Internal Medicine Journal - 2021 - Teh - Consensus Guidelines For Antifungal Prophylaxis in Haematological Malignancy and

doi:10.1111/imj.
15588
S U P P L E M E N T A RT I C L E
Consensus guidelines for antifungal prophylaxis

in haematological malignancy and haemopoietic
stem cell transplantation, 2021
Benjamin W. Teh,1,2,3 Daniel K. Yeoh,2,3,4 Gabrielle M. Haeusler,1,2,3,5,6 Costas K. Yannakou,7 Shaun Fleming,8
Julian Lindsay2,3,9 and Monica A. Slavin,1,2,3,10 Australasian Antifungal Guidelines Steering Committee*
1
Department of Infectious Diseases, and 3National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, 2Sir Peter MacCallum Department
of Oncology, University of Melbourne, 5Department of Infectious Diseases, Royal Children’s Hospital, 7Department of Molecular Oncology and Cancer
Immunology, Epworth Freemasons Hospital, Epworth HealthCare, 8Malignant Haematology and Stem Cell Transplantation Service, Alfred Health, and
10
Immunocompromised Host Infection Service, Royal Melbourne Hospital, Melbourne, 6Murdoch Children’s Research Institute, Parkville, Victoria,
4
Department of Infectious Diseases, Perth Children’s Hospital, Perth, Western Australia, and 9Department of Haematology, Royal North Shore Hospital,
Sydney, New South Wales, Australia
Key words Abstract

antifungal prophylaxis, Aspergillus, Candida,
stem cell transplantation, haematological Antifungal prophylaxis can reduce morbidity and mortality from invasive fungal disease
malignancy. (IFD). However, its use needs to be optimised and appropriately targeted to patients at
highest risk to derive the most benefit. In addition to established risks for IFD, consider-
Correspondence able recent progress in the treatment of malignancies has resulted in the development
Benjamin W. Teh, Department of Infectious of new ‘at-risk’ groups. The changing epidemiology of IFD and emergence of drug
Diseases, Peter MacCallum Cancer Centre, resistance continue to impact choice of prophylaxis, highlighting the importance of
305 Grattan Street, Melbourne, Vic. 3000, active surveillance and knowledge of local epidemiology. These guidelines aim to high-
Australia. light emerging risk groups and review the evidence and limitations around new formu-
Email: ben.teh@petermac.org lations of established agents and new antifungal drugs. It provides recommendations
around use and choice of antifungal prophylaxis, discusses the potential impact of the
. changing epidemiology of IFD and emergence of drug resistance, and future directions
for risk stratification to assist optimal management of highly vulnerable patients.
Introduction antigen receptor (CAR) T-cell therapy).1–3 These thera-

peutic advances have led to significant improvements
In the 7 years since the publication of the last guide-
in disease prognosis and survival; however, in
lines, the treatment of malignancies has undergone a
haematological malignancy, they also appear to be
paradigm shift with the increasing use of targeted oral
associated with new potential risks for invasive fungal
therapies (e.g. Bruton’s tyrosine kinase (BTK) inhibi-
disease (IFD).4 Other well-established risks for IFD,
tors) and the advancement of immune-based therapies
such as prolonged neutropenia and graft-versus-host
(e.g. immune checkpoint inhibitors (ICI), chimeric
disease (GVHD), remain relevant and unchanged from
previous guidelines.5
The landscape for the prevention and treatment of IFD
Funding: None.
Conflict of interest: The following working group members are has also evolved with the development of new antifun-
consultants or advisory committee members or receive gal therapies, as well as new formulations of established
honoraria, fees for service, or travel assistance from; or have agents, for treatment and prophylaxis.6,7 Selection of the
research or other associations with the organisations listed:
B. W. Teh – Merck Sharp and Dohme (MSD), Gilead Sciences,
optimal prophylactic agent is now impacted by new chal-
Janssen and CSL-Behring; J. Lindsay – MSD, Amgen and lenges, such as the emergence of the multi-drug resistant
Mayne; M. A. Slavin – Pfizer, Gilead Sciences and MSD. fungal pathogen Candida auris, increasing rates of anti-
*Australasian Antifungal Guidelines Steering Committee:
fungal resistance in Aspergillus spp., and the changing
Christina C Chang, Christopher C Blyth, Sharon C-A Chen,
Anna Khanina, C. Orla Morrissey, Jason A. Roberts, Karin A epidemiology of invasive candidiasis and non-Aspergillus
Thursky, Leon Worth, Monica A Slavin. moulds.8–10
Internal Medicine Journal (2021) 51(Suppl. 7) 67–88 67

© 2021 Royal Australasian College of Physicians.
14455994, 2021, S7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/imj.15588 by Cochrane Romania, Wiley Online Library on [30/01/2024]. 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
Teh et al.
The current guidelines take all of these developments Question 1. What new therapies for
into account and serve as an update to the 2014 guide- haematological malignancies are
lines.5 Primary antifungal prophylaxis is recommended associated with potential risk for IFD
for disease groups associated with a high risk of IFD. Not and what are the new risk groups?
surprisingly, the higher the baseline prevalence of IFD,
the more marked the beneficial effect of prophylaxis is.11 Recommendations
When implementing prophylaxis regimens, consider-
ation must also be given to institutional epidemiology, • Due to the absence of high-level evidence, the routine
and relevant adjustments made. Most of the available use of antifungal prophylaxis is not recommended for
evidence for prophylaxis relates to haematological malig- the majority of patients undergoing treatment with new
nancies, and this is the primary focus of these guidelines. haematological treatments; rates of IFD with new thera-
For solid organ tumours, the need for prophylaxis pies are summarised in Table 2. Antifungal prophylaxis
remains undefined and expert advice should be sought should be considered on an individual patient risk model
on an individual case-by-case basis. (see Table 3).
• For patients receiving new generation immunomodu-
latory, monoclonal antibody therapy for relapsed and
Methodology refractory myeloma, prophylaxis with fluconazole could
be considered (Marginal recommendation, Level III
Questions asked evidence).
• For patients undergoing CAR T-cell therapy, prophy-
This update addresses the following questions:
laxis with fluconazole should be considered (Strong rec-
ommendation, Level II evidence).
1 What new therapies for haematological malignancies • For patients deemed at higher risk of fungal infection
are associated with potential risk for IFD and what are (e.g. due to severe neutropenia or multiple lines of ther-
the new risk groups? apy, treatment of cytokine release syndrome (CRS)),
2 Is there new evidence to support and guide the use of mould-active azole prophylaxis could be considered
established prophylactic agents? (Moderate recommendation, Level II evidence).
3 What are the new options for antifungal prophylaxis? • For patients with a prior history of IFD, secondary
4 How does the use of mould-active antifungal prophy- prophylaxis should be administered (Marginal recom-
laxis impact diagnostic testing? mendation, Level III evidence).
5 What critical drug–drug interactions do clinicians need
to be aware of and what is the need for therapeutic drug
Given recent advances in the treatment of
monitoring (TDM) in the era of targeted and immune-
haematological malignancies and the potential association
based therapies?
between these newer agents and IFD risk, this section dis-
6 How do antifungal resistance patterns affect choice of
cusses new advances in the treatment of haematological
prophylaxis?
malignancies, their potential association with risk for IFD
7 What special considerations are required in the paedi-
and the resultant recommended approach to prevention of
atric setting?
IFD. Established risk groups for IFD are summarised in
8 How could antifungal prophylaxis recommendations
Table 1.
be implemented into practice?
9 Are there new approaches to defining risk for IFD?
Targeted and immunomodulatory drug
therapies
Search strategy
Since the publication of the previous guidelines, an
A comprehensive literature search was performed increasing number of targeted agents have become avail-
utilising PUBMED to address the questions previously able as standard of care options for the treatment of both
outlined. The search encompassed studies published haematology and medical oncology patients. Such
since 2013 and utilised the following terms in combina- agents, through their effects on immune function, may
tion: ‘haematology’, ‘malignancy’, ‘haemopoietic stem increase the risk of IFD.12 Reported rates of IFD accom-
cell transplantation’, ‘haematopoietic stem cell trans- panying the use of these agents vary according to the
plantation’, ‘leukaemia’, ‘myeloma’, ‘lymphoma’, ‘risk patient group being treated (i.e. treatment naïve vs
factors’, ‘antifungal’, ‘prevention’, ‘prophylaxis’ and relapsed/refractory malignancy); previous treatments
‘invasive fungal infection’. used, including number of lines of therapy; and whether
68 Internal Medicine Journal (2021) 51(Suppl. 7) 67–88

