Invasive fungal infections have become an increasing

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1 A Multicenter, Randomized Trial of Fluconazole versus Amphotericin B for Empiric Antifungal Therapy of Febrile Neutropenic Patients with Cancer* Drew J. Winston, MD, James W. Hathorn, MD, Mindy G. Schuster, MD, Gary J. Schiller, MD, Mary C. Territo, MD PURPOSE: To compare the efficacy and safety of fluconazole and amphotericin B as empiric antifungal therapy of febrile neutropenic patients with cancer. PATIENTS AND METHODS: A total of 317 neutropenic patients ( 500 cells/mm 3 ) with persistent or recrudescent fever despite 4 or more days of antibacterial therapy were randomly assigned to receive either fluconazole (400 mg intravenously once daily) or amphotericin B (0.5 mg/kg once daily). Patients were evaluated for the efficacy and safety of each drug by clinical criteria, frequent cultures and radiological procedures, and laboratory values. A response was classified as satisfactory at the end of therapy if the patient was afebrile, had no clinical or microbiological evidence of fungal infection, and did not require study termination due to lack of efficacy, drug toxicity, or death. RESULTS: A satisfactory response occurred in 68% of the patients treated with fluconazole (107 of 158 patients) and in 67% of patients treated with amphotericin B (106 of 159 patients). Progressive or new fungal infections during therapy occurred in 13 (8%) patients treated with fluconazole (8 with Candida, 5 with Aspergillus) and in 10 (6%) patients treated with amphotericin B (5 with Candida, 3 with Aspergillus, 2 with other fungi). Adverse events related to study drug (especially fever, chills, renal insufficiency, electrolyte disturbances, and respiratory distress) occurred more often in patients treated with amphotericin B (128 [81%] of 159 patients) than patients treated with fluconazole (20 [13%] of 158 patients, P 0.001). Eleven (7%) patients treated with amphotericin B but only 1 (1%) patient treated with fluconazole were terminated from the study owing to an adverse event (P 0.005). Overall mortality (27 [17%] patients treated with fluconazole versus 34 [21%] patients treated with amphotericin B) and mortality from fungal infection (7 [4%] patients treated with fluconazole versus 5 [3%] patients treated with amphotericin B) were similar in each study group. CONCLUSIONS: Intravenous fluconazole can be an effective and safe alternative to amphotericin B for empiric antifungal therapy in many febrile neutropenic patients. However, because fluconazole may be ineffective in the treatment of Aspergillus, patients at risk for that infection should be evaluated by chest radiograph, computed tomographic scanning, and cultures before the use of empiric fluconazole therapy. Am J Med. 2000; 108: by Excerpta Medica, Inc. Invasive fungal infections have become an increasing cause of morbidity and mortality in neutropenic patients receiving chemotherapy (1 3). Candida species are the predominant fungal pathogens in neutropenic patients, followed by Aspergillus species and occasionally other opportunistic fungi. Due to delays in diagnosis, *Access the Journal Club discussion of this paper at elsevier.com/locate/ajmselect/ From the Division of Hematology-Oncology, Department of Medicine (DJW, GJS, MCT), UCLA Center for the Health Sciences, Los Angeles, California; Divisions of Hematology-Oncology and Infectious Diseases (JWH), Department of Medicine, Duke University Medical Center, Durham, North Carolina; and Division of Infectious Diseases (MGS), Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. Supported by research grants from Pfizer, Inc. Requests for reprints should be addressed to Drew J. Winston, MD, Room CHS, Department of Medicine, UCLA Medical Center, Los Angeles, California Manuscript submitted February 5, 1999, and accepted in revised form October 6, these infections are frequently fatal and often diagnosed only at autopsy (4,5). In the early 1980s, the problems associated with the rapid and reliable diagnosis of serious fungal infections in neutropenic patients led to the use of empiric antifungal therapy with intravenous amphotericin B. Although empiric therapy with amphotericin B was shown to be effective in only two small randomized trials (6,7), it has now become standard practice to administer it to neutropenic patients with persistent fever that has not resolved after 4 to 7 days of antibacterial therapy (8,9). This approach, however, is limited by the infusion-related side effects and renal toxicity of amphotericin B, especially in patients receiving other nephrotoxic drugs (10). Alternative strategies are needed. Fluconazole is a triazole antifungal agent with a favorable pharmacokinetic profile, a low incidence of side effects, and activity against many common fungal pathogens that cause infections in neutropenic patients (11,12). Compared with amphotericin B, adverse events by Excerpta Medica, Inc /00/$ see front matter All rights reserved. PII S (99)00457-X

