Voriconazole

tacrolimus, phenytoin, rifabutin, warfarin, and sirolimus. Because the sirolimus AUC increases 11-fold when voriconazole is given, coadministration is contraindicated. Omeprazole dose should be reduced by half if 40 mg or more per day is given. Until more experience with voriconazole is gained, it is prudent to be observant for drug interactions that occur with other azoles (Table 48—1).

therapeutic uses

Voriconazole is superior to C-AMB as primary therapy of invasive aspergillosis. Although not approved, voriconazole has been used for the empirical therapy of neutropenic patients whose fever did not respond to antibacterial therapy. Voriconazole is approved for use in esophageal candidiasis and as salvage therapy in patients with P. boydii and Fusarium infections.

untoward effects

Although the drug is generally well tolerated, hepatotoxicity has been reported and liver function should be monitored. Voriconazole can prolong the QTc interval, which can be significant in patients with other risk factors for torsades de pointes. Approximately 30% of patients note transient visual changes (e.g., blurred vision, altered color perception, and photophobia) beginning about half an hour after administration and lasting for another half hour. Activities that require keen vision should be avoided, but no sequelae occur. Uncommonly, confusion or transient visual hallucinations occur. Patients receiving their first intravenous infusion have had anaphylactoid reactions requiring drug discontinuation. Rash occurs in 6% of patients. Voriconazole is teratogenic in animals and should not be used in pregnancy (category D).

dosage

Treatment usually is initiated with 6 mg/kg every 12 hours for two doses, followed by 4 mg/kg every 12 hours, administered at 3 mg/kg/hour. As the patient improves, oral administration is continued at 200 mg every 12 hours. Patients failing to respond may be given 300 mg every 12 hours. Oral drug should be given either 1 hour before or 1 hour after meals.

Echinocandins

Echinocandins inhibit formation of b(1,3)D-glucans in the cell wall of Candida and caspofungin is approved for clinical use. Susceptible fungi include Candida and Aspergillus species. Resistance can be conferred in C. albicans by mutation in one of the genes that encodes b(1,3)D-glucan synthase. Azole-resistant isolates of C. albicans remain susceptible to echinocandins.

caspofungin

Caspofungin (cancidas, MK-0991) is a water-soluble, lipopeptide synthesized from a fermentation product called pneumocandin Bo. In susceptible yeasts, caspofungin causes lysis.

absorption, distribution, and excretion

Caspofungin is not absorbed orally. After intravenous injection, caspofungin is eliminated from the bloodstream with a t122 of ~10 hours. Catabolism is largely by hydrolysis and N-acetylation, followed by excretion in urine and feces. Mild or moderate hepatic insufficiency increases the AUC by 55% and 76%, respectively. About 97% of serum drug is bound to albumin. Dose adjustment is unnecessary for renal insufficiency or hemodialysis.

therapeutic use

Caspofungin is approved for patients with invasive aspergillosis who are failing or intolerant of drugs such as amphotericin B or voriconazole and for esophageal candidiasis. A clinical trial of caspofungin in deeply invasive candidiasis found noninferiority to C-AMB, leading to approval for that indication. Caspofungin also is approved to treat persistently febrile neutropenic patients with suspected fungal infections.

untoward effects

Caspofungin is well tolerated, with the exception of phlebitis at the infusion site. Histamine-like effects have occurred with rapid infusions. Other effects are comparable to those in patients receiving fluconazole.

dosage

Caspofungin is administered intravenously once daily over 1 hour. In candidemia and salvage therapy of aspergillosis, the initial dose is 70 mg, followed by 50 mg daily. The dose may be increased to 70 mg daily in patients failing to respond. Esophageal candidiasis is treated with 50 mg daily.

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