Special Issue "Antifungal Agents Recently Approved or Under Development"

A special issue of Journal of Fungi (ISSN 2309-608X).

Deadline for manuscript submissions: closed (30 September 2020).

Special Issue Editors

Dr. Ana V. Espinel-Ingroff
Website
Guest Editor
VCU Medical Center, Richmond, VA, USA
Interests: antifungal susceptibility testing and development of ECVs for fungal species; antifungal resistance; medical mycology; epidemiology
Dr. Eric Dannaoui
Website SciProfiles
Guest Editor
1. Unité de Parasitologie-Mycologie, Service de Microbiologie, Hôpital Européen Georges Pompidou, F-75015 Paris, France 2. Faculté de Médecine, Université Paris Descartes, F-75006 Paris, France
Interests: human pathogenic fungi; antifungals; mycoses; aspergillus; in vitro susceptibility testing; antifungal resistance; animal models
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Special Issue Information

Dear Colleagues,

Although several antifungal agents are available for the treatment of invasive fungal infections, some factors demand the development of other agents with different mechanisms of activity against resistant emerging pathogens, cryptic species, and the continued incidence of antifungal resistance among both Candida and Aspergillus. Therefore, some agents have been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) or are in clinical development, such as: isavuconazole (aspergillosis and mucormycosis and/or when amphotericin B is inappropriate), rezafungin (CD101)) and ibrexafungerp (SCY-078), glucan synthase inhibitors (orphan drug for candidemia and invasive candidiasis and fluconazole failure treatment, respectively), encochleated formulation of amphotericin B (MAT2203) for cryptococcosis, and olorofim (F901318), a member of a new class of antifungal agents, the orotomides (invasive fungal infections lacking treatment options). Several more are in earlier developmental stages: manogepix (Amplyx, E1210) (candidemia and IFI), VT-1598 (preclinical development for coccidioidomycosis), and nikkomycin Z, a chitin synthase inhibitor (potential use for uncomplicated coccidioides pneumonia).  

A literature review would explore their molecular mechanisms of action and resistance, availability in vitro, PK/PD, safety and efficacy information data from ongoing clinical trials, and the specific approved designation for the treatment of invasive fungal infections.

Dr. Ana V. Espinel-Ingroff
Dr. Eric Dannaoui
Guest Editors

Manuscript Submission Information

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Keywords

  • Isavuconazole
  • Beta-1-3-glucane synthase inhibitors
  • Rezafungin
  • orotomides
  • chitin syntase inhibitors
  • GPI inhibitors
  • Antifungal resistance

Published Papers (6 papers)

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Research

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Open AccessArticle
Relative Frequency of Paradoxical Growth and Trailing Effect with Caspofungin, Micafungin, Anidulafungin, and the Novel Echinocandin Rezafungin against Candida Species
J. Fungi 2020, 6(3), 136; https://doi.org/10.3390/jof6030136 - 17 Aug 2020
Abstract
Rezafungin is a next-generation echinocandin that has favorable pharmacokinetic properties. We compared the occurrence of paradoxical growth (PG) and trailing effect (TE) characteristics to echinocadins with rezafungin, caspofungin, micafungin and anidulafungin using 365 clinical Candida isolates belonging to 13 species. MICs were determined [...] Read more.
Rezafungin is a next-generation echinocandin that has favorable pharmacokinetic properties. We compared the occurrence of paradoxical growth (PG) and trailing effect (TE) characteristics to echinocadins with rezafungin, caspofungin, micafungin and anidulafungin using 365 clinical Candida isolates belonging to 13 species. MICs were determined by BMD method according to CLSI (M27 Ed4). Disconnected growth (PG plus TE) was most frequent with caspofungin (49.6%), followed by anidulafungin (33.7%), micafungin (25.7%), while it was least frequent with rezafungin (16.9%). PG was relatively common in the case of caspofungin (30.1%) but was rare in the case of rezafungin (3.0%). C. tropicalis, C. albicans, C. orthopsilosis and C. inconspicua exhibited PG most frequently with caspofungin, micafungin or anidulafungin. PG never occurred in the case of C. krusei isolates. Against C. tropicalis and C. albicans, echinocandins frequently showed PG after 24 h followed by TE after 48 h. All four echinocandins exhibited TE for the majority of C. auris and C. dubliniensis isolates. Disconnected growth was common among Candida species and was echinocandin- and species-dependent. In contrast to earlier echinocandins, PG was infrequently found with rezafungin. Full article
(This article belongs to the Special Issue Antifungal Agents Recently Approved or Under Development)
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Review

