title: Quantitation of Candida albicans ergosterol content improves the correlation between in vitro antifungal susceptibility test results and in vivo outcome after fluconazole treatment in a murine model of invasive candidiasis.
abstract: MIC end point determination for the most commonly prescribed azole antifungal drug, fluconazole, can be complicated by "trailing" growth of the organism during susceptibility testing by the National Committee for Clinical Laboratory Standards approved M27-A broth macrodilution method and its modified broth microdilution format. To address this problem, we previously developed the sterol quantitation method (SQM) for in vitro determination of fluconazole susceptibility, which measures cellular ergosterol content rather than growth inhibition after exposure to fluconazole. To determine if SQM MICs of fluconazole correlated better with in vivo outcome than M27-A MICs, we used a murine model of invasive candidiasis and analyzed the capacity of fluconazole to treat infections caused by C. albicans isolates which were trailers (M27-A MICs at 24 and 48 h, </=1.0 and >/=64 microg/ml, respectively; SQM MIC, </=1.0 microg/ml), as well as those which were fluconazole sensitive (M27-A and SQM MIC, </=1.0 microg/ml) and fluconazole resistant (M27-A MIC, >/=64 microg/ml; SQM MIC, 54 microg/ml). Compared with the untreated controls, fluconazole therapy increased the survival of mice infected with a sensitive isolate and both trailing isolates but did not increase the survival of mice infected with a resistant isolate. These results indicate that the SQM is more predictive of in vivo outcome than the M27-A method for isolates that give unclear MIC end points due to trailing growth in fluconazole.
authors.affiliation: Mycotic Diseases Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Arthington-Skaggs
authors.forename: D W
authors.initials: DW
authors.lastname: Warnock
authors.forename: C J
authors.initials: CJ
authors.lastname: Morrison
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002176:Candida albicans / Q000187:drug effects / Q000378:metabolism*; D002177:Candidiasis / Q000188:drug therapy* / Q000401:mortality; D004195:Disease Models, Animal; D004875:Ergosterol / Q000032:analysis*; D005260:Female; D015725:Fluconazole / Q000494:pharmacology / Q000627:therapeutic use*; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008826:Microbial Sensitivity Tests; D013223:Statistics as Topic; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents; D015725:Fluconazole; D004875:Ergosterol