A three-way randomised study (1) of cryptococcal meningitis in Vietnam has convincingly shown the benefit of flucytosine with amphotericin B. Jeremy Day and 22 colleagues in Ho Chi Minh City at the Oxford University Clinical Research Unit studied 299 patients, all with AIDS and cryptococcal meningitis and found that the 100 patients who received amphotericin B (1 mg/Kg/d) and flucytosine (100mg/Kg/d) had a 40% lower chance of dying than amphotericin B alone or combined with fluconazole (800mg/d).
In addition to the 14 day survival benefit, the 70 day and 182 day survival was better with flucytosine as was the speed of yeast clearance from the cerebrospinal fluid.
Commenting on the results (2), Professor John Perfect of Duke University said; “Robust studies like this trial provide important insights for how to manage cryptococcal meningitis better, and it is our job to implement its initial therapeutic principles, such as the use of rapid fungicidal regimens, worldwide.”
Prior studies hinted at immediate benefit but were not conclusive. Relpase rates were higher in AIDS if flucytosine was not used in the original treatment regimen, but this is less relevant with better antiretroviral therapy. Faster CSF sterilization has been shown before, with combined amphotericin B and flucytosine, but the clinical significance of this was not fully explored. In this study clinical improvement mirrored faster CSF sterilization. This dual result is extremely important in showing how antifungal regimens need to work to be clinically effective.
[1] J Day et al NEJM 2013, 368:1291-1302April 4, 2013
[2] Comment by Perfect in NEJM 2013; 368:1354-1356April 4, 2013