Received: 20 March 2023 | Revised: 24 May 2023 | Accepted: 26 May 2023

DOI: 10.1111/myc.13622

ORIGINAL ARTICLE

A systematic review and meta-­analysis of efficacy and safety

of isavuconazole for the treatment and prophylaxis of invasive
fungal infections

Hideo Kato1,2,3 | Mao Hagihara1,4 | Nobuhiro Asai1 | Takumi Umemura1 |

Jun Hirai1 | Nobuaki Mori1 | Yuka Yamagishi1 | Takuya Iwamoto2,3 | ​
Hiroshige Mikamo1

1
Department of Clinical Infectious
Diseases, Aichi Medical University,
Nagakute, Japan
2
Department of Pharmacy, Mie University
Hospital, Tsu, Japan
3
Department of Clinical Pharmaceutics,
Division of Clinical Medical Science, Mie
University Graduate School of Medicine,
Tsu, Japan
4
Department of Molecular Epidemiology
and Biomedical Sciences, Aichi Medical
University Hospital, Nagakute, Japan
Correspondence
Hiroshige Mikamo, Department of
Clinical Infectious Diseases, Aichi Medical
University, 1-­1, Yazakokarimata, Nagakute,
Aichi 480-­1195, Japan.
Email: mikamo@aichi-med-u.ac.jp
Abstract
Background: Isavuconazole is a novel triazole antifungal agent. However, the previous
outcomes were highlighted by statistical heterogeneity. This meta-­analysis aimed to
validate the efficacy and safety of isavuconazole for the treatment and prophylaxis of
invasive fungal infections (IFIs) compared with other antifungal agents (amphotericin
B, voriconazole and posaconazole).
Methods: Scopus, EMBASE, PubMed, CINAHL and Ichushi databases were searched
for relevant articles that met the inclusion criteria through February 2023. Mortality,
IFI rate, discontinuation rate of antifungal therapy and incidence of abnormal hepatic
function were evaluated. The discontinuation rate was defined as the percentage of
therapy discontinuations due to adverse events. The control group included patients
who received other antifungal agents.
Results: Of the 1784 citations identified for screening, 10 studies with an overall total
of 3037 patients enrolled. Isavuconazole was comparable with the control group in
mortality and IFI rate in the treatment and prophylaxis of IFIs, respectively (mortality,
odds rate (OR) 1.11, 95% confidential interval (CI) 0.82–­1.51; IFI rate, OR 1.02, 95% CI
0.49–­2.12). Isavuconazole significantly reduced the discontinuation rate in the treat-
ment (OR 1.96, 95% CI 1.26–­3.07) and incidence of hepatic function abnormalities in
the treatment and prophylaxis, compared with the control group (treatment, OR 2.31,
95% CI 1.41–­3.78; prophylaxis, OR 3.63, 95% CI 1.31–­10.05).
Conclusions: Our meta-­analysis revealed that isavuconazole was not inferior to other
antifungal agents for the treatment and prophylaxis of IFIs, with substantially fewer
drug-­associated adverse events and discontinuations. Our findings support the use of
isavuconazole as the primary treatment and prophylaxis for IFIs.

KEYWORDS
invasive fungal infections, isavuconazole, meta-­analysis, prophylaxis, treatment

© 2023 Wiley-VCH GmbH. Published by John Wiley & Sons Ltd.

