SAN DIEGO — The incidence of cutaneous fungal infections is on the rise in the United States, and the old standby antifungal drugs aren't working as well as they used to, Dr. Ted Rosen said at the American Academy of Dermatology's Academy 2006 conference.
Fortunately, new antifungals are emerging that could stem the mycologic mayhem, at least for a while.
The rise in fungal infections can be partly attributed to an increase in the number of immunosuppressed people living ever-longer lives. HIV-positive people on highly active antiretroviral therapy (HAART), survivors of cancer chemotherapy, and organ transplant recipients on immunosuppressive drugs are all highly susceptible to systemic mycoses, said Dr. Rosen of the department of dermatology at Baylor College of Medicine, Houston.
Another key factor is the unprecedented mobility of the population. More people travel more often and farther than at any other time in history. Immigrants come to the United States from regions that are endemic for fungi seldom seen here in the past.
Tertiary care centers like Baylor are reporting increases in fungi such as Cryptococcus, Histoplasma capsulatum, Sporothrix, Fusarium, Rhizopus, and Fonsecaea, which often go unrecognized or misdiagnosed for a long time. Given the high numbers of military and oil-industry personnel in Texas, Baylor clinicians are seeing a rise in strange fungal infections in troops and oil workers returning from Iraq, the Persian Gulf, and South America.
Moreover, mainstay drugs like fluconazole, itraconazole, ketoconazole, terbinafine, and griseofulvin are more widely used than ever, applying plenty of selective pressure on the fungi to develop resistance.
Which is just what is happening.
Dr. Rosen cited a recent report of terbinafine-resistant Trichophyton rubrum in a patient with onychomycosis who had never before been treated with an antifungal. “We're seeing innate resistance in a garden-variety form of T. rubrum. This old 'friend' is suddenly nonresponsive to a very powerful antifungal drug. This is problematic,” he said.
Fortunately, he noted, a passel of new antifungals is making its way into clinical practice, including a whole new class of cell wall-smashing echinocandins.
All of the azoles, including new ones like voriconazole (Vfend) and posaconazole (Noxafil)—as well as ravuconazole, which is not yet approved—attack fungal cell membranes.
Voriconazole has a broad spectrum and is highly effective against all species of Candida. It also works against Aspergillus and Fusarium, which generally won't yield to fluconazole. In vitro, voriconazole bests griseofulvin and ketoconazole, and it equals terbinafine in killing dermatophytes. It is also extremely bioavailable in oral dosing forms, Dr. Rosen said.
This new drug does have its downside, mainly its strong potential for adverse effects. It is metabolized via two cytochrome P450 enzymes, so it is capable of interacting with other drugs, at least in theory. It induces liver enzyme elevations, which are reversible, and it can also trigger morbilliform eruptions.
The most common adverse effect of voriconazole, though, is visual disturbances. Dr. Rosen said that a number of patients experience photophobia or a very specific visual disturbance characterized by bluish purple halos around objects.
Purple haze aside, Dr. Rosen said he's used this drug a lot, and in his experience, it is reasonably problem free. “I've used it off-label to treat patients who've failed everything else.”
Posaconazole was approved in September under the brand name Noxafil for the treatment of aspergillosis. Metabolism of posaconazole involves only one CYP 450 enzyme, so this drug is less likely to cause interactions. Side effects are “pretty reasonable,” said Dr. Rosen, the most common being headache and nausea.
“What really makes this drug stand out, aside from its ability to deal with weird fungi, is that it really works for zygomycetes—those deep fungi that really penetrate the nasopharynx in diabetes patients and transplant recipients. It's also great for everything refractory, and it does this orally,” Dr. Rosen said.
Ravuconazole initially looked quite promising, with excellent in vitro efficacy against dermatophytes, but further development seems to have stalled for reasons that are not clear, he said.
Albaconazole, the newest triazole, is still in a very early developmental stage, but “it is better than itraconazole, fluconazole, or voriconazole for almost all of the common dermatophytes and saprophytes, and at least as good as or better than all the existing triazoles,” Dr. Rosen said.
The good news for physicians is that albaconazole will be initially formulated as a nail lacquer along with oral and intravenous forms.
The echinocandins bring a new therapeutic mechanism into the antifungal picture: They break down the fungal cell walls by attacking the glucan building blocks and inhibiting the enzyme complexes involved in synthesizing glucans.