Combination Therapy for Cryptococcal Meningitis

The probability of survival was significantly higher with amphotericin B plus flucytosine than with amphotericin B alone.

Since 2010, the Infectious Diseases Society of America has recommended combination antifungal therapy — amphotericin B plus flucytosine — for the induction treatment of cryptococcal meningitis. Despite this recommendation, no previous studies have demonstrated a survival benefit with such therapy. Now, investigators have conducted a three-group, open-label trial of combination therapy involving 299 HIV-infected patients aged >14 years who were treated for cryptococcal meningitis between April 2004 and September 2010 at a medical center in Vietnam.

The patients were randomized to receive one of three antifungal regimens:

• Intravenous amphotericin B, 1 mg/kg daily for 4 weeks, followed by oral fluconazole, 400 mg daily for 6 weeks (Group 1)
• Intravenous amphotericin B, 1 mg/kg daily — plus oral flucytosine, 100 mg/kg daily — for 2 weeks, following by oral fluconazole, 400 mg daily for 8 weeks (Group 2)
• Intravenous amphotericin B, 1 mg/kg daily — plus oral fluconazole, 400 mg twice daily — for 2 weeks, followed by oral fluconazole, 400 mg daily for 8 weeks (Group 3)

At both 14 and 70 days after randomization, the probability of survival was significantly higher for Group 2 patients than for Group 1 patients; no significant difference was observed between Group 3 and Group 1 patients. The rate of fungal clearance from cerebrospinal fluid during the first 14 days was significantly higher in Group 2 patients than in Group or Group 3 patients (–0.42 log10 cfu/mL/day vs. –0.31 and –0.32 log10 cfu/mL/day, respectively). Neutropenia was significantly more common in Group 2 and 3 patients than in Group 1 patients (34% and 32% vs. 19%).

CITATION(S):

Day JN et al. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med 2013 Apr 4; 368:1291. 

Perfect JR. Efficiently killing a sugar-coated yeast. N Engl J Med 2013 Apr 4; 368:1354.