Cryptococcal meningitis

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By Joseph R Berger MD

Authorities have advanced various recommendations regarding the treatment of cryptococcal meningitis in HIV infection. Consensus is that the expectation from treatment is control rather than eradication of infection. Early series reported acute mortalities within 6 weeks of the completion of therapy of 18% to 37% and, generally, within the first 2 weeks (Kovacs et al 1985; Chuck and Sande 1989; Clark et al 1990; Saag et al 1992). A variety of treatment regimens were used both within and between studies. A large study from Vietnam of nearly 300 HIV-infected patients with cryptococcal meningitis randomized to amphotericin B alone, amphotericin B and flucytosine, and amphotericin B and fluconazole, convincingly demonstrated that combining high-dose amphotericin B at 1 mg/kg of body weight per day for 4 weeks with flucytosine 100 mg/kg per day for 2 weeks resulted in a significantly improved survival (Day et al 2013). There was no survival benefit with the coadministration of fluconazole. The addition of interferon-gamma immunotherapy to standard treatment has been demonstrated to increase clearance of Cryptococcus from the CSF (Jarvis et al 2012).

The standard treatment for cryptococcal meningitis has been amphotericin B at doses of 0.7 to 1.0 kg/day intravenously. Dosages used, however, have ranged from 0.3 to 1.0 mg/kg per day, with higher doses given for shorter periods before reduction to a maintenance regimen (Kovacs et al 1985; Zuger et al 1986; Chuck and Sande 1989; Larsen et al 1989; Clark et al 1990; Saag et al 1992; White et al 1992; de Lalla et al 1995). This polyene antibiotic binds to ergosterol in the cryptococcal membrane, altering its permeability. Some authorities suggest a short induction therapy of amphotericin B combined with flucytosine (Alspaugh and Perfect 2002). The duration of treatment may be as little as 2 weeks provided that a lumbar puncture documents negative CSF fungal cultures and the intravenous treatment is followed by at least 10 weeks of high dose fluconazole (400 to 800 mg/day orally) as maintenance therapy (Alspaugh and Perfect 2002). In studies prior to AIDS, amphotericin B was found to be more effective in treating cryptococcal meningitis when administered with flucytosine, an oral antimycotic metabolized to 5-fluorouracil within fungal cells, which inhibits fungal DNA and RNA synthesis. Flucytosine may also inhibit purine and pyrimidine uptake by fungi. Myelosuppression from the usual doses of 100 to 150 mg/kg per day has been problematic in AIDS patients, however, limiting its use; gastrointestinal reactions and hepatotoxicity may also occur and cause problems (Sugar and Saunders 1988; Powderly et al 1992). Many large retrospective studies have failed to show survival benefit from combination therapy in AIDS patients, in part due to the impact of toxicity (Chuck and Sande 1989; Clark et al 1990).

During therapy with amphotericin B, electrolytes and renal function need to be monitored carefully. Renal toxicity, which is related to the cumulative dose administered, is the major limiting adverse effect. During infusion, acute reactions commonly occur with fevers, chills, rigors, headache, and nausea, which may be mitigated by pretreatment with hydrocortisone, nonsteroidal antiinflammatory agents, anti-emetics, and antihistamines. Other potential adverse reactions include seizures, phlebitis, anemia, and edema (Sugar and Saunders 1988). Amphotericin B is contraindicated in persons who are hypersensitive to the drug or who have significant renal insufficiency. In addition to its nephrotoxicity, other side effects include infusion-related erythema, fever, rigors, hypokalemia, and hypomagnesemia. Patients receiving other nephrotoxic agents should be treated with liposomal amphotericin B.

Attempts to mitigate toxicity from amphotericin B therapy have included incorporation into liposomes (Coker et al 1991; 1993) and infusion of amphotericin in a fat emulsion (Leake et al 1994). Successful responses were obtained in a single patient in the latter instance and a dozen patients in the former. Both regimens were well tolerated. Liposomal amphotericin B is administered as 3 to 6 mg/kg per day intravenously. Doses of amphotericin lipid complex are 5 mg/kg per day. At least 3 weeks of induction is required when it is used without flucytosine in the setting of renal insufficiency. In general, this expensive preparation is used in the place of amphotericin B only when concomitant nephrotoxic agents are required, there is significant preexisting renal insufficiency (Alspaugh and Perfect 2002), or patients have failed other therapies (Dupont 2002).

Flucytosine is administered as 100 mg/kg per day orally in 4 divided doses and must also be adjusted for renal insufficiency. It is typically administered for 2 weeks at the inception of therapy. Side effects include bone marrow suppression, azotemia, and hepatic dysfunction. Flucytosine cannot be used as monotherapy due to the rapid development of resistance by the organism.

