British Journal of Haematology, 1998, 103, 198204

A comparative analysis of lipid-complexed and liposomal amphotericin B preparations in haematological oncology

A. D. C LA RK , S. M C K E ND R I C K , P. J. TA N S E Y, I. M. F RA N KL I N A ND R. C HOP RA * Glasgow Royal Inrmary, Glasgow, and *Christie Hospital, Manchester Received 9 March 1998; accepted for publication 30 June 1998

Summary. No comparative clinical information on the properties of lipid-associated amphotericin preparations is presently available. In this single-centre retrospective analysis over a 5-year period the indications, efcacy and toxicity of true liposomal amphotericin (AmBisome) were compared with a lipid complexed preparation (Abelcet). In a novel approach APACHE III scores were used in addition to neutrophil counts, disease status and additional immunosuppression to accurately assess the severity of illness in both groups and enable valid comparison. Overall, AmBisome at a

median dose of 19 mg/kg/d was found to have similar clinical outcome to Abelcet at a median dose of 48 mg/kg/d. Nephrotoxicity and electrolyte abnormalities were similar in both groups. Rigors and febrile episodes were more common with Abelcet. Prospective randomized comparative trials are required to clarify the optimum dosages and therapeutic and economic issues associated with these agents. Keywords: Abelcet, AmBisome, liposomes, lipid complex, fungal infection.

The incidence of systemic fungal infections in neutropenic patients is high and a substantial number are not diagnosed antemortem (Beck Sague & Jarvis, 1993; Bodey et al, 1992; Jantunen et al, 1997). This realization has meant that more patients are now being treated empirically with parenteral antifungal agents. Amphotericin has for many years been the gold standard in treating systemic fungal infection. However, its usage is limited by toxicity, primarily nephrotoxicity (Pizzo, 1993). Over the last decade lipid-associated preparations have become available, which complex amphotericin with lipids, to which this drug has an afnity intermediate between fungal ergosterol, highest afnity, and human cholesterol, lowest afnity (de Marie et al, 1994; Janoff et al, 1993; Ringden et al, 1991; Leenders & de Marie, 1996; Hillery, 1997). This plays a part in reducing the toxicity of the drug and enables higher dosages of amphotericin to be administered. Theoretically this may increase the therapeutic index. The pharmacokinetic and pharmacodynamic properties of these preparations differ and this has led to speculation about the putative efcacy of the different agents (Janknegt et al, 1992; Adler Moore, 1994; Mehta, 1997; Richardson, 1997). Information exists from comparative trials of lipid

formulations and conventional amphotericin (Prentice et al, 1997) but there is a paucity of data concerning comparison between lipid complexed and true liposomal amphotericin. It is possible that one preparation may be clearly superior to another or that they may exhibit a different spectrum of activity related to host- or pathogen-specic factors such as macrophage or fungal phospholipase production (Hiemenz & Walsh, 1996). Alternatively, there may be no difference in efcacy and the choice of drug would then be based on economic considerations and side-effect proles. We have analysed the usage of two such preparations in a single centre over a 5-year period (199297). Initially AmBisome was used as the lipid preparation of amphotericin. As a result of perceived cost considerations, Abelcet replaced AmBisome as the rst-line lipid formulation of amphotericin for the second half of the study period.

PATIENTS AND METHODS Patient selection and details. Between October 1992 and January 1997, 59 adult patients received 68 treatment courses of either liposomal amphotericin (AmBisome), n 32, or lipid complex amphotericin (Abelcet), n 36. AmBisome was the lipid preparation of choice from the start of the study period until February 1995; Abelcet was then used for the remainder of the period. The underlying
1998 Blackwell Science Ltd

Correspondence: Dr Andrew D. Clark, Academic Transfusion Medicine Unit, Department of Medicine, University of Glasgow, Royal Inrmary, 10 Alexandra Parade, Glasgow G31 2ER.

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Table I. Patient characteristics.

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Abelcet Male Female Median age Aetiology CML AML ALL CLL NHL Myeloma Hairy cell leukaemia Aplastic anaemia Breast Biphenoleukaemia Treatment Matched unrelated Allogeneic Autologous Chemotherapy 27 9 42 11 7 1 1 3 10 1 1 0 1 7 7 14 8

AmBisome 17 15 35 14 8 1 0 2 3 1 1 2 0 6 14 9 3

haematological conditions were similar in each group (Table I). There were a larger number of myeloma patients in the Abelcet arm (n 10) compared to the AmBisome arm (n 3). A greater number of allogeneic sibling bone marrow transplantation/peripheral blood stem cell transplantation (BMT/PBSCT) procedures had been performed in the
Table II. Indications for antifungal therapy.

