeted spectrum of ● Cryptococcal meningitis
● Oral activity
● Prolonged t1/2
VT-1598 ● Minimal DDIs ● Higher in vitro MICs ● Potential for MDR infections
● Broad spectrum observed for triazole (C. auris)
of activity resistant A. fumigatus ● Coccidioidomycosis
● Prolonged t1/2
Glucan Synthesis Inhibit 1,3-βD-glucan Rezafungin ● Once weekly ● No oral formulation ● Treatment or prophylaxis options
Inhibitors synthesis dosing ● Lacks activity: for IFIs
(prolonged t1/2) Mucorales, Fusarium ● Potential for MDR infections
● Minimal DDIs spp. (C. auris)
● Minimal AEs (no ● Limited CNS penetra­ ● Improved adherence
hepatoxicity com­ tion ● May retain in vitro activity against
pared to other some caspofungin resistant Candida,
echinocandins) unknown clinical relevance
● Extensive tissue
penetration and
distribution
Ibrexafungerp ● Oral and IV ● Lacks activity: ● Alternative in resistant or intolerant
● Minimal DDIs Mucorales, Fusarium therapies
● Minimal AEs spp. ● May retain in vitro activity against
● Extensive tissue ● Limited CNS penetra­ echinocandin resistant isolates
penetration and tion ● Oral/IV formulation may become
distribution first-line option for IC as initial or
● Broad spectrum stepdown therapy for in IC, IA, VVC,
of activity other refractory IFIs
Polyene Inhibit ergosterol Encochleated ● Oral ● Gastrointestinal AEs ● May not supersede IV therapy in
binding to fungal Amphotericin ● Less toxicity com­ ● Cost clinically unstable
membrane B pared to IV ● Stability ● Potential role in consolidation of
formulation therapy
● Minimal DDIs
Glycosyl- Inhibit Gwt1, GPI anchor Fosmanogepix ● Oral and IV ● No C. krusei coverage ● Potential for first-line treatment in
phosphatidylinositol protein synthesis ● Broad-spectrum ● Mixed Mucorales IFIs
inhibitor of activity activity ● Potential for MDR and difficult-to-
● Once daily dosing treat infections
● Minimal DDIs (No
significant
CYP3A4
inhibition)
● Minimal AEs
● Extensive tissue
penetration and
distribution
● Potential CNS
penetration
Orotomide Inhibit DHODH synthesis Olorofim ● Oral and IV ● Lacks activity: ● Mold targeted or salvage therapy
● Broad-spectrum Mucorales, Candida ● Lomentospora prolificans
of activity Cryptococcus spp. ● CNS coccidioidomycosis, but may
● Potential CNS ● Undergoes CYP3A4 require repetitive dosing and TDM
penetration metabolism/weak
inhibitor of CYP3A4,
potential for DDIs

AE: adverse events; CNS: central nervous system; DDI: drug–drug interactions; DHODH: dihydroorotate dehydrogenase; IA: invasive aspergillosis; IC: invasive
candidiasis; IFIs: invasive fungal infections; IV: intravenous; MDR: multi-drug-resistant; MIC: minimum inhibitory concentration; RVVC: recurrent vulvovaginal
candidiasis; spp: species; t1/2: half-life; VVC: vulvovaginal candidiasis; TDM: therapeutic drug monitoring.

if initial and empiric therapy for IC and IA remain unchanged
(Figures 1 and 2).
5.1. Tetrazoles
Tetrazoles offer many potential advantages over triazoles,
namely safety, tolerability, spectrum, potency and fewer DDIs.
VT-1598 offers a wider range of activity compared to oteseco­
nazole and VT-1129. This agent has superior in vitro activity
against resistant strains, such as C. auris, potentially broadening
its use as a first-line therapy for resistant yeast and mold infec­
tions pending clinical efficacy and safety data. VT-1129 is an
exciting future option for cryptococcal meningitis, especially for
fluconazole-resistant isolates. Tetrazoles will also be an attractive
 EXPERT OPINION ON PHARMACOTHERAPY 11

Table 3. Novel antifungal spectrum of activity [1,61,67,69,98].

Tetrazoles Glucan Synthesis Inhibitors Polyenes GIP Ortomides
Organism Oteseconazole VT-1129 VT-1598 Ibrexafungerp Rezafungin CAmB Fosmanogepix Olorofim
Candida spp. + + + + + +a +b -
C. auris + + + +c + -
C. glabrata + + + + + + + -
Cryptococcus spp. + + + + -
Pneumocystis spp. + +
Aspergillus spp. + + + +d + +
A. fumigatus + + + + + +
Rhizopus spp. + + - - +c ± -
Mucor spp. - - +c ± -
Fusarium spp. - - ±c + +
Lomentospora prolificans ± -c + +
Scedosporium spp. ± ±c + +
Scoulariopsis spp. +
Paecilomyces spp. + +
Trichophyton spp. +
Histoplasma spp. + +c +
Blastomyces spp. + +c +
Coccidiosis spp. + + +c + +
Talaromyces marneffei. + +c +
(+): has shown activity
(-): lacks activity
(±): has mixed activity or mixed activity in some species
()blank indicates: unknown activity at the time of publication
CAmB listed based on in vivo studies unless otherwise specified
Candida spp. includes C. albicans, C. krusei, C. lusitaniae, C. parapsilosis, and C tropicalis unless otherwise specified
Aspergillus spp. includes A. flavus, A. nidulans, A. niger, and A. terrus unless otherwise specified
a
Excluding Candida lusitaniae
b
Fosmanogepix lacks activity against C. krusei and higher MIC to C. kefyr
c
CAmB activity extrapolated from AmB activity
d
Excluding A. terreus
CAmB: encochleated amphotericin B; GIP: Glycosylphosphatidylinositol inhibitor; spp: species.

prophylaxis option where triazoles would otherwise be indi­
cated. Future superiority or non-inferiority trials and registries
comparing tetrazole efficacy and cost-effectiveness to triazoles
are needed to define their role in therapy. Tetrazoles may even­
tually replace triazoles in many indications.
