title: Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial.
abstract: BACKGROUND
  It frequently takes more than 2 weeks for drug treatments for cryptococcal meningitis to sterilise cerebrospinal fluid (CSF). In-vitro and animal studies lend support to the use of combinations of amphotericin B, flucytosine, and fluconazole for treatment of cryptococcosis. We compared the fungicidal activity of combinations of these drugs for initial treatment of patients with cryptococcal meningitis.
  
  
  METHODS
  64 patients with a first episode of HIV-associated cryptococcal meningitis were randomised to initial treatment with: amphotericin B (0.7 mg/kg daily); amphotericin B plus flucytosine (100 mg/kg daily); amphotericin B plus fluconazole (400 mg daily); or triple therapy with amphotericin B, flucytosine, and fluconazole. Our primary endpoint was fungicidal activity, measured by the rate of reduction in CSF cryptococcal colony-forming units (CFU) from serial quantitative CSF cultures on days 3, 7, and 14 of treatment.
  
  
  RESULTS
  Baseline CSF CFU counts were an important prognostic factor. Clearance of cryptococci from the CSF was exponential and was significantly faster with amphotericin B plus flucytosine than with amphotericin B alone (p=0.0006), amphotericin B plus fluconazole ( p=0.02), or triple therapy (p=0.02).
  
  
  CONCLUSIONS
  At these doses, amphotericin B plus flucytosine is the most rapidly fungicidal regimen. Quantification of CSF cultures provides a powerful new means to accurately assess the fungicidal activity of new treatment regimens for cryptococcal meningitis.
authors.affiliation: Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Annemarie E
authors.initials: AE
authors.lastname: Brouwer
authors.forename: Adul
authors.initials: A
authors.lastname: Rajanuwong
authors.forename: Wirongrong
authors.initials: W
authors.lastname: Chierakul
authors.forename: George E
authors.initials: GE
authors.lastname: Griffin
authors.forename: Robert A
authors.initials: RA
authors.lastname: Larsen
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Harrison
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000134:cerebrospinal fluid / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D000328:Adult; D000666:Amphotericin B / Q000008:administration & dosage; D000935:Antifungal Agents / Q000008:administration & dosage*; D000946:Antigens, Fungal / Q000134:cerebrospinal fluid; D002555:Cerebrospinal Fluid / Q000166:cytology / Q000382:microbiology; D015170:Cerebrospinal Fluid Pressure; D015169:Colony Count, Microbial; D003455:Cryptococcus neoformans / Q000302:isolation & purification; D004359:Drug Therapy, Combination; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage; D005437:Flucytosine / Q000008:administration & dosage; D006801:Humans; D008297:Male; D016919:Meningitis, Cryptococcal / Q000134:cerebrospinal fluid / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000935:Antifungal Agents; D000946:Antigens, Fungal; D000666:Amphotericin B; D015725:Fluconazole; D005437:Flucytosine