Eur J Pediatr (2013) 172:437446

DOI 10.1007/s00431-012-1758-9

REVIEW

Antifungal therapy in children: an update

Valerio Cecinati & Chiara Guastadisegni &
Fabio Giovanni Russo & Letizia Pomponia Brescia

Received: 28 March 2012 / Accepted: 9 May 2012 / Published online: 1 June 2012
# Springer-Verlag 2012

Abstract Invasive fungal infections are a common problem

in children affected by primary or secondary immunodeficiencies. Thanks to an increased knowledge about their
mechanisms of action and their pharmacokinetic and toxicity profiles, the use of these drugs in common and uncommon invasive infections in immunocompromised children
has improved over the last decades. Choosing the most
appropriate antifungal drug is a serious challenge for any
clinician, also considering that, in most cases, therapy has to
be started before cultures are available, the choice being
driven by clinical symptoms and statistical criteria only. In
this study, we performed a systematic review of literature,
providing antifungal treatment recommendations for paediatric patients which can help clinicians find the most suitable treatment for each specific case. Principal antifungal
drugsranging from first-generation antimycotics to the

V. Cecinati (*)
Division of Pediatric Hematology and Oncology,
Department of Hematology, Spirito Santo Hospital,
Via Fonte Romana,
Pescara, Italy
e-mail: cecinativalerio@gmail.com
C. Guastadisegni
Department of Occupational Medicine,
Policlinico University Hospital,
Bari, Italy
F. G. Russo
Neonatology, Neonatal Pathology and NICU,
Foundation IRCCS Policlinico San Matteo,
Pavia, Italy
L. P. Brescia
Division of Pediatric OncologyHematology,
Department of Biomedicine in Childhood, University of Bari,
Bari, Italy

latest moleculesare classified according to their targets,

and of each group, the pharmacokinetic profile, clinical
indications and side effects are extensively described.
Keywords Fungal infections . Children . Antimycotic drugs

Introduction
Pharmacological advances in the antifungal agents field led
to extended therapeutic indications to many childhood mycoses, in particular invasive fungal infections (IFIs) in children with primary or secondary immunodeficiencies [81].
Thanks to the wider spectrum of action of these drugs and to
an improved knowledge about their mechanisms of action
and their pharmacokinetic and toxicity profiles, antifungal
agents are currently used in common and uncommon invasive infections in immunocompromised children [2, 16, 22,
48, 66, 81, 82]. We performed a systematic review of
literature to put together appropriate paediatric antifungal
treatment recommendations. Depending on their side targets, principal antifungal drugs are classified in Table 1.

Azoles
The azole antifungal agents are heterocyclic synthetic compounds, divided into two groups: imidazoles and triazoles.
The imidazoles are an older group consisting of miconazole,
ketoconazole and clotrimazole. The first generation of triazoles includes fluconazole and itraconazole; the second
generation of triazole includes voriconazole, posaconazole
and ravuconazole. Isavuconazole, albaconazole and E-1224,
a prodrug of ravuconazole, are the three main azole antifungal agents currently under development [22, 48, 67].

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Eur J Pediatr (2013) 172:437446

Table 1 Classification of antifungal agents based on side targets

Antifungal agents acting on plasmatic membranes
Azole (imidazole, first- and second-generation triazoles)
Polyenes (amphotericin B, nystatin)
Antifungal agents acting on the synthesis of nucleic acids
5-Fluorocytosine
Antifungal agents acting on fungal cell wall
Echinocandins (caspofungin, micafungine, anidulafungine)

First-generation triazoles
First-generation triazoles' main features are shown in
Table 2.
Fluconazole
Fluconazole remains one of the most frequently prescribed
triazoles because of its excellent bioavailability, tolerability
and side effect profile. It is a fungistatic and its activity is

Table 2 First-generation
triazoles

Fluconazole

Itraconazole

Formulations

Oral suspension, tablets (50, 100, 150, 200 mg)

IV formulations (available in 200/400 mg)

Dosage

Children 3 months16 years, 612 mg/kg

Adults, 36 mg/kg
Invasive CI (except C. krusei and C. glabrata)

Oral suspension
Capsules (better absorption in
an acidic environment)
Children, 2.5 mg/kg for two doses
Adults, 2.5 mg/kg
Salvage therapy of invasive
aspergillosis
Allergic aspergillosis
Invasive CI