2 due to fluconazole are uncommon. Studies in animal models of neutropenia, as well as in cancer patients, have demonstrated fluconazole s effectiveness for the treatment and prevention of Candida infections (13 17). Although there are no convincing clinical data that fluconazole is effective for Aspergillus infections, high doses of fluconazole prolong the survival of animals infected with Aspergillus (18). In patients without neutropenia, fluconazole is as effective as amphotericin B for the treatment of candidemia (19). For these reasons, we undertook a randomized trial to compare the efficacy and safety of intravenous fluconazole with that of amphotericin B for the empiric antifungal therapy of neutropenic cancer patients with fever that had not responded to antibacterial therapy. PATIENTS AND METHODS Patients Patients were eligible for the study if they were at least 13 years of age, had cancer, had an absolute neutrophil count of 500 cells/mm 3 due to underlying disease or cytotoxic therapy, had been treated with antibacterial drugs for bacterial infection or unexplained fever for 4 or more days, and had persistent or recrudescent fever (temperature 38.0 C) unrelated to blood products, drugs, or a nonfungal infection. In addition, patients could not have an allergy or severe intolerance to imidazoles, azoles, or amphotericin B. Patients already receiving a systemic antifungal agent for a documented or suspected invasive fungal infection were excluded, as were patients with known colonization of the nasopharynx with Aspergillus. The study was approved by the institutional review board at each study center, and informed consent was obtained from each patient or a relative. Study Design and Drugs Eligible patients were randomly assigned to receive either intravenous fluconazole or intravenous amphotericin B. The dose of fluconazole was 800 mg intravenously on day 1, followed by 400 mg intravenously once daily. Oral fluconazole was not used unless a patient required continuation of therapy for a documented fungal infection after discharge from the hospital and recovery from neutropenia. The daily dose of fluconazole was reduced in patients who developed severe renal failure (20). Based upon previous clinical trials (6,7), the dose of amphotericin B was 0.5 mg/kg intravenously once per day, started immediately after an initial 1-mg test dose on the first day of therapy. If an invasive fungal infection was subsequently documented, the dose of amphotericin B could be increased to 1.0 to 1.5 mg/kg intravenously once per day. If a patient developed nephrotoxicity or a severe infusionrelated toxicity due to amphotericin B, the administration of amphotericin B could be temporarily discontinued or changed to an every-other-day schedule (10). Premedications (acetaminophen and diphenhydramine) were not permitted with the initial dose of amphotericin B but could be given with subsequent infusions if infusion-related fever and chills occurred. The study drug was continued for 24 to 48 hours after both the absolute neutrophil count reached 500 cells/ mm 3 and the patient was afebrile without evidence of infection. Earlier discontinuation of the study drug was allowed for toxicity or lack of efficacy. For patients with proven invasive fungal infection, the study drug could be continued for a longer duration to complete a therapeutic course. Laboratory Studies Fungal and bacterial cultures of blood and other suspected sites of infection were obtained before and, if clinically indicated, during and after therapy with the study drug. Chest radiographs, computed tomographic scans, and ultrasound examinations were also done whenever clinically indicated to diagnose invasive fungal infections. Complete blood cell counts, prothrombin times, serum electrolyte, creatinine, bilirubin, alkaline phosphotase, and aminotransferase levels were obtained before, during, and after therapy to assess treatment-related side effects. Patients were examined daily for symptoms