Strategies for managing systemic fungal infection and the place of itraconazole *

Journal of Antimicrobial Chemotherapy (2005) 56, Suppl. S1, i49–i54
doi:10.1093/jac/dki224
Strategies for managing systemic fungal infection and
the place of itraconazole
Michael Potter1*
1
Department of Haematology, Royal Marsden Hospital (London & Sutton), Downs Road, Sutton,
Surrey SM2 5PT, UK
Systemic fungal infections are an increasing cause of mortality and morbidity in patients with haematological malignancies and certain other conditions associated with profound immunosuppression. The
majority of such infections are caused by Aspergillus and Candida species. In recent years, the number
of available drugs effective in the therapy of these difficult infections has expanded. Large clinical trials
have been performed in different settings such as prophylaxis, empirical and first-line therapy. For prophylaxis, the azoles fluconazole and itraconazole have been most widely studied. These azoles are available
in both oral and intravenous formulations. Itraconazole has a wide spectrum of activity including Aspergillus, Candida albicans and non-albicans species. Two large studies comparing the use of itraconazole
with fluconazole for primary prophylaxis in high-risk patients who were recipients of allogeneic stem cell
transplants have recently been reported. These have confirmed that itraconazole is effective in this setting
in reducing the rate of systemic fungal infections. However, there are concerns with regard to increased
toxicity and the potential for drug interactions with itraconazole compared with fluconazole. In the empirical
setting, large randomized studies support the use of caspofungin and liposomal amphotericin B. Voriconazole and lipid-associated amphotericin B have been shown to be effective in first-line therapy and
caspofungin for salvage. New approaches to management include efforts at improving diagnosis, combination antifungal therapy and treatment strategies for emerging moulds.
Keywords: azoles, prophylaxis, empirical, Aspergillus, Candida
Introduction
Systemic fungal infections (SFIs) are the leading cause of
infection-related mortality in profoundly immunosuppressed
patients treated for haematological malignancies. Within this
area, two groups of patients are particularly at high risk of systemic
fungal infections, of the order of 10–20%. These are recipients of
allogeneic stem cell transplants and patients receiving intensive
chemotherapy for de novo and relapsed acute leukaemias.1,2 In
these patients, systemic fungal infections are predominantly caused
by Aspergillus species. Invasive aspergillosis is also common
amongst certain groups of patients receiving solid organ—
especially lung—transplants.1,2 Patients with chronic granulomatous disease also have a high cumulative risk of invasive aspergillosis.1,2 Non-Aspergillus mould infections remain relatively rare.
These include infections by Mucor, Fusarium and Scedosporium
species. There is evidence from some large institutions in the USA
and other countries that the incidence of these so-called ‘emerging’
SFIs is increasing, though the absolute rate remains low compared
with aspergillosis.3
Systemic candidiasis occurs with less frequency and has a lower
attributable mortality in haematology patients than mould infections.4 The relative importance of these infections is higher in other
fields of medicine, such as intensive care, neonatology and patients
undergoing major surgery.
Two major problems with regard to invasive aspergillosis are
the high associated mortality and the difficulty in diagnosing these
infections. In immunosuppressed patients with invasive aspergillosis, mortality rates vary from 30% to over 90%.5 The highest
mortality rates are seen in recipients of allogeneic stem cell transplants and in those patients where the Aspergillus infection is
disseminated, affecting the central nervous system or with diffuse
lung involvement.5 In terms of diagnosis, the majority of infections
diagnosed clinically are not confirmed by tissue biopsy due to the
practical difficulties and risks involved in obtaining deep tissue
biopsies. Most infections are therefore categorized as probable
or possible as defined by EORTC/MSG diagnostic criteria.6 Preemptive treatment strategies based on the early detection of a serum
marker of infection with a method allowing both high sensitivity
and specificity are not yet in routine clinical practice. The reasons
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*Tel: +44-20-8661-3670; Fax: +44-20-8642-9634; E-mail: Mike.potter@rmh.nhs.uk
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i49
Ó The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail: journals.permissions@oupjournals.org
Potter
for this relate to technical difficulties with assays and interpretation
of the results and the lack of validated quality control systems.7
Therefore empirical treatment remains the standard clinical
approach to the management of SFIs in neutropenic patients. In
such patients, 80–90% of infections are pulmonary in origin.8
High-resolution pulmonary CT scanning has proved to be a highly
effective clinical means of early detection of established Aspergillus infections.9,10 Certain radiographic features (for example, the
halo sign and air crescent sign) have been shown to be highly
specific in this regard.10
In terms of the treatment of established invasive Aspergillus
infections there are a number of antifungal agents clinically available. These include amphotericin B and lipid associated products;
the triazoles, itraconazole and voriconazole, and the echinocandin,
caspofungin. Newer azoles (e.g. posaconazole) and echinocandins
(e.g. micafungin and anidulafungin) are also being evaluated in
clinical trials but are not yet licensed. The development of these
newer antifungal agents has created much debate as to the optimal
approach to the prophylaxis and treatment of SFIs in patients at risk
of infection.
