A Double-Blind, Randomized, Placebo-Controlled Trial of Itraconazole ...

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A Double-Blind, Randomized, Placebo-Controlled Trial of Itraconazole Capsules as Antifungal Prophylaxis for Neutropenic Patients Marcio Nucci,1 Irene Biasoli,1 Tiyomi Akiti,1 Fernanda Silveira,1 Cristiana Solza,2 Gloria Barreiros,1 Nelson Spector,1 Andrea Derossi,2 and Wolmar Pulcheri1

From 1Universidade Federal do Rio de Janeiro and 2Universidade do Estado do Rio de Janeiro, University Hospital, Rio de Janeiro, Brazil

To evaluate the efficacy of itraconazole capsules in prophylaxis for fungal infections in neutropenic patients, we conducted a prospective, double-blind, placebo-controlled, randomized trial. Patients with hematologic malignancies or those who received autologous bone marrow transplants were assigned either a regimen of itraconazole (100 mg orally twice daily; n = 104) or of placebo (n = 106). Overall, fungal infections (superficial or systemic) occurred more frequently in the placebo group (15% vs. 6%; P = .03 ). There were no differences in the empirical use of amphotericin B or systemic fungal infections. Among patients with neutropenia that was profound (!100 neutrophils/mm3) and prolonged (for at least 7 days), those receiving itraconazole used less empirical amphotericin B (22% vs. 61%; P = .0001) and developed fewer systemic fungal infections (6% vs. 19%; P = .04). For patients with profound and prolonged neutropenia, itraconazole capsules at the dosage of 100 mg every 12 h reduce the frequency of systemic fungal infections and the use of empirical amphotericin B.

Systemic fungal infections are a major cause of morbidity and mortality among neutropenic cancer patients [1]. Their incidence varies widely, depending on the underlying condition: 3%–6% in patients with acute myeloid leukemia receiving standard chemotherapy, but 45% in patients who receive allogeneic bone marrow transplants [2]. The mortality associated with systemic fungal infections is high, which is a result of many factors, including delay in diagnosis, persistence of immunodeficiency, and resistance to antifungal drugs. Attempts to reduce mortality have included the development of new diagnostic tools and antifungal drugs, empirical antifungal therapy, and prophylaxis [3]. Over the past 15 years, a series of studies have evaluated the usefulness of antifungal agents in prophylaxis for fungal infections in neutropenic patients; agents studied have included fluconazole [4–6], iv and intranasal amphotericin B [7, 8], and itraconazole [9]. Intraconazole is a triazole compound with activity against yeasts and molds, including Candida species and Aspergillus species. It is administered orally in 2 preparations: capsules, which have an erratic absorption, and a recently introduced oral solution, which is better absorbed [10]. Received 10 May 1999; revised 21 September 1999; electronically published 28 January 2000. Presented in part at the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, held 24–27 September 1998 in San Diego. Financial support: Conselho Nacional de Pesquisa (CNPq 300235/93-3), Brazil. Reprints or correspondence: Dr. Marcio Nucci, Servic¸o de Hematologia, Hospital Universita´rio Clementino Fraga Filho, Av. Brigadeiro Trompovsky, s/n CEP 21941-590 Rio de Janeiro, Brazil ([email protected]). Clinical Infectious Diseases 2000; 30:300–5 q 2000 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2000/3002-0011$03.00

In this study we evaluated the efficacy of itraconazole capsules in prophylaxis for fungal infections in neutropenic cancer patients, in a double-blind, randomized, placebo-controlled trial.

