Special Issue "Antifungal Agents Recently Approved or Under Development"

A special issue of Journal of Fungi (ISSN 2309-608X). This special issue belongs to the section "Fungal Pathogenesis and Disease Control".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 20653

Special Issue Editors

Dr. Ana V. Espinel-Ingroff
E-Mail 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
Special Issues, Collections and Topics in MDPI journals
Dr. Eric Dannaoui
E-Mail Website
Guest Editor
1. Unité de Parasitologie-Mycologie, Service de Microbiologie, Hôpital Européen Georges Pompidou, F-75015 Paris, France
2. Faculté de Médecine, Université Paris Cité, F-75006 Paris, France
Interests: human pathogenic fungi; antifungals; mycoses; Aspergillus; in vitro susceptibility testing; antifungal resistance; animal models
Special Issues, Collections and Topics in MDPI journals

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 (12 papers)

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Editorial

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Editorial
Special Issue: Antifungal Agents Recently Approved or under Development
J. Fungi 2021, 7(3), 239; https://doi.org/10.3390/jof7030239 - 23 Mar 2021
Viewed by 856
Abstract
Many thanks to all contributors to the Special Issue on “Antifungal Agents Recently Approved or Under Development (Current Knowledge and Future Perspectives)” [...] Full article
(This article belongs to the Special Issue Antifungal Agents Recently Approved or Under Development)

