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Use of antifungal drugs in hematology
Rev Bras Hematol Hemoter. 2012;34(5):383-91
these shortcomings, higher doses are frequently given in real life,
especially in the treatment of severe infections such as invasive
fusariosis and mucormycosis, or if the patient is not responding
to standard doses. Although common, these practices are not
evidence-based. Regardless of the differences in side effects
between the three lipid formulations of AMB, they are equally
effective when compared with d-AMB, and this is another reason
to abandon the use of d-AMB in hematologic patients.
Amphotericin B has the largest spectrum of all antifungal
agents, and despite the fact that it has been used for a long
time, resistance is rarely observed in the clinical practice. The
preparations of AMB have been used in hematologic patients in
the empiric antifungal therapy of febrile neutropenia
(6-10)
, as well
as in the treatment of various IFD, including candidemia, acute
and chronic disseminated candidiasis, aspergillosis, fusariosis,
mucormycosis and others
(7,11-13)
.
The azoles are another class of antifungal agents. Fluconazole
is available in both oral and intravenous preparations and is largely
used in hematologic patients, mostly as prophylaxis against
invasive candidiasis in allogeneic HSCT
(14,15)
and in patients with
AML receiving induction chemotherapy regimens with high
potential to induce severe gastrointestinal mucositis
(16)
. The usual
prophylactic dose is 400 mg once per day for both the oral and
intravenous preparations. In addition to prophylaxis, fluconazole
can be used for the treatment of candidemia, although its use
for this indication is limited by the fact that most hematologic
patients have received fluconazole previously, and therefore
are more likely to have infections caused by less-susceptible
species (
Candida glabrata
and
Candida krusei
)
(17)
. Another
indication of fluconazole is in the long-term treatment of chronic
disseminated candidiasis
(18)
. The chronic use of fluconazole,
especially intermittently and at low doses, is the ideal scenario
for the development of resistance which is mediated by various
mechanisms, including mutations in the drug target and efflux
pumps
(19)
. Once resistance develops, cross resistance with other
agents of the class is the rule. Therefore, patients with candidiasis
caused by a fluconazole-resistant (or less-susceptible) isolate are
best treated with a drug belonging to another class.
Itraconazole is available in capsules, oral preparation
and intravenous formulation. It has a broader spectrum than
fluconazole, including activity against
Aspergillus
. While both
the intravenous preparation and oral solution have been used
in hematologic patients as prophylaxis for IFD in allogeneic
HSCT
(20,21)
, itraconazole capsules are not effective as prophylaxis
in hematologic patients because of its poor oral absorption
(22)
.
Neither the oral nor the intravenous preparation of itraconazole is
available in Brazil, thus strongly limiting the use of this agent in
hematologic patients.
The newer generation of azoles is represented by
voriconazole and posaconazole. Voriconazole is available in
oral and intravenous preparations, and has its main indication in
hematology as primary treatment for invasive aspergillosis
(23)
.
Other scenarios in which voriconazole is frequently used include
primary prophylaxis of high risk patients (allogeneic HSCT or
evenAMLpatients in induction remission), secondary prophylaxis
in patients with prior history of invasive aspergillosis, empiric or
preemptive antifungal therapy, and treatment of fusariosis
(9,24-26)
.
Hematologic patients receiving voriconazole usually have
variations in serum levels due to both variable absorption of the
oral preparation and metabolism. In hematologic patients the
bioavailability of the oral preparation is about 63%, contrasting
with the excellent bioavailability (80-95%) in healthy subjects
(27)
.
In addition, polymorphisms in the CYP2C19 P450 enzyme
drive serum levels of voriconazole. The frequency of these
polymorphisms varies according to the ethnic group, with Asian
patients being more frequently homozygous poor metabolizers
(and thus having higher serum levels of voriconazole)
(28)
. The
usual intravenous (300 mg twice daily) and oral (200 mg twice
daily) doses of voriconazole have been challenged recently, and
a study suggested that higher oral doses (300 or 400 mg twice
daily) are needed to achieve optimal serum levels
(27)
. The ideal
scenario would be to monitor serum levels in non-responding
patients or in those with neurologic or hepatic toxicity, but this is
not practical in the overwhelming majority of centers worldwide.
Although the occurrence of resistance is less frequent than with
fluconazole,
Candida
isolates may be resistant to voriconazole.
In addition, recent reports of a few azole-resistant
Aspergillus
species have been reported, mostly in Europe
(29)
. The clinical
relevance of these findings is not known at the present time.
Posaconazole is available as an oral solution. Its main
indication is prophylaxis in patients with AML or myelodysplasia
(MDS) receiving induction remission therapy
(30)
and in allogeneic
HSCT recipients with severe graft versus host disease (GVHD)
or receiving intensive systemic immunosuppressive therapies
(31)
.
Therapeutic drug monitoring is usually recommended for
posaconazole although the adequate trough serum level has not
been established. The oral bioavailability of the oral solution
is variable and dependent on a fatty meal. The usual dose for
prophylaxis is 200 mg three times a day. An oral tablet and an
intravenous formulation of posaconazole are under development.
Isavuconazole is an azole antifungal agent with the largest
antifungal spectrumof all azoles; it is available inoral and intravenous
preparations. Phase III studies with this drug are under way.
The other class of antifungal agents used in hematologic
patients is the echinocandins. Different from the other classes that
have their target in the fungal membrane, the echinocandins act
on the fungal cell wall. This predicts a very good safety profile for
these drugs since human cells do not have a cell wall. The three
agents are caspofungin, micafungin and anidulafungin. There are
some differences between the three agents, but in general they
can be used interchangeably. Caspofungin and anidulafungin
need a loading dose on the first day of therapy (70 mg and 200
mg, respectively), whereas micafungin does not. The adult daily
dose is 50 mg for caspofungin and 100 mg for anidulafungin
and micafungin. Caspofungin is the agent most studied in
neutropenic patients. Although experience with anidulafungin
in neutropenic patients is very limited
(32)
, a neutropenic murine
invasive candidiasis model showed similar activities for
anidulafungin and caspofungin
(33)
. The main indication of the
echinocandins is primary treatment of candidemia and invasive
candidiasis
(13,34-37)
. In addition, caspofungin has been extensively
used as empiric antifungal therapy in persistently neutropenic
patients
(38,39)
. Other potential uses of the echinocandins are as
secondary prophylaxis
(40,41)
and in combination with voriconazole