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Failure of fluconazole prophylaxis to reduce mortality or the requirement of systemic amphotericin B therapy during treatment for refractory acute myeloid leukemia

1998; Wiley; Volume: 83; Issue: 2 Linguagem: Inglês

10.1002/(sici)1097-0142(19980715)83

1097-0142

Wolfgang Kern, Gerhard Behre, Thomas Rudolf, Andrea Kerkhoff, A. Grote‐Metke, Hartmut Eimermacher, U. Kubica, Bernhard W�rmann, Thomas B�chner, Wolfgang Hiddemann,

Fungal Infections and Studies

CancerVolume 83, Issue 2 p. 291-301 Original ArticleFree Access Failure of fluconazole prophylaxis to reduce mortality or the requirement of systemic amphotericin B therapy during treatment for refractory acute myeloid leukemia† Results of a prospective randomized Phase III study Wolfgang Kern M.D., Wolfgang Kern M.D. Department of Hematology and Oncology, Georg-August-University, Göttingen, GermanySearch for more papers by this authorGerhard Behre M.D., Gerhard Behre M.D. Department of Hematology and Oncology, Georg-August-University, Göttingen, GermanySearch for more papers by this authorThomas Rudolf M.D., Thomas Rudolf M.D. Department of Hematology and Oncology, Georg-August-University, Göttingen, GermanySearch for more papers by this authorAndrea Kerkhoff M.D., Andrea Kerkhoff M.D. Department of Hematology and Oncology, Westfälische Wilhelms University, Münster, GermanySearch for more papers by this authorAlbert Grote-Metke M.D., Albert Grote-Metke M.D. Evangelisches Krankenhaus, Hamm, GermanySearch for more papers by this authorHartmut Eimermacher M.D., Hartmut Eimermacher M.D. Katholisches Krankenhaus Hagen, Hagen, GermanySearch for more papers by this authorUrsula Kubica M.D., Ursula Kubica M.D. Zentralkrankenhaus St. Jürgen, Bremen, GermanySearch for more papers by this authorBernhard Wörmann M.D., Ph.D., Bernhard Wörmann M.D., Ph.D. Department of Hematology and Oncology, Georg-August-University, Göttingen, GermanySearch for more papers by this authorThomas Büchner M.D., Ph.D., Thomas Büchner M.D., Ph.D. Department of Hematology and Oncology, Westfälische Wilhelms University, Münster, GermanySearch for more papers by this authorWolfgang Hiddemann M.D., Ph.D., Corresponding Author Wolfgang Hiddemann M.D., Ph.D. Department of Hematology and Oncology, Georg-August-University, Göttingen, GermanyDepartment of Hematology and Oncology, Georg-August-University, Robert-Koch-Strasse 40, 37075 Göttingen, Germany===Search for more papers by this author Wolfgang Kern M.D., Wolfgang Kern M.D. Department of Hematology and Oncology, Georg-August-University, Göttingen, GermanySearch for more papers by this authorGerhard Behre M.D., Gerhard Behre M.D. Department of Hematology and Oncology, Georg-August-University, Göttingen, GermanySearch for more papers by this authorThomas Rudolf M.D., Thomas Rudolf M.D. Department of Hematology and Oncology, Georg-August-University, Göttingen, GermanySearch for more papers by this authorAndrea Kerkhoff M.D., Andrea Kerkhoff M.D. Department of Hematology and Oncology, Westfälische Wilhelms University, Münster, GermanySearch for more papers by this authorAlbert Grote-Metke M.D., Albert Grote-Metke M.D. Evangelisches Krankenhaus, Hamm, GermanySearch for more papers by this authorHartmut Eimermacher M.D., Hartmut Eimermacher M.D. Katholisches Krankenhaus Hagen, Hagen, GermanySearch for more papers by this authorUrsula Kubica M.D., Ursula Kubica M.D. Zentralkrankenhaus St. Jürgen, Bremen, GermanySearch for more papers by this authorBernhard Wörmann M.D., Ph.D., Bernhard Wörmann M.D., Ph.D. Department of Hematology and Oncology, Georg-August-University, Göttingen, GermanySearch for more papers by this authorThomas Büchner M.D., Ph.D., Thomas Büchner M.D., Ph.D. Department of Hematology and Oncology, Westfälische Wilhelms University, Münster, GermanySearch for more papers by this authorWolfgang Hiddemann M.D., Ph.D., Corresponding Author Wolfgang Hiddemann M.D., Ph.D. Department of Hematology and Oncology, Georg-August-University, Göttingen, GermanyDepartment of Hematology and Oncology, Georg-August-University, Robert-Koch-Strasse 40, 37075 