The development of triazole agents, which inhibit cytochrome P450 enzyme activity by limiting fungal ergosterol synthesis (Sugar and Saunders 1988), has had a major impact on control of cryptococcal infections in AIDS patients. Fluconazole has a higher CSF penetration than itraconazole, though both have shown efficacy in AIDS patients with cryptococcal meningitis (Stern et al 1988; Sugar and Saunders 1988; Denning et al 1991; Nightingale et al 1992). Fluconazole is administered as 400 mg/day in acute therapy and 200 mg/day as suppressive therapy. Side effects include nausea, rash, and hepatitis. Itraconazole is administered as 200 to 400 mg twice daily. Its side effects include nausea, abdominal pain, rash, headache, edema, and hypokalemia. Posaconazole, another triazole antifungal agent, is active against Cryptococcus, but experience with neurologic infection is limited (Nagappan and Deresinski 2007).

Comparisons of triazoles with amphotericin B for acute therapy of cryptococcal meningitis in AIDS patients have yielded mixed results to date. The largest trial found no significant difference in overall mortality between fluconazole and amphotericin B, although mortality with fluconazole was concentrated in the first 2 weeks of illness. Doses of the agents and combination therapy with flucytosine were not controlled (Saag et al 1992). Amphotericin B 0.3 mg/kg per day plus flucytosine 150 mg/kg per day was superior to itraconazole 200 mg/day over 6 weeks in one series (de Gans et al 1992). Amphotericin B 0.7 mg/kg per day for a week followed by thrice weekly administration for 9 weeks in combination with flucytosine 150 mg/day was superior to fluconazole 400 mg/day in another series (Larsen et al 1990). Variations in dosages, combinations of medications, severity of illness on entry, and definitions of successful outcome among studies limit direct comparisons (Powderly et al 1992). Fluconazole is administered as 200 to 800 mg/kg per day orally or intravenously. Because of its excellent bioavailability and affordability, the oral preparation is preferred to the parenteral preparation. Alspaugh and Perfect recommend 3 months to 9 months of fluconazole maintenance therapy at doses of 200 mg/kg per day in patients without HIV infection and lifelong therapy in the HIV-infected person (Alspaugh and Perfect 2002). The drug’s chief side effects are mild nausea and hair loss. A related drug, itraconazole, can be substituted at doses of 200 to 400 mg/kg per day orally or intravenously. Oral itraconazole is an effective prophylactic agent for Cryptococcus in AIDS (Chariyalertsak et al 2002).

Although not an approved therapy in the United States or Europe for cryptococcal infection, an increasing body of experience suggests that voriconazole is an effective antifungal agent (Bandettini et al 2009; Carbonara et al 2009; Nierenberg et al 2010). Granulocyte/macrophage colony-stimulating factor and interferon are being evaluated as adjunctive therapies. Other potential future therapies include azole antifungals and anticapsular monoclonal antibodies (Alspaugh and Perfect 2002).

Elevated intracranial pressure is common in patients with cryptococcal meningitis and may result in hydrocephalus. It has been postulated that sustained elevations in intracranial pressure may contribute to early mortality by impairing cerebral circulation (Denning et al 1991). Therapeutic modalities include drainage by serial lumbar punctures, ventricular drainage, and acetazolamide. The former has been recommended by some authorities when CSF opening pressures equal or exceed 250 mm water (Graybill et al 2000). Uncontrollable intracranial hypertension may occur in the absence of hydrocephalus, and ventriculoperitoneal shunting may be lifesaving (Petrou et al 2012). On rare occasion, however, cerebellar tonsillar herniation may occur in the setting of cryptococcal meningitis in the absence of mass lesion (Berger 2000). Acute visual loss in patients with HIV-associated cryptococcal meningitis may be transient, abrupt, or progressive and may result from increased intracranial pressure (Denning et al 1991), although other causes need to be considered--eg, necrotizing optic neuropathy due to cryptococcal invasion (Cohen and Glasgow 1993) and constrictive arachnoiditis (Lipson et al 1989). Patients with papilledema and severely impaired vision may respond to antibiotic therapy alone (Golnik et al 1991), ventricular shunting of CSF (Tan 1988), or lysis of arachnoid adhesions (Maruki et al 1988). The performance of therapeutic lumbar punctures for individuals with high intracranial pressure (>250 mm H2O) or new symptoms were associated with a significantly reduced mortality (18% vs. 7%), but therapeutic lumbar punctures should be undertaken cautiously (Rolfes et al 2014). Optic nerve sheath fenestration resulted in visual recovery of 2 patients with cryptococcal meningitis who had persistent associated papilledema and visual loss despite antibiotic therapy (Garrity et al 1993).

In This Article

Historical note and nomenclature
Clinical manifestations
Clinical vignette
Pathogenesis and pathophysiology
Differential diagnosis
Diagnostic workup
Prognosis and complications
References cited