Brief report: practicability and safety of amphotericin B deoxycholate as continuous infusion in neutropenic patients with hematological malignancies

Fungal infections are a major cause of morbidity and mortality in patients with hematological malignancies. Candida and Aspergillus species are the most important opportunistic fungal pathogens in this patient population. Amphotericin B is the treatment of choice, but its administration is often hampered by severe side-effects, which may be reduced by continuous infusion of this drug. We describe 17 consecutive patients with hematological malignancies, suffering from fever of unknown origin with possible fungal infections, treated with amphotericin B as continuous infusion compared with a control group of 10 patients treated with conventional rapid infusion of amphotericin B over 2 - 6 h. No acute side-effects or severe nephrotoxicity were observed during continuous infusion of amphotericin B. Target doses were reached faster in patients with continuous infusion of amphotericin B than in patients with rapid infusion. We conclude that continuous infusion of amphotericin B is safe in neutropenic patients with hematological malignancies.     

Evaluation of semisolid agar screening tests for determining fluconazole and amphotericin B susceptibilities of Candida strains by using three different media

The susceptibilities of 164 Candida isolates against fluconazole and amphotericin B were determined by semisolid agar screening tests and the microdilution method according to NCCLS M27-A standards. The semisolid agar screening tests were performed with three different media containing 0.5% agar and 2, 8, and 40 microg/ml of fluconazole or 0.5 and 2.0 microg/ml of amphotericin B. These media were MOPS buffered RPMI 1640, brain-heart infusion and 1/3 diluted Sabouraud dextrose agar. The results of both methods were interpreted as susceptible, dose dependent susceptible and resistant for fluconazole and susceptible and resistant for amphotericin B. The agreement rates of semisolid agar screening tests using RPMI 1640, brain-heart infusion and Sabouraud dextrose media with the reference microdilution method were found to be 71.4%, 51.2%, and 57.3% for fluconazole and 79.3%, 53.7%, and 56.7% for amphotericin B, respectively. Overall, we conclude that semisolid agar screening tests using RPMI 1640 can be used for determining the susceptibilities of Candida isolates against fluconazole and amphotericin B in clinical microbiology laboratories.     

三肽化合物酪丝缬肽对小鼠黑色素瘤细胞B16-F10侵袭和转移的抑制作用

背景与目的:三肽化合物酪丝缬肽(tyroservaltide,YSV)对实验性肝癌具有明显抑制作用,本研究观察YSV对小鼠黑色素瘤细胞B16-F10侵袭和转移的抑制作用。方法:MTT法检测YSV对B16-F10的细胞毒作用;利用基质胶Matrigel研究YSV对细胞粘附能力的影响;用Transwell小室侵袭模型研究YSV对肿瘤细胞侵袭能力的改变;经C57/BL6小鼠尾静脉注射B16-F10细胞,建立人工肺转移模型,观察YSV对B16-F10肺转移的影响;免疫组化方法观察YSV对细胞间粘附分子(intercellularadhesionmolecule-1,ICAM-1)在肺组织中表达水平的影响。结果:100μg/mlYSV作用48h对B16-F10细胞的增殖抑制率为24.36%;作用24h对B16-F10细胞在Matrigel胶上的粘附抑制率为36.51%;10μg/mlYSV作用48h对B16-F10细胞的侵袭抑制率为36.53%;640μg·(kg·d)-1YSV抑制B16-F10的肺转移,抑制率为62.21%;YSV组ICAM-1的组织量明显少于生理盐水组。结论:YSV具有抑制B16-F10生长和侵袭转移的作用。     

Deoxycholate amphotericin B and amphotericin B lipid complex exert additive antifungal activity in combination with pulmonary alveolar macrophages against Fusarium solani

Fusarium spp. have emerged as important causes of invasive fungal infections in immunocompromised patients. Rabbit pulmonary alveolar macrophages (PAMs) exhibited fungicidal activity against conidia of Fusarium solani and achieved a time-dependent increase in killing. Neither deoxycholate amphotericin B (DAMB) nor amphotericin B lipid complex (ABLC) exerted a suppressive effect on PAMs by decreasing their conidiocidal activity against F. solani. On the contrary, at a concentration of 0.125 microg ml(-1), ABLC and, to a lesser degree, DAMB additively augmented the fungicidal activity of pulmonary alveolar macrophages against conidia of Fusarium solani.     

