title: Efficacies of fluconazole, caspofungin, and amphotericin B in Candida glabrata-infected p47phox-/- knockout mice.
abstract: Candida glabrata is the second leading cause of adult candidemia, resulting in high mortality. Amphotericin B is considered the treatment of choice, while the efficacy of fluconazole is controversial and caspofungin efficacy is unknown. To ascertain drug efficacy in vivo, the utility of a murine model of C. glabrata infection was investigated. C. glabrata was found to cause progressive, lethal infection when injected intravenously into C57BL/6 mice with reduced oxidative microbicidal capacity due to knockout of the p47(phox) gene. Spleen and kidney organ CFU counts were determined in groups of mice 2 days after the mice completed 6 days of daily intraperitoneal drug treatment, which began on the day of infection. Daily injections of fluconazole at 80 mg/kg did not reduce spleen or kidney CFU counts after infection with C. glabrata strains having in vitro fluconazole MICs of 2, 32, or 256 microg/ml compared to saline-treated controls. However, this fluconazole regimen reduced spleen CFU counts in mice infected with Candida albicans, an infection that is known to be responsive to fluconazole. Caspofungin at 5 mg/kg and amphotericin B at 5 mg/kg were both effective in reducing fungal burden in spleens and kidneys of C. glabrata-infected mice. Ten mice treated for 6 days with caspofungin at 1 mg/kg survived for 15 days, though all 10 saline-injected mice died or were so ill that they had to be sacrificed by 96 h postinfection. This murine model provided evidence of the efficacy of amphotericin B and caspofungin but not of fluconazole against C. glabrata infection.
authors.affiliation: Clinical Mycology Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Justina Y
authors.initials: JY
authors.lastname: Ju
authors.forename: Cynthia
authors.initials: C
authors.lastname: Polhamus
authors.forename: Kieren A
authors.initials: KA
authors.lastname: Marr
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.forename: John E
authors.initials: JE
authors.lastname: Bennett
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002175:Candida / Q000187:drug effects* / Q000472:pathogenicity; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology; D004195:Disease Models, Animal; D005260:Female; D015725:Fluconazole / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases; D010750:Phosphoproteins / Q000235:genetics*; D016896:Treatment Outcome; D014774:Virulence
chemical_list: D000935:Antifungal Agents; D010750:Phosphoproteins; D000666:Amphotericin B; D007371:Interferon-gamma; D015725:Fluconazole; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1