5.2. Glucan synthesis inhibitors
Rezafungin offers enhanced activity against Candida,
Aspergillus spp., P. jiroveci, with a once weekly administration
that may ease transitions of care to an outpatient/home infu­
sion or accelerate discharge near the end of treatment. This
will be an improvement in care for patients requiring pro­
longed echinocandin therapy in cases of triazole-resistant IC
(e.g., endocarditis, osteomyelitis, etc.) or when triazoles are
nonpreferred. The front-loading regimen may improve blood
culture clearance in candidemia, but requires further study.
The role of rezafungin prophylaxis among hematopoietic cell
transplant recipients should soon be elucidated with the
ReSPECT trial, which is of critical importance given a shift
toward outpatient management, overlapping toxicities, and
significant DDIs between triazoles and current and emerging
cancer therapies. Rezafungin may mitigate some limitations of
commonly utilized pneumocystis pneumonia and antifungal
prophylaxis options in the acute setting. Pending positive
results, clinicians should consider the possibility of driving
echinocandin resistance and monitor the impact on this
class. Nevertheless, rezafungin has excellent activity against
Candida and Aspergillus and may maintain clinical effective­
ness for treatment of some FKS mutated Candida spp.
Like other echinocandins, rezafungin is IV only and has
limited CNS penetration. Pharmacoeconomic analyses will
play an important role in determining the cost-effectiveness
and role of rezafungin. By utilizing weekly outpatient infu­
sions, the economic impact of rezafungin may be favorable
for institutions and patients as this could facilitate rapid hos­
pital discharge and reduce unnecessary contact with the
healthcare system.
Of the emerging glucan synthesis inhibitors, ibrexafungerp
shows the greatest step-forward as both a treatment and
preventative option in IFIs. Its spectrum of activity remains
broad, maintaining coverage against echinocandin-resistant
Candida and azole-resistant Aspergillus, but similar to echino­
candins, it lacks activity against Mucor. Ibrexafungerp may
address unmet critical needs for resistant pathogens such as
C. auris as it maintains excellent in vitro activity even in strains
with elevated echinocandin MICs. A fungicidal agent with IV
and oral options that has excellent tissue penetration (except
CNS or urine) is an extremely attractive therapy to facilitate
transitions of care in similar situations as discussed for
rezafungin.
Ongoing clinical studies (CANDLE, CARES, FURI, and
SCYNERGIA) will hopefully soon define ibrexafungerp’s role in
therapy. FURI has already shown a clinical benefit and an accep­
table safety profile in patients with refractory IFIs or those intol­
erant to SOC. Clinicians should interpret these trial results in the
context of the difficult-to-treat patient population. We await
results of SCYNERGIA, testing a combination therapy with two
oral agents (ibrexafungerp plus voriconazole) for pulmonary IA,
which holds promise given in vitro synergy.
 12

Table 4. Novel Antifungals and Phases of Development [46-49,56-59,62,63,83-88,96,103-105,110]

Class Agent Clinical Phase Indication Intervention Outcome
Tetrazoles Oteseconazole Phase 2 Onychomycosis Oteseconazole 300 mg or 600 mg PO daily x2 weeks, then Clinical and mycological cure: Low and high-dose
once weekly vs placebo oteseconazole vs placebo (13.5%-28.1% vs 23.1%)
Phase 3 (ultraVIOLET) RVVC Part 1: Oteseconazole 150 mg PO daily x 2 days vs Culture-verified recurrence: Oteseconazole vs
S. W. MUELLER ET AL.

fluconazole Part 2: Oteseconazole 150 mg PO once fluconazole (5.1% vs 42.2%; p < 0.001)
weekly vs placebo
Phase 3 (VIOLET)* RVVC Oteseconazole 150 mg PO daily x7 days, then 150 mg Culture-verified episodes: No results posted, preliminary
Phase 3 (VIOLET)* weekly vs placebo reports suggest primary endpoint met (p < 0.001)
VT-1129 Phase 1 Cryptococcal VT-1129 in vitro and in vivo No results posted
meningitis
VT-1598 Phase 1 Candida auris VT-1598 in vitro and in vivo No results posted
Cryptococcal
neoformans
Coccidioides
Glucan Synthase Rezafungin (CD101) Phase 3 (ReSTORE) IC and candidemia Rezafungin 400 mg on week 1, then 200 mg weekly vs 30-day all-cause mortality and 14-day global cure
Inhibitors caspofungin
Phase 3 (ReSPECT) IFI prevention in Rezafungin 400 mg on week 1, then 200 mg weekly vs 90-day fungal-free survival
blood and marrow fluconazole 400 mg daily
transplant patients
Ibrexafungerp (SCY-078) Phase 2 (SCYNERGIA) IA Ibrexafungerp 500 mg PO twice daily x2 days, then 500 Primary safety outcome: SAE, discontinuation due to
mg daily in combination with voriconazole vs SAE, death Secondary outcome: global response at
voriconazole monotherapy end of treatment, day 42, and day 84
Phase 3 (FURI) Refractory IFIs Ibrexafungerp 750 mg PO twice daily x2 days, then 750 180-day global response:Interim analysis n=43 with
mg daily; single arm study complete/partial response (56%; n=23) or stable
(27%; n=11)
Phase 3 (CANDLE) RVVC Ibrexafungerp 300 mg PO twice daily for 4 weeks vs 24-week clinical success: No results
placebo
Phase 3 (CARES) Refractory IFIs Ibrexafungerp 750 mg PO twice daily x2 days, then 750 90-day global response: No results (2 cases reported
mg daily; single arm study successful)
Polyenes Encochleated AmB (CAmB; Phase 2 (EnACT) Cryptococcal CAmB dose-escalating study vs IV AmB + 5FC “standard of Reduction in fungal cell counts: no results posted
MAT2203) meningitis care”
Glycosylphos- Fosmanogepix (APX001) Phase 2 (SURGE) IC and candidemia Fosmanoepix 1000 mg IV twice daily x1 day, then 600 mg Treatment success at the end of treatment or 49 days:
phatidylinositol IV once daily, with option to switch to 700 mg PO daily 80% success and 86% survival rates. No treatment
Inhibitors after day 3; single arm study related SAEs or discontinuation
Phase 2 (APEX) Candida auris Fosmanoepix 1000 mg IV twice daily x1 day, then 600 mg Treatment success at the end of treatment or 42 days:
IV daily, with option to switch to 800 mg PO daily after No results posted
day 3; single arm study
Phase 2 (AEGIS) IA and rare molds Fosmanoepix IV load followed by IV/PO (dosing All-cause mortality at day 42: no results posted
unreported); single arm
Orotomides Olorofim (F901318) Phase 2 (FORMULA- IFIs including IA, rare Olorofim PO titrated to plasma levels, maximum 300 mg/ Clinical, mycological and radiological response at day 42:
OLS) and difficult-to- day; single arm no results posted
treat molds
AmB: Amphotericin B; BTD: Breakthrough designation; IA: Invasive Aspergillosis; IC: Invasive Candidiasis; IV: Intravenous; QIDP: Qualified Infectious Disease Product; IFI: Invasive Fungal Infection; PO: Oral; RVVC: Recurrent
Vulvovaginal Candidiasis; SAEs: Study Adverse Events; 5FC: Flucytosine*Oteseconazole phase 3 VIOLET are two global trials with identical study designs
 EXPERT OPINION ON PHARMACOTHERAPY 13

Additionally, ibrexafungerp’s use in prophylaxis of intrinsically resistant molds that result in dismal out­
Pneumocystis, IC, and IA is promising, as currently used agents comes [110].