Antifungal prophylaxis guidelines 2021
Table 1 Established risk groups for IFD and recommended antifungal prophylaxis coverage in adults
Risk level Risk groups Recommended SoR QoE

prophylaxis†
High risk >10% incidence Neutrophil <0.1 109/L for >3 weeks or First line: A I
of IFD <0.5 109/L for >5 weeks (e.g. allogeneic Posaconazole
HSCT) Alternate agents:
Corticosteroids >1 mg/kg prednisolone Voriconazole
equivalent and neutrophils <1 109/L for Itraconazole
>1 week Micafungin
Corticosteroids >2 mg/kg prednisolone Liposomal
equivalent >2 weeks amphotericin
Unrelated, mismatched or cord blood Isavuconazole
allogeneic HSCT
GVHD – extensive or severe
AML – induction/reinduction
ALL – induction/reinduction
MDS
Low risk Less than 5% Autologous HSCT (e.g. patients at high risk First line: B II (context dependent; level I evidence
incidence of IFD for mucositis) Fluconazole in setting of alloHSCT)
Allogeneic HSCT with expected Alternate agents:
neutropenia <14 days Echinocandins
Lymphoma (e.g. intensive/dose-escalated Itraconazole
therapy)
Very low risk‡ Less than 5% Other lymphoproliferative neoplasms (e.g. No prophylaxis B II
incidence of IFD standard chemotherapy for lymphoma,
No mucositis induction therapy for myeloma,
treatment-naïve CLL)
Other myeloproliferative neoplasms
Treatment for solid organ tumours
†Please refer to Table 4 for summary of recommendations and level of evidence supporting choice of antifungal prophylaxis agents.
‡Consider that low and/or sporadic occurrence is not equal to no risk and is dependent on underlying treatment regimen, previous and cumulative
treatments.
ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; CLL, chronic lymphocytic leukaemia; GVHD, graft versus host disease; HSCT,
haemopoietic stem cell transplantation; IFD, invasive fungal disease; MDS, myelodysplastic syndrome; QoE, quality of evidence; SoR, strength of
recommendation.
these agents are used in combination with other thera- patients developed IFD within 3–6 months of starting
pies, especially conventional chemotherapy that induces ibrutinib.
mucositis or prolonged neutropenia. Substantially higher IFD rates of 38.9% (7/18) have
Ibrutinib, a BTK inhibitor commonly used for the treat- been observed in the context of primary CNS lymphoma
ment of chronic lymphocytic leukaemia (CLL) and other treated with ibrutinib, potentially due to the concomitant
B-cell lymphoproliferative disorders, interrupts B-cell recep- use of chemotherapy and corticosteroid agents.17 This
tor signalling and also results in hypogammaglobulinaemia. emphasises the additional risk imposed when combining
There is an association between ibrutinib therapy and risk BTK inhibition with other immunosuppressive therapies.
of IFD. A retrospective study of 378 patients receiving Cases of IFD, including Pneumocystis jirovecii pneumo-
ibrutinib (monotherapy in 84% of cases) reported an IFD nia, have been reported in association with the use of
rate of 4.2%, with the majority of IFD cases lacking classical other tyrosine kinase inhibitors such as Janus kinase
risk factors such as neutropenia or corticosteroid usage.13 (JAK) inhibitors,18,19 phosphatidylinositol 3-kinase
Local, real-world data suggests an IFD rate as high as (PI3K) inhibitors,20 B-cell lymphoma 2 (BCL-2) inhibi-
12.1% in patients treated with ibrutinib monotherapy in tors (venetoclax)21 and mammalian target of rapamycin
the setting of relapsed/refractory CLL.14 These findings con- (mTOR) inhibitors.22 In retrospective studies, the use of
trast the 1% IFD rate reported in the randomised, phase hypomethylating agents, such as azacitidine in patients
3 RESONATE study.15 The majority of fungal infections with myelodysplastic syndromes and acute myeloid leu-
reported were invasive aspergillosis with a predilection for kaemia (AML), has been associated with an IFD risk of
central nervous system (CNS) involvement (40%).16 Most up to 8.3% – consistent with the risk posed by treatment

Teh et al.
of the underlying disease.23,24 The greatest IFD risk was CAR T-cell therapy
observed amongst patients who had received prior inten-
Rates of infective toxicity appear similar in patients receiving
sive chemotherapy.
CAR T-cell therapy or other salvage therapies. Bacterial
In the setting of variable antifungal prophylaxis use
infections are a larger concern, occurring in 23% of patients
(i.e. either an azole, echinocandin, or none), the use of
receiving CAR T-cell therapy, predominately during the first
hypomethylating agents in combination with the BCL-2
28 days following CAR T-cell infusion. IFD rates in trials of
inhibitor venetoclax for newly diagnosed and relapsed or
ALL and B-cell lymphoma have ranged between 5 and 13%
refractory AML, was associated with an overall IFD rate
depending on the disease group.31,32,36 In a dedicated study
of 12.6%.25 The IFD rate in newly diagnosed AML was
of infectious complications with CAR T-cell therapy, 5% of
5.0%.25 The addition of an fms-like tyrosine kinase
patients developed a fungal infection in the setting of flucon-
(FLT3) inhibitor (midostaurin, gilterinib) to standard
azole prophylaxis.4 An IFD rate of 7% has also been reported
chemotherapy for the treatment of FLT3-positive AML
with the use of micafungin prophylaxis in ALL patients man-
has been demonstrated to improve survival.26,27 How-
aged with CAR T-cell therapy.37 Patients with ALL appear to
ever, the impact on IFD rates beyond that expected of
be at a higher risk of infection if they have received four or
the underlying AML remains undefined. In an early clin-
more prior lines of therapy, been treated with higher CAR
ical trial, an IFD rate of 5% was reported.26 These
T-cell therapy doses, developed CRS or used systemic corti-
targeted agents, particularly BTK inhibitors and BCL-2
costeroid agents during their CAR T-cell therapy.4,38,39
inhibitors, have significant CYP3A4 interactions with
Potentially, a subset of patients with prolonged neutropenia
azole antifungals, necessitating their dose adjustment.3
or with higher-grade CRS requiring additional immunosup-
IFD rates of 3.8–5.6% were reported in patients with
pressive treatments (e.g. corticosteroid agents) may be at
multiple myeloma (MM) treated with first-generation
higher risk for mould infections.
immunomodulatory drugs and proteasome inhibi-
tors.28,29 The rate of invasive mould infection was less
than 1.0%.28 An IFD rate of 15% was reported in Bi-specific immune engagers
patients who had received three or more lines of ther-
apy, including conventional chemotherapy.28 In con- At the time of publication, blinatumomab is the only bi-
trast, a recent study of a heavily treated MM patient specific immune engaging agent in clinical practice and is
cohort (median five lines of therapy) treated with next- indicated for patients with ALL, both relapsed/refractory
generation immunomodulatory drugs, proteasome disease and minimal residual disease. Blinatumomab is
inhibitors and new anti-CD38/SLAM-F7 monoclonal only modestly myelosuppressive and does not cause
antibody therapies, reported a low overall IFD rate of mucotoxicity. However, it can be associated with neutro-
3.4%.30 The rates ranged from 2.3 to 7.0% per the spe- penia and risk of infection can be compounded by prior
cific drug classes. Patients with IFD had received more therapies received. Fungal infection is relatively rare; how-
lines of therapy and all proven IFD cases involved yeasts, ever, early development of neutropenia has been associ-
that is cryptococcal infection and Pichia kudriavzeveii (for- ated with an increased risk of possible fungal infection.35,40
merly Candida krusei).30 Rates of IFD associated with these emerging cancer
therapies and potential new risk groups are summarised
in Table 2 and recommended approaches to prophylaxis
are summarised in Table 3. There should be an increased
Adoptive T-cell therapies awareness of the potential risk and clinicians should have
Adoptive T-cell therapies such as CAR T-cell therapy a low threshold for initiating investigations for suspected
and bi-specific constructs such as bi-specific T-cell IFD in the setting of compatible symptoms such as persis-
engagers (BiTE) (e.g. blinatumomab) have now tent fever or pulmonary infiltrates.
become standard of care in relapsed, high-grade B-cell
malignancies: CAR T-cell therapy for diffuse large
Question 2. Is there new evidence
B-cell lymphoma and paediatric acute lymphoblastic
to support and guide the use of
leukaemia (ALL), and blinatumomab for ALL. Patients
established prophylactic agents?
receiving these therapies have often had multiple prior
lines of therapy, including HSCT, which may influence
Recommendations
their fungal infection risk. Other agents such as
fludarabine may be administered prior to CAR T-cell • Posaconazole remains recommended as a first-line
infusion, which may further increase fungal infection agent for IFD prophylaxis in high-risk patients (Strong
risk.31–35 recommendation, Level I evidence).

