1533. Unraveling Drug Penetration of Echinocandin Antifungals at the Site of Infection in an Intra-Abdominal Abscess Model
Session: Poster Abstract Session: Preclinical Study with New Antibiotics and Antifungals
Friday, October 6, 2017
Room: Poster Hall CD
Posters
  • Perlin_PN1533.pdf (764.4 kB)
  • Background: Intra-abdominal candidiasis (IAC) is a prominent invasive fungal infection associated with high mortality. Prompt antifungal therapy and source control are crucial for successful treatment. Echinocandin antifungal drugs are first-line agents. Yet, their clinical effectiveness is highly variable with known potential for breakthrough resistance, and little is known about drug exposure at the site of infection. Using matrix-assisted desorption/ionization (MALDI) mass spectrometry imaging as well as standard analytical techniques, we investigated the spatial and quantitative distribution in tissue lesions for two echinocandin drugs, micafungin and CD101, in a clinically relevant IAC mouse model.

    Methods: Female 6-8 week old CD1 mice weighing 18-22 g were infected intraperitoneally (IP) with 1x107 CFU of C. albicans SC5314 mixed with sterile stool matrix. Single IP doses of CD101 at 5 or 20 mg/kg (equivalent to humanized therapeutic dose) or micafungin at 5 mg/kg (therapeutic dose) were administered to mice at day 3 post-inoculation. Mice were sacrificed at just before antifungal treatment (n=1), and at 1, 3, 6, 24, and 48 h post-dose (n=3 per group per time point). Liver and kidney lesions were collected for MALDI imaging. Laser capture microdissection (LCM) followed by liquid chromatography coupled tandem mass spectrometry (LC/MS-MS) was applied to 6 and 24h samples for drug exposure measurement. In a separate experiment, mice were treated with 2 or 3 doses of micafungin (5 mg/kg), or a single dose of CD101 (20 mg/kg). Drug accumulation was analyzed at 48 and 72h post the first dose.

    Results: Drug accumulation within lesions was observed with both drugs at their humanized therapeutic dose. However, micafungin, even at steady-state, failed to approach the mutant prevention concentration (MPC) (16 µg/ml) of the infecting strain. CD101 demonstrated extensive penetration into the lesions after a single dose administration and persisted in lesions at above MPC level of 29.7 µg/ml at 72h postdose.

    Conclusion: These findings indicate that current echinocandin drugs may be limited by penetration at the site of infection, which have implications for clinical outcomes and emergence of resistance in patients with IAC.

    Yanan Zhao, Ph.D.1, Brendan Prideaux, Ph.D.1, Yoji Nagasaki, MD1, Min Hee Lee, MS1, Pei-Yu Chen, MS1, Landry Blanc, Ph.D.1, Hsinpin Ho, Ph.D.1, Cornelius J. Clancy, M.D.2, Minh-Hong Nguyen, MD3, Veronique Dartois, Ph.D.1 and David Perlin, Ph.D.1, (1)Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ, (2)Infectious Diseases, University of Pittsburgh, Pittsburgh, PA, (3)University of Pittsburgh, School of Medicine, Pittsburgh, PA

    Disclosures:

    Y. Zhao, None

    B. Prideaux, None

    Y. Nagasaki, None

    M. H. Lee, None

    P. Y. Chen, None

    L. Blanc, None

    H. Ho, None

    C. J. Clancy, Merck: Received research funding , Research support
    Astellas: Received research funding , Research support
    Cidara: Received research funding , Research support
    Astellas: Scientific Advisor , Advisory board
    Merck: Scientific Advisor , Advisory board
    Cidara: Scientific Advisor , Advisory board
    Medicines Company: Scientific Advisor , Advisory board

    M. H. Nguyen, None

    V. Dartois, None

    D. Perlin, Cidara: Research Contractor and Scientific Advisor , Research grant
    Amplyx: Research Contractor and Scientific Advisor , Research grant
    Matinas: Scientific Advisor , Research support
    Scynexis: Research Contractor and Scientific Advisor , Research grant
    Merck: Research Contractor , Research grant
    Astellas: Research Contractor , Research grant

    Findings in the abstracts are embargoed until 12:01 a.m. PDT, Wednesday Oct. 4th with the exception of research findings presented at the IDWeek press conferences.