Anidulafungin pharmacokinetics and microbial response in neutropenic mice with disseminated candidiasis.
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.
Gumbo
Tawanda
T
Division of Infectious Diseases, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9113, USA. Tawanda.Gumbo@UTSouthwestern.edu
Drusano
George L
GL
Liu
Weiguo
W
Ma
Lei
L
Deziel
Mark R
MR
Drusano
Michael F
MF
Louie
Arnold
A
D000465:Algorithms; D000666:Amphotericin B / Q000494:pharmacology / Q000627:therapeutic use; D000077612:Anidulafungin; D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D019540:Area Under Curve; D041221:Candida glabrata / Q000187:drug effects; D002177:Candidiasis / Q000378:metabolism* / Q000382:microbiology*; D015169:Colony Count, Microbial; D004305:Dose-Response Relationship, Drug; D054714:Echinocandins; D005260:Female; D015725:Fluconazole / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000378:metabolism* / Q000382:microbiology*; D010456:Peptides, Cyclic / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*
D000935:Antifungal Agents; D054714:Echinocandins; D010456:Peptides, Cyclic; D000666:Amphotericin B; D015725:Fluconazole; D000077612:Anidulafungin