AmBisome patients. In total, 57 episodes occurred in transplanted patients and 11 in the setting of high-dose chemotherapy. Indication for antifungal therapy. All patients received antifungal prophylaxis with Fluconazole 100 mg daily p.o. and oral polyenes. Patients were commenced on parenteral antifungal therapy for one of two reasons (Table II). First, microbiological culture conrmation of fungal infection, i.e. proven infection. Second, strongly suspected fungal infection on the basis of either (i) severe mucositis, fever and positive cultures from stools suggesting colonization with Candida species, or (ii) suggestive CXR/CT scan appearances, or (iii) pyrexia of unknown origin (PUO) resistant to broadspectrum antibiotics for 96 h. Indications for liposomal or lipid complex amphotericin. Patients were treated with lipid formulations (Table III) if (i) there was progression of underlying proven or suspected fungal infection as judged on clinical or radiological grounds on conventional amphotericin treatment, or (ii) if there was renal or hepatic impairment. This could be pre-existing at the start of antifungal therapy or have deteriorated as a result of therapy with conventional amphotericin B. (iii) In occasional patients there was difculty in obtaining central venous access and in one patient there was an unacceptable reaction to conventional amphotericin B with chills and rigors unresponsive to pethidine and piriton. Abnormal renal function was dened as either doubling of baseline creatinine on amphotericin or a creatinine value > 200 mmol/l at time of institution of antifungal agent. Abnormal hepatic function was dened as bilirubin or transaminases > 5 times the upper limit of the normal range.

Abelcet Proven Broncho-alveolar lavage 8 4 Mucor spp. Aspergillus fumigatus Aspergillus fumigatus Aspergillus fumigatus 1 Candida tropicalis

AmBisome 7 2 Aspergillus avus Aspergillus fumigatus

Blood

3 Candida albicans Candida albicans Candida tropicalis 1 Candida parapsilosis 1 Aspergillus fumigatus 0 0 11 14

Cerebrospinal uid Sputum Peripheral blood stem cell Oesophageal biopsy Suspected Pyrexia of unknown origin

1 Candida parapsilosis 0 1 Candida albicans 1 Candida albicans* 15 13

* Deep-seated invasive infection. 1998 Blackwell Science Ltd, British Journal of Haematology 103: 198204

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Table III. Indication for lipid preparations.

Abelcet Renal Hepatic Renal and hepatic No central access Disease progression Reaction 27 1 1 3 4 0

AmBisome 18 0 4 5 4 1

Administration. AmBisome (NeXstar Pharmaceuticals, Boulder, Colorado, U.S.A.) and Abelcet (The Liposomal Company, Princeton, New Jersey, U.S.A.) were prepared and infused according to standard protocols. Statistics. Parametric data were analysed using an unpaired t-test and non-parametric data by the Chi-squared method. RESULTS Dosages The duration of therapy, daily and cumulative dosages of lipid formulations of amphotericin are shown in Table IV. Overall, AmBisome patients received a median dose of 19 mg/kg/d. Abelcet patients received a median dose of 48 mg/kg/d. In both groups patients with proven infections were treated with higher doses and for longer periods. Lipid preparations enabled amphotericin B therapy to be salvaged when toxicity prevented continuation of therapeutic dosages of conventional amphotericin. There was no signicant difference between preparations. In Abelcet patients 19/32 (59%) and in AmBisome patients 17/31 (55%) had received previous conventional amphotericin therapy. Median number of days on conventional therapy were 5 d (range 224) for Abelcet and 4 d (range 118) for AmBisome patients. The median cumulative dosages of conventional amphotericin were 240 mg (range 501340) for Abelcet patients and 190 mg (range 201100 mg) for AmBisome patients (P NS).

Lipid formulation amphotericin B was commenced in line with licensed dosages. AmBisome most usually was prescribed at 23 mg/kg and Abelcet at 5 mg/kg. Assessment of disease severity and facilitation of valid intraand inter-group comparisons. We assessed neutrophil counts at commencement and cessation of therapy, disease status in terms of stable or progressive disease, and additional immunosuppressive agents used, i.e. any combination of cyclosporin with or without corticosteroids, CAMPATH, antilymphocyte globulin or donor lymphocytes. The acute physiology, age and chronic health evaluation (APACHE III) scores (Knaus et al, 1991) and predicted likelihood of hospital mortality (APACHE Investigators, personal communication) were calculated. These parameters were then used as an additional indicator that the groups were equivalent, further validating the comparison.

