Anidulafungin pharmacokinetics and microbial response in neutropenic mice with disseminated candidiasis

Abstract

Candidemia is often fatal, especially in patients with persistent neutropenia. New therapies are needed. We performed 24-h pharmacodynamic studies to compare the efficacies of anidulafungin, fluconazole, and amphotericin B in neutropenic mice with disseminated candidiasis caused by one of three strains of Candida glabrata. Anidulafungin produced a maximal fungal kill (E(max)) of 1.4 to 1.9 log(10) CFU/g in kidneys and was not influenced by resistance to either fluconazole or amphotericin B. Fluconazole produced an E(max) of 1.3 log(10) CFU/g in mice infected with fluconazole-susceptible C. glabrata, but the E(max) was 0 for mice infected with a C. glabrata strain that had a fluconazole MIC of >/=32 mg/liter. Amphotericin B achieved an E(max) of 4.2 log(10) CFU/g in mice infected with amphotericin B-susceptible C. glabrata, but the E(max) was 0 for mice infected with a C. glabrata strain with an amphotericin B MIC of 2 mg/liter. In all instances, anidulafungin's maximal microbial kill was superior to that of fluconazole. Next, we performed a 96-h anidulafungin pharmacokinetic-pharmacodynamic study. Anidulafungin exhibited delayed peak concentrations in kidneys compared to those in serum, after which the concentrations declined, with a serum terminal half-life of 21.6 (+/-4.6) h. This was accompanied by a persistent 96-h decrease in the kidney fungal burden after treatment with a single anidulafungin dose of >/=8 mg/kg of body weight. This pharmacokinetic-pharmacodynamic picture of anidulafungin persistence in tissues and the resultant persistent fungal decline should be exploited to improve the efficacy of anidulafungin therapy for candidemia.

FIG. 1.

Inhibitory sigmoid E_max curve 24 h after treatment of neutropenic mice infected with a C. glabrata strain resistant to both fluconazole and amphotericin B. The mice were treated with a single dose of anidulafungin at 0 h.

FIG. 2.

Concentration-time profiles for anidulafungin in serum (▵) and in kidney tissue (▴) over 96 h in mice treated with a single 10-mg/kg dose of intraperitoneal anidulafungin. The lines represent idealized exponential declines of serum drug concentrations (hatched line) and kidney drug concentrations (solid line).

FIG. 3.

Microbial responses in kidneys of mice after treatment with single intraperitoneal doses of anidulafungin at 0 h. Data for mice that received 2 and 3 mg/kg, which did not differ significantly from the controls, were not presented for clarity. Mice in the group receiving 6 mg/kg died from bacterial superinfection between the 72-h and 96-h time points. Doses of 8 and 10 mg/kg resulted in progressive declines in kidney fungal density. Ninety-six hours after treatment with the 8- and 10-mg/kg doses, the fungal burdens in kidneys of some mice were below the limit of detection. Mice had been infected with dose-dependently fluconazole-susceptible C. glabrata (strain 2).

FIG. 4.

Relationship between tissue or serum anidulafungin exposure and microbial response in mice infected with C. glabrata strain 2. Mice had been treated with a single anidulafungin dose 96 h earlier. AUC_0-96, area under the concentration-time curve from 0 to 96 h.