Bone Marrow Transplantation (2000) 25, 853–859  2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt Fluconazole vs low-dose amphotericin B for the prevention of fungal infections in patients undergoing bone marrow transplantation: a study of the North American Marrow Transplant Group

SN Wolff1, J Fay2, D Stevens3, RH Herzig4, B Pohlman5, B Bolwell5, J Lynch6, S Ericson6, CO Freytes7, F LeMaistre7, R Collins2, L Pineiro2, J Greer1, R Stein1, SA Goodman1 and S Dummer1

1Vanderbilt University, Nashville, TN; 2Baylor University Medical Center, Dallas, TX; 3University of Louisville, Louisville, KY; 4Jewish Hospital, Cincinnati, OH; 5Cleveland Clinic, Cleveland, OH; 6West Virginia University, Morgantown, WV; and 7University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

Summary: recipients (p Ͻ 0.05). Approximately 44% of all patients were removed from prophylaxis for presumed fungal Systemic fungal infections are a major problem in bone infection. Proven fungal infections occurred in 4.1% marrow transplant recipients who have prolonged neu- and 7.5% of Fluconazole and amphotericin-treated tropenia or who receive high-dose corticosteroids. patients, respectively. Proven fungal infections occurred Prophylaxis with Fluconazole or low-dose amphotericin in 9.1% and 14.3% of related allogeneic marrow recipi- B reduces, but does not eliminate these infections. To ents receiving Fluconazole or amphotericin B, respect- determine which prophylactic agent is better, we perfor- ively, and 2.1% and 5.6% of autologous marrow recipi- med a prospective randomized study. Patients undergo- ents receiving Fluconazole or amphotericin B, ing allogeneic (related or unrelated) or autologous mar- respectively (P Ͼ 0.05). In this prospective trial, low- row or peripheral stem cell transplantation were dose amphotericin B prophylaxis was as effective as Flu- randomized to receive Fluconazole (400 mg/day p.o. or conazole prophylaxis, but Fluconazole was significantly i.v.) or amphotericin B (0.2 mg/kg/day i.v.) beginning 1 better tolerated. Bone Marrow Transplantation (2000) 25, day prior to stem cell transplantation and continuing 853–859. until recovery of neutrophils to Ͼ500/␮l. Patients were Keywords: fungal infection prophylaxis; Fluconazole; removed from their study drug for drug-associated tox- amphotericin B icity, invasive fungal infection or suspected fungal infec- tion (defined as the presence of fever Ͼ38؇C without positive culture while on broad-spectrum anti-bacterial antibiotics). Proven or suspected fungal infections were Intense cytotoxic therapy combined with hematopoietic treated with high-dose amphotericin B (0.5– stem cell rescue is now front-line or salvage treatment for 0.7 mg/kg/day). Patients were randomized at each insti- a variety of malignancies. However, this form of treatment tution and stratified for the type of transplant. The pri- is associated with an abundance of severe side-effects, mary end-point of the study was prevention of docu- either directly from the cytotoxic therapy or arising from mented fungal infection; secondary endpoints included the ensuing myelosuppression.1,2 Foremost among these fungal colonization, drug toxicity, duration of hospi- toxicities is infection associated with neutropenia.3–6 These talization, duration of fever, duration of neutropenia, infectious consequences remain despite reduction in the duration and total dose of high-dose amphotericin B duration of neutropenia with the use of hematopoietic and overall survival to hospital discharge. From July growth factors such as G-CSF or GM-CSF. 1992 to October 1994, a total of 355 patients entered Opportunistic fungal infections were uncommon prior to into the trial with 159 patients randomized to ampho- the initiation of dose-intensive therapy.7 Two clinical situ- tericin B and 196 to Fluconazole. Patient groups were ations predominate – fungemia and dissemination with comparable for diagnosis, age, sex, prior antibiotic or yeast forms and pulmonary infection with hyphal organ- antifungal therapy, use of corticosteroids prior to trans- isms.2,8 The contribution of neutropenia to fungal infections plantation and total duration of neutropenia. Ampho- is noted by approximately a 15% incidence after therapy tericin B was significantly more toxic than Fluconazole of acute leukemia or marrow transplantation.9–11 Fungal especially in related allogeneic transplantation where infections require long-term treatment and even with 19% of patients developed toxicity vs 0% of Fluconazole prompt initiation of therapy, lead to substantial mortality.12 Overall, fungal infections account for more than 50% of infection-related mortality during neutropenia.13 Correspondence: Dr SN Wolff, Bone Marrow Transplant Program, 2617 The standard of therapy for serious fungal infections is TVC, Vanderbilt University, Nashville, TN 37232–5505, USA amphotericin B, although its administration can be limited Received 11 August 1999; accepted 2 November 1999 by side-effects.14 Lipid-associated or liposomal ampho- Fluconazole vs amphotericin B after BMT SN Wolff et al 854 tericin B provides some protection against renal toxicity University of Louisville, Louisville, Kentucky; University and infusion-related chills and fever.15–19 The triazoles are of Texas Health Science Center at San Antonio, San a newer class of anti-fungal agents with a much improved Antonio, Texas; Vanderbilt University, Nashville, Ten- toxicity profile compared with amphotericin B.20 nessee; and West Virginia University, Morgantown, West A number of prophylactic approaches have been Virginia. implemented to protect neutropenic patients from fungal Patients eligible for entry into the trials were required to infections.21–27 One study used low-dose amphotericin