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Nucci M
Rev Bras Hematol Hemoter. 2012;34(5):383-91
in the treatment of invasive aspergillosis
(42)
. Resistance to
echinocandins among
Candida
isolates has been increasingly
reported and involves mutations in the drug target
(43)
.
Strategies of antifungal use in hematology
Antifungal agents can be used in different ways in patients
with hematologic diseases: as prophylaxis, empiric therapy,
preemptive therapy (or diagnostic-driven), and for the treatment
of a documented IFD.
Antifungal prophylaxis
Antifungal prophylaxis in hematologic patients is very
tempting because the incidence of IFD is high, the diagnosis
is not easily performed, and the mortality may be very high.
Nevertheless, prophylaxis is not indicated in all patients. In
general, the higher the incidence of an IFD and the shorter the
period at risk, the more likely prophylaxis will work. The problem
is that both an estimation of the magnitude (probable incidence)
and the duration of risk are not easily advanced at the bedside.
The first question to be answered in order to define if
antifungal prophylaxis is indicated is if the patient is at risk for both
invasive candidiasis and invasive mould disease (mostly invasive
aspergillosis). The main risk factors for invasive candidiasis are
neutropenia, gastrointestinal mucositis and a central venous
catheter. By contrast, prolonged (usually > 10 days) and severe
(< 100/mm
3
) neutropenia and severe T-cell immunodeficiency
are the main risk factor for invasive aspergillosis. If the patient
is at risk for invasive candidiasis only, fluconazole is the agent
of choice for prophylaxis, given at a dose of 400 mg daily (adult
dose). The strongest benefit of fluconazole prophylaxis is observed
in allogeneic HSCT recipients. In these patients, two randomized
clinical trials showed that fluconazole reduced the frequency of
superficial and systemic candidiasis, as well as infection-related
mortality
(14,15)
. In addition, in one of these trials fluconazole was
given until day +75 post-transplant, and a post-hoc analysis of
the trial showed that fluconazole was associated with prolonged
protection against invasive candidiasis, even beyond the period
of prophylaxis
(44)
. The benefit of prophylaxis against invasive
candidiasis was not as apparent in other settings, such as in patients
with acute leukemia and autologous HSCT recipients
(45)
. However,
the ineffectiveness of fluconazole in non-HSCT neutropenic
patients is probably related to the heterogeneity of the populations of
neutropenic patients studied (with different incidences of invasive
candidiasis) rather than an absence of efficacy. Fluconazole is
not effective in preventing infection caused by
Candida krusei
and most
Candida glabrata
isolates, which exhibit high minimal
inhibitory concentrations (MICs) to fluconazole.
Other agents that can be used as prophylaxis for invasive
candidiasis include micafungin
(46)
, itraconazole (oral solution
and intravenous preparation only, not available in Brazil)
(20,21)
,
voriconazole
(24,47)
and posaconazole
(31 )
. The latter two drugs are
indicated if anti-mould prophylaxis is also needed.
The group with the highest incidence of invasive
aspergillosis is represented by patients with AML or MDS
undergoing induction remission chemotherapy, and allogeneic
HSCT recipients. In these patients, the at-risk period encompasses
both early pre-engraftment (in which neutropenia is the leading
risk factor) and post-engraftment (T-cell immunodeficiency due
to GVHD and its treatment).
In the setting of AML/MDS, posaconazole (200 mg 3x/day)
was superior to fluconazole or itraconazole oral solution in a large
randomized controlled trial, and is considered the drug of choice for
anti-
Aspergillus
prophylaxis
(30)
. Voriconazole has not been tested in
trials of AML patients, but has been frequently used as prophylaxis.
In allogeneic HSCT, itraconazole oral solution, given in the
pre- and post-engraftment periods, was tested against fluconazole
in two randomized clinical trials
(20,21)
. One trial showed a
reduction in the incidence of IFD in itraconazole recipients
(21)
,
while the other showed a reduction in the incidence of invasive
mould disease
(21)
. The problem with itraconazole oral solution
(once again, not available in Brazil), is that as high as one fourth
of patients discontinued the study drug due to gastrointestinal
intolerance. Another option in the allogeneic HSCT setting is
posaconazole. In a randomized trial, this agent was compared
with fluconazole in patients with GVHD (however, in the post-
engraftment period only)
(31)
. There was a significant difference in
the incidence of invasive aspergillosis favoring the posaconazole
arm (2.3% vs. 7%, p-value = 0.006), although for the primary
endpoint (incidence of IFD on day 112 of prophylaxis) there was
a non-significant advantage of posaconazole (p-value = 0.07).
Another option for anti-mould prophylaxis in allogeneic
HSCT recipients is voriconazole. In one randomized study,
voriconazole was compared with itraconazole oral solution, given
just after conditioning regimen until > 100 days
(47)
. Among 465
patients randomized, only eight IFD were diagnosed, three in the
voriconazole arm (1.3%) and five in the itraconazole arm (2.1%).As
in the other trials of itraconazole, gastrointestinal intolerance was
significantly more frequent in itraconazole recipients. In another
trial, allogeneic HSCT recipients received either voriconazole or
fluconazole given in both pre- and post-engraftment periods
(24)
.
The number of cases of invasive aspergillosis was lower in the
voriconazole arm, but the difference was not statistically significant
(9 vs. 17 cases, p-value = 0.09). An interesting feature of this trial
is that all patients were monitored with bi-weekly (until day 60)
or weekly (from day 60 to day 100) serum galactomannan tests,
with empiric antifungal therapy being initiated based on positive
galactomannan tests and other findings (radiology or clinical
parameters). Therefore, another way of interpreting these results
is that fluconazole prophylaxis plus structured galactomannan
monitoring (and initiation of appropriate antifungal therapy) is as
good as voriconazole prophylaxis.
Outside the setting of AML/MDS and allogeneic HSCT
no formal recommendations can be made regarding antifungal
prophylaxis. In autologous HSCT recipients the use of
antifungal agents is controversial. Recent guidelines recommend
administering anti-
Candida
prophylaxis to a sub-population
of autologous recipients who have underlying hematologic
malignancies (for example, lymphoma, leukemia or myeloma)
and who have or will have prolonged neutropenia and mucosal
damage from intense conditioning regimens or graft manipulation,
or have received fludarabine or 2-CDA within 6 months before
HSCT, with a BIII level of evidence (moderate strength of