In vitro activity (MIC and MFC) of voriconazole, amphotericin B, and itraconazole against 192 filamentous fungi: the GISIA-2 study

We evaluated the in vitro activity of voriconazole, amphotericin B, and itraconazole against 192 clinical mould isolates recovered in twenty Italian microbiology laboratories. The vast majority of isolates belonged to the genus Aspergillus (94.2%) with A. fumigatus (58.3%) being the most frequently isolated species. Antifungal susceptibility testing was performed using the broth microdilution method defined by the CLSI M38-A standard, and results were compared to those obtained with Sensititre panels. Aspergillus flavus ATCC 204304 was employed as reference strain and results were within all expected ranges. Voriconazole's activity against the 192 mould isolates was comparable to that of amphotericin B and itraconazole: voriconazole MIC90 (CLSI 1 microg/ml, Sensititre 1 microg/ml), itraconazole MIC90 (CLSI 0.5 microg/ml, Sensititre 0.5 microg/ml), amphotericin B MIC90 (CLSI 1 microg/ml, Sensititre 1 microg/ml). In conclusion, these in vitro data highlight voriconazole's broad spectrum activity against filamentous fungi and support its use as a first line agent for the treatment of fungal diseases.     

In vitro testing of Aspergillus fumigatus clinical isolates for susceptibility to voriconazole, amphotericin B and itraconazole: comparison of sensititre versus NCCLS M38-A using two different inocula

Voriconazole, amphotericin B and itraconazole were tested in vitro against 18 strains of Aspergillus fumigatus isolated from cystic fibrosis patients. Susceptibility was tested with the broth microdilution method (M38-A protocol-NCCLS). Results of this reference method were compared with those of an experimental commercial microdilution broth method (Sensititre). Two different inocula, prepared from 2- and 7-day cultures, were used. Minimum inhibitory concentrations (MICs) of the reference method ranged from 0.25 to 2 microg/ml for voriconazole, 0.06 to 1 microg/ml for amphotericin B, 0.016 to >16 microg/ml for itraconazole. There were no significant differences in the MIC ranges or MIC90 values obtained with the two testing methods or with the two types of inocula. These findings confirm the good in vitro activity of voriconazole, itraconazole and amphotericin B against A. fumigatus. They also indicate that reliable susceptibility data can be generated more rapidly by commercial systems and use of 2-day cultures for inoculum preparation.     

Antifungal activity of voriconazole (UK-109,496), fluconazole and amphotericin B against hematogenous Candida krusei infection in neutropenic guinea pig model

Voriconazole (UK-109,496) is a new triazole with in vitro activity against a wide spectrum of fungi including yeasts intrinsically resistant to fluconazole such as Candida krusei. In this study the efficacy of voriconazole was compared to amphotericin B and fluconazole in a neutropenic guinea pig model of hematogenously disseminated C. krusei infection. In guinea pigs, neutropenia was established by using cyclophosphamide (intraperitoneally, i.p., 100 mg/kg on day 1 and 4), and dexamethasone (orally, 2 mg/kg/day, for 8 days). Neutropenic guinea pigs were infected with 0.5 ml of yeast cell suspension (1 x 10(8) CFU) intravenously. Challenged animals were treated with antifungals starting 1 h postinfection for 7 days. The animals were divided into five groups: untreated control, amphotericin B (1 mg/kg i.p. on alternate days), fluconazole (20 mg/kg orally twice daily), and voriconazole (two groups: 5 and 10 mg/kg orally twice daily) groups. Guinea pigs were sacrificed 1 day after the last treatment. Brain, liver, and kidneys were removed and weighed, tissues were homogenized and fungal burden determined by serial quantitative counts. Voriconazole at dosages of 5 or 10 mg/kg b.i.d. was shown to be significantly more efficacious than either amphotericin B or fluconazole in eradicating C. krusei from brain, liver and kidney tissue. These data indicate that voriconazole could be efficacious for the treatment of infections caused by fluconazole-resistant Candida, such as C. krusei.     

Pancreatic toxicity after liposomal amphotericin B

Though liposomal amphotericin B has been available in Germany since 1992, efficacy and safety of this formulation of amphotericin B are still not well-documented in children. As far as gastrointestinal side-effects are concerned, an elevated alkaline phosphatase and elevated transaminases have been reported. In our department, liposomal amphotericin B had been used since 1994 to treat patients with proven or suspected fungal infections in a daily dose of 1-3 mg kg-1. Additionally, patients with high-dose chemotherapy and autologous stem cell support received liposomal amphotericin B prophylactically in a dose of 1 mg kg(-1) three times per week. We performed a retrospective analysis of all 31 patients who had received liposomal amphotericin B by 1999. In five patients, an isolated transient elevation of the serum lipase level during, or shortly after, the therapy with liposomal amphotericin B was detected. Three of these patients showed clinical signs of pancreatitis, with one patient displaying slightly elevated transaminases. So far, elevated levels of serum lipase have not been described as a possible side-effect of a liposomal amphotericin B therapy. The pathogenesis of this elevation is unclear. As possible reasons, an enzyme induction due to fat overload or a toxic damage of the pancreatic tissue by the liposomes or amphotericin B itself are discussed.     

