a comparative analysis of lipid-complexed and liposomal
TRANSCRIPT
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A comparative analysis of lipid-complexed and liposomal
amphotericin B preparations in haematological oncology
A. D. CL A RK, S. MCKE N DRI C K , P. J. TA N S E Y, I . M. F RA N KL I N A N D R. CH O P RA*
Glasgow Royal Infirmary, Glasgow, and *Christie Hospital, Manchester
Received 9 March 1998; accepted for publication 30 June 1998
Summary. No comparative clinical information on theproperties of lipid-associated amphotericin preparations is
presently available. In this single-centre retrospective analy-
sis over a 5-year period the indications, efficacy and toxicity
of true liposomal amphotericin (AmBisome
) were com-
pared with a lipid complexed preparation (Abelcet
). In a
novel approach APACHE III scores were used in addition to
neutrophil counts, disease status and additional immuno-
suppression to accurately assess the severity of illness in both
groups and enable valid comparison. Overall, AmBisome at a
median dose of 19mg/kg/d was found to have similarclinical 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 neutropenicpatients 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 (Pizz o, 1993).
Over the last decade lipid-associated preparations have
become available, which complex amphotericin with lipids,
to which this drug has an affinity intermediate between
fungal ergosterol, highest affinity, and human cholesterol,
lowest affinity (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 adminis-
tered. 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 efficacy 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-specific factors such as
macrophage or fungal phospholipase production (Hiemenz &
Walsh, 1996). Alternatively, there may be no difference in
efficacy and the choice of drug would then be based on
economic considerations and side-effect profiles.
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 ampho-
tericin. As a result of perceived cost considerations, Abelcet
replaced AmBisome as the first-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),
n32, or lipid complex amphotericin (Abelcet), n36.
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
British Journal of Haematology, 1998, 103, 198204
198 1998 Blackwell Science Ltd
Correspondence: Dr Andrew D. Clark, Academic Transfusion
Medicine Unit, Department of Medicine, University of Glasgow,
Royal Infirmary, 10 Alexandra Parade, Glasgow G31 2ER.
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199Analysis of Lipid-associated Amphotericin B Preparations
1998 Blackwell Science Ltd, British Journal of Haematology 103: 198204
haematological conditions were similar in each group
(Table I). There were a larger number of myeloma patients
in the Abelcet arm (n10) compared to the AmBisome arm
(n3). A greater number of allogeneic sibling bone marrow
transplantation/peripheral blood stem cell transplantation
(BMT/PBSCT) procedures had been performed in the
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 confirmation 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 broad-
spectrum 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 wasrenal 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 difficulty 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 defined as either doubling of
baseline creatinine on amphotericin or a creatinine value
>200mmol/l at time of institution of antifungal agent.
Abnormal hepatic function was defined as bilirubin or
transaminases>5 times the upper limit of the normal range.
Table I. Patient characteristics.
Abelcet AmBisome
Male 27 17Female 9 15
Median age 42 35
Aetiology
CML 11 14
AML 7 8
ALL 1 1
CLL 1 0
NHL 3 2
Myeloma 10 3
Hairy cell leukaemia 1 1
Aplastic anaemia 1 1
Breast 0 2
Biphenoleukaemia 1 0
TreatmentMatched unrelated 7 6
Allogeneic 7 14
Autologous 14 9
Chemotherapy 8 3
Table II. Indications for antifungal therapy.
Abelcet AmBisome
Proven 8 7
Broncho-alveolar lavage 4 2
Mucor spp. Aspergillus flavus
Aspergillus fumigatus Aspergillus fumigatus
Aspergillus fumigatus
Aspergillus fumigatus
Blood 1 3
Candida tropicalis Candida albicans
Candida albicans
Candida tropicalis
Cerebrospinal fluid 1 1
Candida parapsilosis Candida parapsilosis
Sputum 0 1
Aspergillus fumigatus
Peripheral blood stem cell 1 0
Candida albicans
Oesophageal biopsy 1 0
Candida albicans*
Suspected 15 11
Pyrexia of unknown origin 13 14
* Deep-seated invasive infection.
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Lipid formulation amphotericin B was commenced in line
with licensed dosages. AmBisome most usually was pre-
scribed at 2 3 mg/kg and Abelcet at 5 mg/kg.
Assessment of disease severity and facilitation of valid intra-
and inter-group comparisons. We assessed neutrophil counts at
commencement and cessation of therapy, disease status in
terms of stable or progressive disease, and additionalimmunosuppressive 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 evalua-
tion (APACHE III) scores (Knaus et al, 1991) and predicted
likelihood of hospital mortality (APACHE Investigators,
personal communication) were calculated. These para-
meters were then used as an additional indicator that the
groups were equivalent, further validating the
comparison.
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 anunpaired 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
19mg/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 therapeu-tic dosages of conventional amphotericin. There was no
significant 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 (PNS).
1998 Blackwell Science Ltd, British Journal of Haematology 103: 198204
200 A. D. Clark et al
Table III. Indication for lipid preparations.
Abelcet AmBisome
Renal 27 18Hepatic 1 0
Renal and hepatic 1 4
No central access 3 5
Disease progression 4 4
Reaction 0 1
Table IV. Dosages, duration of therapy and outcome in liposomal and lipid complex treated
patients. Non-evaluable patients had received