and signs of fungal infection or drug-related toxicity. Evaluation of Response Patients were observed for 21 days after completion of the study drug or until death. At the end of antifungal therapy, a response was classified as satisfactory if the patient was afebrile (temperature 38 C), had no clinical or microbiological evidence of fungal infection, and required no additional antifungal therapy. A response was considered unsatisfactory if any one of the following events occurred: 1) persistent fever of uncertain cause at end of therapy; 2) new or progressive fungal infection during therapy; 3) change to another systemic antifungal agent due to persistent fever or worsening clinical condition; 4) termination of study drug due to toxicity; 5) decision by patient or primary physician to withdraw from the study; or 6) death during treatment with the study drug. Documented fungal infections were defined by previously reported criteria (15). Adverse events were classified as related or unrelated to the study drug. Nephrotoxicity was defined as an increase in serum creatinine level of 0.4 mg/dl from baseline. Hypokalemia was defined as a decrease in the serum potassium level of 0.5 meq/l from baseline to 3.5 meq/l. Hypomagnesemia was defined as a decrease in the serum magnesium level 0.5 meq/l from baseline to 1.5 meq/l. Drug-related hepatotoxicity was defined as an increase in serum bilirubin, aminotransferase, or alkaline phosphatase levels to more than 1.5 times baseline and beyond the normal range. March 2000 THE AMERICAN JOURNAL OF MEDICINE Volume

3 Table 1. Characteristics of the Patients, by Treatment Group Characteristic Fluconazole (n 158) Amphotericin B (n 159) P Value Number (Percent) or Mean SD Age (years) Male sex 79 (50) 77 (49) 0.82 Female sex 79 (50) 82 (51) 0.78 Underlying disease Acute leukemia 68 (43) 76 (48) 0.43 Myelodysplastic syndrome 2 (1) 1 (1) 0.62 Chronic myelogenous leukemia 3 (2) 7 (4) 0.34 Chronic lymphocytic leukemia 0 3 (2) 0.25 Lymphoma 12 (8) 7 (4) 0.25 Multiple myeloma 2 (1) 2 (1) 0.99 Solid tumor 6 (4) 8 (5) 0.79 Bone marrow or stem cell transplant 65 (41) 55 (35) 0.25 Acute leukemia Chronic myelogenous leukemia 8 5 Lymphoma Multiple myeloma 8 6 Solid tumor Other 4 2 Previous antifungal prophylaxis 130 (82) 123 (77) 0.33 Nystatin or clotrimazole Nystatin and ketoconazole 1 0 Median (range) duration of antibiotic therapy 5 (4 25) 6 (4 39) 0.15 before randomization, days Neutrophil count at time of randomization, cells/mm 3 Median duration of neutropenia ( 500 cells/ 6.0 (1 41) 7.5 (1 72) 0.14 mm 3 ) during study, days Receiving hematopoietic growth factor during 29 (18) 26 (16) 0.66 study Concomitant cyclosporine use 28 (18) 18 (11) 0.11 Concomitant aminoglycoside use 40 (25) 50 (31) 0.26 Statistics All statistical tests were performed as two-sided tests. Fisher s exact test was used to compare proportions. Medians were compared with the Wilcoxon rank-sum test, while means were compared with the unpaired t test. All patients who received the study drug were evaluated for both efficacy and safety (intention-to-treat analysis). A sample size of 185 patients per group was planned in order to detect a difference of 15% between the satisfactory response rates for fluconazole and amphotericin B (assuming a rate of 60% in the amphotericin B group) with 80% power at an alpha level of 0.05 (21). RESULTS Patient Characteristics A total of 322 patients were enrolled in the trial. Two patients randomly assigned to fluconazole and 3 patients assigned to amphotericin B did not receive the study drug and were excluded from all analyses. Thus, 158 patients received fluconazole, and 159 patients were given amphotericin B. The two groups of patients were similar in terms of age, sex, underlying disease, previous antifungal prophylaxis with nystatin or clotrimazole, median duration of antibiotic therapy before randomization, mean neutrophil at time of randomization, and median duration of neutropenia during the study (Table 1). A similar number of patients treated with fluconazole or amphotericin B received growth factors, cyclosporine, and aminoglycosides. Chest radiographs were abnormal at the time of randomization in 92 (62%) of 149 patients in the fluconazole group and 85 (58%) of 147 patients in the amphotericin B group (P 0.49). The median duration of fluconazole therapy was 8 days (range 1 to 46), while the median duration of amphotericin B therapy was 10 days (range 1 to 72, P 0.15). The 284 March 2000 THE AMERICAN JOURNAL OF MEDICINE Volume 108

