Treatment of Invasive Fungal Disease: Will Combination
Antifungal Therapy Reduce Mortality?
Frank C. Odds, PhD, FRCPath, posted on medscape.com
Introduction
Life-threatening fungal disease arises primarily in patients who are
already suffering from serious underlying illness. Susceptibility to fungal
infection in this regard may be enhanced by therapeutic administration of
cytotoxic chemotherapy or by major surgical procedures. The same patients
are also vulnerable to bacterial septicemias, and it is normal practice to
administer at least 2 antibacterial agents when signs of septicemia arise,
mainly to ensure coverage of the most likely causative organisms.
For fungal diseases, the broad spectrum of amphotericin B has long been
seen as providing appropriate cover for empiric antifungal treatment when
sepsis fails to respond to antibacterial agents, but the arrival of novel
antifungal agents in the clinic opens the possibility of combining drugs to
provide broader, more effective coverage.
This Conference Report reviews new and evolving options for combination
antifungal therapy, with a focus on advances discussed at the 13th European
Congress of Clinical Microbiology and Infectious Diseases (ECCMID), which
took place in Glasgow, Scotland, from May 10-13, 2003.
Invasive Fungal Infections: The Problems
Fungal sepsis and fungal diseases of deep organs have become well
recognized as important causes of death in seriously immunocompromised
hosts. Many epidemiologic studies have highlighted the main problems. While
the incidence of candidemia and mortality from Candida infections
started to decline through the late 1990s, the incidence of other mycoses,
particularly those caused by molds after bone marrow transplantation, has
increased relentlessly since the 1980s.[1-4] This trend is due in
large part to steady progress in chemotherapeutic and transplantation
technology, and resulting increases in the number of patients who are
therapeutically immunosuppressed and/or undergo transplantation surgery,
including solid organ transplants. Such patients are at the greatest risk
for developing nosocomial fungal infections.[1,2,5-7]
Other significant changes in clinical mycology have occurred as well.
Certain fungi that were once regarded as rare footnotes in the specialist
literature -- eg, Fusarium spp, Scedosporium spp, and the
Zygomycota -- have become well known to both hematologists and
infectious disease physicians.[5] With regard to clinical and
host factors, the concept that invasive fungal disease is typically
associated with neutropenic episodes must now be discarded: In bone marrow
and stem cell transplant patients, they commonly arise long after recovery
from neutropenia.[5,6]
What hasn't changed substantially, however, is the high mortality
associated with untreated invasive infections caused by Aspergillus
spp and other mold species. Attributable death rates are as high as 90% in
some patient groups,[7,8] and antifungal therapy so far has
offered only a partial solution. Patterson and colleagues[9]
documented treatment failure in 36% of 595 patients with invasive
aspergillosis who received amphotericin B, itraconazole, or sequential
therapy with both drugs. Treatment failed for nearly half (48%) of patients
classified as having severe immunosuppression; patients with disseminated
and cerebral aspergillosis were also found to be particularly unlikely to
respond to therapy.
Overall therapeutic response rates appear to be better with newer
treatments. A recent prospective, comparative trial of voriconazole and
amphotericin B for the treatment of aspergillosis demonstrated a
significantly higher survival rate in the voriconazole arm (70.8% of 144
patients 12 weeks post treatment) than the amphotericin B arm (57.9% of 133
patients),[10] but response rates among patients with
extrapulmonary infections were below 50% even in the voriconazole-treated
patients, and were as low as 32% in the allogeneic, hematopoietic-cell
transplantation subgroup.
Such poor therapeutic response in the worst-affected patients has
inevitably prompted physicians to wonder whether combining antifungal agents
might reduce mortality rates in nosocomial mold infections. The list of
antifungals presently available for possible use in the treatment of
aspergillosis (although not all of these agents have yet been officially
licensed for primary therapy for the indication) has recently grown to
include 2 triazole drugs, voriconazole and itraconazole, and the
echinocandin caspofungin, in addition to amphotericin B. Four other agents,
posaconazole and ravuconazole (triazoles) and the anidulafungin and
micafungin (echinocandins), are in phase 3 clinical trials. The pressure for
therapeutic improvement is so great that several investigators have already
tried combinations of some of these agents in small, open studies of
patients with aspergillosis and refractory mold infections. To date, results
have appeared only in abstract form.
Kontoyiannis and colleagues[11] found no improvement in the
response rates of 50 patients with invasive aspergillosis who were treated
with a combination of caspofungin and liposomal amphotericin B. Thiébaut and
associates[12] tried combinations of caspofungin or voriconazole
with amphotericin B in a small number of patients with refractory
aspergillosis and achieved a modest response rate of 37% overall, while
Gentina and colleagues[13] administered caspofungin combined with
either voriconazole or amphotericin B to 6 patients who had amphotericin-refractory
invasive aspergillosis and observed improvements in all 6 patients.