carry a greater risk of DDIs, toxicities, and resistance in compar­ Antifungal development has provided us with some
ison to early ibrexafungerp data. This may translate to overall improved options for IFIs that we continue to optimize in
better outcomes in patient quality of life, safety, and cost. practice to date. Coupled with better diagnostics and com­
Ibrexafungerp is fast-tracked for VVC, but has already proven parative clinical studies, patient outcomes have improved.
useful for step-down therapy in IC and for refractory IFIs. With an emerging armamentarium of antifungals with unique
mechanisms of action and substantial improvements on famil­
iar mechanisms, we anticipate patient outcomes will continue
5.3. Polyenes
to improve with appropriate use of these agents. We can have
CAmB is a potent and broad-spectrum oral antifungal activity confidence that the cavalry is coming.
against Candida, Aspergillus, and Cryptococcus spp (presumably
all AmB susceptible fungus). CAmB has fewer side effects and
increased convenience compared to IV AmB formulations. An List of abbreviations
oral regimen offers a practical approach for prophylaxis in
AmB: Amphotericin B
patients with hematological malignancies and for outpatient ARAF: Azole-resistant A. fumigatus
treatment of cryptococcal meningitis. However, based on its AUC: Area under curve
encochleated formulation, there are concerns regarding the CAmB: Encochleated amphotericin B
cost, chemical stability, and tolerability. If nephrotoxicity is CNS: Central nervous system
minimized with CAmB, studies confirming bioavailability in DDIs: Drug-drug interactions
those with expected poor absorption (e.g., critically ill) are DHODH: Dihydroorotate dehydrogenase
needed. CAmB appears well suited as a consolidation regimen EUCAST: European Committee on Antimicrobial Susceptibility
in clinically improving patients or as initial therapy for other­ Testing
wise stable patients that would benefit from AmB at a much FDA: Food and Drug Administration
lower toxicity profile (e.g., Cryptococcus, certain endemic IFIs, GI: Gastrointestinal
GPI: Glycosylphosphatidylinositol
or visceral leishmaniasis). CAmB is being evaluated for crypto­
IA: Invasive aspergillosis
coccal meningitis and could become an initial therapy or IC: Invasive candidiasis
alternative to fluconazole for consolidation, particularly in flu­ ICU: Intensive Care Unit
conazole-resistant strains. Upcoming clinical trials will provide IDSA: Infectious Disease Society of America
additional insight regarding efficacy and safety of IFIs. IFI: Invasive Fungal Infections
IV: Intravenous
MDR: Multi-drug-resistant
5.4. Glycosylphosphatidylinositol (GPI) inhibitors MIC: Minimum inhibitory concentration
PD: Pharmacodynamic
Fosmanogepix has great potential to be used as a first-line PK: Pharmacokinetic
treatment for IFIs. It has broad activity against Candida (includ­ RVVC: Recurrent vulvovaginal candidiasis
ing C. auris), Aspergillus spp., dimorphic fungi, and rare molds SOC: Standard of care
that are often difficult-to-treat, such as Fusarium, Scedosporium TDM: Therapeutic drug monitoring
spp., and some of the Mucorales group. Fosmanogepix has U.S.: United States
excellent bioavailability, allowing for both oral and IV admin­
istration, and is expected to have an acceptable safety profile.
With its broad spectrum of activity and wide tissue distribution Declaration of interest
(including some CNS penetration), fosmanogepix is of great The authors have no other relevant affiliations or financial involvement
appeal for MDR and difficult-to-treat IFIs. with any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed.
5.5. Orotomides
Olorofim is a novel antifungal with excellent activity against
Reviewer Disclosures
a broad range of rare or resistant molds and dimorphic fungi.
This includes azole-resistant aspergillosis, endemic mycoses, Peer reviewers on this manuscript have no relevant financial or other
and other rare molds with limited antifungal treatments, relationships to disclose.
such as L. prolificans, Scedosporium, and Scopulariopsis spp.;
however, lacks activity against Candida, Cryptococcus, and Funding
Mucorales. Olorofim may be best suited for cases of confirmed
or suspected rare or resistant pathogens where it retains The authors are supported by a National Institutes of Health (NIH)/
National Center for Advancing Translational Sciences (NCATS) Colorado
activity or as salvage treatment in those unresponsive to
CTSA [Grant Number UL1 TR002535]. Its contents are the authors' sole
therapy. This novel antifungal agent allows for IV or oral responsibility and do not necessarily represent official NIH views. The
administration with limited toxicities and mild CYP3A4 DDIs, funding source was not involved in manuscript writing or in the decision
which may prove to be helpful with rarer pathogens and to submit the article for publication.