Mycoses. 2023;00:1–10.  wileyonlinelibrary.com/journal/myc | 1

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2 KATO et al.
1 | I NTRO D U C TI O N
Invasive fungal infections (IFIs) are highly lethal diseases.1 Aspergillus
and Mucor spp. are recognized causes of IFIs and are responsible
for a large proportion of all reported deaths due to fungal disease. 2
Moreover, hospitalizations for invasive aspergillosis and mucormy-
cosis have increased since 2000.3 Therefore, the appropriate se-
lection of IFI therapy is critical to achieve successful outcomes and
manage the risk of mortality, toxicity associated with antifungal
agents and the development of resistance.
Available antifungal agents for managing IFIs in the United
States include polyenes, echinocandins and triazoles,4,5 each of
which has serious shortcomings.6–­8 Polyenes play a limited role due
to toxicity concerns and the requirement for intravenous adminis-
tration.6 Echinocandins may be considered as combination therapy
with an azole or as salvage therapy. 5,7 There are no data to support
the first-­line use of posaconazole. Voriconazole use has various
concerns, such as drug interactions, pharmacokinetic variability,
toxicities, β-­c yclodextrin administration in the setting of impaired
renal function and recommendations for therapeutic drug moni-
toring (TDM). 8
Isavuconazole (ISAV) is a novel, broad-­spectrum triazole with
potent activity against invasive aspergillosis, mucormycosis, candi-
diasis and cryptococcosis.9–­12 Well-­known adverse events of ISAV is
hepatotoxicity, whereas it is considered well tolerated.13 ISAV can
be administered to patients with renal impairment without dose
adjustment since the injectable formation does not consist of po-
tentially nephrotoxic excipients such as β-­c yclodextrin. Moreover,
since cytochrome P450 (CYP) 2C9, CYP2C19 and CYP2D6, which
polymorphisms affect pharmacokinetics, are not involved in the
metabolism of ISAV and the variability of plasma levels is low,14,15
ISAV use has no recommendation for TDM. Therefore, ISAV has
several clinical advantages over other antifungal agents. However,
the guidelines for treating IFIs from the Infectious Diseases Society
of America (IDSA) recommend ISAV as an alternative to primary
therapy. 5 Moreover, a previous meta-­analysis of patients receiving
ISAV for the treatment of aspergillosis was marred by statistical
heterogeneity. No meta-­analysis of this group of patients for IFI
prophylaxis has been undertaken to evaluate its efficacy and safety
comprehensively.
In this study, we performed a meta-­a nalysis of data compar-
ing patients receiving ISAV and other antifungal agents from pro-
spective and retrospective studies to comprehensively evaluate
the efficacy and safety of ISAV in the treatment and prophylaxis
of IFIs.
2 | M ATE R I A L S A N D M E TH O DS
We conducted a systematic review and meta-­analysis guided by the
PRISMA guidelines on Reporting Items for Systematic Reviews and
meta-­analyses.16,17
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2.1 | Data sources and search strategy
We performed a systematic search of Scopus, EMBASE, PubMed,
CINAHL and Ichushi for published articles in the English and
Japanese language up to 7 February 2023, using the following
terms: (“isavuconazole [All Fields]” AND (“randomize control trial
[All Fields]” or “RCT [All Fields]” or “non-­randomized control trial
[All Fields]” or “nRCT [All Fields]” or “cohort study [All Fields]” or
“retrospective study [All Fields]” or “prospective study [All Fields]”
or “case series [All Fields]”). Articles meeting the following PICO
criteria were selected: patient population (P), patients with IFIs;
Intervention (I), patients treated with ISAV; Comparison (C), pa-
tients treated with antifungal agents other than ISAV (control
group); outcome (O), mortality, IFI rate, discontinuation rate of anti-
fungal therapy due to adverse events, or incidence of hepatic func-
tion abnormalities.
2.2 | Study selection
All titles and abstracts were independently screened by two re-
searchers (HK and MH) to exclude irrelevant articles. Full-­text
articles were then reviewed based on the inclusion and exclusion
criteria, and articles for the final qualitative synthesis and meta-­
analysis were identified. Disagreements that a consensus could not
resolve were reviewed by a third author (HM). For the inclusion cri-
teria, randomized controlled trials (RCT), retrospective and cohort
studies that reported mortality, IFI rate, discontinuation rate due
to adverse events, or incidence of hepatic function abnormal in pa-
tients treated with and without ISAV for the treatment and proph-
ylaxis of invasive fungal infections were included. Mycological
criteria for diagnosing IFIs include detecting fungal elements by
cytology or microscopy, indicating a mould, or by culture. In con-
trast, studies that did not separately report data on treatment or
prophylaxis were excluded.
2.3 | Data extraction and risk-­of-­bias assessment
The following variables were extracted: design, setting, period,
region, infection, pathogen, purpose (treatment and prophylaxis),
other antifungal agents (control), age of patients (years), number
of patients, antifungal agent regimen and outcomes. The primary
outcomes were overall mortality for the treatment and IFI rate for
the prophylaxis, and the secondary outcomes were the discontin-
uation rate and the incidence of abnormal hepatic function. The
discontinuation rate was defined as the percentage of discontinu-
ation of therapy owing to adverse events. Based on previous stud-
ies,18,19 the risk of bias was assessed using the Modified Downs
and Black risk assessment scale for RCT and retrospective stud-
ies. 20 The risk of bias was assessed using the Modified Downs and
Black risk assessment scale for RCT and retrospective studies. This
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KATO et al. 3

scale consists of 27 items evaluating study characteristics, such as 3 | R E S U LT S