recipients of chemotherapy. Significant benefits for systemic
prophylaxis included reductions in the empirical use of parenteral
antifungal therapy and more importantly reductions in the incidence of superficial and invasive fungal infection and attributable
fungus-related mortality. Although systemic prophylaxis did
not reduce overall mortality for the whole patient group, certain
sub-groups showed benefits including those with prolonged neutropenia and recipients of stem cell transplantation.
In conclusion, there appears to be evidence supporting the use of
systemic antifungal drugs, particularly in patients with more
severe/prolonged immune suppression.
In the last decade, most attention has been focused on the azoles
fluconazole and itraconazole in this regard. The use of conventional amphotericin B is limited by its highly toxic profile and
need for intravenous administration. Lipid-associated amphotericin B usage is limited by its high cost and relative lack of
clinical data in the prophylactic setting. Inhalation of
nebulized amphotericin B was shown not to be effective in preventing aspergillosis in one randomized trial in neutropenic
patients.13
Prophylaxis of SFIs
Which azole should be used for prophylaxis?
The rationale for adopting a prophylactic strategy for SFIs
includes: (i) the risk of developing SFI may exceed 10% in certain
patients groups; (ii) the high attributable mortality of such infections (especially moulds); (iii) the high cost of treating established
and suspected infections; (iv) recurrent infection is common if the
patient requires and receives further immunosuppressive therapy;
(v) environmental control, e.g. by air filtration is only partially
successful in reducing the incidence of invasive aspergillosis.
Infections may still occur presumably as a result of transmission
via other sources, e.g. water or food and possibly by colonization of
sinuses/airways prior to admission for treatment.11 Environmental
control may also be impractical or impossible in recipients of
allogeneic stem cell transplant and in whom T cell-based immune
suppression is very prolonged, far exceeding the initial neutropenic
episode.
Fluconazole fulfils some of the criteria for an ideal prophylactic
agent including availability in oral and intravenous formulations,
high bioavailability in oral administration, few side effects and
relatively low cost of administration. A recent pharmacy-based
survey of major centres in the USA showed that this drug is widely
used in the prophylactic setting in haematology patients.14 Its use is
supported by two randomized studies against placebo.15,16 An
updated report of the Slavin study,17 which focused on recipients
of allogeneic stem cell transplantation, shows a long-term benefit
in terms of survival for patients receiving fluconazole. However,
the main limitation of fluconazole prophylaxis is its limited spectrum of activity. The clinical benefit is limited to a reduction in
infection by Candida albicans. Furthermore, there is evidence that
the use of fluconazole in this setting may lead to an increase in
colonization and infection rates by Candida species other than
C. albicans.4,18 Fluconazole has little or no activity against Aspergillus and other mould infections.
Itraconazole is available in three formulations: oral capsule, oral
solution and intravenous. Clinical use of the oral capsule formulation is limited by relatively poor absorption and bioavailability.
To a large extent, these problems have been overcome with the
introduction of the oral solution formulation which is cyclodextrin
based. There is, however, a potential for increased side effects with
this formulation including nausea and diarrhoea, which may influence compliance. There is also the potential for more drug interactions with itraconazole compared with fluconazole. The
overriding advantage of itraconazole over fluconazole is its broader
spectrum of activity, which includes Aspergillus species and nonalbicans Candida. Early studies of itraconazole in a prophylactic
setting focused mainly on patients who received chemotherapy for
haematological malignancies with short periods of neutropenia.