B be у18 years old, give written informed consent approved (0.1 mg/kg/day) to prevent fungal infections after autolog- by the treating institution’s IRB, be undergoing dose-inten- ous marrow transplantation and showed a reduction in sive therapy and hematopoietic stem cell (marrow or per- colonization but not invasive infection.28 Aerosolized ipheral blood) transplantation with an anticipated duration amphotericin B, suggested to be useful for prophylaxis, was of neutropenia of at least 10–14 days, have no clinical evi- not confirmed as effective in a randomized evaluation.29,30 dence of infection at the time of study entry, have no known A recent study using 2 mg/kg/day of liposomal ampho- allergy or intolerance to the study drugs, have no laboratory tericin three times a week demonstrated little toxicity, but evidence of significant hepatic or renal dysfunction (defined did not show a significant reduction in fungal infections.31 as a SGOT or SGPT у4 × upper limit of normal, total bili- Three large-scale series have compared Fluconazole and rubin у3 × upper limit of normal and serum creatinine oral placebo, either in patients with acute leukemia or those у2 × upper limit of normal) and not be actively receiving 9–11 undergoing bone marrow transplantation. These trials antibiotics or non-topical anti-fungal therapy with either demonstrated a substantial reduction in the incidence of Fluconazole or amphotericin B. All patients were required colonization and/or invasive fungal infection and showed to receive prophylactic antibiotics active against gram- that Fluconazole is an appropriate agent for fungal prophy- negative bacteria until resolution of neutropenia. The spe- laxis in patients with prolonged neutropenia. However, it cific antibiotic for gram-negative prophylaxis, addition of is still possible that aggressive empiric use of anti-fungals additional antibiotics for fever and the use of prophylactic would be as successful as prophylaxis. Additionally, antibiotics to prevent gram-positive infection was defined amphotericin B is an antifungal with a greater spectrum of by standard care at each treatment center. activity including Aspergillus species and yeast forms, such 32 Fluconazole was administered at a dose of 400 mg/day as Candida kruseii, that are resistant to Fluconazole. orally or intravenously for patients unable to tolerate oral Here, we describe a trial conducted by The North Amer- administration. Amphotericin B was administered intra- ican Marrow Transplant Group (NAMTG) comparing Flu- venously at a daily dose of 0.2 mg/kg (based on ideal body conazole with amphotericin B for antifungal prophylaxis weight) with a maximum dose of 20 mg. Both drugs were in patients undergoing dose-intensive therapy. Our study begun at the conclusion of the cytotoxic therapy (1 day indicates that Fluconazole and amphotericin B have similar prior to stem cell infusion) and continued until recovery of efficacy but Fluconazole is less toxic. neutrophils (Ͼ 500/␮l), unless a severe adverse reaction due to the prophylactic drug occurred. Methods Prophylaxis was stopped and high-dose amphotericin B (0.5–0.7 mg/kg/day) was initiated with documentation of The study was a prospective, randomized, stratified and any proven invasive fungal infection. A proven fungal non-blinded trial comparing antifungal prophylaxis with infection required positive culture from a normally sterile amphotericin B with Fluconazole. Patients were stratified source or histologic evidence of invasive fungal elements in into three groups; matched related allogeneic marrow (allo) tissue section. Empiric high-dose amphotericin B replaced transplants, matched unrelated allogeneic (MUD) trans- prophylactic treatment for suspected fungal infection. Sus- Ͼ ° plants and autologous marrow or stem cell (PBSC) trans- pected fungal infection was defined as fever 38 C per- plants. These strata were chosen due to the anticipated dif- sisting for 3–5 days without positive blood cultures. There ference in fungal infection rate with each type of transplant. were thus three reasons for failure of prophylaxis: (1) Patients were randomized at each study center. adverse event, (2) proved fungal infection and (3) suspected The primary endpoint of the study was the incidence of fungal infection. proven fungal infection. Secondary endpoints were sus- Toxicity was graded using the NAMTG marrow trans- pected fungal infection, duration of fever, duration of hos- plant toxicity system which is similar to the toxicity scale pitalization, duration of absolute neutropenia Ͻ500/␮l, fun- of Bearman et al.33 This system grades toxicities from 0– gal colonization of skin and gastrointestinal tract, use of 4 using the following generalization: grade 0 = none; grade intensified empiric amphotericin B therapy for suspected 1 = mild; grade 2 = severe; grade 3 = life-threatening; and fungal infection, toxicities of anti-fungal prophylaxis, and grade 4 = fatal. In our study, the major toxicity noted was patient survival to the time of hospital discharge. Follow- renal and the definitive scale for this organ system is: up of patients after hospital discharge was not undertaken. These endpoints were established prospectively. Renal grade 0: BUN р20 mg/dl or creatinine р1.4 mg/dl, The trial was conducted by the North American Marrow creatinine clearance Ͼ90% of baseline; Transplant Group, a multi-center collaborative group. The Renal grade 1: BUN 21–40 mg/dl or creatinine = 1.5– following institutions entered patients into the trial: Baylor 2.0 mg/dl creatinine clearance 76–90% University Medical Center, Dallas, Texas; Cleveland of baseline; Clinic, Cleveland, Ohio; Jewish Hospital, Cincinnati, Ohio; Renal grade 2: BUN 41–75 mg/dl or creatinine = 2.1 to

