These antifungal medications inhibit synthesis of ergosterol, resulting in inhibition of membrane-associated enzyme activity, cell wall growth, and replication.
Clotrimazole, taken orally in the form of 10-mg troches five times daily, can prevent and treat oral candidiasis. Vaginal azole tablets inserted daily for 1–7 days are effective for vaginal candidiasis. Topical preparations for treatment of cutaneous dermatophytes are also available.
Fluconazole, a bis-triazole with activity similar to that of ketoconazole, is water-soluble and can be given both orally and intravenously. Absorption of the medication after oral administration is not pH-dependent. It penetrates well into the cerebrospinal fluid and eye. The medication is effective primarily in the treatment of Candida, Cryptococcus, and Blastomyces infections. C albicans, C tropicalis, and C parapsilosis are usually sensitive to fluconazole, but many other species of Candida (C krusei, C glabrata, etc) are often resistant. Fluconazole-resistant strains of C albicans are primarily observed in patients receiving long-term fluconazole therapy. Candida auris, closely related to C krusei and C lusitaniae, is commonly fluconazole resistant. C auris has emerged as a global health threat due to its propensity to cause nosocomial outbreaks. Additionally, multidrug resistance (voriconazole, amphotericin B, echinocandins) has been reported with C auris. Since echinocandin resistance is less common overall, these medications are typically recommended for the treatment of C auris infections. The medication is inactive against Aspergillus, Mucor, and Pseudallescheria. Fluconazole is effective in oropharyngeal candidiasis and candidal esophagitis. A single oral dose of 150 mg is as effective or more effective than vaginal creams and suppositories in vaginal candidiasis. Fluconazole, 400 mg intravenously and orally daily, is as effective as amphotericin B, 0.5–0.6 mg/kg/day, for candidemia in both neutropenic and nonneutropenic patients. Fluconazole (200 mg/day) is effective as long-term suppressive therapy of cryptococcal meningitis in patients with HIV/AIDS. In the treatment of cryptococcal meningitis, response rates and overall mortality rates are the same in patients treated with oral fluconazole and with amphotericin B. However, the mortality rate in the first 2 weeks is higher with fluconazole, and sterilization of cerebrospinal fluid is slower with fluconazole. Consequently, cryptococcal meningitis induction therapy generally takes place with amphotericin B (in combination with flucytosine) for 2 weeks, followed by oral fluconazole. A dosage of 400 mg of fluconazole daily is effective therapy for coccidioidal meningitis (80% response), but improvement is slow, taking as long as 4–8 months. Increased doses (800–1200 mg/day) have been used in the treatment of coccidiomycosis; however, they have not been found to be superior to usual doses. Fluconazole, 400 mg daily, is effective prophylaxis against superficial and invasive fungal infections in bone marrow and liver transplant recipients, but this practice results in superinfection with resistant organisms (C krusei, C glabrata). Increased doses of fluconazole may be necessary to achieve adequate drug exposure in critically ill pediatric cancer patients. Fluconazole is also effective for the therapy of cutaneous leishmaniasis due to Leishmania major in a dose of 200 mg/day for 6 weeks.
Fluconazole is well absorbed after oral administration (greater than 90% bioavailability), and serum levels approach those seen after administering the same dose intravenously. Thus, unless the patient cannot take medication by mouth or is hemodynamically unstable, the preferred route of administration is by mouth. While generally well tolerated, fluconazole is associated with dose-dependent nausea and vomiting. Altered liver biochemical tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) and clinical hepatitis have been reported. While less potent than other azoles (itraconazole, ketoconazole, posaconazole, voriconazole), fluconazole inhibits cytochrome P450, resulting in reduced elimination of certain agents. Rifampin and phenytoin increase metabolism of fluconazole, necessitating increased fluconazole dosage.
Itraconazole is an oral triazole with variable bioavailability. It is moderately well absorbed from the gastrointestinal tract (food increases absorption from 30% to 60%; antacids, proton pump inhibitors, and H2-receptor antagonists decrease absorption). While the tablet formulation should be administered with food, the solution is best absorbed on an empty stomach. A SUBA-itraconazole (super bioavailability itraconazole) formulation was developed to improve oral bioavailability and increase the gastrointestinal tolerability of itraconazole. Itraconazole is widely distributed in tissues with the notable exception of the central nervous system, where levels in cerebrospinal fluid are undetectable. Itraconazole solution is more predictably absorbed than the tablets. The medication is metabolized by the liver, and no dosage adjustment is needed in kidney disease. Itraconazole is very active against most strains of Histoplasma capsulatum, Blastomyces dermatitidis, Cryptococcus neoformans, Sporotrichum schenkii, and various dermatophytes. It is also active against Aspergillus species but inactive against Fusarium and Zygomycetes. Itraconazole in doses of 200–400 mg/day is effective and approved therapy for localized or disseminated histoplasmosis. It is also effective in sporotrichosis, dermatophytic infections (including those of the nails), and oral and esophageal candidiasis. Itraconazole is at least as effective as fluconazole in the treatment of nonmeningeal coccidioidomycosis and may be superior in the management of skeletal disease. At doses of 200 mg twice daily, itraconazole increases exercise tolerance and decreases corticosteroid requirements in patients with allergic bronchopulmonary aspergillosis. Itraconazole pulse therapy with 200 mg twice daily for 1 week each month, repeated for 4 consecutive months, is effective in the treatment of onychomycosis.