Patients and Methods Patients. The trial was conducted at the university hospitals of Universidade Federal do Rio de Janeiro and Universidade do Estado do Rio de Janeiro. Eligibility criteria included the following characteristics: hematologic malignancy or autologous bone marrow transplant; anticipated neutropenia (!1000 neutrophils/mm3 and a duration of at least 7 days); no clinical evidence of fungal infection at randomization; no systemic antifungal drug therapy within 14 days before randomization; and no allergy to azoles. Patients who were pregnant or nursing, had a high probability of death within the first 48–72 h, or had difficulty ingesting oral drugs were excluded. The scientific committees of each participating institution approved the study. Study drugs. After signing informed consent forms, the patients were randomly assigned to a regimen of itraconazole or placebo at a 1 : 1 ratio. The randomization code was sealed and was available only to the study coordinator in the case of a serious adverse event. Vials containing 100-mg capsules of itraconazole (Janssen-Cilag, Sa˜o Paulo, Brazil) or identical-appearing placebo capsules were given to each patient in a double-blinded manner. The capsules were administered at mealtime. The itraconazole or placebo regimen was started at the time of initiation of chemotherapy, at a dosage of 1 capsule every 12 h. The prophylaxis was discontinued in the following situations: bone marrow recovery, defined as an absolute neutrophil count 11000/mm3 for 3 consecutive days; initiation of empirical antifungal therapy; documentation of any fungal infection, either superficial or systemic; occurrence of adverse side effect(s) related to the study drug; or death.

CID 2000;30 (February)

Itraconazole Prophylaxis for Neutropenic Patients

Evaluation. Patients were clinically evaluated at baseline, twice weekly for the duration of the study, and 14 days after the prophylactic regimen was stopped. Standard biochemical tests were performed, including those to determine levels of serum potassium, magnesium, creatinine, aminotransferases, alkaline phosphatase, and amylase; complete blood cell counts, prothrombin times, and hemoglobin levels were monitored at least twice weekly. In addition, blood was drawn at days 14 and 21 of prophylaxis for the assessment of itraconazole serum levels. We assessed fungal colonization at baseline and weekly by culturing specimens from the oropharynx, nasopharynx, and perirectal area and of urine. Fungal colonization was defined by the presence of fungi in >1 surveillance cultures and no clinical sign or symptom of infection at that site. Cultures of blood or of specimens from other suspected sites of fungal infection were performed during the study at the discretion of the attending physician. If patients developed fever, empirical antibiotic therapy was started with ceftazidime, amikacin, and an antibiotic active against gram-positive organisms (either oxacillin or a glycopeptide). Empirical administration of amphotericin B was started after 6 days of fever and neutropenia if they had persisted despite empirical antibiotic therapy or if there was a reasonable clinical suspicion of systemic fungal infection (because of nasal discharge, pleuritic chest pain, dry cough, or skin nodules). A superficial fungal infection was diagnosed when a fungus was isolated from a clinical specimen and if there was any evidence of infection, such as inflammation, ulceration, plaque, or exudate. A systemic fungal infection was diagnosed by the finding of fungus in the blood (yeasts or molds), sinuses (molds in sinus lavage or biopsy material), pulmonary secretions (molds), or other organs when symptoms and signs of infection were evident. The prophylaxis was considered to have failed if the patient developed a fungal infection, either superficial or systemic, or needed empirical antifungal therapy. Compliance was assessed by counting the number of capsules that remained in the vials after the patients left the study. It was considered excellent if the patient took all doses of the study drug, good if the patient took at least 80% of the prescribed doses and did not skip 13 consecutive doses of the study drugs, and poor if the patient took !80% of the prescribed doses or skipped 13 consecutive doses. Statistics and sample size calculation. The study end point used for calculation of the sample size was the initiation of empirical therapy with amphotericin B. On the basis of our database, we estimated that ∼50% of our neutropenic patients needed empirical antifungal therapy (data not published). We assumed that an absolute reduction of 20% would be clinically significant. With an a error of 0.05 and a b error of 0.20, a total of 103 patients in each group would be necessary to detect such a difference. All statistical tests were performed as two-tailed tests. In comparing dichotomous variables, the P value was calculated with Fisher’s exact test or the x2 test. In addition, the 95% CI for the differences between proportions was calculated. For continuous variables, the P value was calculated by the Wilcoxon two-sample test. To compare the elapsed times for specific events, we used the log-rank test.

