Progress in antifungal chemotherapy

Journalof Medicaland VeterinaryMycology(1992), 30, Supplement1, 197-199 Progress in antifungal chemotherapy P. H. JACOBS 1, D. J. D R U T Z 2, U. BUDIMULJA 3, G. C A U W E N B E R G H 4, Y. KOLTIN 5, S. NOLTING 6 ANt) P. DE DONCKER 4 Treatment of vaginal candidiasis Vaginal candidiasis is an extremely common disorder (18-51%) of Indonesian women. Host factors implicated in the transformation from asymptomatic colonization to symptomatic vaginitis include antibiotic usage (especially if broad-spectrum and prolonged), the effects of endogenous or exogenous hormones (oestrogen, corticosteroids), pregnancy, immunosuppression, uncontrolled diabetes mellitus, poor local hygiene, and an extragenital reservoir such as the gastrointestinal tract. In managing these infections, it is important to identify the predisposing factors and reverse them. However, antifungal therapy of some sort is nearly always required as well. Oral therapy is generally superior to topical therapy in that it eliminates Candida from the deeper mucosal layers of the vagina, while simultaneously reducing intestinal tract carriage. Studies have confirmed that patients universally prefer oral therapy over topical preparations, with resulting improved compliance. In patients with acute Candida vaginitis, single-day therapy is preferable (e.g. itraconazole, 200 mg twice a day, or fluconazole, three 50 mg capsules administered once). Single-day therapy has the advantage of convenience and low incidence of side effects when compared with longer or repeated doses of systemic therapeutic agents. However, in chronic recurrent vaginal candidiasis, longer or repeated courses of therapy may be required, including the possibility of prophylactic pulse therapy prior to menstruation. Cytochrome P-450 selectivity with azole antifungais Azoles interact with P-450 enzyme systems in fungal cells, resulting in impaired ergosterol synthesis, accumulation of abnormal sterols, a defective cell wall, and ultimate fungal death. However, azoles also interact with mammalian P-450 enzyme systems that are responsible for synthesis of a number of normal 'endobiotics' (e.g. cholesterol, leukotrienes, thromboxanes, retinoic acid, glucocorticoids, mineralocorticoids, androgens). Interference with the synthesis of these key metabolic products accounts for many of the side-effects of azole therapy. However, it is not always certain whether interference with endobiotic synthesis is necessarily undesirable. For example, above and beyond their intrinsic antifungal effects, azoles exhibit a variety of interesting phenomena: (i) oral and topical ketoconazole have shown therapeutic efficiency in scalp psoriasis, seborrheic dermatitis, and dandruff; (ii) topical ketocona197 1Department of Dermatology, Stanford University Medical Center, Stanford, CA, USA; 2Daiichi Pharmaceutical Corporation, Fort Lee, N J, USA; 3Department of Dermato-Venerology, University of Indonesia, Jakarta, Indonesia; 4Janssen Research Foundation, Beerse, Belgium; 5Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv, Israel, and 6Department of Dermatology, Universitas-Hautklinik, Munster, Germany 198 JACOBS E T A L . Topical ketoconazole in seborrheic dermatitis and dandruff Both ketoconazole 2% cream (for local seborrheic dermatitis on glabrous skin) and ketaconazole 2% shampoo (for scalp seborrheic dermatitis and dandruff) exhibit dramatic therapeutic efficacy in seborrheic dermatitis and dandruff. A variety of double-blind and comparative studies of ketoconazole vs. placebo, corticosteroids, selenium sulphide, zinc pirythrone and econazole have demonstrated that topical ketoconazole is able not only to relieve symptoms, but is also usually superior to the alternative treatments. While acknowledging that metabolic effects of the ketoconazole might account for some of the therapeutic efficacy (inhibition of 5-1ipoxygenase; inhibition of the metabolism of all-trans retinoic acid; inhibition of cholesterol production in keratinocytes and sebocytes), the effects that ketoconazole has on the yeast Pityrosporurn are important. Pityrosporum is a normal skin commensal, for which there has long been a suspected pathogenic role in seborrheic dermatitis and dandruff. Ketoconazole, in vitro, is an extremely potent inhibitor of Pityrosporum when compared with other antifungal agents (clotrimazole, econazole, miconazole, fluconazole). Since improvement in seborrheic dermatitis and dandruff occurs in parallel with a decline in recoverability of Pityrosporum from involved skin, one can conclude that the efficacy of ketoconazole in these conditions is related primarily to its antifungal effects. Molecular strategies for devising improved antifungal agents A major limitation to the development of new antifungal drugs is a limited understanding of the basic virulence mechanisms of pathogenic fungi. Thus, it is difficult for appropriate targets to be identified. The great molecular similarities that exist between fungi and mammalian cells also pose problems. Indeed, simple yeasts such as Saccharomyces cerevisiae commonly serve as model systems for understanding the basic biology of higher eukaryotes. An extremely powerful tool for identifying virulence mechanisms is gene disruption, wherein a single gene and its products are selectively eliminated, and the impact on fungal cell survival and virulence can be assessed. Although a transformation system for Candida albicans has been developed, the absence of a sexual cycle in this fungus has limited the applicability and interpretability of gene disruption experiments. It is the sexual cycle and identification of those cells that do not survive because of the gene disruption, that allows interpretation of a lethal event. Sequence analysis of genes from fungi and from higher eukaryotes has revealed zole is active in acne and has also shown anti-inflammatory effects; and (iii) oral ketoconazole has shown activity in hirsutism and in prostatic cancer. This raises the question of whether or not the ability of ketoconazole to regulate the inflammatory response and cell proliferation might not contribute beneficially to the healing process of fungal infections. Therefore, when new candidate azoles are examined for activity in screening systems, these should examine as many fungal and mammalian P-450 isoenzymes as possible. In this way, agents might be identified that have not only antifungal activity, but also exhibit desirable effects on specific mammalian enzyme targets. ANTIFUNGAL CHEMOTHERAPY 199 CONTRIBUTORS The contributors to this symposium were: V. Budimulja, Treatment of vaginal candidiasis; G. Cauwenbergh, Cytochrome P-450 selectivity with azoles; Y. Koltin, Strategies for devising improved antifungal agents; S. Nolting & P. De Donker, Topical ketoconazole in seborrhoeic dermatitis and dandruff." a review. The co-convenors were P. H. Jaeohs and D. J. Drutz. a high degree of conservation (...truncated)