Adverse effects are similar to those of fluconazole, with anorexia, nausea, vomiting, and abdominal pain occurring most commonly. Skin rash has been reported in up to 8% of patients. Hepatitis and hypokalemia occur uncommonly. Medications that increase hepatic cytochrome P450 (rifampin, phenytoin, phenobarbital) may increase itraconazole metabolism, and increased doses may be needed when these medications are administered concurrently with itraconazole. Itraconazole decreases the metabolism of cyclosporine, digoxin, and warfarin.
The usual dosage varies depending on the formulation and indication.
Voriconazole is a triazole antifungal with broad in vitro activity against most species of Candida and molds (eg, Aspergillus, Fusarium, Pseudallescheria, and others). It is as efficacious as liposomal amphotericin in the therapy of documented and suspected fungal infections in febrile neutropenic patients and superior to liposomal amphotericin in preventing breakthrough fungemia in this patient population. Voriconazole is superior to conventional amphotericin in the treatment of disseminated aspergillosis. Animal data also suggest voriconazole to be the most effective agent against Aspergillus, particularly in combination with caspofungin or another echinocandin. Voriconazole is the medication of choice in the treatment of Fusarium and Scedosporium infections. Voriconazole is widely used in the treatment of neutropenic patients with suspected or documented fungal infection. Voriconazole has limited activity against zygomycete pathogens, and some centers have reported increased rates of infection due to Rhizopus and Mucor in stem cell transplantation patients receiving voriconazole. Similar to fluconazole, oral administration leads to predictable absorption.
The primary early toxicity associated with voriconazole is infusion-related, transient visual disturbances, particularly during the first week of therapy. Of all the azole antifungal agents, voriconazole is associated with the most frequent elevation in liver biochemical tests and frank hepatitis. Long-term therapy may be associated with a multistep phototoxic process, followed by actinic keratosis, then squamous cell carcinoma. It has been recommended that discontinuation of voriconazole take place in patients experiencing chronic photosensitivity. The trifluorinated molecular structure of voriconazole has been associated with increased fluoride levels and periostitis in patients receiving voriconazole for long-term therapy. Also, when voriconazole is administered intravenously, it must be delivered in a cyclodextrin solution. In mice and rat animal models, the cyclodextrin (unlike the voriconazole) accumulates in kidney disease and has been associated with kidney toxicity. However, in human patients with kidney dysfunction, administration of voriconazole in cyclodextrin has not been associated with worsening kidney function. Similar to itraconazole, voriconazole is associated with numerous drug interactions. Enzyme inducers can decrease voriconazole plasma levels with potential for reduction in efficacy. Pharmacogenomic differences in cytochrome P450 2C19 can result in large differences in voriconazole clearance; therapeutic trough levels should be 1–5 mcg/mL. Voriconazole is also an inhibitor of cytochrome P450 activity, reducing the clearance of numerous substrates including cyclosporine and tacrolimus.
Posaconazole is an antifungal derivative of itraconazole with similar spectrum of activity as voriconazole, including yeast and Aspergillus spp. Unique from voriconazole, posaconazole has activity against the zygomycete fungi approaching that of amphotericin. Salvage treatment studies demonstrate efficacy in the treatment of these pathogens. Posaconazole is superior to fluconazole as fungal prophylaxis of neutropenia. Oral posaconazole should always be administered with food to ensure adequate oral bioavailability; the oral delayed-release product is associated with improved oral bioavailability when compared to the oral solution. Intravenous posaconazole should be used in patients unable to tolerate oral therapy or at risk for malabsorption from the gastrointestinal tract. Similar to voriconazole, posaconazole is primarily eliminated via nonrenal mechanisms. As with the other azole agents, posaconazole has primarily upper gastrointestinal adverse events and occasional liver biochemical test abnormalities. While not as problematic as voriconazole, posaconazole is also an inhibitor of cytochrome P450. Higher concentrations of posaconazole have been associated with pseudohyperaldosteronism.
Isavuconazole, the most recently approved azole, demonstrates excellent in vitro activity against both yeast and molds, including Aspergillus and the Mucorales. The medication is administered as the prodrug, isavuconazonium, which is available both as a highly absorbed oral preparation and a cyclodextrin-free intravenous formulation. Isavuconazole is at least as effective as voriconazole in the treatment of invasive mold infection due to Aspergillus and other filamentous fungi and much better tolerated. However, isavuconazole is less effective than caspofungin in the treatment of patients with invasive candidiasis. The rate of hepatobiliary, ocular, and skin disorders is significantly less with isavuconazole than with voriconazole. Isavuconazole is both a sensitive substrate and a mild to moderate inhibitor of CYP 3A4. Medications that alter gastric pH do not alter the oral bioavailability of the drug, and the oral preparation does not have dietary requirements.
Ketoconazole, the first orally bioavailable azole, previously was used in the treatment of a variety of fungal infections. However, the improved spectrum of activity, reduced toxicity, and superior pharmacokinetics of newer azoles have reduced ketoconazole to a secondary role.