Göttingen, Germany===Search for more papers by this author First published: 09 November 2000 https://doi.org/10.1002/(SICI)1097-0142(19980715)83:2 3.0.CO;2-OCitations: 29 † Presented at the Annual Congress of the German Society for Hematology and Oncology, Düsseldorf, Germany, 1996 (Kern W, Behre G, Büchner Th, Hiddemann W, for the German AML Cooperative Group. Failure of fluconazole prophylaxis to reduce mortality during treatment for refractory acute myeloid leukemia: a phase III multicenter study. Ann Hematol 1996;73[Suppl 2]:A10). AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract BACKGROUND Invasive fungal infections have increasingly become a matter of concern with regard to patients receiving intensive myelosuppressive therapy for hematologic malignancies. Such infections, especially prolonged neutropenia systemic fungal infections, may contribute substantially to infectious complications and early death. Measures for early detection and effective prophylactic strategies using active and nontoxic antifungal agents are therefore urgently needed. METHODS The current randomized study was initiated to assess the efficacy of oral fluconazole as systemic antifungal prophylaxis for high risk patients with recurrent acute myeloid leukemia undergoing intensive salvage therapy. RESULTS Of 68 fully evaluable patients, 36 were randomized to fluconazole in addition to standard prophylaxis with oral co-trimoxazol, colistin sulphate, and amphotericin B suspension, and 32 were randomized to standard prophylaxis only. No major differences between the two groups were observed in the number of episodes of fever of unknown origin (61% vs. 50%) or clinically defined infections (56% vs. 50%). Microbiologically defined infections were more frequent in the fluconazole group (50% vs. 31%), mainly due to a higher incidence of bacteremias (42% vs. 22%). There were two cases of proven invasive fungal infections in each group. Systemic amphotericin B was administered more frequently to patients receiving fluconazole prophylaxis (56% vs. 28%). Fluconazole prophylaxis had no impact on the rate of early death or overall survival. CONCLUSIONS For patients with high risk recurrent acute myeloid leukemia undergoing intensive salvage therapy, antifungal prophylaxis with fluconazole was not superior to standard prophylaxis only. Cancer 1998;83:291-301. © 1998 American Cancer Society. Invasive fungal infections (IFIs) in patients receiving intensive myelosuppressive therapy for hematologic malignancies have increasingly become a matter of concern.1-4 Especially in cases with prolonged neutropenia,5 systemic fungal infections may contribute substantially to infectious complications and early deaths. Measures for early detection and effective prophylactic strategies using active, nontoxic antifungal agents are therefore urgently needed. Until now, oral administration of amphotericin B suspension was the most frequently used approach. This treatment has been found to reduce the rate of IFI during chemotherapy-induced neutropenia6 but is hampered by moderate-to-poor patient compliance and a lack of systemic activity. As a member of the new group of azole antifungals, fluconazole features a broad range of activity and has an excellent oral bioavailability.7 It causes few side effects and thereby offers a promising option for systemic antifungal prophylaxis in immunocompromised patients with severe, prolonged granulocytopenia. Therefore, the German AML Cooperative Group initiated a prospective randomized multicenter study to evaluate the impact of fluconazole prophylaxis on the incidence of proven or suspected IFI and the need for systemic antifungal therapy with amphotericin B in high risk patients with relapsed and refractory acute myeloid leukemia (AML). In preceding Phase II studies, patients undergoing intensive salvage therapy with sequential high dose cytosine arabinoside and mitoxantrone (S-HAM) for refractory or relapsed AML were found to experience a median duration of critical neutropenia of more than 5 weeks and an early death rate of 28%.8 These patients were therefore selected as