14 S. W. MUELLER ET AL.
ORCID
Scott W. Mueller http://orcid.org/0000-0003-1238-8199
References
1. Rauseo AM, Coler-Reilly A, Larson L, et al. Hope on the horizon:
novel fungal treatments in development. Open Forum Infectious
Diseases. 2020;7:ofaa016.
2. Vincent J-L, Rello J, Marshall J, et al. International study of the
prevalence and outcomes of infection in intensive care units.
JAMA. 2009;302:2323.
3. Donnelly JP, Chen SC, Kauffman CA, et al. Revision and update of
the consensus definitions of invasive fungal disease from the
European Organization for Research and Treatment of Cancer and
the Mycoses Study Group Education and Research Consortium. Clin
Infect Dis. 2020;71:1367-1376 https://doi.org/10.1093/cid/ciz1008.
● An updated consensus definition of IFIs including
diagnostics.
4. Delaloye J, Calandra T. Invasive candidiasis as a cause of sepsis in
the critically ill patient. Virulence. 2014;5:161–169.
5. Bassetti M, Righi E, Montravers P, et al. What has changed in the
treatment of invasive candidiasis? A look at the past 10 years and
ahead. J Antimicrob Chemother. 2018;73:i14–i25.
6. Statistics Invasive candidiasis, candidiasis, types of diseases Fungal
Diseases | CDC [Internet]. 2020 [cited 2020 Nov 21]. Available from:
https://www.cdc.gov/fungal/diseases/candidiasis/invasive/statis
tics.html.
7. Schauwvlieghe AFAD, Rijnders BJA, Philips N, et al. Invasive asper­
gillosis in patients admitted to the intensive care unit with severe
influenza: a retrospective cohort study. Lancet Respir Med.
2018;6:782–792.
8. Taccone F, Van Den Abeele A-M, Bulpa P, et al. Epidemiology of
invasive aspergillosis in critically ill patients: clinical presentation,
underlying conditions, and outcomes. Crit Care. 2015;19:7.
9. Oliver JD, Sibley GEM, Beckmann N, et al. F901318 represents
a novel class of antifungal drug that inhibits dihydroorotate
dehydrogenase. Proc Natl Acad Sci USA. 2016;113:12809–12814.
10. Van Der Linden JWM, Snelders E, Kampinga GA, et al. Clinical
implications of azole resistance in aspergillus fumigatus, the
Netherlands, 2007–2009. Emerg Infect Dis. 2011;17:1846–1854.
11. Van Matre ET, Evans SL, Mueller SW, et al. Comparative evaluation
of isavuconazonium sulfate, voriconazole, and posaconazole for
the management of invasive fungal infections in an academic
medical center. Ann Clin Microbiol Antimicrob. 2019;18:13.
12. Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guide­
line for the management of candidiasis: 2016 update by the infec­
tious diseases Society of America. Clin Infect Dis. 2016;62:e1–e50.
● IDSA clinical practice guideline discussing current manage­
ment strategies for IC.
13. Cornely OA, Bassetti M, Calandra T, et al. ESCMID guideline for the
diagnosis and management of Candida diseases 2012:
non-neutropenic adult patients. Clin Microbiol Infect.
2012;18:19–37.
14. Patterson TF, Thompson GR, Denning DW, et al. Practice guidelines
for the diagnosis and management of aspergillosis: 2016 update by
the infectious diseases society of America. Clin Infect Dis. 2016;63:
e1–e60.
● IDSA clinical practice guideline discussing current manage­
ment strategies for IA.
15. Ullmann AJ, Aguado JM, Arikan-Akdagli S, et al. Diagnosis and
management of Aspergillus diseases: executive summary of the
2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect. 2018;24:
e1–e38.
●● ESCMID clinical practice guideline discussing management
strategies for IA.
16. Chapman SW, Dismukes WE, Proia LA, et al. Clinical practice guide­
lines for the management of blastomycosis: 2008 update by the
infectious diseases society of America. Clin Infect Dis.
2008;46:1801–1812.
17. Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines
for the management of patients with histoplasmosis: 2007 update
by the infectious diseases Society of America. Clin Infect Dis.
2007;45:807–825.
18. Galgiani JN, Ampel NM, Blair JE, et al. Executive summary: 2016
Infectious Diseases Society of America (IDSA) clinical practice
guideline for the treatment of coccidioidomycosis. Clin Infect Dis.
2016;63:717–722.
19. Nivoix Y, Ledoux M-P, Herbrecht R. Antifungal therapy: new and
evolving therapies. Semin Respir Crit Care Med. 2020;41:158–174.
DOI: 10.1055/s-0039-3400291.
20. Ashley ESD, Lewis R, Lewis JS, et al. Pharmacology of systemic
antifungal agents. Clin Infect Dis. 2006;43:S28–S39.
21. Magill SS, Edwards JR, Bamberg W, et al. Multistate point-
prevalence survey of health care–associated infections. N Engl
J Med. 2014;370:1198–1208.
22. Centers for Disease Control and Prevention (U.S.). Antibiotic resis­
tance threats in the United States, 2019 [Internet]. Centers for
Disease Control and Prevention (U.S.); [cited 2020 Nov 21].
Available from: https://stacks.cdc.gov/view/cdc/82532.
23. Novak AR, Bradley ME, Kiser TH, et al. Azole-resistant Aspergillus
and echinocandin-resistant candida: what are the treatment
options? Curr Fungal Infect Rep. 2020;14:141–152.
24. Miller MA, Lee YM. Applying pharmacogenomics to antifungal
selection and dosing: are we there yet? Curr Fungal Infect Rep.
2020;14:63–75.
25. Mahmoud G, Long Lisa L, Emily L. Susceptibility of recent Candida
auris isolates to the novel echinocandin CD101 and comparator
antifungal agents. ECCMID; 2017.
