[A co-operative study on prophylaxis of fungal infection in patients with hematological diseases: prophylactic effect of oral administration of amphotericin B (author's transl)]. Fungal prophylaxis with AmBisome in liver and bone marrow transplant recipients: results of two randomized double-blind studies. Prevention of mycosis in granulocytopenic patients with prophylactic ketoconazole treatment. Prolonged fluconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: long-term follow-up of a randomized, placebo-controlled trial. Does ketoconazole prevent fungal infection in children treated with high dose chemotherapy and bone marrow transplantation? Results of a randomized placebo-controlled trial. Efficacy of itraconazole in the prevention of fungal infections among neutropenic patients with hematologic malignancies and intensive chemotherapy. A double blind, placebo controlled study. Ketoconazole in the prevention of candidiasis in patients with cancer. A prospective, randomized, controlled, double-blind study. Prophylactic treatment with miconazole in patients highly predisposed to fungal infection. A placebo-controlled double-blind study. Prophylactic use of fluconazole in neutropenic cancer patients. Prevention of fungal sepsis in patients with prolonged neutropenia: a randomized, double-blind, placebo-controlled trial of intravenous miconazole. Ketoconazole and candidiasis: a controlled study. Prophylactic intravenous amphotericin B in neutropenic autologous bone marrow transplant recipients. Early AmBisome in febrile neutropenia in patients with haematological disorders. Liposomal amphotericin (AmBisome) in the prophylaxis of fungal infections in neutropenic patients: a randomised, double-blind, placebo-controlled study. Antifungal chemoprophylaxis in cancer children: a prospective randomized controlled study. Effect of fluconazole prophylaxis on fever and use of amphotericin in neutropenic cancer patients. Bone Marrow Transplantation Team. Infection prophylaxis in acute leukemia. Comparative effectiveness of sulfamethoxazole and trimethoprim, ketoconazole, and a combination of the two. Itraconazole is not effective for the prophylaxis of fungal infections in patients with neutropenia. [Empiric therapy with fluconazole in granulocytopenic patients with carcinoma or leukemia]. Oral ketoconazole prophylaxis for Candida infections during induction therapy for acute leukaemia in adults: more bacteraemias. Empiric antifungal therapy in febrile granulocytopenic patients. EORTC International Antimicrobial Therapy Cooperative Group. Itraconazole oral solution as prophylaxis for fungal infections in neutropenic patients with hematologic malignancies: a randomized, placebo-controlled, double-blind, multicenter trial. GIMEMA Infection Program. Gruppo Italiano Malattie Ematologiche dell' Adulto. Effect of prophylactic fluconazole on the frequency of fungal infections, amphotericin B use, and health care costs in patients undergoing intensive chemotherapy for hematologic neoplasias.
nan nan nan Two randomized, placebo-controlled trials previously showed that fluconazole (400 mg/d) administered prophylactically decreases the incidence of candidiasis in blood and marrow transplant (BMT) recipients. However, there exists conflicting data regarding the optimal duration of fluconazole administration, specifically whether prophylaxis through acute graft-versus-host disease (GVHD) results in improved survival in allograft recipients. Reported here are the results of long-term follow-up and a detailed analysis of invasive candidiasis and candidiasis-related death in 300 patients who received fluconazole (400 mg/d) or placebo for 75 days after BMT at the Fred Hutchinson Cancer Research Center. Patients in both treatment arms were compared for survival, causes of death, and the incidence of invasive fungal infections early (less than 110 days) and late (more than 110 days) after BMT. After 8 years of follow-up, survival is significantly better in fluconazole recipients compared with placebo recipients (68 of 152 vs 41 of 148, P =.0001). The overall incidence of invasive candidiasis was increased in patients who received placebo compared with fluconazole (30 of 148 vs 4 of 152, P <.001). More patients who received placebo died with candidiasis early (13 of 148 vs 1 of 152, P =.001) and late (8 of 96 vs 1 of 121, P =.0068) after BMT. The incidence of severe GVHD involving the gut was higher in patients who did not receive fluconazole (20 of 143 vs 8 of 145, P =.02), and fewer patients who received fluconazole died with this complication. Thus, administration of fluconazole (400 mg/d) for 75 days after BMT appears to be associated with decreased gut GVHD, a persistent protection