Itraconazole has been compared against placebo, polyenes and
fluconazole in this regard.19–21 The conclusions from these studies
have been hampered by the low absolute incidences of SFIs, particularly aspergillosis in these patient groups. Recently however,
itraconazole has been compared with fluconazole in two trials
focusing on patients at highest risk for Aspergillus infections,
i.e. recipients of allogeneic stem cell transplantation. In the
Which drug should be used for prophylaxis?
Characteristics of the ideal drug for prophylaxis against SFIs would
include: (i) a broad spectrum of cover including Candida albicans
and non-albicans, Aspergillus species and other moulds; (ii) proven
efficacy in this setting; (iii) available orally with high bioavailability; (iv) available in intravenous formulation especially if problems with compliance or bioavailability are anticipated following
oral administration; (iv) acceptable toxicity profile; (v) few drug
interactions; (vi) low cost.
Although there is no drug currently available which fulfils all of
these criteria, recent evidence does support the use of systemically
active agents in this setting.
Which class of drug should be used for
prophylaxis?
The meta-analysis by Bow et al.12 included randomized controlled
trials of the azoles fluconazole, itraconazole, ketoconazole and
miconazole or intravenous amphotericin B formulations compared
with placebo, no treatment or oral polyenes in severely neutropenic
i50
Itraconazole and systemic fungal infection
study by Winston et al.,22 itraconazole was compared with fluconazole from day 1 until day 100 after transplantation. Both drugs
were allowed to be given intravenously and/or orally. Both were
well tolerated though the incidence of gastrointestinal side effects
was higher in the itraconazole group. Importantly, whilst the overall
mortality was similar in each group of patients, there were fewer
invasive fungal infections caused by yeasts and moulds in the
itraconazole arm and this translated into a reduced fungusattributable mortality. Discontinuations due to adverse events or
death were higher in the itraconazole arm. In a larger study of
allogeneic stem cell transplant recipients randomized to receive
fluconazole or itraconazole (oral solution/intravenous) for 180
days post-transplant,23 an intention-to-treat analysis showed that
fewer patients in the itraconazole arm developed invasive fungal
infections during the treatment period (15% fluconazole versus 7%
itraconazole; P = 0.03). The benefit was confined to invasive mould
infections. There was no difference in overall or fungus-free survival in this study. There was more toxicity including gastrointestinal and hepatic in the itraconazole arm and this led to a higher rate
of discontinuation from treatment (36% versus 16%; P < 0.001).
Further evidence supporting itraconazole in the prophylactic
setting is provided by the meta-analysis by Glasmacher et al.24
Importantly, this study showed that itraconazole was only active in
doses equivalent to at least 200 mg per day of bioavailable drug (i.e.
at least 400 mg per day oral solution or 200 mg per day intravenous
solution). At this bioavailable dose, the rate of fungal infection
mortality was reduced by 42% and invasive aspergillosis by 48%
on average.
Voriconazole shares with itraconazole a broad spectrum of
activity against a wide range of Candida and Aspergillus species.
Like itraconazole, it is also available in intravenous, oral capsule
and oral solution formulations. Bioavailability following oral
administration is excellent and compliance good, though a proportion of patients develop visual side effects which are reversible
following discontinuation of the drug. Drug interactions are similar
to those seen with itraconazole, though more data are required with
regard to certain drugs, e.g. vincristine, cyclophosphamide and
other cancer chemotherapy agents. It is generally considered
that measurement of plasma levels of voriconazole is not required
on a routine clinical basis. However, few pharmacokinetic data are
available compared with itraconazole and further studies are
required examining possible associations between voriconazole
levels, toxicity and efficacy.
Clinical studies of voriconazole for primary or secondary prophylaxis of invasive fungal infections are under way.
Which patients require azole prophylaxis?