a main target group for whom a beneficial effect of antifungal prophylaxis could be expected. METHODS Patients and Antileukemic Therapy Consecutive patients with relapsed and refractory AML who were admitted to the participating centers were eligible to participate in this study. Refractoriness against standard chemotherapy was defined according to previously established criteria,9 which included 1) primary resistance against 2 cycles of induction therapy, 2) first early relapse with a remission duration of less than 6 months, and 3) second and subsequent relapse. Patients with first relapses after 6 months of remission were not considered refractory to standard therapy and were included as relapsed AML. All patients were recruited from the first-line trials of the German AML Cooperative Group and had thus received standardized first-line treatment. For patients younger than 60 years, first-line therapy consisted of double induction therapy with either the repetitive application of the 9-day regimen of thioguanine, cytosine arabinoside (ara-C), and daunorubicin (TAD-9/TAD-9) or the sequential application of TAD-9 followed by high dose ara-C and mitoxantrone. Older patients all received one course of TAD-9 and were given a second TAD-9 course only when there was inadequate response to the first TAD-9 cycle. Patients of all ages who achieved a complete remission subsequently received TAD-9 for consolidation and monthly maintenance therapy for 3 years.10, 11 Patients meeting the entry criteria were enrolled into the current study and were treated with S-HAM,12 which consisted of high dose ara-C 3 g/m2 or 1 g/m2 every 12 hours by a 3-hour infusion on Days 1, 2, 8, and 9 and mitoxantrone 10 mg/m2/day as a 30-minute infusion on Days 3, 4, 10, and 11, respectively (Fig. 1 (1K)). The dose of ara-C was adjusted to the disease status according to the results of a previous trial that compared 3 g/m2 with 1 g/m2 ara-C in the treament of patients with refractory AML.8 Patients with refractory disease who were younger than 60 years received 3 g/m2 ara-C, whereas all other cases were treated with 1 g/m2 ara-C. Figure 1Open in figure viewerPowerPoint The schedule for the sequential high-dose cytosine arabinoside and mitoxantrone protocol used in this study is shown. To prevent photophobia and conjunctivitis induced by high dose ara-C, all patients received glucocorticoid eye drops every 6 hours starting before the first dose of the drug and continuing for 24 hours after the last dose. All patients also received granulocyte-colony stimulating factor (G-CSF) 5μg/kg/day subcutaneously starting on Day 12 after the beginning of therapy. G-CSF was discontinued if a bone marrow examination on Day 18, i.e., 1 week after completion of S-HAM, revealed more than 5% residual leukemic blasts. In patients with adequate blast cell clearance on Day 18, G-CSF was continued until the neutrophil count reached a value of more than 1500/mm3 for 3 consecutive days. Patients with antecedent hematologic disorders, secondary leukemias, and a preceding autologous or allogeneic bone marrow transplantation were excluded from the study. Other patients excluded were those with abnormal liver function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], or alkaline phosphatase [AP] more than 3 times the upper normal limits, respectively; total bilirubin 2.0 mg/dL); impaired renal function (serum creatinine 2.0 mg/dL); severe infections; or pregnancy. Study Design and Antimicrobial Strategies On the basis of the above-mentioned antileukemic strategy, the current study aimed to assess the efficacy of fluconazole in addition to standard antimicrobial prophylaxis for the prevention of IFI and the need for empiric systemic antifungal therapy with amphotericin B. The study had the design of a prospective randomized multicenter analysis. Prior to the start of chemotherapy, patients were randomly assigned to either 1) systemic antifungal prophylaxis with fluconazole 400 mg administered orally (p.o.) daily in addition to standard antimicrobial prophylaxis consisting of co-trimoxazol 960 mg p.o. 3 times daily, colistine