4 Table 2. Response to Empiric Antifungal Therapy, by Treatment Group Response Fluconazole (n 158) Amphotericin B (n 159) P Value Number (Percent) Satisfactory response 107 (68) 106 (67) 0.90 Unsatisfactory response 51 (32) 53 (33) Persistent fever of uncertain cause 25 (16) 16 (10) 0.13 New or progressive fungal infection during 13 (8) 10 (6) 0.53 therapy Termination of study drug due to toxicity 1 (1) 11 (7) Death from nonfungal cause during therapy 6 (4) 10 (6) 0.44 Patient withdrawn from study before completion of therapy 6 (4) 6 (4) 0.99 mean ( SD) cumulative dose of amphotericin B was mg (range 31 to 2950 mg). During the study, 124 (78%) of the patients receiving amphotericin B were maintained on the initial dose of 0.5 mg/kg once per day. Due to the development of toxicity related to amphotericin B, 1 patient was changed to a reduced dose of 0.25 mg/kg once per day, 11 (7%) patients were changed to a dose of 0.5 mg/kg to 1.0 mg/kg once every other day, and 11 (7%) patients had their amphotericin B discontinued. Twelve (8%) patients with documented fungal infection had their amphotericin B dose increased to 1.0 mg/kg once per day. Response to Therapy The satisfactory response rate for fluconazole was 68% (107 of 158 patients), similar to the response rate of 67% (106 of 159 patients) in the amphotericin B group (Table 2). Thus, the difference in response rates (fluconazole amphotericin B) was 1%, with a 95% confidence interval from 10% to 12%. Persistent fever of uncertain cause, which sometimes prompted a change to amphotericin B, was the most common cause of treatment failure in the fluconazole group. Drug-related toxicity (severe chills, nephrotoxicity) leading to termination of study drug, as well as persistent fever, were common reasons for treatment failure in the amphotericin B group. New or progressive fungal infection during therapy, death from nonfungal causes, and withdrawal from the study occurred at similar rates in the two groups. Among patients who were enrolled in the study after 7 or less days of antibiotic therapy, response rates were 72% (86 of 120) in the fluconazole group and 70% (75 of 107) in the amphotericin B group. Among patients who were enrolled in the study after more than 7 days of antibiotic therapy, response rates were 58% (22 of 38) in the fluconazole group and 62% (32 of 52) in the amphotericin B group. A fungal infection at the time of enrollment was diagnosed in 10 patients treated with fluconazole and in 9 patients treated with amphotericin B. Baseline infections in the fluconazole group were C. tropicalis fungemia (5 patients), C. albicans fungemia (2 patients), Aspergillus fumigatus pneumonia (1 patient), Fusarium species softtissue infection (1 patient), and C. albicans oropharyngeal infection (1 patient). Three of these 10 infections responded to intravenous fluconazole. Five other patients were changed to amphotericin B, 3 of whom subsequently improved. Two patients (1 case each of C. albicans fungemia and pulmonary aspergillosis) treated initially with intravenous fluconazole followed by amphotericin B, and 2 patients with C. tropicalis fungemia treated only with intravenous fluconazole, died from their infection. The nine baseline fungal infections in the amphotericin B group were disseminated C. albicans infection (3 patients), C. albicans pneumonia (2 patients), Candida hepatitis (1 patient), pulmonary aspergillosis (1 patient), Aspergillus sinusitis (1 patient), and an Aspergillus ear infection (1 patient). Five of these nine infections improved with amphotericin B therapy. Four infections (2 cases of disseminated C. albicans infection, 1 case of C. albicans pneumonia, and 1 case of pulmonary aspergillosis) were fatal despite treatment with amphotericin B. In addition, 6 (4%) patients treated with fluconazole and 7 (4%) patients treated with amphotericin B developed new fungal infections during therapy. The new fungal infections appearing during treatment with fluconazole were pulmonary aspergillosis (4 patients), C. glabrata fungemia (1 patient), and C. albicans fungemia (1 patient). Three (2 cases of pulmonary aspergillosis, 1 case of C. glabrata) were fatal despite subsequent treatment with amphotericin B. The seven new fungal infections developing on amphotericin B therapy were C. krusei fungemia, C. glabrata and C. krusei fungemia, Cladosporium fungemia, C. glabrata pneumonia, Penicillium species pneumonia, and 2 patients with pulmonary aspergillosis. Three of these new infections (2 cases of pulmonary March 2000 THE AMERICAN JOURNAL OF MEDICINE Volume

