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\begin{document}

\title{Switching antifungals drugs within the triazole drug class: a potential
treatment approach to drug-related hepatotoxicity}



\author[1]{Eloise Silvester}%
\author[1]{Christine Plover}%
\author[1]{Amanda Gwee}%
\affil[1]{The Royal Children's Hospital Melbourne}%


\vspace{-1em}



  
  \date{May 19, 2024}


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\selectlanguage{english}
\begin{abstract}
There are limited data on the best approach to managing azole-induced
hepatotoxicity. One described approach is switching between different
triazole agents to prevent the need for intravenous therapy. This case
series describes the outcomes of this approach in seven children. The
most common azole switch was voriconazole to fluconazole (3/7), followed
by fluconazole to voriconazole (2/7). One child each switched from
voriconazole to itraconazole, and posaconazole to fluconazole. Of the
seven cases, five had Grade 3 liver injury and two had Grade 2 liver
injury. These LFT abnormalities were deemed as `possibly' in four cases,
and `probably' in three cases to be related to the first azole
antifungal as per the Naranjo criteria. All had improvement in their LFT
abnormalities after the switch to an alternative azole antifungal. These
data suggest that switching azole antifungals offers a potential
treatment approach to azole-induced hepatotoxicity.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Invasive fungal infections are an important cause of morbidity and
mortality in children. Triazole antifungal agents are increasingly used
for prophylaxis and treatment of mould infections in paediatric oncology
settings, however, confer a risk of azole-induced hepatotoxicity (AIH),
particularly when concomitantly administered with other hepatotoxic
medications. There are limited data on the best approach to AIH. As
triazole antifungal agents are the only antifungal formulation available
in oral form for children, one described approach is switching between
different triazole agents within the azole class to prevent the need for
intravenous (IV) therapy. To date, there have only been three case
reports and one retrospective audit in adults of this
approach\textsuperscript{1-4}. This study therefore aimed to describe
the outcomes of switching triazole antifungal agents for AIH in
children.

\textbf{Methods}

Using an electronic medical record report in Epic, we identified
children aged 0 to 18 years who switched from one triazole antifungal to
a different triazole while an inpatient at a tertiary referral pediatric
hospital, The Royal Children's Hospital Melbourne (RCH), Australia over
a five-year period (Nov 2016 to Oct 2021). Children were included if
they had: received [?]48 hours of antifungal therapy with the first
triazole; had abnormal liver function tests (LFTs) consistent with
Common Terminology Criteria for Adverse Events
(CTCAE)\textsuperscript{5} Grade 2 liver injury or above prior to
switching triazole antifungals; the first triazole antifungal was
assessed as a possible or probable cause of the LFT abnormality as per
the Naranjo criteria by a paediatric clinical pharmacologist
(AG)\textsuperscript{6}; the child received the second triazole
antifungal within 48 hours of cessation of the first drug and the
abnormal LFTs improved after the switch. Children were included only if
the results of their LFTs were available at baseline (prior to azole
therapy), at the end of their first triazole antifungal course, and
within 2 to 14 days after the antifungal switch and end of therapy.

Clinical data on patient demographics, medical comorbidities, antifungal
agents received, and other hepatotoxic medications administered were
collected. Concomitant hepatotoxic medications and the probability of
effect on deranged LFTs were identified as per
LiverTox\textsuperscript{7}. Ethics approval was obtained from RCH human
research ethics committee (HREC 76476).

\textbf{Results}

Over the five-year period, seven cases fulfilled the inclusion criteria.
The median age was 7.3 years (range 4.2-16.6) and 6/7 were male (Table
1). Four had a hematological malignancy, two had a primary
immunodeficiency and five were hematopoietic stem cell transplant
recipients (HSCT) (Table 1). The most common azole switch was
voriconazole to fluconazole (3/7), followed by fluconazole to
voriconazole (2/7). One child each switched from voriconazole to
itraconazole, and posaconazole to fluconazole.

Of the seven cases, five had Grade 3 liver injury and two had Grade 2
liver injury. All children had an elevated Gamma-glutamyl Transferase
(GGT) level (Grade 2 to 3) and three had Grade 2 Alanine
Aminotransferase (ALT) abnormalities (Table 1; Figure 1). These LFT
abnormalities were deemed as `possibly' in four cases, and `probably' in
three cases to be related to the first azole antifungal as per the
Naranjo criteria \textsuperscript{6}. All had improvement in their LFT
abnormalities after the switch to an alternative azole antifungal,
however, in only two patients, did the LFTs normalise by the end of
treatment (Case 3 and 4, Table 1). The most common concomitant
medications include acetaminophen in all cases,
penicillin/beta-lactamase inhibitors in 5 cases, antiemetics in 4 cases
and chemotherapeutics in 3 cases (Table 1).