Emergence of resistance to amphotericin B and triazoles in Candida glabrata vaginal isolates in a case of recurrent vaginitis

Emergence of resistance to triazoles and amphotericin B in Candida glabrata vaginal isolates is documented by Etest. During the 18-month follow-up of a case of vaginitis, 14 consecutive isolates of C. glabrata were examined. The isolates exhibited development of in vitro resistance beginning with itraconazole (>32 microg/ml), followed by fluconazole (>256 microg/ml), amphotericin B (>32 microg/ml), and voriconazole (>32 microg/ml). The DNA sequence analyses and finger printing of the isolates strongly suggest that our patient remained colonized with a single strain. The report underscores the propensity of C. glabrata to acquire resistance during antifungal therapy and the importance of susceptibility testing in the management of infections caused by this species.     

Early empiric antifungal therapy of infections in neutropenic patients comparing fluconazole with amphotericin B/flucytosine

We compared the efficacy and tolerability of fluconazole (FCA) with amphotericin B/flucytosine (ABF) in neutropenic patients with haematological malignancies. Antifungal therapy started on day 4 when fever was unresponsive to antibiotics or on day 1 together with the antibiotics, if there was evidence of mycosis. If patients did not respond to FCA after 7 days they switched to ABF. 98 patients, 51 FCA and 47 ABF were included in the study. Response to fever was achieved in 28/51 FCA patients and in another 16 after switching to ABF. So in overall 44/51 (86.2%) of the FCA and 37/47 (78.8%) of the ABF group defervescence was observed. 46 patients (21 FCA, 25 ABF) developed radiological signs of pneumonia. Resolution of infiltrates was achieved in 5/21 FCA and 20/25 ABF patients, and another 10 of 15 initially not responding patients showed regression when switched to ABF, 5 of these had highly suspected aspergillosis. Adverse events occurred in 19.6% of FCA and 97.9% of ABF patients. In conclusion fluconazole and amphotericin B/flucytosine seem to be equally effective. In view of its lower toxicity fluconazole may be preferred as first line empiric antifungal agent, but in case of nonresponse, pneumonia or aspergillosis it may be replaced by amphotericin B combined with flucytosine.     

In vitro activities of voriconazole (UK-109, 496), fluconazole, itraconazole and amphotericin B against 132 non-albicans bloodstream yeast isolates (CANARI study)

The aim was to evaluate the in vitro activity of voriconazole compared with those of amphotericin B, itraconazole and fluconazole against 132 bloodstream isolates of Candida non-albicans and Saccharomyces cerevisiae species. The minimal inhibitory concentrations (MICs) were determined by an adapted National Committee for Clinical Laboratory Standards (NCCLS) M27-A method using RPMI 1640 as test medium supplemented with 2% glucose. MIC end-points were determined with a spectrophotometer after incubation for 48 h at 35 degrees C. Optical density data were used for the calculation of the MIC end-points. For amphotericin B, the end-point was defined as the minimal antifungal concentration that exerts 90% inhibition compared with the control well growth. For the azoles, the end-points were determined at 50% inhibition of growth. Amphotericin B is highly active with 97% of isolates inhibited by < or =1 microg ml(-1). Decreased susceptibility or resistance to fluconazole was the rule among C. krusei, which is intrinsically resistant to fluconazole. For C. glabrata isolates, resistance to fluconazole and itraconazole was measured in 13% and 17% of the isolates respectively. Voriconazole was quite active in vitro against all the isolates with a MIC90% of < or =1 microg ml(-1) and we conclude that it may be useful in the treatment of non-albicans bloodstream infections.     