26. Geddes-mcalister J, Shapiro RS. New pathogens, new tricks: emer­
ging, drug-resistant fungal pathogens and future prospects for
antifungal therapeutics. Ann N Y Acad Sci. 2019;1435:57–78.
27. Lockhart SR, Etienne KA, Vallabhaneni S, et al. Simultaneous emer­
gence of multidrug-resistant Candida auris on 3 continents con­
firmed by whole-genome sequencing and epidemiological
analyses. Clin Infect Dis. 2017;64:134–140.
28. Livengood SJ, Drew RH, Perfect JR. Combination therapy for inva­
sive fungal infections. Curr Fungal Infect Rep. 2020;14:40–49.
29. Arensman K, Miller J, Chiang A, et al. Clinical outcomes of patients
treated for candida auris infections in a multisite health system,
Illinois, USA. Emerg Infect Dis. 2020;26:876–880.
30. Herbrecht R, Dw D, Tf P, et al. Voriconazole versus amphotericin
B for primary therapy of invasive aspergillosis. N Engl J Med.
2002;347:408–415.
31. Marr KA, Schlamm HT, Herbrecht R, et al. Combination antifungal
therapy for invasive aspergillosis. Ann Intern Med. 2015;162:81–89.
32. Antifungal resistance in Aspergillus, fungal diseases, CDC [Internet].
2020 [cited 2020 Nov 22]. Available from: https://www.cdc.gov/
fungal/diseases/aspergillosis/antifungal-resistant.html.
33. Lestrade PPA, Buil JB, Van Der Beek MT, et al. Paradoxal trends in
azole-resistant Aspergillus fumigatus in a national multicenter sur­
veillance program, the Netherlands, 2013–2018. Emerg Infect Dis.
2020;26:1447–1455.
34. Vahedi-Shahandashti R, Lass-Flörl C. Novel antifungal agents and
their activity against Aspergillus species. J Fungi. 2020;6:213.
35. Gonçalves SS, Souza ACR, Chowdhary A, et al. Epidemiology and
molecular mechanisms of antifungal resistance in Candida and
Aspergillus. Mycoses. 2016;59:198–219.
36. Rybak JM, Fortwendel JR, Rogers PD. Emerging threat of
triazole-resistant Aspergillus fumigatus. J Antimicrob Chemother.
2019;74:835–842.
37. Yi WM, Schoeppler KE, Jaeger J, et al. Voriconazole and posacona­
zole therapeutic drug monitoring: a retrospective study. Ann Clin
Microbiol Antimicrob. 2017;16:60.
38. Lepak A, Andes D. Fungal sepsis: optimizing antifungal therapy in
the critical care setting. Crit Care Clin. 2011;27:123–147.
39. Erasmus Medical Center. PCR based detection of azole resistance in
a. fumigatus to improve patient outcome. (azorMan) [Internet].
clinicaltrials.gov; [cited 2020 Nov 18]. Report No.: NCT03121235.
Available from: https://clinicaltrials.gov/ct2/show/NCT03121235.

40. Lepak AJ, Marchillo K, VanHecker J, et al. Posaconazole pharmaco­
dynamic target determination against wild-type and Cyp51 mutant
isolates of Aspergillus fumigatus in an in vivo model of invasive
pulmonary Aspergillosis. Antimicrob Agents Chemother.
2013;57:579–585.
41. Chen L, Krekels EHJ, Verweij PE, et al. Pharmacokinetics and phar­
macodynamics of posaconazole. Drugs. 2020;80:671–695.
42. Schauwvlieghe AFAD, Buil JB, Verweij PE, et al. High-dose posaco­
nazole for azole-resistant aspergillosis and other difficult-to-treat
mould infections. Mycoses. 2020;63:122–130.
43. Schauwvlieghe A. Risk factors, diagnosis and management of
(azole-resistant) invasive aspergillosis. 2020.
44. Buil JB, Brüggemann RJM, Wasmann RE, et al. Isavuconazole sus­
ceptibility of clinical Aspergillus fumigatus isolates and feasibility of
isavuconazole dose escalation to treat isolates with elevated MICs.
J Antimicrob Chemother. 2018;73:263.
45. Warrilow AGS, Hull CM, Parker JE, et al. The clinical candidate
VT-1161 is a highly potent inhibitor of Candida albicans CYP51
but fails to bind the human enzyme. Antimicrob Agents
Chemother. 2014;58:7121–7127.
46. Viamet. A phase 2, randomized, double-blind, placebo-controlled,
dose-ranging study to evaluate the efficacy and safety of VT-1161
oral tablets in the treatment of patients with distal lateral subun­
gual onychomycosis of the toenail [internet]. clinicaltrials.gov; 2020
[cited 2020 Nov 19]. Report No.: NCT02267356. Available from:
https://clinicaltrials.gov/ct2/show/NCT02267356.
47. Mycovia Pharmaceuticals Inc. A phase 3, randomized, double-blind,
placebo-controlled study to evaluate the efficacy and safety of
VT-1161 oral capsules in the treatment of subjects with recurrent
vulvovaginal candidiasis [internet]. clinicaltrials.gov; 2020 [cited
2020 Nov 19]. Report No.: NCT03562156. Available from: https://
clinicaltrials.gov/ct2/show/NCT03562156.
● One of various trials anticipated to be crucial for the
approval of oteseconazole.
48. Mycovia Pharmaceuticals Inc. A phase 3, randomized, double-blind,
placebo-controlled study to evaluate the efficacy and safety of
VT-1161 oral capsules in the treatment of subjects with recurrent
vulvovaginal candidiasis [internet]. clinicaltrials.gov; 2020 [cited
2020 Nov 19]. Report No.: NCT03561701. Available from: https://
clinicaltrials.gov/ct2/show/NCT03561701.
● One of various trials anticipated to be crucial for the
approval of oteseconazole.
49. Mycovia Pharmaceuticals Inc. A phase 3, randomized, double-blind
study to evaluate the efficacy and safety of VT-1161 oral capsules
versus fluconazole and placebo in the treatment of acute vulvova­
ginal candidiasis episodes in subjects with recurrent vulvovaginal
candidiasis [internet]. clinicaltrials.gov; 2020 [cited 2020 Nov 19].