Indications

Side effects

Interactions

IV intravenous, IFI invasive

fungal infections, pts patients, CI
candida infections

concentration independent. Fluconazole is relatively lipophobic and shows limited binding to plasma proteins. As a
result of these characteristics, it passes into tissues and fluids
very rapidly. Drug concentrations in cerebrospinal fluid
(CSF) and vitreous humour are around 80 % of those found
in blood [80, 83]. Oral absorption remains unchanged in
patients receiving acid-suppressive therapy (proton pump
inhibitors and H2 blockers) [6]. Fluconazole may be used
for invasive candidiasis (IC) caused by susceptible organisms in paediatric patients of all ages who are in stable
conditions and who have not received prior azole therapy
[22]. Concerning the use of fluconazole as a prophylaxis for
IFI, it has been demonstrated that this drug is safe and
effective for reducing Candida infections in neutropenic
paediatric patients and in those undergoing chemotherapy
[25, 32, 75, 84]. Recent guidelines from the Infectious
Diseases Society of America (IDSA) recommend considering fluconazole or an echinocandin for empiric therapy in
immunocompromised children at high risk for candida infection, with a preference for an echinocandin in patients
with moderate-to-severe disease, recent azole exposure or at

Oropharyngeal candidiasis
Cryptococcosis, cryptococcical meningitis
histoplasmosis
Prophylaxis for IFI in pts undergoing chemotherapy
Empiric therapy in immunocompromised pts at high
risk for CI
Frequent:
Anorexia
Vomiting
Diarrhoea
Transaminase elevation
Rare:
Skin rash, alopecia
Headache
Increases serum levels of:
Phenytoin
Glipizide
Gyburide
Warfarin
Rifabutin
Cyclosporine

Other invasive mycosis

Prophylaxis in children with HIV
Nausea
Vomiting
Abdominal pain
Transaminase elevation

Cyclophosphamide
Rifampin
Phenytoin
Carbamazepime
Phenobarbital

Eur J Pediatr (2013) 172:437446

high risk for Candida glabrata or Candida krusei infection

[47]. Fluconazole or an echinocandin is also to be preferred
as initial therapy for patients with non-neutropenic candidemia, depending on disease severity and other characteristics
[50, 83]. Several reports demonstrated that fluconazole
clearance is more rapid in children than in adults [11]. The
mean plasma half-life was approximately 20 h in children
compared to 30 h in adults. Therefore, to achieve a similar
drug exposure in children aged 3 months to 16 years, daily
fluconazole dosage needs to be approximately doubled compared to the suggested dosage in adults [6]. Generally,
fluconazole is well tolerated by paediatric patients, even
when long-term treatment is necessary.
Itraconazole
Itraconazole, only available as oral formulation, is a highly
protein-bound fungicidal agent with less than 1 % free drug
available and with a relatively high volume of distribution [16,
25, 61, 75]. Oral absorption of itraconazole is optimal in an
acidic environment and the concomitant administration of H2
receptor antagonists, proton pump inhibitors or antacids
causes erratic and unpredictable drug absorption. Thus, it
has been recommended that itraconazole capsules must be
taken with food or a cola beverage but the oral suspension is
better absorbed when taken on an empty stomach [74]. Itraconazole has been licensed in the USA for salvage therapy of
invasive aspergillosis (IA) and for allergic bronchopulmonary
aspergillosis [48, 73, 74]. Regarding the indications in IC, a
recent randomised trial compared fluconazole and itraconazole for the treatment of IC in a paediatric intensive care unit:
Itraconazole showed clinical and mycological cure rates similar to those of fluconazole [40]. The development of new and
more effective antifungal agents has relegated itraconazole to
second-line therapy for the treatment of invasive mycoses so
that itraconazole is currently more appealing as a prophylactic
rather than a therapeutic agent and may be superior to fluconazole for this purpose in adult patients [41, 42]. Therefore,
itraconazole remains the drug of choice for prophylaxis in
children affected by HIV with a history of histoplasmosis
before immune reconstitution with antiretroviral therapy
[80]. Itraconazole is usually well tolerated and few side effects
are reported in the paediatric population.