Bone Marrow Transplantation Fluconazole vs amphotericin B after BMT SN Wolff et al 855 4.0 mg/dl, creatinine clearance 50–75% Table 2 Pre-treatment demographics of baseline; Renal grade 3: creatinine clearance Ͻ50% of baseline, Parameter BMT Fluconazole Amphotericin B P BUN Ͼ75 mg/dl or creatinine valuea Ͼ4.0 mg/dl, symptomatic renal failure requiring dialysis, nephrotic syndrome; Age median (range) Allo 41 (21–55) 39 (18–58) Mud 33 (20–41) 34 (30–46) Renal grade 4: fatal renal toxicity. Auto 46 (21–68) 44 (19–59) Total 43 (20–68) 42 (18–59) Sex (male:female)b Allo 27:17 (61.4) 26:16 (61.5) Statistical design and analysis Mud 5:5 (50.0) 4:3 (57.1) Auto 45:97 (31.7) 39:71 (35.5) The trial was designed to detect a 10% difference in fungal Total 77:119 (39.3) 69:90 (43.4) infection incidence (primary endpoint) with an ␣ error of Prior antibacterialsc Allo 5 (11.4) 7 (16.7) 0.05 and ␤ error of 0.10 (power of 90%) assuming the inci- Mud 3 (30.0) 1 (14.3) dence of infection in the inferior group was 15%. A total Auto 16 (12.9) 15 (13.6) of 187 patients were scheduled to enter each treatment arm. Total 24 (12.2) 23 (14.5) Prior antifungalsc Allo 2 (4.5) 1 (2.4) Proportions were compared by the method of Simon and Mud 1 (10.0) 0 (0) required confirmation by chi-square analysis. Group com- Auto 3 (2.1) 0 (0) parison for continuous variables were compared with t-tests Total 6 (3.1) 1 (0.6) or Wilcoxon rank sum test. Prior steroidsc Allo 3 (6.8) 8 (19.0) Mud 3 (30.0) 2 (28.6) Auto 18 (12.7) 8 (7.3) Total 24 (12.2) 18 (11.3) Results Abnormal LFTsc Allo 6 (13.6) 12 (28.6) Mud 1 (10.0) 3 (42.7) From 21 July 1992 to 16 October 1994 a total of 355 Auto 30 (21.1) 20 (18.2) Total 37 (18.9) 35 (22.0) patients were entered into the trial. The distribution of Creatinine median Allo 0.77 (0.5–1.2) 0.91 (0.5–1.4) 0.05 patients at each treatment center and strata is shown in (range) Mud 0.75 (0.4–1.0) 0.73 (0.6–1.0) Table 1. Imbalance at one treatment center (Baylor Univer- Auto 0.83 (0.4–1.6) 0.83 (0.4–2.0) sity Medical Center) was due to a misinterpretation of the Total 0.82 (0.4–1.6) 0.84 (0.4–2.0) autologous randomization codes. Patient diagnoses (data aϾ not shown) were of equal distribution (P Ͼ 0.05) between 0.05 unless otherwise noted. bMale:female with % male in parenthesis. the two prophylactic groups. Additional demographic para- cNumber (percent) within the month before study entry. meters are shown in Table 2. None of these comparisons are statistically different except creatinine (P = 0.05) among related allogeneic recipients receiving amphotericin Overall, 47.4% (95% confidence interval 40.6–54.4%) B (median 0.91 mg/dl, range 0.5–1.4) compared with Flu- and 57.9% (95% confidence interval 50.1–65.3%) of all conazole-treated patients (median 0.77 mg/dl, range 0.5– patients receiving prophylaxis with Fluconazole and 1.2). However, all creatinine values (as required by the amphotericin B respectively, stopped prophylaxis early. eligibility criteria) were normal (р1.4 mg/dl). Therefore, These frequencies did not differ significantly either globally all treatment groups were comparable for pre-treatment fea- or by type of marrow transplant. Duration of prophylaxis tures that could influence development of fungal infection is also shown in Table 3 and did not differ between ampho- or toxicity. tericin B or Fluconazole or by transplant strata. The most critical feature for the development of fungal Table 4 reviews the reasons noted for discontinuation of infection is the duration of neutropenia. Table 3 indicates prophylactic anti-fungal therapy. As shown, 43.9% (95% that the distribution of neutropenia was similar between confidence interval 38.9–49.1%) of all patients had their treatments for all groups and strata. prophylaxis discontinued because of persistent fever while

