British Journal of Huematology, 1995, 91, 684-690

Experience with liposomal Amphotericin-B in 60 patients undergoing high-dose therapy and bone marrow or peripheral blood stem cell transplantation

WILLIAM KRUGER, MARCUS STOCKSCHLADER, BETTINA RUSSMANN, CAROLINA BERGER, MATTHIAS HOFFKNECHT, INGO SOBOTTKA,* BRIGITTE KOHLSCH~TTER, GERD KROSCHKE, NICOLAUS KROGER, MARTIN HORSTMANN, HARTMUT KABISCH AND AXEL R . ZANDER Bone Marrow Transplantation Unit, Department of OncologylHaematology and *Institute for Medical Microbiology and Immunology, University Hospital Eppendorf, Hamburg, Germany

Received 13 February 1995; accepted for publication 17 July 1995

Summary. 60 patients undergoing bone marrow or stem cell transplantation were treated with liposomal Amphotericin-B for documented or suspected mycosis. 34 patients had a prior course of conventional Amphotericin-B with the following adverse effects: increasing creatinine above 1.4 mg/dl (n = 17), increasing creatinine below 1-5 mg/dl (n = 9), no response (n = 6), and clinical side-effects (n = 4). Liposomal Amphotericin-B failed in 6/7 patients with culture-proven mycosis who died from infection with Aspergillus (n = 2) and Candida (n = 4), respectively. One patient with Candida Zambica sepsis was cured. No patient with clinically or serologically suspected or diagnosed infection died from mycosis. Liposomal Amphotericin-B was well tolerated in 57 patients, even after side-effects of the conventional formulation. Adverse effects occurred in

three cases, requiring the withdrawal of the drug in one patient. Due to toxic side-effects of the high-dose therapy and transplant-related complications, it was difficult to evaluate the influence of liposomal Amphotericin-B on laboratory parameters. Eight patients showed a decrease of creatinine levels, which had increased above normal values under preceding therapy with conventional Amphotericin-B. Liposomal Amphotericin-B is well tolerated in patients undergoing high-dose therapy and bone marrow transplan- tation. The efficacy of liposomal Amphotericin-B needs to be investigated in randomized studies in comparison with conventional Amphotericin-B.

Keywords: BMT, neutropenia, liposomal Amphotericin-B, invasive mycosis, fungal sepsis.

Patients undergoing myeloablative high-dose chemo- or chemo-radiotherapy and bone marrow transplantation are highly susceptible for systemic fungal infections during neutropenia (Working Party of the British Society for Antimicrobial Chemotherapy, 1993). The most frequently isolated fungal pathogens from neutropenic patients are Candida and Aspergillus species, and infections with these pathogens are often fatal (Saral, 1991). In an autopsy study, fungi have been responsible for 28% of deaths in patients with haematological malignancies (Nosari et aZ, 1991). Fever in neutropenic patients requires immediate broad- spectrum antibiotic therapy. Even in culture-negative cases a systemic antimycotic therapy should be considered early (Pizzo et al, 1991a. b: Wade, 1993: Walsh et al, 1991).

Correspondence: Dr William Kriiger, Knwhenmarktransplantation, Abteilung Onkologie/Hhatologie, Universitits-Krankenhaus Eppen- dorf, Martitrasse 52,20246 Hamburg, Germany.

684

The therapy of choice in documented or suspected invasive mycosis or fungal sepsis is intravenous Amphoter- icin-B. Adverse events such as fever, chills, thrombophlebitis, nausea or vomiting are common: cardiac arrhythmia and hepatic dysfunction have been described. A more serious adverse event is the potential renal impairment. Amphoter- icin-B may cause a tubular damage. The clinical picture of renal damage may vary from a mild increase of the serum creatinine to a diabetes insipidus and a renal failure requiring haemodialysis (Butler et al, 1964: Douglas & Healey, 1968: Meyer, 1992). It should be pointed out that patients undergoing bone marrow transplantation often receive several other potentially nephrotoxic drugs such as cyclosporin-A, aciclovir, cephalosporines, vancomycin and aminoglycosides.

