Treatment of Cryptococcal Meningitis
In the absence of therapy cryptococcal meningoencephalitis is uniformly fatal. Early diagnosis and prompt treatment is critical to improve survival. The classes of antifungal drugs that have activity against Cryptococcus are the polyenes (amphotericin B formulations), the azoles, and flucytosine. Treatment of cryptococcal meningitis typically consists of a 2-week induction phase of therapy followed by 8 weeks of consolidation therapy, and additional maintenance therapy that acts as secondary prophylaxis against recurrence. The recommended treatment regimens are indicated in Table 3.
Combination therapy with amphotericin B and flucytosine was established as the superior regimen in the mid-1990s, and globally is the preferred regimen. However, both amphotericin B and flucytosine are associated with significant toxicities that included renal toxicity, anemia, and neutropenia, and require intravenous administration and monitoring of toxicities. In much of sub-Saharan Africa and parts of Asia flucytosine is either not registered or is too expensive for clinical use. Amphotericin B is not often available, particularly in remote settings far from central hospitals. The cost of amphotericin B, the monitoring and management of its associated toxicities, and the prolonged hospital admission make it an expensive treatment option in resource-limited settings. Several studies have assessed the efficacy of alternative regimens that either contain Amphotericin B alone, amphotericin with fluconazole, fluconazole with flucytosine, fluconazole monotherapy or short courses of amphotericin B. The results of the key studies are summarized in Table 4. The greatest limitation is that most of the studies are small, single center studies that are not adequately powered to assess mortality benefit of a given regimen. Most patients in sub-Saharan Africa continue to receive induction therapy with fluconazole monotherapy despite the associated high mortality rates.
In addition to antifungal therapy, optimal management of raised intracranial pressure is required to reduce morbidity and mortality. Patients who have CSF opening pressures ≥ 25 cm of H2O should undergo repeat lumbar puncture until CSF pressures have normalized. Daily lumbar punctures may be required. If pressures remain persistently elevated a lumbar drain should be considered.