Table 2 Summary of IFD rates associated with emerging use of new generation cancer therapies
Therapy Population IFD rates (%) Comments
BTK inhibitor (e.g. ibrutinib) Relapsed/refractory B-cell 3–12 Rates of 1% reported in clinical trials of BTK
lymphoproliferative disorder inhibitors
Invasive aspergillosis with CNS involvement
up to 40%
Cryptococcus spp.
Pneumocystis jirovecii pneumonia
Primary CNS lymphoma 5–44 In combination with corticosteroids and
conventional chemotherapy
PI3K inhibitor (e.g. idelalisib) Relapsed/refractory B-cell 3 Pneumocystis jirovecii pneumonia
lymphoproliferative disorder
BCL-2 inhibitor (e.g. venetoclax) CLL 1 Aspergillus spp., Pneumocystis jirovecii
pneumonia
Hypomethylating agents (e.g. MDS 5–13 Rates higher in relapsed/refractory disease
azacitadine) AML versus its use as front-line therapy
Rate of 13% when used in combination with
BCL-2 inhibitor venetoclax
Aspergillus spp., Candida spp.
FLT-3 inhibitors (e.g. midostaurin, AML 5 Limited data from clinical trial
gliteritinib)
Second generation IMiD, PI Relapsed/refractory myeloma 2–7 Candida spp., Cryptococcus spp.
CD38 or SLAMF7 monoclonal
antibodies
CAR T-cell therapy Relapsed/refractory ALL 5–8 In the setting of fluconazole or micafungin
Relapsed/refractory NHL prophylaxis
Rates up to 13% in patients with ALL
Aspergillus spp., Candida spp., Mucor spp.
Bi-specific antibody therapies (e.g. Relapsed/refractory ALL 2 Limited clinical trial data
blinatumomab) Relapsed/refractory NHL
ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; BCL-2, B-cell lymphoma 2; BTK, Bruton’s tyrosine kinase; CAR, chimeric antigen
receptor; CLL, chronic lymphocytic leukaemia; CNS, central nervous system; FLT-3, fms-like tyrosine kinase; IFD, invasive fungal disease; IMiD, immuno-
modulatory drug therapy; MDS, myelodysplastic syndrome; NHL, non-Hodgkin lymphoma; PI, proteasome inhibitor; PI3K, phosphatidylinositol
3-kinase; SLAMF7, signalling lymphocytic activation molecule F7.
• Voriconazole is considered to be an alternate agent for Network meta-analyses of randomised controlled trials
IFD prophylaxis due to higher rates of adverse events of triazole prophylaxis confirm posaconazole’s efficacy for
(e.g. liver function abnormalities) and variable metabo- the prevention of proven or probable IFD and invasive
lism (Strong recommendation, Level II evidence). aspergillosis, reducing the requirement for empiric anti-
• Use of micafungin could be considered during periods of fungal therapy and all-cause mortality compared to flu-
neutropenia in high-risk patients if the use of azoles is con- conazole and itraconazole.41–43 Although posaconazole
traindicated or in the setting of expected poor gastrointestinal was not significantly better than voriconazole for preven-
absorption (Moderate recommendation, Level II evidence). tion of IFD and invasive aspergillosis, it was the highest-
• Itraconazole is considered to be an alternate agent due ranked agent for achieving these outcomes in two publi-
to a lower number of clinical trials and cohort studies shed network meta-analyses.41,43 When evaluated, its use
(Moderate recommendation, Level II evidence). appears to be cost-effective compared to voriconazole.41
• Use of liposomal amphotericin B could be considered if Cohort studies evaluating posaconazole against
the use of azoles is contraindicated due to drug–drug voriconazole, itraconazole or micafungin consistently
interactions, adverse events or poor absorption (Moderate report lower rates of IFD with posaconazole ranging
recommendation, Level II evidence). from 0 to 5% versus 5 to 11%.44–48 For patients
undergoing HSCT, observational cohort studies have
shown that rates of breakthrough IFD during prophy-
Posaconazole
laxis with posaconazole suspension remain low at
Posaconazole remains the preferred agent for prophy- between 3 and 8%.49,50 Cohort studies of AML patients
laxis against IFD in high-risk patients with AML or for report similarly low rates of proven or probable break-
those undergoing allogeneic HSCT. through IFD (0–7%).45,51,52

Teh et al.
Table 3 Summary of key new haematological treatments and recommended approaches to prophylaxis in adults and children
Therapy Patient group Infection Measures SoR QoE
Targeted therapies (e.g. BTK Relapsed/refractory B-cell Yeast and Need for prophylaxis should be B II
inhibitors) lymphoproliferative disorders mould determined taking into account
infections recent therapy (e.g. fludarabine-
based), ongoing immune
suppression and presence/
absence of previous IFD
Immunomodulatory drug therapy, Relapsed/refractory myeloma Yeast infection Need for prophylaxis should be C III
monoclonal antibody therapy determined by number of previous
(CD38/SLAMF7) lines of therapy, risk factors for IFD
such as prolonged neutropenia
and presence/absence of previous
IFD
CAR T-cell therapy Relapsed/refractory Yeast and Yeast prophylaxis with fluconazole A II
lymphoproliferative disorders mould or micafungin
infections Consider mould prophylaxis in the
setting of prolonged neutropenia
or additional treatments for high-
grade cytokine release syndrome
following CAR T-cell therapy
Previous therapies including recent
allogeneic or autologous HSCT
should be taken into account
Bi-specific antibody therapies ALL Yeast and Need for prophylaxis should be C III
Being evaluated for other mould determined taking into account
aggressive B-cell infections recent therapy (e.g. fludarabine-
lymphoproliferative disorders based), ongoing immune
suppression and presence/
absence of previous IFD
ALL, acute lymphoblastic leukaemia; BTK, Bruton’s tyrosine kinase; CAR, chimeric antigen receptor; HSCT, haemopoietic stem cell transplantation; IFD,
invasive fungal disease; QoE, quality of evidence; SLAMF7, signalling lymphocytic activation molecule F7; SoR, strength of recommendation.
Voriconazole The only new data supporting the use of intravenous

itraconazole or its solution are from a few cohort studies
Voriconazole is an alternate agent for IFD prophylaxis.
reporting IFD rates of 1–7% for HSCT patients and 5%
Meta-analyses show no significant difference between
for patients with AML.53,57,58
posaconazole and voriconazole efficacy for the prevention
of proven or probable IFD and invasive aspergillosis.41–43
However, a significantly higher risk for treatment-related
liver abnormalities was noted, compared to other azo- Micafungin
les.41,43 In the same analysis, this agent is ranked second
There have been further studies evaluating the use of
as an effective prophylaxis agent.41 In cohort studies of
micafungin during the neutropenic period in HSCT
AML patients, the use of voriconazole prophylaxis was
patients. In two trials, the rate of IFD was not signifi-
associated with an IFD rate of 3–5%.48,53,54 Due to vari-
cantly different when assessed against fluconazole and
able metabolism, CYP2C19 testing prior to commence-
itraconazole at 7.3 and 4.4% respectively.57,59 Adverse
ment could assist with dose selection (please refer to the
event rates were significantly higher with itraconazole.57
accompanying optimising antifungal therapy and TDM
Different doses have been assessed but, in general, dos-
guidelines by Chau et al. 2021182, which can be found
ing with 100–150 mg intravenous (IV) daily followed by
elsewhere in this supplement).55,56
oral voriconazole or posaconazole on discharge, led to
proven or probable IFD rates of between 1 and 4%.60–62
In the AML cohort, the rate was 6.3%.47 Overall, the use
Itraconazole
of micafungin could be considered during the neutrope-
Since the 2014 guidelines, a new formulation of nic period in high-risk patients if use of azoles is con-
itraconazole has been introduced (see later discussion). traindicated or there are concerns about absorption.

