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N Engl J Med. 2013 Apr 4;368(14):1291-1302. doi: 10.1056/NEJMoa1110404.

Combination antifungal therapy for cryptococcal meningitis.

Author information

1
Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme Vietnam (J.N.D., T.T.H.C., M.W., N.H.M., N.H.P., H.D.N., C.Q.T., L.H.T., V.A.D., T.N.H., P.T.D., S.G.B., T.T.H., J.J.F.), and the Hospital for Tropical Diseases (T.T.H.C., P.P.M., N.T.D., N.H.M., N.H.P., H.D.N., N.D.P., L.V.C., D.X.S., T.P.M.S., N.V.V.C.) - both in Ho Chi Minh City, Vietnam; and the Centre for Tropical Medicine, Oxford University, Oxford (J.N.D., M.W., J.I.C., S.G.B., T.T.H., J.J.F.), and the Liverpool School of Tropical Medicine, Liverpool (D.G.L.) - both in the United Kingdom.
#
Contributed equally

Abstract

BACKGROUND:

Combination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis but has not been shown to reduce mortality, as compared with amphotericin B alone. We performed a randomized, controlled trial to determine whether combining flucytosine or high-dose fluconazole with high-dose amphotericin B improved survival at 14 and 70 days.

METHODS:

We conducted a randomized, three-group, open-label trial of induction therapy for cryptococcal meningitis in patients with human immunodeficiency virus infection. All patients received amphotericin B at a dose of 1 mg per kilogram of body weight per day; patients in group 1 were treated for 4 weeks, and those in groups 2 and 3 for 2 weeks. Patients in group 2 concurrently received flucytosine at a dose of 100 mg per kilogram per day for 2 weeks, and those in group 3 concurrently received fluconazole at a dose of 400 mg twice daily for 2 weeks.

RESULTS:

A total of 299 patients were enrolled. Fewer deaths occurred by days 14 and 70 among patients receiving amphotericin B and flucytosine than among those receiving amphotericin B alone (15 vs. 25 deaths by day 14; hazard ratio, 0.57; 95% confidence interval [CI], 0.30 to 1.08; unadjusted P=0.08; and 30 vs. 44 deaths by day 70; hazard ratio, 0.61; 95% CI, 0.39 to 0.97; unadjusted P=0.04). Combination therapy with fluconazole had no significant effect on survival, as compared with monotherapy (hazard ratio for death by 14 days, 0.78; 95% CI, 0.44 to 1.41; P=0.42; hazard ratio for death by 70 days, 0.71; 95% CI, 0.45 to 1.11; P=0.13). Amphotericin B plus flucytosine was associated with significantly increased rates of yeast clearance from cerebrospinal fluid (-0.42 log10 colony-forming units [CFU] per milliliter per day vs. -0.31 and -0.32 log10 CFU per milliliter per day in groups 1 and 3, respectively; P<0.001 for both comparisons). Rates of adverse events were similar in all groups, although neutropenia was more frequent in patients receiving a combination therapy.

CONCLUSIONS:

Amphotericin B plus flucytosine, as compared with amphotericin B alone, is associated with improved survival among patients with cryptococcal meningitis. A survival benefit of amphotericin B plus fluconazole was not found. (Funded by the Wellcome Trust and the British Infection Society; Controlled-Trials.com number, ISRCTN95123928.).

PMID:
23550668
PMCID:
PMC3978204
DOI:
10.1056/NEJMoa1110404
[Indexed for MEDLINE]
Free PMC Article
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