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Results Characteristics at baseline. From September 1992 through July 1997, 219 patients were enrolled in the study. Five patients randomized to the itraconazole group and 4 patients randomized to the placebo group were excluded, because the duration of neutropenia was !7 days. The characteristics of the other 210 patients are shown in table 1. One hundred and four patients received itraconazole and 106 received placebo. There were no significant differences between the 2 groups with regard to age, sex, underlying diseases, median duration of neutropenia, and number of patients colonized by Candida species at baseline. Nasal colonization by Aspergillus species at baseline was more frequent in the placebo group, but the difference was not statistically significant (P = .1 ; 95% CI, 20.1% to 18%). Fifteen patients in the itraconazole group and 16 patients in the placebo group received autologous bone marrow transplants. The median number of on-study days was higher in the itraconazole group (P = .09). Fungal infections and need for amphotericin B. Table 2 shows the success and failure rates for both groups. Empirical antifungal therapy was started for 26 patients (25%) in the itraconazole group and 36 (34%) in the placebo group (P = .15; 95% CI, 221% to 3%). The time to initiation of therapy with amphotericin B was not significantly different between the 2 groups (P = .1; log-rank test). A fungal infection occurred in 6 patients (6%) in the itraconazole group and in 16 (15%) in the placebo group (P = .03; 95% CI, 1%–17%). The fungal infection was superficial in 1 patient in the itraconazole group and in 7 patients in the placebo group (P = .06; 95% CI, 0.5% to 11%), whereas sysTable 1. Baseline characteristics of neutropenic patients randomized to receive itraconazole or placebo. Characteristic Sex (males : females) Age in y, median (range) Age !12 y Underlying disease Acute myeloid leukemia Acute lymphocytic leukemia Hodgkin’s disease Non-Hodgkin’s lymphoma Multiple myeloma Chronic myeloid leukemia, blast crisis Solid tumor Bone marrow transplant Days of neutropenia, median (range) !1000 neutrophils/mm3 !100 neutrophils/mm3 Colonized by Candida at BL Nasal colonization by Aspergillus at BL Median no. of days in study (range)

Itraconazole (n = 104)

Placebo (n = 106)

52 : 52 25.5 (5–63) 7 (7)

56 : 50 30 (6–67) 7 (7)

58 25 10 7 2

67 18 9 6 2 1 3 16

(56) (24) (10) (7) (2) — 1 (1) 15

12 (7–38) 6 (0–38) 22/61 (36) 2/61 (3) 19.5 (6–39)

11 6 20/65 8/65 17

(63) (17) (8) (6) (2) (1) (3)

(7–30) (0–28) (31) a (12) b (7–30)

NOTE. Data are no. (%) of patients or no./no. examined (%), except as indicated. BL, baseline. a P = 1; 95% CI, 20.1% to 18%. b P = .09.

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Table 2.


Outcome of antifungal prophylaxis in neutropenic patients.

Subgroup of patients Received empirical amphotericin B Overall a Profound and prolonged neutropenia Fungal infection b Superficial fungal infection Systemic fungal infection Overall a Profound and prolonged neutropenia c Therapy failed Overall a Profound and prolonged neutropenia

Itraconazole (n = 104)

Placebo (n = 106)

95% CI

P

26 11/50 6 1

(25) (22) (6) (1)

36 28/46 16 7

(34) (61) (15) (7)

221 to 3 21–57 1–17 0.5–11

.15 .0001 .03 .06

5 3/50 28 28 13/50

(5) (6) (27) (27) (26)

9 9/46 43 43 32/46

(8) (19) (41) (41) (70)

23 to 10 0.3–27 1–26 1–26 25–62

.28 .04 .04 .04 .00002

NOTE. Data are no. (%) of patients or no./no. examined (%). a Profound neutropenia, !100 neutrophils/mm3; prolonged neutropenia, >7 days’ duration. b Itraconazole group, oropharyngeal candidiasis (1); placebo group, oropharyngeal candidiasis (5), esophageal and oropharyngeal candidiasis (1), and cutaneous candidiasis (1). c No. of failures is total no. of patients who received amphotericin B and/or developed a fungal infection.

