PROCEEDINGS
ARE COMBINATIONS OF ANTIFUNGALS
BENEFICIAL OR DELETERIOUS?*
—
Manuel Cuenca-Estrella, MD, PhD
ABSTRACT
Concomitant combination therapy has been
used in recent years to treat invasive fungal infections, but limited data from in vitro, animal, and
clinical studies have been reported. We review in
this article amphotericin B plus flucytosine,
amphotericin B plus azoles, azoles plus flucytosine, amphotericin B or azoles plus terbinafine,
and amphotericin B or azoles plus caspofungin,
as well as some of the available data on these
combinations.
Clinical trial data in which combination therapy was compared with monotherapy are available for 3 of the combinations. Overall,
combination therapy was similar and sometimes
more effective compared with monotherapy.
However, with the exception of cryptococcal
meningitis, none of the combinations was clearly
superior to monotherapy.
Clinical trial findings and clinical experience
suggest that combination therapy may be an alternative to monotherapy for invasive infections due to
multiresistant fungi, as well as an alternative for
patients who fail to respond to monotherapy.
(Advanced Studies in Medicine. 2003;3(1A):S14-S17)
*Based on a presentation given by Dr Cuenca-Estrella at
the 12th European Congress of Clinical Microbiology and
Infectious Diseases.
Address correspondence to: Manuel Cuenca-Estrella,
MD, Unidad de Micologia, Instituto de Salud Carlos III,
Centro Nacional de Microbiologia, Ctra. Majadahonda a
Pozuelo, km.2, 28220 Majadahonda, Madrid, Spain.
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ombination therapy for invasive fungal
infections is typically considered as a
therapeutic option to improve results of
treatment with a single agent, as well as
in cases of treatment failure with
monotherapy. However, clinical trial data regarding
the safety and efficacy of combination therapy remain
limited, underscoring the need for further study.
Several combinations of various antifungal agents have
been used in recent years (Table 1); these combinations, as well as some of the in vitro, animal, and clinical data, are discussed in greater detail below.
C
AMPHOTERICIN B PLUS FLUCYTOSINE
Concomitant combination therapy with amphotericin B and flucytosine is now considered the standard treatment of cryptococcal meningitis. However, a
review of the evidence reveals that, except in
Cryptococcus infections,1 the combination is not clearly
superior to monotherapy with amphotericin B. In
reviewing in vitro studies, results obtained by the
checkerboard method show that this combination
exhibits indifferent, additive, or synergistic effects
against Candida and Aspergillus species. Antagonism
has not been reported.
In contrast to the checkerboard method, which
provides only inhibitory data, other procedures, such
as the time-kill curve technique, measure microbiocidal activity and offer a dynamic picture of antimicrobial action. Data from studies using the killing curve
technique have indicated that the combination of
amphotericin B and flucytosine has additive or synergistic effects against Candida albicans isolates. Animal
models have provided limited data showing the com-
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bination is similar to or better than amphotericin B
monotherapy against Candida and molds.
Results from 5 clinical trials evaluating the combination have shown it is generally similar to and sometimes better than monotherapy with either agent alone
efficacy and is similar to monotherapy with amphotericin B in terms of safety (Table 2).2-6
Successful outcomes with this combination are
documented in case reports. Aerosolized amphotericin B plus itraconazole was more effective than
monotherapy in a patient with acquired immune
deficiency syndrome (AIDS) who developed tracheobronchial aspergillosis. In another case, amphotericin B plus itraconazole was effective in a patient
AMPHOTERICIN B PLUS AZOLES
As with the previous combination, checkerboard
studies of amphotericin B plus an azole have yielded a
variety of results, such as indifference, additive effects,
synergy, and outstandingly, antagonism. Studies using
time-kill methods have found antagonism between
amphotericin B and fluconazole toward Candida and
Cryptococcus species and between amphotericin B and
itraconazole for Aspergillus isolates.
Results from studies using animal models, however, show that amphotericin B plus either fluconazole or
itraconazole is similar to or more effective than
amphotericin B monotherapy against Candida and
Cryptococcus species, and that amphotericin B plus
itraconazole is similar to amphotericin B monotherapy, but better than itraconazole therapy against
Aspergillus species. Yet, there are some animal data that
show antagonism with this combination.
Table 1. Drug Combinations Used to Treat
Invasive Fungal Infections
Amphotericin B + flucytosine
Amphotericin B + azoles
Azoles + flucytosine
Amphotericin B or azoles + terbinafine
Amphotericin B or azoles + caspofungin
Other combinations, including amphotericin B + rifampin,
amphotericin B + quinolones, azoles + quinolones,
fluconazole + cyclosporine
Table 2. Summary Findings From 5 Reports of Combined Amphotericin B and Flucytosine Therapy
Smego et al2
Goldman et al3
Verweij et al4
Abele-Horn et al5
Silling et al6
Infection
Neonates
(n = 17)
Candida meningitis
Neutropenic
(n = 62)
Candida krusei
Monotherapy
Amphotericin B
Intensive care unit
(n = 72)
Systemic
candidiasis
Fluconazole
(400 mg)
Neutropenic
(n = 98)
Febrile
neutropenia
Fluconazole
Response rate with
combined vs
monotherapy
Combined better
Amphotericin B
(0.5 mg)
Amphotericin B (1 mg)
Combined better
than low-dose
monotherapy
Neutropenic
(n = 28)
Invasive fungal
infections
Amphotericin B
(0.5 mg)
Similar
Similar
Similar
Adverse events
with combined
vs monotherapy
Similar
Similar
Higher
with combined
Higher
with combined
Patients
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Similar
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with hepatic abscesses caused by Aspergillus terreus and
an invasive sinonasal infection due to Scopulariopsis.