Liposomal amphotericin B non-inferiority compared to voriconazole in the SECURE

trial and for the treatment of mucormycosis, either as
Evidence supporting the use of liposomal amphotericin
primary treatment or for treatment of infection refrac-
B (L-AMB) remains limited. A recent randomised trial of
tory or intolerant to other antifungals, based on a mixed
L-AMB at 5 mg/kg twice a week compared to placebo
group of patients in the VITAL study.6,65 Based on its
for prophylaxis in ALL reported no difference in the rate
broader spectrum of activity and improved side-effect
of proven or probable IFD (7.9 vs 11.7%; P = 0.24);
profile, it is being evaluated as prophylaxis in patients
however, a significantly higher rate of adverse events led
with AML and allogeneic HSCT in prospective trials. In
to interruption of L-AMB in 20.3% of patients.63 Post hoc
an early Phase 2 dose-escalation study, the rate of break-
analysis did report a trend for lower IFD rates in patients
through invasive fungal infection was 10%.66
who were administered L-AMB prophylaxis (7.6 vs
Results from its use as prophylaxis, as reported in pro-
14.4%; P = 0.07).63 In a cohort study of Australian ALL
spective studies, retrospective studies and case reports,
patients, use of L-AMB at a median dose of 100 mg three
have been variable.67–71 In a mixed population of relapsed
times per week had a similar rate of IFD to posaconazole
refractory and HSCT patients, a breakthrough rate of 5.8%
(6 vs 7%), and a lower rate compared to both flucona-
was reported.70 However, the use of isavuconazole as pro-
zole (14.3%) and no prophylaxis (21%).64 At this stage,
phylaxis in newly diagnosed AML was associated with a
evidence supporting its use remains poor but this agent
rate of 7.9%. This is higher than the rate reported with
could be considered in the setting of azole intolerance or
posaconazole (2.7%), but is not statistically significant
contraindication. Optimal dosing of this agent for pro-
(P = 0.06).68 Posaconazole was used for a longer period in
phylaxis requires further evaluation. Doses ranging from
patients with a longer duration of neutropenia.68 A pro-
50 to 200 mg, three times per week, have been used.
spective single-centre, single-arm, primary prophylaxis
Recommendations by risk group and grading of evi-
study in AML and myelodysplastic syndrome reported an
dence for the selection and dosing of an antifungal pro-
overall breakthrough rate of 18.0% with a proven/
phylactic agent are summarised in Table 4.
probable rate of 6.0%.71 Half the patients were receiving
treatment with oral targeted anti-leukaemic agents such as
Question 3. What are the new options venetoclax, which has CYP3A4-mediated drug–drug inter-
for antifungal prophylaxis? actions when co-administered with other azoles.71
Use of isavuconazole as prophylaxis in the setting of
Recommendations relapsed or refractory AML has been associated with break-
through rates of between 12 and 18.5%,68,69 higher
• Isavuconazole is not recommended as a first-line agent than that reported with posaconazole and voriconazole
for prophylaxis against IFD in high-risk patients due to (5.5%).68 When performed in a subset of patients,
higher reported rates of IFD in cohort studies. Its use can isavuconazole levels appeared to be adequate.68,70,71 In the
be considered if azoles are contraindicated (e.g. QTc pro- majority of cases, breakthrough infections were due to
longation) (Moderate recommendation, Level II evidence). Aspergillus spp. and Mucor spp.68,69 The use of isavuconazole
• There is insufficient evidence to support use of the new following micafungin prophylaxis in HSCT patients has
formulation of itraconazole as a first-line agent for prophy- been associated with an IFD rate of 3.1%. In this study, all
laxis against IFD (Moderate recommendation, Level II evi- IFD were bloodstream infections with Candida parapsilosis
dence). However, it is used in several Australian centres. and Candida glabrata.72 Tolerability appears to be good with
• Oral posaconazole remains recommended as a first- a low risk of QTc prolongation in the setting of potential
line agent for IFD prophylaxis in high-risk patients (tab- drug–drug interactions.71 Evidence from trials being con-
lets are preferred but in some cases, suspension may be ducted may provide further clarity.
necessary, in which case, prescribers should consult with Currently, the use of isavuconazole as a first-line agent
pharmacy regarding levels and dosing) (Strong recom- for prophylaxis in patients with AML and HSCT cannot
mendation, Level I evidence). Intravenous formulation be recommended due to higher observed IFD rates in
is an option for continuation of posaconazole prophy- uncontrolled cohort studies. Its use could be considered
laxis in the setting of poor or limited oral intake. in the setting of intolerance or if use of other azoles is
contraindicated.
Isavuconazole
New formulation of itraconazole
Isavuconazole is a recently introduced broad-spectrum
triazole antifungal agent. It has been licensed for the A novel formulation of itraconazole (SUper BioAvailabil-
treatment of invasive mould disease on the basis of ity (SUBA)-itraconazole) has been approved in Australia

Teh et al.
Table 4 Recommendations for choice and dose of antifungal prophylaxis agent in adults
Risk group Antifungal agent SoR QoE Comments
High risk First line Posaconazole A I Intravenous formulation can be used to continue
Oral (tablets) prophylaxis if poor oral intake/absorption
Loading with 300 mg twice daily on Day 1,
followed by 300 mg daily
Alternate Voriconazole A II High rates of adverse events (liver function
agents Oral or intravenous abnormalities); variable CYP metabolism
4 mg/kg twice daily†
Micafungin B II Could be used during periods of neutropenia if
Intravenous azoles contraindicated, poor oral intake/
100–150 mg daily absorption
Itraconazole B II Less new data supporting its use compared to
Oral other azoles
200 mg twice daily
Liposomal amphotericin B II Could be used if azoles contraindicated due to
Intravenous drug–drug interactions, adverse events, poor
50–200 mg three times per week oral intake/absorption
Isavuconazole C II Higher rates of IFD in cohort studies; could be
Oral used if other azoles contraindicated due to
200 mg three times per day for 48 h followed by adverse events such as QTc prolongation
200 mg daily
Low risk First line Fluconazole A I
Oral
200–400 mg daily
Alternate Echinocandin A II
agents Intravenous
Dosing dependent on agent
Itraconazole A II
Oral
200 mg twice daily
Very low No prophylaxis B II
risk
†Dose used in prophylaxis studies have been 200 mg twice daily; measure voriconazole levels to ensure achievement of target level (refer to accom-
panying optimising antifungal therapy and TDM guidelines by Chau et al. 2021182, which can be found elsewhere in this supplement).
CYP, cytochrome P450; IFD, invasive fungal disease; QoE, quality of evidence; QTc, corrected QT interval; SoR, strength of recommendation.
since 2014.73,74 At the time of the 2014 guidelines, only formulations.76 In another small retrospective cohort
data from healthy volunteer studies were available on study (n = 74) of myeloma, AML, ALL, autologous and
the SUBA-itraconazole formulation, which demon- allogeneic HSCT patients, therapeutic concentrations
strated that this formulation is not affected by gastric pH were achieved at a median of 7 days by 87% of
with dosing recommendations differing from the previ- patients.76 The incidence of IFD reported in both studies
ous conventional itraconazole capsule formulation.75 was low at 3 and 1% respectively; however, the studies
However, recently there have been several small cohort were too small to accurately assess efficacy. It should be
studies demonstrating good tolerability and levels in noted that despite the manufacturer’s recommendation
the therapeutic range using SUBA-itraconazole in to use half the relative dose of the conventional capsules,
haematology and HSCT recipients.76,77 One small pro- both studies used SUBA-itraconazole at the rec-
spective cohort (n = 57) compared SUBA-itraconazole ommended dose range of the itraconazole oral solution
for primary prophylaxis in an allogeneic HSCT cohort to (i.e. 200 mg twice daily with TDM used to monitor levels
itraconazole oral solution. Therapeutic concentrations and dose-adjust accordingly).
were achieved significantly more quickly in the SUBA-
itraconazole group (median of 6 vs 14 days) with thera-
Posaconazole: tablet and intravenous
peutic concentrations achieved in 69 versus 21% of
formulation
patients (P < 0.01). Of note, there were no treatment
failures due to gastrointestinal intolerance, which has Posaconazole modified-release tablet and intravenous
previously limited the use of conventional itraconazole (IV) formulation have been licensed in Australia since

