146. Pharmacodynamic Optimization for the Treatment of Invasive Candida auris Infection
Session: Poster Abstract Session: Candida Auris: Coming Soon to a Patient Near You
Thursday, October 5, 2017
Room: Poster Hall CD
Posters
  • C auris ID Week 2017 V1.pdf (1.2 MB)
  • Background: C. auris is an emerging, nosocomial multidrug-resistant threat with high treatment failure rate and mortality.  The optimal antifungal agent to use and susceptibility breakpoints are based on limited clinical data.

    Methods: 9 clinical C. auris strains were used. MICs were determined by CLSI standards. Drug treatment studies consisted of: fluconazole (FLC) dose range 0.78 – 200 mg/kg/12h, micafungin (MFG) dose range 0.3125 – 80 mg/kg/24h, or amphotericin B deoxycholate (AMB) dose range 0.0.78 – 20 mg/kg/24h. Plasma PK was previously determined in the murine model for all three drugs. A 96 h neutropenic murine model of invasive candidiasis (IC) was used for all studies. The Emax Hill equation was used to model the dose-response data to PK/PD index AUC/MIC (FLC and MFG) and Cmax/MIC (AMB). The static and 1 log kill doses (when achieved) and the associated PK/PD targets (AUC/MIC or Cmax/MIC) were determined and compared with previous murine IC studies with C. albicans, C. glabrata, and C. parapsilosis.

    Results: MIC range: FLC 2 – 256 mg/L, MFG 0.125 – 4 mg/L, and AMB 0.38 – 6 mg/L. Dose-dependent activity was observed with all three drugs. Net stasis was achieved against 7 strains for FLC, 8 strains for MFG, and 8 strains for AMB.  However, MFG performed significantly better than comparators for cidal endpoints. A 1 log kill endpoint was achieved in 8 strains for MFG; whereas this endpoint was only achieved in 1 strain for FLC and 3 strains for AMB.  PK/PD analyses demonstrated a strong relationship between AUC/MIC and treatment outcome for FLC (R2 0.61) and MFG (R2 0.77); and Cmax/MIC and treatment outcome for AMB (R2 0.64). The median static dose and 1 log kill dose (MFG only) and associated AUC/MIC or Cmax/MIC values are shown (Table).

    Drug

    Stasis

    1 log kill

    Dose (mg/kg/24h)

    AUC/MIC or [Cmax/MIC]

    Dose (mg/kg/24h)

    AUC/MIC

    FLC

    107

    26.3

     

     

    MFG

    1.25

    53.7

    3.36

    130

    AMB

    3.86

    [0.87]

     

     

    Conclusion: MFG was the most potent drug over the dose range achieving up to 2 log kill against 8 of 9 strains.  PK/PD targets for C. auris against FLC and AMB were similar to other Candida species; however, MFG targets were ≥20-fold lower than C. albicans, C. glabrata, and C. parapsilosis.  Using the median stasis targets and human PK for each drug, resistance thresholds could be 16 mg/L for FLC, 2-4 mg/L for MFG, and 1-2 mg/L for AMB.

    Alexander J. Lepak, M.D.1, Miao Zhao, MS2, Elizabeth Berkow, PhD3, Shawn Lockhart, PhD3 and David R. Andes, M.D., FIDSA4, (1)Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, (2)Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, (3)Mycotic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, GA, (4)Infectious Disease, University of Wisconsin School of Medicine and Public Health, Madison, WI

    Disclosures:

    A. J. Lepak, None

    M. Zhao, None

    E. Berkow, None

    S. Lockhart, None

    D. R. Andes, None

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