Second-generation triazoles
Core information of these drugs is shown in Table 3.
Voriconazole
Voriconazole, a synthetic second-generation broad-spectrum
triazole derivative of fluconazole, inhibits the cytochrome

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P450 (CYP)-dependent enzyme 14-alpha-sterol demethylase, thereby disrupting the cell membrane and halting fungal growth [58]. It combines the broad spectrum of antifungal
activity of itraconazole with the increased bioavailabity of
fluconazole [26, 83].
Several case series and single case reports have described
the safety and efficacy of voriconazole in paediatric patients
with cancer and other immunocompromised children with
invasive mycoses [15, 69, 76, 78, 79] and it has been used to
treat aspergillus airway disease in paediatric patients with
cystic fibrosis [27, 76]. Paediatric patients are known to
hypermetabolise voriconazole for this reason requiring
higher doses than adults to obtain similar serum concentrations over time [6, 22, 83]. The IDSA guidelines state that
measurement of serum voriconazole levels may be useful in
some patients receiving voriconazole therapy in order to
evaluate potential toxicity or to prove adequate drug exposure, in particular in patients receiving oral therapy [3].
Therapeutic drug monitoring may be especially important
in paediatric patients receiving voriconazole therapy, given
the relatively limited database upon which dosing recommendations are based and the well-known differences in
pharmacokinetics between adult and paediatric patients.
However, caution is needed in interpreting voriconazole
serum levels as it is unclear which level correlates with
clinical efficacy [65].
Posaconazole
Posaconazole is a novel oral antifungal triazole with a potent
and broad-spectrum activity against opportunistic endemic
and dermatophytic fungi in vitro [22, 24, 33, 57]: it is a
second-generation oral triazole closely related to itraconazole.
Posaconazole absorption is increased with food [56]. Recently, some reports demonstrated that posaconazole is active
against mucormycosis in diabetic and immunocompromised
children and, when combined with other antifungal drugs,
could be effective against Rhizopus microsporus infections
in immunocompromised children [7, 36, 61, 65, 68]. Surveillance of clinical Aspergillus spp. isolates indicates that, so far,
resistance to posaconazole is extremely rare [51, 52].
Posaconazole has been approved in the European Union
in patients of 18 years of age for second-line treatment of
aspergillosis, fusariosis, chromoblastomycosis and coccidioidomycosis [28, 50]. In addition, posaconazole was approved in 2006 by the US Food and Drug Administration
(FDA) for antifungal prophylaxis (as aspergillus and candida infections) in patients with acute myeloid leukaemia,
myelodisplastic syndrome, graft versus host disease or in
patients submitted to hematopoietic stem cell transplant in
whom a long neutropenic period due to chemotherapy is to
be expected [9, 18, 22, 55, 61]. There is no clinical evidence
that combination therapies with other antifungal drugs

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Eur J Pediatr (2013) 172:437446

Table 3 Second-generation
triazoles
Formulations
Dosage

Voriconazole

Posaconazole

Oral formulation
IV formulation
Dose per kg

Oral formulation

7 mg/kg IV every 12 h
Children <40 kg:

Indications

200 mg every 12 h on day 1 then

100150 mg every 12 h
Children >40 kg:
400 mg every 12 h on day 1 then
200300 mg every 12 h
All species of Candida, including
Candida krusei and C. glabrata,
resistant to FLU
Asp spp., including A. terreus,
resistant to AMB
Cryptococcus neoformans
Scedosporium spp.
Fusarium spp.
Primary cutaneous ASP in
immunocompetent pts

Side effects

Interactions

IV intravenous, Pts patients,

AMB amphotericin B, Asp
Aspergillosis, FLU fluconazole,
AML acute myeloid leukaemia,
MDS myelodysplastic syndrome, GVHD graft versus host
disease, HSCT haematopoietic
stem cell transplantation

Dosage
adaption

Refractory infections by
Scedosporium and Fusarium spp.
Bone and central nervous system
ASP
- Invasive mycoses of
immunocompromised pts
Pulmonary ASP in cystic fibrosis pts
Liver toxicity
Rash
Photophobia
Blurred vision
Rifampicin
Penobarbital
Carbamazepime
Ritonavir
Sirolimus
Tacrolimus
Cyclosporine
Efavirenz
Terfenadine

No paediatric dosage schedules have been

established yet
No recommendations for patients younger than
18 years (EMEA recommendations)
Prophylaxis in pts older than 13 years old,
200 mg, 3 times daily (FDA
recommendation)