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Open AccessReview
Fosmanogepix: A Review of the First-in-Class Broad Spectrum Agent for the Treatment of Invasive Fungal Infections
J. Fungi 2020, 6(4), 239; https://doi.org/10.3390/jof6040239 - 22 Oct 2020
Abstract
Fosmanogepix is a first-in-class antifungal currently in Phase 2 clinical trials for the treatment of invasive fungal infections caused by Candida, Aspergillus and rare molds. Fosmanogepix is the N-phosphonooxymethylene prodrug of manogepix, an inhibitor of the fungal enzyme Gwt1. Manogepix demonstrates broad spectrum [...] Read more.
Fosmanogepix is a first-in-class antifungal currently in Phase 2 clinical trials for the treatment of invasive fungal infections caused by Candida, Aspergillus and rare molds. Fosmanogepix is the N-phosphonooxymethylene prodrug of manogepix, an inhibitor of the fungal enzyme Gwt1. Manogepix demonstrates broad spectrum in vitro activity against yeasts and molds, including difficult to treat pathogens. Because of its novel mechanism of action, manogepix retains potency against many resistant strains including echinocandin-resistant Candida and azole-resistant Aspergillus. Manogepix is also active against pathogens that demonstrate intrinsic resistance to other drug classes, such as Scedosporium, Lomentospora prolificans, and Fusarium with variable activity against Mucorales. Fosmanogepix demonstrates significant in vivo efficacy in mouse and rabbit disseminated infection models due to C. albicans, C. glabrata, C. auris, C. tropicalis, Coccidioides immitis, and F. solani as well as pulmonary infection models of A. fumigatus, A. flavus, S. prolificans, S. apiospermum and Rhizopus arrhizus. Clinical trials demonstrated high oral bioavailability (>90%), enabling switching between fosmanogepix intravenous and oral formulations without compromising blood levels. Favorable drug-drug interaction, tolerability, and wide tissue distribution profiles are observed making fosmanogepix an attractive option for the treatment of invasive fungal infections. This systematic review summarizes the findings of published data on fosmanogepix. Full article
(This article belongs to the Special Issue Antifungal Agents Recently Approved or Under Development)
Open AccessReview
Isavuconazole—Animal Data and Clinical Data
J. Fungi 2020, 6(4), 209; https://doi.org/10.3390/jof6040209 - 06 Oct 2020
Abstract
The treatment of invasive fungal infections has deeply evolved in the last years with the inclusion of new antifungals, mainly new azoles (i.e., posaconazole, isavuconazole), to the therapeutic armamentarium. This review focuses on the role of isavuconazole for treating the most important invasive [...] Read more.
The treatment of invasive fungal infections has deeply evolved in the last years with the inclusion of new antifungals, mainly new azoles (i.e., posaconazole, isavuconazole), to the therapeutic armamentarium. This review focuses on the role of isavuconazole for treating the most important invasive fungal infections both in animals and humans (hematological and non-hematological patients). Full article
(This article belongs to the Special Issue Antifungal Agents Recently Approved or Under Development)
Open AccessReview
Review of the Novel Echinocandin Antifungal Rezafungin: Animal Studies and Clinical Data
J. Fungi 2020, 6(4), 192; https://doi.org/10.3390/jof6040192 - 28 Sep 2020
Abstract
Rezafungin is a novel echinocandin drug being developed as a first-line option for treatment and prevention of invasive fungal infections. As a result of a structural modification in its parent molecule anidulafungin, rezafungin has acquired unique chemical stability conferring prolonged pharmacokinetics, as well [...] Read more.
