Effect of neutropenia and treatment delay on the response to antifungal agents in experimental disseminated candidiasis.
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.
Hope
William W
WW
Pediatric Oncology Branch, NCI/NIH, CRC Room 1-5750, 10 Center Dr., MSC 1100, Bethesda, MD 20892-1100, USA. hopew@mail.nih.gov
Drusano
George L
GL
Moore
Caroline B
CB
Sharp
Andrew
A
Louie
Arnold
A
Walsh
Thomas J
TJ
Denning
David W
DW
Warn
Peter A
PA
D000666:Amphotericin B / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002176:Candida albicans / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D054714:Echinocandins; D005437:Flucytosine / Q000494:pharmacology / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055666:Lipopeptides; D008074:Lipoproteins / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D000077551:Micafungin; D051379:Mice; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000473:pathology / Q000503:physiopathology*; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors
D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D008074:Lipoproteins; D010456:Peptides, Cyclic; D000666:Amphotericin B; D005437:Flucytosine; D000077551:Micafungin