5 Table 3. Adverse Events Related to the Study Drugs, by Treatment Group Adverse Event Fluconazole (n 158) Amphotericin B (n 159) P Value Number (Percent) Any adverse events 20 (13) 128 (81) Terminated from study due to 1 (1) 11 (7) adverse events Type of adverse events Fever 1 (1) 11 (7) Chills 1 (1) 79 (50) Nausea 3 (2) 7 (4) 0.34 Vomiting 3 (2) 4 (3) 0.99 Renal insufficiency* 1 (1) 53 (33) Hypokalemia 5 (3) 67 (42) Hypomagnesemia 0 8 (5) 0.01 Hypotension 0 1 (1) 0.99 Respiratory distress 0 5 (3) 0.06 Skin rash 7 (4) 1 (1) 0.04 Diarrhea 4 (3) Hepatic dysfunction 2 (1) 1 (1) 0.62 * An increase in serum creatinine level of 0.4 mg/dl from baseline. A decrease in serum potassium level of 0.5 meq/l from baseline to 3.5 meq/l. A decrease in serum magnesium level of 0.5 meq/l from baseline to 1.5 meq/l. See Methods. aspergillosis, 1 case of C. glabrata and C. krusei fungemia) were fatal. Twenty (13%) of the patients treated with fluconazole were changed to amphotericin B, whereas only 3 (2%) of the patients treated with amphotericin B were changed to fluconazole (P 0.001). The reasons for changing treatment to amphotericin B were lack of clinical improvement associated with a newly documented or progressive baseline infection (8 patients), persistent fever associated with a new pulmonary infiltrate suspicious for Aspergillus infection (6 patients), and persistent fever of uncertain cause (6 patients). Severe chills, nephrotoxicity, and persistent fever of uncertain cause were the reasons for changing treatment to fluconazole. The response to empiric antifungal therapy was also evaluated in relation to the duration of neutropenia ( 500 cells/mm 3 ) during the study. The satisfactory response rates for patients with neutropenia of 7 days or less were 70% (70 of 100 patients) for fluconazole and 72% (58 of 81 patients) for amphotericin B. The satisfactory response rates for patients with a duration of neutropenia between 8 to 14 days was 78% (25 of 32 patients) for fluconazole and 68% (28 of 41 patients) for amphotericin B. For patients with more prolonged neutropenia ( 14 days), the satisfactory response rates were 62% (16 of 26 patients) for fluconazole and 65% (24 of 37 patients) for amphotericin B. The mean time to defervescence was days (range 1 to 22) in the fluconazole group and days (range 1 to 15) in the amphotericin B group (P 0.71). Adverse Events One hundred twenty-eight (81%) of the patients treated with amphotericin B experienced adverse events, compared with only 20 (13%) of the patients treated with fluconazole (P 0.001). Fever, chills, renal insufficiency, hypokalemia, hypomagnesemia, and respiratory distress occurred more often in the amphotericin B group than in the fluconazole group (Table 3). Drug-related skin rash and diarrhea developed more often in the patients treated with fluconazole. Liver dysfunction attributable to study drug occurred in 2 patients treated with fluconazole and 1 patient treated with amphotericin B. Eleven (7%) patients treated with amphotericin B but only 1 (1%) patient treated with fluconazole were terminated from the study because of an adverse event (P 0.005). Adverse events causing termination of study drug in the amphotericin B group were renal insufficiency (7 patients), severe chills (3 patients), and elevation of serum bilirubin level (1 patient). One patient treated with fluconazole was removed from the study because of an elevation of the serum bilirubin level. Survival Twenty-seven (17%) of the patients treated with fluconazole and 34 (21%) of the patients treated with amphotericin B died during treatment with the study drug or within 21 days after its discontinuation. The number of 286 March 2000 THE AMERICAN JOURNAL OF MEDICINE Volume 108

6 Table 4. Mortality and Causes of Death, by Treatment Group Event Fluconazole (n 158) Amphotericin B (n 159) P Value Number (Percent) Deaths 27 (17) 34 (21) 0.39 Cause of death Fungal infection 7 (4) 5 (3) 0.57 Candidiasis 4 (3) 2 (1) Aspergillosis 3 (2) 3 (2) Nonfungal infection 7 (4) 10 (6) 0.62 Hemorrhage 3 (2) 5 (3) 0.72 Toxicity of chemotherapy or radiation 5 (3) 8 (5) 0.57 Hematologic malignancy 5 (3) 4 (3) 0.75 Graft-versus-host disease 0 2 (1) 0.50 deaths from fungal infection and other causes was similar in each treatment group (Table 4). DISCUSSION Invasive fungal infections, which are mostly caused by Candida and Aspergillus, are a major threat to the survival of neutropenic patients