During the last few years lipids have been employed to overcome the frequent toxicity of Amphotericin-B. Caillot rt al (1993) diluted the drug in a lipid emulsion commonly

0 1995 Blackwell Science Ltd

used for parenteral nutrition and noted a decrease of side- effects. Another approach consisted of liposomal encapsula- tion of Amphotericin-B resulting in a higher therapeutic index of the drug with minimal side-effects (Emminger et aI, 1994). There is evidence for a higher effectiveness of liposomal Amphotericin-B compared with the conventional drug (Lopez-Berenstein et al, 1989). Laboratory studies comparing the in vitro activity of both free and liposomal encapsulated Amphotericin-B did not give identical results. Anaisse et d (1991) described comparable activities whereas Hopfer et al (1984) reported a decrease of antifungal activity of a liposomal formulation.

Recently, Mills et a1 (1994) have published their results with liposomal Amphotericin-B in 116 patients with haematological malignancies undergoing conventional anti- neoplastic chemotherapy or high-dose therapy and trans- plantation. 38 patients received an autograft, 16 an allograft, and the remaining 79 patients were treated with conventional antineoplastic therapy. 17 neutropenic patients were treated with liposomal Amphotericin-B for culture-proven aspergillosis. Therapy with liposomal Amphotericin-B led to success in 13/17 patients in this study.

In this study we present our experience with liposomal Amphotericin-B in a group of 60 patients treated with high- dose therapy and bone marrow or peripheral stem cell transplantation. Antimycotic therapy was given for docu- mented or suspected fungal infection during neutropenia.

MATERIAL AND METHODS

From March 1991 to November 1994 systemic antifungal therapy with liposomal Amphotericin-B (AmBisome@, Vestar Company, San Dimas, Calif., U.S.A.) was given for suspected or documented mycosis to 60 patients undergoing allogeneic or autologous bone marrow or stem cell transplantation. The patient’s details are given in Table I; 36 patients were male (60%) and 24 female (40%). The median age was 30 years with a range from 8 months to 64 years. The underlying disease was AML in 20 cases ( 3 3 % ) , ALL in 12 cases (20%), CML in seven cases (11.7%). non- Hodgkin’s lymphoma in seven cases (1 1-7%), multiple myeloma, severe aplastic anaemia and morbus Farquahr in three cases (5%) each, and myelodysplastic syndrome, myeloproliferative syndrome, metachromatic leucodystro- phia, neuroblastoma and sarcoma in one case (1.7%) each. 28 patients (46.7%) were transplanted with an allograft from a HLA-matched related donor, six patients (10%) from a related donor with one antigen-mismatch, one (1.7%) from a haploidentical related donor and two patients (3.3%) had a syngeneic donor. Nine patients (1 5%) had received an allogeneic transplantation from a matched unrelated donor. The autograft consisted of mafosfamide-purged bone marrow in four cases (6*7%), unpurged marrow and peripheral stem cells in five patients (8.3%) each.

All patients were nursed in isolation rooms with positive pressure filtered air: 39 patients were treated under laminar air flow conditions additionally. For antimycotic prophy- laxis, fluconazole was given to 49 patients (82%), itracona-

zole to six patients (10%) two patients (3.3%) received Fluconazole and oral Amphotericin-B, two patients (3’3%) oral Amphotericin-B alone. One woman (1.7%) with a short time interval after a previously documented Aspergillus pneumonia received liposomal Amphotericin for antimyco- tic prophylaxis. Additionally, in three cases nebulized Amphotericin-B was given. Nine patients (15%) had a history of suspected or documented Aspergillus pneumonia.

