Prophylaxis Against Fungal Infections and Cytomegalovirus Disease After Bone Marrow Transplantation

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(Drug information on nystatin) or oral amphotericin B(Drug information on 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(Drug information on ketoconazole) (Nizoral) and intravenous miconazole(Drug information on miconazole) (Monistat) are limited by drug interactions and other adverse effects.[8] The development of newer triazole antifungals—ie, fluconazole (Diflucan) and itraconazole(Drug information on 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(Drug information on 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(Drug information on 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.