PMID- 31818813 OWN - NLM STAT- MEDLINE DCOM- 20201218 LR - 20201218 IS - 1098-6596 (Electronic) IS - 0066-4804 (Print) IS - 0066-4804 (Linking) VI - 64 IP - 3 DP - 2020 Feb 21 TI - Fosmanogepix (APX001) Is Effective in the Treatment of Immunocompromised Mice Infected with Invasive Pulmonary Scedosporiosis or Disseminated Fusariosis. LID - 10.1128/AAC.01735-19 [doi] LID - e01735-19 AB - There are limited treatment options for immunosuppressed patients with lethal invasive fungal infections due to Fusarium and Scedosporium Manogepix (MGX; APX001A) is a novel antifungal that targets the conserved Gwt1 enzyme required for localization of glycosylphosphatidylinositol-anchored mannoproteins in fungi. We evaluated the in vitro activity of MGX and the efficacy of the prodrug fosmanogepix (APX001) in immunosuppressed murine models of hematogenously disseminated fusariosis and pulmonary scedosporiosis. The MGX minimum effective concentration (MEC) for Scedosporium isolates was 0.03 mug/ml and ranged from 0.015 to 0.03 mug/ml for Fusarium isolates. In the scedosporiosis model, treatment of mice with 78 mg/kg and 104 mg/kg of body weight fosmanogepix, along with 1-aminobenzotriazole (ABT) to enhance the serum half-life of MGX, significantly increased median survival time versus placebo from 7 days to 13 and 11 days, respectively. Furthermore, administration of 104 mg/kg fosmanogepix resulted in an approximately 2-log(10) reduction in lung, kidney, or brain conidial equivalents/gram tissue (CE). Similarly, in the fusariosis model, 78 mg/kg and 104 mg/kg fosmanogepix plus ABT enhanced median survival time from 7 days to 12 and 10 days, respectively. A 2- to 3-log(10) reduction in kidney and brain CE was observed. In both models, reduction in tissue fungal burden was corroborated with histopathological data, with target organs showing reduced or no abscesses in fosmanogepix-treated mice. Survival and tissue clearance were comparable to a clinically relevant high dose of liposomal amphotericin B (10 to 15 mg/kg). Our data support the continued development of fosmanogepix as a first-in-class treatment for infections caused by these rare molds. CI - Copyright (c) 2020 Alkhazraji et al. FAU - Alkhazraji, Sondus AU - Alkhazraji S AD - Division of Infectious Diseases, The Lundquist Institute at Harbor-University of California Los Angeles (UCLA) Medical Center and St. John's Cardiovascular Research Center, Torrance, California, USA. FAU - Gebremariam, Teclegiorgis AU - Gebremariam T AD - Division of Infectious Diseases, The Lundquist Institute at Harbor-University of California Los Angeles (UCLA) Medical Center and St. John's Cardiovascular Research Center, Torrance, California, USA. FAU - Alqarihi, Abdullah AU - Alqarihi A AD - Division of Infectious Diseases, The Lundquist Institute at Harbor-University of California Los Angeles (UCLA) Medical Center and St. John's Cardiovascular Research Center, Torrance, California, USA. FAU - Gu, Yiyou AU - Gu Y AD - Division of Infectious Diseases, The Lundquist Institute at Harbor-University of California Los Angeles (UCLA) Medical Center and St. John's Cardiovascular Research Center, Torrance, California, USA. FAU - Mamouei, Zeinab AU - Mamouei Z AD - Division of Infectious Diseases, The Lundquist Institute at Harbor-University of California Los Angeles (UCLA) Medical Center and St. John's Cardiovascular Research Center, Torrance, California, USA. FAU - Singh, Shakti AU - Singh S AUID- ORCID: 0000-0001-6521-0998 AD - Division of Infectious Diseases, The Lundquist Institute at Harbor-University of California Los Angeles (UCLA) Medical Center and St. John's Cardiovascular Research Center, Torrance, California, USA. FAU - Wiederhold, Nathan P AU - Wiederhold NP AUID- ORCID: 0000-0002-2225-5122 AD - University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA. FAU - Shaw, Karen J AU - Shaw KJ AD - Amplyx Pharmaceuticals, Inc., San Diego, California, USA kshaw@amplyx.com ibrahim@labiomed.org. FAU - Ibrahim, Ashraf S AU - Ibrahim AS AD - Division of Infectious Diseases, The Lundquist Institute at Harbor-University of California Los Angeles (UCLA) Medical Center and St. John's Cardiovascular Research Center, Torrance, California, USA kshaw@amplyx.com ibrahim@labiomed.org. AD - David Geffen School of Medicine at UCLA, Los Angeles, California, USA. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200221 PL - United States TA - Antimicrob Agents Chemother JT - Antimicrobial agents and chemotherapy JID - 0315061 RN - 0 (APX001A) RN - 0 (Aminopyridines) RN - 0 (Antifungal Agents) RN - 0 (Drug Combinations) RN - 0 (Isoxazoles) RN - 0 (Prodrugs) RN - 0 (Triazoles) RN - 1614-12-6 (1-aminobenzotriazole) RN - scedosporiosis SB - IM MH - Aminopyridines/blood/pharmacokinetics/*pharmacology MH - Animals MH - Antifungal Agents/blood/pharmacokinetics/*pharmacology MH - Biological Availability MH - Brain/drug effects/immunology/microbiology MH - Drug Administration Schedule MH - Drug Combinations MH - Fusariosis/*drug therapy/immunology/microbiology/mortality MH - Fusarium/*drug effects/growth & development/immunology MH - Half-Life MH - Humans MH - *Immunocompromised Host MH - Invasive Fungal Infections/*drug therapy/immunology/microbiology/mortality MH - Isoxazoles/blood/pharmacokinetics/*pharmacology MH - Kidney/drug effects/immunology/microbiology MH - Lung/drug effects/immunology/microbiology MH - Male MH - Mice MH - Mice, Inbred ICR MH - Microbial Sensitivity Tests MH - Prodrugs MH - Scedosporium/*drug effects/growth & development/immunology MH - Survival Analysis MH - Triazoles/pharmacology PMC - PMC7038288 OTO - NOTNLM OT - APX001 OT - APX001A OT - Fusarium OT - Gwt1 OT - Scedosporium OT - antifungal OT - antifungal agents OT - fosmanogepix OT - infection model OT - manogepix OT - murine EDAT- 2019/12/11 06:00 MHDA- 2020/12/19 06:00 PMCR- 2020/02/21 CRDT- 2019/12/11 06:00 PHST- 2019/08/25 00:00 [received] PHST- 2019/12/02 00:00 [accepted] PHST- 2019/12/11 06:00 [pubmed] PHST- 2020/12/19 06:00 [medline] PHST- 2019/12/11 06:00 [entrez] PHST- 2020/02/21 00:00 [pmc-release] AID - AAC.01735-19 [pii] AID - 01735-19 [pii] AID - 10.1128/AAC.01735-19 [doi] PST - epublish SO - Antimicrob Agents Chemother. 2020 Feb 21;64(3):e01735-19. doi: 10.1128/AAC.01735-19. Print 2020 Feb 21.