temic fungal infections occurred in 5 patients in the itraconazole group and in 9 in the placebo group (P = .28; 95% CI, 23% to 10%). Of the 6 fungal infections in the itraconazole group, 4 (1 superficial and 3 systemic) were diagnosed while the patients were receiving empirical amphotericin B, whereas among the 16 fungal infections in the placebo group, 9 (1 superficial and 8 systemic) were diagnosed when the patient was receiving empirical amphotericin B. The overall failure rates in the itraconazole and placebo groups (defined as the sum of patients who received empirical amphotericin B and/or developed a fungal infection) were 27% and 41%, respectively (P = .04; 95% CI, 1%–26%). In patients with neutropenia that was profound (!100 neutrophils/mm3) and prolonged (of at least 7 days’ duration), the use of itraconazole significantly reduced the frequency of systemic fungal infections (3 of 50 vs. 9 of 46; P = .04; 95% CI, 0.3%–27%), as well as the need for empirical amphotericin B (22% vs. 61%; P = .0001; 95% CI, 21%–57%). Table 3 shows the distribution of fungal isolates, characteristics, and outcomes of the systemic fungal infections in both groups. The most frequent infection was candidemia, which occurred in 8 patients, including 3 with clinical signs of disseminated candidiasis. There was only 1 case of aspergillosis, which occurred in the placebo group. The median time from randomization until the occurrence of the fungal infection was 16 days (range, 6–38 days). Fungal colonization. During the observation period, the proportion of patients colonized by Candida species increased from 36% to 38% in the itraconazole group (P = .85 ; 95% CI, 219% to 15%) and from 31% to 58% in the placebo group (P = .001; 95% CI, 11% to 44%). The difference in the proportion of patients colonized at the end of prophylaxis in the 2 groups was statistically significant (P = .02 ; 95% CI, 4%–38%). Colonization by Candida albicans and non-albicans Candida species varied among the 2 groups: at baseline the proportion of colonization by non-albicans species of Candida

was 54% in the itraconazole group and 60% in the placebo group (P = .66; 95% CI, 230% to 19%), whereas at the end of prophylaxis 73% of patients in the itraconazole group and 55% in the placebo group were colonized by non-albicans Candida species (P = .07; 95% CI, 21% to 38%). Candida tropicalis was the most frequent non-albicans Candida species in both groups. The nasal colonization by Aspergillus species increased from 3% to 8% in the itraconazole group (P = .44; 95% CI, 213% to 3%) and from 12% to 18% in the placebo group (P = .33; 95% CI, 218% to 6%). Side effects and compliance. Side effects possibly attributed to the study drug occurred in 6 patients in the itraconazole group and in 7 patients in the placebo group (P = .8 ; 95% CI, 26% to 7%). A skin rash developed in 3 patients in the itraconazole group and in 1 patient in the placebo group. The other manifestations were transient elevations in liver enzyme levels (3 patients in the itraconazole group and 4 in the placebo group) and nausea (2 patients in the placebo group). Three patients in the itraconazole group and 4 patients in the placebo group were removed from the study because of toxicity (P = 1.0; 95% CI, 24% to 6%). Compliance was considered poor by 8 patients in the itraconazole group and by 7 patients in the placebo group (P = .76; 95% CI, 26% to 8%). Itraconazole serum levels. Itraconazole serum levels at day 14 of prophylaxis were determined for 35 of the 83 patients assigned to receive itraconazole. The mean serum level was 272 ng/mL, within a range of 0–974 ng/mL. Twenty patients had serum levels !250 ng/mL. Prophylaxis failed for none of the patients whose serum levels were measured. The serum level of itraconazole at day 21 of prophylaxis was assessed for 15 patients, and the mean value was 349.2 ng/mL (range, 60–878 ng/ mL). Survival. Eight patients in the itraconazole group and 7 in the placebo group died (P = .76; 95% CI, 26% to 8%). In the itraconazole group, death was due to bacterial infection in 2


Table 3. infections.

Characteristics and outcomes of the systemic fungal

Organism isolated Itraconazole recipients Candida tropicalis Candida lusitaniae Rhodotorula rubra Exophiala jeanselmei Placebo recipients Candida species

C. tropicalis Candida glabrata Candida albicans Aspergillus fumigatus E. jeanselmei a b


Site(s) involved

Time of a diagnosis

Outcome

Blood, skin Blood Blood Blood Blood

38 22 15 6 11

Died Died b Died Lived Lived

Blood Blood Blood, brain, kidney Blood, skin Blood Blood Sinuses Blood Blood

23 10 28 20 13 18 16 15 16

Lived Lived Died Lived Lived Lived Lived Lived Lived

Days from randomization to diagnosis. Death was due to uncontrolled underlying acute lymphoid leukemia.

patients (with Escherichia coli in 1 and methicillin-resistant Staphylococcus aureus in the other), advanced underlying malignancy in 4 patients (including 1 patient with fungemia due to Rhodotorula rubra), candidemia in 1 patient, and CNS bleeding in 1 patient. In the placebo group, death was due to bacterial infection in 2 patients (with a-hemolytic Streptococcus in 1 and methicillin-resistant S. aureus in the other), whereas candidemia, typhlitis, pneumonia, CNS bleeding, and cerebellar toxicity each caused 1 death. Among the patients with systemic fungal infections, there was a trend toward a higher death rate in the itraconazole group than in the placebo group (3 of 5 vs. 1 of 9), although the death of 1 patient in the itraconazole group was not due to the fungal infection itself.