A comparative study of the efficacy and safety of fluconazole oral suspension and amphotericin B oral suspension in cancer patients with mucositis

This randomized study compared the efficacy and safety of fluconazole suspension with that of amphotericin B suspension in patients with head and neck cancer who were suffering from candidiasis during cancer treatment with radiotherapy and/or chemotherapy. A total of 123 evaluable patients received 50 mg fluconazole once daily and 120 evaluable patients received 0.5 g amphotericin B thrice daily for 7-14 days depending on clinical response. A positive culture result was obtained in 121 of 264 (46%) patients; Candida albicans was most common. At the end of treatment, fluconazole and amphotericin B were equivalent (CI(90) of -10.7 to +14.9) in terms of clinical cure and improvement, but the rate of mycologic cure was higher for fluconazole (48%) than amphotericin B (35%). The incidence of adverse events was 39% for fluconazole and 44% for amphotericin B. Fluconazole suspension appeared effective and safe.     

A retrospective clinical comparison between antifungal treatment with liposomal amphotericin B (AmBisome) and conventional amphotericin B in transplant recipients

Invasive fungal infections are an important cause of morbidity and mortality in immunosuppressed bone marrow and solid organ transplant recipients. Treatment with amphotericin B, the drug of choice for these infections, is however often limited by toxicity. Ten transplant patients receiving a liposomal amphotericin B formulation (AmBisome) were compared to ten retrospective control patients given conventional amphotericin B. Each group included bone marrow (8), kidney (1), and liver transplant (1) recipients. Conventional amphotericin B treatment was instituted due to nine Candida infections, and one Aspergillus fumigatus infection. In the AmBisome group treatment was instituted due to eight Candida infections, one infection caused by Saccharomyces cerevisiae and in one case as prophylactic treatment. In the amphotericin B group, maximal daily doses ranged from 0.1 to 0.65 mg kg-1 and cumulative doses were 21-836 mg kg-1 and were given over 3-32 days. In the AmBisome group, maximal daily doses ranged from 0.9 to 2.3 mg kg-1 and cumulative doses ranged from 225 to 3525 mg kg-1 over 8-28 days. All patients in the amphotericin B group experienced severe toxicity, especially nephrotoxicity which in four cases caused withdrawal of the drug. In contrast, the only adverse reaction in the AmBisome group was cholestasis in one patient. Only three out of ten patients in the amphotericin B group responded to treatment, seven patients died and six patients still had evidence of invasive fungal infection at autopsy. In contrast, eight out of nine patients in the AmBisome group responded to treatment, and the patient that received prophylaxis had a successful course.     

In vitro antifungal susceptibility testing of filamentous fungi with Sensititre Yeast One

Sensititre is a colorimetric microdilution method for in vitro antifungal susceptibility testing based on the M27-A document (National Committee for Clinical Laboratory Standards) for yeasts. Difference between both methods is the presence of Alamar-blue and RPMI 1640 (glucose 2%) as culture medium. Antifungal susceptibility to amphotericin B, fluconazole, itraconazole, ketoconazole and flucytosine, 100 opportunistic filamentous fungi (Aspergillus spp., Fusarium spp., Scedosporium spp.) obtained from pathological samples was determined by the Sensititre method. Induction to conidium and sporangiospore formation at 35 degrees C was used to get inoculum and plates were covered by 1 ml of saline and suspensions were made by gently probing by a sterile loop. Optical densities of the conidial suspensions were adjusted to 80-82% transmittance for Aspergillus spp. and 68-70% for the rest of strains tested. Final inoculum concentration size was 0.4 x 10(4)-5 x 10(4) CFU ml(-1). Readings were made at 72 h of incubation at 35 degrees C; amphotericin B and itraconazole was active against Aspergillus fumigatus with CMI90 1 and 0.5 microg ml(-1), respectively, opposite to Scedosporium prolificans and Scedosporium apiospermum. As it was expected, a CMI90 of 256 microg ml(-1) for fluconazole and CMI90 for flucytosine amounting to 64 g ml(-1) were obtained. Sensititre Yeast One is a useful method and an alternative to reference methods to determine antifungal susceptibility of filamentous fungi for clinical laboratory routine. Correlation with microdilution results is studied. New triazole derivatives should be included as soon as their clinical use will be feasible.     

