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Use of Newer Antifungal Therapies in Clinical Practice: What Do the Data Tell Us?

Use of Newer Antifungal Therapies in Clinical Practice: What Do the Data Tell Us?

ABSTRACT: Considering the significant morbidity and mortality associated with invasive fungal infections in immunocompromised patients, it is particularly important to make the diagnosis as early as possible and to make best use of the available antifungal drugs for prophylaxis and treatment. The newer antifungal drugs include the lipid products of amphotericin B, such as amphotericin B lipid complex (ABLC) and liposomal amphotericin B; voriconazole (a triazole); and caspofungin (an echinocandin). ABLC and liposomal amphotericin B are as effective as amphotericin B deoxycholate but are less nephrotoxic; ABLC is probably the drug of choice for zygomycosis. Voriconazole is approved for use in the treatment of invasive aspergillosis and may have a role in preventing breakthrough fungal infections in patients with persistent fever and neutropenia. Caspofungin is effective against both invasive aspergillosis and invasive candidiasis.

The prevention and management
of invasive fungal infections are
of enormous importance in the
care of patients undergoing cancer
chemotherapy or bone marrow transplantation.
Fungal infections such as
invasive aspergillosis and candidiasis
continue to be important causes of
mortality in these patients. Key management
strategies include accurate
and rapid diagnosis, optimal use of antifungal
drugs for prophylaxis and empiric
therapy, and, in select patients,
additional interventions such as
immunomodulation therapies and surgery.

This article will evaluate the newer
antifungal agents, along with some
agents that are still being investigated,
for use in specific patient populations
and for management of specific mycoses.
Although not uniformly successful
in every patient, these new
agents nevertheless will have a very
positive impact on the management of
difficult invasive mycoses.

Overview

Some of the major developments
in the treatment of invasive mycoses
can be highlighted by a brief review
of three landmark, evidence-based
studies:

  • Combination therapy for cryptococcal
    meningitis:
    van der Horst et
    al[1] compared amphotericin B (0.7
    mg/kg/d) with a combination of amphotericin
    B and flucytosine (100 mg/
    kg/d) for the treatment of cryptococcal
    meningitis in patients with AIDS.
    After 2 weeks of treatment, cerebrospinal
    fluid (CSF) cultures were
    negative in 60% of those who received
    combination therapy, compared with
    51% of those who received amphotericin
    B alone (P = .06).
  • Voriconazole vs amphotericin B
    for invasive aspergillosis:
    Herbrecht
    et al[2] compared voriconazole at two
    doses (6 mg/kg on day 1, followed by
    4 mg/kg twice daily) with amphotericin
    B deoxycholate (1 to 1.5 mg/kg/d)
    in patients with invasive aspergillosis.
    Successful outcomes were achieved in
    52.8% of the voriconazole group, compared
    with 31.6% of the amphotericin
    B group.
  • Caspofungin vs amphotericin B
    for invasive candidiasis:
    Mora-Duarte
    et al[3] compared the echinocandin
    caspofungin with amphotericin B in
    patients with invasive candidiasis. In
    a secondary analysis, caspofungin's
    success rate was approximately 15%
    higher than the success rate for amphotericin
    B. In addition, caspofungin
    was associated with a lower incidence
    of adverse events.

    It is important to note that the treatment
    success rates achieved in these
    robust, large, comparative studies
    clearly do not approach 100% (Table
    1). Although the measurement of results
    in some clinical trials might be
    debatable because treatment success
    was based on specific study criteria,
    overall, the failure rates are still considerable,
    regardless of the clinical
    criteria used.

Diagnosis

Considering the significant morbidity
and mortality associated with invasive
fungal infections in
immunocompromised patients, it is
particularly important to diagnose a
fungal infection as early as possible.
Unfortunately, the diagnosis is often
challenging. In invasive aspergillosis,
for example, the signs and symptoms
are nonspecific, and blood cultures are
rarely positive.

Although it is often difficult to obtain
samples for histopathology and
culture, it is important to make every
attempt to identify the organism because
the findings will influence treatment.
The combination of histopathology
and culture is necessary because
the results of one method might not
be definitive. For example, regarding
the technique of histopathology, the
presence of branching septae and hyphae
could indicate Fusarium, Aspergillus,
or Scedosporium species,
and only a culture would identify the
correct pathogen.

