Terbinafine interferes with ergosterol biosynthesis, and thereby with the formation of the fungal cell membrane. It is absorbed from the gastrointestinal tract and undergoes extensive metabolism in the liver (tY2 14 h). Terbinafine is used topically for dermatophyte infections of the skin and orally for infections of hair and nails where the site (e.g. hair), severity or extent of the infection render topical use inappropriate (see p. 315). Treatment (250 mg/d) may need to continue for several weeks. It may cause nausea, diarrhoea, dyspepsia, abdominal pain, headaches and cutaneous reactions.
Griseofulvin prevents fungal growth by inhibiting mitosis. The therapeutic efficacy of griseofulvin depends on its capacity to bind to keratin as it is being formed in the cells of the nail bed, hair follicles and skin, for dermatophytes specifically infect keratinous tissues. Griseofulvin does not kill fungus already established, it merely prevents infection of new keratin so that the duration of treatment is governed by the time that it takes for infected keratin to be shed; on average, hair and skin infection should be treated for 4-6 weeks while toenails may need a year or more. Treatment must continue for a few weeks after both visual and microscopic evidence have disappeared. Fat in a meal enhances absorption of griseofulvin; it is metabolised in the liver and induces hepatic enzymes (t\ 15 h).
Adverse reactions include gastrointestinal upset, rashes, photosensitivity, headache, and also various central nervous system disturbances.
Flucytosine (5-fluorocytosine) is metabolised in the fungal cell to 5-fluorouracil which inhibits nucleic acid synthesis. It is well absorbed from the gut, penetrates effectively into tissues and almost all is excreted unchanged in the urine (t/, 4 h). The dose should be reduced for patients with impaired renal function, and the plasma concentration should be monitored. The drug is well tolerated when renal function is normal. Candida albicans rapidly becomes resistant to flucytosine which ought not to be used alone; it may be combined with amphotericin (see Table 14.2) but this increases the risk of adverse effects (leucopenia, thrombocytopenia, enterocolitis) and it is reserved for serious infections where the risk-benefit balance is favourable (e.g. Cryptococcus neoformans meningitis).
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