reporting, external validity, internal validity (bias and confounding)
and statistical power. The scale yields total scores ranges from 0
to 32. Based on these scores, the risk of bias in each study was
identified as low (score > 23), moderate (score = 16–­23) or high
(score = 0–­15). Two authors (HK and MH) independently performed
bias assessments.
2.4 | Statistical analysis
We performed a meta-­analysis based on the findings of previous
studies.18,19 Statistical heterogeneity was assessed using the chi-­
squared test and the I2 measure. A p-­value of <0.1 or I2 of >50% was
considered to show significant heterogeneity. Fixed-­ and random-­
effects models were used to assess homogeneity and heterogene-
ity, respectively. We calculated each risk using odds ratios (ORs) and
95% confidence intervals (CIs). The pooled ORs and 95% CIs were
calculated using a fixed-­effects model (Mantel–­Haenszel method)
and a random-­effects model (DerSimonian-­L aird method), and ORs
from these results were compared. All analyses were performed
using the Review Manager software (RevMan, version 5.4; Nordic
Cochrane StataCorp LLC, USA).
3.1 | Systematic review
The number of articles extracted from the electronic databases was
1784. After removing duplicates, the titles and abstracts of 1531
articles were screened. Their titles and abstracts were screened to
exclude irrelevant studies, resulting in 16 potentially eligible studies.
The full texts of the 16 articles were then reviewed. Figure 1 shows
the full list of the reasons for exclusion. Consequently, ten studies
met the inclusion criteria.21–­30 The basic characteristics of these stud-
ies are summarized in Tables 1 and 2. Two were RCTs, and one was a
double-­blind study.21 One was a prospective case–­control study, and
the others were retrospective cohort studies. Single-­centre studies
represented six studies, and four were multicentre studies. One of the
two RCTs was conducted in a multinational setting, 21 and the other
was conducted in Japan.30 Retrospective studies have been con-
ducted in the United States and the United Kingdom. Fungal infec-
tions caused by Aspergillus, Mucor and Candida spp. were included.
The ISAV regimen consisted of 200 mg three times for six doses, fol-
lowed by 200 mg once daily. In the control group, amphotericin B,
voriconazole and posaconazole were administered to patients with
invasive fungal infections. Three studies reported the voriconazole

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^ƚƵĚŝĞƐŝŶĐůƵĚĞĚŝŶƋƵĂůŝƚĂƚŝǀĞƐLJŶƚŚĞƐŝƐ
;ŶсϭϬͿ
/ŶĐůƵĚĞĚ