2014 and 2015 respectively. The tablet is listed on the (0.69–2.06) mg/L, taken 3–7 days after commencement.
Pharmaceutical Benefits Scheme (PBS) for prophylaxis The median duration for prophylaxis was 10 days. No
of IFD in specific high-risk groups, namely patients with severe adverse events specifically attributable to IV
anticipated neutropenia while receiving chemotherapy posaconazole were documented, although six courses
for AML or myelodysplastic syndrome, and patients with were curtailed due to potential toxicity.88
acute (Grades II–IV) or extensive-chronic GVHD receiv-
ing intensive immunosuppressive therapy following an
Question 4. How does the use of
allogenic HSCT. The evidence for its efficacy in these set-
mould-active antifungal prophylaxis
tings is extrapolated from the prophylaxis studies using
impact diagnostic testing?
posaconazole oral solution.78,79 Advantages of the tablet
formulation are once-daily dosing, higher drug exposure The performance of diagnostic tests for fungal infection
than with the oral solution,80 and no requirement for is highly dependent on pre-test probability and incidence
concurrent intake of fatty food to improve absorption.81 of IFD.89 Primary antifungal prophylaxis in high-risk
The safety profile is similar between the two formula- patients successfully reduces the incidence of proven or
tions.7 Although, gastric pH was not thought to influence probable IFD to around 5%, with a corresponding reduc-
absorption (which occurs in the small intestine), recent tion in test performance, in particular galactomannan
studies in patients with haematological malignancies or (GM) testing.44,51,90,91 The utility of performing serum
HSCT receiving posaconazole tablets as prophylaxis have GM or Aspergillus PCR testing for IFD surveillance in the
indicated that proton pump inhibitors and corticosteroid setting of primary antifungal prophylaxis appears to be
agents (>0.7 mg/kg daily) may lead to lower plasma con- limited.89–91 However, these assays remain useful as part
centrations with the tablet formulation.82 of a diagnostic-driven algorithm for suspected break-
In real-life studies reporting trough levels in approxi- through IFD in high-risk patients.91,92 The impact of
mately 230 haematological malignancy or HSCT patients antifungal prophylaxis on the performance of a range of
receiving posaconazole tablets, between 3 and 18% of diagnostic tests is discussed in further detail in subse-
patients had sub-therapeutic levels, defined as <700 quent sections of these guidelines.
ng/mL with prophylaxis and <1000 ng/mL with treat-
ment.83–86 These studies may be biased towards
Question 5. What critical drug–drug
detecting lower levels, as levels were not routinely mea-
interactions should clinicians be
sured in all series reported and when performed, it was
aware of and what is the need for TDM
due to clinical concerns about absorption or failure. Cor-
in the era of targeted and immune-
relations with higher posaconazole levels and hepatotox-
based therapies?
icity were not clearly seen in these real-world studies,
although one small report linked through levels >1830
Recommendations
ng/mL and pre-existing liver damage with Grade 3–4
liver injury.84 In these studies, breakthrough infection • Dose adjustment of targeted therapies is required in
did not always occur within the context of low levels, the setting of major CYP3A4 interaction (Strong recom-
indicating that host factors continue to play a role in pro- mendation, Level II evidence).
phylaxis failure. • Use of CYP testing may assist with ascertainment of tar-
IV posaconazole remains an option for continuing get drug level (refer to the accompanying optimising anti-
posaconazole administration when oral medication can- fungal therapy and TDM guidelines by Chau et al. 2021182,
not be taken (e.g. severe mucositis, nausea, vomiting, which can be found elsewhere in this supplement).
GVHD of the gut or a requirement to remain fasting). In • Due to real-world evidence of sub-therapeutic drug
one study, IV posaconazole was given as antifungal pro- levels in up to 20–30% of patients, TDM is still important
phylaxis to 237 neutropenic patients with AML, for new formulations of azole antifungal agents
myelodysplastic syndrome or recipients of allogeneic (Marginal recommendation, Level III evidence).
HSCT.87 The dose was 300 mg of posaconazole IV twice
daily on Day 1, followed by 300 mg IV once daily for at With the introduction of novel targeted therapies for
least 5 days followed by a switch to the oral suspension. haematological malignancies and HSCT, managing the
The mean posaconazole trough level on Day 6 was 1320 drug–drug interactions associated with azole antifungals
ng/mL and posaconazole was well tolerated.87 A real-life requires careful consideration. Of particular note, when
study of patients treated for haematological malignancy using a strong CYP3A4 inhibitor, such as posaconazole,
and HSCT recipients – the majority of whom received itraconazole or voriconazole, in combination with novel
prophylaxis – reported a median trough level of 1.16 targeted therapies that are major CYP3A4 substrates

Teh et al.
such as venetoclax and ibrutinib, manufacturer recom- consideration in lower-risk patients receiving fluconazole
mendations of up to 75% dose reductions of the novel prophylaxis. Multi-drug resistance remains uncommon in
agents are indicated.3,93,94 However, other commonly isolates responsible for candidaemia but azole resistance is
used novel agents such as midostaurin and gilteritinib at 17% and thus ongoing surveillance is vital.10
are considered weak/moderate CYP3A4 substrates and In the last 5 years, Candida auris has emerged as a
dose adjustment is not recommended.95,96 Therefore, healthcare-associated, multi-drug resistant yeast, which
manufacturer recommendations and/or specialist advice has caused significant outbreaks in multiple countries
should be considered before using azoles in combination around the world. It is an effective coloniser of the hos-
with novel targeted therapies. There is also growing evi- pital environment and patients, causing invasive infec-
dence that agents such as letermovir and flucloxacillin, tion (predominantly candidaemia).9 Candida auris is
significantly reduce voriconazole concentrations.97,98 resistant to at least two antifungal drug classes in nearly
These potential interactions further emphasise the 25% of cases.9 At last count, less than 10 cases of this
importance of TDM of azole antifungal agents, particu- infection have been reported in Australia.9,104 An Aus-
larly during changes in concomitant medications, as well tralasian diagnostic, infection prevention and clinical
as during periods of critical illness such as intensive care management approach to this infection has recently
unit admissions.99 In addition, despite superior level been developed with multi-stakeholder involvement.9
attainment from new oral and IV formulations of Multi-triazole-resistant Aspergillus fumigatus have been
posaconazole,7,100 post-marketing experience has isolated in up to 30% of clinical isolates in countries
reported subtherapeutic serum trough concentrations in overseas.105 A 13-year review of Aspergillus fumigatus iso-
approximately 20–30% of haematology patients.84,88,101 lates in the National Mycology Reference Laboratory
Therefore, ongoing use of TDM for these new formula- detected only two isolates carrying the TR34/L98H muta-
tions should be considered. For further information, tion of CYP51A.105 Fortunately, rates of azole resistance
please refer to the accompanying optimising antifungal in Aspergillus fumigatus isolates in Australia appear to be
therapy and TDM guidelines by Chau et al. 2021182, low at 2% of clinical isolates in a limited screen of
which can be found elsewhere in this supplement. human, animal and environmental isolates.106 No azole-
resistant isolates were detected in animal or environmen-
tal isolates.106 Testing of clinical isolates of non-Aspergillus
Question 6. How do antifungal
fungal pathogens in Australia has confirmed expected
resistance patterns affect choice of
susceptibility patterns for the isolated species.107
prophylaxis?
In the setting of antifungal prophylaxis, between 6 and
17% of IFD episodes were due to non-Aspergillus moulds,
Recommendation
which have intrinsic resistance to a range of azole anti-
• The antifungal prophylaxis recommendations in this fungals.108–110 In a national study, Scedosporium spp. and
guideline take into account currently available data on mucormycetes were the dominant species, contributing
antifungal resistance rates and patterns; however, a local up to 80% of IFD caused by non-Aspergillus moulds, with
organisational approach for ongoing surveillance of the underlying haematological malignancy associated with
rates and epidemiology of IFD in high-risk patients is significantly higher odds of mortality.110 Increasing use
important for guiding effective prophylaxis choice of mould-active antifungal prophylaxis will contribute to
(Strong recommendation, Level II evidence). changing epidemiology of IFD in high-risk patients and
active surveillance of breakthrough IFD should continue
Clinicians continue to be challenged by the changing to guide choice of antifungal prophylaxis.
epidemiology of fungal infections over time, emergence
of multi-drug resistant fungi such as Candida auris, and
Question 7. What special
primary antifungal resistance in human and environ-
considerations are required in the
mental isolates.
paediatric setting?
The epidemiology of Candida spp. infection continues to
evolve with increasing use of azoles and echinocandins. A
Recommendations
nationwide surveillance of candidaemia revealed a 1.7-fold
increase in the proportion of candidaemia due to Candida Risk groups for IFD are summarised in Table 5
glabrata.10 Candida glabrata is now responsible for up to
30% of candidaemia102 and is the leading cause of can- • Indications for antifungal prophylaxis in children
didaemia in haematology patients.103 Between 13 and 23% (adapted from Lehrnbecher et al.)11 are provided in
of Candida glabrata isolates are fluconazole-resistant, a key Table 6.