Report No.: NCT03840616. Available from: https://clinicaltrials.gov/
ct2/show/NCT03840616.
● One of various trials anticipated to be crucial for the
approval of oteseconazole.
50. Nishimoto AT, Wiederhold NP, Flowers SA, et al. In vitro activities of
the novel investigational tetrazoles VT-1161 and VT-1598 com­
pared to the triazole antifungals against azole-resistant strains
and clinical isolates of Candida albicans. Antimicrob Agents
Chemother. 2019;63:e00341–19.
51. Nishimoto AT, Whaley SG, Wiederhold NP, et al. Impact of the
major Candida glabrata triazole resistance determinants on the
activity of the novel investigational tetrazoles VT-1598 and
VT-1161. Antimicrob Agents Chemother. 2019;63:e01304–19.
52. Brand SR, Sobel JD, Nyirjesy P, et al. A randomized phase 2 study of
VT-1161 for the treatment of acute vulvovaginal Candidiasis. Clin
Infect Dis. 2020;ciaa1204. https://doi.org/10.1093/cid/ciaa1204
53. Brand SR, Degenhardt TP, Person K, et al. A phase 2, randomized,
double-blind, placebo-controlled, dose-ranging study to evaluate
the efficacy and safety of orally administered VT-1161 in the treat­
ment of recurrent vulvovaginal candidiasis. Am J Obstet Gynecol.
2018;218:624.e1-624.e9.
54. Desai J, Break T, Natarajan M, et al. VT-1129 and VT-1161 have
in vitro activity against Candida isolates from patients with chronic
EXPERT OPINION ON PHARMACOTHERAPY 15
mucocutaneous candidiasis. Open Forum Infect Dis. 2016;3
(S1):1635. https://doi.org/10.1093/ofid/ofw172.1335
55. Schell WA, Jones AM, Garvey EP, et al. Fungal CYP51 inhibitors
VT-1161 and VT-1129 exhibit strong in vitro activity against can­
dida glabrata and C. krusei isolates clinically resistant to azole and
echinocandin antifungal compounds. Antimicrob Agents
Chemother. 2017;61:e01817–16.
56. Nielsen K, Vedula P, Smith KD, et al. Activity of VT-1129 against
Cryptococcus neoformans clinical isolates with high fluconazole
MICs. Med Mycol. 2017;55:453–456.
57. Wiederhold NP, Xu X, Wang A, et al. In vivo efficacy of VT-1129
against experimental cryptococcal meningitis with the use of
a loading dose-maintenance dose administration strategy.
Antimicrob Agents Chemother. 2018;62:e01315–18.
● Animal model activity of VT-1129 against cryptococcal
meningitis.
58. Wiederhold NP, Patterson HP, Tran BH, et al. Fungal-specific Cyp51
inhibitor VT-1598 demonstrates in vitro activity against Candida
and Cryptococcus species, endemic fungi, including Coccidioides
species, Aspergillus species and Rhizopus arrhizus. J Antimicrob
Chemother. 2018;73:404–408.
●● In vitro activity of VT-1598 demonstrating potential for
broad activity as a tetrazole but potential for triazole cross-
resistance.
59. Wiederhold NP, Lockhart SR, Najvar LK, et al. The fungal
Cyp51-specific inhibitor VT-1598 demonstrates in vitro and in vivo
activity against Candida auris. Antimicrob Agents Chemother.
2019;63:e02233–18.
● Demonstrates VT-1598 as active against many C. auris
isolates.
60. Chatelon J, Cortegiani A, Hammad E, et al. Choosing the right
antifungal agent in ICU patients. Adv Ther. 2019;36:3308–3320.
61. Pound MW, Townsend ML, Dimondi V, et al. Overview of treat­
ment options for invasive fungal infections. Med Mycol.
2011;49:561–580.
62. Cidara Therapeutics Inc. A phase 3, multicenter, randomized,
double-blind study of the efficacy and safety of rezafungin for
injection vs. intravenous caspofungin followed by oral fluconazole
step down in the treatment of subjects with Candidemia and/or
Invasive Candidiasis [internet]. clinicaltrials.gov; 2020 [cited 2020
Nov 19]. Report No.: NCT03667690. Available from: https://clinical
trials.gov/ct2/show/NCT03667690.
● Will be a pivotal trial for rezafungin approval.
63. Cidara Therapeutics Inc. A phase 3, multicenter, randomized,
double-blind study of the efficacy and safety of rezafungin for
injection versus the standard antimicrobial regimen to prevent
invasive fungal diseases in adults undergoing allogeneic blood
and marrow transplantation (The ReSPECT study) [internet]. clini­
caltrials.gov; 2020 [cited 2020 Nov 19]. Report No.: NCT04368559.
Available from: https://clinicaltrials.gov/ct2/show/NCT04368559.
● Will be a pivotal trial for rezafungin approval and use as a
prophylaxis agent.
64. Zhao Y, Prideaux B, Nagasaki Y, et al. Unraveling drug penetration
of echinocandin antifungals at the site of infection in an
intra-abdominal abscess model. Antimicrob Agents Chemother.
2017;61:e01009–17.
65. Ong V, James KD, Smith S, et al. Pharmacokinetics of the novel
echinocandin CD101 in multiple animal species. Antimicrob Agents
Chemother. 2017;61:e01626–16.
66. Lakota E, Bader J, Ong V, et al. Pharmacological basis of CD101
efficacy: exposure shape matters. Antimicrob Agents Chemother.
2017;61:AAC.00758–17.
67. Gintjee TJ, Donnelley MA, Thompson GR. Aspiring antifungals:
review of current antifungal pipeline developments. J Fungi.
2020;6:28. DOI:10.3390/jof6010028
68. Pfaller M, Carvalhaes C, Messer S, et al. Activity of a long-acting
echinocandin, rezafungin, and comparator antifungal agents tested
against contemporary invasive fungal isolates: SENTRY program
2016-2018. Antimicrobial Agents and Chemotherapy. 2020;64.