Rezafungin is a novel echinocandin drug being developed as a first-line option for treatment and prevention of invasive fungal infections. As a result of a structural modification in its parent molecule anidulafungin, rezafungin has acquired unique chemical stability conferring prolonged pharmacokinetics, as well as an administration advantage in the clinical setting compared to other drugs in the same class. Rezafungin displays potent in vitro activity against a wide spectrum of fungal pathogens, which is reflected in robust in vivo efficacy and/or pharmacodynamic studies using various animal models as well as in promising clinical trials data. This review describes in vivo characterization of rezafungin using animal models, current status of clinical development and key findings from these studies. Full article
(This article belongs to the Special Issue Antifungal Agents Recently Approved or Under Development)
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Open AccessReview
Review of the Novel Investigational Antifungal Olorofim
J. Fungi 2020, 6(3), 122; https://doi.org/10.3390/jof6030122 - 30 Jul 2020
Abstract
The incidence of invasive fungal infections caused by molds and endemic fungi is increasing. There is also concern regarding increased rates of reduced susceptibility or frank resistance among Aspergillus and Coccidioides species, while Scedosporium species, Lomentospora prolificans, and Fusarium species are inherently less [...] Read more.
The incidence of invasive fungal infections caused by molds and endemic fungi is increasing. There is also concern regarding increased rates of reduced susceptibility or frank resistance among Aspergillus and Coccidioides species, while Scedosporium species, Lomentospora prolificans, and Fusarium species are inherently less susceptible or intrinsically resistant to clinically available antifungals. Olorofim (formerly F901318) is the first member of the orotomide class of antifungals to be evaluated clinically for the treatment of invasive mold infections. This agent inhibits dihydroorotate dehydrogenase, a key enzyme in the biosynthesis of pyrimidines. Olorofim has activity against many molds and thermally dimorphic fungi, including species that are resistant to azoles and amphotericin B, but lacks activity against yeasts and the Mucorales. It is currently being developed for both oral and intravenous administration. Although published clinical outcome data have been limited to case reports to date, the results against invasive and refractory infections are promising. This review describes the mechanism of action of olorofim, its in vitro spectrum of activity, and what is currently known about its pharmacokinetic profile and clinical efficacy. Full article
(This article belongs to the Special Issue Antifungal Agents Recently Approved or Under Development)
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Open AccessReview
Encochleated Amphotericin B: Is the Oral Availability of Amphotericin B Finally Reached?
J. Fungi 2020, 6(2), 66; https://doi.org/10.3390/jof6020066 - 18 May 2020
Abstract
As the oldest and for many decades the only available agent for the treatment of life-threatening invasive fungal diseases, amphotericin B (AmB) is known for its broad-spectrum fungicidal activity against a wide range of yeasts and molds. However, the main drawback of the [...] Read more.
As the oldest and for many decades the only available agent for the treatment of life-threatening invasive fungal diseases, amphotericin B (AmB) is known for its broad-spectrum fungicidal activity against a wide range of yeasts and molds. However, the main drawback of the present formulations remains its toxicity, the limited use to intravenous administration, and the higher costs associated with the better tolerated lipid formulations. The novel nanoparticle-based encochleated AmB (CAmB) formulation encapsulates, protects, and delivers its cargo molecule AmB in the interior of a calcium-phospholipid anhydrous crystal. Protecting AmB from harsh environmental conditions and gastrointestinal degradation, CAmB offers oral availability in conjunction with reduced toxicity. Matinas BioPharma, Bedminster, NJ is on the way to develop CAmB named MAT2203, currently undergoing Phase II clinical trials. Full article
(This article belongs to the Special Issue Antifungal Agents Recently Approved or Under Development)
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