against disseminated candidal infections and candidiasis-related death, resulting in an overall survival benefit in allogeneic BMT recipients. Between August 1985 and October 1988 125 children who were candidates for a bone marrow transplantation entered a randomized double-blind placebo-controlled trial (63 children in ketoconazole (K) group and 62 children in placebo (P) group) to evaluate the efficacy of ketoconazole in decreasing the incidence of digestive yeast colonization. Among the 38 children who were initially colonized, the proportion of children who became decolonized was higher (p less than 0.05) in group K (47%) than in group P (16%). Among the 87 children without initial colonization, the proportion of children in whom digestive colonization occurred was lower (p less than 0.01) in group K (20%) than in group P (49%). Three children in group K (5%) and six children in group P (9%) developed a documented fungal infection (NS). Thirty-nine children in each group developed a fever of unknown origin which did not respond to a 7-day course of antibiotherapy. One hundred and three children received amphotericin B (Ampho B) (83% in group K and 82% in group P). The mean duration (+/- SD) of Ampho B was similar in group K (28 +/- 26 days) and in group P (28 +/- 25 days). The mean total dose of Ampho B was similar in group K (475.5 +/- 1060 mg) and in group P (540.4 +/- 979 mg). The actuarial survival from the day of randomization until bone marrow recovery was not different in the two groups. We conclude that ketoconazole is efficient in preventing gut yeast colonization but does not reduce the incidence of fungal documented infections and fevers of unknown origin unresponsive to antibiotherapy which necessitate empirical coverage and treatment with Ampho B. We studied the efficacy and safety of itraconazole for the prevention of fungal infection in neutropenic patients given cytotoxic chemotherapy for hematologic malignancies. Patients were randomly allocated to receive either itraconazole (200 mg bd) or placebo in addition to oral amphotericin B until the patient either developed fungal infection or had completed antileukemic treatment. Forty six patients (83 neutropenic episodes) treated with itraconazole and 46 placebo treated patients (84 neutropenic episodes) were evaluable. No specific toxicity was noted. Nine fungal infections developed in the itraconazole group, of which four were histologically or microbiologically proven and 15 in the patients given placebo (eight proven) (p < 0.12). All these patients received IV amphotericin B. The incidence of Candida albicans infections tended to be lower in the itraconazole group, but overall, there was no measurable improvement in the prevention of fungal infections and mortality by itraconazole. A prospective, randomized, controlled, double-blind study was performed between 1982 and 1985 to assess the ability of ketoconazole to prevent fungal infections in selected patients with cancer. Fifty-six patients receiving induction chemotherapy for acute leukemia, autologous bone marrow transplant for refractory nonhematopoietic malignant neoplasms, multidrug chemotherapy for malignant lymphoma, or corticosteroids for brain metastases were randomized to receive either oral ketoconazole, 400 mg/d, or placebo and observed until leukopenia resolved or corticosteroid therapy was stopped. Oral candidiasis developed in eight (28%) of 29 patients receiving placebo compared with none of 27 receiving ketoconazole. However, ketoconazole failed to prevent Candida esophagitis and vulvovaginitis in two patients and one patient, respectively. Furthermore, prophylactic use of ketoconazole did not significantly alter the total number of hospital days, febrile days, or antibiotic days or the requirement for amphotericin B in patients with acute leukemia and autologous bone marrow transplant. Since oral candidiasis can be successfully managed by several different treatment modalities when it does occur, we do not think that the routine prophylactic use of ketoconazole is justified. In a placebo-controlled double-blind study the prophylactic value of oral systemic treatment with the antimycotic agent miconazole was assessed in 30 highly predisposed patients receiving intensive cytostatic chemotherapy because of haematological malignancies. Patients colonized with Candida before treatment were not freed from this micro-organism by miconazole treatment. However, only 3 out of 6 initially non-colonized miconazole-treated patients became colonized during the study, against 10 out of 10 placebo-treated patients (p = 0.036). Seven out of 15 patients in the placebo group developed clinical mycosis, against only two out of 15 in