\emph{Voriconazole to fluconazole:}

Of the three cases that switched from voriconazole to fluconazole, two
were changed due to suspected drug-related toxicity and the third
stepped down from treatment of possible invasive fungal infection to
prophylaxis (Table 1). All had Grade 3 liver injury prior to the
antifungal switch with peak GGT levels, from 518 to 735 IU/L (12.9 to
18.3 times the upper limit of normal (x ULN)) and two cases had elevated
ALT levels of 140 to 186 IU/L (4.1 to 5.0 x ULN). Immediately prior to
triazole antifungal switch, voriconazole levels were subtherapeutic in
one patient (Case 1 0.34 mg/L one week prior) and within target range in
two others (Case 2 1.48 mg/L three days prior; Case 3 2.87 mg/L five
days prior). However, for Case 3, LFT abnormalities developed two weeks
after a supratherapeutic level, when their voriconazole trough
concentration was 5.94 mg/L. Notably, Case 3's LFT results did not
improve with initial dose reduction. Although all three cases had
improvement in their LFT results with the antifungal switch, one
developed LFT abnormalities on day 50 coinciding with an episode of
febrile neutropenia (Case 3). Case 2 was re-challenged with voriconazole
1 week later and had recurrence of their LFT abnormalities requiring a
change in treatment to an alternative antifungal, micafungin.

\emph{Fluconazole to voriconazole:}

The two children that switched from fluconazole to voriconazole did so
for the treatment of a possible mold infection in the setting of febrile
neutropenia (Table 1). One child (Case 4) was post-HSCT with concurrent
GVHD (grade 1 skin and upper gastrointestinal disease). The GGT peaked 3
days after the switch to voriconazole (333 IU/L, 8.3 x ULN) and
normalised by the end of the 55-day treatment course. Causality was
assessed as `possible' (Naranjo score 4) as the child was not
subsequently rechallenged with fluconazole. The second child (Case 5,
Table 1) was prescribed fluconazole after initial switch to voriconazole
and the GGT derangement continued to improve despite this rechallenge.
The case was also assessed as `possible' (Naranjo score 2).

\emph{Voriconazole to itraconazole:}

The child that was switched from voriconazole to itraconazole had
supratherapeutic voriconazole concentrations 15 days prior (6.12 mg/L),
with associated LFT abnormalities and rash (Case 6, Table 1). The dose
was reduced by 16\% however a repeat level was not taken. After the
switch to itraconazole the LFTs normalised by day 34.

\emph{Posaconazole to fluconazole:}

Posaconazole was switched to fluconazole in one case (Case 7, Table 1)
in the setting of potential drug interactions with venetoclax during
HSCT. This patients GGT peaked 10 days prior to the switch (137 IU/L,
2.8 x ULN) and remained elevated (113 IU/L) three days prior to switch
but had improved within 11 days post switch (GGT 42 IU/L, 1.1 x ULN).
However, the GGT began to uptrend reaching a peak of 290 IU/L 20 days
post switch in the context of HSCT.

\textbf{Discussion}

This is the first pediatric case series to describe the outcome of
switching triazole antifungal agents in the setting of AIH, highlighting
this as a potential approach to managing drug-related hepatotoxicity.
Given oral antifungal options in children are limited to triazole
antifungals and AIH is the most common adverse event resulting in
cessation of therapy \textsuperscript{8}, identifying an approach to
managing AIH and preserving the use of this drug class is critical.

Published data on this approach to AIH are limited. Three case reports
and one audit in adults demonstrated improvement after switching between
triazole antifungals. Spellberg et al. described an adult with
coccidioidal meningitis and fluconazole-related hepatotoxicity that
improved with switching to voriconazole \textsuperscript{2}. Further, a
retrospective audit of 23 adults with acute myeloid leukemia who had
switched from posaconazole to isavuconazole, demonstrated improvement in
all 20 patients with CTCAE Grade 1 hepatotoxicity or
more\textsuperscript{1}. Of these, six patients had grade 3-4
abnormalities in liver transaminases with all patients showing
improvement and in 2/6 patients, the LFTs normalised 4 weeks after the
change in therapy\textsuperscript{1}. A further case report described a
patient with intracerebral aspergillosis who developed
voriconazole-related hepatotoxicity which resolved after changing to
posaconazole\textsuperscript{3}. Similarly switching from voriconazole
to posaconazole in combination with caspofungin was found to result in
resolution of hepatotoxicity in an immunocompetent adult with invasive
aspergillosis \textsuperscript{4}. These data suggest a lack of
cross-hepatotoxicity between triazole antifungals that requires further
study.