Research

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Article
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
Cited by 7 | Viewed by 1051
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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Review
Ibrexafungerp: A First-in-Class Oral Triterpenoid Glucan Synthase Inhibitor
J. Fungi 2021, 7(3), 163; https://doi.org/10.3390/jof7030163 - 25 Feb 2021
Cited by 14 | Viewed by 2130
Abstract
Ibrexafungerp (formerly SCY-078 or MK-3118) is a first-in-class triterpenoid antifungal or “fungerp” that inhibits biosynthesis of β-(1,3)-D-glucan in the fungal cell wall, a mechanism of action similar to that of echinocandins. Distinguishing characteristics of ibrexafungerp include oral bioavailability, a favourable safety profile, few [...] Read more.
Ibrexafungerp (formerly SCY-078 or MK-3118) is a first-in-class triterpenoid antifungal or “fungerp” that inhibits biosynthesis of β-(1,3)-D-glucan in the fungal cell wall, a mechanism of action similar to that of echinocandins. Distinguishing characteristics of ibrexafungerp include oral bioavailability, a favourable safety profile, few drug–drug interactions, good tissue penetration, increased activity at low pH and activity against multi-drug resistant isolates including C. auris and C. glabrata. In vitro data has demonstrated broad and potent activity against Candida and Aspergillus species. Importantly, ibrexafungerp also has potent activity against azole-resistant isolates, including biofilm-forming Candida spp., and echinocandin-resistant isolates. It also has activity against the asci form of Pneumocystis spp., and other pathogenic fungi including some non-Candida yeasts and non-Aspergillus moulds. In vivo data have shown IBX to be effective for treatment of candidiasis and aspergillosis. Ibrexafungerp is effective for the treatment of acute vulvovaginal candidiasis in completed phase 3 clinical trials. Full article
(This article belongs to the Special Issue Antifungal Agents Recently Approved or Under Development)
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Review
PC945, a Novel Inhaled Antifungal Agent, for the Treatment of Respiratory Fungal Infections
J. Fungi 2020, 6(4), 373; https://doi.org/10.3390/jof6040373 - 17 Dec 2020
Cited by 6 | Viewed by 1842
Abstract
Disease due to pulmonary Aspergillus infection remains a significant unmet need, particularly in immunocompromised patients, patients in critical care and those with underlying chronic lung diseases. To date, treatment using inhaled antifungal agents has been limited to repurposing available systemic medicines. PC945 is [...] Read more.
Disease due to pulmonary Aspergillus infection remains a significant unmet need, particularly in immunocompromised patients, patients in critical care and those with underlying chronic lung diseases. To date, treatment using inhaled antifungal agents has been limited to repurposing available systemic medicines. PC945 is a novel triazole antifungal agent, a potent inhibitor of CYP51, purpose-designed to be administered via inhalation for high local lung concentrations and limited systemic exposure. In preclinical testing, PC945 is potent versus Aspergillus spp. and Candida spp. and showed two remarkable properties in preclinical studies, in vitro and in vivo. The antifungal effects against Aspergillus fumigatus accumulate on repeat dosing and improved efficacy has been demonstrated when PC945 is dosed in combination with systemic anti-fungal agents of multiple classes. Resistance to PC945 has been induced in Aspergillus fumigatus in vitro, resulting in a strain which remained susceptible to other antifungal triazoles. In healthy volunteers and asthmatics, nebulised PC945 was well tolerated, with limited systemic exposure and an apparently long lung residency time. In two lung transplant patients, PC945 treated an invasive pulmonary Aspergillus infection that had been unresponsive to multiple antifungal agents (systemic ± inhaled) without systemic side effects or detected drug–drug interactions. Full article
(This article belongs to the Special Issue Antifungal Agents Recently Approved or Under Development)
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Review
Isavuconazole: Mechanism of Action, Clinical Efficacy, and Resistance
J. Fungi 2020, 6(4), 324; https://doi.org/10.3390/jof6040324 - 29 Nov 2020
Cited by 20 | Viewed by 1956
Abstract
Increasing incidence of invasive fungal infections combined with a growing population of immunocompromised hosts has created a rising need for antifungal agents. Isavuconazole, a second-generation broad-spectrum triazole with activity against yeasts, dimorphic fungi, and molds, has a favorable safety profile and predictable pharmacokinetics. [...] Read more.
Increasing incidence of invasive fungal infections combined with a growing population of immunocompromised hosts has created a rising need for antifungal agents. Isavuconazole, a second-generation broad-spectrum triazole with activity against yeasts, dimorphic fungi, and molds, has a favorable safety profile and predictable pharmacokinetics. Patients typically tolerate isavuconazole well with fewer drug–drug interactions. Clinical trials have found it to be noninferior to voriconazole for invasive aspergillosis, an alternative therapy for salvage treatment of mucormycosis, and suitable for stepdown therapy with invasive candidiasis. Cross-resistance with other triazoles is common. More studies are needed to determine the role of isavuconazole in anti-mold prophylaxis in high-risk patients. Full article
(This article belongs to the Special Issue Antifungal Agents Recently Approved or Under Development)
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Review
Rezafungin—Mechanisms of Action, Susceptibility and Resistance: Similarities and Differences with the Other Echinocandins
J. Fungi 2020, 6(4), 262; https://doi.org/10.3390/jof6040262 - 01 Nov 2020
Cited by 16 | Viewed by 1375
Abstract
Rezafungin (formerly CD101) is a new β-glucan synthase inhibitor that is chemically related with anidulafungin. It is considered the first molecule of the new generation of long-acting echinocandins. It has several advantages over the already approved by the Food and Drug Administration (FDA) [...] Read more.
Rezafungin (formerly CD101) is a new β-glucan synthase inhibitor that is chemically related with anidulafungin. It is considered the first molecule of the new generation of long-acting echinocandins. It has several advantages over the already approved by the Food and Drug Administration (FDA) echinocandins as it has better tissue penetration, better pharmacokinetic/phamacodynamic (PK/PD) pharmacometrics, and a good safety profile. It is much more stable in solution than the older echinocandins, making it more flexible in terms of dosing, storage, and manufacturing. These properties would allow rezafungin to be administered once-weekly (intravenous) and to be potentially administered topically and subcutaneously. In addition, higher dose regimens were tested with no evidence of toxic effect. This will eventually prevent (or reduce) the selection of resistant strains. Rezafungin also has several similarities with older echinocandins as they share the same in vitro behavior (very similar Minimum Inhibitory Concentration required to inhibit the growth of 50% of the isolates (MIC50) and half enzyme maximal inhibitory concentration 50% (IC50)) and spectrum, the same target, and the same mechanisms of resistance. The selection of FKS mutants occurred at similar frequency for rezafungin than for anidulafungin and caspofungin. In this review, rezafungin mechanism of action, target, mechanism of resistance, and in vitro data are described in a comparative manner with the already approved echinocandins. Full article
(This article belongs to the Special Issue Antifungal Agents Recently Approved or Under Development)
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Review
Nikkomycin Z—Ready to Meet the Promise?
J. Fungi 2020, 6(4), 261; https://doi.org/10.3390/jof6040261 - 30 Oct 2020
Cited by 17 | Viewed by 1347
Abstract
Nikkomycin Z (NikZ) has fungicidal activity against some fungal species which currently requires patients to endure chronic therapy, sometimes for years. This review highlights reports of NikZ activity against fungal species for which current therapeutics are still inadequate, as a potential roadmap for [...] Read more.
Nikkomycin Z (NikZ) has fungicidal activity against some fungal species which currently requires patients to endure chronic therapy, sometimes for years. This review highlights reports of NikZ activity against fungal species for which current therapeutics are still inadequate, as a potential roadmap for continuing investigation. The possibility of faster and more complete clinical resolution by using NikZ has attracted scientific attention for decades. NikZ inhibits chitin structure formation, which is important for fungi, but not found in mammals. NikZ raised no safety concerns in a human Phase 1 trial or in extensive toxicology studies. NikZ showed strong clinical benefit in dogs with natural Coccidioides infection. NikZ has protected animals against fatal infections of Candida albicans. NikZ provides high protection in synergistic combination with several agent classes against Candida and Aspergillus species. Full article
(This article belongs to the Special Issue Antifungal Agents Recently Approved or Under Development)
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Review
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
Cited by 39 | Viewed by 3123
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)
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Review
Isavuconazole—Animal Data and Clinical Data
J. Fungi 2020, 6(4), 209; https://doi.org/10.3390/jof6040209 - 06 Oct 2020
Cited by 2 | Viewed by 1178
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)
Review
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
Cited by 12 | Viewed by 1309
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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Review
Review of the Novel Investigational Antifungal Olorofim
J. Fungi 2020, 6(3), 122; https://doi.org/10.3390/jof6030122 - 30 Jul 2020
Cited by 28 | Viewed by 2074
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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Review
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
Cited by 15 | Viewed by 1642
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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