the miconazole group. The miconazole-treated patients remained clinically free of mycosis for 252 out of 264 treatment days, while the placebo-treated patients remained free of mycosis for only 263 out or 338 treatment days (p = 0.0001). The results indicate that systemic miconazole treatment protects highly predisposed patients from colonization with Candida and prevents or postpones clinically established candidosis. This study was carried out on 70 patients with haematological or solid malignancies who were receiving chemotherapy and/or radiotherapy. Forty-one patients were randomly assigned to receive fluconazole, 400 mg/day, while they were neutropenic. Systemic fungal infection developed in four of the 41 patients (9%) receiving prophylaxis in comparison to nine of 29 patients (31%) not receiving prophylaxis. The incidence of systemic fungal infection was significantly different between the groups receiving prophylaxis and those not receiving it (p < 0.05). Fluconazole was found to be effective for preventing systemic fungal infections in neutropenic patients with cancer. Patients treated with cytotoxic therapy expected to produce neutropenia lasting two or more weeks were randomly assigned in a double-blind study to receive intravenous miconazole or placebo concomitant with empiric antibiotics to test whether miconazole can prevent fungal sepsis. The study drug was initiated at the time of first fever along with antibiotics and was continued until neutropenia resolved, fungal sepsis occurred, or persistent or recurrent unexplained fever after six or more days prompted substitution of the study drug by amphotericin B. Two hundred eight treatment courses in 180 patients were evaluated. Fungal sepsis occurred in only one patient receiving miconazole compared with eight patients receiving placebo (p = 0.03). Fatal fungal sepsis occurred in four patients receiving placebo and in none of the patients receiving miconazole (p = 0.08). There was no evidence for the development of resistance to polyenes or imidazoles in fungal isolates recovered from patients in this randomized trial or an increase in Aspergillus infections in patients who received miconazole in this randomized trial or in 121 subsequently treated patients who received unblinded use of miconazole. Thus, intravenous miconazole was more effective than placebo in preventing fungal sepsis in patients with chemotherapy-induced prolonged neutropenia. A double-blind, placebo-controlled study was undertaken to determine the efficacy of ketoconazole in the treatment of candidiasis. The drug was administered orally in the dosage of 200 mg/m2 of body surface per day for two weeks to cancer patients with oral candidiasis. Randomization in a 2:1 ratio provided 36 patients treated with ketoconazole and 20 managed with a placebo. Regression of visible lesions was achieved in 26 (72%) of 36 ketoconazole-treated and four (20%) of 20 untreated patients; eradication of culturable organisms occurred in 12 (36%) of 33 ketoconazole-treated and one (7%) of 14 untreated patients; and resolution of lesions plus eradication of Candida albicans occurred in nine (25%) of 36 ketoconazole-treated and one (5%) of 20 untreated patients. Although the therapeutic efficacy of ketoconazole was demonstrated for oropharyngeal candidiasis, the magnitude of its efficacy was less than that desired. This study assessed the efficacy, toxicity, and pharmacology of low-dose amphotericin B given prophylactically to patients (serum concentrations of 0.2-0.4 microgram/ml) undergoing bone marrow transplantation. Yeast isolates from patients' oropharyngeal areas had MICs of 0.1-0.2 microgram/ml, and none were amphotericin B resistant. The effect of low-dose amphotericin B on reducing the numbers of yeast colonizing the oropharyngeal area was significant (P less than .01). The average delay in switching to high-dose prophylactic amphotericin B was only 1 day; the decision to do so because of a perceived fungal infection occurred more frequently for the placebo group (P = .06). Fewer patients from the low-dose amphotericin B group (8.8%) than from the placebo group (14.3%) had fungi isolated from normally sterile body sites (P = .35). Infusion-related side effects but not systemic toxicities were significantly greater (P less than .001) in the amphotericin B group. The 6-week survival was greater in those receiving amphotericin B (P less than .03), but the improved survival could not be attributed to the prevention of fungal infections. Our previous experiences with liposomal amphotericin have suggested that it is an effective antifungal agent in neutropaenic patients with relatively few toxicity problems compared with conventional amphotericin