Table 1 Distribution of patients according to treatment center

Institution Fluconazole Amphotericin B

Allo Mud Auto Total Allo Mud Auto Total

Baylor Medical Center 10 1 57 68 7 2 32 41 Vanderbilt University 20 9 21 50 22 5 20 47 Cleveland Clinic 21 21 21 21 West VA University 6 15 21 3 14 17 Jewish Hospital 2 14 16 3 10 13 UT San Antonio 6 9 15 6 5 11 University of Louisville 5 5 1 8 9

Total 44 10 142 196 42 7 110 159

Bone Marrow Transplantation Fluconazole vs amphotericin B after BMT SN Wolff et al 856 Table 3 Overall results Table 5 Infection-related outcomes

Parameter BMT Fluconazole Amphotericin B Parameter BMT Fluconazole Amphotericin B P valuea Neutropenia duration Allo 17 (3–30)a 17 (2–35) (days)a Mud 16 (7–29) 19 (16–25) Overall invasive Allo 4 (9.1) 6 (14.3) Auto 11 (3–35) 12 (1–56) fungal infectionsb Mud 1 (10) 9 (0.0) Total 13 (3–35) 13 (1–56) Auto 3 (2.1) 6 (5.6) Stopping prohylaxisb Allo 20 (45.5) 23 (54.8) Total 8 (4.1) 12 (7.5) Mud 5 (50) 6 (87.7) With positive Allo 7 (29.2) 9 (48.4) Auto 68 (47.9) 63 (58.3) surveillancec Mud 1 (100) 0 (0) Total 93 (47.4) 92 (57.9) Auto 32 (27.2) 39 (43.8) Ͻ0.01 Prophylaxis duration Allo 13 (4–46) 15 (2–41) Total 40 (27.2) 48 (43.6) Ͻ0.01 (days)a Mud 13 (1–30) 17 (0–20) Therapeutic Allo 9.5 (2–20) 11 (2–43) Auto 13 (1–142) 11 (0–118) Ampho B Mud 15 (2–36) 6 (5–8) Total 13 (1–142) 12 (0–118) duration (days)b Auto 5 (0–49) 5 (1–49) Deaths during treatmentb Allo 11 (25) 12 (28.6) Total 7 (0–49) 5 (1–49) Mud 5 (50) 1 (14.3) Cumulative Ther. Allo 265 (50–7776) 412 (100–2000) Auto 8 (5.6) 6 (5.6) Ampho B dose Mud 350 (75–1100) 237 (165–360) Total 24 (12.2) 19 (11.9) (mg)b Auto 196 (14–2300) 178 (30–1530) Total 221 (14–7776) 210 (30–2000) P value Ͼ0.05 unless otherwise noted. Total duration of Allo 9 (0–28) 8 (0–35) Ͼ ° aMedian (range). fever 38 C Mud 8 (2–27) 6 (3–19) b bNumber (percent). (days) Auto 7 (0–38) 6 (0–52) Total 9 (0–38) 6 (0–52) Duration Allo 39 (19–59) 42 (18–126) hospitalization Mud 51 (31–69) 39 (29–69) Table 4 Reasons noted for stopping prophylaxis (days)b Auto 28 (2–81) 27 (13–75) Total 29 (2–81) 29 (13–126) Type BMT Reason Fluconazole Amphotericin P valuea B aP value Ͼ0.05 unless otherwise noted. bMedian (range). Suspectedb 18 (40.9) 14 (33.3) cNumber (percent) developing positive culture after initial negative cul- Allo Toxicity 0 (0) 8 (19.0) Ͻ0.05 ture; 147 fluconazole and 112 amphotericin B patients underwent surveil- Infection 2 (4.5) 1 (2.4) lance. Suspected 4 (40) 3 (42.9) MUD Toxicity 0 (0) 3 (42.9) Ͻ0.05 Infection 1 (10) 0 (0) icities were six episodes of infusion-related fever and chills Suspected 65 (45.8) 52 (48.1) and one episode of hepatic dysfunction. By contrast, only Ͻ Auto Toxicity 1 (0.7) 9 (8.3) 0.05 one Fluconazole recipient (0.5%, 95% confidence interval Infection 2 (1.4) 2 (1.8) Suspected 87 (44.4) 