Combination Antifungal Therapy for Cryptococcal Meningitis

Abstract

BACKGROUND Combination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis but has not been shown to reduce mortality, as compared with amphotericin B alone. We performed a randomized, controlled trial to determine whether combining flucytosine or high-dose fluconazole with high-dose amphotericin B improved survival at 14 and 70 days. METHODS We conducted a randomized, three-group, open-label trial of induction therapy for cryptococcal meningitis in patients with human immunodeficiency virus infection. All patients received amphotericin B at a dose of 1 mg per kilogram of body weight per day; patients in group 1 were treated for 4 weeks, and those in groups 2 and 3 for 2 weeks. Patients in group 2 concurrently received flucytosine at a dose of 100 mg per kilogram per day for 2 weeks, and those in group 3 concurrently received fluconazole at a dose of 400 mg twice daily for 2 weeks. RESULTS A total of 299 patients were enrolled. Fewer deaths occurred by days 14 and 70 among patients receiving amphotericin B and flucytosine than among those receiving amphotericin B alone (15 vs. 25 deaths by day 14; hazard ratio, 0.57; 95% confidence interval [CI], 0.30 to 1.08; unadjusted P = 0.08; and 30 vs. 44 deaths by day 70; hazard ratio, 0.61; 95% CI, 0.39 to 0.97; unadjusted P = 0.04). Combination therapy with fluconazole had no significant effect on survival, as compared with monotherapy (hazard ratio for death by 14 days, 0.78; 95% CI, 0.44 to 1.41; P = 0.42; hazard ratio for death by 70 days, 0.71; 95% CI, 0.45 to 1.11; P = 0.13). amphotericin B plus flucytosine was associated with significantly increased rates of yeast clearance from cerebrospinal fluid (−0.42 log10 colony-forming units [CFU] per milliliter per day vs. −0.31 and −0.32 log10 CFU per milliliter per day in groups 1 and 3, respectively; P<0.001 for both comparisons). Rates of adverse events were similar in all groups, although neutropenia was more frequent in patients receiving a combination therapy. CONCLUSIONS Amphotericin B plus flucytosine, as compared with amphotericin B alone, is associated with improved survival among patients with cryptococcal meningitis. A survival benefit of amphotericin B plus fluconazole was not found. (Funded by the Wellcome Trust and the British Infection Society; Controlled-Trials.com number, ISRCTN95123928.)

Antifungal Drug Development: Challenges, Unmet Clinical Needs, and New Approaches

“…One of the primary drawbacks of polyenes is their significant toxicity, although the development of lipid formulations of amphotericin B has reduced this problem significantly (Hamill 2013); such formulations are quite expensive and not available in some regions. Amphotericin B, in combination with the adjunctive drug 5-flucytosine, is the treatment of choice for cryptococcal meningitis (Day et al 2013) as well as for awide range of less common invasive mycoses. For many of the most common invasive fungal infections, the better tolerated azoles and echinocandins have emerged as first-line agents.…”

“…In part, this enthusiasm is based on the shown therapeutic superiority of coadministering amphotericin B and 5-flucytosine (5-FC) to treat cryptococcal meningitis (Day et al 2013). It is further based on the extensive network of synthetic lethal genetic interactions identified between loss-of-function (or hypomorphic) mutations otherwise singly tolerated by S. cerevisiae (Costanzo et al 2010).…”

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

“…The use of the most rapidly fungicidal combinations in the induction phase of treatment (at least 2 wk, and longer in the immunocompetent host and/ or C gattii infection) is thus recommended for any patient with CNS disease. The combination of AmBd (0.7 -1.0 mg/kg/d) and 5FC (25 mg/ kg four times a day) sterilizes the CSF most rapidly (van der Horst et al 1997;Brouwer et al 2004;Day et al 2013), and showed long-term survival benefit in a recent phase III trial (Day et al 2013). The use of adjunctive interferon (IFN)-g with AmBd and 5FC leads to even faster rates of clearance and can be considered in refractory cases (Perfect et al 2010;Jarvis et al 2012).…”

“…In organ transplant recipients on concomitant nephrotoxic drugs, liposomal AmB (3 -4 mg/kg/d) should be substituted for the deoxycholate preparation (Perfect et al 2010). 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.…”