Clinical Pharmacology of Systemic Antifungal Agents: A Comprehensive Review of Agents in Clinical Use, Current Investigational Compounds, and Putative Targets for Antifungal Drug Development

Two isolates of Candida albicans from chronic mucocutaneous candidosis patients who initially responded to ketoconazole treatment but who later relapsed, have shown an abnormal response to ketoconazole in four out of five systems in vitro and in three animal models of vaginal or systemic infection. They have also shown abnormal resistance to inhibition of ergosterol biosynthesis in whole cells, but not in cell-free systems, and to inhibition of amino acid uptake. We conclude that the behaviour of the isolates is consistent with the development of drug resistance to ketoconazole. In all systems the two isolates have shown cross-resistance to the triazole antifungal ICI 153,066. In addition they fail to take up radiolabelled ICI 153,066--in contrast to normal isolates--indicating that resistance is due to changes in the properties of the cell membrane rather than internal enzymology.

Azole resistance in Candida albicans

The currently available drugs for the treatment of systemic fungal infections are amphotericin B, flucytosine, miconazole and ketoconazole.

Clinical Pharmacokinetics of Systemic Antifungal Drugs

Ketoconazole is a well-tolerated oral antifungal agent with a broad spectrum of activity in vitro, but in vitro testing has not yet been correlated to in vivo results. In addition, many variables that can alter in vitro test results have been identified. The drug shows effectiveness in the treatment of paracoccidioidomycosis, chronic mucocutaneous candidiasis, oral thrush, coccidioidomycosis and histoplasmosis. It was recently approved for use in blastomycosis. It is not yet approved for use in dermatophyte infections, but a large body of literature exists supporting this application. Ketoconazole has several reported drug interactions, including lower bioavailability with cimetidine, accumulation of cyclosporin during concurrent therapy and a possible disulfiram-like reaction with alcohol. It is highly protein bound to albumin and is extensively metabolized. Dosage adjustment is not required in renal failure. The main side effects are gastrointestinal and occur in 5-10% of the patients. Rare side effects include gynecomastia and hepatotoxicity. The latter is reported to occur in 1 of 12,000 patients. Ketoconazole impairs testosterone synthesis, and therefore it is recommended that administration more than once daily be avoided in men. The usual dosage is 200-400 mg administered once daily. Few comparative or controlled studies have been published thus far. How it compares to amphotericin B is not known. The optimum dosage and the optimum duration of therapy are not established.

C.H Kirkpatrick

Papers

Ketoconazole and the liver.