An 8-year-old boy is brought to the office due to worsening thrush and angular cheilitis, which causes difficulty eating. The patient has a history of chronic mucocutaneous candidiasis and has had recurrent Candida infections of the skin, oral mucosa, and nails since infancy. He is currently on suppressive therapy with fluconazole, which has been successful in preventing infections until this most recent episode. Physical examination shows extensive oral mucosal candidiasis. Scrapings from a lesion are obtained for culture, and intravenous antifungal therapy is initiated. Sensitivity testing of the colonies that grow in culture show Candida that is resistant to fluconazole. Which of the following changes in the pathogen best explains this patient's breakthrough infection?
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Fluconazole is a triazole antifungal that treats yeast infections but has no activity against molds. It is a first-line therapy for Candida albicans and Cryptococcus neoformans and offers some efficacy against most other Candida species, as well as endemic fungi (eg, Histoplasma, Coccidioides, Blastomyces).
Azole antifungals exert their effect by blocking lanosterol 14-alpha-demethylase, a cytochrome p-450–dependent enzyme that converts lanosterol to ergosterol. Because ergosterol is a crucial component of the cell membrane of fungi, treatment with azole antifungals causes fungal cell membrane weakening and subsequent cell lysis and death. However, use of azole antifungals as long-term suppressive therapy or repeat use for recurrent fungal infections can lead to resistance.
Azole resistance is typically due to ≥1 of the following mechanisms:
Mutations to the gene for 14-alpha-demethylase, which alters the enzyme shape or azole binding site
Increased expression of 14-alpha-demethylase, which increases the minimum inhibitory concentration to prevent ergosterol synthesis
Overexpression of drug efflux pumps, which reduces intracellular azole levels
Patients who develop azole resistance may require higher doses or treatment with an alternate antifungal (eg, echinocandin).
(Choice A) Azole antifungals do not bind directly to cell membrane sterols; they bind to the enzyme that generates ergosterol. In contrast, amphotericin B binds to ergosterol, generating pores in the cell membrane that lyse the cell; alterations to ergosterol's structure can impair amphotericin B binding and lead to resistance, but would have no effect on azoles.
(Choice B) Filamentous fungi such as Rhizopus and Aspergillus can cause ischemic necrosis by binding to components of the vascular wall (eg, basement membrane, extracellular matrix). This feature is not targeted by azole antifungals.
(Choice D) Echinocandin antifungals inhibit the synthesis of beta-D-glucan, a branched polysaccharide that serves as a crucial cross-linking element in the cell wall of many fungi. Mutations to the enzyme that produces beta-D-glucan can lead to echinocandin resistance.
(Choice E) The hyphal form is required for Candida to be pathogenic, and Candida with and without the hyphal form is typically seen in tissue cultures during infection. However, mutations to the gene that triggers the hyphal form would not alter sensitivity to azole antifungal medications.
Educational objective:
Azole antifungal medications (eg, fluconazole) block the fungal enzyme lanosterol 14-alpha-demethylase, a cytochrome p-450–dependent enzyme that converts lanosterol to ergosterol. Mutations to the gene for 14-alpha-demethylase can lead to azole resistance.