The effect of neutropenia and treatment delay on the response to antifungal agents

Antimicrob Agents Chemother. 2006 Nov 6; [Epub ahead of print]

The effect of neutropenia and treatment delay on the response to antifungal agents in experimental disseminated candidiasis.

Hope WW, Drusano GL, Moore CB, Sharp A, Louie A, Walsh TJ, Denning DW, Warn PA. School of Medicine, 1.800 Stopford Building, University of Manchester, Oxford Road, Manchester, M13 9PT, UK., Emerging Infections and Host Defense Section, Ordway Research Institute, Albany, NY, 12208, USA., Immunocompromised Host Section, Pediatric Oncology Branch, NCI/NIH, Bethesda, MD, 20892, USA., Wythenshawe Hospital, Manchester, M23 9LT, UK.

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 to 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 kill 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 rapid rate of Candida kill and a sustained anti-C. albicans effect. In neutropenic mice, 5 mg/kg 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.

PMID: 17088486 [PubMed - as supplied by publisher]

Full Article Available Online