title: Comparison of the early fungicidal activity of high-dose fluconazole, voriconazole, and flucytosine as second-line drugs given in combination with amphotericin B for the treatment of HIV-associated cryptococcal meningitis.
abstract: BACKGROUND
  HIV-associated cryptococcal meningitis is associated with an estimated 600 000 deaths worldwide per year. Current standard initial therapy consists of amphotericin B (AmB) plus flucytosine (5-FC), but 5-FC remains largely unavailable in Asia and Africa. Alternative, more widely available, and/or more effective antifungal combination treatment regimens are urgently needed.
  
  
  METHODS
  Eighty HIV-seropositive, antiretroviral naive patients presenting with cryptococcal meningitis were randomized to 4 treatment arms of 2 weeks duration: group 1, AmB (0.7-1 mg/kg) and 5-FC (25 mg/kg 4 times daily); group 2, AmB (0.7-1 mg/kg) and fluconazole (800 mg daily); group 3, AmB (0.7-1 mg/kg) and fluconazole (600 mg twice daily); and group 4, AmB (0.7-1 mg/kg) and voriconazole (300 mg twice daily). The primary end point was the rate of clearance of infection from the cerebrospinal fluid (CSF) or early fungicidal activity (EFA), as determined by results of serial, quantitative CSF cryptococcal cultures.
  
  
  RESULTS
  There were no statistically significant differences in the rate of clearance of cryptococcal colony-forming units (CFU) in CSF samples among the 4 treatment groups; the mean (±standard deviation) EFA for treatment groups 1, 2, 3, and 4 were -0.41 ± 0.22 log CFU/mL CSF/day, -0.38 ± 0.18 log CFU/mL CSF/day, -0.41 ± 0.35 log CFU/mL CSF/day, and -0.44 ± 0.20 log CFU/mL CSF/day, respectively. Overall mortality was 12% (9 of 78 patients died) at 2 weeks and 29% (22 of 75 patients died) at 10 weeks, with no statistically significant differences among groups. There were few laboratory abnormalities related to the second agents given; in particular, there were no statistically significant (≥grade 3) increases in alanine transaminase level or decreases in neutrophil count.
  
  
  CONCLUSIONS
  There was no statistically significant difference in EFA between AmB in combination with fluconazole and AmB plus 5-FC for the treatment of HIV-associated cryptococcal meningitis. AmB plus fluconazole (800-1200 mg/day) represents an immediately implementable alternative to AmB plus 5-FC. AmB plus voriconazole is an effective alternative combination in patients not receiving interacting medications.
authors: Infectious Diseases Unit, GF Jooste Hospital, Cape Town, South Africa. angelaloyse@hotmail.com
authors: Angela
authors: A
authors: Loyse
authors: Douglas
authors: D
authors: Wilson
authors: Graeme
authors: G
authors: Meintjes
authors: Joseph N
authors: JN
authors: Jarvis
authors: Tihana
authors: T
authors: Bicanic
authors: Leesa
authors: L
authors: Bishop
authors: Kevin
authors: K
authors: Rebe
authors: Anthony
authors: A
authors: Williams
authors: Shabbar
authors: S
authors: Jaffar
authors: Linda-Gail
authors: LG
authors: Bekker
authors: Robin
authors: R
authors: Wood
authors: Thomas S
authors: TS
authors: Harrison
mesh_terms: D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage*; D002555:Cerebrospinal Fluid / Q000382:microbiology; D015169:Colony Count, Microbial; D003454:Cryptococcus / Q000302:isolation & purification; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D015658:HIV Infections / Q000150:complications*; D006801:Humans; D008297:Male; D016919:Meningitis, Cryptococcal / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents