Direct comparison of the pharmacodynamics of four antifungal drugs in a mouse model of disseminated candidiasis using microbiological assays of serum drug concentrations.
The aim of this study was to compare the pharmacodynamics of the azole antifungal drugs fluconazole, itraconazole and ketoconazole, and the polyene antifungal amphotericin B, in a mouse model of disseminated Candida albicans infection. In order to directly compare effective serum concentrations of these antifungals, drug concentrations were assayed microbiologically by measuring inhibition of C. albicans mycelial growth (mMIC) in a mouse serum-based assay (serum antifungal titer). Efficacy in the mouse infection model was determined using an organ-based (kidney burden) endpoint. For all four drugs, the serum antifungal titers, 8 hr after administration of single doses of drugs at a range of drug concentrations, correlated closely with C. albicans kidney fungal burden in the mouse model. The results showed that determining serum antifungal titer may be used to accurately represent kidney fungal burden in a mouse model of disseminated candidiasis and allowed direct comparison of the pharmacodynamics of differing classes of antifungal drugs.
Maki
Katsuyuki
K
Pharmacology Research Laboratories, Astellas Pharma, Inc., Osaka, Japan. katsuyuki.maki@jp.astellas.com
Holmes
Ann R
AR
Watabe
Etsuko
E
Iguchi
Yumi
Y
Matsumoto
Satoru
S
Ikeda
Fumiaki
F
Tawara
Shuichi
S
Mutoh
Seitaro
S
D000666:Amphotericin B / Q000493:pharmacokinetics; D000818:Animals; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics*; D002176:Candida albicans / Q000187:drug effects; D002177:Candidiasis / Q000097:blood / Q000378:metabolism*; D004195:Disease Models, Animal; D015725:Fluconazole / Q000493:pharmacokinetics; D017964:Itraconazole / Q000493:pharmacokinetics; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008826:Microbial Sensitivity Tests
D000935:Antifungal Agents; D017964:Itraconazole; D000666:Amphotericin B; D015725:Fluconazole