sulphate 2 million units p.o. 4 times daily, and amphotericin B suspension 40 mg p.o. 6 times daily; or 2) standard antimicrobial prophylaxis only. To avoid imbalances in the risk profile, patients were stratified according to age (< or ≥ 60 years) and disease status (primary refractoriness, relapse after ≤6 months of first remission, relapse after 6 months and ≤18 months of first remission, relapse after >18 months of first remission, or second/subsequent relapse).13 Antimicrobial prophylaxis was continued until parenteral antimicrobial therapy was required or until a leukocyte count of more than 1000/μL was reached. Parenteral antimicrobial therapy was initiated on the occurence of fever of unknown origin (FUO) or fever with clinical and/or microbiologically verified infection. Antimicrobial treatment for FUO comprised two drug combinations of an aminoglycoside with either a third-generation cephalosporin or ureidopenicillin. On persistence or recurrence of fever, a combination of carbapenems with glycopeptides was initiated. In addition, intravenous antifungal therapy was begun. This comprised amphotericin B in patients who were randomized to fluconazole prophylaxis. In patients randomized to the control, intravenous fluconazole was given instead, which was replaced by amphotericin B only when there was no response. Patients with pneumonia, however, were uniformly started on amphotericin B in addition to antibiotic therapy. The addition of other antifungal agents was dependent on the patient's clinical condition and was left at the discretion of the responsible physician. Study Parameters Infectious complications were classified according to the Consensus Report of the Immunocompromised Host Society,14 as 1) FUO not accompanied by either clinical or microbiologic evidence of infection; 2) clinically defined infections referring to the diagnosis of a site of infection without determination of the infectious agent; or 3) microbiologically defined infections consisting of bacteremia, fungemia, a microbiologically defined site of infection, or a combination of the three. In addition, IFIs were classified according to criteria suggested by Behre et al. (Table 1).15 Table 1. Definition of Invasive Fungal Infections in Neutropenic Patients Invasive pulmonary aspergillosis Proven Histology ± culture Probable Pneumonia or other organ infection unresponsive to antibiotics, with no other microbiologically documented causative organism and one of the following conditions: Culture of normally sterile tissues, bronchoalveolar lavage, blood sputum, or nose Repeated antigen detection or increasing antibody titers in blood Pulmonary lesions with halo sign or air crescent sign in computed tomography scan Possible Fever unresponsive to antibiotics, with no other microbiologically documented causative organism and one of the following conditions: Culture of normally sterile tissues, bronchoalveolar lavage, blood sputum, or nose Repeated antigen detection or increasing antibody titers in blood Invasive candidiasis Proven Histology ± culture or Histology or culture of normally sterile tissues, including blood, with fever unresponsive to antibiotics and no other microbiologically documented causative organism Probable Pneumonia or other organ infection unresponsive to antibiotics, with no other microbiologically documented causative organism and one of the following conditions: Culture or bronchoalveolar lavage Increasing antigen or antibody titers in blood Multiple hepatic and splenic lesions in computed tomography scan/sonogram Possible Fever unresponsive to antibiotics with no other microbiologically documented causative organism and one of the following conditions: Culture, excluding blood Increasing antigen or antibody titers in blood Possible invasive fungal infection No invasive pulmonary aspergillosis or candidiasis as defined above, but one of the following conditions: Pneumonia unresponsive to antibiotics and/or responsive to antimycotics ± antibiotics Fever unresponsive to antibiotics and responsive to antimycotics ± antibiotics Toxicity was evaluated according to the World