Abstract
Fluconazole, voriconazole, and itraconazole may potentiate the hypercalcemic effect of other medications, although to date, triazoles alone have not been linked to hypercalcemia. We describe a case of new-onset hypercalcemia in the setting of high-dose fluconazole that resolved after changing the antifungal regimen. We reviewed our institutional database to assess the frequency of moderate or severe hypercalcemia (serum calcium ≥12 mg/dL) among patients with coccidioidomycosis treated with a triazole. We identified 2,133 patients, seen from January 1, 2005, through December 20, 2012, with a diagnosis of coccidioidomycosis. Twenty-three patients (1%) had subsequent hypercalcemia; of these, 20 patients (87%) had moderate or severe hypercalcemia. Nine of the 20 patients (45%) with moderate or severe hypercalcemia were taking triazoles, and most had comorbid conditions that were risk factors for hypercalcemia (tertiary hyperparathyroidism, n=4; multiple myeloma, n=2; adrenal insufficiency, n=1). The effect of fluconazole on calcium metabolism possibly is small or not clinically significant until the dose is high. Fluconazole may also contribute to hypercalcemia in patients with underlying hyperparathyroidism because of the loss of calcium’s inhibitory effect on parathyroid hormone secretion. In summary, moderate or severe hypercalcemia is uncommon in coccidioidomycosis and rare in those treated with triazoles. High-dose fluconazole may be associated with symptomatic hypercalcemia, especially in patients with predisposing comorbid conditions.
Highlights
Triazoles are a class of commonly used antifungal agents that includes fluconazole, itraconazole, voriconazole, and posaconazole
Voriconazole and itraconazole are thought to potentiate the adverse effects of all-trans retinoic acid, hypercalcemia, by inhibiting cytochrome P450 (CYP), thereby increasing serum concentration of all-trans retinoic acid [3,4]
Coccidioidomycosis is rarely linked with hypercalcemia, despite its association with a granulomatous immune response [11,12,13,14,15,16]
Summary
Triazoles are a class of commonly used antifungal agents that includes fluconazole, itraconazole, voriconazole, and posaconazole. Its mechanism of action is inhibition of fungal cytochrome P450 (CYP)dependent demethylation of lanosterol to ergosterol, which interferes with cytoplasmic membrane synthesis. Voriconazole and itraconazole are thought to potentiate the adverse effects of all-trans retinoic acid, hypercalcemia, by inhibiting CYP, thereby increasing serum concentration of all-trans retinoic acid [3,4]. Fluconazole, a first-generation triazole, is generally well tolerated, with few clinically significant toxicities. It is commonly used in prophylaxis or treatment of various fungal infections, including candidiasis, cryptococcosis, and coccidioidomycosis [1,5]
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