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Prophylaxis Against Fungal Infections and Cytomegalovirus Disease After Bone Marrow Transplantation

Prophylaxis Against Fungal Infections and Cytomegalovirus Disease After Bone Marrow Transplantation

ABSTRACT: Among the serious complications associated with bone marrow transplantation are invasive fungal infections caused by organisms such as Candida and Aspergillus species and end-organ disease caused by cytomegalovirus (CMV). Successful prevention of these complications can have a significant impact on morbidity and mortality. The primary option for prophylaxis against fungal infections is fluconazole (Diflucan). Low doses of intravenous amphotericin B may be useful where there is a higher rate of aspergillosis. Itraconazole (Sporanox) and nasal amphotericin B are other options that have been less well studied. The development of fluconazole-resistant candidiasis may become problematic. Ganciclovir (Cytovene) is useful for the prevention of end-organ disease caused by CMV but carries a significant risk for neutropenia. New techniques for the early detection of CMV infection should allow prophylaxis to be targeted to patients at highest risk of developing CMV disease. It is critical to clearly define the risk factors for fungal and CMV disease in the individual patient in order to minimize adverse effects and provide the optimal prophylactic benefit. [ONCOLOGY 14(12):1701-1719, 2000]

The therapeutic modalities used to treat
hematologic and solid-organ malignancies and to permit successful bone marrow or
peripheral stem-cell transplantation dramatically increase the risk for
infection in patients who are already immunocompromised because of their primary
diagnosis. A myriad of possible infectious complications of bacterial, viral,
fungal, or parasitic origin may develop as a result of immunosuppressive
treatments. The risk for infection depends on the underlying disease process,
previous infections, and most importantly, the degree and type of
immunosuppression caused by the effects of pretransplant chemotherapeutic
conditioning and posttransplant antirejection regimens on the immune system.

Neutrophil function, T-cell mediated immunity, humoral immunity,
and intact integumentary and gastrointestinal systems are all altered to varying
degrees by particular regimens. For example, disruption of cell-mediated
immunity increases the risk for Pneumocystis carinii, tuberculosis and
other mycobacterial diseases, Varicella zoster, Herpes simplex, and
cytomegalovirus (CMV), while neutropenia predisposes a patient to bacterial and
invasive fungal infections.[1]

Patients who are immunosuppressed as a result of bone marrow
transplantation (or aggressive chemotherapy for leukemia or lymphoma) are at
particular risk for these potentially devastating infections; effective,
nontoxic prophylaxis would clearly be beneficial. Invasive fungal infections and
end-organ disease caused by CMV are two of the most serious complications,
leading to significant morbidity and mortality. Although there has been progress
in the pharmacologic options available to prevent disease due to fungi and
cytomegalovirus infections, the optimal approach to disease prevention that also
minimizes the adverse effects of prophylaxis remains to be determined.

Prevention of Invasive Fungal Infections

Invasive fungal infections due to Candida, Aspergillus,
and other pathogenic fungi are a significant problem, particularly in the
setting of severe neutropenia. Candida species, usually Candida
albicans,
are the most common pathogens in this population. The risk of
acquiring a severe candidal infection varies from one transplantation center to
another. In a review of 1,506 bone marrow transplants performed over a 6-year
period in Seattle, invasive infections developed in 11.4% of patients.[2]
Fungemia was associated with a mortality rate of 40%, while patients with
tissue-invasive disease had a mortality rate of 90%.

Predisposition to Infection

Candidiasis: The defects in host defenses that predispose
a patient to candidal infections often occur in those undergoing cytotoxic
chemotherapy for bone marrow transplant or neoplastic disease. To cause disease,
Candida must first breach the defenses of the integumentary system,
either through disrupted skin or gastrointestinal mucosa, and then disseminate
through the bloodstream to organs such as the liver, spleen, and heart.
Indwelling intravenous access devices, mucositis, and exposure to broad-spectrum
antibiotics that suppress the normal bacterial flora and permit overgrowth of
endogenous Candida are all risk factors for invasive fungal disease.[3]
Defects in lymphocyte function and number predispose to mucocutaneous
candidiasis, as typified by patients with human immunodeficiency virus (HIV)
infection, but candidemia and deep-tissue infection are uncommon in HIV disease.