^ƚƵĚŝĞƐŝŶĐůƵĚĞĚŝŶƋƵĂŶƚŝƚĂƚŝǀĞƐLJŶƚŚĞƐŝƐ;ŵĞƚĂͲĂŶĂůLJƐŝƐͿ
F I G U R E 1 PRISMA flow diagram for ;ŶсϭϬͿ
the selection of eligible studies.
 |
4 KATO et al.
dosage regimen, whereas the regimens of other antifungal agents
were not reported. The results of the risk-­of-­bias assessment are
shown in Table 1. The average Downs and Black score was 20, with
a range between 17 and 27. All studies, except for one blind-­label
RCT, 21 had a moderate risk of bias.
3.2 | Meta-­analysis
3.2.1 | Mortality
Pooled analyses based on the six studies involving 870 participa-
tors that evaluated mortality for the treatment showed that there
was no significant reduction in the ISAV group compared with the
control group in a fixed-­effects model (treatment, OR 1.11, 95% CI
0.82–­1.51, I2 = 0%, Figure 2). Numerically, the mortality is lower in
the ISAV group than in the control group (ISAV vs. control, 28.3%
vs. 33.6%).
3.2.2 | IFI rate
Pooled analysis of ISAV administration for the prophylaxis in the
two studies involving 577 participators was comparable with the
control groups in IFI rate (OR 1.02, 95% CI 0.49–­2 .12, I2 = 0%,
Figure 3).
3.2.3 | Discontinuation rate
Data on the discontinuation rates in 387 participants receiving ISAV
and 390 patients receiving other antifungal agents for the treatment
were reported in five studies, and the discontinuation rates in the
two groups were 9.8% and 16.9%, respectively. The control group
showed a significant reduction in continued rate compared with the
ISAV group (OR 1.96, 95% CI 1.26–­3.07, I2 = 0%, Figure 4A). In the
prophylaxis, the discontinuation rate was not significantly different
between the two groups (ISAV vs. control, 9.4% vs. 17.9%; OR 2.01,
95% CI 0.60–­6.78, Figure 4B).
3.2.4 | Incidence of hepatic function abnormal
Three studies assessed the incidence of hepatic function abnormal
in the treatment, and the pooled analysis showed a significant in-
crease in the incidence in the control group compared with the ISAV
group (8.0% vs. 16.3%; OR 2.31, 95% CI 1.41–­3.78, Figure 5A). Only
one study reported the incidence of hepatic function abnormalities
during prophylaxis. The ISAV group significantly decreased the in-
cidence of hepatic function over the control group (3.6% vs. 11.9%,
OR 3.63, 95% CI 1.31–­10.05, Figure 5B).
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4 | DISCUSSION
This is the first meta-­analysis to compare the efficacy and safety of
ISAV for the treatment and prophylaxis of IFIs and to compare its
effects with those of other antifungal agents. Mortality and IFI rate
outcomes in ISAV for the treatment and prophylaxis of IFIs were not
inferior to those of other antifungal agents. The discontinuation rate
and incidence of hepatic function abnormalities in the treatment and
prophylaxis of IFIs were significantly better for ISAV than for others.
Thus, these results support that ISAV is more benefit as a first-­line
treatment and prophylaxis for patients with IFIs than others.
Invasive aspergillosis and mucormycosis are life-­threatening
diseases. In clinical practice, rapidly distinguishing between these
pathogens is difficult, and patients can often be infected with mul-
tiple pathogens. A retrospective observational study of patients
with IFIs reported that multiple fungal pathogens were present in
13% of diseases.31 Moreover, the only licenced antifungal agent for
mucormycosis is amphotericin B, which is currently the standard of
care.32 Therefore, appropriate antifungal agents that have been ap-
proved for the treatment and prophylaxis of both fungal infections
are required.
Considering the equivalent efficacy of ISAV and other antifun-
gal agents for the treatment and prophylaxis of IFIs demonstrated
in this meta-­analysis, the choice of an appropriate antifungal agent
may be best guided by consideration of other factors, such as flex-
ibility in the route of administration, tolerability and potential for
drug–­drug interactions.33 The availability of oral formulations and
good tolerability of ISAV can be beneficial for patients requiring pro-
longed courses and outpatient therapy. These are also corroborated
by our findings. Therefore, ISAV is a promising first-­line treatment
and prophylaxis for IFIs.
Therapeutic drug monitoring (TDM) is frequently used to
optimize the efficacy and safety of antifungal agents. Unlike
voriconazole, the pharmacokinetic features of ISAV indicate that
therapeutic drug monitoring (TDM) is not required in clinical set-
tings. It has been shown that ISAV exposure is less variable than
voriconazole exposure and patients, who could not continue to be
treated with voriconazole due to adverse effects, are tolerated with
ISAV well.34 Moreover, when comparing the intra-­individual coeffi-
cient of variation (CV) for ISAV and voriconazole in the same patients
who have received both drugs in sequence, the intra-­individual CV is
reported to be lower for ISAV than for voriconazole.35 This may sup-
port that ISAV has low discontinuation rate due to its stable serum
concentrations. Patients with high inter-­individual exposure of ISAV
are possible exception to the stable serum concentration of ISAV,
while it remains to be established whether adjusted dosage for the
patients might improve the discontinuation rate.
Studies investigating the ISAV exposure-­response relationship
for efficacy in patients with IFIs showed no statistically significant
relationship between its exposure and the minimum inhibitory con-
centration (MIC) values of cultured fungi and clinical outcomes. 21
 KATO et al.

TA B L E 1 Characteristics of the studies included in the meta-­analysis.

Risk of
Study Design Setting Period Region Infection type Pathogen Purpose Control Outcomes bias

Maertens JA (2016) RCT MC double-­ 2007 to 2013 Global Fungal Aspergillus; Treatment VRCZ MO; DR; 27
blind infections Mucor IHFA
Marty FM (2016) Prospective MC April 2008 to Global Mucormycosis Mucor Treatment AMB MO 19
(case–­control) Open-­ October 2008;
label April 2011 to
June 2013
Cheng MP (2018) Retrospective SC March 2015 to United States Aspergillosis Aspergillus Treatment VRCZ; DR 17
(cohort) January 2018 POSA
Bongomin F (2019) Retrospective SC December 2015 United Aspergillosis Aspergillus Treatment VRCZ DR 20
(cohort) to Kingdom
December 2016
Stull K (2019) Retrospective SC January 2013 to United States Aspergillosis; Aspergillus; Treatment; AMB; MO 19
(cohort) August 2017 mucormycosis Mucor VRCZ;
POSA
Van Matre ET (2019) Retrospective SC January 2015 to United States Fungal Aspergillus; Treatment VRCZ; MO 20
(cohort) December 2017 infections Mucor POSA
Cheng M (2020) Retrospective Two March 2015 to United States Aspergillosis Aspergillus Treatment VRCZ; MO; DR; 18
(cohort) December 2017 POSA IHFA
Samanta P (2021) Retrospective SC September 2013 United States Fungal Aspergillus; Prophylaxis VRCZ IFIR; DR 20
(cohort) to infections Mucor (immunocompromised)
February 2018
Rausch CR (2022) Retrospective SC March 2016 to United States Fungal Aspergillus; Prophylaxis VRCZ; IFIR; DR 19
(cohort) July 2019 infections Mucor; (immunocompromised) POSA
Candida
Kohno S (2023) RCT MC April 2018 to Japan Fungal Aspergillus; Treatment VRCZ MO; DR; 21
April 2021 infections Mucor; IHFA
Cryptococcus