16 S. W. MUELLER ET AL.
69. Van Daele R, Spriet I, Wauters J, et al. Antifungal drugs: what brings
the future? Med Mycol. 2019;57:S328–S343.
70. Thompson GR, Soriano A, Skoutelis A, et al. Rezafungin versus
caspofungin in a phase 2, randomized, double-blind study for the
treatment of candidemia and invasive candidiasis- the STRIVE trial.
Clin Infect Dis. 2020;ciaa1380. https://doi.org/10.1093/cid/ciaa1380
●● Comparative rezafungin to a standard of care regimen for
candidemia and IC.
71. Cushion MT, Ashbaugh A, Ong V. Rezafungin prevention of pneu­
mocystis pneumonia and pneumocystis reactivation using different
doses and durations of prophylaxis in a mouse model. Blood.
2019;134:3266.
72. Barat S, Borroto-Esoda K, Ghannoum M, et al. Activity of
Ibrexafungerp (Formerly SCY-078) against candida auris: in vitro,
in vivo, and clinical case studies of candidemia. Open Forum Infect
Dis. 2019;6:S307.
73. Pfaller MA, Messer SA, Motyl MR, et al. Activity of MK-3118, a new oral
glucan synthase inhibitor, tested against Candida spp. by two inter­
national methods (CLSI and EUCAST). J Antimicrob Chemother.
2013;68:858–863.
74. Pfaller MA, Messer SA, Motyl MR, et al. In vitro activity of a new oral
glucan synthase inhibitor (MK-3118) tested against Aspergillus spp.
by CLSI and EUCAST broth microdilution methods. Antimicrob
Agents Chemother. 2013;57:1065–1068.
75. Wring S, Murphy G, Atiee G, et al. Clinical pharmacokinetics and
drug-drug interaction potential for coadministered SCY-078, an
oral fungicidal glucan synthase inhibitor, and tacrolimus. Clin
Pharmacol Drug Dev. 2019;8:60–69.
76. Lima SL, Colombo AL, de Almeida Junior JN. Fungal cell wall:
emerging antifungals and drug resistance. Front Microbiol.
2019;10.
77. Arendrup MC, Jørgensen KM, Hare RK, et al. Vitro activity of ibrex­
afungerp (SCY-078) against Candida auris isolates as determined by
EUCAST methodology and comparison with activity against
C. albicans and C. glabrata and with the activities of six comparator
agents. Antimicrob Agents Chemother. 2019;64:e02136–19.
78. Ghannoum M, Arendrup MC, Chaturvedi VP, et al. Ibrexafungerp:
a novel oral triterpenoid antifungal in development for the treat­
ment of candida auris infections. Antibiotics. 2020;9:539.
79. Azie N, Angulo D, Dehn B, et al. Oral Ibrexafungerp: an investiga­
tional agent for the treatment of vulvovaginal candidiasis. Expert
Opin Investig Drugs. 2020;29:893–900.
80. Berkow EL, Angulo D, Lockhart SR. In vitro activity of a novel glucan
synthase inhibitor, SCY-078, against clinical isolates of candida
auris. Antimicrob Agents Chemother. 2017;61:e00435–17.
81. Zhu Y, Barat S, Borroto-Esoda K, et al. In vitro efficacy of novel
glucan synthase inhibitor, ibrexafungerp (SCY-078), against
multidrug- and pan-resistant Candida auris isolates from the out­
break in New York. 2019.
● In vitro data of ibrexafungerp in an important role of treat­
ing C. auris.
82. Spec A, Pullman J, Thompson GR, et al. MSG-10: a phase 2 study of
oral ibrexafungerp (SCY-078) following initial echinocandin therapy
in non-neutropenic patients with invasive candidiasis. J Antimicrob
Chemother. 2019;74:3056–3062.
● Viability of ibrexafungerp as a stepdown agent.
83. Scynexis, Inc. A multicenter, randomized, double-blind study to
evaluate the safety and efficacy of the coadministration of
SCY-078 with voriconazole in patients with invasive pulmonary
aspergillosis [internet]. clinicaltrials.gov; 2020 [cited 2020 Nov 19].
Report No.: NCT03672292. Available from: https://clinicaltrials.gov/
ct2/show/NCT03672292.
●● Results from this study could point to a new treatment
regimen in IA.
84. SCYNEXIS, Inc. (SCYX) [Internet]. SCYNEXIS, Inc. [cited 2020 Nov 22].
Available from: https://www.scynexis.com.
85. Scynexis, Inc. Open-label study to evaluate the efficacy and safety of
SCY-078 (Ibrexafungerp) in patients with fungal diseases that are
refractory to or intolerant of standard antifungal treatment (FURI)
[internet]. clinicaltrials.gov; 2020 [cited 2020 Nov 19]. Report No.:
NCT03059992. Available from: https://clinicaltrials.gov/ct2/show/
NCT03059992.
●● Important future role for ibrexafungerp.
86. Scynexis, Inc. A phase 3, multicenter, randomized, double-blind,
placebo-controlled study to evaluate the efficacy and safety of oral
ibrexafungerp (SCY-078) compared to placebo in subjects with
recurrent vulvovaginal candidiasis (VVC) [Internet]. clinicaltrials.
gov; 2020 [cited 2020 Nov 19]. Report No.: NCT04029116.
Available from: https://clinicaltrials.gov/ct2/show/NCT04029116.
87. Scynexis, Inc. Open-label study to evaluate the efficacy, safety,
tolerability and pharmacokinetics of oral ibrexafungerp (SCY-078)
as an emergency use treatment for patients with candidiasis,
including candidemia, caused by candida auris [internet]. clinical­
trials.gov; 2020 [cited 2020 Nov 19]. Report No.: NCT03363841.
Available from: https://clinicaltrials.gov/ct2/show/NCT03363841.
●● An important future role for ibrexafungerp.
88. Juneja D, Singh O, Tarai B, et al. Successful treatment of two patients
with Candida auris Candidemia with the investigational agent, oral
ibrexafungerp (formerly SCY-078), from the CARES study. 2019.