There have been several attempts at risk stratification of patients
(reviewed in Ref. 25). Clearly, the risk of infection increases with
both the severity and duration of neutropenia following chemotherapy. The situation in recipients of allogeneic stem cell transplantation is more complex, however. Late SFIs are common in
non-neutropenic patients and are associated with the development
of graft versus host disease (GVHD) and the use of corticosteroids.26,27 Therefore it is difficult to define exact patient groups who
may benefit from prophylaxis and in part this may depend on
perceptions of the cost-effectiveness of this approach. One pragmatic solution would be to suggest prophylaxis to patient groups
with an expected incidence of SFI of greater than 5%. This would
include patients requiring intensive chemotherapy for the treatment
of acute leukaemias and those undergoing allogeneic stem cell
transplantation but may exclude patients receiving less intense
chemotherapy with short durations in neutropenia and recipients
of autologous transplantation.
Patients who have recovered from an initial SFI but require
further chemotherapy/transplantation have a high incidence of
reactivation of infection.28 Secondary prophylaxis using systemic
antifungal drugs has become a common clinical approach in these
patients.29,30
How long should prophylaxis continue for?
There are few specific data that address this issue. For patients
receiving intensive chemotherapy, it would seem logical to continue prophylaxis for the duration of neutropenia. Invasive fungal
infections commonly occur beyond this period in allogeneic stem
cell recipients and recent studies have focused on continuing prophylaxis for between 150 and 180 days.22,23 However, patients may
require prophylaxis beyond this period should they develop
GVHD, especially if prolonged periods of corticosteroid therapy
are required.
Is loading required when prophylaxis commences?
It would seem logical to adopt a loading strategy in high-risk
patients. With itraconazole oral suspension, the use of high
doses orally is difficult because the cyclodextrin induces nausea
and diarrhoea. Two strategies have been shown to be effective. The
first includes the use of itraconazole capsules with itraconazole oral
suspension for the first few days of prophylaxis.31 The second
involves the use of intravenous itraconazole with switching to
oral suspension following a short loading period.32 In either
case, it is recommended that loading commences following completion of conditioning chemotherapy in the transplant setting due
to potential interactions between this azole and chemotherapy
agents such as cyclophosphamide.23,33 Intravenous voriconazole may also be used for rapid loading prior to prolonged oral
administration.34
Is it important to measure plasma levels of azoles
on a routine basis?
This would seem to be particularly important with itraconazole and
evidence would support improved efficacy in patients obtaining a
plasma level of greater than 500 ng/mL.35 High-risk patients in
whom such levels are not attained may be offered intravenous
itraconazole (e.g. in period of mucositis) or an alternative agent.
Available data support switching between intravenous and oral
suspension formulations of itraconazole to maintain adequate
levels of this drug and its active metabolite.36
Which drug interactions are clinically important
in the haematology setting?
The main interactions involve the use of itraconazole and voriconazole with rifampicin, ciclosporin A, tacrolimus and certain
chemotherapy drugs including vincristine and cyclophosphamide.
Rifampicin and other agents which are potent inducers of hepatic
i51
Potter
microsomal enzymes result in markedly suboptimal levels of
itraconazole and in patients receiving these drugs, an alternative
antifungal agent would be recommended.37 The effect of rifampicin on itraconazole metabolism is particularly profound and may
persist for several weeks after discontinuation. Itraconazole and
voriconazole inhibit the metabolism of ciclosporin A and tacrolimus.38,39 Clinicians should be aware of this interaction and reduce
the dose accordingly and be guided by regular plasma levels of
these medications. A number of reports have indicated that
itraconazole may potentiate vincristine-induced neuropathies
including severe autonomic neuropathy.40,41 Although specific
recommendations have yet to be defined, caution should be exercised in the use of itraconazole prophylaxis in patients receiving
protocols where vincristine is administered regularly, e.g. children
and adults with acute lymphoblastic leukaemia and certain types of
lymphoma. If itraconazole is used in such patients, a wash-out
period of several days may be required prior to administration
of a vinca alkaloid in order to prevent severe neurotoxicity. Itraconazole has also been implicated in enhancing hepatic toxicity in
patients receiving high-dose cyclophosphamide, e.g. stem cell
transplant recipients following conditioning treatment. This has
been shown to be a result of increased plasma levels of toxic
cyclophosphamide metabolites.23,33 Further data are required
with respect to voriconazole in this regard. Until further data are
available on possible interactions between both azoles and other
chemotherapy drugs, particularly those used at high dose, it may be
advisable to commence prophylaxis following completion of this
treatment, e.g. by a rapid loading strategy.