Abbreviations: AMB, amphotericin B; DR, discontinuation rate; IFIR, invasive fungal infection rate; IHFA, incidence of hepatic function abnormality; ISAV, isavuconazole; MC, multicentre; MO, mortality;
RCT, randomized controlled study; POSA, posaconazole; SC, single-­centre; VRCZ, voriconazole.
| 5

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6 KATO et al.

TA B L E 2 Characteristics of the patients of studies included in the meta-­analysis.

Age (median), ISAV No of patients, ISAV

Study versus Control versus Control Regimen, ISAV Control Comorbidities

Maertens JA (2016) Mean 258 versus 258 200 mg, every 8 h for 12 mg/kg/day on Acute myeloid leukaemia,
51 versus 51 six doses, day 1, lymphoma, acute
followed by 200 mg 8 mg/kg/day on lymphoblastic leukaemia,
once daily day 2 or Myelodysplastic
400 mg/day from syndrome, chronic
day 3 lymphocytic leukaemia,
onwards aplastic anaemia,
chronic myeloid
leukaemia, multiple
myeloma, COPD,
Hodgkin's disease,
diabetes
Marty FM (2016) 51 versus 57 21 versus 33 200 mg, every 8 h for NA Haematological
six doses, malignancy, diabetes,
followed by 200 mg solid-­organ
once daily transplantation
Cheng MP (2018) Overall 29 versus 44 NA NA NA
61 (VRCZ, n = 36; POSA,
n = 8)
Bongomin F (2019) 65 versus 66 20 versus 21 200 mg, every 8 h for NA COPD, tuberculosis,
six doses, Pulmonary sarcoidosis,
followed by 200 mg Lung cancer, asthma,
once daily community-­acquired
pneumonia, asbestosis,
bronchiectasis
Stull K (2019) Overall treatment, 22 versus 59 NA NA Myeloid leukaemia,
treatment 52; (AMB, n = 24; VRCZ, haematopoietic stem cell
prophylaxis, 54 n = 20; transplantation,
POSA, n = 15) diabetes, solid-­organ
prophylaxis, 9 versus 33 transplantation
(AMB, n = 7; VRCZ,
n = 11;
POSA, n = 16)
Van Matre ET Overall 33 versus 67 NA NA NA
(2019) Mean 56 (VRCZ, n = 34; POSA,
n = 33)
Cheng M (2020) Overall 28 versus 40 200 mg, every 8 h for VRCZ, 400 mg/ Haematological
62 (VRCZ, n = 32; POSA, six doses, day; malignancy,
n = 8) followed by 200 mg POSA, NA haematopoietic stem cell
once daily transplantation,
diabetes, solid-­organ
transplantation, solid
malignancy, others
Samanta P (2021) 58 versus 60 144 versus 156 NA NA Cystic fibrosis, COPD,
rheumatologic disorders
Rausch CR (2022) Overall 53 versus 224 NA NA Acute myeloid
62 (VRCZ, n = 84; POSA, leukaemia
n = 140)
Kohno S (2023) Overall 52 versus 27 200 mg, every 8 h for 12 mg/kg/day on COPD, bronchiectasis
68 six doses, day 1,
followed by 200 mg 8 mg/kg/day on
once daily day 2 or
400 mg/day from
day 3
onwards

Abbreviations: AMB, amphotericin B; COPD, chronic obstructive pulmonary disease; ISAV, isavuconazole; NA, not available; POSA, posaconazole;
VRCZ, voriconazole.
 |

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KATO et al. 7

F I G U R E 2 Forest plot presenting odds ratios for mortality in patients treated with antifungal agents for the treatment of invasive fungal
infections. CI, confidence interval; IVSA, isavuconazole; M-­H, Mantel–­Haenszel; OR, risk rate.

F I G U R E 3 Forest plot presenting odds ratios for the invasive fungal infection rate in patients treated with antifungal agents for
prophylaxis of invasive fungal infections. CI, confidence interval; IVSA, isavuconazole; M-­H, Mantel–­Haenszel; OR, risk rate.

F I G U R E 4 Forest plot presenting odds ratios for discontinuation rate in patients with invasive fungal infections. (A) treatment, (B)
prophylaxis. CI, confidence interval; IVSA, isavuconazole; M-­H, Mantel–­Haenszel; OR, risk rate.