89. Aigner M, Lass-Flörl C. Encochleated amphotericin b: is the oral
availability of amphotericin B finally reached? J Fungi. 2020;6:66.
90. Shende P, Khair R, Gaud RS. Nanostructured cochleates: a
multi-layered platform for cellular transportation of therapeutics.
Drug Dev Ind Pharm. 2019;45:869–881.
91. Cuddihy G, Wasan EK, Di Y, et al. The development of oral ampho­
tericin B to treat systemic fungal and parasitic infections: has the
myth been finally realized? Pharmaceutics. 2019;11:99.
● An overview of amphotericin b development as an oral
agent.
92. Mannino R, Perlin D Oral dosing of encochleated amphotericin
B (CAmB): rapid drug targeting to infected tissues in mice with
invasive Candidiasis. 2015.
93. Delmas G, Park S, Chen ZW, et al. Efficacy of orally delivered
cochleates containing amphotericin B in a murine model of
aspergillosis. Antimicrob Agents Chemother. 2002;46:2704–2707.
94. Skipper CP, Atukunda M, Stadelman A, et al. Phase I EnACT trial of
the safety and tolerability of a novel oral formulation of amphoter­
icin B. Antimicrob Agents Chemother. 2020;64:e00838–20.
95. Matinas BioPharma Nanotechnologies, Inc. A multi-center rando­
mized study to evaluate the safety, tolerability, and efficacy of oral
encochleated amphotericin B (CAMB/MAT2203) compared with
oral fluconazole in the treatment of moderate to severe
Vulvovaginal Candidiasis (VVC) [Internet]. clinicaltrials.gov; 2018
[cited 2020 Nov 19]. Report No.: NCT02971007. Available from:
https://clinicaltrials.gov/ct2/show/NCT02971007.
96. Matinas BioPharma Nanotechnologies, Inc. Encochleated oral
Amphotericin for Cryptococcal meningitis Trial (EnACT) [Internet].
clinicaltrials.gov; [cited 2020 Nov 22]. Report No.: NCT04031833.
Available from: https://clinicaltrials.gov/ct2/show/results/
NCT04031833.
97. Shaw KJ, Ibrahim AS. Fosmanogepix: a review of the first-in-class
broad spectrum agent for the treatment of invasive fungal
infections. J Fungi. 2020;6:239.
98. Perfect JR. The antifungal pipeline: a reality check. Nat Rev Drug
Discov. 2017;16:603–616.
99. Gebremariam T, Alkhazraji S, Alqarihi A, et al. Fosmanogepix
(APX001) is effective in the treatment of pulmonary murine mucor­
mycosis due to Rhizopus arrhizus. Antimicrob Agents Chemother.
2020;64:e00178–20.
100. Mansbach R, Shaw KJ, Hodges MR, et al. Absorption, distribution,
and excretion of 14C-APX001 after single-dose administration to
rats and monkeys. Open Forum Infect Dis. 2017;4:S472.
101. Pfaller MA, Huband MD, Flamm RK, et al. In vitro activity of APX001A
(manogepix) and comparator agents against 1,706 fungal isolates
collected during an international surveillance program in 2017.
Antimicrob Agents Chemother. 2019;63:e00840–19.
 EXPERT OPINION ON PHARMACOTHERAPY 17

102. Hager CL, Larkin EL, Long L, et al. In vitro and in vivo evaluation of ● Fosmanogepix clinical use reports.
the antifungal activity of APX001A/APX001 against Candida auris. 106. Wiederhold NP. Review of the novel investigational antifungal
Antimicrob Agents Chemother. 2018;62:e02319–17. olorofim. J Fungi. 2020;6:122.
103. Amplyx Pharmaceuticals. An open-label study to evaluate the efficacy ● Olorofim specific review.
and safety of APX001 in non neutropenic patients with candidemia, 107. Kennedy T, Allen G, Steiner J, et al. An open label study in healthy
with or without invasive candidiasis, inclusive of patients with sus­ volunteers to evaluate the potential for cytochrome P450 3A4
pected resistance to standard of care antifungal treatment [internet]. inhibition by f901318 using oral midazolam as a probe. 2017.
clinicaltrials.gov; 2020 [cited 2020 Nov 19]. Report No.: NCT03604705. 108. Buil JB, Rijs AJMM, Meis JF, et al. In vitro activity of the novel
Available from: https://clinicaltrials.gov/ct2/show/NCT03604705. antifungal compound F901318 against difficult-to-treat
104. Amplyx Pharmaceuticals. An open-label study to evaluate the effi­ Aspergillus isolates. J Antimicrob Chemother. 2017;72:2548–2552.
cacy and safety of APX001 in patients with candidemia and/or 109. Biswas C, Law D, Birch M, et al. In vitro activity of the novel
invasive candidiasis caused by candida auris [internet]. clinical­ antifungal compound F901318 against Australian Scedosporium
trials.gov; 2020 [cited 2020 Nov 19]. Report No.: NCT04148287. and Lomentospora fungi. Medical Mycology. 2018;56:1050-1054.
Available from: https://clinicaltrials.gov/ct2/show/NCT04148287. https://doi.org/10.1093/mmy/myx161
● Fosmanogepix clinical use reports. 110. F2G Ltd. Phase IIb Study of F901318 as Treatment of Invasive
105. Amplyx Pharmaceuticals. A phase 2, open-label study to evaluate Fungal Infections Due to Lomentospora Prolificans,
the safety and efficacy of APX001 in the treatment of patients with Scedosporium Spp., Aspergillus Spp., and Other Resistant Fungi
invasive mold infections caused by Aspergillus species or rare in Patients Lacking Suitable Alternative Treatment Options
molds [internet]. clinicaltrials.gov; 2020 [cited 2020 Nov 19]. [Internet].. clinicaltrials.gov; 2021 [cited 2021 Feb 25]. Report
Report No.: NCT04240886. Available from: https://clinicaltrials.gov/ No.: NCT03583164. Available from: https://clinicaltrials.gov/ct2/
ct2/show/NCT04240886. show/NCT03583164.