In addition, with histopathology,
some patients may have conidia in
tissue that produce adventitial forms
of Fusarium, Acremonium, and
Paecilomyces.
The histopathology report
may indicate that one of those
organisms is the likely pathogen. In
contrast, the finding of conidia and
hyphae in tissue is not seen with Zygomycetes,
Aspergillus fumigatus,
or
Aspergillus flavus.
Thus, the histopathology
results can help complement
culture results.

Although there is no absolute proof
that early diagnosis results in less burden
of organisms, there is some evidence
that early diagnosis affects outcome.
One study of patients with pulmonary
aspergillosis indicated that
more frequent use of bronchoscopy
and high-resolution CT led to a more
rapid diagnosis and, therefore, earlier
treatment.[4] The mortality rate was
41% when the diagnosis was made
within 10 days or less after the onset
of signs and symptoms, compared
with 90% when the diagnosis was
made after 10 days.

CT scanning can be very useful in
the diagnosis of invasive pulmonary
aspergillosis. The most characteristic
CT findings are the halo sign and aircrescent
formation. The halo sign is
visualized as an area of low attenuation
around a nodule or pleural-based
lesion. Although these signs can occur
in other diseases, they are highly
suggestive of invasive pulmonary aspergillosis
in febrile neutropenic patients.
The halo sign has a short duration;
therefore, the use of early CT can
be quite valuable. A more nonspecific
but common finding is the presence
of nodular lesions on a CT scan; this
has less predictive value.

The diagnosis of invasive aspergillosis
can be confirmed by serologic
tests to detect circulating antigens,
such as cell wall galactomannan
and measurement of β-1,3-D glucan
concentrations. For example, Kami et
al[5] evaluated the sensitivity and
specificity of real-time polymerase
chain reaction (PCR), enzyme-linked
immunosorbent assay (ELISA) for
galactomannan, and the β-D glucan
test for the diagnosis of invasive aspergillosis
(Table 2). The study included
33 patients with invasive aspergillosis
and 89 controls.

The sensitivities and specificities
ranged from 58% to 79%, and 84% to
97%, respectively.[5] Real-time PCR
was more sensitive than the other two
tests; it was also highly specific for
Aspergillus infection. This same study
also evaluated the relationship between
test results and CT findings.
Positive findings on PCR preceded
those of CT by -0.3 ± 6.6 days; the
corresponding figures were 2.8 ± 4.1
days for ELISA and 6.5 ± 4.9 days for
the β-D glucan test.

In high-risk patients, it is particularly
important to use every tool available-
whether it is a serologic test or
CT scan-to identify these invasive
fungal infections as soon as possible.
Often, CT scans show a small nodule,
which the radiologist interprets as po-
tentially being fungal-related. In this
situation, serologic findings could help
support the diagnosis of aspergillosis.
Although these tests are not perfect,
using a combination of them in highrisk
patients may result in an earlier
diagnosis. The diagnosis of invasive
candidiasis could be improved by better
serologic tests, since at present,
blood cultures are positive in only 50%
to 60% of patients with invasive candidiasis.

Immunomodulation

Although immunomodulation has
been extensively studied at the basic
science level, clinically, its use has yet
to be optimized. Some studies indicate
that immunomodulation therapies
do not improve outcome in
immunocompromised patients. For
example, a large, multicenter, European
Organization for Research on
Treatment of Cancer (EORTC) study
demonstrated that the use of growth
factors-primarily granulocyte
colony-stimulating factor (G-CSF)-
had no impact on outcome in hematology
patients who had invasive aspergillosis.[
6] This study included
130 cases, 20 hospitals, and 8 countries.

Safdar et al,[7] at the M. D. Anderson
Cancer Center, evaluated treatment
with G-CSF-primed white blood
cells (WBCs), given every other day,
in 29 patients with candidemia; 76%
of the patients were neutropenic. The
control group consisted of 441 cancer
patients with candidemia, 45% of
whom were neutropenic. The associated
mortality was 48% in patients
who received WBC transfusions and
45% in the control group. The authors
suggested that patients who received
the WBC transfusions may have had
worse prognostic factors than the control
patients, and therefore, their comparable
mortality may have actually
represented a favorable response, but
this interpretation will require further
validation.

Another approach to immunomodulation
involves immune reconstitution.
In a study by Pappas and associates,[
8] two doses of adjuvant recombinant
interferon-gamma were
given to patients with cryptococcal
meningitis. A trend toward faster decline
in CSF yeast counts was seen in
those patients who received the interferon,
compared with those who received
placebo. It is likely that the results
were not statistically significant
because there were not enough patients
in the study. However, interferon
may be difficult to use in organ transplant
recipients because of the rejection
risk to the transplanted organ.

