Medication Summary
The duration of treatment and the combination of agents depend on the patient's immune status and whether the infection is disseminated. [17, 46]
Immunocompetent patients
In primary cutaneous cryptococcosis, as per published case reports, treat with fluconazole at a dose of 200-800 mg/day for a duration ranging from 2 weeks to 6 months or itraconazole at a dose of 100-400 mg/day for 3-6months.
For patients with nondisseminated, non-CNS Cryptococcus infection, treat with oral fluconazole for 3-6 months or with itraconazole for 6-12 months.
For non-CNS disseminated pulmonary Cryptococcus infection, treat as CNS disease.
Patients with fungemia or dissemination (involvement of at least two noncontiguous sites or evidence of high fungal burden based on cryptococcal antigen titer ≥1:512) are treated as CNS disease.
For CNS disease, use amphotericin B at 0.7-1 mg/kg/day plus flucytosine at 100 mg/kg/day for 6-10 weeks. Alternatively, use amphotericin B/flucytosine for 2 weeks, followed by fluconazole at 400 mg/day for 10 weeks. This is then followed by fluconazole for 6-12 months. Voriconazole is another possible treatment, but its use is not well reported for cutaneous cryptococcosis.
Immunocompromised patients
For non-CNS disseminated Cryptococcus infection, treat as described. Maintenance fluconazole therapy is recommended for life. Studies have shown that treatment can be discontinued after 1-2 years if the patient is receiving highly active antiretroviral therapy (HAART) and has had a CD4 count greater than 200/µL for at least 6 months, a nondetectable viral load, and a negative serum Cryptococcus antigen test result.
For CNS disease, use amphotericin B at 0.7-1 mg/kg/day plus flucytosine at 100-150 mg/kg/day for 2 weeks, fluconazole at 400 mg/day for at least 10 weeks, and then, in some cases, maintenance fluconazole for life. Studies have shown that treatment can be discontinued after 1-2 years if the patient is receiving HAART and has had a CD4 count greater than 200/µL for at least 6 months, a nondetectable viral load, and a negative serum Cryptococcus antigen test result.
Liposomal formulations of amphotericin B may be used as needed. Newer azoles, such as voriconazole, appear to have good activity against Cryptococcus and may be used more frequently in the future. Caspofungin lacks significant activity against Cryptococcus and is not recommended.
Antifungal Agent, Systemic
Class Summary
Antifungal agents are used in the management of infectious diseases caused by fungi.
Fluconazole (Diflucan)
Fluconazole is a synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes. It has little affinity for mammalian cytochromes, which is believed to explain its low toxicity. Fluconazole is available as a tablet for oral administration, as powder for oral suspension, and as sterile solution for intravenous use. It has fewer adverse effects and better tissue distribution than older systemic imidazoles. Fluconazole is active against many yeast and dimorphic fungi. In general, it has poor activity against molds and filamentous fungi.
Itraconazole (Sporanox)
Itraconazole has fungistatic activity. It is a synthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes.
Amphotericin B deoxycholate (Amphocin)
Amphotericin B deoxycholate is produced from a strain of Streptomyces nodosus. Its antifungal activity results from its ability to insert itself into fungal cytoplasmic membrane at sites containing ergosterol or other sterols. Aggregates of amphotericin B accumulate at sterol sites, resulting in an increase in cytoplasmic membrane permeability to monovalent ions (eg, potassium, sodium). At low concentrations, its main effect is increased intracellular loss of potassium, resulting in reversible fungistatic activity; however, at higher concentrations, 40- to 105-nm pores are produced in the cytoplasmic membrane, leading to large losses of ions and other molecules. A second effect of amphotericin B is its ability to cause auto-oxidation of the cytoplasmic membrane and release of lethal free radicals. The main fungicidal activity of amphotericin B may reside in its ability to cause auto-oxidation of cell membranes.
If therapy is supplemented by oral flucytosine, therapy can be used until the patient is afebrile and alert and spinal fluid cultures are negative for 6 weeks; then, the patient can begin fluconazole therapy.
Flucytosine (Ancobon)
Although the exact mode of action is unknown, flucytosine may act directly on fungal organisms by competitive inhibition of purine and pyrimidine uptake and indirectly by intracellular metabolism, where it is converted to 5-fluorouracil after penetrating fungal cells. It inhibits RNA and protein synthesis. Flucytosine is active against candidal and cryptococcal species and generally used in combination with amphotericin B.
Use it in combination with another agent because acquired resistance develops frequently when administered alone. Flucytosine is well absorbed orally but should be administered intravenously to critically ill patients.
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Umbilicated papule of cutaneous Cryptococcus infection on the face of a male.