Broad-spectrum antibiotic therapy was started immedi- ately, when temperature rose above 38~2°C or higher. Blood cultures were drawn prior to antibiotic therapy and then daily until fever decreased. Serologic tests for Aspergillus or Candidu antigen were done at least weekly. Urine culture, oral, rectal and nose swabs were done prior to antibiosis and

Table I. Patients’ characteristics.

Patients (%)

Experience with Liposomal Amphotericin-B in BMT Patients 68 5

0 1995 Blackwell Science Ltd, British Journal ofHaematology 91: 684-690

Diagnosis AML ALL CML NHL MM SAA Morbus Farquahr MDS MPS MLD Neuroblastoma Sarcoma

20 (33) 12 (20)

7 (11.7) 7 (11.7) 3 (5) 3 (5) 3 (5) l (1 .7) l(1.7) l (1 .7) l(1.7) l(1.7)

Transplantation type Allo-MRD Allo-MM Ah-HID Allo-MUD Syngeneic PBSC Auto Auto-purged

29 (48.3) 5 (8.3) l (1 .7) 9 (15) 2 (3.3) 5 (8.3) 5 (8.3) 4 (6.7)

Sex: male: 36 (60%): female: 24 (40%); age: median: 30 years, range: 8 months to 64 years.

AML: acute myeloid leukaemia: ALL: acute lymphoblastic leukaemia; CML: chronic myeloid leukaemia: NHL: non- Hodgkin’s lymphoma: MM. multiple myeloma: SAA: severe aplastic anae- mia; MDS myelodysplastic syndrome: MDL metachromatic leucodystrophia: MPS: myeloproliferative syndrome, allo: allogeneic. MRD: HLA-matched related donor: MM: one HLA- mismatched related donor; HID: haploidentical related donor: MUD: HLA-matched-unrelated donor, PBSC: peripheral blood stem cells: auto: auto- logous; auto-purged: autologous purged marrow.

686 William Kriiger et a1

then at least once weekly. The systemic antifungal treatment was initiated when fever did not respond to antibiotics within 72 h, when patients developed a second episode of fever after successful antibiotic therapy, or for documented or suspected mycosis. Suspicious clinical signs for mycosis were fever or pulmonary infiltrates unresponding to anti- biotics.

RESULTS

Diagnosis of fungal infection From March 1991 to November 1994, 60 patients under- going aliogeneic or autologous bone marrow transplanta- tion were treated with liposomal Amphotericin-B for suspected or documented mycosis.

The indications for treatment with liposomal Amphoter- icin-B were at least fever or in 17 patients pulmonary signs on chest X-ray examination without response to antibiotic therapy. Additionally, 30 patients had serological evidence for invasive mycosis. Cundida antigen was detected in the serum of 28 patients, and Aspergillus and Cundida plus Aspergillus antigen in one patient's serum each. Fungi were cultured from specimens of seven patients. Candida lumbica was cultured several times from blood of patient 2. Candidu krusei was cultured repeatedly from urine, stool, BAL and blood of patients 3, 6 and 7. Candidu glubrata was recovered from blood of patient 4. Patient 1 developed an Aspergillus pneumonia and patient 5 an Aspergillus sinusitis and pneumonia both with subsequent fungaemia. All patients had corresponding fungal antigens in the serum. Addition- ally, both patients culture-positive for Aspergillus flavus and fumigatus respectively, showed Candida antigenaemia.