However, in vivo and ex vivo models have demonstrated that MIC ISAV exposure. In contrast, recent antifungal resistance profiles
values have a clear impact on exposure-­response relationships.36,37 of isolates from patients with IFIs have reported that ISAV exhib-
These differences may have been caused by narrow variability in its good activity against Aspergillus spp. and Mucorales, with MIC90
 |
8 KATO et al.
F I G U R E 5 Forest plot presenting odds ratios for incidence of hepatic function abnormal in patients with invasive fungal infections. (A)
treatment, (B) prophylaxis. CI, confidence interval; IVSA, isavuconazole; M-­H, Mantel–­Haenszel; OR, risk rate.
values of 2 and 1 mg/L, respectively.38 Successful treatment that has
been reported in patients with MIC values of up to 8 mg/L has been
reported to be successfully treated. 21 Therefore, ISAV may have
beneficial effects on the treatment and prophylaxis of IFIs without
TDM.
Finally, it is important to evaluate novel drugs against existing
standard drugs by comparing their cost, efficacy and safety to de-
termine optimal drugs. Two economic evaluations showed that ISAV
is associated with a lower total cost per patient, which is a result
of lower drug, adverse events, initial hospitalization and hospital re-
admission costs.39,40 Therefore, ISAV may be a more cost-­effective
drug than voriconazole for the treatment of IFIs.
This study has several limitations. First, most patients in this
study are from various comorbidities, different drug dosages
and duration of therapy. Some studies had incomplete reports
of patient backgrounds and were not considered in the analysis.
Moreover, all studies included in the meta-­analysis of incidence
of hepatic function abnormal did not define hepatotoxicity.
Therefore, these factors could be a source of bias due to vari-
able selection. However, there was less heterogeneous among
the included studies. The second limitation is the paucity of RCTs
and high-­quality observational studies on various IFI subtypes.
Moreover, the duration of treatment with various antifungal
agents was also one of factors contributing to the heterogeneity41;
however, this could not be addressed in the present meta-­analysis.
Moreover, we could not conduct stratified analyses on severity
and duration of infection since individual data were not available.
Thus, our meta-­analysis indicates an urgent need for studies on
the management of different types of IFIs.
In conclusion, our meta-­analysis revealed that ISAV was not in-
ferior to other antifungal agents for the treatment and prophylaxis
of IFIs, with substantially fewer drug-­associated adverse events
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and discontinuations. Our findings suggest that ISAV is a useful
first-­line antifungal agent for the treatment and prophylaxis of
IFIs.
AU T H O R C O N T R I B U T I O N S
Hiroshige Mikamo: Supervision; funding acquisition. Hideo Kato:
Conceptualization; methodology; software; validation; formal analy-
sis; investigation; resources; writing –­ original draft; data curation;
project administration; visualization. Mao Hagihara: Methodology;
investigation; formal analysis; visualization. Nobuhiro Asai: Data cu-
ration; resources.
AC K N O​W L E​D G E​M E N T S
We thank Editage (http://www.edita​ge.com) for the English lan-
guage editing.
F U N D I N G I N FO R M AT I O N
None of the authors have any financial relationships with any com-
mercial entity interested in the subject of this manuscript.
C O N F L I C T O F I N T E R E S T S TAT E M E N T
The authors declare no conflicts of interest. None of the authors
have any financial relationships with any commercial entity inter-
ested in the subject of this manuscript.
DATA AVA I L A B I L I T Y S TAT E M E N T
All data are applicable in the paper.
ORCID
Hideo Kato https://orcid.org/0000-0002-5272-9560
Takumi Umemura https://orcid.org/0000-0003-3160-5136
Hiroshige Mikamo https://orcid.org/0000-0001-8876-6411