B. This interim report presents early data from a single-centre, prospective randomised study with AmBisome. The study was designed to compare the early initiation of AmBisome in febrile neutropaenic patients (with haematological malignancy) with its later use, and to examine the efficacy and toxicity of different doses of this antifungal agent. Our experiences from the first 137 patients recruited (n = 200) are discussed, in addition to some of the difficulties that have arisen during the study. Liposomal amphotericin (AmBisome) 2 mg/kg three times weekly was compared with placebo as prophylaxis against fungal infection in patients undergoing chemotherapy or bone marrow transplantation (BMT) for haematological malignancies. Prophylaxis began on day 1 of chemotherapy and continued until neutrophils regenerated or infection was suspected. Of 161 evaluable patients, 74 received AmBisome and 87 received placebo. Proven fungal infections developed in no patients on AmBisome and in three on placebo (3.4%) (P = NS). Suspected fungal infections requiring intervention with systemic antifungal therapy (usually amphotericin B) occurred in 31 patients on AmBisome (42%) and in 40 on placebo (46%) (P = NS). Suspected deep-seated infections developed in 21 (28.3%) and 31 (35.6%) patients, respectively (P = NS). Time to develop a suspected or proven deep-seated infection showed a trend in favour of AmBisome (P = 0.11). Fifty patients had fungal colonisation (48 with Candida spp, two with Aspergillus spp) of at least one body site during prophylaxis; 15 patients while receiving AmBisome (20%) and 35 while on placebo (40%) (P < 0.01). Time to colonisation was significantly delayed in the group receiving AmBisome (P < 0.05). Treatment-related toxicity was modest and no additional toxicity was observed in patients receiving AmBisome. AmBisome 2 mg/kg three times weekly is safe and reduces fungal colonisation in patients receiving intensive chemotherapy or BMT. However, despite encouraging trends, prophylactic AmBisome did not lead to a significant reduction in fungal infection or in requirement for systemic antifungal therapy. We report a prospective, randomized, controlled study of antifungal chemoprophylaxis in forty immunocompromised children with hematologic malignancies, receiving respectively itraconazole, ketoconazole, amphotericin-B and no prophylaxis. Fungal isolates from patients' saliva or stools were obtained from 19/40 patients (Candida albicans from 15 patients). Disseminated infection was never observed. Fungal isolates were significantly less frequent in the ketoconazole group of patients vs any other group. Systemic antifungal chemoprophylaxis with ketoconazole appears more effective even than the recently introduced itraconazole. We studied the impact of fluconazole prophylaxis (400 mg/day) on clinical features including fever and use of amphotericin in a randomized, double-blind, placebo-controlled (1:1 randomization) study among patients undergoing chemotherapy for leukemia and those undergoing bone marrow transplantation. Fluconazole or placebo was given throughout the period of neutropenia. Amphotericin was administered to 5 of 23 (22%) fluconazole recipients and 14 of 23 (58%) placebo recipients (p < 0.01). Median duration of amphotericin used in fluconazole and placebo groups was 9 days (mean 10.8) and 13 days (mean 14) respectively. Patients who received fluconazole had significantly shorter duration of fever prior to treatment with amphotericin (days, median 5 vs. 9, p < 0.05). Superficial fungal infections were noted in 8 (34%) fluconazole recipients and 19 (79%) placebo recipients (p = 0.002). Fluconazole was well tolerated. Prophylaxis with fluconazole resulted in a significant reduction in the empiric use of amphotericin, duration of fever and incidence of superficial fungal infections. In a comparative study of infection prophylaxis, patients with acute leukemia receiving remission induction therapy were assigned either no prophylaxis, sulfamethoxazole and trimethoprim, ketoconazole, or the combination of sulfamethoxazole and trimethoprim and ketoconazole. Both sulfamethoxazole and trimethoprim and the combination of sulfamethoxazole and trimethoprim and ketoconazole substantially reduced the overall incidence of infection consequent to a marked decrease in bacterial infection. However, sulfamethoxazole and trimethoprim were associated with an increased rate of fungal infection, while ketoconazole decreased this complication. No form of prophylaxis reduced infectious mortality or increased the complete remission rate. However, because of its effect in reducing infectious morbidity, we conclude that patients with acute leukemia receiving remission