Treatment with liposomal Ampho tericin- B Liposomal Amphotericin-B was given as the primary antifungal therapy in 26 patients. 34 patients had a course of conventional Amphotericin-B prior to the liposo- ma1 formulation in a dose of lmg/kg bodyweight with a median duration of 4 d (range 1-3 8 d). The reasons for the switch to the liposomal formulation were an increased serum creatinine above 1.4 mg/dl in 17 cases, no response to the conventional formulation in six cases, and intolerable

side-effects of conventional Amphotericin-B in four cases. Nine patients showed an increasing serum creatinine under conventional Amphotericin-B with values < 1.5 mg/dl. The administration of liposomal Amphotericin-B was started with a dose between 1 and 4mgJkg bodyweight (median 2.8 mg). In 20 patients the dose was increased up to a dose of 5mg/kg. At the endpoint of treatment with liposomal Amphotericin-B the median dose was 2*9mg/kg with a range of 1-5 mg. The median cumulative dose was 34-5 mg/ kg with a range from 2.8 to 186*9mg/kg. The median duration of treatment was 1 3 d with a range from 1 to 5 5 d. In one case the drug was withdrawn because of intolerable side-effects after 1 d of treatment.

Side-effects of liposomal Amphotericin-B Liposomal Amphotericin-B was tolerated without any clinical side-effects in 57 patients. Two patients developed fever respectively headache and abdominal pain during and after the drug infusion. One of these patients had developed renal impairment with increased creatinine 1-5 mg/dl during preceding therapy with conventional Amphoteri- cin-B. His creatinine decreased after switching to the liposomal drug. The second patient received the liposomal drug as primary antimycotic therapy. Only one patient receiving liposomal Amphotericin-B as primary antimycotic therapy responded with massive chills and fever requiring the withdrawal of the drug.

The median serum creatinine level prior to the therapy with liposomal Amphotericin-B was 1.0 mg/dl (range 0.2- 2.20; normal 0-6-1-4). At the end of the treatment period the median serum creatinine was 1-3 mg/dl(0*4-4.20). The median increase under therapy was 117% (65-433%) compared to the start level (100%). The creatinine decreased in eight patients below the starting point. Seven of these eight patients have received conventional Amphotericin-B prior to the liposomal formulation. Furthermore, 3/8 patients with decreasing creatinine under liposomal Ampho- tericin-B had a history of renal impairment under earlier conventional Amphotericin-B administration. Nine patients had no change of serum creatinine. The creatinine increased in 29 patients up to 150%, in seven patients up to 200% respectively to 433% each. In all cases other potentially

Table II. Maximum values for laboratory parameters under therapy with liposomal Amphotericin-B compared with the start level prior to the onset of the drug. Data are the number of patlents and the percentage in parentheses.

Increase up to % of upper normal value Creatinine Bilirubin OT PT

Decrease 7 (11.7) 10 (16.7) 3 (5) 9 (15) No change 9 (15) 4 (6.7) 3 (5) 2 (3.3) < 150% 29 (48.3) 12 (20) 8 (13.3) 11 (18.3) < 200% 7 (11.7) 7 (11.7) 9 (15) 10 (16.7) < 400% 6 (10) 12 (20) 16 (26.7) 17 (28.3)

> 500% 0 14 (23.3) 16 (26.7) 8 (13.3) < 500% l ( 1 - 7 ) l (1 .7 ) 5 (8.3) 3 ( 5 )

0 1995 Blackwell Science Ltd, British Iournal of Haemtology 91: 684-690

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688 William Kriiger et a1 nephrotoxic drugs such as cyclosporine, aciclovir, amino- glycosides and cotriioxazole were given. An overview of the maximal increases of creatinine, bilirubin and transami- nases is given in Table 11. It is difficult to evaluate the influence of liposomal Amphotericin-B on laboratory para- meters, because eight patients developed severe GvHD > III and a VOD, 13 patients had a severe GvHD 2 I11 without VOD, and 11 patients had a VOD alone. Additionally, all patients received one or more potentially hepatotoxic drugs, such as antibiotics, antiviral agents or metho- trexate. An increase of bilirubin > 150% compared to the start level under liposomal Amphotericin-B was associated with VOD and/or GvHD 2 111 (22134 v 10126). Conven- tional Amphotericin-B may cause potassium loss. Due to severe i.v. morphine-requiring mucositis, nearly all patients undergoing high-dose therapy require total parenteral nutrition. Thus, the only parameter we evaluated, is the time of additional intravenous potassium substitution during the course of liposomal Amphotericin- B. In 26 patients, additional potassium substitution was not necessary. 34 patients required additional potassium infusions for a median duration of 6.5 d (1-23 d). Sodium losses known from conventional Amphotericin-B could not be evaluated.

