According to the authors of this study, clinical practice guidelines from the Infectious Diseases Society of America recommend that cryptococcal meningitis be treated with amphotericin B deoxycholate (0.7-1mg/kg/day) and flucytosine (100mg/kg/day) induction. However the addition of flucytosine has not been shown to improve mortality over amphotericin alone and its cost and concerns over side-effects have limited its use in some settings. Fluconazole is recommended as an alternative to flucytosine, but increased doses of amphotericin B and fluconazole have not been tested in combination.
The purpose of the current study was to determine whether adding either flucytosine (100mg/kg/day) or fluconazole (400mg twice daily) to amphotericin B (1mg/kg/day) induction therapy offered any survival advantage compared with use of the latter as monotherapy for four weeks. There were fewer deaths in those receiving amphotericin and flucytosine than in those receiving amphotericin monotherapy at days 14 (15 vs. 25 deaths; hazard ratio 0.57; 95% CI 0.30 to 1.08; unadjusted P=0.08) and 70 (30 vs. 44 deaths; hazard ratio 0.61; 95% CI 0.39 to 0.97; unadjusted P=0.04). The combination also increased rates of yeast clearance from the CSF. The use of fluconazole in combination with amphotericin was not associated with any survival advantage over amphotericin alone.
The study population was characterised by high CSF fungal burdens and a large proportion had a Glasgow Coma Scale score of less than 15 at presentation – these variables are known to be important predictors of a poor outcome. The authors of a related editorial say that these results confirm the combination of amphotericin B and flucytosine is the preferred regimen for the induction treatment of cryptococcal meningitis in such a population, and show that the rapid killing of yeasts at the site of infection translates into a better long-term outcome.