Are there any other concerns with regard to
azole prophylaxis?
Azoles have limited activity against most non-Aspergillus moulds.
Recent reports indicate that the use of azole prophylaxis, particularly voriconazole, may be associated with an increase in the incidence of non-Aspergillus mould infections including species of
zygomycete, Fusarium and Scedosporium.42 The exact mechanism
whereby azoles may increase the incidences of non-Aspergillus
moulds is unknown. One possible explanation is that these infections have occurred in patients with the most prolonged and profound immune suppression who may have succumbed to
Aspergillus infections prior to the era of azole prophylaxis.
Treatment of invasive fungal infection
Evidence is available supporting the use of several agents in this
setting, including conventional and lipid-associated amphotericin
B, azoles and echinocandins. Few data are available from randomized comparative studies though two such trials have supported the
use of voriconazole34 and liposomal amphotericin B46 both against
conventional amphotericin B in terms of efficacy in this setting.
Central nervous system aspergillosis carries a high mortality. Voriconazole may be the preferred agent in this setting due to its
relatively good CNS penetration.47 Caspofungin is a licensed therapy for second-line or salvage therapy of invasive Aspergillus
infections.48 Response rates of around 40% have been reported
in this difficult group of patients. Conventional and lipidassociated amphotericin B, voriconazole, itraconazole and the echinocandins have a broad spectrum of activity against Candida
albicans and non-albicans species. Zygomycoses including
Mucor are difficult to treat but amphotericin B/AmBisome may
be the preferred agents for these infections.49 Fusarium infections
and those caused by certain Scedosporium species may respond to
voriconazole treatment.50–52
New approaches to the treatment of
fungal infection
Although there are a small number of new agents in clinical development, it is likely that most progress will be achieved by novel
approaches using existing antifungal agents. Carefully designed
clinical trials are required in several areas including: (i) defining
optimal approaches to primary and secondary prophylaxis of invasive fungal infections in patients at risk; (ii) evaluating early diagnosis and ‘pre-emptive therapy’ as an alternative to the empirical
approach, e.g. by the use of serum PCR or galactomannan detection
and/or the early use of high-resolution pulmonary CT scanning;
(iii) the use of combination antifungal therapy using agents acting
by different mechanisms. The greatest clinical need is in aspergillosis and other mould infections. Early data are encouraging with
regard to tolerability and possibly efficacy,53–55 though data from
randomized trials are currently lacking for these SFIs; (iv) the
modulation of host defences, e.g. the use of growth factors, lymphokines and neutrophil transfusions.
Data from well-designed clinical trials in these areas will
provide a platform for the development of novel therapeutic
strategies in future years.
Empirical antifungal therapy
This is the setting in which the largest trials of antifungal therapy
have been assessed. In recent years, analysis has been based upon a
composite end point response with the assessment of both efficacy
and toxicity. Available evidence most strongly supports the use of
liposomal amphotericin B or caspofungin in this setting.43,44 The
use of amphotericin B is hampered by a high incidence of toxic side
effects and necessary discontinuations.43 Voriconazole failed to
meet the primary end point of non-inferiority in a large randomized
trial when compared with liposomal amphotericin B.45 This agent
was, however, more effective in reducing the incidences of breakthrough fungal infections. Itraconazole has been compared with
amphotericin B in one large randomized study.32 It was found to be
equally efficacious and associated with a superior toxicity profile.
In patients receiving this agent for prophylaxis however, it would
seem logical to change to a different agent in the empirical setting.
Transparency declaration
M. P. has received fees for speaking on behalf of MSD, Pfizer,
Gilead and Ortho Biotech/Janssen-Cilag. He has participated as
a member of advisory boards for MSD (caspofungin), Pfizer
(voriconazole), Gilead (AmBisome), Elan (Abelcet) and Ortho
Biotech/Janssen-Cilag (itraconazole). Further support for research
projects has been provided by MSD and Gilead.
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