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      The Combination Treatment of Fosmanogepix and Liposomal Amphotericin B Is Superior to Monotherapy in Treating Experimental Invasive Mold Infections

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          ABSTRACT

          Invasive pulmonary aspergillosis (IPA), invasive mucormycosis (IM), and invasive fusariosis (IF) are associated with high mortality and morbidity. Fosmanogepix (FMGX) is a first-in-class antifungal in clinical development with demonstrated broad-spectrum activity in animal models of infections. We sought to evaluate the benefit of combination therapy of FMGX plus liposomal amphotericin B (L-AMB) in severe delayed-treatment models of murine IPA, IM, and IF. While FMGX was equally as effective as L-AMB in prolonging the survival of mice infected with IPA, IM, or IF, combination therapy was superior to monotherapy in all three models. These findings were validated by greater reductions in the tissue fungal burdens (determined by quantitative PCR) of target organs in all three models versus the burdens in infected vehicle-treated (placebo) or monotherapy-treated mice. In general, histopathological examination of target organs corroborated the findings for fungal tissue burdens among all treatment arms. Our results show that treatment with the combination of FMGX plus L-AMB demonstrated high survival rates and fungal burden reductions in severe animal models of invasive mold infections, at drug exposures in mice similar to those achieved clinically. These encouraging results warrant further investigation of the FMGX–plus–L-AMB combination treatment for severely ill patients with IPA, IM, and IF.

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          Most cited references38

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          Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis.

          Mononuclear phagocytes, including monocytes, macrophages, and dendritic cells, contribute to tissue integrity as well as to innate and adaptive immune defense. Emerging evidence for labor division indicates that manipulation of these cells could bear therapeutic potential. However, specific ontogenies of individual populations and the overall functional organization of this cellular network are not well defined. Here we report a fate-mapping study of the murine monocyte and macrophage compartment taking advantage of constitutive and conditional CX(3)CR1 promoter-driven Cre recombinase expression. We have demonstrated that major tissue-resident macrophage populations, including liver Kupffer cells and lung alveolar, splenic, and peritoneal macrophages, are established prior to birth and maintain themselves subsequently during adulthood independent of replenishment by blood monocytes. Furthermore, we have established that short-lived Ly6C(+) monocytes constitute obligatory steady-state precursors of blood-resident Ly6C(-) cells and that the abundance of Ly6C(+) blood monocytes dynamically controls the circulation lifespan of their progeny. Copyright © 2013 Elsevier Inc. All rights reserved.
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            Novel perspectives on mucormycosis: pathophysiology, presentation, and management.

            Mucormycosis is a life-threatening fungal infection that occurs in immunocompromised patients. These infections are becoming increasingly common, yet survival remains very poor. A greater understanding of the pathogenesis of the disease may lead to future therapies. For example, it is now clear that iron metabolism plays a central role in regulating mucormycosis infections and that deferoxamine predisposes patients to mucormycosis by inappropriately supplying the fungus with iron. These findings raise the possibility that iron chelator therapy may be useful to treat the infection as long as the chelator does not inappropriately supply the fungus with iron. Recent data support the concept that high-dose liposomal amphotericin is the preferred monotherapy for mucormycosis. However, several novel therapeutic strategies are available. These options include combination therapy using lipid-based amphotericin with an echinocandin or with an azole (largely itraconazole or posaconazole) or with all three. The underlying principles of therapy for this disease remain rapid diagnosis, reversal of underlying predisposition, and urgent surgical debridement.
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              Combination antifungal therapy for invasive aspergillosis: a randomized trial.

              Invasive aspergillosis (IA) is associated with poor outcomes in patients with hematologic malignancies (HMs) and hematopoietic cell transplantation (HCT). Small studies suggest a role for combination antifungal therapy. To assess the safety and efficacy of voriconazole and anidulafungin compared with voriconazole monotherapy for treatment of IA. Randomized, double-blind, placebo-controlled multicenter trial. (ClinicalTrials.gov: NCT00531479). 93 international sites. 454 patients with HM or HCT and suspected or documented IA were randomly assigned to treatment with voriconazole and anidulafungin or placebo. Primary analysis was done in the modified intention-to-treat population of 277 patients in whom IA was confirmed. The primary outcome was 6-week mortality; secondary outcomes included 12-week mortality, mortality in major subgroups, and safety measures. Mortality rates at 6 weeks were 19.3% (26 of 135) for combination therapy and 27.5% (39 of 142) for monotherapy (difference, -8.2 percentage points [95% CI, -19.0 to 1.5]; P  = 0.087). Secondary mortality outcomes favored combination therapy. Multivariable regression analysis suggested that maximum galactomannan value, Karnofsky score, and baseline platelet count had prognostic significance. Most patients (218 of 277 [78.7%]) had IA diagnosis established by radiographic findings and maximum galactomannan positivity. In a post hoc analysis of this dominant subgroup, 6-week mortality was lower in combination therapy than monotherapy (15.7% [17 of 108] vs. 27.3% [30 of 110]; difference, -11.5 percentage points [CI, -22.7 to -0.4]; P = 0.037). Safety measures, including hepatotoxicity, were not different. Mortality at 6 weeks was higher than expected, and the difference in mortality was lower than expected, which reduced power to detect a treatment effect. Enrollment was restricted to patients with HM or HCT, which limited generalizability. Compared with voriconazole monotherapy, combination therapy with anidulafungin led to higher survival in subgroups of patients with IA. Limitations in power preclude definitive conclusions about superiority. Pfizer.
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                Author and article information

                Contributors
                Journal
                Antimicrob Agents Chemother
                Antimicrob Agents Chemother
                AAC
                Antimicrobial Agents and Chemotherapy
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                0066-4804
                1098-6596
                7 June 2022
                July 2022
                7 June 2022
                : 66
                : 7
                : e00380-22
                Affiliations
                [a ] The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, California, USA
                [b ] Beni-Suef University, Beni-Suef, Egypt
                [c ] Hearts Consulting Group, LLC, Poway, California, USA
                [d ] David Geffen School of Medicine at UCLA, Los Angeles, California, USA
                Author notes

                The authors declare a conflict of interest. A.S.I. has received research support from and served on advisory boards for Amplyx, Astellas, Cidara and Navigen. K.J.S. was an employee of Amplyx and is now a consultant for Pfizer. All other authors have no conflicts.

                Author information
                https://orcid.org/0000-0003-3787-8530
                Article
                00380-22 aac.00380-22
                10.1128/aac.00380-22
                9295579
                35670592
                06aaadf6-9d4a-4cb2-bdeb-3069b7e4f9e3
                Copyright © 2022 Gebremariam et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                : 11 March 2022
                : 4 April 2022
                : 11 May 2022
                Page count
                Figures: 6, Tables: 2, Equations: 0, References: 42, Pages: 11, Words: 7396
                Funding
                Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID), FundRef https://doi.org/10.13039/100000060;
                Award ID: AI063503
                Award Recipient :
                Funded by: Amplyx (Amplyx Pharmaceuticals), FundRef https://doi.org/10.13039/100017467;
                Award Recipient :
                Categories
                Experimental Therapeutics
                antimicrobial-chemotherapy, Antimicrobial Chemotherapy
                Custom metadata
                July 2022

                Infectious disease & Microbiology
                apx001,apx001a,gwt1,antifungal,aspergillosis,mucormycosis,fusariosis infection model,ipa,1-aminobenzotriazole,manogepix,fosmanogepix,fusariosis,infection model

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