Table IV. Dosages, duration of therapy and outcome in liposomal and lipid complex treated patients. Non-evaluable patients had received < 4 d therapy.

Abelcet Overall Total patients Total evaluable patients Total dose (mg), median (range) Days (d), median (range) Daily dose (mg/kg/d), median (range) Responders Non-responders Proven Total patients Total evaluable patients Total dose (mg), median (range) Days (d), median (range) Daily dose (mg/kg/d), median (range) Responders Non-responders Suspected Total patients Total evaluable patients Total dose (mg), median (range) Days (d), median (range) Daily dose (mg/kg/d), median (range) Responders Non-responders

AmBisome

36 32 4200 (125012070) 14 (442) 48 (1958) 25 (78%) 7 (22%) 8 8 8000 (150012070) 28 (542) 43 (2850) 5 (62%) 3 (38%) 28 24 3835 (12508800) 13 (424) 49 (1958) 20 (83%) 4 (17%)

32 31 1200 (2004900) 9 (439) 19 (074) 22 (71%) 9 (29%) 7 7 1800 (6502700) 14 (428) 21 (144) 3 (42%) 4 (58%) 25 24 1100 (2004900) 9 (439) 19 (074) 19 (79%) 5 (21%)

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Analysis of Lipid-associated Amphotericin B Preparations

Table V. Host characteristics in patients treated with lipid complexed and liposomal preparations of Amphotericin B.

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Abelcet Overall Neutrophil count 109/l Commencement, median (range) Cessation, median (range) Disease status (% progressive disease) Immunosuppression APACHE III, median (range) Predicated mortality (%), median (range) Responders Neutrophil count 109/l Commencement, median (range) Cessation, median (range) Disease status (% progressive disease) Immunosuppression APACHE III, median (range) Predicated mortality (%), median (range) Non-responders Neutrophil count 109/l Commencement, median (range) Cessation, median (range) Disease status (% progressive disease) Immunosuppression APACHE III, median (range) Predicated mortality (%), median (range) Proven Neutrophil count 109/l Commencement, median (range) Cessation, median (range) Disease status (% progressive disease) Immunosuppression APACHE III, median (range) Predicated mortality (%), median (range) Suspected Neutrophil count 109/l Commencement, median (range) Cessation, median (range) Disease status (% progressive disease) Immunosuppression APACHE III, median (range) Predicated mortality (%), median (range) Unpaired t test; * chi-squared test.

AmBisome

P value

03 (051) 18 (073) 15/32 (47%) 11/32 (34%) 51 (2494) 21 (477)

06 (08) 18 (015) 9/31 (29%) 16/31 (52%) 43 (1799) 18 (380)

ns ns ns* ns* ns ns

03 (051) 23 (0173) 10/25 (40%) 8/25 (32%) 50 (2477) 19 (456)

10 (05) 195 (015) 7/22 (32%) 9/22 (41%) 41 (1779) 16 (355)

ns ns ns* ns* ns ns

01 (035) 03 (0331) 5/7 (71%) 3/7 (43%) 58 (3694) 61 (1777)

00 (08) 15 (056) 2/9 (22%) 7/9 (78%) 65 (2599) 37 (780)

ns ns ns* ns* ns ns

01 (030) 22 (071) 4/8 (50%) 3/8 (38%) 50 (3771) 28 (1077)

21 (080) 12 (048) 3/7 (43%) 5/7 (71%) 33 (2579) 18 (780)

ns ns ns* ns* ns ns

04 (051) 155 (0173) 11/24 (46%) 8/24 (33%) 51 (2494) 19 (473)

055 (050) 195 (015) 6/24 (25%) 11/24 (46%) 49 (1799) 21 (377)

ns ns ns* ns* ns ns

Outcomes There was no statistically signicant difference in outcome (P ns) overall (Table IV). Of the 36 Abelcet patients, 28 survived and eight died. However, three survivors and one patient who died had received therapy for < 4 d and were not considered to have received adequate therapy to be evaluable in terms of efcacy, although toxicity data was still obtained. In total, of the 32 patients in the Abelcet group evaluable for efcacy, 25 (78%) responded to therapy; 7/32 (22%) did not and subsequently died. In the AmBisome group there were 32 patients, of whom 31 were evaluable for efcacy data: 22 responded and 10 failed to respond.

One of the non-responders had received therapy for < 4 d. In total, for AmBisome patients, 22/31 (71%) responded and 9/31 (29%) did not. Four AmBisome patients and three Abelcet patients died of fungal infections. In the Abelcet group a further four patients and in the AmBisome group a further ve patients died with clinical diagnoses of primarily non-fungal aetiology. This did not preclude fungus as a potentially contributory factor in their deaths. Post-mortem information was unfortunately available only for three patients: two had CMV pneumonitis and one had Pneumocystis pneumonia as the primary cause of death.

