Amphotericin B Lipid Complex in the Treatment of Invasive Fungal Infections: Results of the Collaborative Exchange of Antifungal Research (CLEAR), an Industry-Supported Patient Registry
CLEAR Database Overview • CID
Amphotericin B Lipid Complex in the Treatment of Invasive Fungal Infections: Results of the Collaborative Exchange of Antifungal Research (CLEAR), an Industry-Supported Patient Registry
Peter G. Pappas 0
0 Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham , USA
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Many factors confound the conduct,
reproducibility, and interpretation of
prospective therapeutic trials of antifungal
agents. In general, clinical trials of
antifungal agents involve relatively small
numbers of patients, owing to the relative rarity
of certain mycoses, strict eligibility criteria,
and the complexity of the comorbid
conditions encountered among patients who
develop invasive fungal infections.
Compounding these problems is the relative
lack of diagnostic methods that permit
accurate identification of potential study
candidates early enough during the course
of the infection to facilitate study
enrollment. In recognition of these substantial
obstacles, some investigators have
advocated the use of a more innovative
approach to the study of invasive mycoses—
for example, the use of surrogate markers
and nonculture techniques to identify
potential study candidates and to assess
response [
1
]. Finally, despite the growing
size of the population of at-risk patients
and the recognition of new and emerging
fungal pathogens, the study of the
diagnosis and treatment of invasive fungal
infections is underfunded at all levels.
The Collaborative Exchange of
Antifungal Research (CLEAR) database was
developed in the mid-1990s in response
to some of these unresolved issues. The
database has enhanced our understanding
of the epidemiology of invasive fungal
infections and clinical experience with
amphotericin B lipid complex (ABLC)
injection (Enzon Pharmaceuticals). ABLC is a
composition of amphotericin B and 2
phospholipids
(dimyristoylphosphatidylcholine and
dimyristoylphosphatidylglycerol) in a 1:1 drug-to-lipid molar ratio
[
2
]. ABLC was developed to reduce the
nephrotoxicity associated with the
conventional formulation of amphotericin B
deoxycholate (AmB), thus allowing for
administration of higher doses of ABLC than
AmB for longer therapeutic courses [
3
].
Although conventional AmB has been
considered as the reference standard of
antifungal therapy for many invasive
mycoses, the high incidence of renal toxicity
and other side effects associated with its
use have resulted in a recent reevaluation
of its position as first-line therapy for
many mycoses [
4–7
]. ABLC is rapidly
absorbed by the reticuloendothelial system,
resulting in a lower concentration of
amphotericin B in the plasma and kidneys
and a greater distribution of active drug
at tissue sites. Therefore, ABLC may be
beneficial in the treatment of fungal
infections when renal dysfunction is a
concern or as second-line therapy when
AmBinduced nephrotoxicity occurs.
The CLEAR database provides data on
efficacy and renal safety for 3514 patients
treated with ABLC from 1996 to 2000 at
1160 institutions in the United States and
Canada. One of the strengths of the
CLEAR database is that it reflects a broad
spectrum of patients treated for invasive
fungal infections in North America and
avoids the risk of excluding particular
groups of patients, which often occurs
during recruitment of patients for phase
3 clinical trials. Similar to other
observational and retrospective studies of
antifungal therapy, the CLEAR database has
its distinct limitations: it was retrospective,
the data collection method was based on
voluntary reporting and, thus, was subject
to potential enrollment bias, objectively
defined response criteria were lacking, and
follow-up was limited to completion of
therapy with ABLC or discharge from the
hospital, whichever was sooner. However,
this database has value because it provides
a unique opportunity to examine various
aspects of therapy with ABLC among a
broad scope of patients with various
invasive fungal infections.
Table 1 depicts the demographic
charCLEAR Database Overview • CID 2005:40 (Suppl 6) • S379
large number of patients enrolled, the
varying underlying conditions studied,
and the range of fungal pathogens treated.
These pathogens include not only Candida
S380 • CID 2005:40 (Suppl 6) • Pappas
and Aspergillus species but also new and
emerging pathogens, such as
non-Aspergillus moulds (e.g., Fusarium species and
the Zygomycetes), the endemic dimorphic
fungi (e.g., Histoplasma capsulatum and
Coccidioides immitis), and Cryptococcus
species. Patients included in CLEAR are
stratified according to unresponsiveness to
or intolerance of prior antifungal agents
and according to whether they received
ABLC as first-line or second-line therapy.
The patient-specific data collected in
CLEAR allow for clinical assessment based
on the presence or absence of significant
underlying disease, thus permitting the
investigator to examine the relationship
between underlying disorders and clinic (...truncated)