A word of caution: the use of
growth factors to treat pulmonary aspergillosis
has the potential complication
of acute respiratory distress syndrome.
This may be related to the
massive amount of degranulation of
WBCs in the area of the infection.
There is some evidence that boosting
the WBC count too fast is detrimental.
For example, in a small study, the
immediate mortality rate was 50% in
patients who received G-CSF for aspergillosis
who had a rapid increase
in WBC count (0 to 4,500/μL in less
than 5 days), compared with 17% in
those who had a more gradual increase
in WBC count.[9] It is clear that we
need further studies to optimize our
use of immunomodulation as adjunctive
therapy for successful management
of fungal infections.

Antifungal Therapy: Drug
Regimens or Prescriptions

A number of key questions remain
about antifungal drug regimens. The
following is a representation of just
some of these questions:

  • What is the best dosage for liposomal
    amphotericin B?
    Ruiz et al[10]
    retrospectively studied 13 patients
    with proven, probable, or possible in-
    vasive aspergillosis. Four of the patients
    had received prophylaxis with
    itraconazole, and eight had neutropenia.
    Treatment with 10 mg/kg/d of liposomal
    amphotericin B was successful
    in 9 of 10 patients with proven or
    probable disease, and none of the patients
    had nephrotoxicity. This finding
    does not prove that 10 mg/kg/d is the
    best dosage, but it suggests that the
    possibility that the higher doses might
    be beneficial should be considered.
  • Are the dosages of echinocandins
    too low?
    This is a concern, particularly
    in neutropenic patients who have high
    relapse rates of candidemia. Schranz
    et al[11] evaluated the efficacy of three
    different doses of anidulafungin, an
    investigational glucan synthesis
    inhibitor, in the management
    of candidemia. The success rate was
    72% for the lowest dose (100 mg loading
    dose/50 mg daily dose), 87% for
    the intermediate dose (150 mg/75 mg),
    and 87% for the highest dose (200
    mg/100 mg). This result may reflect
    dose-dependent efficacy.

    Echinocandins have dose-dependent
    killing in vitro. In neutropenic
    patients, the organisms have to be
    killed primarily by the drug, because
    the host defense is limited. Since the
    echinocandins are relatively nontoxic,
    it is reasonable to ask whether we are
    underdosing when we give 50 mg of
    caspofungin.

  • Is there a role for the aerosolized
    route of administration?
    There is a
    moderate amount of experience with
    aerosolized amphotericin B lipid complex
    (ABLC). Pharmacokinetic data
    suggest that the lipid formulations in
    suspension might be more effective
    than the deoxycholate preparation of
    amphotericin B. Certainly, the lipid
    products are much easier to aerosolize.

    In an open trial in which 51 lung
    transplant recipients received aerosolized
    ABLC, the incidence of toxicity
    was less than 5%.[12] There were
    no lung infections, two anastomosis
    infections, and four extrapulmonary
    infections, which you might expect to
    occur simply because this drug is not
    absorbed into the systemic circulation.

    In a randomized double-blind
    study, 100 consecutive lung transplant
    recipients were given aerosolized
    ABLC or aerosolized amphotericin B
    deoxycholate.[13] The incidence of
    adverse events was lower in the ABLC
    group than in the amphotericin B
    deoxycholate group (13.7% vs 28.6%;
    P = .03). Failures of prophylaxis occurred
    in 11.8% of the ABLC group
    and in 14.3% of the amphotericin B
    deoxycholate group.

    More studies are needed to determine
    whether fungal infections in the
    lung can be prevented with minimal
    amounts of inhaled antifungal drug,
    particularly when the drug needs to be
    given for long periods, as is the case
    with bone marrow transplant (BMT)
    recipients.

  • To what extent does the site of
    infection influence the efficacy of
    specific therapies?
    CNS fungal infections
    remain quite difficult to treat.
    Troke et al[14] reported a 34% complete
    or partial response rate in 86 patients
    with CNS aspergillosis who
    were given voriconazole. Among
    BMT recipients, the success rate was
    15%, while among the other patients,
    the success rate was 42% to 50%.

    Scedosporium prolificans and
    Scedosporium apiospermum
    can also
    cause CNS infection; the latter is relatively
    susceptible to voriconazole. In
    one study, voriconazole was effective
    in 7 out of 11 patients (64%) with S
    apiospermum infection
    but failed in
    2 of 2 patients with S prolificans infection.