69 (43.4) 0.1–2.8%) undergoing autologous transplantation Total Toxicity 1 (0.50) 20 (12.6) Ͻ0.05 developed drug toxicity (skin rash) requiring termination of Infection 5 (2.6) 3 (1.9) prophylaxis. In analysis of the individual strata, 19%, 42.9% and 8.3% of patients undergoing allogeneic related, aP value Ͼ0.05 unless otherwise noted. allogeneic unrelated and autologous transplants, respect- b Suspected infection defined as persistent fever while on antibiotics with- ively, developed toxicity while receiving prophylactic out source noted (as described in the Methods section). amphotericin B. The incidence of renal toxicity was 16.3% in all allogeneic recipients and 4.5% in autologous recipi- on broad-spectrum anti-bacterials. Documented fungal ents (P Ͻ 0.05). infection developed during prophylaxis in 2.3% (95% con- Overall, 5.6% (95% confidence intervals of 3.7–8.5%) of fidence interval 1.1–4.4%) including 2.6% and 1.9% the patients entered into the study ultimately developed a (P Ͼ 0.05) of patients receiving Fluconazole or ampho- documented fungal infection including 4.1% and 7.5% tericin B, respectively. Neither the rate of documented fun- (P Ͼ 0.05) of patients receiving Fluconazole or ampho- gal infection nor of suspected fungal infection differed sig- tericin B, respectively (Table 5). These included infections nificantly between Fluconazole or amphotericin B groups noted during and after discontinuation of prophylaxis. The globally or by strata as shown in Table 4. frequency of infection did not differ between prophylactic However, drug toxicity leading to discontinuation of groups or by type of marrow transplantation. Fungal infec- prophylaxis was statistically more frequent in amphotericin tion in recipients of amphotericin B prophylaxis was caused B recipients. Twenty such patients (12.6%, 95% confidence by Candida albicans in eight patients, Candida glabrata interval of 8.3–18.6%) developed toxicity with 13 having in one patient, Candida parapsilosis in two patients and renal toxicity. Renal toxicity was categorized as grade 2 in Aspergillus sp. in one patient. In recipients of Fluconazole nine patients and grade 3 in four. Three patients required prophylaxis, fungal infection was caused by Candida dialysis while receiving amphotericin B. The baseline creat- albicans in two patients, Candida glabrata in three patients, inine values of the 13 patients who developed renal toxicity Candida parapsilosis in one patient, Candida krusei in two were normal with a median of 0.75 mg/dl (range 0.5–1.1) patients and Aspergillus sp. in two patients (two patients and not different from the Fluconazole-treated patients had dual infections with Candida glabrata combined with (median 0.82 mg/dl, range 0.4–1.6). The other seven tox- either Aspergillus sp. or Candida krusei. These infections