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Table VI. Toxicities of lipid complexed and liposomal amphotericin B.

Abelcet Creatinine start (mmol/l), median (range) Creatinine end (mmol/l), median (range) K levels < 30 Mg levels < 07 Rigors Bronchospasm 173 (65310) 145 (63340) 18 (50%) 28 (78%) 13 (36%) 1

AmBisome 160 (67310) 158 (65440) 12 (38%) 23 (72%) 2 (6%) 0

P value ns ns ns ns < 001

Indicators of disease severity Overall. Neutrophil counts pre- and post-therapy, the degree of immunosuppression, disease status in terms of progressive or stable disease, APACHE III scores and predictive mortality for the two lipid formulations are shown in Table V. There was no statistically signicant difference in any parameter between groups. There was a non-signicant reduced level of immunosuppression in the Abelcet group, relating to fewer allogeneic sibling donor transplants. This was offset by the higher degree of progressive disease, slightly higher APACHE III scores and slightly higher predicted mortality in the Abelcet patients compared to the AmBisome group. Non-responders. In both groups the neutrophil counts at commencement of therapy were lower in the non-responders. Interestingly, in the AmBisome patients neutrophil counts at death were higher than in the Abelcet group, although this did not reach statistical signicance. AmBisome non-responders also had, on average, higher APACHE III scores but decreased predicted mortality and more immunosuppression but less progressive disease than their Abelcet counterparts. Proven. In proven infections the AmBisome patients again had non-signicantly increased levels of immunosuppression compared to the Abelcet group. Most of the patients commenced on AmBisome, in contrast the Abelcet patients, were not neutropenic at commencement of antifungal therapy. Abelcet patients had increased levels of progressive disease and higher APACHE III scores and predicted mortality. Toxicity. There were two febrile reactions in the AmBisome group (6%) and 13 in the Abelcet group (36%) (P < 001). In addition, there was one episode of severe bronchoconstriction in the Abelcet group necessitating discontinuation of therapy and none in the AmBisome group. Median creatinine levels at the start and cessation of AmBisome were 160 mmol/l and 158 mmol/l, respectively. In the Abelcet group the median level was 173 mmol/l at the start and 143 mmol/l at cessation of therapy. Electrolyte abnormalities were present in both arms, 12/ 32 (38%) in the AmBisome group and 18/36 (50%) patients on Abelcet experienced a fall in serum potassium levels on therapy to < 3 mmol/l (P ns). Also 23/32 (72%) in the AmBisome arm and 28/36 (78%) in the Abelcet arm showed a fall in serum magnesium concentrations to < 07 mmol/l. This effect appeared to be irrespective of concomitant diuretic or cyclosporin therapy.

DISCUSSION Lipid preparations of amphotericin are expensive and, as such, in most centres usage is conned to treatment failures of conventional amphotericin B (Franklin et al, 1997). The value of these agents was underlined in this study. In the two treatment groups combined, 36 patients had salvage therapy with lipid preparations after toxicity prevented further conventional amphotericin B treatment; 28 survived. Decisions regarding which lipid formulation to use and the optimum dosages remain controversial. In our study when outcomes, assessed by the extremely rigid criteria of fungalfree survival or death, were analysed there was no signicant difference between patients who received AmBisome at a median dose of 19 mg/kg/d and Abelcet at a median dose of 48 mg/kg/d in all treatment groups combined. The numbers are too small to comment on outcome in subgoups such as proven infections or non-responders. We could not nd any other published direct comparative information. There is support for the efcacy of relatively low dose AmBisome (1 mg/kg) in PUO (Prentice et al, 1997) and in presumed and proven fungal infection (unpublished observations) in neutropenic patients. These studies have shown equivalent or possibly superior efcacy of 1 mg/kg and 3 mg/ kg AmBisome compared to conventional amphotericin B at 1 mg/kg in the PUO setting (Prentice et al, 1997). In proven infections preliminary analysis of the EORTC study comparing 1 mg/kg and 4 mg/kg of AmBisome showed no signicant difference in outcome in terms of survival and response of fungal infection to treatment between arms (unpublished observations). Recently, evidence from two prospective randomized trials comparing AmBisome with conventional amphotericin B have become available. AmBisome (36 mg/kg) has been shown to be superior over conventional amphotericin B (06 mg/kg) in terms of reducing breakthrough fungal infections in febrile neutropenic patients with PUO treated empirically (Richardson & Kokki, 1998). Leenders et al (1998) compared 5 mg/kg AmBisome with 1 mg/kg conventional amphotericin B and found the two to be equivalent, although in poor-prognosis patients with progressive disease AmBisome appeared to be superior. Abelcet has been shown to be effective in fungal infection when toxicity precludes the use of conventional amphotericin B (unpublished observations). Prospective randomized trials have shown Abelcet to be equivalent to conventional