    Pitisuttithum et al[15] reported a
    40% success rate with posaconazole
    in patients with CNS fungal infections,
    such as those caused by Aspergillus,
    Scedosporium, Coccidioides immitis,
    Histoplasma capsulatum,
    black molds,
    and Zygomycetes. Posaconazole's
    success rate was 59% in patients with
    cryptococcal meningitis.

Surgery

The role of surgery for the management
of invasive fungal infections
should not be overlooked. Surgery
does have a role in select patients with
Zygomycetes and black mold infections
and in some patients with invasive
infections with Aspergillus and
other hyalohyphomycetes. Caillot et
al[16] reported that combined medical-
surgical therapy achieved a cure
rate of 84% in 25 neutropenic patients
who had surgically proven pulmonary
aspergillosis.

Another study involved 87 patients
with hematologic malignancies in
whom invasive pulmonary aspergillosis
was suspected.[17] Of the 39 patients
who underwent resection on the
basis of CT findings, 35 actually had
invasive pulmonary aspergillosis. The
2-year survival rate was 36% in the
resected group and 20% in the
unresected group.

Thus, there is evidence that in some
circumstances, surgery can have a
positive outcome, although it is important
to note that these are very select
patient populations regarding the ability
to tolerate surgery.

Antifungal Therapy: A Focus on the Newer Drugs

Invasive fungal infections continue to be a significant cause of morbidity
and mortality among patients undergoing cancer chemotherapy or bone marrow
or stem cell transplantation. The toxicity associated with amphotericin B
deoxycholate and the incidence of treatment failures have led to the development
of new antifungal drugs, such as the lipid formulations of amphotericin
B, the triazoles, and the echinocandins.

Liposomal Amphotericin B
The lipid formulations of amphotericin B are approved for use in the treatment
of invasive fungal infections when amphotericin B deoxycholate fails or
when it is associated with unacceptable toxicity. Liposomal amphotericin B
has been reported to have an overall response rate of about 60% in this setting[
46,47] and is associated with less nephrotoxicity than amphotericin B
deoxycholate.[48,49]

Triazoles
Voriconazole is a broad-spectrum triazole with efficacy against invasive aspergillosis,[
2,50] fluconazole-resistant candidiasis,[51] and a variety of other
mycoses.[52] It is also effective in preventing breakthrough fungal infections
in patients with fever and neutropenia. Voriconazole has been approved by the
FDA for primary treatment of acute invasive aspergillosis and for salvage therapy
for serious infections caused by Scedosporium apiospermum and Fusarium
species.

Data from 85 patients who received voriconazole have been reviewed.[53]
Approximately 50% of the patients were bone marrow transplant recipients,
approximately 27% had aspergillosis, and 24% had neutropenia; 13% received
combination therapy. Within 72 hours of initiating voriconazole therapy, the
most common drug interactions were with cyclosporin A (52%) and tacrolimus
(29%); for both, the levels fell outside the therapeutic range. Liver function test
results were elevated in 10% of patients. Therefore, when using voriconazole,
it is important to be aware of these drug interactions and to carefully consider
the cost-benefit ratio.

Echinocandins
The echinocandins include caspofungin, micafungin, and anidulafungin.
These drugs are glucan synthesis inhibitors. Caspofungin is active against Aspergillus
and Candida species, but it does not have significant activity against
Cryptococcus neoformans. It has good in vitro activity against Candida species,
including those resistant to fluconazole and itraconazole.[54,55]
Caspofungin has been demonstrated to be effective in the treatment of oropharyngeal
and esophageal candidiasis,[56-58] fluconazole-resistant esophageal
candidiasis,[59] and invasive candidiasis.[3]

Caspofungin is approved by the FDA for salvage therapy in patients with
invasive aspergillosis who have been refractory to or intolerant of amphotericin
B, amphotericin B lipid complex, and/or itraconazole. It is also approved
for the treatment of oropharyngeal and esophageal candidiasis and invasive
candidiasis. The standard dosage is 50 mg/d IV after a 70-mg loading dose;
higher dosages (70 mg/d) have been safely used. The duration of treatment
depends on the severity of the patient's underlying disease, recovery from immunosuppression,
and clinical response. Caspofungin has an excellent safety
profile and does not appear to be antagonistic when combined with other antifungal
therapies.[60]

Micafungin is an investigational agent that has a broad spectrum of activity
against Candida species[61] and Aspergillus species. Anidulafungin is also an
investigational agent that is active against Candida species.[62,63]

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