The mechanism of liver injury from triazole antifungals is poorly
understood but thought to be due to triazole alteration of inhibition of
cytochrome P450 enzymes, acute inflammatory response, and mitochondrial
dysfunction. An \emph{in vivo} study in rats demonstrated worsening
toxicity when fluconazole or itraconazole were administered a CYP450
inhibitor compared with azole therapy alone, suggesting CYP450
inhibition may have an important role in the mechanism of
hepatotoxicity\textsuperscript{9}. However, for posaconazole-induced
hepatotoxicity, an \emph{in vitro} study suggested a different
mechanism, through mitochondrial dysfunction \textsuperscript{10}. Data
are limited on the relationship between azole dose and AIH for
itraconazole and posaconazole, however, no clear relationship has been
identified in pediatric studies of fluconazole and voriconazole
\textsuperscript{8, 11}.

This case series adds to the growing body of evidence suggesting that
there is a lack of cross-hepatotoxicity between azole antifungals and
switching within the class is a potential approach to management of AIH.
Further large clinical studies are needed to determine whether this
approach could be routinely considered.

\textbf{Acknowledgements:} N/A

\textbf{Conflict of interest statement:} AG attended the MSD Asia
Pacific Forum in 2019. All other authors have no conflicts of interest
to disclose.

\textbf{Funding information:} No specific funding was received for this
work. AG receives salary support from an National Health and Medical
Research Council Investigator Grant.



\textbf{References}

\begin{enumerate}
\tightlist
\item
  DiPippo AJ, Rausch CR, Kontoyiannis DP. Tolerability of isavuconazole
  after posaconazole toxicity in leukaemia patients. \emph{Mycoses} .
  2019;62(1):81-6.
\item
  Spellberg B, Rieg G, Bayer A, Edwards JE, Jr. Lack of
  cross-hepatotoxicity between fluconazole and voriconazole. \emph{Clin
  Infect Dis} . 2003;36(8):1091-3.
\item
  Foo H, Gottlieb T. Lack of Cross-Hepatotoxicity between Voriconazole
  and Posaconazole. \emph{Clin Infect Dis} . 2007;45(6):803-5.
\item
  Mart\selectlanguage{ngerman}ínez-Casanova J, Carballo N, Luque S, Sorli L, Grau S.
  Posaconazole achieves prompt recovery of voriconazole-induced liver
  injury in a case of invasive aspergillosis. \emph{Infection Drug
  Resistance} . 2018;11:317-21.
\item
  Common Terminology Criteria for Adverse Events (CTCAE) Version 5
  {[}Internet{]}. US Department of Health and Human Services, National
  Institutes of Health, National Cancer Institute.
\item
  Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the
  probability of adverse drug reactions. \emph{Clin Pharmacol Ther} .
  1981;30(2):239-45.
\item
  LiverTox: Clinical and Research Information on Drug-Induced Liver
  Injury {[}Internet{]}: Bethesda (MD): National Institute of Diabetes
  and Digestive and Kidney Diseases; {[}Available from:
  livertox.nih.gov/.
\item
  Egunsola O, Adefurin A, Fakis A, et al. Safety of fluconazole in
  paediatrics: a systematic review. \emph{Eur J Clin Pharmacol} .
  2013;69(6):1211-21.
\item
  Somchit N, Wong CW, Zuraini A, et al. Involvement of phenobarbital and
  SKF 525A in the hepatotoxicity of antifungal drugs itraconazole and
  fluconazole in rats. \emph{Drug Chem Toxicol} . 2006;29(3):237-53.
\item
  Haegler P, Joerin L, Krähenbühl S, Bouitbir J. Hepatocellular Toxicity
  of Imidazole and Triazole Antimycotic Agents. \emph{Toxicol Sci} .
  2017;157(1):183-95.
\item
  Neely M, Rushing T, Kovacs A, Jelliffe R, Hoffman J. Voriconazole
  pharmacokinetics and pharmacodynamics in children. \emph{Clin Infect
  Dis} . 2010;50(1):27-36.
\end{enumerate}

