Penetration of Ibrexafungerp (Formerly SCY-078) at the Site of Infection in an Intra-abdominal Candidiasis Mouse Model

被引:20
作者
Lee, Annie [1 ]
Prideaux, Brendan [2 ]
Zimmerman, Matthew [1 ]
Carter, Claire [1 ]
Barat, Stephen [3 ]
Angulo, David [3 ]
Dartois, Veronique [1 ]
Perlin, David S. [1 ]
Zhao, Yanan [1 ,4 ]
机构
[1] Hackensack Meridian Hlth, Ctr Discovery & Innovat, Nutley, NJ 07110 USA
[2] Univ Texas Med Branch, Dept Neurosci Cell Biol & Anat, Galveston, TX 77555 USA
[3] Scynexis Inc, Jersey City, NJ USA
[4] Seton Hall Univ, Hackensack Meridian Sch Med, Dept Med Sci, Nutley, NJ 07110 USA
关键词
ibrexafungerp; intra-abdominal candidiasis; lesion; drug penetration; matrix-assisted desorption ionization-mass spectrometry imaging (MALDI-MSI); laser capture microdissection (LCM); GLUCAN SYNTHASE INHIBITOR; MICAFUNGIN; PHARMACOKINETICS; ASPERGILLUS; GLABRATA; MK-3118; MANAGEMENT; ALBICANS;
D O I
10.1128/AAC.02268-19
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Ibrexafungerp (IBX), formerly SCY-078, is a novel, oral and intravenous, semisynthetic triterpenoid glucan synthase inhibitor in clinical development for treating multiple fungal infections, including invasive candidiasis. Intra-abdominal candidiasis (IAC) is one of the most common types of invasive candidiasis associated with high mortality largely due to poor drug exposure in infected lesions. To better understand the potential of IBX to treat such infections, we investigated its penetration at the site of infection. Using matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) and laser capture microdissection (LCM)-directed high-pressure liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), we investigated tissue distribution and lesion-specific drug exposure of IBX in a clinically relevant IAC mouse model. After a single-dose treatment, IBX quickly distributed into tissues and efficiently accumulated within lesions. Drug concentrations of IBX within the liver abscesses were almost 100-fold higher than the serum concentration. In addition, drug penetration after repeated treatment of IBX was compared with micafungin. IBX exhibited robust and long-lasting lesion penetration after repeated treatment. These data indicate that IBX penetrates into intra-abdominal abscesses highly efficiently and holds promise as a potential therapeutic option for IAC patients.
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页数:11
相关论文
共 40 条
[1]   In Vivo Comparison of the Pharmacodynamic Targets for Echinocandin Drugs against Candida Species [J].
Andes, D. ;
Diekema, D. J. ;
Pfaller, M. A. ;
Bohrmuller, J. ;
Marchillo, K. ;
Lepak, A. .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2010, 54 (06) :2497-2506
[2]   In vivo pharmacodynamic target investigation for micafungin against Candida albicans and C-glabrata in a neutropenic murine candidiasis model [J].
Andes, D. R. ;
Diekema, D. J. ;
Pfaller, M. A. ;
Marchillo, K. ;
Bohrmueller, J. .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2008, 52 (10) :3497-3503
[3]  
[Anonymous], 2002, JPN J CHEMOTHER
[4]   A research agenda on the management of intra-abdominal candidiasis: results from a consensus of multinational experts [J].
Bassetti, Matteo ;
Marchetti, Monia ;
Chakrabarti, Arunaloke ;
Colizza, Sergio ;
Garnacho-Montero, Jose ;
Kett, Daniel H. ;
Munoz, Patricia ;
Cristini, Francesco ;
Andoniadou, Anastasia ;
Viale, Pierluigi ;
Della Rocca, Giorgio ;
Roilides, Emmanuel ;
Sganga, Gabriele ;
Walsh, Thomas J. ;
Tascini, Carlo ;
Tumbarello, Mario ;
Menichetti, Francesco ;
Righi, Elda ;
Eckmann, Christian ;
Viscoli, Claudio ;
Shorr, Andrew F. ;
Leroy, Olivier ;
Petrikos, George ;
De Rosa, Francesco Giuseppe .
INTENSIVE CARE MEDICINE, 2013, 39 (12) :2092-2106
[5]   In Vitro Activity of a Novel Glucan Synthase Inhibitor, SCY-078, against Clinical Isolates of Candida auris [J].
Berkow, Elizabeth L. ;
Angulo, David ;
Lockhart, Shawn R. .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2017, 61 (07)
[6]   Candida peritonitis [J].
Blot, Stijn I. ;
Vandewoude, Koenraad H. ;
De Waele, Jan J. .
CURRENT OPINION IN CRITICAL CARE, 2007, 13 (02) :195-199
[7]   Profiling of Candida albicans Gene Expression During Intra-abdominal Candidiasis Identifies Biologic Processes Involved in Pathogenesis [J].
Cheng, Shaoji ;
Clancy, Cornelius J. ;
Xu, Wenjie ;
Schneider, Frank ;
Hao, Binghua ;
Mitchell, Aaron P. ;
Hong Nguyen, M. .
JOURNAL OF INFECTIOUS DISEASES, 2013, 208 (09) :1529-1537
[8]   Drug-Resistant Candida glabrata Infection in Cancer Patients [J].
Farmakiotis, Dimitrios ;
Tarrand, Jeffrey J. ;
Kontoyiannis, Dimitrios P. .
EMERGING INFECTIOUS DISEASES, 2014, 20 (11) :1833-1840
[9]   Activity of a Novel 1,3-Beta-D-Glucan Synthase Inhibitor, Ibrexafungerp (Formerly SCY-078), against Candida glabrata [J].
Ghannoum, M. ;
Long, L. ;
Isham, N. ;
Hager, C. ;
Wilson, R. ;
Borroto-Esoda, K. ;
Barat, S. ;
Angulo, D. .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2019, 63 (12)
[10]  
Ghannoum M, 2018, ANTIMICROB AGENTS CH, V62, DOI [10.1128/AAC.00244-18, 10.1128/aac.00244-18]