Amphotericin B plus fluconazole has also been successful in treating a patient with prosthetic valve endocarditis caused by Candida, and a burn patient with an
invasive infection due to Trichosporon.
A retrospective study by Caillot et al included 30
neutropenic patients with invasive pulmonary
aspergillosis who were treated with amphotericin B
plus itraconazole or itraconazole alone; 8 of the 30
patients failed to respond to combination therapy.7 Of
the 22 patients who were cured or showed improvement with the combination or itraconazole monotherapy, 15 were also treated surgically (lung resection).
This makes it difficult to determine the extent to
which each of the treatment methods—monotherapy,
monotherapy plus surgery, combination drug therapy,
and combination drug therapy plus surgery—contributed to cure or improvement.
The most important clinical trial of the amphotericin
B plus an azole combination was conducted by Rex et
al.8 Patients with candidemia (n=236; 60% caused by C
albicans) were randomized either to amphotericin B plus
fluconazole or fluconazole plus placebo. The overall
response rates were 68% in the patients receiving 2 antifungal agents and 56% in those receiving 1 agent plus
placebo. However, the patients receiving monotherapy
had significantly higher Acute Physiology and Chronic
Health Evaluation scores (ie, they were more seriously
ill), which could have affected the results of the trial.
Despite the promising results in studies reported thus far,
more clinical studies of combinations of amphotericin B
and azoles are needed.
AZOLES PLUS FLUCYTOSINE
In vitro studies of azoles plus flucytosine have
found additive and synergistic effects against
Cryptococcus neoformans and indifference against
Candida and Aspergillus species. No antagonism in
vitro has been reported. Animal studies have found the
combination to be better than or as effective as
monotherapy, with some studies finding synergistic
effects between azoles and flucytosine, mainly in animal infections due to Cryptococcus. Clinical evidence
includes a case report of a patient with lymphoma
who developed pulmonary aspergillosis and was
treated successfully with itraconazole and flucytosine,
and another in which a patient with renal failure who
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developed disseminated candidiasis was successfully
treated with fluconazole plus flucytosine.
A double-blind randomized study compared the efficacy of fluconazole plus placebo, itraconazole plus flucytosine, and placebo plus placebo in 85 patients with
AIDS who had esophageal candidiasis.9 The 53 men and
32 women were diagnosed endoscopically and clinically
at the first episode of esophageal candidiasis and then
randomized in double-blind fashion into the 3 treatment
groups. After 2 weeks of treatment, patients previously
randomized to placebo plus placebo were then randomized in double-blind fashion to either fluconazole plus
placebo or itraconazole plus flucytosine. Endoscopic and
clinical examinations were performed at weeks 2 and 4
and at the end of follow-up (3 months). Endoscopic and
clinical cure rates at week 2 and the end of follow-up are
shown in Table 3.
The results show that both monotherapy and combination therapy are effective in the short-term treatment of esophageal candidiasis in patients with AIDS.
The results also suggest that combination therapy may
be an alternative in patients with fluconazole-resistant
Candida esophagitis.9
AMPHOTERICIN B OR AZOLES PLUS TERBINAFINE
Some in vitro studies have reported indifference for
Aspergillus and Zygomycetes species with the combination of amphotericin B and terbinafine, and there have
Table 3. Results of Monotherapy vs Combination
Therapy at 2 Weeks and 3 Months in Patients
With AIDS and Esophageal Candidiasis
Fluconazole +
Placebo (%)
Itraconazole +
Flucytosine (%)
2 Weeks
Endoscopic cure
Clinical cure
68.0
75.8
72.4
72.4
3 Months
Endoscopic cure
Clinical cure
89.8
94.8
94.8
97.3
Results
Data from Barbaro et al.9
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been some reports of antagonism with this combination in Aspergillus species. On the other hand, the
combination of an azole agent and terbinafine has
shown synergistic effects against yeasts and molds.
Animal studies evaluating voriconazole plus
terbinafine have found that its effects against Candida,
Zygomycetes, and Scedosporium species are synergistic10;
however, there are no clinical trial data at this time.
AMPHOTERICIN B OR AZOLES PLUS CASPOFUNGIN
Studies of the in vitro activity of amphotericin B plus
caspofungin have found indifference and additive or synergistic effects against various isolates of Candida,
Aspergillus, and Cryptococcus, with the type of effect varying according to the isolate. There are 3 case reports with
successful outcome, including 1 report focusing on the
combination of amphotericin B and caspofungin to treat
aspergillosis, and 2 reports on the combination of itraconazole and caspofungin in A fumigatus and A terreus
infections.11 Clinical trial data are needed to evaluate
these combinations more fully.
OTHER COMBINATIONS
Several other combinations of antifungal agents have
been studied in vitro. Amphotericin B plus rifampin has
shown additive and synergistic effects against Candida
and Aspergillus species, whereas combinations of amphotericin B plus a quinolone and fluconazole plus a
quinolone have shown additive and synergistic effects
against Candida and Mucoraceae species. Another combination, fluconazole plus cyclosporine, has shown additive and synergistic effects in vitro against C albicans.
CONCLUSIONS
Of the various antifungal combinations described
here, there are clinical trial data for only 3 of them:
amphotericin B plus flucytosine, amphotericin B plus
azoles, and azoles plus flucytosine. Except for the efficacy of amphotericin B plus flucytosine against
Cryptococcus infection, none of the 3 combinations
was clearly superior to monotherapy.
Concomitant combination therapy could be an
alternative to monotherapy for invasive infections due
to multiresistant fungi, such as Scedosporium,
Fusarium, Scopulariopsis, and Rhodotorula, and may
also be an alternative for patients who fail to respond
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to other treatments. Data from well-designed stratified
clinical trials are needed. These trials should analyze
results not only regarding patients, but also regarding
risk factors, infection, and species.
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