Table I: Overview of patients with azole-induced hepatotoxicity whose
liver functions tests improved after switching to another triazole
antifungal\selectlanguage{english}
\begin{longtable}[]{@{}llllllllllllll@{}}
\toprule
\begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
ID\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Age, Sex\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Underlying diagnosis\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Antifungal 1 \& dose prior to switch\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Indication for antifungal therapy\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Maximal LFT abnormalities; [?]ULN or patient's baseline\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Maximal LFT abnormalities; [?]ULN or patient's baseline\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
CTCAE grade prior to switch \textsuperscript{a}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Antifungal 2 \& starting dose\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Indication for switch\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
LFT results post switch; [?]ULN or patients' baseline\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
LFT results post switch; [?]ULN or patients' baseline\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Time to improvement of LFT results post switch\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Naranjo score \textsuperscript{b}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to fluconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to fluconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to fluconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to fluconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to fluconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to fluconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to fluconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to fluconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to fluconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to fluconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to fluconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to fluconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to fluconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to fluconazole\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
4.2y M\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Chronic granulomatous disease (HSCT)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Voriconazole 15.4mg/kg oral BD\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Possible fungal infection\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
ALT GGT\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
x4.1 x18.3\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
2 3\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Fluconazole 7.3mg/kg oral OD\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Drug-related hepatotoxicity\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
ALT GGT\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
normalised normalised\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
End of therapy (15 weeks)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
4\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
13.4y M\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Acute myeloid leukemia (induction), acute appendicitis\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Voriconazole 12.8mg/kg oral BD\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Fungal prophylaxis\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
GGT\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
x12.9\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Fluconazole 11.8mg/kg oral OD\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
None given\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
GGT\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
x7.2\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
End of therapy (1-week)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
6\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
7.5y M\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Acute myeloid leukemia (HSCT)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Voriconazole 10.0mg/kg oral BD\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Fungal prophylaxis\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
ALT GGT\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
x5.0 x15.5\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
2 3\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Fluconazole 9.1mg/kg OD\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Drug related hepatotoxicity\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
ALT GGT\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
x2.6 x1.1\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
End of therapy (1-week)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
7\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Fluconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Fluconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Fluconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Fluconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Fluconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Fluconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Fluconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Fluconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Fluconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Fluconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Fluconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Fluconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Fluconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Fluconazole switch to voriconazole\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
16.6y F\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Blastic plasmacytoid dendritic cell neoplasm (HSCT)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Fluconazole 4.7mg/kg oral OD\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Fungal prophylaxis\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
GGT\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
x8.3\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Voriconazole 2.3mg/kg oral BD\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Febrile neutropenia - antifungal prophylaxis\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
GGT\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
normalised\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
End of therapy (8 weeks)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
3\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
7.0y M\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X-linked Hyper-IgM syndrome (HSCT)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Fluconazole 8.4mg/kg IV OD\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Fungal prophylaxis\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
ALT GGT\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
x3.5 x6.8\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
2 3\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Voriconazole 9.0mg/kg IV BD\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Febrile neutropenia - treatment of possible infection\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
ALT GGT\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
x1.4 x3.6\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
End of therapy (\textless{}1 week)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
2\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to itraconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to itraconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to itraconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to itraconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to itraconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to itraconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to itraconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to itraconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to itraconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to itraconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to itraconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to itraconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to itraconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Voriconazole switch to itraconazole\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
6\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
5.7y M\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
T-cell acute lymphoblastic leukemia, febrile neutropenia\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Voriconazole 7.5mg/kg oral BD\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Fungal prophylaxis\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
GGT\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
x4.8\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Itraconazole (2.5mg/kg oral twice a day)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Drug related hepatotoxicity\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
GGT\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
x3.0\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
1-2 weeks\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
5\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Posaconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Posaconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Posaconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Posaconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Posaconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Posaconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Posaconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Posaconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Posaconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Posaconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Posaconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Posaconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Posaconazole switch to voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Posaconazole switch to voriconazole\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
7\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
15.0y M\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Acute myeloid leukemia relapse (HSCT)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Posaconazole MR 4.3mg/kg OD 5 days/week \& 5.8mg/kg OD 2 days/week\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Fungal prophylaxis\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
GGT\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
x2.8\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Fluconazole 5.8mg/kg IV daily\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Pre-HSCT, potential drug interactions\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
GGT\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
x1.1\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
1-2 weeks\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
3\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

References:

\textsuperscript{a} CTCAE {[}5{]}: grade 2 (ALT grade 2
\textgreater{}3-5x ULN or patients baseline if baseline abnormal; ALT
grade 3 \textgreater{}5-20; GGT grade 2 \textgreater{}2.5; GGT grade 3
\textgreater{}5-20x ULN).

\textsuperscript{b} Naranjo score {[}6{]}: 1-4 possible association,
score 5-8 probable association.

Abbreviations: LFT (Liver Function Test), CTCAE (Common Terminology
Criteria for Adverse Events), ULN (Upper Limit of Normal), y (year), M
(male), F (female), HSCT (Hematopoietic Stem Cell Transplant), ALT
(Alanine Aminotransferase), GGT (Gamma Glutamyl Transferase), BD (Twice
a Day), OD (Once a Day) MR (Modified Release)

\textbf{Figure legends}

Figure 1. Liver function tests before and after switching to another
triazole antifungal agent. Panel A - Gamma-glutamyl transferase results;
Panel B - Alanine aminotransferase results\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1A/Figure-1A}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1B/Figure-1B}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