Bone Marrow Transplantation Fluconazole vs amphotericin B after BMT SN Wolff et al 857 were predominantly blood stream (15) with the remaining in which Fluconazole was continued into the post- pulmonary (four) and genitourinary (one). engraftment period did show improved survival. Our study, One hundred and ten patients receiving amphotericin B without an untreated control arm, cannot resolve this issue. and 147 patients receiving Fluconazole underwent surveil- Negative aspects of prophylaxis, such as the substantial lance cultures of throat and rectum during prophylaxis. emergence of resistant organisms were not noted in our Forty-eight (43.6%, 95% confidence interval 34.7–53.0%) study. and 40 (27.2%, 95% confidence interval 20.7–34.9%) of The choice of amphotericin B dosing was an important the patients receiving amphotericin B and Fluconazole, aspect of this trial.34 Since our study did not demonstrate respectively, developed a positive surveillance culture the superiority of amphotericin B, it is possible that we during prophylaxis (P Ͻ 0.01). used a ‘sub-optimal’ dose. Supporting this hypothesis is the Death during therapy occurred in 19 patients (11.9%, lack of success of a lipid formulation for prophylaxis when 95% confidence interval 7.8–17.9%) receiving ampho- used at doses less than recommended for therapeutic tericin B and in 24 patients (12.2%, 95% confidence inter- administration.31 It is also possible that we could have achi- val 8.3–17.6%) receiving Fluconazole (P Ͼ 0.05). Causes eved similar efficacy and avoided toxicity with a lower of death included progressive neoplastic disease, toxicity, amphotericin B dose. infection and graft-versus-host disease. Two patients in the The prophylactic use of lipid formulations of ampho- amphotericin B arm (1.3%, 95% confidence interval 0.3– tericin B might overcome the dose-limiting toxicity of con- 4.5%) and five patients in the Fluconazole arm (2.6%, 95% ventional amphotericin B. However, these formulations confidence interval 1.1–5.8%) died directly from a fungal were not readily available during the design of our trial. In infection (P Ͼ 0.05). Data on the duration of therapeutic addition, a comparative trial would have to be massive to amphotericin B, total dose of therapeutic amphotericin B, detect an improvement in the 4.1% rate of fungal infections duration of fever and total duration of hospitalization are seen with Fluconazole prophylaxis. shown in Table 5. Comparison of these values between Fungal infections developed in a total of 5.6% of our recipients of amphotericin B or Fluconazole did not show patients. Most of these infections were due to yeast forms any significant differences. and 19 of the 22 isolates were due to Candida species (10 albicans, two krusei, three parapsilosis and four glabrata). The remainder were due to Aspergillus sp. infections. Thus, Discussion most of these infections were likely to be sensitive to Flu- conazole and Candida krusei was only isolated in two The results of this trial are consistent with other reports patients on the Fluconazole arm. Candida krusei is an showing successful prophylaxis of serious fungal infections uncommon isolate even at centers using Fluconazole after dose-intensive therapy for cancer. Utilizing either Flu- routinely, and one major outbreak was likely due to conazole or amphotericin B, we observed an overall invas- nosocomial spread from a point source.32 ive fungal infection rate of 5.6%. Since we did not have Seventy percent of the patients in our trial underwent an untreated or placebo control group, this number must surveillance cultures, an adequate number for valid obser- be compared to historically-derived data. The incidence of vation. Fluconazole was superior in the prevention of fungal infection seen in this trial is quite similar to the rates colonization with yeasts as detected by oral and rectal sur- (2.8–7.0%) seen in the Fluconazole treatment arms of three veillance cultures. Since this was not associated with a sig- large randomized trials.9–11 In their placebo control arms, nificant reduction in the actual number of invasive infec- these trials had a fungal infection rate of 8.0–18%. tions, its clinical significance is uncertain. Our results are The ultimate aim of our study was to compare the anti- similar to previous reports using Fluconazole.35 fungal efficacy of Fluconazole and amphotericin B. The This trial was not designed to evaluate the prevention results showed therapeutic equivalence. However, ampho- of fungal infections in long-term follow-up. Aspergillosis tericin B was more toxic especially in allogeneic transplant remains the most problematic fungal infection after patients due to a higher rate of renal dysfunction. Consider- engraftment, at least in allogeneic transplant recipients. We ing this toxicity, further evaluation of additional allogeneic had hoped that prophylactic amphotericin B would offer transplant, to increase the statistical power for this group some protection against Aspergillus as suggested in another of patients, would not seem warranted. The increased tox- study.36 However, during the study only three infections icity was likely due to the nephrotoxic effect of combining with Aspergillus were noted, divided between prophylactic amphotericin B with the immunosuppressive agents cyclo- arms. This may have been due to the aggressive use of sporine or tacrolimus. Patients who developed renal toxicity empiric high-dose (0.5–0.7 mg/kg/day) of amphotericin B had normal serum creatinine values (median 0.75 mg/dl, for persistently febrile patients. range 0.5–1.1) prior to initiation of prophylaxis. The requirement for the initiation of therapeutic dose It still remains unclear whether prophylactic approaches amphotericin B was planned using a conventional definition lead directly to improved survival since careful clinical of presumed fungal infection, ie 3–5 days of unexplained observation and rapid institution of empiric anti-fungal fever occurring while patients were receiving broad-spec- therapy will enable most patients to recover, especially with trum anti-bacterial antibiotics. This practice was developed concurrent recovery of neutropenia.10 The study by Good- prior to the widespread use of anti-fungal prophylaxis. In man et al did not show improved overall survival although our study, only 3.4% of patients were proven to have a death due to invasive fungal infection was reduced by fungal infection after discontinuation of prophylaxis. Thus, prophylaxis. On the other hand, the study by Slavin et al11 it is possible that in patients receiving prophylaxis, the

