FUNGAL INFECTIONS

What are fungal infections?

Fungi include both yeasts and moulds. Thousands exist and a few infect humans. Of these, some invade the skin, causing mild infections, such as ringworm and athlete's foot. Yeasts, especially Candida, infect the mucous membranes of the mouth and vagina, and cause thrush. Aspergillus, Candida, Pneumocystis and Cryptococcus can also invade the body in people with weak or suppressed immune systems (e.g. AIDS, transplant patients, cancer patients) and cause life-threatening infections.

Who do fungal infections affect?

Anyone can pick up minor fungal infections of the skin or nails. But infections requiring hospital treatment, especially invasive candidiasis and aspergillosis, have doubled in the past 15 years to around 4 per 1000 patients. They are the hidden killers, reflecting the increased use of immunosuppressive therapy in cancer and transplantation, which allow infections to take hold more easily. Patients undergoing surgery form the largest at risk group for such invasive infections and a recent analysis has shown that preventive use of an antifungal medication can reduce invasive fungal infections by a half and overall deaths by a quarter.

Present treatments and shortcomings

One class of powerful antifungal molecules, the azoles, hold most of the top ten places for antifungal medicines. They include fluconazole (Diflucan, Pfizer), itraconazole (Sporanox, Janssen- Cilag), and ketoconazole (Nizoral, Janssen-Cilag). They work by blocking the formation of ergosterol, a key component of fungal cell membranes. Fluconazole is able to cure candidiasis with a single oral dose, is active against cryptococcal meningitis in AIDS patients, and also has a role in preventing infection in bone marrow transplant recipients. However, as with bacteria (see Bacterial Infections), resistant strains are becoming an increasing problem. Two newer azole antifungals that may help in this respect are voriconazole (VFEND, Pfizer) and posaconazole (Noxafil, Schering-Plough), both of which are indicated for use in invasive fungal infections.

An older medicine with an important role to play in fungal infections is amphotericin B. Abelcet (Zeneus) and Ambisome (Gilead) show less kidney damage and can be given at a higher dose than the conventional formulation. Other oral antifungals include terbinafine (Lamisil, Novartis, also available in topical form) which is used for the treatment of skin and nail infections. Terbinafine acts by inhibiting an enzyme which is involved in the production of ergosterol.

A completely new class of antifungal agents is represented by caspofungin (Cancidas, Merck Sharp & Dohme), which has been developed for the intravenous treatment of invasive aspergillosis and invasive candidiasis and for the treatment of suspected fungal infections in patients with fever who have low levels of white blood cells. Caspofungin belongs to the echinocandin family of antifungals, which block the production of a major component of the fungal cell wall and are effective in killing fungi, rather than just stopping them growing.

What's in the development pipeline?

Further compounds are in development for the treatment of invasive Candida infections. Astellas has developed micafungin (Mycamine) and Pfizer's anidulafungin has completed Phase 3 trials. Indevus is also developing aminocandin, but this compound has so far only completed Phase 1 trials.

A completely different approach to systemic candidiasis has been taken by Neutec Pharmaceuticals (now Novartis), whose Mycograb has also completed trials. Mycograb works with amphotericin B in candidiasis and data suggest that it may have activity against Aspergillus and against the organism Cryptococcus, which causes meningitis in people with AIDS.

In other developments, Basilea Pharmaceuticals has conducted Phase 2 trials of a new broad-spectrum azole (BAL8557) that was active against fluconazole-resistant Candida, Novartis has completed Phase 3 studies of the use of terbinafine (Lamisil) cream to treat the scalp infection tinea capitis in children, and York Pharma has a topically applied agent (abafungin, Abasol) of a new type, with both antifungal and antibacterial activity, for fungal skin infections.

The longer-term future

With several compounds in development, the range of treatment options, especially for systemic fungal infections, looks set to be greater than for many years. Nevertheless, the constant emergence of resistant strains is a factor that will make necessary continuing efforts to pinpoint the small but distinctive weak points of fungal cells that can be exploited to eliminate them.