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Antimicrobial Agents and Chemotherapy, November 2006, p. 3695-3700, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00507-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Anidulafungin Pharmacokinetics and Microbial Response in Neutropenic Mice with Disseminated Candidiasis{triangledown}

Tawanda Gumbo,1* George L. Drusano,1 Weiguo Liu,1 Lei Ma,1 Mark R. Deziel,1 Michael F. Drusano,1,2 and Arnold Louie1

Emerging Infections and Pharmacodynamics Laboratory, Ordway Research Institute, Albany, New York,1 University of Maryland School of Medicine, Baltimore, Maryland2

Received 24 April 2006/ Returned for modification 5 July 2006/ Accepted 27 August 2006

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 (Emax) of 1.4 to 1.9 log10 CFU/g in kidneys and was not influenced by resistance to either fluconazole or amphotericin B. Fluconazole produced an Emax of 1.3 log10 CFU/g in mice infected with fluconazole-susceptible C. glabrata, but the Emax was 0 for mice infected with a C. glabrata strain that had a fluconazole MIC of ≥32 mg/liter. Amphotericin B achieved an Emax of 4.2 log10 CFU/g in mice infected with amphotericin B-susceptible C. glabrata, but the Emax 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.

* Corresponding author. Present address: Division of Infectious Diseases, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9113. Phone: (214) 648-9914. Fax: (214) 648-2741. E-mail: Tawanda.Gumbo{at}UTSouthwestern.edu.

{triangledown} Published ahead of print on 5 September 2006.

Antimicrobial Agents and Chemotherapy, November 2006, p. 3695-3700, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00507-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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