The prevention and treatment of invasive fungal infections is being
improved by the relatively recent introduction of new antifungal
agents. While some of these agents offer better efficacy, others are
proving their value more in improved tolerability, said John R.
Wingard, md, at a session on Supportive Care for the
Immunocompromised Host during the 1999 American Society of Hematology
meeting. Dr. Wingard is professor of medicine and director of the
bone marrow transplant program at the University of Florida at Gainesville.
One of the most important recent advances is a better formulation of
amphotericin, specifically the lipid compounds, he said. These agents
were developed to improve upon the narrow therapeutic ratio of
amphotericin B, increase efficacy, and reduce toxicity. In the United
States, there are three commercial products with different molecular
structures: amphotericin B lipid complex (ABLC, Abelcet),
amphotericin B cholesteryl (ABCD, Amphotec), and liposomal
Compared to standard amphotericin B, Dr. Wingard said, these
agents achieve lower concentrations in the kidneys, the site of the
principal toxicity, and higher concentrations in the liver, lungs,
and spleen, where infection frequently occurs.
Four Randomized Trials
Dr. Wingard said that four prospective randomized controlled trials
have evaluated the lipid formulations of amphotericin B in treating
established invasive fungal infections. Settings have included Candida
infection, invasive Aspergillus infection, proven and
suspected fungal infections in the neutropenic patient, and
cryptococcal meningitis. All three lipid formulations have been much
less toxic than amphotericin B, demonstrating substantially lower
rates of nephrotoxicity and (with liposomal amphotericin) less
infusional toxicity. While these findings are the good
news, Dr. Wingard said, the disappointing finding has been a
lack of superior responses and survival rates vs standard
amphotericin B in clinical trials, although there have been trends
toward improved responses and the study populations have been limited.
In the allogeneic transplant patients, who are very susceptible
to severe nephrotoxicity to start with, a lipid formulation makes
sense, Dr. Wingard stated. While they are substantially
more expensive, the cost of nephrotoxicity and hemodialysis are higher.
I do not use lipid formulations with the idea that I am going
to get a better therapeutic advantage except in amphotericin
failures, but clearly they are substantially less toxic, he
explained. ABCD has more cardiorespiratory infusional reactions
compared to the other lipid formulations and the parent compound.
AmBisome clearly has substantially fewer infusional toxicities but
tends to be more expensive, so one has to weigh what one would value
in terms of those greater rates of infusional toxicities. Different
people are coming down on different sides of that issue, he commented.
Efforts are underway to find the most effective and least toxic doses
of the newer lipid compounds, he said. Most clinical trials have used
4 to 5 mg/kg/d, although several studies have evaluated lower doses.
A European Organization for Research and Treatment of Cancer (EORTC)
randomized study of liposomal amphotericin B in invasive Aspergillus
infections gave ABLC at a dose of either 1 mg/kg/d or 4 mg/kg/d
to neutropenic cancer patients and bone marrow recipients with proven
or probable infections. The lower dose produced results similar to
the higher dose: No statistically significant differences were shown
in either response or mortality, although the higher doses tended to
be more effective in persons with proven infection. The study lent
support to the view that lower and therefore less expensive doses
might achieve the same desirable benefits, Dr. Wingard said, but
because of its small sample size, more study is needed.
About the Triazoles
Another family of antifungal compounds, the triazoles, are highly
efficacious in the treatment of yeast infections, Dr. Wingard said.
Studies comparing fluconazole (Diflucan) with amphotericin for the
treatment of established systemic Candida infections have
found similar efficacy, in the range of 71% to 79%. As with the lipid
formulations of amphotericin B, fluconazole has been associated with
substantially fewer nephrotoxic events than standard amphotericin.
But the majority of study subjects have not been neutropenic;
therefore, data remain lacking as to the adequacy of this approach in
neutropenic patients. There are also substantial gaps in the
antimicrobial coverage provided by fluconazole, especially with
several species of Candida and Aspergillus, he noted.
The newest of these agentsitraconazole (Sporanox)has
substantial in vitro activity against Aspergillus. While this
antifungal drug might provide an alternative to the polyenes in the
management of Aspergillus infections, in the group most
susceptible to these infectionsleukemic patients and bone
marrow recipientsthe pharmacokinetic profile of itraconazole is
quite variable and may be seriously compromised, according to recent
While a cyclodextran formulation has been developed to improve
bioavailability, the taste is unpleasant. Moreover, itraconazole is
prone to more drug interactions than fluconazole, particularly in
combination with cyclosporin and FK506, Dr. Wingard added.