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Analysis of Lipid-associated Amphotericin B Preparations

amphotericin B in terms of efcacy, although there was less nephrotoxicity (Leenders & de Marie, 1996). However, a retrospective analysis did suggest an advantage over conventional amphotericin (Hiemenz et al, 1995). There are as yet no published studies regarding the use of Abelcet in the context of neutropenic patients undergoing BMT/PBSCT, below the licensed dose of 5 mg/kg (Mehta et al, 1997). However, recent subgroup analysis of a large open-label multicentre trial suggested 3 mg/kg Abelcet may be efcacious in certain circumstances, mainly yeast infections (unpublished observations). Small dose-nding studies and post-marketing experience from the collaborative exchange of antifungal research database, as yet presented in abstract form, give some indication that lower doses of Abelcet are used and may be effective. Prospective trials are in progress to clarify the issue. There are signicant drawbacks to retrospective studies, some of which we addressed by ensuring that the trial populations were not signicantly different for any important clinical variable. We assessed neutrophil counts, disease severity in terms of stable or progressive disease and immunosuppression. To avoid a bias between groups caused by a disparity in clinical severity of the acute illness in the context of underlying disease and age not fully addressed by any single parameter, we calculated APACHE III scores and predicted mortality (Knauss et al, 1991; APACHE investigators, personal communication). Although it is accepted that APACHE III scores were designed to assess ITU admissions and predict likely outcome in this setting, we felt it was appropriate to use this scoring system for comparative purposes in groups of severely unwell patients (Knaus et al, 1985, 1991). Absolute predictive values may not be accurate but allow an appreciation of disease severity. Any confounding variables introduced, for instance as a result of patients staying in the ward rather than being transferred to an ITU, are likely to occur equally in all groups and do not detract from the validity of using this approach for comparative purposes. There were no statistically signicant differences in host characteristics between AmBisome and Abelcet patients overall or in any subset. There was, however, a trend suggesting that pharmacological immunosuppression may be an independent risk factor predicting poor outcome. It is probable that there are at least two distinct populations of immunocompromised patients. The rst group are those who have regenerated their neutrophil counts following myeloablative therapy yet remain immunocompromised due to pharmacological immunosuppression with agents such as cyclosporin A. The second group are those who are immunocompromised secondary to myeloablative therapy alone and who recover signicant antimicrobial activity on regeneration of counts. The interplay between host and fungal pathogens may be different in these groups and their responses to antifungal agents may be fundamentally different. There was a polarization of heavily immunocompromised patients in the AmBisome group and this may account for the slightly worse outcome despite lower median APACHE III scores, higher neutrophil counts and lower predicted mortality. Economic considerations play an increasing role in the National Health Service. All lipid-associated preparations are

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expensive (Tollemar & Ringden 1995), AmBisome being more costly at hitherto standard dosages of 3 mg/kg when compared to Abelcet at 5 mg/kg. Our study suggested that a received dose of approximately 2 mg/kg of AmBisome was as effective as 5 mg/kg of Abelcet, certainly in suspected fungal infections, and at these doses the two preparations were cost equivalent. Studies of lower doses of Abelcet in neutropenic BMT/PBSCT patients are in progress (Rogers & Conway, 1998). In this study both drugs had a similar renal sparing effect, and although electrolyte abnormalities did occur there was no difference in incidence between drug groups. However, in common with previous studies (de Marie, 1996), we found that signicantly more rigours and febrile episodes occurred in the Abelcet patients. This perhaps reected the higher total dose of amphotericin delivered. These unpleasant sideeffects are not life-threatening in themselves. However, the possible adverse effects of corticosteroids, often given prophylactically or to treat rigors, should not be underestimated in fungal infections and should be avoided where possible. Only prospective randomized comparative trials will be able to denitively differentiate the relative efcacies of Abelcet and AmBisome in the diverse clinical contexts in which they are used. At present no differences are apparent. Further studies to identify the minimum effective doses of each drug in proven and suspected fungal infections will assist in the eventual replacement of conventional amphotericin B by these far less toxic products. ACKNOWLEDGMENTS The authors thank Brenda Jack for her tireless help with the typescript. A.C. is supported by the Leukaemia Research Fund. REFERENCES
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