Phase II study of 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU, NSC No. 409962) with amphotericin B in bronchogenic carcinoma

Eighteen patients with unresectable bronchogenic carcinoma were treated with amphotericin B (7.5 mg/m2 on day 1, 15 mg/m2 on day 2, and 30 mg/m2 on days 3 and 4) plus BCNU (250 mg/m2 on day 4 following amphotericin B) with courses of therapy repeated every 8 weeks. All patients had metastatic disease, and 5 had received prior chemotherapy. Antitumor responses were observed in 8 patients. Six patients had partial responses (greater than 50% decrease in tumor area): 1 of 3 with small cell undifferentiated carcinoma, 1 of 4 patients with large cell undifferentiated carcinoma, 2 of 7 patients with adenocarcinoma, and 2 of 4 patients with epidermoid carcinoma. Two patients had objective improvement (25--50% decrease in tumor area): 1 with small cell undifferentiated carcinoma and 1 with epidermoid carcinoma. The median duration of remission was 3 months. The median duration of survival was 7 months for patients achieving partial response, and only 2 months for other patients. Myelosuppression was the dose limiting toxicity. One patient died with hepatocellular dysfunction, possibly related to BCNU. Transient hypotension was observed in 2 patients. We conclude that amphotericin B plus BCNU produced an encouragingly high response rate in patients with bronchogenic carcinoma, and that a randomized phase III trial is warranted to determine whether amphotericin B enhances the antitumor effects of nitrosoureas or other known antitumor agents.     

Review of comparative studies between conventional and liposomal amphotericin B (Ambisome) in neutropenic patients with fever of unknown origin and patients with systemic mycosis

Fungal infections are an important cause of morbidity and mortality in immunocompromised patients. Treatment with amphotericin B is the main therapeutic approach. However, this treatment is limited by the substantial toxicity. We present the data of the first randomized prospective comparative trial in adults (134 patients with fever of unknown origin) with conventional amphotericin B and a liposomal formulation of amphotericin B (AmBisome, published in 1997 by Prentice et al. (Br. J. Haematol. 98, 711-718) and the data of adults with documented fungal infections (59 patients), treated in this trial. Patients received either conventional amphotericin B 1 mg kg-1 per day, liposomal amphotericin B 1 mg kg-1 per day or liposomal amphotericin B 3 mg kg-1 per day. Patients were entered if they had fever of unknown origin (FUO), defined as temperature of 38 degrees C or more, not responding to 96 h of systemic broad-spectrum antibiotic treatment, and neutropenia (< 0.5 x 10(9) l-1). Efficacy of treatment was assessed, with success defined as resolution of fever for three consecutive days (< 38 degrees C) in the group of patients with FUO and the freedom of clinical signs and/or the elimination of fungus in the group of patients with documented fungal infections. The safety of treatment and renal and hepatic toxicity of liposomal and conventional amphotericin B were compared. No statistically significant difference was found in the treatment efficacy in the three study arms. However, there is a tendency of better treatment results in the two groups of patients, who received liposomal amphotericin B. Thirty-five per cent of patients with documented fungal infections and 46% of patients with FUO responded to amphotericin B. In the patients group, that received 1 mg kg-1 liposomal amphotericin B it was 63 and 49%, in the group of patients that received 3 mg kg-1 liposomal amphotericin B it was 47 and 64%. Evidence of toxicity due to amphotericin B was seen in 50 patients (83%), toxicity due to liposomal amphotericin B, 1 mg kg-1, was seen in 35 patients (50%), and due to liposomal amphotericin B 3 mg kg-1 in 34 patients (54%). This was a statistically significant difference (P = 0.001). It was concluded that liposomal amphotericin B was safer than conventional amphotericin B, but both formulations are equivalent in treatment efficacy. The prophylactic use of amphotericin B in these immunocompromised patients is discussed.     

A co-operative study on prophylactic effect of oral administration of high-dose amphotericin B syrup for systemic fungal infection in patients with hematological neoplasms. Chugoku-Shikoku Study Group of Mycosis with Hematologic Disease

The prophylactic effect of the oral administration of high-dose amphotericin B syrup for the systemic fungal infection was studied in 36 patients with hematological neoplasms. Twenty nine patients received 2,400 mg/day of Amphotericin B syrup for during the remission induction therapy. One patient received 1,200 mg/day, 3 received 800 mg/day and 3 received 400 mg/day of Amphotericin B syrup. The prophylactic effect was recognized in 24 of 36 patients, 66.7%. As adverse effects gastrointestinal symptoms such as nausea and vomiting, hypochloremia and hypopotassemia associated with hypochloremia was observed in one patient, respectively, however, they were all controllable. The blood levels of Amphotericin B in patients received 2,400 mg/day was 0.092 +/- 0.055 micrograms/ml (n = 40) on 7th day and 0.110 +/- 0.046 micrograms/ml (n = 21) on 28th day, respectively. The administration of high-dose of Amphotericin B syrup is expected not only for the prophylaxis but also for the treatment of the systemic fungal infection.     

