Page 1635 - Hematology_ Basic Principles and Practice ( PDFDrive )

1456 Part VIII Comprehensive Care of Patients with Hematologic Malignancies

Use of Antifungal Agents in Combination
The development of new antifungal drugs gives the clinician more
options for prophylaxis and therapy than in previous years. There is an
overall level of simplicity to the drug choices once their mechanisms of
action are understood. The polyenes, including amphotericin products
and the topical agent nystatin, attach onto ergosterol in the fungal
cell membrane and are considered fungicidal, because cytoplasm
leaks out, and individual cells die. The azoles, including fluconazole,
itraconazole, voriconazole, and posaconazole, prevent the formation of
new ergosterol. Azoles are considered fungistatic, because removal of
the drug permits cell regrowth. Theoretically, use of an azole together
with a polyene may have an overall static effect for an established
infection as the ergosterol target for the fungicidal polyene is depleted.
However, this combination may have advantages in terms of enhanced
spectrum of activity. The echinocandins, including caspofungin, mica-
fungin, and anidulafungin, prevent interaction of the catalytic and
regulatory subunits of the β-glucan synthesis enzyme, so less β-glucan
is formed for the cell wall. The scaffolding for the fungal cell wall is
not maintained, and a dividing cell may burst open when trying to
extend the new cell wall over daughter cells. The echinocandins are
considered fungicidal for yeasts but fungistatic for molds, because drug
activity is concentrated at only the tips of the extending hyphae with
little effect on less metabolically active subapical compartments of the
fungus. Combination therapy may have the most effect when a cell wall
agent (an echinocandin) is used together with a cell membrane agent
(a polyene or an azole). There is no role for three-drug therapy (an
A echinocandin, a polyene, and an azole). Aside from cases of cryptococ-
cal meningitis, in which the importance of combination therapy is well
established, the benefits of frontline use of combination antifungal for
molds remain controversial, although active investigation continues in
clinical trials. The value of combination regimens as salvage therapy
for refractory mold infections remains uncertain.

bloodstream or invasive isolates can be helpful in the management of
infections, especially if the patient will require transition to longer-
term oral therapy. Long-term treatment with newer azoles may be
valuable in responding patients. Echinocandins cannot be used to
treat Cryptococcus or Mucorales as monotherapy, but there may be
a role for echinocandin in combination treatment for Mucorales.
Mucorales species are generally susceptible to amphotericin B and
posaconazole and isavuconazole, although there are interspecies varia-
tions in susceptibility. In the case of mold infections, echinocandin
agents may be fungistatic, rather than fungicidal, because interrup-
tion of fungal cell wall synthesis is limited to areas of hyphal branch
B points and growing hyphal tips. Because susceptibility testing for the
echinocandin agents is of uncertain reliability, use of an echinocandin
Fig. 89.5 EXAMPLES OF ASPERGILLOSIS. (A) Cutaneous aspergillosis after the susceptibility profile has returned should be limited to non-
in a patient with lymphoma treated with high-dose steroids. (B) Invasive neutropenic patients with uncomplicated candidemia. At present, the
aspergillosis with organism invading into blood vessel wall (black arrows). efficacy of combination drug therapy is unproven, but such therapy
is often used in situations associated with high mortality. Clinical
experience, but little clearly documented evidence, supports the value
Although less common than Candida infections, mold infections of extended combination antifungal therapy. Molds that often are
in immunocompromised hosts are a significant source of mortality, resistant to amphotericin but may be susceptible to voriconazole or
with aspergillosis being the most common (Fig. 89.5). Because such posaconazole include Fusarium, Scedosporium or Pseudallescheria, and
infections are difficult to diagnose using standard microbiologic Trichosporon (see box on Use of Antifungal Agents in Combination).
techniques, there has been significant interest in developing more
effective screening tests. When used regularly, the serum Aspergillus
galactomannan enzyme-linked immunosorbent assay (ELISA) may Malignancy-Associated Fever and Drug Fever
27
allow for earlier diagnosis of invasive aspergillosis in some patients.
The test is troubled by difficulties with both false-positive and false- Although fever usually indicates the presence of infection, relapsing
negative results and thus needs to be interpreted as part of the overall malignancy, autoimmune-granulomatous, collagen vascular diseases,
clinical picture rather than as a stand-alone diagnostic tool. The or immunologic drug reactions can also be sources of fever in the
29
development of a fungal infection in a patient receiving voriconazole immunocompromised host. Malignancy or drug-associated fevers
should raise concern for mucormycosis, which is the second-most are the most common causes of persistent noninfectious fevers in
common mold infection in many transplant centers. Mucormycosis cancer patients, but these are “diagnoses of exclusion” that require
can rapidly disseminate through the lungs, sinuses, GI tract, and skin, extensive clinical, radiographic, and microbiologic workup for occult
which is uniformly fatal in patients with hematologic malignancies if infection until a noninfectious cause is considered most likely. All too
not diagnosed early and aggressively treated. 28 often, patients receive escalating empiric broad-spectrum antibiotic
Although in vitro antifungal susceptibility testing for yeasts is therapy during this workup, which should be discouraged in clinically
not as well established as antibacterial testing, susceptibility from stable patients. Several clinical clues may favor a diagnosis of