Discussion Systemic fungal infections represent a major challenge in the care of patients who undergo cancer chemotherapy and bone marrow transplantation. Their incidence has increased, their diagnosis is elusive, and the therapeutic options are limited. Therefore, antifungal prophylaxis has a potential role among the strategies designed to overcome this problem. Although there are a few published randomized trials that show antifungal prophylaxis is beneficial in cases of invasive candidiasis, no study to date has demonstrated that it reduces the incidence of invasive aspergillosis [11]. In the present study there was a significant difference favoring the itraconazole arm (P = .03) with regard to the total number of fungal infections (superficial plus systemic) but not with regard to systemic fungal infections (P = .28 ). Similar results have been reported following 2 randomized trials. Among patients with acute leukemia, Winston et al. [6] randomized 255 patients to receive either fluconazole (400 mg daily) or placebo. The use

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of fluconazole reduced the frequency of superficial fungal infections (15% in the placebo group and 6% in the fluconazole group; P = .01) but not systemic infections (8% and 4%; P = .3). Likewise, Schaffner et al. [12] compared the efficacy of fluconazole (400 mg daily) and placebo in 151 neutropenic patients. Superficial fungal infections occurred in 1 of 75 patients in patients receiving fluconazole and in 9 of 76 patients receiving placebo (P = .018), whereas systemic infections occurred in 8 patients receiving fluconazole and in 7 patients receiving placebo (P = .76). A possible explanation for the absence of statistical significance in a comparison of the frequency of systemic fungal infections is that the sample size was calculated to detect differences with respect to the use of amphotericin B. Therefore, the power of the study could well be insufficient for events less frequent than the initiation of empirical antifungal therapy. Candida species accounted for the majority of cases of systemic fungal infections in the present series. An analysis of the impact of the use of itraconazole on the incidence of invasive aspergillosis was hampered by the low observed incidence of this infection (only 1 case, 0.5%). A similar low incidence of invasive aspergillosis has been observed in other trials of antifungal prophylaxis [4, 6]. There were also 2 cases of fungemia due to Exophiala jeanselmei in each group. These infections occurred in the setting of an outbreak that took place in 1 of the participating hospitals, which was related to the contamination of the hospital water supply [13]. The use of empirical amphotericin B was more frequent in the placebo group, but the difference was not statistically significant. In the calculation of the sample size, we estimated that the frequency of amphotericin B use in the placebo arm would be 50%, based on the analysis of a database of 1300 previous febrile episodes. However, the actual proportion of patients in the placebo arm who received empirical amphotericin B was only 34%. The frequency of initiation of empirical therapy with amphotericin B in the various clinical trials of antifungal prophylaxis has ranged from 18% [14] to 61% [6]. The reasons for these discrepancies may be related to different antibiotic regimens and guidelines for initiation of empirical amphotericin B. In the study by Menichetti et al. [14], febrile patients received triple antibiotic therapy, and administration of amphotericin B was started if fever persisted despite 4–6 days of systemic antibiotic therapy. In the study by Schaffner et al. [12] (40% empirical antifungal therapy), empirical antibacterial therapy consisted of administration of a b-lactam antibiotic plus an aminoglycoside, and empirical amphotericin B was added (1) after 4 days of fever that persisted despite antibiotic therapy, if there were signs of systemic fungal infection on radiographs and tomographs, or (2) after 7 days of antibiotic therapy if there were no signs of fungal infection. On the other hand, in the study by Winston et al. [6], there is no mention of the antibiotic regimen or of the protocol for