Neutropenia—particularly severe episodes below 500 cells per
mm3 that predictably occur with some cytotoxic
chemotherapy regimens—increases the risk for invasive fungal infection. In a
large series of bone marrow transplant patients followed by Goodrich and
colleagues, risk factors for invasive candidiasis included older age, a
diagnosis of acute myelogenous leukemia, mismatched allograft donor, acute
graft-vs-host disease, and longer time to engraftment.[2] A study involving
allogeneic bone marrow transplant recipients found high-dose corticosteroid
therapy, prolonged neutropenia, and graft-vs-host disease to be significant risk
factors.[4]

Aspergillosis: Aspergillus is the other common
invasive fungus in immunocompromised patients. The rate of aspergillosis varies
considerably from center to center and over time. This infection has been
reported to occur in 5% to 24% of patients with acute leukemia and 0.5% to 9% of
patients receiving bone marrow transplants.[5] Despite treatment, the mortality
rate for invasive aspergillosis is at least 75%.[6]

Aspergillus is widely distributed in the environment. It
has a predilection for the lung but can invade sinuses, brain, skin, and other
organs. The primary risk factor for the development of aspergillosis is
prolonged neutropenia, with a risk of 1% per day during the first 3 weeks of
neutropenia, and 4% per day thereafter.[7] Other risk factors for aspergillosis
that have been identified among bone marrow transplant recipients include older
age, conditioning regimen, donor mismatch, and acute graft-vs-host disease.[6]

Prophylactic Antifungal Agents

Nonabsorbable antifungal agents such as nystatin or oral
amphotericin B solution can treat and prevent oropharyngeal candidiasis and
diminish the risk of colonization, but do not appear to prevent the development
of invasive disease.[8] Intravenous amphotericin B produces significant
toxicity, including nephrotoxicity. Ketoconazole (Nizoral) and intravenous
miconazole (Monistat) are limited by drug interactions and other adverse
effects.[8] The development of newer triazole antifungals—ie, fluconazole
(Diflucan) and itraconazole (Sporanox)—and investigation of lower doses of
amphotericin B have provided the best options for antifungal prophylaxis.

Fluconazole

Fluconazole has several advantages as a prophylactic agent,
including its oral formulation, few adverse effects (primarily gastrointestinal
upset and transaminase elevation), close to 100% bioavailability, and a long
half-life that permits once daily dosing. It is active against Candida
albicans
and most other Candida species, with the notable exceptions
of C glabrata, C krusei, and C parapsilosis. Fluconazole is
not active against Aspergillus and other molds, and fluconazole-resistant
strains of Candida albicans are increasingly common.

Fewer Fungal Infections: A randomized, double-blind,
multicenter trial of fluconazole, 400 mg/d, vs placebo in neutropenic bone
marrow transplant patients demonstrated a significant reduction in the incidence
of systemic and superficial fungal infections.[9] Approximately half of 350
patients who received allogeneic transplants were given fluconazole or placebo
until their neutrophil count rose to more than 1,000 cells per mm3
or until they developed a (proven or suspected) fungal infection.

Invasive fungal infections developed in 15.8% of the placebo
group, compared to 2.8% in the fluconazole group (P < .001). Although
there was no difference in overall mortality at 90 days, significantly fewer
deaths were attributable to fungal diseases in the treatment group than in the
placebo group (1 vs 10, P < .001). The incidence of
aspergillosis was low in both groups. Colonization and superficial fungal
infections were also less common in the fluconazole group.[9]

Survival Benefit: Slavin and colleagues demonstrated a
survival benefit with the use of prophylactic fluconazole from the onset of
neutropenia to 75 days posttransplant.[10] In their study, 300 patients were
randomized to fluconazole, 400 mg/d, or placebo and followed until either the
development of systemic fungal infection or empiric amphotericin B use. Systemic
fungal infection developed in 18% of patients in the placebo arm and 7% in the
fluconazole arm (P = .004). Fluconazole use also lowered the incidence of
fungal colonization, superficial fungal infection, and empiric amphotericin B
use. At 110 days, a survival advantage was noted for the fluconazole arm, with
31 deaths vs 52 deaths in the placebo arm (P = .004).