Fusarium spp. infections in pts with AMB

resistant/intolerant
Chromoblastomycosis
Coccydioidomycosis in pts with AMB or flu
resistant
Oropharyngeal candidiasis in
immunocompromised pts
IFI prophylaxis
Second-line treatment for aspergillosis,
fusariosis, chromoblastomycosis
coccidioidomycosis in the EU for pts more
than 18 years
Prophylaxis in pts with AML, MDS, GVHD
and HSTC

Liver toxicity

Tacrolimus
Cyclosporine
Vincristine
Midazolam
Phenytoin

Reduced by 50 % in liver
dysfunction. Preferred oral
formulations in renal failure

causes an improve in benefits [61]. Clinical experiences

with posaconazole in children are limited to compassionate

release data and dosing continues to be experimental in

children with different ages [60]. For interested readers,

Eur J Pediatr (2013) 172:437446

we like to refer to the most recent literature [18, 22, 31, 54,
59, 61, 66]. In most paediatric patients, posaconazole is well
tolerated and even long-term therapy (>6 months) is frequently without toxicity [66].
Ravuconazole, isavuconazole and albaconazole
Ravuconazole, isavuconazole and albaconazole are secondgeneration extended-spectrum triazoles that showed their
potential in the treatment of fungal infections [49]. Data on
the use of these drugs in the paediatric age are not available.
These drugs have demonstrated a potent in vitro activity
against Candida and Aspergillus species that appear more
effective than fluconazole. Conversely, these newer triazoles
showed poor or limited activity against emerging fungi as
species of Fusarium, Scedosporium and Zygomycetes [53].

Echinocandins
There are three echinocandins approved by both the FDA
and the European Medicines Agency (EMEA): capsofungin,
micafungin and anidulafungin [53]. Caspofungin is the only
echinocandin approved for paediatric use, since July 2008,
for use in children 3 months of age and above [12, 72]. The
echinocandins have a unique mechanism of action, inhibiting beta-(1,3)-D-glucan synthase, an enzyme that is necessary for the synthesis of an essential component of the cell
wall of several fungi. The echinocandins show fungistatic
activity against Aspergillus spp. and fungicidal activity
against most Candida spp., including strains that are
fluconazole-resistant [64]. No evidence of antagonism with
the combination of caspofungin plus amphotericin B for
Candida albicans or Aspergillus fumigatus infections in
animal models has been reported [39, 57, 61]. However,
there was no additive effect with this combination in invasive pulmonary aspergillosis caused by A. fumigatus, although surveillance data collected from a large number of
centres worldwide over the last years have not revealed any
evidence of emergence of resistance to echinocandins [51].
An unusual paradoxical resistance has been reported in
some isolates of Candida spp. following their in vitro exposure to high concentrations of caspofungin: one explanation for this appears to be that a compensatory repair
mechanism, involving upregulation of chitin synthesis,
allows the fungal cells to survive [62].
Core information of these drugs is shown in Table 4.
Caspofungin
Caspofungin acetate is a semi-synthetic lipopeptide synthesised from a fermentation product of Glarea lozoyensis.
Caspofungin is only available as i.v. formulation, due to

