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Antimicrobial Agents and Chemotherapy, January 2007, p. 285-295, Vol. 51, No. 1
0066-4804/07/$08.00+0     doi:10.1128/AAC.00601-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Effect of Neutropenia and Treatment Delay on the Response to Antifungal Agents in Experimental Disseminated Candidiasis{triangledown}

William W. Hope,1,2,3* George L. Drusano,2 Caroline B. Moore,1 Andrew Sharp,1 Arnold Louie,2 Thomas J. Walsh,3 David W. Denning,1,4 and Peter A. Warn1

School of Medicine, 1.800 Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom,1 Emerging Infections and Host Defense Section, Ordway Research Institute, Albany, New York 12208,2 Immunocompromised Host Section, Pediatric Oncology Branch, NCI/NIH, Bethesda, Maryland 20892,3 Wythenshawe Hospital, Manchester M23 9LT, United Kingdom4

Received 16 May 2006/ Returned for modification 15 July 2006/ Accepted 28 October 2006

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.

* Corresponding author. Mailing address: Pediatric Oncology Branch, NCI/NIH, CRC Room 1-5750, 10 Center Dr., MSC 1100, Bethesda, MD 20892-1100. Phone: (301) 496-8061. Fax: (301) 480-2308. E-mail: hopew{at}mail.nih.gov.

{triangledown} Published ahead of print on 6 November 2006.

Antimicrobial Agents and Chemotherapy, January 2007, p. 285-295, Vol. 51, No. 1
0066-4804/07/$08.00+0     doi:10.1128/AAC.00601-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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