Use in Hematologic Malignancies: In a study population
that included both bone marrow transplant recipients and patients with
hematologic malignancies, a lower dose of fluconazole (200 mg/d) was
examined for prevention of fungal infections during critical neutropenia.[11]
Compared to the combination of clotrimazole, nystatin, and diphenhydramine,
fluconazole was associated with both a lower incidence of systemic infection
(7.1% vs 22.9%, P < .05) and death due to fungal infection (4.8% vs
18.8%, P < .06). The rate of colonization with Candida species
was also lower with fluconazole.

Winston et al studied the use of prophylactic fluconazole in
about 250 neutropenic patients undergoing chemotherapy for acute leukemia or
blast crisis in chronic myelogenous leukemia.[12] Once again, fluconazole
decreased the rate of both fungal colonization and the number of proven fungal
infections (including superficial infections) from 21% to 9% (P = .02).
However, a clear decrease in the incidence of invasive fungal infections,
empiric use of amphotericin B, or mortality was not demonstrated.

A smaller trial of fluconazole in 151 neutropenic patients
undergoing intensive chemotherapy with or without subsequent bone marrow
transplant for acute myelogenous or lymphoblastic leukemia or high-grade
lymphoma did not show a difference in mortality or in the number of invasive
fungal infections. There were, however, fewer cases of oropharyngeal candidiasis
and a longer time to empiric use of amphotericin B.[13] While no documented
invasive candidal infections occurred in the fluconazole group, 8 of 75 patients
developed mold infections, primarily Aspergillus species.[13] Despite
controlling for both the type of underlying malignancy and the type of
immunosuppressive therapy, the fluconazole recipients experienced a longer
duration of severe neutropenia (less than 100 cells per mm3).
Fluconazole was not associated with this effect in the studies described
previously.

A multicenter European trial compared fluconazole, 3 mg/kg, to
oral nystatin, 50,000 U/kg, or amphotericin B oral suspension, 25 mg/kg, in 502
pediatric patients with hematologic and solid tumor malignancies. Although
overall there were fewer fungal infections among those randomized to
fluconazole, no difference was seen in the incidence of invasive disease among
the arms.[14]

Risks Associated With Prophylaxis: Since fluconazole is
not active against all species of Candida or against molds such as Aspergillus,
there is a risk that prophylactic use will select for these organisms or
increase the prevalence of resistant C albicans. One center noted an increase in
colonization by C krusei and disseminated infection following widespread
prophylactic use of fluconazole,[15] and later, an increase in fungemia due to C
glabrata
among leukemic patients and those undergoing bone marrow
transplantation.[16] It is notable that up to 46% of systemic candidal infections in oncology patients are due to species other than

C albicans.
[17]

Amphotericin B

Amphotericin B is the gold standard for treatment of invasive
fungal infections and for empiric antifungal therapy in neutropenic patients
with persistent fever despite the use of broad-spectrum antibiotics. Adverse
effects (particularly nephrotoxicity) and parenteral administration have limited
its utility for prophylaxis. Oral amphotericin B has limited absorption, acting
only within the oropharynx and gastrointestinal tract. It is no longer
commercially available, although pharmacists can formulate a product intended
for oral use from the intravenous product.

