Thymidylate dUMP--^dTMP

FIGURE 48-2 Action of flucytosine in fungi. 5-Flucytosine is transported by cytosine permease into the fungal cell, where it is deaminated to 5-fluorouracil (5-FU). The 5-FU is then converted to 5-fluorouracil-ribose monophosphate (5-FUMP) and then is either converted to 5-fluorouridine triphosphate (5-FUTP) and incorporated into RNA or converted by ribonucleotide reductase to 5-flu or o-2'-deoxyuridine-5'-monophosphate (5-FdUMP), which is a potent inhibitor of thymidylate synthase. 5-FUDP, 5-fluorouridine-5'-diphosphate; dUMP, deoxyuridine-5'-monophosphate; dTMP, deoxyuridine-5 -monophosphate UPRTase, uracil phosphoribosyl transferase.

absorption, distribution, and excretion

Flucytosine is absorbed rapidly and well from the GI tract, widely distributed, and minimally bound to plasma proteins. Flucytosine concentration in CSF is 65—90% of that found simultaneously in plasma. Approximately 80% of a dose is excreted unchanged in the urine. The t/2 of the drug normally is 3-6 hours but may reach 200 hours in renal failure. Dose modification is necessary in patients with decreased renal function, and plasma concentrations should be measured periodically to maintain peak concentrations of 50-100 jlg/mL. Flucytosine is cleared by hemodialysis, and patients should receive a single dose of 37.5 mg/kg after dialysis; the drug also is removed by peritoneal dialysis.

therapeutic uses

Flucytosine (ancobon) is clinically useful for Cryptococcus neoformans, Candida spp., and chro-moblastomycosis. It is given orally at 100 mg/kg/day, in divided doses at 6-hour intervals and is used predominantly in combination with amphotericin B. An all-oral regimen of flucytosine plus fluconazole has been advocated for therapy of AIDS patients with cryptococcosis, but the combination has substantial GI toxicity without evidence that flucytosine improves the outcome. The combination of flucytosine with C-AMB runs the risk of substantial bone marrow suppression or colitis if the flucytosine dose is not promptly adjusted downward if amphotericin B—induced azotemia occurs. It is common practice in HIV-negative patients with cryptococcal meningitis to begin with C-AMB or ambisome plus flucytosine and change to fluconazole after the patient has improved.

untoward effects Flucytosine may cause leukopenia and thrombocytopenia. Rash, nausea, vomiting, diarrhea, and enterocolitis also have been noted. In ~5% of patients, hepatic transaminases are elevated, but this reverses when therapy is stopped. Toxicity is more frequent in patients with AIDS or azotemia or when plasma drug concentrations are >100 ^g/mL.

Imidazoles and Triazoles

The azole antifungals include the imidazoles and triazoles. These drugs have the same spectrum of antifungal activity and share a common mechanism by inhibiting fungal CYPs that are essential for ergosterol biosynthesis (Figure 48-1). Of the drugs available in the U.S., clotrimazole, miconazole, ketoconazole, econazole, butoconazole, oxiconazole, sertaconazole, and sulconazole are imidazoles; terconazole, itraconazole, fluconazole, and voriconazole are triazoles.

antifungal activity Azoles are active against C. albicans, C. tropicalis, C. parap-silosis, C. glabrata, C. neoformans, Blastomyces dermatitidis, Histoplasma capsulatum, Coccid-ioides species, Paracoccidioides brasiliensis, and dermatophytes. Aspergillus spp., Scedosporium apiospermum (Pseudallescheria boydii), Fusarium, and Sporothrix schenckii are intermediate in susceptibility. C. krusei and the agents of mucormycosis are resistant.

Azoles inhibit 14-a-sterol demethylase, a microsomal CYP that is essential for ergosterol biosynthesis (Figure 48-1). This results in the accumulation of 14-a-methylsterols that disrupt the packing of acyl chains of phospholipids and impair the functions of membrane-bound enzymes such as ATPase and those of the electron transport system, resulting in inhibited fungal growth.

Azole resistance has caused clinical failure in patients with far-advanced HIV infection and oropha-ryngeal or esophageal candidiasis. The primary mechanism of resistance in C. albicans is accumulation of mutations in the gene encoding 14-a-sterol demethylase; cross-resistance to all azoles results.


Ketoconazole has been replaced by itraconazole for the treatment of all mycoses except when cost is the primary determinant. Itraconazole lacks ketoconazole's corticosteroid suppression, while retaining most of its properties and expanding the antifungal spectrum.

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