Effect of neutropenia and treatment delay on the response to antifungal agents in experimental disseminated candidiasis

William W. Hope, George L. Drusano, Caroline B. Moore, Andrew Sharp, Arnold Louie, Thomas J. Walsh, David W. Denning, Peter A. Warn

Research output: Contribution to journalArticle

Abstract

Disseminated candidiasis is associated with a high rate of morbidity and mortality. The presence of neutrophils and the timely administration of antifungal agents are likely to be critical factors for a favorable therapeutic outcome of this syndrome. The effect of neutropenia on the temporal profile of the burden of Candida albicans in untreated mice and those treated with amphotericin B was determined using a pharmacodynamic model of disseminated candidiasis. A mathematical model was developed to describe the rate and extent of the C. albicans killing attributable to neutrophils and to amphotericin B. The consequences of a delay in the administration of amphotericin B, flucytosine, or micafungin were studied by defining dose-response relationships. Neutrophils caused a logarithmic decline in fungal burden in treated and untreated mice. The combination of amphotericin B and neutrophils resulted in a high rate of Candida killing and a sustained anti-C. albicans effect. In neutropenic mice, 5 mg/kg of body weight of amphotericin B was required to prevent progressive logarithmic growth. An increased delay in drug administration resulted in a reduction in the maximum effect to a point at which no drug effect could be observed. Neutrophils and the timely initiation of antifungal agents are critical determinants in the treatment of experimental disseminated candidiasis.

Original languageEnglish (US)
Pages (from-to)285-295
Number of pages11
JournalAntimicrobial agents and chemotherapy
Volume51
Issue number1
DOIs
StatePublished - Jan 2007

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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    Hope, W. W., Drusano, G. L., Moore, C. B., Sharp, A., Louie, A., Walsh, T. J., Denning, D. W., & Warn, P. A. (2007). Effect of neutropenia and treatment delay on the response to antifungal agents in experimental disseminated candidiasis. Antimicrobial agents and chemotherapy, 51(1), 285-295. https://doi.org/10.1128/AAC.00601-06