Cryptococcal Disease

Patients with cryptococcal meningitis should be hospitalized to start 2 weeks of induction therapy with amphotericin B (0.7 mg/kg/day) given intravenously plus flucytosine (25 mg/kg) given orally every 6 hours.

Amphotericin B causes many adverse effects, including fever, rigors, hypotension, nausea, nephrotoxicity and electrolyte disturbances, anemia, and leukopenia. The patient's hemoglobin, white blood cell (WBC) count, platelets, electrolytes, magnesium, and creatinine must be monitored closely during treatment. Note that liposomal forms of amphotericin (AmBisome and Abelcet) cause fewer adverse effects and appear to be effective. These liposomal forms should be considered for patients who have difficulty tolerating the standard amphotericin B. Because amphotericin B is highly irritating to the veins, it should be given through a central line. High levels of flucytosine are associated with bone marrow toxicity, and levels should be monitored (target peak 70-80 mg/L; trough 30-40 mg/L). Note that the dosage of flucytosine must be adjusted for patients with renal insufficiency.

If amphotericin is not available, is contraindicated, or is not tolerated by the patient, alternative induction therapies may be considered. The primary alternative to amphotericin-based therapy is fluconazole (400-800 mg orally per day), with or without flucytosine. Of the newer antifungal agents, echinocandins have little activity against Cryptococcus. Voriconazole has good in vitro activity, but few clinical data are available and none suggest superiority over fluconazole. The efficacy of alternative regimens is not well defined.

After clinical improvement with 2 weeks of induction therapy (possibly sooner for patients with substantial improvement), the treatment can be switched to oral fluconazole (400 mg once daily to complete 8 weeks of acute treatment). Itraconazole (200 mg orally twice daily) sometimes is used as an alternative for patients who cannot take fluconazole. It should be noted that itraconazole is less effective than fluconazole and has significant drug interactions with commonly used medications.

After completing acute treatment, the patient should receive chronic maintenance therapy with fluconazole (200 mg orally once daily) to prevent recurrence of cryptococcosis. An alternative treatment is itraconazole (200 mg orally once or twice daily)--with the caution as indicated above.

Maintenance therapy should be continued for life, unless the patient has sustained CD4 cell recovery in response to effective antiretroviral therapy (ART) (CD4 count >100-200 cells/µL for at least 6 months during ART). Maintenance therapy should be restarted if the CD4 count declines to <100-200 cells/µL.

Elevated ICP significantly increases the morbidity and mortality of cryptococcal meningitis and should be treated by the removal of CSF. The CSF opening pressure should be checked on the initial LP. If the initial opening pressure is >250 mm H2O, remove up to 30 mL of CSF to lower the ICP by 50%, if possible. LP and CSF removal should be repeated daily as needed for ICP reduction. Ventriculostomy or a ventriculoperitoneal shunt may be needed if the initial opening pressure is >400 mm H2O, or in refractory cases. There is no role for acetazolamide, mannitol, or steroids in the treatment of elevated ICP.

A repeat LP is not required for patients who did not have elevated ICP at baseline and are responding to treatment. If new symptoms develop, a repeat LP is indicated. Serum CrAg titers are not useful in monitoring response to treatment.