Ratanatharathorn and coworkers[14] treated 84 refractory
aspergillosis patients with either a combination of micafungin plus an
amphotericin B formulation (n = 71) or a triple combination of micafungin
plus amphotericin B plus a triazole (n = 13), claiming an overall success
rate of 39%.
Despite the understandable rush to conduct open studies with antifungal
combinations in salvage therapy, respect for scientific evidence to support
the use of particular combinations requires prospective, blinded trials --
and these are unlikely to produce results for several years, even if they
are undertaken in the near future. It is a sobering consideration that 24
years elapsed between the first prospective clinical trial of an antifungal
combination (amphotericin B ± flucytosine in patients with cryptococcosis),
conducted in 1979,[15] and the second (fluconazole ± amphotericin
B for treatment of candidemia).[16] The paucity of high-quality
evidence for antifungal combinations reflects the size and technical
complexity of blinded trials with 2 or more drugs.
Recent Advances
Presentations at this year's ECCMID reflected the persistent difficulties
of proving the clinical benefit of antifungal combinations. In a keynote
lecture, John Rex (Astra-Zeneca, Wilmington, Delaware), the senior author of
the recent fluconazole ± amphotericin B study, made a point that goes to the
heart of the whole problem of treating invasive mycoses.[17] In
the fluconazole combination trial, it turned out that the patients given the
fluconazole + amphotericin B combination, although randomly assigned to the
treatment arms, showed a significantly lower mean acute physiological and
chronic ill-health evaluation II (APACHE II) score than the group treated
with fluconazole alone. This difference biased the results statistically in
favor of the combination therapy.
Rex re-analyzed the study data as a graph of treatment success vs initial
APACHE II score, and showed that, while there was a difference in outcome
for patients with APACHE scores between the extremes, there was no
difference at the extreme scores. Rex interpreted from these data that
patients with invasive mycosis can be classified into 3 categories:(1) those
whose underlying disease is not too serious and who are highly likely to
respond to antifungal therapy; (2) those whose underlying disease is so
serious they are much less likely to respond to antifungals; (3) and those
in between. Rex suggested the third category is the one in which
improvements in treatment response might be achieved with combination
therapy.
The rationale for combining antimicrobial agents typically begins with
susceptibility studies in vitro. The number of agents to evaluate in
combination is large, and the range of pathogenic fungi to test even larger,
but tests in vitro are rapid and relatively easy to perform. Adding to the
many such studies already published, Eric Dannoui and his colleagues from
the Institut Pasteur in Paris, France,[18] showed a predominance
of favorable interactions in vitro between flucytosine and caspofungin
against Aspergillus spp, while flucytosine plus voriconazole showed a
tendency toward more antagonistic interactions against the same panel of
fungi. Data for caspofungin plus amphotericin B trended in the direction of
favorable interactions, whereas the combination of caspofungin plus
voriconazole tended to show no interactive effects. Throughout the data, the
trends were of a fairly low magnitude; there was no evidence of dramatic
synergy or antagonism. However, the positive flucytosine-caspofungin
interaction is of interest since flucytosine to date has not been generally
regarded as a useful agent for the treatment of aspergillosis, alone or in
combination with other antifungals.
Similar conclusions can be drawn from the data shown by Sevtap Arikan's
group from the University of Ankara, Turkey.[19] They tested
combinations of amphotericin B and caspofungin against 69 isolates of
Trichosporon asahii, an uncommon pathogen but one that is typically
difficult to treat clinically, and the majority of results showed no notable
interactions, with no antagonism evident for any isolate. Like the 2 in
vitro studies presented at ECCMID, the considerable amount of published
research on antifungal combinations in vitro seldom shows high degrees of
positive or negative interactions between pairs of agents, regardless of the
fungi under study. The sole exception is the case of amphotericin B plus a
triazole, where antagonism can be easily demonstrated in vitro but cannot be
regarded as clinically significant in the light of the results of the trial
conducted by Rex and associates.[16]
It is disappointing that in vitro data give such a low-potency indication
of which combinations may be of clinical value. It is unlikely that, in the
clinic, the same antifungal combinations will improve outcome in all types
of mycosis or even in all types of patient. The potential advantages of
antifungal combinations were outlined by Raoul Herbrecht, from the
University Hospital Hautpierre in Strasbourg, France.[20] These
advantages include:
- the amplified antifungal actions that can be achieved by effects on
different molecular targets in fungi,
- differences in pharmacokinetic/pharmacodynamic behavior of different
agents,
- the possibility of shorter treatment durations and lower doses,
- broader coverage for empiric therapy, and
- a reduced probability of development of resistance to antifungals.