Health Organization (WHO) grading system.16 Response to therapy was assessed according to Cancer and Leukemia Group B criteria.17 Complete remission (CR) was defined as normal cellular bone marrow with normal erythroid and myeloid elements as well as myeloblasts, promyelocytes, and other leukemic cells totaling less than 5%, and with normal peripheral blood platelet and white blood cell counts for at least 4 weeks. Patients who had more than 5% myeloblasts but fewer than 25% blasts, with otherwise normal bone marrow, were considered to be in partial remission (PR), as were patients who fulfilled the criteria of CR except for full recovery of peripheral blood platelet and/or white blood cell counts. Patients with persistent leukemic blasts in the bone marrow or blood or with leukemic regrowth within 4 weeks after initial response were considered nonresponders (NRs). Patients dying within 6 weeks after completion of antileukemic therapy without evidence of leukemic regrowth were classified as early deaths (EDs). The duration of critical cytopenia was evaluated by the time of leukocyte recovery to more than 1000/μL from the onset of S-HAM treatment. The time to CR was measured from the onset of treatment to the date of documented CR, and disease free survival was measured from the date of documented CR to relapse or death during remission. Survival was measured as the time from the beginning of treatment to death. Time to treatment failure was measured as the time from the beginning of treatment to death without evidence of leukemia, documentation of persistent leukemia, or relapse. Statistics The primary end point of the current study was the impact of fluconazole prophylaxis in addition to standard antimicrobial prophylaxis on the incidence of IFI and the requirement of additional systemic antifungal therapy with amphotericin B as compared with a randomly assigned control group receiving standard antimicrobial prophylaxis alone. The secondary end point was the ED rate. Assuming a reduction of 20% in the incidence of IFI or the requirement of systemic antifungal therapy by fluconazole prophylaxis, with α = 0.05 and β = 0.20, it was anticipated that 73 patients would be enrolled into each treatment arm. Numeric values were compared by the chi-square test, Fisher's exact test, and Student's t test. Remission duration and survival were calculated for the fluconazole and control groups according to Kaplan-Meier estimates, respectively, and were compared using the log rank test. After enrollment of 75 patients into the study, 68 of whom could be fully evaluated, a scheduled interim analysis disclosed a difference between the study and control groups in the number of patients who required systemic amphotericin B. Based on these data, a hypothetical analysis of the total of 146 originally planned patients was performed, assuming that none of the following patients with fluconazole prophylaxis and 50% of the following patients without fluconazole prophylaxis would receive amphotericin B. Under this best-case assumption, no significant advantage for fluconazole prophylaxis could be detected. Therefore, it was decided to stop further recruitment of patients into the trial. Study Conduct Prior to receiving therapy, all patients gave their informed consent for participation in the current evaluation after having been advised about the purpose and investigational nature of the study as well as the potential risks of participation. The study design adhered to the Declaration of Helsinki and was approved by the ethics committees of the participating institutions prior to its initiation. RESULTS Patient Characteristics Between May 1992 and January 1996, 84 patients entered the study, 68 of whom could be fully evaluated. Causes for exclusion from analysis were secondary leukemia (for 3 patients), application of the study drug before randomization (for 2 patients), treatment not in accordance with the results of the randomization (for 1 patient), discontinuation of the S-HAM chemotherapy after the first 4 days (for 2 patients), and incomplete documentation (for 8 patients). Of the