Eficacy of liposomal Amphotericin-B In 10 patients the efficacy of liposomal Amphotericin-B was not evaluable, because they had responded to conventional Amphotericin-B prior to the start of liposomal drug, non- fungal pathogens had been isolated as pathogens or liposomal Amphotericin-B was given for antifungal prophy- laxis (one case). 27 patients showed a clinical response and 23 patients had no clinical response until engraftment or death. Fungi were responsible for the death of seven patients. Pulmonary infiltrations on chest X-ray examination resolved in 911 7 patients under therapy with liposomal Amphotericin- B. Six patients with pulmonary signs unresponsive to liposomal Amphotericin-B died from culturally proven mycosis.

Culture documented mycosis Six of seven patients with culturally documented mycosis died from their fungal infection. Five of six had no engraftment. The pathogens were Aspergillus f l a w and fumigatus in one case each, Candida krusei in three cases, and Candida glabrata in one case. A man with a Candida lambica sepsis was cured by liposomal Amphotericin-B. Six patients received the liposomal drug after preceding therapy with conventional Amphotericin-B. The reasons for the switch were failure of the conventional drug (patients 1, 5 and 6), increasing creatinine under conventional Amphotericin-B (patients 2 and 3), and clinical side-effects (patient 7). Patient 4 received the liposomal formulation as primary antimycotic therapy, Further details about the culture- positive patients are given in Table III.

Serological documented mycosis A woman with an increasing titre for Aspergillus antigen titre from 118 to 1/16 under therapy died from an highly

Table IV. a c a c y of treatment with liposomal Amphotericin-B. 10 patients are excluded because they responded to conventional Amphotericin-B prior to the start of a liposomal drug, non-fungal pathogens had been isolated as pathogens, or liposomal Amphoter- icin-B had been given for antifungal prophylaxis (one case).

Diagnosis of fungal infection

Death due to fungal

Patients infection

All patients* 50 7 Clinical diagnosis 13 0 AspergiZlus antigen positive 1 0 Candida antigen positive 28 0 Aspergillus + Candida antigen positive 1 1 Culture positive 7 6

*AU patients evaluable are shown. The seven patients who died from mycosis are the six culture positive and one with cerebral aspergillosis and positive Aspergillus plus Candida antigen.

suspected and CT-documented cerebral aspergillosis. An autopsy was not permitted. A clearance of Aspergillus antigen from serum from 1 : 2 was reached in one case. Candida antigen was cleared from 11 patients’ sera. None from the remaining 29 patients with serologic evidence for a mycosis died from a fungal infection.

Patients with a history of aspergillosis One of nine patients with a history of Aspergillus pneumonia died from fungal infection and had engraftment failure. There was no evidence for a recurrence of Aspmyillus infection in the other eight patients. Table IV shows an overview about the results of treatment with liposomal Amphotericin-B in the 60 patients.

Duration of neutropenia and fever Fifty-three patients had engraftment with recovery of leucocytes. Seven patients died in aplasia between day + 21 and + 43 after allogeneic transplantation. In the latter cases the day of death was used as the end of aplasia in statistical evaluations. The duration of neutropenia (neu- trophils < 1 x 109/1) was at median 20.5 d (6-78 d). It was slightly increased to 29 d (18-43 d) in culture-positive patients compared to culture negative patients with 20d (6-78 d). The median duration of fever were comparable with 7 d (4-28 d) in the culture positive versus 8 d (2-41 d) in the culture negative group.

