title: Combination antifungal therapy for cryptococcal meningitis.
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.).
authors.affiliation: 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.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Day
authors.affiliation: 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.
authors.forename: Tran T H
authors.initials: TTH
authors.lastname: Chau
authors.affiliation: 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.
authors.forename: Marcel
authors.initials: M
authors.lastname: Wolbers
authors.affiliation: 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.
authors.forename: Pham P
authors.initials: PP
authors.lastname: Mai
authors.affiliation: 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.
authors.forename: Nguyen T
authors.initials: NT
authors.lastname: Dung
authors.affiliation: 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.
authors.forename: Nguyen H
authors.initials: NH
authors.lastname: Mai
authors.affiliation: 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.
authors.forename: Nguyen H
authors.initials: NH
authors.lastname: Phu
authors.affiliation: 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.
authors.forename: Ho D
authors.initials: HD
authors.lastname: Nghia
authors.affiliation: 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.
authors.forename: Nguyen D
authors.initials: ND
authors.lastname: Phong
authors.affiliation: 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.
authors.forename: Cao Q
authors.initials: CQ
authors.lastname: Thai
authors.affiliation: 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.
authors.forename: Le H
authors.initials: LH
authors.lastname: Thai
authors.affiliation: 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.
authors.forename: Ly V
authors.initials: LV
authors.lastname: Chuong
authors.affiliation: 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.
authors.forename: Dinh X
authors.initials: DX
authors.lastname: Sinh
authors.affiliation: 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.
authors.forename: Van A
authors.initials: VA
authors.lastname: Duong
authors.affiliation: 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.
authors.forename: Thu N
authors.initials: TN
authors.lastname: Hoang
authors.affiliation: 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.
authors.forename: Pham T
authors.initials: PT
authors.lastname: Diep
authors.affiliation: 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.
authors.forename: James I
authors.initials: JI
authors.lastname: Campbell
authors.affiliation: 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.
authors.forename: Tran P M
authors.initials: TPM
authors.lastname: Sieu
authors.affiliation: 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.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Baker
authors.affiliation: 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.
authors.forename: Nguyen V V
authors.initials: NVV
authors.lastname: Chau
authors.affiliation: 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.
authors.forename: Tran T
authors.initials: TT
authors.lastname: Hien
authors.affiliation: 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.
authors.forename: David G
authors.initials: DG
authors.lastname: Lalloo
authors.affiliation: 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.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Farrar
mesh_terms: D000328:Adult; D000666:Amphotericin B / Q000009:adverse effects / Q000627:therapeutic use*; D000935:Antifungal Agents / Q000009:adverse effects / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D005437:Flucytosine / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D060828:Induction Chemotherapy; D053208:Kaplan-Meier Estimate; D008297:Male; D016919:Meningitis, Cryptococcal / Q000188:drug therapy* / Q000401:mortality
chemical_list: D000935:Antifungal Agents; D000666:Amphotericin B; D005437:Flucytosine
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