patients who could be evaluated, 36 and 32 were randomized to the fluconazole arm and the control arm, respectively. The patient characteristics and risk profiles of the two groups were comparable. The patients' ages ranged from 21 to 73 and from 17 to 72 years (median, 52 and 45 years) for the fluconazole prophylaxis and control groups (P > 0.05), respectively. All patients had received prior chemotherapy for their disease as indicated above. Two patients (6%) in each group were younger than 60 years and had AML refractory to first-line therapy. Early and late relapses after a first complete remission of ≤ and 6 months' duration occurred in 7 (19%) and 19 (53%) vs. 7 (22%) and 18 (56%) patients younger than 60 years, respectively. The patients were older than 60 years in 8 (22%) vs. 4 (13%) cases (P > 0.05) (Table 2). All patients who could be evaluated received one course of S-HAM therapy. Table 2. Patient Characteristics and Risk Factors Fluconazole (n = 36) Control (n = 32) Age, yrs (median/range) 52/21-73 45/17-72 Gender (male/female) 20/16 17/15 Disease status age <60 yrs + refractory AML 2 (6%) 2 (6%) age <60 yrs + CR duration ≤6 mos 7 (19%) 7 (22%) age 6 mos 19 (53%) 18 (56%) age 60 yrs 8 (22%) 4 (13%) Antifungal treatment during preceeding neutropenias 30 (83%) 24 (75%) for invasive pulmonary aspergillosis 2 1 for invasive candidiasis 3 3 for suspected IFI 15 14 for FUO 10 6 Infections at study entry 7 (19%) 2 (6%) FUO 6 1 Gastrointestinal tract infection 1 - Soft tissue infection - 1 Recovery of leukocytes to >1000/μL (days after start of chemotherapy; median/range) 35/22-58 34/19-59 Time to complete remission (days after start of chemotherapy; median/range) 51/30-71 57/37-93 Duration of fluconazole prophylaxis (days; median/range) 23/2-56 - AML: acute myeloid leukemia; CR: complete remission; IFI: invasive fungal infection; FUO: fever of unknown origin. During preceding neutropenias, systemic antifungal therapy was given to 30 patients (83%) versus 24 patients (75%), in 9 of whom IFI had been documented (Aspergillus species, 2 vs. 1; Candida species, 3 vs. 3). Antifungal therapy had been initiated for suspected IFI and for FUO resistant to antibiotic treatment in 15 and 10 versus 14 and 6 cases, respectively. Infections at study entry were more frequent within the fluconazole prophylaxis group (7 patients [19%] versus 2 patients [6%]), mainly due to a higher prevalence of FUO (6 [17%] vs. 1 [3%]; P = 0.07). The median duration of critical cytopenia was similar in both groups, with the recovery of leukocytes to more than 1000/μL occurring at a median of 35 versus 34 days after the start of therapy (Table 2). Consequently, there was no significant difference in the median time to CR (51 vs. 57 days after the start of therapy; P = 0.06; Fig. 2 (3K)). Fluconazole prophylaxis was carried out for a median of 23 days (range, 2-56 days). Figure 2Open in figure viewerPowerPoint Time to complete remission is shown. Toxicity of Antileukemic Therapy Severe nonhematologic toxicities (WHO Grade 3/4) during S-HAM therapy were not dependent on the use of fluconazole prophylaxis and consisted mainly of nausea/vomiting, stomatitis, and diarrhea (Table 3). Furthermore, mild or severe elevation of liver enzymes and parameters for cholestasis were not different between the fluconazole prophylaxis group and the control group. Table 3. Nonhematologic Toxicity Fluconazole (n = 36) Control (n = 32) WHO 3/4 WHO 3/4 WHO 3/4 WHO 3/4 Nausea/vomiting 5 (14%) 14 (39%) 10 (31%) 7 (22%) Stomatits 13 (36%) 5 (14%) 10 (31%) 5 (16%) Diarrhea 8 (22%) 6 (17%) 5 (16%) 5 (16%) Bilirubin 10 (28%) 1 (3%) 4 (13%) 3 (9%) AP 7 (19%) - 2 (6%) - AST/ALT 3 (8%) 2 (6%) 5 (16%) 1 (3%) Bleeding 11 (31%) - 2 (6%) 2 (6%) Creatinine 7 (19%) - 1 (3%) - Lung - 1 (3%) - 2 (6%) Allergy 3 (8%) - - - Cardiac rhythm 3 (8%) 1 (3%) 2 (6%) 2 (6%) Cardiac function 1 (3%) 1 (3%) - 1 (3%) Pericarditis - - 1 (3%) - Peripheral nervous system 1 (3%) - - - Consciousness 1 (3%) 1 (3%) - 1 (3%) WHO: World Health Organization; AP: alkaline phosphatase; AST: aspartate aminotransferase; ALT: alanine aminotransferase. Infectious