Cryptococcal meningitis is fatal if left untreated. Because pneumonia frequently precedes dissemination of disease and subsequent meningitis, all patients with culture-, histopathology-, or serology-proven disease should receive antifungal therapy. In patients with isolated pulmonary cryptococcosis, fluconazole is generally considered to be the therapy of choice (see Table 84-2)41 Alternatively, itraconazole, voriconazole, or combination therapy (fluconazole plus flucytosine) has also been used with some success but these regimens are generally considered inferior to amphotericin B and are recommended only for persons unable to tolerate or unresponsive to standard treatment. Echinocandins do not have clinically useful activity against C. neoformans.

Disseminated or CNS cryptococcosis requires a more aggressive treatment approach. Pretreatment predictors of poor outcome with antifungal therapy include:

• Progressive underlying disease or immunodysfunction

• Abnormal mental status at the time of presentation

• Increased opening pressure on lumbar puncture (greater than 260 mm H2O)

• High fungal burden as reflected by a CSF antigen titer (in AIDS patients) of greater than 1:2,048

Prospective randomized trials completed prior to the recognition of AIDS demonstrated high response rates (approximately 80%) with the combined use of ampho-tericin B and flucytosine for 4 to 6 weeks. Although sterilization of the CSF could be achieved in most patients within 2 weeks with this regimen, a substantial number of patients (30-40%) developed dose-limiting toxicities and relapse was seen in roughly 50% of patients. Therefore, a treatment approach was devised that consisting of distinct treatment phases to minimize toxicity and reduce the risk of relapse.

Clinical trials performed by the National Institute of Allergy and Infectious Diseases

(NIAID) Mycoses Study Group after the recognition of AIDS showed that 2 weeks of induction antifungal therapy with combination amphotericin B (0.7 mg/kg/day) plus flucytosine (100 mg/kg/day) for cryptococcal meningitis, followed by consolidation therapy with fluconazole (400 mg daily) for 8 weeks was as effective as 4 weeks of combination therapy, with fewer toxicities (see Table 84-2).12,41 Other studies have suggested fluconazole plus amphotericin may be an acceptable option in patients who

cannot tolerate therapy with flucytosine (see Table 84-2). prophylaxis

Fluconazole (200 mg/day) is recommended as maintenance therapy for life in patients with persistent underlying immune dysfunction to prevent recurrent cryptococcal 12

meningitis. Available data have demonstrated that it is safe to discontinue maintenance therapy in AIDS patients who have had a sustained immunologic response on

effective antiretroviral therapy. Occasionally, initiation of HAART can result in the reactivation of a subclinical, immunologic manifestation of cryptococcal infection (or other opportunistic infections). Manifestations of this so-called immune reconstitution syndrome (IRIS) may include exacerbations of meningitis or necrotizing pneumonia.

Antifungal therapy plus a nonsteroidal anti-inflammatory agent or prednisone have been used successfully in patients with cryptococcal-associated immune reconstitu-12

tion syndrome. However, the optimal management of this recently defined clinical entity remains unknown.

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