Diffusion of oral and intravenous 400 mg once-daily moxifloxacin into lung tissue at pharmacokinetic steady-state

The degree of penetration of an antibiotic into the infection site is an important factor for its therapeutic efficacy, particularly in respiratory tract infections. In the present study, we examined the lung tissue diffusion of moxifloxacin at a dose of 400 mg administered intravenously or orally once-daily, and the results were correlated to microbiological data to estimate the clinical efficacy of moxifloxacin in lower community-acquired respiratory infections. This was a prospective, randomized, parallel-group trial, open-label, single-center study. Patients undergoing lung surgery for bronchial cancer which necessitates the removal of an anatomical piece of lung tissue were randomized into twelve treatment groups, dependent upon the time of surgery and the moxifloxacin formulation, i.v. or oral, administered. During surgery, one blood sample was taken at the time of tissue collection to determine moxifloxacin plasma concentration. At the same time, tissue samples were taken by pulmonary exeresis. A validated new high performance liquid chromatography assay was used to determine moxifloxacin concentrations in plasma and lung tissue. A total of 49 patients (25 for i.v. administration, 24 for oral administration, 44 men and 5 women, mean age, 61 years, mean body weight, 72 kg, mean creatinine clearance was 84 ml/min/1.73 m2) were enrolled. The mean +/- SD steady-state moxifloxacin ratios between lung and plasma concentrations were respectively: 3.53 +/- 1.89 and 4.36 +/- 1.48 for i.v. and oral administration. The mean steady-state moxifloxacin maximal lung concentrations (Cmax) were respectively 12.37 microg/g and 16.21 microg/g for i.v. and oral administration. Moxifloxacin both intravenously and orally exhibits high penetration in lung tissue, with tissue concentrations far above the MIC90s for most of the susceptible pathogens commonly involved, thus underlining its suitability for the treatment of community-acquired, lower respiratory tract infections.     

Augmentation of production of TNF-alpha and anti-tumour activity by an amphotericin B preparation for clinical use in mice.

Effects of amphotericin B on production of endogenous tumour necrosis factor alpha (TNF-alpha) and anti-tumour activity in mice was examined. Intravenous administration of Fungizone, an amphotericin B preparation complexed with deoxycholate, augmented the induction of endogenous TNF in response to a second stimulus with intravenous doses of FK23 (heat-killed Enterococcus faecalis). This augmentation was observed when more than 1.8 microg of Fungizone was injected intravenously before intravenous dosing of FK23. The time interval between priming injection of Fungizone and secondary injection of FK23 for the maximal effect was 3 h. Similar augmentation of TNF production was also observed in amphotericin B-primed and FK23-injected mice. Correspondingly, anti-tumour activity of the combined, intravenous injection of Fungizone and FK23 with a 3-h interval was examined. Growth of Meth A fibrosarcoma was clearly inhibited by this combination but not by administration of either one alone. These results suggest that amphotericin B is able to elicit anti-tumour activity, perhaps through activation of the immune system, and in particular augmentation of the induction of endogenous TNF.     

Pharmacoeconomic analysis of liposomal amphotericin B versus conventional amphotericin B in the empirical treatment of persistently febrile neutropenic patients.

PURPOSE: In a randomized, double-blind, comparative, multicenter trial, liposomal amphotericin B was equivalent to conventional amphotericin B for empirical antifungal therapy in febrile neutropenic patients, using a composite end point, but was more effective in reducing proven emergent fungal infections, infusion-related toxicities, and nephrotoxicity. The purpose of this study was to compare the pharmacoeconomics of liposomal versus conventional therapy. PATIENTS AND METHODS: Itemized hospital billing data were collected on 414 patients from 19 of the 32 centers that participated in the trial. Hospital length of stay and costs from the first dose of study medication to the time of hospital discharge were assessed. RESULTS: Hospital costs from the time of first dose to discharge were significantly higher for all patients who received liposomal amphotericin B ($48,962 v $43,183; P =.022). However, hospital costs were highly sensitive to the cost of study medication ($39,648 v $43,048 when drug costs were not included; P =.416). Using decision analysis models and sensitivity analyses to vary the cost of study medications and the risk of nephrotoxicity, the break-even points for the cost of liposomal therapy were calculated to range from $72 to $87 per 50 mg for all patients and $83 to $112 per 50 mg in allogeneic bone marrow transplant patients. CONCLUSION: The cost of liposomal amphotericin B and patient risk for developing nephrotoxicity play large roles in determining whether liposomal amphotericin B is cost-effective as first-line empirical therapy in persistently febrile neutropenic patients.