441

limited oral bioavailability and is metabolised by the liver

not mediated by CYP450 enzymes [19, 23]. Its antifungal
properties derive from inhibition of synthesis of the glucose
homopolymer beta-(1,3)-D-glucan which is not present in
mammalian cells, but is a component essential of fungi [19].
Caspofungin is licensed in the European Union for adult
and paediatric patients, including neonates, for second-line
therapy of IA, for primary therapy in non-neutropenic
patients with IC and for empirical antifungal therapy in
persistently febrile neutropenic patients [13, 20, 22, 37, 38,
53, 63, 64, 71, 84]. It was only recently that the landmark
study leading to the FDA approval of caspofungin for use in
children was published. Zaoutis et al. [85, 86] performed an
open-label prospective study of caspofungin for the treatment of IC and IA in patients aged 3 months to 17 years. Of
48 patients with proven infections, 10 had aspergillus infections and 38 had candida infections. Success (defined by
complete or partial response) at the end of therapy was seen
in five out ten patients with IA and 30 out 48 patients with
IC. However, patients with IC were more likely to have been
treated for primary infections, whereas all children with IA
had failed to respond to other antifungals. There were no
serious drug adverse events. Thus, caspofungin seems to
provide an effective, well-tolerated alternative for the treatment of candida and aspergillus infections in paediatric
patients. Maertens et al. [38] prospectively evaluated caspofungin in 83 patients, most of whom were refractory to other
therapies. An overall favourable response to caspofungin was
noted in 45 % of patients. Prior to these studies, published data
on the use of caspofungin in children had largely been limited
to neonatal candidiasis [4346], although its use in
managing IC infections was retrospectively described
within larger paediatric cohort studies [12]. Moreover, caspofungin has been evaluated for the treatment of paediatric
patients with persistent febrile neutropenia. One paper compared the efficacy of caspofungin (50 mg/m2) and liposomal
amphotericin B (3 mg/kg/day) in 82 children aged 217 years
with fungal infections [12]. Efficacy and safety were similar
for both study arms as was noted in a similar study in adults
[37, 43]. In addition, Koo et al. [77] retrospectively reviewed
56 children aged 117 years with febrile neutropenia treated
empirically with caspofungin. Of 67 courses of therapy,
successful treatment of baseline fungal infection was
reported in 53 out 67 patients, with no breakthrough
IFIs. Patients with fungal infections should be treated at
least for 14 days and the treatment has to be continued for at
least 7 days after the resolution of neutropenia and symptoms.
Treatment of IA should continue for a period depending
on the underlying disease severity, immunosuppression
recovery and clinical response of patient [19]. Caspofungin use is not currently recommended in the USA in patients
aged <3 months and in neonates, and efficacy data are not
available in this population [39].

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Table 4 Echinocandins
Formulations
Dosage

Indications

Side effects

Interactions

pts patients, IA invasive aspergillosis, IC invasive candidiasis

Caspofungin
IV

Micafungin
IV

70 mg/m2 on day 1
50 mg/m2 from day 2
70 mg/m2
(if any clinical improvement with
50 mg/m2)
25 mg/m2 in pts younger <3 months
Second-line treatment of IA
First-line treatment non-neutropenic pts
with IC
Empirical therapy in persistently febrile
granulocytopenic pts
Fever
Hypokalemia
Nausea
Vomiting
Pyrexia
Diarrhoea
Skin rash

For body weight less than 40 kg,13 mg/kg/day

Liver toxicity
Chills
Hypotension
Rifampicin
Phenytoin
Efavirenz
Carbamazepine, dexamethasone
Tacrolimus

Hypokalemia
Neutropenia
Haemolytic anaemia
Cyclosporine
Tacrolimus
Sirolimus

Dosage
adaption

Micafungin
Micafungin is a semi-synthetic lipopeptide obtained
from Coleophoma empetri. Intravenous administration
of micafungin is approved in Japan and the EU for the
treatment of paediatric patients (including neonates)
with IC and as prophylaxis against candida infections
in paediatric patients undergoing allogenic hematopoietic stem cell transplantation [70, 72]. In the EU,
micafungin use is also approved in paediatric patients
expected to have neutropenia for 10 days. In Japan,
children may also receive micafungin for the treatment
of or as prophylaxis against IA [72]. Micafungin is not
currently approved for use in paediatric patients in the
USA. Micafungin has a very good antifungal activity
against a wide range of Candida spp. in vitro [30]. It
has a favourable pharmacokinetic profile allowing for
once-daily administration has few drugdrug interactions and reports of resistance are rare [8, 29, 64].
Micafungin was studied in a single open-label

For body weight more than 40 kg, 50150

mg/day

IC and IA
Prophylaxis against candida infections in pts
undergoing allogenic HSCT

Fever
Abdominal pain
Nausea
Diarrhoea
Headache
Leukopenia
Liver toxicity

Not recommended in severe liver impairment

noncomparative study [17] to assess its safety and

efficacy when used alone and in combination with
another antifungal agent in the primary or salvage
therapy of IA. Favourable responses were achieved in
6 of 12 patients who received micafungin monotherapy
as primary treatment and in 9 of 22 patients who
received it as salvage therapy. Seventeen patients received primary therapy with micafungin in combination with another agent, with a favourable response in
five; the response rate was 34.5 % (60 of 174 patients)
in instances of salvage therapy [17]. In addition, the
initial dose of micafungin employed was lower
(75 mg/day, although this could be increased after
day 5) [12]. In a randomised double-blind trial of
micafungin (2 mg/kg/day) versus liposomal amphotericin B (AMB) (3 mg/kg/day) in 98 children aged
<16 years, both drugs achieved similar success rates
for treating candidaemia/invasive candidiasis [74]. A
similar phase I paediatric febrile neutropenia study
(212 years old) found that doses up to 4 mg/kg/day

Eur J Pediatr (2013) 172:437446

were well tolerated without any side effects [10, 53].