Overall outcome of all patients treated with liposomal Arnphotericin-B At a median follow-up of 28-5 d (14-76 d) after BMT, 44 patients were discharged from the BMT-unit without any signs of fungal infection. Seven patients have died of fungal infections, nine patients have died of GvHD IV (three patients), cerebral bleeding (two patients), VOD and multi- organ failure (two patients), relapse (one) and atypical pneumonia (one).

0 1995 Blackwell Science Ltd, British Journal of Huematology 91: 684-690

Experience with Liposomal Amphotericin-B in BMT Patients 689 DISCUSSION

Sixty patients undergoing myeloablative high-dose therapy and allogeneic or autologous transplantation were treated with liposomal Amphotericin-B for suspected or documented mycosis. 50 cases were evaluable; 10 cases were excluded because they had responded to prior therapy with conven- tional Amphotericin-B. non-fungal pathogens were isolated or liposomal Amphotericin-B was given prophylactically. In seven cases the diagnosis was based on cultured fungi. In the blood of 28 patients Candida antigen was detectable, in one patient’s blood Aspergillus antigen and in one patient’s blood both Candida and Aspergillus antigen. Six of seven culture- positive patients died of mycosis, a man with sepsis caused by Candida lambica was cured by liposomal Amphotericin-B despite GvHD 111. A woman with cerebral aspergillosis and Aspergillus and Candida antigen in her blood also died of mycosis. One Aspergillus antigen positive patient and 28 Candida antigen positive patients were treated successfully. Suspected pulmonary infiltrations on chest X-ray examina- tion resolved in 9/17 patients under therapy with liposomal Amphotericin-B.

Favourable results of treatment of culturally documented mycosis in immunocompromised patients with liposomal Amphotericin-B have been described by several groups (Coker et al, 1991; Gokhale et d, 1993). Unfortunately we cannot c o h these positive results. Mills et a2 (1994) treated 13/17 patients with proven aspergillosis with success. Two of three patients treated with allogeneic bone marrow transplantation showed a complete response to the drug, the third patient died from his infection and two of five autograft recipients died from their aspergillosis. Our two patients with proven aspergillosis died of mycosis. Four patients from our study with Candida krusei or glubrata sepsis were not cured by liposomal Amphotericin-B. Candida krusei with higher MICs to known antimycotics emerged in BMT patients due to fluconazole prophylaxis (Dermoumi, 1994; Wingard et al, 1991). The clinical suspectibility of Candida krusei to liposomal Amphotericin-B has not been discussed in the literature. Karyotakis et a1 (1993) achieved with both conventional and liposomal Amphotericin an increased survival and a reduction of fungal burden in neutropenic mice experimentally infected with Candida krusei, but Candida krusei was not cleared despite higher doses of both drugs than used in man. In our study, only in one case was Candida larnbica cleared from the blood of a young man with fungal sepsis. Recently, a review of the literature has shown that Caddu krusei sepsis is associated with a high mortality rate (4040%). but can be cured, even in the presence of neutropenia, with liposomal Amphotericin-B (Goldman et al, 1993). Data about Candida krusei sepsis in marrow recipients is lacking.

In this study we present the largest collection of bone marrow transplantation patients treated with liposomal Amphotericin-B. It should be emphasized that 6/7 patients with culture-documented mycosis were at very high risk for systemic fungal infection due to 2 I11 GvHD and high-dose steroid therapy, due to prolonged aplasia or due to a history of mycotic infection. However, the number of our patients,

even with proven mycosis, is too small for a definite conclusion. Despite our disappointing results in the cases with culturally proven mycosis, the value of liposomal Amphotericin-B in bone marrow recipients should be examined in randomized studies.