KATO et al.
REFERENCES
1. Gavalda J, Meije Y, Fortun J, et al. Invasive fungal infections in solid
organ transplant recipients. Clin Microbiol Infect. 2014;20:27-­48.
2. Brown GD, Denning DW, Gow NAR, Levitz SM, Netea MG,
White TC. Hidden killers: human fungal infections. Sci Transl Med.
2012;4:1-­10.
3. Formanek PE, Dilling DF. Advances in the diagnosis and manage-
ment of the invasive fungal disease. Chest. 2019;156:834-­8 42.
4. Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline
for the management of candidiasis: 2016 update by the Infectious
Diseases Society of America. Clin Infect Dis. 2016;62:e1-­e50.
5. Patterson TF, Thompson GR, Denning DW, et al. Practice guide-
lines for the diagnosis and management of aspergillosis: 2016 up-
date by the Infectious Diseases Society of America. Clin Infect Dis.
2016;63:e1-­e60.
6. Lanternier F, Lortholary O. Liposomal amphotericin B: what is its
role in 2008? Clin Microbiol Infect. 2008;14:71-­83.
7. Enoch DA, Idris SF, Aliyu SH, Micallef C, Sule O, Karas JA.
Micafungin for the treatment of invasive aspergillosis. J Infect.
2014;68:507-­526.
8. Mikulska M, Novelli A, Aversa F, et al. Voriconazole in clinical prac-
tice. J Chemother. 2012;24:311-­327.
9. Lepak AJ, Marchillo K, Vanhecker J, Andes DR. Isavuconazole
(BAL4815) pharmacodynamic target determination in an in vivo
murine model of invasive pulmonary aspergillosis against wild-­t ype
and cyp51 mutant isolates of Aspergillus fumigatus. Antimicrob
Agents Chemother. 2013;57:6284-­6289.
10. Luo G, Gebremariam T, Lee H, Edwards JE Jr, Kovanda L,
Ibrahim AS. Isavuconazole therapy protects immunosup-
pressed mice from mucormycosis. Antimicrob Agents Chemother.
2014;58:2450-­2453.
11. Lepak AJ, Marchillo K, VanHecker J, Diekema D, Andes DR.
Isavuconazole pharmacodynamic target determination for Candida
species in an in vivo murine disseminated candidiasis model.
Antimicrob Agents Chemother. 2013;57:5642-­5648.
12. Espinel-­Ingroff A, Chowdhary A, Gonzalez GM, et al. Multicenter
study of isavuconazole MIC distributions and epidemiological cut-
off values for the Cryptococcus neoformans-­Cryptococcus gat-
tii species complex using the CLSI M27-­A3 broth microdilution
method. Antimicrob Agents Chemother. 2015;59:666-­668.
13. Miceli MH, Kauffman CA. Isavuconazole: a new broad-­spectrum
triazole antifungal agent. Clin Infect Dis. 2015;61:1558-­1565.
14. Jenks JD, Mehta SR, Hoenigl M. Broad spectrum triazoles for inva-
sive mould infections in adults: which drug and when? Med Mycol.
2019;57:S168-­S178.
15. FDA. Clinical Pharmacogenomics: Premarket evaluation in early-­
phase clinical studies and recommendations for labeling. 2013
https://www.fda.gov/files/​d rugs/​p ubli​shed/Clini​c al-­Pharm​a coge​
nomic​s-­- P
­ rema​r ket-­Evalu​a tion​-­in-­E arly​- ­P hase​- ­C lini​c al-­Studi​e s-­
and-­Recom​menda​tions​-­for-­L abel​ing.pdf
16. The guidelines of preferred reporting items for systematic review
and meta-­analysis (PRISMA) statement. http://prism​a-­state​ment.
org
17. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group.
Preferred reporting items for systematic reviews and me-­t a-­
analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.
18. Kato H, Hagihara M, Shibata Y, et al. Comparison of mortality be-
tween echinocandins and polyenes for an initial treatment of can-
didemia: a systematic review and meta-­analysis. J Infect Chemother.
2021;27:1562-­1570.
19. Kato H, Yamagishi Y, Hagihara M, et al. Systematic review and
meta-­analysis for impacts of oral antibiotic treatment on pregnancy
outcomes in chronic endometritis patients. J Infect Chemother.
2022;28:610-­615.
|
14390507, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/myc.13622 by Lain Entralgo, Wiley Online Library on [12/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
9
20. Downs SH, Black N. The feasibility of creating a checklist for the
assessment of the methodological quality both of randomised and
non-­randomised studies of health care interventions. J Epidemiol
Community Health. 1998;52:337-­384.
21. Maertens JA, Raad II, Marr KA, et al. Isavuconazole versus
voriconazole for primary treatment of invasive mould disease
caused by Aspergillus and other filamentous fungi (SECURE):
a phase 3, randomised-­controlled, non-­inferiority trial. Lancet.
2016;387:760-­769.
22. Marty FM, Ostrosky-­Zeichner L, Cornely OA, et al. Isavuconazole
treatment for mucormycosis: a single-­arm open-­label trial and case-­
control analysis. Lancet Infect Dis. 2016;16:828-­837.
23. Cheng MP, Orejas JL, Arbona-­H addad E, Marty FM, Koo S,
Hammond S. Comparison of voriconazole (VORI), isavuconazole
(ISAV), and posaconazole (POSA) in the initial treatment of pa-
tients with invasive aspergillosis (IA). Open Forum Infect Dis.
2018;5:S141.
24. Bongomin F, Maguire N, Moore CB, Felton T, Rautemaa-­Richardson
R. Isavuconazole and voriconazole for the treatment of chronic
pulmonary aspergillosis: A retrospective comparison of rates of ad-
verse events. Mycoses. 2019;62:217-­222.
25. Stull K, Esterberg E, Ajmera M, et al. Use of antifungals and out-
comes among inpatients at risk of invasive aspergillosis or mucor-
mycosis in the USA: a retrospective cohort study. Infect Dis Ther.
2019;8:641-­655.
26. Van Matre ET, Evans SL, Mueller SW, MacLaren R, Fish DN,
Kiser TH. 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.
27. Cheng MP, Orejas JL, Arbona-­Hoddad E, et al. Use of triazoles for
the treatment of invasive aspergillosis: A three-­year cohort analy-
sis. Mycoses. 2020;63:58-­6 4.
28. Samanta P, Clancy CJ, Marini RV, et al. Isavuconazole is as ef-
fective as and better tolerated than voriconazole for antifun-
gal prophylaxis in lung transplant recipients. Clin Infect Dis.
2021;73:416-­426.
29. Rausch CR, DiPippo A, Jiang Y, et al. Comparison of mold active tri-
azoles as primary antifungal prophylaxis in patients with newly di-
agnosed acute myeloid leukemia in the era of molecularly targeted
therapies. Clin Infect Dis. 2022;75:1503-­1510.
30. Kohno S, Izumikawa K, Takazono T, et al. Efficacy and safety of is-
avuconazole against deep-­seated mycoses: A phase 3, randomized,
open-­label study in Japan. J Infect Chemother. 2023;29:163-­170.
31. Klingspor L, Saaedi B, Ljungman P, Szakos A. Epidemiology and out-
comes of patients with invasive mould infections: a retrospective
observational study from a single centre (2005-­2009). Mycoses.
2015;58(8):470-­477.
32. Cornely OA, Arikan-­Akdagli S, Dannaoui E, et al. ESCMID and
ECMM joint clinical guidelines for the diagnosis and management
of mucormycosis 2013. Clin Microbiol Infect. 2014;20:5-­26.
33. Natesan SK, Chandrasekar PH. Isavuconazole for the treatment
of invasive aspergillosis and mucormycosis: Current evidence,
safety, efficacy, and clinical recommendations. Infect Drug Resist.
2016;9:291-­3 00.
34. Risum M, Vestergaard MB, Weinreich UM, Helleferg M, Vissing
NH, Jorgensen R. Therapeutic drug monitoring of isavuconazole:
Serum concentration variability and success rates for reaching tar-
get in comparison with voriconazole. Antibiotics. 2021;10:487.
35. Desai AV, Kovanda LL, Hope WW, et al. Exposure-­response re-
lationships for isavuconazole in patients with invasive aspergil-
losis and other filamentous fungi. Antimicrob Agents Chemother.
2017;61:e01034-­17.
36. Kovanda LL, Petraitiene R, Petraitis V, et al. Pharmacodynamics of
isavuconazole in experimental invasive pulmonary aspergillosis:
 |