Bone Marrow Transplantation Fluconazole vs amphotericin B after BMT SN Wolff et al 858 introduction of therapeutic doses of amphotericin B could Diseases Mycoses Study Group. New Engl J Med 1999; 340: be delayed for longer durations of fever (eg Ͼ7–10 days) or 764–771. for more definitive criteria (eg pulmonary infiltrates without 16 Pasic S, Flannagan L, Cant AJ. Liposomal amphotericin known bacterial cause).37 (AmBisome) is safe in bone marrow transplantation for pri- In summary, we have demonstrated that low-dose mary immunodeficiency. Bone Marrow Transplant 1997; 19: 1229–1232. amphotericin B (0.2 mg/kg/day) and Fluconazole 17 Chopra R, Fielding A, Goldstone AH. Successful treatment of (400 mg/day) are equivalent for prophylaxis of fungal fungal infections in neutropenic patients with liposomal infection after dose-intensive cytotoxic therapy followed by amphotericin (AmBisome) – a report on 40 cases from a single stem cell transplantation. However, especially in allogeneic centre. Leuk Lymphoma 1992; 7 (Suppl 1): 73–77. transplant recipients, the greater safety of Fluconazole 18 Kruger W, Stockschlader M, Russmann B et al. Experience makes it the preferred agent. with liposomal Amphotericin-B in 60 patients undergoing high-dose therapy and bone marrow or peripheral blood stem cell transplantation. Br J Haematol 1995; 91: 684–690. 19 Kruger W, Stockschlader M, Sobottka I et al. Antimycotic References therapy with liposomal amphotericin-B for patients undergo- ing bone marrow or peripheral blood stem cell transplantation. 1 Khardori N, Bodey, GP. Infections in hematologic malig- Leuk Lymphoma 1997; 24: 491–499. nancies. Hematology 1991; 14: 363–424. 20 Fluconazole. Med Lett 1990; 32: 50–52. 2 Verfaillie C, Weisdorf D, Haake R et al. Candida infections 21 Gotzsche PC, Johansen HK. Meta-analysis of prophylactic or in bone marrow transplant recipients. Bone Marrow Trans- empirical antifungal treatment vs placebo or no treatment in plant 1991; 8: 177–184. patients with cancer complicated by neutropenia. Br Med J 3 Klastersky J. Febrile neutropenia. Curr Opin Oncol 1993; 5: 1997; 314: 1238–1244. 625–632. 22 Ehninger G, Schuler HK, Sarnow E. Fluconazole in the 4 Koll BS, Brown AE. Changing patterns of infections in the prophylaxis of fungal infection after bone marrow transplan- immunocompromised patient with cancer. Hematol/Oncol tation. Mycoses 1996; 39: 259–263. Clin North Am 1993; 7: 753–769. 23 O’Donnell MR, Schmidt GM, Tegtmeier BR et al. Prediction 5 Heurlin N, Bergstrom SE, Winiarski J et al. Fungal pneu- of systemic fungal infection in allogeneic marrow recipients: monia: the predominant lung infection causing death in chil- impact of amphotericin prophylaxis in high-risk patients. J dren undergoing bone marrow transplantation. Acta Paediatr Clin Oncol 1994; 12: 827–834. 1996; 85: 168–172. 24 Powles RL, Milliken S. The prophylaxis of fungal infections. 6 Gamis AS, Gudnason T, Giebink GS, Ramsay NKC. Dissemi- J Antimicrob Chemother 1991; 28 (Suppl. A): 97–103. nated infection with fusarium in recipients of bone marrow 25 Quabeck K, Muller KD, Beelen DW et al. Prophylaxis and transplants. Rev Infect Dis 1991; 13: 1077–1088. treatment of fungal infections with fluconazole in bone mar- 7 Uderzo C, Angelo PD, Rizzari C et al. Central venous cath- row transplant patients. Mycoses 1992; 35: 221–224. eter-related complications after bone marrow transplantation 26 Tollemar J, Ringden O, Andersson S et al. Randomized dou- in children with hematological malignancies. Bone Marrow ble-blind study of liposomal amphotericin B (AmBisome) Transplant 9 1991; : 113–117. prophylaxis of invasive fungal infections in bone marrow 8 Guiot HF, Fibbe WE, van’t Wout JW. Risk factors for fungal transplant recipients. Bone Marrow Transplant 1993; 12: infection in patients with malignant hematologic disorders: 577–582. implications for empirical therapy and prophylaxis. Clin Infect 27 Ringden O, Andstrom EE, Remberger M et al. Prophylaxis Dis 1994; 18: 525–532. and therapy using liposomal amphotericin B (AmBisome) for 9 Goodman JL, Winston DJ, Greenfield RA et al. A controlled invasive fungal infections in children undergoing organ or trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. New Engl J Med allogeneic bone-marrow transplantation. Pediatr Transplant 1992; 326: 845–851. 