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initiation of empirical amphotericin B. It is possible that the difference between our expected and observed frequencies of amphotericin B use was due to the fact that, with use of a protocol, the use of empirical amphotericin B was disciplined, thereby reducing its frequency. Not all neutropenic patients have the same risk for systemic fungal infections [2]. Accordingly, a prophylactic regimen may be effective in a subset of patients and not in another [15]. Although there are no studies specifically addressing which subpopulations of cancer patients are at a higher risk for systemic fungal infections, there is evidence that patients with profound and prolonged neutropenia are at an increased risk [3]. Therefore, we analyzed this subset of patients, defined as having !100 neutrophils/mm3 for at least 7 days. In this group, itraconazole capsules effectively reduced both the use of empirical amphotericin B (from 61% to 22%; P = .0001) and the frequency of systemic fungal infections (from 19% to 6%; P = .04). Itraconazole also reduced the prevalence of colonization by Candida species. At the end of prophylaxis, the percentage of patients colonized was much higher in the placebo group. It is interesting that the effect of itraconazole seemed to be more pronounced on C. albicans than on non-albicans Candida species. The proportion of sites colonized by C. albicans at baseline was 46% in the itraconazole group and 40% in the placebo group, whereas at the end of prophylaxis it was 27% and 40%, respectively (P = .07). From trials with fluconazole there were reports of increased colonization and infection by fluconazole-resistant strains, such as Candida krusei [16] and Candida glabrata [17]. Unfortunately, at the time this trial was conducted the antifungal susceptibility tests were not yet standardized, and the strains were not available for further testing. With regard to nasal colonization by Aspergillus species, the unbalanced baseline colonization hampered any analysis. Itraconazole capsules were well tolerated; only 6 patients developed either a skin rash or elevated liver enzyme levels. These 2 manifestations occurred in equal proportions in the placebo group. Compliance was good, even by patients with mucositis. A major concern about itraconazole capsules is that in certain circumstances it is only erratically bioavailable. In patients with chemotherapy-induced damage to the intestinal mucosa, dosages up to 600 mg/d were needed to achieve serum levels considered satisfactory (1250 ng/mL) [18], whereas the same levels could be achieved with doses of 100 mg/d in healthy volunteers [10]. In an uncontrolled study, plasma levels of itraconazole correlated with efficacy for prophylaxis [19]. In the present study itraconazole serum levels were measured at day 14 in only 35 of 83 patients. The mean serum level was within the appropriate range. However, in 20 patients the serum level was !250 ng/mL. Prophylaxis failed for none of the patients whose serum levels were determined. Unfortunately, the


number of serum samples available for measurement of itraconazole levels was very low, hampering analysis of the correlation between serum levels and efficacy. Nevertheless, the very low serum itraconazole levels in many patients suggest that the use of a better-absorbed preparation or higher doses of itraconazole may offer more effective prophylaxis. Recently, an oral solution of itraconazole with a better pharmacokinetic profile was developed, and it provided adequate serum levels in neutropenic patients [20]. This preparation was tested in prophylaxis for fungal infections in neutropenic patients in a double-blind randomized clinical trial [21]. A dosage of 2.5 mg/kg every 12 h was used for 201 patients, and 205 other patients received a placebo. Proven and suspected fungal infections occurred in 24% of patients receiving itraconazole and in 33% of patients receiving placebo (P = .03 ). The use of itraconazole also reduced the frequency of candidemia (P = .01) and of death due to candidemia (P = .06). These results with use of a better-absorbed formulation of itraconazole further support our results with the use of capsules. As observed in other clinical trials of antifungal prophylaxis in neutropenic patients [22], the overall survival of our patients was not influenced by the use of itraconazole. A reliable evaluation of the impact of antifungal prophylaxis on survival, however, would require a much larger sample of patients and stricter definitions of the causes of death than are usually possible for these patients with multiple concurrent complications of uncontrolled malignancy and its treatment. In summary, itraconazole in capsule form decreased fungal colonization and fungal infections (superficial and systemic) in neutropenic cancer patients, mainly owing to a reduction in superficial infections. In patients with profound and prolonged neutropenia, itraconazole decreased the use of empirical amphotericin B and the frequency of systemic fungal infections. It was well tolerated and was not associated with clinically significant adverse events. The prophylactic use of itraconazole capsules should be considered for patients with profound and prolonged neutropenia.

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