A randomized trial in Italy compared fluconazole, 150 mg/d, and
oral amphotericin B solution, 500 mg administered every 6 hours, in 820
neutropenic patients with leukemia, and found the subsequent rate of invasive
fungal infections in both groups to be less than 3%.[18]

Low-Dose Intravenous Therapy and Risk of Toxicity: The use
of a lower dose of intravenous amphotericin B than that routinely used for
treatment may minimize the risk of toxicity while providing protection against
invasive fungal infections, including organisms such as Aspergillus. In a
comparison of fluconazole, 400 mg/d, and low-dose amphotericin B, 0.5 mg/kg 3
days a week, in 90 neutropenic patients with acute leukemia, 80% of those
receiving fluconazole successfully completed the prophylaxis period, compared to
58% of amphotericin B recipients.[19] The rate of proven infections was less
than 7% in both groups, although nephrotoxicity was more common in the
amphotericin B arm.

However, in several studies using different dosing regimens,
prophylactic intravenous amphotericin B showed no significant increase in renal
toxicity in bone marrow transplant recipients. Riley and colleagues examined the
use of low-dose amphotericin B,
0.1 mg/kg/d, in a small, randomized, placebo-controlled trial.[20] The
incidence of systemic fungal infections was reduced, with no infections seen
among the 17 patients in the amphotericin arm and five infections among the 18
patients receiving placebo (P = .045). A decrease in the duration of empiric
amphotericin B use at standard dosage was noted in the amphotericin arm, as well
as a trend toward improved survival and shorter hospital stay. However, this
study was terminated early, without having accrued the planned number of
participants, after Slavin et al reported a benefit for fluconazole over
placebo.[10]

Perfect and colleagues investigated the use of low-dose
amphotericin B in 182 autologous bone marrow transplant patients who were
randomized to receive amphotericin B, 0.1 mg/kg/d, or placebo during neutropenia
(mean duration: 14 to 16 days). [21] There was a decrease in oropharyngeal
colonization but no statistically significant difference in empiric amphotericin
B usage or in documented invasive mycoses. The low overall rate of fungal
infection seen in this study—14.3% in patients randomized to placebo and 8.8%
in those randomized to amphotericin B—compared to the studies described above
may, in part, explain why no difference was demonstrated.

Comparisons to Historical Controls: Other studies are
limited by comparison with historical controls rather than a randomized,
concurrent placebo or active control group. Interpretation of these studies must
be tempered by the fact that the rate of fungal infections, particularly
aspergillosis, may vary over time due to factors such as changes in
environmental contamination.

In the late 1980s, an uncontrolled trial of low-dose
amphotericin B (5 to 10 mg/d) was conducted in allogeneic bone marrow transplant
recipients who received the drug until hospital discharge.[4] In comparison to
historical controls, the overall incidence of fungal infections in this trial
decreased from 30% to 9%. The incidence of aspergillosis within the first 100
days decreased from 15.8% to 5.6%. Amphotericin B was not associated with
increased nephrotoxicity, despite concomitant administration of multiple
potential nephrotoxic agents.

In another center with a historically high incidence of
aspergillosis, the use of prophylactic low-dose amphotericin B, 20 mg/d, plus
nonabsorbable antifungal agents was initiated in 186 consecutive patients
undergoing allogeneic bone marrow transplantation.[22] When compared to two
historical cohorts, including one with strict environmental controls, there was
a significant improvement in both confirmed aspergillosis and mortality;
aspergillosis decreased from an incidence of approximately 24% to 9% by day 120,
with no excess nephrotoxicity observed.

Lipid Formulations: With the advent of various lipid
formulations of amphotericin B (Abelcet, Amphotec, AmBisome) and the lower
incidence of dose-limiting nephrotoxicity, there has been renewed interest in
prophylactic use of the drug. In one trial of liposomal amphotericin B
(AmBisome), 76 patients undergoing bone marrow transplantation were randomized
to a low dose (1 mg/kg/d) or placebo.[23] The active drug produced a decrease in
the rate of fungal colonization but no difference in presumed or proven fungal
infection. The only significant adverse effects were allergic reactions, which
occurred in three patients.

Given the cost of the various liposomal preparations, the low
toxicity rate reported with prophylactic doses of standard amphotericin B, and
the limited data from randomized clinical trials, it would seem prudent to await
the results of further trials before using liposomal formulations for this
indication.

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