Table 5 Updated risk groups for IFD in children (Adapted from Groll tolerated or contraindicated and daily echinocandin
et al.,111 Science et al.,112 Fisher et al.113 and Lehrnbecher et al.11 with administration is not feasible (Marginal recommenda-
permission.) tion, Level III evidence).
Risk level Clinical examples • Where antifungal prophylaxis is indicated, adminis-
tered during periods of observed or expected severe neu-
High risk (>10%) AML
Recurrent/relapsed acute leukaemia tropenia (Strong recommendation, Level II evidence).
High-risk ALL† • Secondary prophylaxis is recommended for children
Allogeneic HSCT with proven or probable IFD undergoing subsequent
Allogeneic with acute Grade 2–4 GVHD or chronic immunosuppression, particularly during intensive phases
extensive GVHD of chemotherapy (Moderate recommendation, Level III evi-
Low risk (<5%)‡ Standard-risk or low-risk ALL†
dence). For agent selection and duration, specialist infec-
Non-Hodgkin lymphomas
tious diseases advice is recommended.
Autologous HSCT
Sporadic Paediatric solid tumours, Brain tumours, • Dosing recommendations in children are summarised
occurrence‡ Hodgkin lymphoma in Table 7.
Unknown CAR T-cell therapy
Other immunotherapy
†Key change from previous Australian antifungal prophylaxis guidelines

New therapies for haematological
based on TERIFIC study results.114,115 Note, high-risk ALL includes T-cell
ALL, infant ALL, Philadelphia-positive ALL and high-risk B-cell ALL. malignancy and new patient risk groups in
‡Consider that low and sporadic occurrence is not equal to no risk and children
dependant on underlying chemotherapy regimen.
Since the publication of the previous guidelines, the risk
ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia;
CAR, chimeric antigen receptor; GVHD, graft-versus-host disease; HSCT, factors for IFD in children have been further refined
haemopoietic stem cell transplantation; IFD, invasive fungal disease. (Table 5).5 In addition to previously recognised associa-
tions, including haematological malignancy, prolonged
• Where antifungal prophylaxis is indicated, a mould- neutropenia, high-dose corticosteroids and severe-acute
active agent is recommended (Strong recommendation, (grade II or above) or chronic GVHD, age (>7.5 years)
Level I evidence). has now also been identified as a risk factor.113 In an
• The choice of mould-active agent will depend on age, Australian, multisite, 10-year cohort study of IFD in chil-
potential drug interactions and patient location (inpatient vs dren, IFD prevalence in AML and HSCT cohorts was
outpatient), with preference given to mould-active azoles or 28.2 and 11.7% respectively.114,115 IFD prevalence was
echinocandins (Strong recommendation, Level II evidence). <5% in autologous HSCT recipients (3.1%) and children
• Intermittent liposomal amphotericin is an alternative with solid tumours (4.4%). Amongst ALL patients, IFD
option for children in whom azole prophylaxis is not prevalence was 23.5% for relapsed/refractory ALL,
Table 6 Indications for primary antifungal prophylaxis in children based on clinical practice guideline by Lehrnbecher et al.11
Risk classification Clinical example Prophylaxis recommended SoR QoE
High-risk IFD AML (de novo or relapsed) Routine mould-active prophylaxis recommended† A I
ALL (high-risk or relapsed) Routine mould-active prophylaxis should be considered† B III
Allogeneic HSCT (pre-engraftment‡ Routine mould-active prophylaxis recommended† A II
and treatment of GVHD)
Low-risk IFD ALL (standard risk)§ Routine prophylaxis not recommended A III
Solid tumours§ Routine prophylaxis not recommended A II
Most lymphomas§ Routine prophylaxis not recommended A II
Autologous HSCT§ Routine prophylaxis not recommended C III
Prophylaxis recommendations used with permission from lead authors and journal. Strength of recommendations adapted from Lehrnbecher et al.,11
to align with Australian guideline methodology. See in-text discussion for type of agent recommended.
†Choice of mould-active agent will depend on age, potential drug interactions and patient location (e.g. inpatient versus outpatient), with preference
given to mould-active azoles or echinocandins.
‡Fluconazole is a reasonable alternative to a mould-active agent for patients undergoing allogeneic HSCT in the pre-engraftment phase, provided they
do not have a history of proven or probable mould IFD and where local epidemiology supports its use.
§Consider that low risk is not equal to no risk and dependant on underlying disease and chemotherapy regimen. For autologous HSCT, there is less
certainty in the setting of tandem transplantations where the cumulative duration of neutropenia may be longer.
ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; GVHD, graft-versus-host disease; HSCT, haemopoietic stem cell transplantation;
IFD, invasive fungal disease; N/A, not applicable; QoE, quality of evidence; SoR, strength of recommendation.