Episodes The median number of febrile episodes was 1 in both groups (range, 0-3), whereas the total number of febrile days was higher in the group receiving fluconazole prophylaxis (median, 9 vs. 6 days; range, 0-29 vs. 0-60 days; P > 0.05; Table 4). The median time to the first febrile episode was 10 versus 15 days after the start of therapy (P > 0.05, Fig. 3 (3K)). Figure 3Open in figure viewerPowerPoint Time to the first febrile episode is shown. Table 4. Infectious Complications Fluconazole (n = 36) Control (n = 32) No. of febrile episodes (median/range) 1/0-3 1/0-3 No. of febrile days (median/range) 9/0-29 6/0-60 Time to first infection (days; median/range) 10/0-33 15/0-22 No infection 1(3%) 2 (6%) FUO 22 (61%) 16 (50%) Clinically defined infections 20 (56%) 16 (50%) Pneumonia 6 (17%) 6 (19%) Sepsis syndrome - - Septic shock 2 (6%) 1 (3%) Gastrointestinal tract infection 9 (25%) 3 (9%) Perianal infection - 3 (9%) Catheter-related infection 1 (3%) 2 (6%) Other 2 (6%) 1 (3%) Microbiologically defined infections 18 (50%) 10 (31%) Bacteriemia 15 (42%) 7 (22%) Gram positive 12 (33%) 4 (13%) Gram negative 3 (8%) 3 (9%) Fungemia 2 (6%) 1 (3%) Pneumonia 6 (17%) 3 (9%) Sepsis syndrome 2 (6%) 2 (6%) Septic shock 2 (6%) 2 (6%) Gastrointestinal tract infection 1 (3%) 2 (6%) Perianal infection - - Catheter related infection 1 (3%) 2 (6%) Other 2 (6%) 1 (3%) FUO: fever of unknown origin. The infectious complications that were encountered during S-HAM therapy are summarized in Table 4. Three patients remained free of infections throughout the whole study period. No major differences between the two study groups were observed for the incidence of FUO (22 episodes [61%] vs. 16 episodes [50%]) or clinically defined infections (20 [56%] vs. 16 [50%]). There was a trend toward more infections of the gastrointestinal tract among patients who received fluconazole prophylaxis; this trend was not statistically significant (9 vs. 3; P = 0.08). Marked differences were seen in the incidence of microbiologically defined infections (18 [50%] vs. 10 [31%]; P = 0.09), mainly due to a strong trend toward more bacteremias in the fluconazole group (15 [42%] vs. 7 [22%]; P = 0.07), which reached significance for gram positive bacteremias (33% vs. 13%; P = 0.04). Bacteremias also occurred earlier in this group. The frequencies of all other categories of infection were similar for both groups. Overall, 12 patients (33%) versus 9 patients (28%) developed pneumonia, which occurred earlier in patients who received fluconazole prophylaxis. In total, causative organisms were predominantly gram positive and gram negative bacteria identified in 26 and 14 cases, respectively. Fungal infections were documented in only 4 patients (Table 5). There were 2 versus 2 cases with proven invasive candidiasis, whereas invasive pulmonary aspergillosis was not observed. Possible IFI occurred in 19 (53%) versus 11 (34%) patients (P = 0.10; Table 6). Table 5. Isolated Causative Organisms Fluconazole (n = 26) Control (n = 19) Total (n = 44) Gram positive bacteria 17 (68%) 9 (47%) 26 (59%) Gram negative bacteria 6 (24%) 8 (42%) 14 (32%) Fungi 2 (8%) 2 (11%) 4 (9%) Table 6. Fungal Infections Fluconazole Control Proven Probable Possible Proven Probable Possible Invasive fungal infection 19 11 Invasive candidiasis 2 - - 2 - - Invasive aspergillosis - - - - - - Antimicrobial Therapy Antifungal therapy was initiated in 22 (61%) versus 18 (56%) patients (Table 7). Systemic amphotericin B was given to more patients in the fluconazole prophylaxis group (20 [56%] vs. 9 [28%]). Seven patients within the control group received fluconazole intravenously as initial antifungal therapy, none of which required subsequent parenteral amphotericin B. The median number of antibiotic regimens was 3 versus 2 (range, 0-7 vs. 0-6). Table 7. Antimicrobial Therapy P value Fluconazole (n = 36) Control (n = 32) Systemic antifungal therapy 22 (61%) 18 (56%) Amphotericin B 0.02 20 (56%) 9 (28%) Fluconazole - - 7 (22%) 5-Flucytosine 0.07 15 (42%) 7 (22%) Itraconazole 0.07 1 (3%) 5 (16%) Ambisome 0.72 1 (3%) 1 (3%) No. of antibiotic regimens (median/range)