induction treatment should be given antibacterial and antifungal prophylaxis. Fungal infections are a major problem among patients with hematological malignancies. To evaluate the efficacy of itraconazole (200 mg twice daily) in the prophylaxis of fungal infections in neutropenic patients, we conducted a prospective trial. A total of 61 patients with acute leukemia (113 cytotoxic chemotherapy episodes) were enrolled in the study. One patient in the itraconazole group was excluded because itraconazole was not taken due to gastrointestinal hemorrhage. Because the duration of neutropenia (neutrophil count, <0.5 x 10(9)/l) did not reach 7 days, 3 (1 patient) and 13 (4 patients) cytotoxic chemotherapy episodes in the itraconazole and control groups, respectively, were excluded. After these exclusions, the study population consisted of 31 patients (54 cytotoxic chemotherapy episodes) who had taken itraconazole and 24 patients (43 cytotoxic chemotherapy episodes) who had not taken itraconazole. Prophylactic treatment was initiated on the first day of chemotherapy and was continued until the end of the neutropenic period (absolute neutrophil count, >1 x 10(9)/l) unless a systemic fungal infection was documented or suspected. Thirteen episodes (24%) in the itraconazole group and 7 episodes (16%) in the control group proceeded to intravenous amphotericin B (P > 0.05). Fungal infections occurred in 9 episodes (17%) in the itraconazole group and in 5 episodes (12%) in the control group (P > 0.05). Overall mortality was five deaths in the itraconazole group and two in the control group. These deaths were not due to clinically documented fungal infection. In our study, efficacy of itraconazole in the prophylaxis of fungal infections in neutropenic patients was not detected. We performed a randomized clinical trial in granulocytopenic patients with carcinoma or leukemia. Patients with persistent fever for more than 2 days despite antibiotic therapy were randomized to antibiotic plus fluconazole therapy group (FLCZ group) or antibiotic therapy only group (antibiotic group) by the envelope method. It was possible to evaluate clinical efficacies in 62 patients (37 patients in FLCZ group and 25 patients in antibiotics group). In patients whose neutrophil counts were less than 100/microliters on the initial day of therapy, clinical efficacy rates were 72.0% (18/25) in FLCZ group and 57.1% (8/14) in antibiotics group. In patients whose neutrophil counts continued to be less than 100/microliters during therapy, clinical efficacy rates were 64.3% (9/14) and 50.0% (3/6), respectively. Further, in patients whose neutrophil counts continued to be less than 500/microliters during therapy, they were 76.9% (20/26) and 53.3% (8/15), respectively. No severe side effects nor severe case of abnormal change in laboratory test values due to fluconazole were observed in this trial. These data suggest that empiric antifungal therapy with fluconazole is effective for fungal infections in granulocytopenic patients with carcinoma and leukemia. We determined whether ketoconazole prophylaxis might reduce Candida colonization and infections in adult patients with acute leukaemia. During first-remission induction therapy 50 patients were treated with 200 mg ketoconazole administered orally daily, while 57 patients received placebo in a double-blind, randomized trial. The duration of severe neutropenia (granulocytes less than 0.1 x 10(9) l-1) represented 36% of the study period in the ketoconazole group and 26% in the placebo group (P = 0.043). Although fewer patients presented with positive Candida surveillance cultures and serological evidence of Candida infection in the ketoconazole group compared to the placebo group, two candidaemias and one Trichosporum fungaemia were observed in the ketoconazole group. Moreover, significantly more bacteraemias were noted in the ketoconazole group (n = 37) than in the placebo group (n = 21) (P = 0.004). Thus, although oral ketoconazole prophylaxis might be associated with less Candida colonization and fewer seroconversions, it also resulted in more bacteraemias and longer duration of severe neutropenia, suggesting that caution should be exercised when ketoconazole (or related drugs) is given to this group of immunocompromised hosts. The optimal management of fever in granulocytopenic patients remains controversial. Invasive fungal infections are common and life-threatening but are difficult to diagnose early. In this randomized study, we investigated the potential value of empiric administration of amphotericin B (versus no empiric antifungal therapy) in 132 patients remaining febrile and granulocytopenic despite broad-spectrum antibiotic therapy for four days.