Teh et al.
Table 7 Suggested dosing for antifungal prophylaxis in children a new infection or progression of a previously docu-
Medication Recommended dose mented probable pulmonary invasive mould
infection.120
Posaconazole† Able to swallow tablets Unable to swallow
Oral (modified-release tablets
tablets) Oral (suspension) New evidence for established prophylactic
300 mg daily (>30 kg)‡ 200 mg three times a agents in children
For dosing options for day (≥13 years)
children weighing <30 For dosing options for An international clinical practice guideline for antifungal
kg, please refer to children <13 years, prophylaxis in children with cancer or HSCT has been
Tragiannidis et al.116 please refer to recently published.11 Underpinning these recommenda-
Boonsathorn et al.100
tions were rigorous and comprehensive systematic
Itraconazole† Oral liquid
2.5 mg/kg (max 200 mg) twice daily
reviews addressing: (i) which paediatric patients should
Voriconazole† 2–<12 years of age OR ≥15 years of age OR routinely receive antifungal prophylaxis and (ii) what
12–14 years of age and 12–14 years of age and agents should be used. Only randomised clinical trials
<50 kg: Oral >50 kg: Oral were considered and evidence rated according to the
9 mg/kg (max 350 mg) 200 mg twice daily Grading of Recommendations Assessment, Develop-
twice daily Intravenous ment, and Evaluation (GRADE) approach.
Intravenous 4 mg/kg twice daily
Below is a summary of the new evidence for prophy-
8 mg/kg twice daily (loading dose 6 mg/kg
laxis in children. For a review of the paediatric literature
(loading dose 9 mg/kg twice daily on Day 1)
twice daily on Day 1) up to 2014, please see the previous Australian guidelines.5
Micafungin Intravenous For a comprehensive review of all published randomised
1 mg/kg (max 50 mg) daily control trials investigating antifungal prophylaxis in adult
Caspofungin Intravenous and paediatric patients, please refer to the recently publi-
50 mg/m2 (max 50 mg) daily shed paediatric antifungal guidelines.11
(70 mg/m2 loading dose on Day 1)
Liposomal Intravenous
amphotericin 1 mg/kg three times per week117 Mould-active azoles
B or
3 mg/kg three times per week118 In a systematic review and meta-analysis, predominantly
or adult pooled data found a significant reduction in proven
2.5 mg/kg twice weekly119 or probable IFD, mould infection or invasive aspergillosis
†Adjust based on therapeutic drug monitoring target trough levels: in patients receiving any mould-active azole compared
posaconazole 0.7 mg/L; itraconazole 0.5–4 mg/L; voriconazole 1–5.5 to fluconazole.11 Compared to echinocandins, there was
mg/L. ‡Not TGA-approved for use in children <13 years of age in no difference in proven or probable infections or mortal-
Australia. ity, although there were more adverse effects in the
TGA, Therapeutic Goods Administration. group receiving mould-active azole prophylaxis. TDM is
recommended for children receiving mould-active azo-
14.5% for high-risk ALL and 7.3% for standard-risk les. Please refer to the accompanying optimising antifun-
ALL, with IFDs more common during induction, consoli- gal therapy and TDM guidelines by Chau et al. 2021182,
dation and delayed intensification phases.114 Across both which can be found elsewhere in this supplement.
relapsed and non-relapsed ALL, mould infections were
more common than non-mould infections. These data
Posaconazole
suggest that a tailored prophylaxis approach is required
for patients with ALL, taking into consideration disease Since 2014, observational studies of children with cancer
risk status, chemotherapy intensity, remission status and or following HSCT have reported a breakthrough
phase of treatment. proven/probable IFD rate between 0 and 4.3% with
There are limited data on risk of IFD with targeted and posaconazole.121–125 Many of these breakthrough IFDs
adoptive T-cell therapies in children. For an overview of occurred in the setting of subtherapeutic levels and all
adult data and approach to prophylaxis in both adults studies included children less than 12 years of age where
and children, please refer to earlier discussion on this data are specifically lacking.
topic, as well as Table 3. In a review of infective compli- In Australia, posaconazole suspension and modified-
cations in 83 children and young adults receiving CAR release tablets are approved for use in children ≥13 years
T-cell therapy, one patient (1.2%) developed a proven of age. There are emerging pharmacokinetic-population
IFD in the first 30 days, although it is unclear if this was studies to guide dosing of both formulations in younger

children (<13 years) (Table 7).100,126 Poor attainment of prophylaxis remains unknown, and varied doses, includ-
target levels using the suspension are reported121,125,127– ing 1 mg/kg thrice weekly, 2.5 mg/kg twice weekly and
129
and tablets are preferred when this is possible (see dis- 3–5 mg/kg thrice weekly, have been used.111,118,140
cussion on new evidence for established agents in chil-
dren).100,127 Where suspension is necessary, higher doses,
increasing dose fractionation (e.g. four times daily (QID) Echinocandins
dosing rather than three times daily (TDS)) and co- Echinocandins are considered a suitable option, along-
administration with a fatty meal are recommended.130 side mould-active triazoles, for primary prophylaxis with
similar efficacy in preventing proven/probable IFD.11
Voriconazole
Since 2014, observational studies of children with cancer Caspofungin
or following HSCT have reported a breakthrough
A recent randomised controlled trial assessing the effi-
proven/probable IFD rate between 0 and 12% with
cacy of echinocandin prophylaxis in 517 children and
voriconazole.131–134 In the study reporting a 12% break-
young adults with AML found a significant reduction in
through rate, patients received voriconazole doses of
proven/probable IFD with caspofungin compared with
between 5 and 10 mg/kg/day,134 which is below the cur-
fluconazole (3.1 vs 7.2%; P = 0.03).141 Both agents were
rently recommended dose (Table 7).135
well tolerated.
Itraconazole
Micafungin
Since 2014, observational studies of children with
Since 2014, observational studies of micafungin prophy-
haematological malignancy or following HSCT have
laxis (predominantly using 1 mg/kg/day) in children
reported a breakthrough proven/probable IFD rate
with cancer or undergoing HSCT, have reported break-
between 0 and 3.2%with itraconazole.122,123,136 No
through IFD rates of 1.5 and 12.8%.131,142–146 Serious
studies included patients receiving SUBA-itraconazole.
drug-related adverse events were rare (0–3%).142–146
Higher micafungin doses (2 and 3 mg/kg daily)147–149
Amphotericin B and intermittent high-dose micafungin (up to 5 mg/kg
weekly)150,151 have been assessed in observational pae-
The aforementioned clinical practice guidelines for anti-
diatric studies, yet comparative data to support wide-
fungal prophylaxis in children with cancer or HSCT
spread use of these strategies are still lacking.152
includes a recommendation against the routine use of
amphotericin B for prophylaxis based on a meta-analysis
of randomised controlled trial data showing amphotericin Evidence for newer antifungal prophylactic
B was not more effective than fluconazole in preventing agents and formulations in children
IFD (risk ratio 0.99; 95% confidence interval (CI): 0.52–
1.88) but was associated with more adverse effects (risk Please refer to the earlier discussion on new options for
ratio 5.63; 95% CI: 1.17–27.02).11 However, while this antifungal prophylaxis in adults, including isavuconazole,
recommendation includes both conventional and lipid for- tablet and IV formulations of posaconazole and SUBA-
mulations, only one randomised controlled trial investi- itraconazole. Specific paediatric data follows.
gated the lipid formulation and none assessed liposomal
amphotericin B (L-AMB) specifically.
Isavuconazole in children
Published data on paediatric isavuconazole dosing, efficacy
Liposomal amphotericin B
and safety is limited to small case series predominantly
Despite the limited supporting data, intermittent L-AMB reporting on its use in the treatment of IFD rather than
continues to be prescribed for prophylaxis, particularly prophylaxis.153–156 In the largest series to date, 29 children
where triazole prophylaxis is not tolerated or con- (median age 14.5 years) received isavuconazole
traindicated and daily IV echinocandins are not feasi- 200 mg/day (>30 kg) or 100 mg/day (<30 kg) following
ble.137 Since 2014, observational studies report a initial loading (TDS dosing for 48 h); no IFD occurred
breakthrough proven/probable IFD rate with L-AMB of amongst five patients receiving isavuconazole for IFD pro-
between 0 and 8%118,131,138,139 and mild renal toxicity phylaxis.153 Weight-based isavuconazole dosing for chil-
of between 8.8 and 22%.118,138 Optimal dosing for dren aged 2–17 years of 10 mg/kg (maximum 372 mg)

Teh et al.
TDS for 48 h and once daily thereafter has been Awareness of potential interactions with novel agents
proposed.153 in paediatric leukaemia treatment is required when pre-
scribing mould-active triazole prophylaxis. Inotuzomab
and gemtuzumab are included in open studies for ALL
New formulation of itraconazole in children and AML treatment respectively.170–172 Monitoring of
There are also limited data on SUBA-itraconazole dosing, QT interval is recommended in the setting of concomi-
efficacy and safety in children. A prophylactic dose of 2.5 tant triazole prophylaxis.3 Venetoclax is increasingly
mg/kg/day has been proposed based on a small paediat- used in children with relapsed or refractory leukae-
ric cohort study.157 mia173,174 and dose reduction by up to 75% is rec-
ommended with concomitant triazole use.3
Posaconazole: tablet and intravenous

