Antifungal Resistance on the Increase

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 flucytosine (Ancobon).

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 standing-room-only crowd.

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. Andriole added.

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. Powderly added.

New Drugs

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.