Combination flucytosine and high-dose fluconazole compared with fluconazole monotherapy for the treatment of cryptococcal meningitis: a randomized trial in Malawi.
BACKGROUND
Cryptococcal meningitis is a major cause of human immunodeficiency virus (HIV)-associated morbidity and mortality in Africa. Improved oral treatment regimens are needed because amphotericin B is neither available nor feasible in many centers. Fluconazole at a dosage of 1200 mg per day is more fungicidal than at a dosage of 800 mg per day, but mortality rates remain unacceptably high. Therefore, we examined the effect of adding oral flucytosine to fluconazole.


METHODS
From 13 February through 2 December 2008, HIV-seropositive, antiretroviral-naive patients experiencing their first episode of cryptococcal meningitis were randomized to receive (1) 14 days of fluconazole (1200 mg per day) alone or (2) in combination with flucytosine (100 mg/kg per day) followed by fluconazole (800 mg per day), with both groups undergoing 10 weeks of follow-up. The primary end point was early fungicidal activity, derived from quantitative cerebrospinal fluid cultures on days 1, 3, 7, and 14. Secondary end points were safety and 2- and 10-week mortality.


RESULTS
Forty-one patients were analyzed. Baseline mental status, cryptococcal burden, opening pressure, CD4(+) cell count, and HIV load were similar between groups. Combination therapy was more fungicidal than fluconazole alone (mean early fungicidal activity +/- standard deviation -0.28 +/- 0.17 log colony-forming units [CFU]/mL per day vs -0.11 +/- 0.09 log CFU/mL per day; P < .001). The combination arm had fewer deaths by 2 weeks (10% vs 37%) and 10 weeks (43% vs 58%). More patients had grade III or IV neutropenia with combination therapy (5 vs 1, within the first 2 weeks; P = .20), but there was no increase in infection-related adverse events.


CONCLUSIONS
The results suggest that optimal oral treatment for cryptococcal meningitis is high-dose fluconazole with flucytosine. Efforts are needed to increase availability of flucytosine in Africa. Clinical trials registration. isrctn.org Identifier: ISRCTN02725351.
Nussbaum
Jesse C
JC
University of North Carolina (UNC) Project and 2Kamuzu Central Hospital, Lilongwe, Malawi. jesse.nussbaum@ucsf.edu
Jackson
Arthur
A
Namarika
Dan
D
Phulusa
Jacob
J
Kenala
Jullita
J
Kanyemba
Creto
C
Jarvis
Joseph N
JN
Jaffar
Shabbar
S
Hosseinipour
Mina C
MC
Kamwendo
Deborah
D
van der Horst
Charles M
CM
Harrison
Thomas S
TS
D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002555:Cerebrospinal Fluid / Q000382:microbiology; D003454:Cryptococcus / Q000302:isolation & purification; D004359:Drug Therapy, Combination; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005437:Flucytosine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015658:HIV Infections / Q000150:complications; D006801:Humans; D008295:Malawi; D008297:Male; D016919:Meningitis, Cryptococcal / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D008875:Middle Aged; D016896:Treatment Outcome; D055815:Young Adult
D000935:Antifungal Agents; D015725:Fluconazole; D005437:Flucytosine