A Randomized and Blinded Multicenter Trial of High‐Dose Fluconazole plus Placebo versus Fluconazole plus Amphotericin B as Therapy for Candidemia and Its Consequences in Nonneutropenic Subjects

Abstract

A randomized, blinded, multicenter trial was conducted to compare fluconazole (800 mg per day) plus placebo with fluconazole plus amphotericin B (AmB) deoxycholate (0.7 mg/kg per day, with the placebo/AmB component given only for the first 5-6 days) as therapy for candidemia due to species other than Candida krusei in adults without neutropenia. A total of 219 patients met criteria for a modified intent-to-treat analysis. The groups were similar except that those who were treated with fluconazole plus placebo had a higher mean (+/- standard error) Acute Physiology and Chronic Health Evaluation II score (16.8+/-0.6 vs. 15.0+/-0.7; P=.039). Success rates on study day 30 by Kaplan-Meier time-to-failure analysis were 57% for fluconazole plus placebo and 69% for fluconazole plus AmB (P=.08). Overall success rates were 56% (60 of 107 patients) and 69% (77 of 112 patients; P=.043), respectively; the bloodstream infection failed to clear in 17% and 6% of subjects, respectively (P=.02). In nonneutropenic subjects, the combination of fluconazole plus AmB was not antagonistic compared with fluconazole alone, and the combination trended toward improved success and more-rapid clearance from the bloodstream.

Fungicidal versus fungistatic therapy of invasive Candida infection in non-neutropenic adults: a meta-analysis

“…A total of 1335 eligible subjects were enrolled in the eight included trials (Kujath et al 1993; Rex et al 1994, 2003; Abele-Horn et al 1996; Anaissie et al 1996; Phillips et al 1997; Kullberg et al 2005; Reboli et al 2007) (Table 2). All of the studies were published in peer-reviewed, English-language journals between 1993 and 2014.…”

“…Of the eight studies, half enrolled more than 100 eligible patients (Rex et al 1994, 2003; Kullberg et al 2005; Reboli et al 2007) and 6 were multicentre (Rex et al 1994, 2003; Anaissie et al 1996; Phillips et al 1997; Kullberg et al 2005; Reboli et al 2007). Although all studies were randomised, only two claimed blinding through the study (Rex et al 2003; Reboli et al 2007). In two cases, the study was blinded at initial randomisation but not during the entire course of the study (Rex et al 1994; Kullberg et al 2005) (Table 1).…”

“…Candidemia was the enrolment criterion in four of the trials (Rex et al 1994, 2003; Phillips et al 1997; Kullberg et al 2005); the others allowed entry on the basis of invasive candidiasis without documented candidemia (Kujath et al 1993; Abele-Horn et al 1996; Anaissie et al 1996; Reboli et al 2007). Five of the studies specifically excluded neutropenic subjects (Rex et al 1994, 2003; Abele-Horn et al 1996; Phillips et al 1997; Kullberg et al 2005). In one study, invasive Candida cases associated with neutropenia (polymorphonuclear leucocyte count <1000/μL) were removed from the data set with only the remaining cases retained for analysis (Anaissie et al 1996).…”

“…In seven trials, the fungistatic therapy utilised was fluconazole (Kujath et al 1993; Rex et al 1994, 2003; Abele-Horn et al 1996; Anaissie et al 1996; Phillips et al 1997; Reboli et al 2007); the remaining study utilised voriconazole (Kullberg et al 2005). Seven of the eight studies used standard amphotericin B deoxycholate as the fungicidal therapy (Kujath et al 1993; Rex et al 1994, 2003; Abele-Horn et al 1996; Anaissie et al 1996; Phillips et al 1997; Kullberg et al 2005); the other study used the echinocandin, anidulafungin (Reboli et al 2007).…”

“…In two cases, amphotericin B deoxycholate was supplemented with flucytosine for a variable duration (Kujath et al 1993; Abele-Horn et al 1996). In one case, amphotericin B was supplemented by fluconazole at the same dose used in the fungistatic therapy arm (Rex et al 2003). For the fungistatic arm, the dose of fluconazole ranged between 200 and 800 mg daily; most studies utilised a dose of 400 mg/day (Rex et al 1994; Anaissie et al 1996; Phillips et al 1997; Reboli et al 2007) (Table 2).…”