Patients undergoing highdose therapy and bone marrow transplantation are at high risk for therapy-related organ impairment (Bearman et al, 1988). Due to the side-effects of high-dose therapy and complications such as veno-occlusive disease of the liver and GvHD it is dfficult to evaluate toxic side-effects on laboratory parameters such as creatinine and bilirubin (Carreras et al, 1993; Vogelsang & Wagner, 1990). In our patients, impairment of liver and kidney was highly associated with VOD particularly GvHD 2 111. The creatinine level decreased in eight patients after onset of therapy with liposomal Amphotericin-B. We saw no case with rising creatinine or liver parameters due to liposomal Amphoter- icin-B. Clinical side-effects were seen in three patients, necessitating withdrawal of the drug in one patient because of massive chills. In our experience liposomal Amphotericin- B is safe and well tolerated in patients undergoing marrow transplant. The safety of the therapy with liposomal Amphotericin-B is comparable in patient populations with and without BMT.

The use of liposomal Amphotericin-B in patients under- going bone marrow transplantation is safe. Documented fungal infections in BMT patients are associated with a high mortality independent from therapy. In our series, six of seven patients with a culturally proven mycosis died from their infection. These patients were all at high risk for systemic fungal infection due to GvHD and high-dose steroid therapy, due to a history of preceding mycosis or due to prolonged neutropenia. The efficacy of liposomal Amphoter- icin-B in marrow recipients needs further investigation.

REFERENCES

Anaissie, E.. Paetznick, V., Proffitt, R., Adler-Moore, J, & Bodey, G.P. (1991) Comparison of the in vitro antifungal activity of free and liposome encapsulated Amphotericin-B. European Journal of Clinical Microbiology and Infectious Diseases, 10, 665-668.

Bearman, S.I.. Appelbaum, F.R., Buckner, C.D., Petersen. F.B.. Fisher, L.D., Clift. R.A. & Thomas, E.D. (1988) Regimen-related toxicity in patients undergoing bone marrow transplantation. Journal of Clinical Oncology, 6 , 1562-1568.

Butler, W.T.. Bennett, J.E., EUing, D.W., Wertlake. P.T.. Utz, J.P. & Hill, G.J. (1964) Nephrotoxicity of Amphotericin-B early and late effects in 81 patients. Annuls of Internal Medicine, 2, 175-187.

Caillot, D., Casasnovas. 0.. Solary. E., Chavanet, P.. Bonnotte. B.. Reny. G., Enkzam, P.. Lopez, J., Bonnin, A. IS Guy. H. (1993) Ef6cacy and tolerance of an Amphotericin-B lipid (Intralipid) emulsion in the treatment of candidaemia in neutropenic patients. Journal ofAntimicrobiu1 Chemotherapg. 31, 161-169.

Carreras. E.. Granena. C. & Roman, C. (1993) Hepatic veno- occlusive disease after bone marrow transplant. Blood Reviews, 7 ,

Coker, R., Tomlinson, D. & Harris, J. (1991) Successful treat- ment of cryptococcal meningitis with liposomal Amphotericin-B after failure of treatment with fluconazole and conventional Amphotericin-B. AIDS. 5, 231-232.

Dermoumi, H. (1994) In vitro suspectibility of fungal isolates of

43-51.

0 1995 Blackwell Science Ltd, British Journal of Haemutology 91: 684-690

690 William Kriiger et al clinically important specimens to itraconazole, fluconazole and Amphotericin-B. ChemotherapH, 40. 92-98.

Douglas. J.B. & Healy, K.J. (1968) Nephrotoxic effects of Amphoter- icin-B, including renal acidosis. American Journal of Medicine, 46,

Emminger, W., Graninger, W., Emminger-Schmidtmeier, W., Zoubek, K.. Pillwein. K.. Susani. M., Wasserer, A. & Gadner. H. (1994) Tolerance of high doses of Arnphotericin-B by infusion of a liposomal formulation in children with cancer. Annals of Hematology, 68, 27-31.

