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Mechanisms of Action: Physiological Effects

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

Beth A. Arthington-Skaggs, David W. Warnock, Christine J. Morrison
Beth A. Arthington-Skaggs
Mycotic Diseases Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333
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David W. Warnock
Mycotic Diseases Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333
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Christine J. Morrison
Mycotic Diseases Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333
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DOI: 10.1128/AAC.44.8.2081-2085.2000
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    Fig. 1.

    Survival curves for mice infected with C. albicans isolates which were, by the M27-A method, susceptible (A), resistant (B), or resistant with trailing (C and D) to fluconazole. The results represent the means of at least two separate experiments. There were 10 mice per group in each experiment. FLZ, fluconazole; MKD, milligrams per kilogram per day.

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  • Table 1.

    Comparison of fluconazole susceptibilities of isolates by the NCCLS M27-A method and the SQM

    Isolate no.M27-A methodSQM
    MIC (μg/ml) at:InterpretationaMIC (μg/ml)Interpretation
    24 h48 h
    10.1250.125S≤1.0S
    23264R54R
    30.25≥64R (tr)≤1.0S
    40.25≥64R (tr)≤1.0S
    • ↵a S, susceptible; R (tr), resistant with trailing growth.

  • Table 2.

    Effect of fluconazole on recovery of CFU from kidney tissue of C. albicans-infected mice

    Isolate no.bFluconazole dose (mg/kg/day)CFU per g of kidney tissue (104) at day 6 sacrificePa for indicated pairs of doses (mg/kg/day)
    MedianRange0 vs 10 vs 51 vs 5
    1 (S)05741–73
    110.9–1.4<0.005
    50.530.32–0.74<0.005n.s.
    2 (R)033740–630
    1177120–235n.s.
    5583300–1,100n.s.n.s.
    3 (Rtr)0453.5–78
    153.5–7.1<0.05
    51.50.7–2.4<0.05<0.01
    4 (Rtr)012763–192
    10.440.3–0.6<0.025
    50.080.05–0.11<0.025<0.005
    • ↵a P values were obtained using Student's t test; n.s., not significant (P> 0.05).

    • ↵b Interpretation of fluconazole susceptibilities as determined by the M27-A broth microdilution method are in parentheses. S, susceptible; Rtr, resistant with trailing growth; R, resistant.

  • Table 3.

    Correlation between the SQM MICs and treatment response compared with the M27-A MICs and treatment response

    IsolateMICDay 3Day 6
    SQMM27-A method% SurvivalaFungal burdenb% SurvivalFungal burden
    1 mg/kg/day [0.9, 0.5]c5 mg/kg/day [1.0, 0.3]1 mg/kg/day [0.6, 0.8]5 mg/kg/day [1.0, 0.2]1 mg/kg/day [0.9, 0.5]5 mg/kg/day [1.0, 0.3]1 mg/kg/day [1.0, 0.3]5 mg/kg/day [1.0, 0.2]
    11.00.1259090131990901.99.3
    254>64335510612333558586
    31.0>64 (trd)9095510.0290950.150.06
    41.0>64 (tr)6590931165900.670.13
    • ↵a Number of animals alive at the indicated day/total number of animals infected × 100.

    • ↵b 104 CFU/g of kidney tissue.

    • ↵c Pearson's coefficients of correlation between the SQM and M27-A MICs (in that order) and therapeutic outcome are given in brackets.

    • ↵d tr, trailing growth.

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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
Beth A. Arthington-Skaggs, David W. Warnock, Christine J. Morrison
Antimicrobial Agents and Chemotherapy Aug 2000, 44 (8) 2081-2085; DOI: 10.1128/AAC.44.8.2081-2085.2000

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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
Beth A. Arthington-Skaggs, David W. Warnock, Christine J. Morrison
Antimicrobial Agents and Chemotherapy Aug 2000, 44 (8) 2081-2085; DOI: 10.1128/AAC.44.8.2081-2085.2000
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KEYWORDS

antifungal agents
Candida albicans
candidiasis
ergosterol
fluconazole

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