receiving treatment for a hematological malignancy or solid tumor. Autopsy studies have shown that the incidence of fungal infection may be 15% to 25% for patients with leukemia or undergoing bone marrow transplantation, 10% for patients with lymphoma, and 5% for patients with solid tumors (5). The lack of rapid, sensitive, and specific diagnostic procedures for invasive fungal infections has greatly hampered the effectiveness of antifungal therapy in these patients (4). Consequently, many patients with invasive fungal infections die before receiving appropriate therapy (5). These diagnostic and therapeutic dilemmas, together with the success of empiric antibacterial therapy in febrile neutropenic patients, formed the basis for the first two randomized trials of empiric antifungal therapy in neutropenic patients in the 1980s (6,7). The first study, in 50 patients who were still febrile and granulocytopenic after 7 days of empiric antibacterial therapy but had no documented infection, suggested that the addition of empiric antifungal therapy with amphotericin B could prevent fungal superinfections (6). The second trial, in 132 patients with persistent fever and granulocytopenia despite 4 days of antibiotic therapy, found that resolution of fever was somewhat more common in patients who had amphotericin B added to their antibiotic regimen (7). Moreover, documented fungal infection and deaths due to fungal infection were less common in the patients given empiric amphotericin B. Despite the relatively small number of patients enrolled in these two trials, as well as in other nonrandomized studies, empiric antifungal therapy with amphotericin B is now considered standard practice by physicians caring for neutropenic patients with fever (8,9). The toxicity of amphotericin B makes this approach less than ideal, however, and has been the stimulus for investigations of alternative agents for empiric antifungal therapy. The results of this study suggest that fluconazole can be an effective and safe alternative to amphotericin B for empiric antifungal therapy in these patients. The overall satisfactory response rate with empiric fluconazole therapy was 68%, similar to the 67% success rate achieved with amphotericin B. Overall mortality and deaths from fungal infection were also similar in both groups of patients. However, adverse events were much less frequent with fluconazole. We estimated that a sample size of 185 patients in each treatment group would be needed for this study. However, the initiation of competing investigational protocols slowed enrollment into the study, and the trial was stopped after 322 patients had been enrolled, thereby reducing the power of the study to 75% to detect a 15% difference in response rates between the two groups. Nevertheless, this is the largest reported trial of empiric fluconazole therapy in febrile neutropenic patients, and the 95% confidence interval for the difference in efficacy between the two therapies of 10% to 12% excludes a clinically important difference. Our results are also consistent with those of four other trials that compared the effectiveness and safety of fluconazole and amphotericin B as empiric antifungal therapy in febrile neutropenic patients (22 25). In each trial, the satisfactory response and mortality rates were similar for fluconazole and amphotericin B, while drug-related adverse events were much more frequent in patients treated with amphotericin B. One of the concerns about using fluconazole for empiric antifungal therapy in neutropenic patients is its lack of reliable activity for Aspergillus and certain Candida species (C. glabrata, C. krusei). However, as we and others March 2000 THE AMERICAN JOURNAL OF MEDICINE Volume

7 (22 27) have found, the incidence of these infections in neutropenic patients meeting the criteria for empiric antifungal therapy is low. Indeed, only 14 (4%) of the patients in this study had an infection or superinfection with Aspergillus, C. glabrata, or C. krusei, and the incidence of these infections was similar in the two study groups. Perhaps as a result of a shorter duration of neutropenia due to the increasing use of hematopoietic growth factors and stem cell infusions, we and other investigators have also observed fewer cases of aspergillosis during neutropenia (28 30). Nevertheless, infections caused by Aspergillus, C. glabrata, and C. krusei may develop during therapy or prophylaxis with fluconazole (31 33), especially in patients with established risk factors (colonization, prolonged neutropenia, corticosteroid therapy, persistent fever with new pulmonary infiltrates) (1 3). During this study, which was not blinded, these sorts of considerations may explain why more patients who were initially treated with fluconazole were changed to an alternative antifungal therapy (amphotericin B). Despite this potential bias against fluconazole, the overall satisfactory response rates were similar in patients treated with fluconazole or with amphotericin B. Fluconazole is commonly used for the prophylaxis of fungal infections in cancer patients. This practice has been shown to be effective in several large randomized, placebo-controlled trials but has also raised concerns about the indiscriminate use of fluconazole, the emergence of resistant organisms, and excessive drug costs (14,15,34). Based on the results of this study and similar trials (22 25), reserving the use of fluconazole for empiric antifungal therapy of febrile neutropenic patients at high risk for fungal infection could be a more cost-effective alternative to routine fluconazole prophylaxis of all neutropenic patients, and might also reduce the development of resistant organisms. When this study was performed, the lipid formulations of amphotericin B were not available for empiric antifungal therapy. Recently, two randomized clinical trials comparing either amphotericin B colloidal dispersion (ABCD) or liposomal amphotericin B (AmBisome) with amphotericin B in the empiric antifungal therapy of persistently febrile neutropenic patients have been completed. In one trial, 50% of the patients treated with the colloidal dispersion and 43% of the patients treated with the usual formulation of amphotericin B had a satisfactory response (27). The use of the colloidal dispersion formulation was associated with less nephrotoxicity but more infusion-related hypoxia and chills. In the other trial, a satisfactory response occurred in 50% of the patients treated with liposomal amphotericin B and 49% of the patients treated with the usual formulation of amphotericin B (35). Treatment with the liposomal form was associated with both less nephrotoxicity and fewer infusion-related adverse events. However, nephrotoxicity occurred in about 20% of neutropenic patients treated empirically with either of these new formulations of amphotericin B (27,35). The high cost of the new formulations ($500 to $800 per day) as compared with the usual formulation of amphotericin B ($25 per day) or intravenous fluconazole ($120 per day) also argues against the routine use of the new formulations for empiric antifungal therapy (36). In summary, we found that intravenous fluconazole can be an effective and safe alternative to amphotericin B for empiric antifungal therapy in many neutropenic patients with persistent fever that does not respond to antibacterial therapy. However, due to fluconazole s lack of reliable activity for Aspergillus and certain Candida species, the use of fluconazole as empiric antifungal therapy requires careful assessment of each patient. For patients who have been colonized with Aspergillus, C. glabrata, or C. krusei, or for patients with persistent fever associated with an abnormal chest radiograph or computed tomographic scan showing new or progressive pulmonary infiltrates suspicious for Aspergillus, amphotericin B will likely be needed. On the other hand, other patients at risk for toxicity from amphotericin B may benefit from empiric therapy with fluconazole. The strategy of reserving fluconazole for empiric antifungal therapy rather than routine prophylaxis may reduce the cost of antifungal therapy, and may also lessen the chance for the emergence of fluconazole-resistant organisms. ACKNOWLEDGMENT The authors thank Dr. Lichen Teng and Margaret Frane for performing statistical analyses. The authors are also grateful to Lisa Torres, RN, and Ann Gogesch, RN, for their assistance, the staffs of the UCLA Pharmacy Service and the UCLA Clinical Microbiology Laboratories for technical assistance, Katharine Fry for preparation of the manuscript, the UCLA house officers and Hematology-Oncology fellows for their cooperation, and the nurses of the UCLA 8th and 10th floor Oncology wards for helping in the care of these patients. REFERENCES 1. Anaissie EJ. Opportunistic mycoses in the immunocompromised host: experience at a cancer center and review. Clin Infect Dis. 1992; 14(suppl 1):S43 S Walsh TJ, Hiemenz JW, Anaissie E. 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