Chemotherapy of the Systemic Mycoses

Graybill, John R.

doi:10.1055/s-2007-1012707

Cited by 3 publications

(2 citation statements)

References 60 publications

(74 reference statements)

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“…The most frequent adverse effects observed during griseofulvin therapy are gastrointestinal disturbances and headache. The most serious adverse effect of flucytosine is myelosuppression (Graybill 1987).…”

Section: Antifungal Activity Therapeutic Use and Adverse Effectsmentioning

confidence: 99%

Pharmacokinetic Optimisation of Oral Antifungal Therapy

Schäfer‐Korting

1993

Clinical Pharmacokinetics

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The range of oral antifungal therapy has been expanded recently by the introduction of itraconazole, and terbinafine. These agents have a broader spectrum of activity than griseofulvin and flucytosine, and induce less liver toxicity than ketoconazole. Treatment with these agents may be optimised by application of pharmacokinetic principles. Griseofulvin, ketoconazole and itraconazole should be administered with food to ensure adequate absorption. Maximal absorption of griseofulvin is achieved by administration of the drug as a solid solution in polyethylene glycol. Absorption of azole antifungal agents is impaired by high gastric pH, which is observed in some patients with acquired immunodeficiency syndrome. It is also impaired by frequent vomiting, which commonly occurs in patients with neutropenia. Furthermore, antacids, H2-antagonists and sucralfate interfere with absorption of ketoconazole. The newer oral antifungals are more slowly eliminated and associated with less pronounced drug interactions than ketoconazole. As with ketoconazole, itraconazole and fluconazole influence cyclosporin metabolism. These effects are of clinical relevance and necessitate cyclosporin dosage reduction. However, the cyclosporin dosage reduction required during coadministration of itraconazole and fluconazole (50 to 55%) is less than that required when ketoconazole is concomitantly administered (85%). Monitoring of cyclosporin concentrations during coadministration with these agents is necessary to avoid nephrotoxicity. Drug monitoring is also advisable when phenytoin, carbamazepine or rifampicin (rifampin) are administered concomitantly with azoles, due to a mutual influence on drug metabolism. The antifungal activity of itraconazole is not related exclusively to free drug concentrations. Therefore, the low protein binding of fluconazole does not place this agent at an advantage over itraconazole in the treatment of fungal meningitis. However, terbinafine may be superior to itraconazole for the treatment of tinea unguium, another recalcitrant fungal disease, because terbinafine more rapidly penetrates the nail plate. During repeated use, itraconazole concentrations increase slowly in the nail plate. Steady-state concentrations are reached in the stratum corneum only after several weeks' administration. Following cessation of treatment, terbinafine, itraconazole and ketoconazole concentrations in keratinised tissues decline slowly. This allows a short duration of drug treatment. Some clinical trials suggest that low concentrations of flucytosine, griseofulvin and itraconazole are associated with treatment failure. Flucytosine-induced myelotoxicity also appears to be concentration dependent. This adverse reaction may be caused by fluorouracil (which is produced by metabolism of flucytosine by enterobacillary flora in the gut) rather than by the parent compound.

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Section: Antifungal Activity Therapeutic Use and Adverse Effectsmentioning

confidence: 99%

Pharmacokinetic Optimisation of Oral Antifungal Therapy

Schäfer‐Korting

1993

Clinical Pharmacokinetics

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“…To the Editor: Graybill,1 in an otherwise exemplary report on the chemotherapy of infection with Blastomycosis dermatitidis (BD), observed that the first drugs available for the treatment of such patients were the polyenes (amphotericin B), followed by a fluorinated pyrimidine (flucytosine), and then the azole compounds (ketoconazole). I would invite his attention to the use of the aromatic diamidines which were actually the first effective agents used and indeed their use may be considered to have initiated the period of effective chemotherapy of the fungal diseases.…”

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confidence: 99%