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.