1997; 1: 124–129. 10 Winston DJ, Chandrasekar PH, Lazarus HM et al. Fluconazole 28 Perfect JR, Klotman ME, Gilbert CC et al, Prophylactic intra- prophylaxis of fungal infections in patients with acute leuke- venous Amphotericin B in neutropenic autologous bone mar- mia. Results of a randomized placebo-controlled, double- row transplant recipients. J Infect Dis 1992; 165: 891–897. blind, multicenter trial. Ann Intern Med 1993; 118: 495–503. 29 Schwartz S, Behre G, Heinemann V et al. Aerosolized ampho- 11 Slavin MA, Osborne B, Adams R et al. Efficacy and safety tericin B inhalations as prophylaxis of invasive aspergillus of fluconazole prophylaxis for fungal infections after marrow infections during prolonged neutropenia: results of a prospec- transplantation – a prospective, randomized, double-blind tive randomized multicenter trial. Blood 1999; 93: 3654–3661. study. J Infect Dis 1995; 171: 1545–1552. 30 Hertenstein B, Kern WV, Schmeiser T et al. Low incidence of 12 Kruger W, Sobottka I, Stockschlader M et al. Fatal outcome invasive fungal infections after bone marrow transplantation in of disseminated candidosis after allogeneic bone marrow patients receiving amphotericin B inhalations during neutro- transplantation under treatment with liposomal and conven- penia. Ann Hematol 1994; 68: 21–26. tional amphotericin-B. A report of 4 cases with determination 31 Kelsey SM, Goldman JM, McCann S et al. Liposomal ampho- of the Mic values. Scand J Infect Dis 1996; 28: 313–316. tericin (AmBisome) in the prophylaxis of fungal infections 13 Jehu V. Managing fungal and viral infections in the immuno- in neutropenic patients: a randomised, double-blind, placebo- compromised host. Rec Res Cancer Res 1988; 108: 61–70. controlled study. Bone Marrow Transplant 1999; 23: 163– 14 Winston DJ. Prophylaxis and treatment of infection in the 168. bone marrow transplant recipient. Curr Clin Topics Infect Dis 32 Wingard JR, Merz WG, Rinaldi MG et al. Increase in Candida 1993; 13: 293–321. krusei infection among patients with bone marrow transplan- 15 Walsh TJ, Finberg RW, Arndt C et al. Liposomal ampho- tation and neutropenia treated prophylactically with flucona- tericin B for empirical therapy in patients with persistent fever zole. New Engl J Med 1991; 325: 1274–1277. and neutropenia. National Institute of Allergy and Infectious 33 Bearman SI, Appelbaum FR, Buckner CD et al. Regimen-

Bone Marrow Transplantation Fluconazole vs amphotericin B after BMT SN Wolff et al 859 related toxicity in patients undergoing bone marrow transplan- 36 Rousey SR, Russler S, Gottlieb M, Ash RC, Low-dose ampho- tation. J Clin Oncol 1988; 6: 1562–1568. tericin B prophylaxis against invasive aspergillus infections in 34 De Laurenzi A, Matteocci A, Lanti A et al. Amphotericin B allogeneic marrow transplantation. Am J Med 1991; 91: prophylaxis against invasive fungal infections in neutropenic 484–492. patients: a single center experience from 1980 to 1995. Infec- 37 Chandrasekar PH, Gatny CM. Effect of fluconazole prophy- tion 1996; 24: 361–366. laxis on fever and use of amphotericin in neutropenic cancer 35 Chandrasekar PH, Gatny CM, The effect of fluconazole patients. Bone Marrow Transplantation Team. Chemotherapy prophylaxis on fungal colonization in neutropenic cancer 1994; 40: 136–143. patients. Bone Marrow Transplantation Team. J Antimicrob Chemother 1994; 33: 309–318.

Bone Marrow Transplantation