Gokhale, P.C.. Barapatre, R.J., Advani, S.H.. Kshirsagar, N.A. & Pandya, S.K. (1993) Successful treatment of dissiminated candidiasis resistant to Amphotericin-B by liposomal Amphoter- icin-B: a case report. Journal of Cancer Research and Clinical

Goldman, M.. Pottage, J.C. & Weaver, D.C. (1993) Cundida krusei fungemia: report of four cases and review of the literature. Medicine, 72, 143-150.

Hopfer, R.L.. Mills, K.. Mehta. R., LopelrBerensteii. G., Fainstein. V. & Juliano. R-L. (1984) In vitro antifungal activities of Amphoter- icin-B and liposome-encapsulated Amphotericin-B. Antimicrobial Agents and Chemotherapy, 25, 387-389.

Karyotakis, N.C., Anaisse, E.J., Hachem, R., Dignani, M.C. & Samonis. G. (1993) Comparison of the d c a c y of polyenes and triazoles against hematogenous Candida krusei infection in neutropenic mice. Journal ofhfectious Diseuses, 5. 1311-1313.

Lopez-Berenstein, G., Bodey, G.P., Fainstein. V., Keating, M., Frankel, L.S., %luff. B., Gentry, L. & Mehta, K. (1989) Treatment of systemic fungal infections with liposomal Amphotericin-B. Archives of Internal Medicine, 149, 2533-2536.

Meyer, R.D. (1992) Current role of therapy with Amphotericin-€3. Clinical Infectious Diseuses, 14, (Suppl. l), 154-160.

Mills, W., Chopra, R., Linch. D.C. & Goldstone, A.H. (1994) Liposomal Amphotericin-B in the treatment of fungal infections

154-162.

Onc010gy. 119.569-571.

in neutropenic patients: a single-centre experience of 13 3 episodes in 116 patients. British Journal of Haematologg. 86, 754-760.

Nosari, A.. Baberis, M.. Landonio, G., Magnani. P.. Majno, M., Oreste, P. & Sozzi, P. (1991) Infections in haematologic neoplasms: autopsy findings. Haematologica, 76, 135-140.

Pizzo, P.A., Rubin, M.. Freifeld, A. & Walsh, T.J. (1991a) The child with cancer and infection. I. Fmpiric therapy for fever and neutropenia, and preventive strategies. Journal of Pediatrics, 5,

Pizzo, P.A., Rubin, M., Freifeld, A. & Walsh. T.J. (1991b) The child with cancer and infection. II. Nonbacterial infections. Journal of Pediatrics, 6. 845-857.

Saral, R. (1991) Cundida and Aspergillus infections in immunocom- promised patients: an overview. Reviews of Infectious Diseases, 13.

Vogelsang. G.B. & Wagner, J.E. (1990) Graft-versus-host disease. Hematological Oncological Clinics of North America, 4, 625-639.

Wade, J.C. (1993) Management of infection in patients with acute leukemia. Hematological Oncobgid Clinics of North America, 7,

Walsh, T.J., Lee, J., Lecciones, J., Rubin, M., Butler, K., Francis, P., Weinberger, M., Roilides, E., Marshall, D., Gress, J. & Pizzo, P.A. (1991) Ernpiric therapy with Amphotericin-B in febrile granulo- cytopenic patients. Reviews of Infectious Diseases. 13.496-503.

Wingard, J.R., Merz, W.G.. Rinaldi, M.G., Johnson, T.R., Karp, J.E. & Saral, R. (1991) Increase in Cundida krusei infection among patients with bone marrow transplantation treated prophylacti- cally with fluconazole. New England journal of Medicine, 325.

Working Party of the British Society for Antimicrobial Chemother- apy (1993) Chemoprophylaxis for candidosis and aspergillosis in neutropenia and transplantation: a review and recommendation. Journal of Antimicrobial Chemotherapy, 32, 5-21.

679-694.

487-492.

293-315.

12 74- 12 77.

0 1995 Blackwell Science Ltd, British Journal of Haematokgy 91: 684-690