Nevertheless, Dr. Wingard called itraconazole a potentially
exciting approach because it not only controls yeast infections
but potentially also Aspergillus. A randomized double-blind
study of 405 patients compared prophylactic itraconazole (2.5 mg/kg
twice daily of the cyclodextran solution) vs placebo. Patients were
neutropenic for about 2 weeks and were receiving autologous bone
marrow transplants or chemotherapy for acute leukemia and other
cancers. The itraconazole group had significantly fewer episodes of
fungemia (0.5% vs 4%), but there was no reduction in proven Aspergillus
infections. Moreover, there was a trend toward fewer suspected
infections of all types, but no difference in mortality.
We need more data to help us understand whether itraconazole is
just another way of controlling yeast infections, like fluconazole,
or whether it will play a substantial role in preventing Aspergillus,
he told the audience.
Several new triazoles are now in randomized trials. Their potential
clinical and pharmacologic advantages include a substantially broader
spectrum of antifungal activity, improved bioavailability, and fewer
Other new generations of antifungal compounds look promising in
clinical trials, including the echinocandins. They have a broad
spectrum of activity, lack cross-resistance with the azoles and may
have additive or synergistic effects with other antifungals, thus
opening the possibility of more effective combination therapy.
Invasive Infections: Changes in Approach
Invasive fungal infections are hard to diagnose early in their
course, when they could be most effectively treated. In the
immunocompromised host, signs and symptoms are attenuated and
clinical clues may be masked by deficits in host defenses. Empiric or
prophylactic approaches, therefore, are often relied upon in these
patients, and empiric antifungal therapy has become standard in the
setting of neutropenia and persistent fever, based on the findings of
the EORTC group and other investigators.
The lipid formulations have been evaluated as an alternative to this
approach, with mixed results, Dr. Wingard said. Walsh and colleagues
conducted a randomized, double-blind trial in neutropenic patients
with persistent fever. Subjects received 4 days of antibiotics, then
were randomized to either amphotericin B or liposomal amphotericin
given at doses of 0.6 mg/kg/d or 3 mg/kg/d, respectively. Success was
defined as survival with defervescence, with no breakthrough
infection or withdrawal due to toxicity.
We were disappointed to see that we did not have greater rates
of success, survival, or defervescence with liposomal amphotericin.
Also, there were no fewer rates of withdrawal from the study in
patients receiving the new agent, Dr. Wingard reported.
There were, however, fewer proven invasive fungal
infections3% vs 8%in the AmBisome group. . . So if you
analyze only the proven infections, there is a clear-cut advantage.
Also, as with lipid formulations, there was a substantial benefit in
terms of nephrotoxicity and infusional toxicity, he said.
Dr. Wingard reiterated that itraconazole clearly has a role in
invasive fungal infections, although its specific place is still
being defined. The new intravenous formulation of itraconazole with
suspension in cyclodextran has been compared to amphotericin B in a
prospective, randomized, open-label trial in patients with
hematologic malignancies and neutropenia. In nearly 400 patients
treated for 7 to 8 days, the investigators found a trend toward a
better response rate with itraconazole48% vs 38% (P =
.055). Only five infections developed in each group (Candida and
Aspergillus in both).
Clearly, itraconazole has a role, Dr. Wingard observed.
Fluconazole also has an established prophylactic role in allogeneic
bone marrow transplant, where it achieves not only an antifungal
effect but a survival advantage as well. The current question is
whether fluconazole has a role in nonallogeneic bone marrow
transplant patient groups.
A multicenter, randomized, double-blind study from a Canadian
cooperative group used 400 mg/d of fluconazole in patients receiving
induction therapy for acute leukemia or undergoing autologous bone
marrow transplant. The study found a substantial reduction in
invasive infections3% vs 17%as well as fewer superficial
infections and fewer fungal deaths0.6% vs 4%with
fluconazole. Unfortunately, substantial numbers of patients still had
persistent unexplained fever. A meta-analysis of all the fluconazole
prophylaxis studies has shown a reduced need for empiric amphotericin
B when fluconazole is used prophylactically, he added.
Need for Quicker Diagnosis
If we could diagnose these infections much earlier, we would be
less reliant on empiric and prophylactic approaches, Dr.
Wingard observed. That would have important advantages in terms
of reducing patients exposure to these drugs, cost of drugs,
antifungal resistance, and toxicity, as well as in improving survival
rates. To accomplish this, we need improved diagnostic techniques.
A number of tests have been under evaluation, including antigenic
panels, immunodiagnostic panels, DNA and RNA probes, and polymerase
chain reaction (PCR) assays. While all appear promising, these tests
are not yet commercially available in the United States. (In Europe,
there is an antigen assay for Aspergillus.)
It is also important to enhance host resistance by reducing the
exposure of patients to these organisms, he said. We need to be
mindful of infection-control measures in place in our hospitals to
prevent breakthrough infections and to reduce nosocomial
transmission. And we need to be vigilant with regard to the managed
care environment, where more and more patients are seen as
out-patients and in home-care settings.