Resistance is thought to be mediated through altered metabolism of flucytosine, and, although uncommon in primary isolates, it develops rapidly in the course of flucytosine monotherapy.
The spectrum of activity of flucytosine is restricted to C neoformans, some Candida sp, and the dematiaceous molds that cause chromoblastomycosis. Flucytosine is rarely used as a single agent because of its demonstrated synergy with other agents and to avoid the development of secondary resistance. At present clinical use is confined to combination therapy with amphotericin B for cryptococcal meningitis, or with itraconazole for chromoblastomycosis. Flucytosine also has limited utility as monotherapy for fluconazole-resistant candidal urinary tract infections.
The adverse effects of flucytosine result from metabolism (possibly by intestinal flora) to the toxic antineoplastic compound fluorouracil. Bone marrow toxicity with anemia, leukopenia, and thrombocytopenia are the most common adverse effects, with derangement of liver enzymes occurring less frequently. A form of toxic enterocolitis can occur. There seems to be a narrow therapeutic window, with an increased risk of toxicity at higher drug levels and resistance developing rapidly at subtherapeutic concentrations. The use of drug concentration measurements may be helpful in reducing the incidence of toxic reactions, especially when flucytosine is combined with nephrotoxic agents such as amphotericin B.
Azoles are synthetic compounds that can be classified as either imidazoles or triazoles according to the number of nitrogen atoms in the five-membered azole ring, as indicated below. The imidazoles consist of ketoconazole, miconazole, and clotrimazole
FIGURE 48–2 Structural formulas of some antifungal azoles.
(Figure 48–2). The latter two drugs are now used only in topical therapy. The triazoles include itraconazole, fluconazole, voriconazole, isavuconazole, and posaconazole. Other triazoles are currently under investigation.
N X X = C, imidazole X = N, triazole N
The pharmacology of each of the azoles is unique and accounts for some of the variations in clinical use. Table 48–2 summarizes the differences among six of the azoles.
Mechanisms of Action & Resistance
The antifungal activity of azole drugs results from the reduction of ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes (Figure 48–1). The selective toxicity of azole drugs results from their greater affinity for fungal than for human cytochrome P450 enzymes. Imidazoles exhibit a lesser degree of selectivity than the triazoles, accounting for their higher incidence of drug interactions and adverse effects.
Resistance to azoles occurs via multiple mechanisms. Once rare, increasing numbers of resistant strains are being reported, suggesting that increasing use of these agents for prophylaxis and therapy may be selecting for clinical drug resistance in certain settings.
Clinical Uses, Adverse Effects, & Drug Interactions
The spectrum of action of azole medications is broad, including many species of Candida, C neoformans, the endemic mycoses (blastomycosis, coccidioidomycosis, histoplasmosis), the dermatophytes, and, in the case of itraconazole, posaconazole, isavuconazole, and voriconazole, even Aspergillus infections. They are
TABLE 48–2 Pharmacologic properties of six systemic azole drugs.
also useful in the treatment of intrinsically amphotericin-resistant organisms such as P boydii.
As a group, the azoles are relatively nontoxic. The most common adverse reaction is relatively minor gastrointestinal upset. All azoles have been reported to cause abnormalities in liver enzymes and, very rarely, clinical hepatitis. Adverse effects specific to individual agents are discussed below.