Once-weekly micafungin therapy is as effective as daily therapy for disseminated candidiasis in mice with persistent neutropenia

Abstract

The effect of micafungin dose scheduling on the treatment of candidemia is unknown. Neutropenic mice with disseminated Candida glabrata infection were treated with single intraperitoneal micafungin doses of 0 to 100 mg/kg of body weight and sacrificed 7 days later. The maximal decline in kidney fungal burden was 5.8 log(10) CFU/g. A 1-week pharmacokinetic-pharmacodynamic study revealed a micafungin serum half-life of 6.13 h. In mice treated with > or =50 mg/kg, there was maximal fungal decline without regrowth during the 1-week dosing interval. Next, doses associated with 34% (34% effective dose [ED(34)]) and 50% (ED(50)) of maximal kill were administered at one of three dose schedules: a single dose at t = 0, two equal doses at t = 0 and t = 3.5 days, and 7 equal doses daily. Some mice received a single dose of 100 mg/kg. Fungal burden was examined on days 1, 5, and 7. In mice treated with the ED(34), microbial kill with the daily therapy initially lagged behind the intermittent doses but exceeded it by day 7. In mice treated with the ED(50), daily and intermittent doses had equivalent day 7 effects. In mice treated with 100 mg/kg, there was no regrowth. The relative likelihoods that the area under the concentration-time curve/MIC ratio was linked to microbial kill versus peak concentration/MIC ratio or time above the MIC was 10.3 and 10,161.2, respectively. In all the experiments, no paradoxical increase in fungal burden was observed with high micafungin doses. However, only a single Candida isolate was tested. Regimens that simulated micafungin concentration-time profiles in patients treated with a single micafungin dose of 1,400 mg once a week demonstrated maximal fungal decline. Once-weekly micafungin therapy is as efficacious as daily therapy in a murine model of disseminated candidiasis.

FIG. 1.

Changes in mouse kidney fungal burden after a single dose of micafungin.

FIG. 2.

The inhibitory sigmoid E_max relationship between micafungin exposure and kidney fungal density.

FIG. 3.

Effect of dose scheduling on micafungin efficacy. Changes in kidney fungal density with time in mice treated with 5 mg/kg (ED₃₄) (A), 20 mg/kg (ED₅₀) (B), and 100 mg/kg (C) of intraperitoneal micafungin are shown.

FIG. 4.

Microbial effect of mimicking micafungin concentration-time profiles encountered with once-weekly doses in humans. (A) Dosing regimen in mice that mimics the mathematically derived pharmacokinetic profile of humans treated with 700 mg once a week; (B and C) effect of mimicking human concentration-time profile of 700-mg (B) and 1,400-mg (C) once-weekly doses compared to the 100-mg/kg dose.