Combination Flucytosine and High‐Dose Fluconazole Compared with Fluconazole Monotherapy for the Treatment of Cryptococcal Meningitis: A Randomized Trial in Malawi

Abstract

Background Cryptococcal meningitis is a major cause of HIV-associated morbidity and mortality in Africa. Improved oral treatment regimens are needed, as amphotericin B is neither available nor feasible in many centers. Fluconazole 1200 mg/d is more fungicidal than 800 mg/d, but mortality remains unacceptably high. Therefore we examined the effect of adding oral flucytosine to fluconazole. Methods HIV-seropositive, antiretroviral-naive patients with their first episode of cryptococcal meningitis were randomized to 14 days fluconazole 1200 mg/d alone, or with flucytosine 100 mg/kg/d, followed by fluconazole 800 mg/d with 10 weeks followup. The primary endpoint was early fungicidal activity (EFA), derived from quantitative cerebrospinal fluid cultures on Days 1, 3, 7, and 14. Secondary endpoints were safety, and 2- and 10-week mortality. Results Forty-one patients were analyzed. Baseline mental status, cryptococcal burden, opening pressure, CD4 count, and HIV viral load were similar between groups. Combination therapy was more fungicidal than fluconazole alone: EFA −0.28 +/− 0.17 log CFU/ml/d vs. −0.11 +/− 0.09 log CFU/ml/d (p < 0.001). 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 first 2 weeks, p=0.2), 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.

Pharmacokinetics and Pharmacodynamics of Fluconazole for Cryptococcal Meningoencephalitis: Implications for Antifungal Therapy andIn VitroSusceptibility Breakpoints

“…The use of Ն1,200 mg of fluconazole/day as monotherapy is recommended in guidelines from the Infectious Diseases Society of America (15). While improved clinical responses are observed with higher fluconazole dosages (circa 1,200 to 2,000 mg/day) (2, 3), the additional antifungal activity that is observed with the addition of flucytosine (3,14,22) suggests that these higher dosages of fluconazole (as monotherapy) do not produce maximal antifungal activity. Thus, further studies are required to investigate ways in which fluconazole-containing antifungal regimens can be further optimized.…”

“…We determined the predicted decline in fungal burden in the brains of mice exposed to fluconazole AUCs that are the same as those that are expected in humans receiving 1,200 mg of fluconazole per day. This dosage was chosen on the basis of a recent clinical trial and current recommendations from Infectious Diseases Society of America (IDSA) (14,15). A regimen of 1,200 mg of fluconazole per day results in a higher rate of decline in fungal burden in the cerebrospinal fluid (CSF) of patients with cryptococcal meningitis compared with the use of 800 mg/day and is therefore generally recommended for induction therapy (2).…”

Kryptokowe zapalenie opon mózgowych i mózgu u pacjentów zakażonych HIV

“…nie dorównuje skutecznością terapii skojarzonej amfoterycyną i flucytozyną [17][18][19][20]. Najmniej skuteczna jest monoterapia flukonazolem -stwierdzono o 30% wyższą śmier-telność w 10. tygodniu leczenia w porównaniu z leczeniem opartym na amfoterycynie [21].…”

Treatment Principles for Candida and Cryptococcus

“…Where 5FC is not available, fluconazole 800 -1200 mg/d can be combined with AmBd (Pappas et al 2009;Loyse et al 2012;Day et al 2013). Where AmBd cannot be safely administered for 14 d, alternatives include shorter (5 -7 d) courses (Muzoora et al 2012) or the oral combination of fluconazole 1200 mg/d plus 5FC (Nussbaum et al 2010), currently undergoing phase III randomized controlled trials in Africa (see www. controlled-trials.com/ISRCTN45035509).…”