Herbrecht also pointed out the shortcomings of studies in vitro to date:
- lack of uniformity of definitions for interactive effects,
- lack of consensus on appropriate methodology (checkerboard testing vs
time-kill studies based on different models of interaction),
- and lack of a strong correlation between effects in vitro and in
animal models.
His own experience of a clinical trial investigating combinations of
terbinafine and amphotericin B for invasive mycoses has not yet been
published, but Herbrecht indicated the results do not suggest obvious
benefits for this combination. In his own practice, Herbrecht has used
various antifungal combinations to treat a range of invasive mycoses, with
results judged as successful for liposomal amphotericin B combined with
caspofungin in 4/4 cases of invasive Candida infection and 5/7 cases
of invasive aspergillosis. His experience with a voriconazole + caspofungin
combination is too limited to permit conclusions.
The failure of preclinical research to give clear pointers for antifungal
combinations was seen in the poster from Cacciapuoti and colleagues from
Schering-Plough (Kenilworth, New Jersey) and San Antonio, Texas,[21]
who tested posaconazole with and without concomitant amphotericin B in mouse
models of invasive aspergillosis and candidiasis. Their main conclusion,
that the combination was not antagonistic, is similar to that of previously
published animal studies; the good news for antifungal combinations is the
absence of negative effects rather than the presence of unequivocally
positive effects.
A different approach to combination therapy for invasive mycoses was
outlined by Bart-Jan Kullberg, from the University of Nijmegen in The
Netherlands.[22] Since the obvious underlying problem in patients
with invasive disease is their poor immune function, the use of
immunomodulatory agents in combination with antifungals might be sufficient
to tip the balance between therapeutic success and failure. The background
research into immunomodulators clearly shows the important step is to
convert a T-helper 2 (Th)2-type immune status, dominated by interleukin 10
secretion, to a Th1 immunity, characterized by interferon (IFN)-gamma and
interleukin (IL)-12 production. A recently completed double-blind clinical
study, presented at the 41st Interscience Conference on Antimicrobial Agents
and Chemotherapy (ICAAC),[23] tested 2 doses of IFN-gamma vs
placebo in combination with standard antifungal therapies for cryptococcosis.
By several criteria, the results showed a definite margin of improvement
over placebo in the patients who received IFN-gamma at either dose. On the
strength of these data, to be presented in full at this year's ICAAC
meeting, a new, phase 3 trial of IFN-gamma vs placebo has been started by
the Mycoses Study Group.
Notwithstanding Kullberg's promising data, the majority of trials with
immunomodulators have been small-scale and equivocal in terms of outcome.
Emmanuel Roilides, from the University of Thessaloniki in Greece,[24]
reviewed published data on the clinical use of immunomodulators in invasive
aspergillosis and accepted that the results give no clear signal of benefit
or risk. He suggested that (1) granulocyte or granulocyte-macrophage
colony-stimulating factors (G-CSF or GM-CSF) might be given beneficially for
prophylaxis in patients at high risk of invasive mycoses, (2) that these
cytokines plus macrophage-CSF might be beneficial when fever arises in
neutropenia, and (3) that GM-CSF, possibly combined with IFN-gamma, could be
usefully combined with antifungal treatment for established disease.
However, randomized, prospective, blinded clinical studies to support these
ideas are lacking; a protocol has been designed to study IFN-gamma combined
with voriconazole for refractory mold infections.
The most extensive clinical data presented came from Andrew Ullmann at
the University of Mainz, Germany, and colleagues from the United Kingdom and
the United States.[25] The data augment those in the abstract
presented last year by Ratanatharathorn and associates (see above). This
open trial was designed to study the effects of micafungin added to existing
therapy, or given in place of it, in refractory cases of proven or probable
invasive aspergillosis. Out of 283 patients enrolled, 179 were analyzable
per protocol. Complete or partial therapeutic responses were documented in
45% of 38 patients who received micafungin alone, and in 35% of 141 who were
given micafungin combined with other antifungal therapy.
Conclusions
It is clear that major improvements in treatment outcomes for invasive
fungal infections are still awaited, and that, so far, combining antifungal
agents to reduce the high mortality rates in mold infections has not taken
treatment success beyond the levels achieved by monotherapy in prospective
clinical trials. The diversity and relative safety of the newly available
systemic antifungals will continue to stimulate physicians confronted with
intractable fungal disease to experiment with combinations, but anecdotal
reports of successes and failures in small numbers of cases will do little
to advance our serious understanding of therapeutic possibilities. The
serious underlying disease and poor prognostic indicators common in many
patients with invasive mycoses probably contribute as much to fatal outcomes
as the fungi, in many cases. The need for improvements in both diagnosis and
therapy of these difficult infections remains as urgent as ever.
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