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High-Dose Amphotericin B for Cryptococcal Meningitis

High-dose AmB is already the standard of care in many clinics, but its use is now supported by data from a randomized trial.

Current guidelines for the treatment of AIDS-related cryptococcal meningitis recommend amphotericin B (AmB) at a daily dose of 0.7 to 1.0 mg/kg, along with flucytosine. Many clinicians today use the higher dose of AmB (1 mg/kg), but it has never been compared against the "standard dose" (0.7 mg/kg) in a head-to-head randomized, prospective trial. Now, researchers have performed such a trial (albeit nonblinded) among 64 AIDS patients in South Africa with cryptococcal meningitis.

All study participants were cerebrospinal fluid (CSF) culture–positive; no one was taking antiretroviral therapy (ART). Thirteen percent had altered mental status, which has been shown in prior studies to be the most important predictor of poor prognosis. Patients received their assigned treatments, along with flucytosine (100 mg/kg daily), for 2 weeks and then were switched to fluconazole. ART was begun 4 weeks after initiation of meningitis treatment, and median follow-up was 1 year. The primary endpoint was the rate at which the infection cleared, as determined by serial, quantitative CSF cultures obtained within the first 2 weeks of therapy, a period previously described as crucial to the ultimate success of therapy and to survival. Secondary outcomes were rates of renal impairment, anemia, and death.

Infections cleared at a significantly faster rate in the high-dose group than in the low-dose group (P=0.02), with a mean difference of approximately 0.11 log Cryptococcus cfu/mL of CSF per day. High-dose AmB was well tolerated. The incidence of renal impairment at 2 weeks was not significantly different between the two groups. Anemia was associated with female sex and, to a lesser extent, with receipt of the higher AmB dose. Both renal dysfunction and anemia resolved after patients were switched to fluconazole. Mortality rates did not differ between the study groups at any point during follow-up. Overall, 10-week survival was 76%, the highest reported rate from Africa to date.

Comment: This study demonstrates that, during the first 2 weeks of treatment, high-dose AmB is more effective and not significantly more toxic than "standard-dose" AmB. Given that use of the higher dose has already become the de facto standard of care in many centers, the results of this randomized trial are reassuring.

— Judith Feinberg, MD

Published in AIDS Clinical Care June 23, 2008

Citation(s):

Bicanic T et al. High-dose amphotericin B with flucytosine for the treatment of cryptococcal meningitis in HIV-infected patients: A randomized trial. Clin Infect Dis 2008 Jul 1; 47:123.

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