Rates of antifungal resistance and choice of
formulation in children
prophylaxis in children
In keeping with the adult literature, the administration
For detailed discussion, please refer to Question 6.
of posaconazole modified-release tablets is associated
with superior attainment of therapeutic levels in children
compared to oral suspension.100,116,158–160 Attainment of Question 8. How could antifungal
target level (>700 ng/mL) in 94% (32/34) of children prophylaxis recommendations be
receiving modified-release tablets using weight-banded implemented into practice?
dosing has been reported (Table 7).116
The adult and paediatric recommendations for antifungal
In two small studies of IV posaconazole for IFD prophy-
prophylaxis outlined in these guidelines take into account
laxis, attainment of target levels was reported in 95–100%
the latest available evidence. While agents are licensed
of children using doses of 6–7 mg/kg/day.161,162 A new
for use by the Therapeutic Goods Administration (TGA),
posaconazole powder formulation for suspension (PFS)
not all agents are reimbursable for use as prophylaxis for
was also assessed in children in one study, with attain-
all at-risk groups under the PBS, which will impact avail-
ment of target levels in 89–94% of patients and no serious
ability and their use, particularly in the paediatric popula-
drug-related adverse effects.161 Although not yet widely
tion. For successful implementation, these guidelines will
available, the PFS could replace liquid posaconazole for
need to be adapted for use at a local institutional level.
children unable to swallow tablets.
Early consideration of potential needs and barriers will
facilitate local adaptation and adoption. Factors for con-
Impact of antifungal prophylaxis on sideration include haematology patient population (leu-
diagnostic testing in children kaemia, HSCT), use of targeted agents, haematology
clinical trials, local epidemiology (i.e. incidence of IFD,
While adult studies have suggested a reduced utility of pattern of fungal infection, rates of fungal resistance), and
GM for IFD screening in patients on mould-active pharmacy cost and budgets. Expertise in infectious dis-
prophylaxis,90,163,164 paediatric specific data are lacking. eases, microbiology and pharmacology are required to
Paediatric guidelines suggest the GM assay, particularly implement these guidelines to optimise the use of pro-
on bronchoscopy specimens, remains useful in children phylaxis and diagnosis of breakthrough infection.
on mould-active prophylaxis with clinically suspected
IFD.165,166
Question 9. Are there new approaches
to defining risk for IFD?
Significant drug–drug interactions and TDM
Antifungal prophylaxis is effective in reducing incidence
in children
of IFD but its use should be optimised and targeted to
Vincristine and azole therapy remain problematic in chil- derive the most benefit. Accurate assessment of risk for
dren undergoing ALL treatment. Concomitant vincris- IFD remains an ongoing challenge with new, emerging
tine use with itraconazole or voriconazole is more haematological treatments that are not associated with
problematic than with fluconazole.167 With increasing known risk factors such as prolonged neutropenia.14
use of posaconazole in the paediatric population, there Genetic polymorphisms of pattern recognition recep-
are also reports of associated severe neuropathic pain,168 tors or soluble acute phase reactants, critical components
myalgia and autonomic neuropathy in patients receiving of mounting an innate response against IFD, have been
concurrent vinka-alkaloids.169 associated with risk for invasive fungal infection.175 In

particular, single nucleotide polymorphisms (SNP) of prophylaxis in high-risk groups remains unclear. New
genes that code for reduced expression or production of antifungal agents introduced for therapy such as
Toll-like receptor 4 (TLR4), Dectin-1, Pentraxin-3 and rezafungin, are undergoing evaluation for use as
mannose-binding lectin, are significantly associated with prophylaxis.180
increased risk for invasive aspergillosis in HSCT and Evidence gaps remain around the need for antifungal
patients with haematological malignancies (odds ratio prophylaxis in the setting of new haematological treat-
between 2.8 and 7.3).175,176 To date, testing for known ments such as BTK inhibitors and CAR T-cell therapy,
SNP has not been translated into clinical practice to help the choice of antifungal prophylaxis for ALL in adults
identify higher-risk patients that may benefit from anti- and children, dosing of the newer formulations in chil-
fungal prophylaxis. dren, and the role of long-acting antifungal agents. These
In the last several years, there have been further are active issues for future research.
advances in platforms for the use of genetic and functional The rapid advances in immune-based haematological
immune profiling. By integrating genome-wide analysis therapies with non-classical impact on immunity and
and systems-level immune profiling (RNA sequencing and risk for IFD highlights the need for new approaches for
cytokine analysis), several genes such as the SERPINA1 IFD risk assessment and early, active systems-based
and MAP3K8 genes, have been identified as potential detection of new at-risk groups. Emergence of drug-
markers for increased susceptibility to candidaemia.177 resistant fungal pathogens requires ongoing active sur-
Cytokine analysis has revealed that higher baseline veillance and knowledge of local IFD epidemiology in
interlukin-2 receptor (IL-2R) and monocyte chemo- order to help tailor recommendations for choice of pro-
attractant protein-1 (MCP-1/CCL2) levels have been asso- phylaxis. While challenges remain, novel antifungal
ciated with higher rates of invasive aspergillosis.178 therapies in development offer new options and will
Due to increased understanding of intestinal micro- change the prophylaxis landscape in the near future.181
biota, a relationship between stem cell transplant-related
dysbiosis, expansion of pathogenic Candida species, and
Acknowledgements
translocation and subsequent invasive bloodstream
infection, has been established.179 Progress has been B. W. Teh is supported by a National Health and Medical
made in identifying genetic markers, immune profiles Research Council Early Career Fellowship and Medical
and mycobiomes associated with increased risk for IFD. Research Future Fund Investigator Fellowship. M. A.
However, the use of testing for known SNP associated Slavin is supported by the Medical Research Future Fund
with increased risk has not been evaluated for its impact Investigator Fellowship. G. M. Haeusler is supported by a
in large prospective cohorts. Validation of potential Murdoch Children’s Research Institute Clinician Scientist
newly identified biomarkers has yet to occur. While not Fellowship and a Victorian Cancer Agency Early Career
yet ready for use in clinical practice, genetic and immune Fellowship. J. Lindsay is supported by a Leukaemia
profiling offers great potential for guiding the optimal Foundation (LF) and Haematology Society of Australia
use of antifungal prophylaxis in the near future. and New Zealand (HSANZ) New Investigator Grant.
The authors would also like to thank members of the
Australasian Leukaemia & Lymphoma Group (ALLG),
Conclusion
the Australasian Society for Infectious Diseases (ASID),
While there have been limited changes to recommenda- the Australian & New Zealand Children’s Haematology/
tions for antifungal prophylaxis in adults since the last Oncology Group (ANZCHOG), the Medical Oncology
published guidelines, there has been a shift in the Group of Australia (MOGA) and the Haematology Society
recognised risk groups and type of prophylaxis (mould vs of Australia and New Zealand (HSANZ) for their review of
non-mould) for children. New formulations have the draft manuscript, and Dr Candice O’Sullivan and
addressed some of the limitations of established agents, Angelica Papanicolaou from Wellmark Pty Ltd. for their
while the utility of newer antifungal agents for assistance in preparing the manuscript for submission.
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doi:10.1111/imj.

Consensus guidelines for antifungal prophylaxis

Key words Abstract

Introduction antigen receptor (CAR) T-cell therapy).1–3 These thera-

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68 Internal Medicine Journal (2021) 51(Suppl. 7) 67–88

Risk level Risk groups Recommended SoR QoE

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Therapy Population IFD rates (%) Comments

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Therapy Patient group Infection Measures SoR QoE

Voriconazole The only new data supporting the use of intravenous

72 Internal Medicine Journal (2021) 51(Suppl. 7) 67–88

Liposomal amphotericin B non-inferiority compared to voriconazole in the SECURE

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Risk group Antifungal agent SoR QoE Comments

74 Internal Medicine Journal (2021) 51(Suppl. 7) 67–88

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76 Internal Medicine Journal (2021) 51(Suppl. 7) 67–88

†Key change from previous Australian antifungal prophylaxis guidelines

Risk classiﬁcation Clinical example Prophylaxis recommended SoR QoE

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78 Internal Medicine Journal (2021) 51(Suppl. 7) 67–88

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Posaconazole: tablet and intravenous

80 Internal Medicine Journal (2021) 51(Suppl. 7) 67–88

References therapies: an infectious diseases leukaemia: mitigating risk in the era of

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82 Internal Medicine Journal (2021) 51(Suppl. 7) 67–88

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86 Internal Medicine Journal (2021) 51(Suppl. 7) 67–88

Internal Medicine Journal (2021) 51(Suppl. 7) 67–88 87

156 De Leonardis F, Novielli C, Giannico B,

88 Internal Medicine Journal (2021) 51(Suppl. 7) 67–88

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