In general, the terminal half-life of micafungin does
not change appreciably in paediatric versus adult
patients, and the volume of distribution is only slightly
higher in children [34]. When evaluating therapeutic
indications, one should consider that the decision to
use micafungin should take into account a potential risk
for development of liver tumours and it should therefore only
be used if other antifungals are not appropriate [53].
Anidulafungin
Anidulafungin is a semi-synthetic lipopeptide obtained
from of Aspergillus nidulans with a spectrum of activity
similar to caspofungin. Its use is not approved in children [53]. Only one paper is available in literature on
the safety and potential dosage of anidulafungin in a
paediatric population [5].

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5-Fluorocytosine
Flucytosine is deaminated to 5-fluorouracil (5-F) by fungal
cytosine deaminase. 5-FC is thought to enhance the antifungal
activity of AMB, especially in anatomical sites where AMB
penetration is poor such as heart valves and vitreal body. It is
well adsorbed after oral administration and it distributes widely, attaining therapeutic concentrations in most body sites such
as the CSF, vitreous and peritoneal fluids and into inflamed
joints because it is small and highly water soluble and not
bound by serum proteins to a great extent [83]. Core information of AMB and 5-F is shown in Table 5.
Table 5 Amphotericin B and 5-fluorocytosine
Formulations
Dosage
Indications

Amphotericin B
The oldest antifungal classes are the polyene macrolides, AMB and nystatin. Nystatin is for topical use
only. AMB binds to ergosterol, the major sterol found
in cytoplasmatic membranes, causing changes in cell
permeability that lead to cellular lysis and death [61,
66]. There is also evidence that AMB acts as a proinflammatory agent further stimulating innate host immunity. This process involves the interaction of AMB with
toll-like receptor 2, the CD14 receptor, inducing the
release of cytokines, chemokines and other immunologic
mediators. It has been suggested that AMB may interact
with host humoral immunity after the observation of a
synergistic activity of AMB and antibodies directed at
heat shock protein 90, although further confirmatory
data are needed [4, 66]. AMB is the gold standard for
the therapy of many invasive fungal infections [14].
Three lipid-associated formulations are currently available: amphotericin B lipid complex (Abelced), amphotericin B colloidal dispersion (Amphocil and Amphotec)
and liposomal amphotericin B (AmBisome). The latter is
the most used formulation in childhood [22, 83]. A 56-centre
prospective study evaluated the safety and efficacy of AMB
administrated to 260 adults, 242 children (<15 years old) and
43 infants (<2 months old). In general, infants and children
tolerated the largest doses of AMB administrated for the
longest time (median 18 days) [1].
AMB has approved first-line indications for empirical
therapy of persistently neutropenic patients and for treatment of invasive mycoses, including IA and IC. Other
indications are blastomycoses, coccidioidiomycoses, histoplasmosis and endemic mycoses [21, 35].

Side effects

Liposomal amphotericin B
IV

5-Fluorocytosine
Oral

35 mg/kg
Empirical therapy of
persistently neutropenic pts
Treatment of IA and IC

150 mg/kg
Candida spp.

Common
Fever
Chills
Rigor

Cryptococcus
Cladosporium
phialophora
Saccharomyces
Aspergillus spp.
Zygomycetes
Rash
Diarrhoea
Transaminase
elevation
Bone marrow
suppression

Nausea
Vomiting
Diarrhoea
Rare
Increases of urea and creatinine
levels
Hypokalemia
Hypomagnesaemia
Hypocalcemia
Hyperglycaemia
Hyperbilirubinemia
Related to infusion
Dyspnoea
Wheezing
Tachycardia
Rush
Hypertension
Back pain
Interactions

AMB

AMB amphotericin B, pts patients, IA invasive aspergillosis, IC invasive candidiasis

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Conflict of interest The authors declare that there is no conflict of
interest and no financial support or any other personal connection to
the work submitted.

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