                The patients were divided into two groups: 68 who were randomly assigned to receive empiric amphotericin B, and 64 who were randomly assigned to continue only the protocol antibiotics that they were already receiving. Amphotericin B was administered intravenously as follows: every other day at a dose of 1.2 mg/kg body weight or daily at a dose of 0.6 mg/kg body weight. Clinical response was evaluated as success or failure, depending upon the febrile course after randomization.
                Based on the evolution of fever, the response rate was 69% in the group of patients receiving empiric amphotericin B and 53% for the other group (p = 0.09). There were six documented (four severe) fungal infections in 64 patients randomized not to receive the antifungal therapy as compared to only one fungemia among 68 patients treated empirically with amphotericin B (p = 0.1). No deaths due to fungal infection occurred among the patients receiving empiric amphotericin B compared to four in the other group (p = 0.05). However, this study did not demonstrate a difference in survival between the two groups of patients (with or without empiric amphotericin B). The benefit of empiric administration of amphotericin B was primarily observed in specific subgroups of patients, such as those who did not receive any antifungal prophylaxis (78% versus 45%, p = 0.04), those who were severely granulocytopenic (69% versus 46%, p = 0.06), febrile patients with a clinically documented infection (75% versus 41%, p = 0.03), and patients older than 15 years of age (67% versus 47%, p = 0.06).
                These data suggest a benefit for early amphotericin B treatment in granulocytopenic patients with continued fever despite antibiotic therapy. To evaluate the efficacy and safety of itraconazole oral solution for preventing fungal infections, a randomized, placebo-controlled, double-blind, multicenter trial was conducted: 405 neutropenic patients with hematologic malignancies were randomly assigned to receive either itraconazole, 2.5 mg/kg every 12 hours (201 patients), or placebo (204 patients). Proven and suspected deep fungal infection occurred in 24% of itraconazole recipients and in 33% of placebo recipients, a difference of 9 percentage points (95% confidence interval [CI], 0.6% to 22.5%; P = .035). Fungemia due to Candida species was documented in 0.5% of itraconazole recipients and in 4% of placebo recipients, a difference of 3.5 percentage points (95% CI, 0.5% to 6%; P = .01). Deaths due to candidemia occurred in none of the itraconazole recipients compared with 4 placebo recipients, a difference of 2 percentage points (95% CI, 0.05% to 4%; P = .06). Aspergillus infection was documented in four itraconazole recipients (one death) and one placebo recipient (one death). Side effects causing drug interruption occurred in 18% of itraconazole recipients and 13% of placebo recipients. Itraconazole oral solution was well-tolerated and effectively prevented proven and suspected deep fungal infection as well as systemic infection and death due to Candida species. Fungal infections are a major problem in patients with hematologic malignancy. Attempts to reduce their frequency with antifungal agents have not been successful. A double-blind, controlled, single-center trial was conducted with 96 consecutive patients undergoing 154 episodes of chemotherapy. Patients received 400 mg of fluconazole or placebo until bone marrow recovery or initiation of intravenous amphotericin B infusions. End points were amphotericin B use, fungal infection, stable neutrophil count > 0.5 x 10(9)/L, toxicity precluding further fluconazole use, and death. By Kaplan-Meier estimation, the time to initiation of amphotericin B therapy was shorter in 76 patients treated with placebo than in 75 treated with fluconazole (P = .003). Also, fluconazole reduced the number of febrile days by 20% (P = .002) and prevented oropharyngeal candidiasis (1/75 vs. 9/76, P = .018). The frequency of deep mycoses (8/76 vs. 8/75) and outcome were unaffected. Fluconazole did not have a favorable effect on infection-related health care costs and was associated with prolonged severe neutropenia (P = .01).
Intravenous amphotericin B was the only antifungal agent that reduced total mortality. It should therefore be preferred when prophylactic or empirical antifungal therapy in cancer patients with neutropenia is instituted.