NEW ORLEANS--The number of presentations and overflowing symposia
devoted to antifungal resistance were testament to the concerns of
physicians attending the 36th Interscience Conference on
Antimicrobial Agents and Chemotherapy (ICAAC).
Only a decade ago, medical textbooks claimed antifungal resistance
was rare. But today, up to 10% of patients with advanced AIDS have
candida unresponsive to fluconazole (Diflucan), and rates of innately
resistant infections are rising rapidly in neutropenic patients. It
is not just resistance to the azoles but also to ampho-tericin B and
Dr. John Rex, of the University of Texas Health Science Center,
Houston, said that his presentation on the treatment of antifungal
resistance was based "on laboratory observations, clinical
anecdotes, and guesswork" because the data on new approaches
"are less than pristine."
The goal now is to determine the optimal combination therapy in each
type of infection. "People are leaning toward this targeted
simultaneous combination therapy, as with cancer," Dr. Vincent
Andriole, of Yale University School of Medicine, told a
But this can be like flying by the seat of the pants, since no
studies have validated any regimens, and physicians must rely on
anecdotal reports. "These combinations work selectively and vary
tremendously, and there is little to guide their use," Dr.
Unfortunately, the specter of resistance hanging over the azoles
precludes the almost-universal use of fluconazole, said Dr. William
Powderly, of Washington University, St. Louis, in a session on
opportunistic fungal infections in AIDS.
"For candidiasis, the strategy is to initiate local therapy,
then try ketoconazole (Nizoral), and finally fluconazole, in order to
preserve fluconazole's efficacy for more advanced disease,
particularly candida esophagitis, which has considerable
morbidity," he said.
The AIDS patient with candida who is most likely to be resistant to
fluconazole (and other azoles) has had recurrent episodes, prolonged
antifungal and systemic azole therapy, and lower CD4 counts, Dr.
In a concerted attempt to outfox these resistant organisms,
antifungal drug development has crescendoed, Dr. Andriole said.
The failure of amphotericin B in certain patients has spurred trials
of two liposomal preparations (Abelcet, Amphocil), which have
produced complete or partial responses in 28% to 50% of patients with
invasive infections. "These two preparations may be the first
step toward improving the situation," he commented.
A number of new azoles are also in the pipeline, most showing good
efficacy in animal models. Clinical data are available on UK-109,496,
or voriconazole, now in phase II European trials. This wide-spectrum
sibling of fluconazole has been shown to be effective in oral
candidiasis, chronic invasive aspergillosis and candidiasis, and
acute invasive aspergillosis, Dr. Andriole reported.
Aspergillus has also responded to several other new classes of drugs,
some now in clinical trials. These include the rapidly fungicidal
echinocandins and the pneumocandins. The new nikkomycins and
allylamines also show increased activity when used with azoles, he said.
For now, combination approaches may help, such as amphotericin B with
or without fluorouracil or itraconazole (Sporanox) for aspergillosis;
amphoteri-cin B with or without fluorouracil or fluconazole for
candidemia; fluconazole with or without amphotericin B for
trichosporosis; and fluorouracil plus fluconazole for cryptococcosis.
"But even these combinations are usually not enough," Dr.
Rex said. "Antibiotics often just buy time until the patient
gets better and his immune system takes over."
Therefore, an alternative approach is to focus on the host response.
Protease inhibitors do this in AIDS patients. And in cancer patients,
colony stimulating factors (CSFs) can lessen neutropenia. And
finally, Dr. Rex and co-workers have shown that white blood cells
collected from healthy donors treated with G-CSF can be used to
temporarily reverse neutropenia in selected patients.
"The cells are stronger, sturdier, longer lasting. This may
prove to be a tool we can use while we are waiting for the patient's
own response to take over," Dr. Rex said.