14390507, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/myc.13622 by Lain Entralgo, Wiley Online Library on [12/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
10 KATO et al.

implications for clinical breakpoints. J Antimicrob Chemother. 41. Kato H, Hagihara M, Asai N, et al. A systematic review and meta-­
2016;71:1885-­1891. analysis efficacy and safety of azithromycin versus moxifloxacin for
37. Petraitis V, Petraitiene R, Moradi PW, et al. Pharmacokinetics and the initial treatment of Mycoplasma genitalium infection. Antibiotics
concentration-­dependent efficacy of isavuconazole for treatment (Basel). 2022;11:353.
of experimental invasive pulmonary aspergillosis. Antimicrob Agents
Chemother. 2016;60:2718-­2726.
38. Jing R, Morrissey I, Xiao M, et al. In vitro activity of isavuconazole
and comparators against clinical isolates of molds from a multi-
How to cite this article: Kato H, Hagihara M, Asai N, et al. A
center study in China. Infect Drug Resist. 2022;15:2101-­2113.
39. Harrington R, Lee E, Yang H, et al. Cost-­effectiveness analysis off systematic review and meta-­analysis of efficacy and safety
isavuconazole vs. voriconazole as first-­line treatment for invasive of isavuconazole for the treatment and prophylaxis of
aspergillosis. Adv Ther. 2017;34:207-­220. invasive fungal infections. Mycoses. 2023;00:1-10.
40. Floros L, Kuessner D, Posthumus J, Bagshaw E, Sjolin J. Cost-­
doi:10.1111/myc.13622
effectiveness analysis of isavuconazole versus voriconazole for
the treatment of patients with possible invasive aspergillosis in
Sweden. BMC Infect Dis. 2019;19:134.