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.