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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 78157

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Special Issue Editors

Dr. Ana V. Espinel-Ingroff

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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

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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

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Keywords

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

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Published Papers (12 papers)

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Editorial

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2 pages, 182 KiB

Open AccessEditorial

Special Issue: Antifungal Agents Recently Approved or under Development

by Ana Espinel-Ingroff and Eric Dannaoui

J. Fungi 2021, 7(3), 239; https://doi.org/10.3390/jof7030239 - 23 Mar 2021

Cited by 2 | Viewed by 2499

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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9 pages, 882 KiB

Open AccessArticle

Relative Frequency of Paradoxical Growth and Trailing Effect with Caspofungin, Micafungin, Anidulafungin, and the Novel Echinocandin Rezafungin against Candida Species

by Zoltán Tóth, Lajos Forgács, Tamás Kardos, Renátó Kovács, Jeffrey B. Locke, Gábor Kardos, Fruzsina Nagy, Andrew M. Borman, Awid Adnan and László Majoros

J. Fungi 2020, 6(3), 136; https://doi.org/10.3390/jof6030136 - 17 Aug 2020

Cited by 13 | Viewed by 3372

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 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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19 pages, 1626 KiB

Open AccessReview

Ibrexafungerp: A First-in-Class Oral Triterpenoid Glucan Synthase Inhibitor

by Sabelle Jallow and Nelesh P. Govender

J. Fungi 2021, 7(3), 163; https://doi.org/10.3390/jof7030163 - 25 Feb 2021

Cited by 73 | Viewed by 8491

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 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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13 pages, 2212 KiB

Open AccessReview

PC945, a Novel Inhaled Antifungal Agent, for the Treatment of Respiratory Fungal Infections

by Alison Murray, Lindsey Cass, Kazuhiro Ito, Nicole Pagani, Darius Armstrong-James, Paras Dalal, Anna Reed and Pete Strong

J. Fungi 2020, 6(4), 373; https://doi.org/10.3390/jof6040373 - 17 Dec 2020

Cited by 26 | Viewed by 5308

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 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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10 pages, 557 KiB

Open AccessReview

Isavuconazole: Mechanism of Action, Clinical Efficacy, and Resistance

by Misti Ellsworth and Luis Ostrosky-Zeichner

J. Fungi 2020, 6(4), 324; https://doi.org/10.3390/jof6040324 - 29 Nov 2020

Cited by 84 | Viewed by 7167 | Correction

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. 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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23 pages, 1827 KiB

Open AccessReview

Rezafungin—Mechanisms of Action, Susceptibility and Resistance: Similarities and Differences with the Other Echinocandins

by Guillermo Garcia-Effron

J. Fungi 2020, 6(4), 262; https://doi.org/10.3390/jof6040262 - 1 Nov 2020

Cited by 71 | Viewed by 8701

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) 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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14 pages, 464 KiB

Open AccessReview

Nikkomycin Z—Ready to Meet the Promise?

by David J. Larwood

J. Fungi 2020, 6(4), 261; https://doi.org/10.3390/jof6040261 - 30 Oct 2020

Cited by 52 | Viewed by 5826

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 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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21 pages, 938 KiB

Open AccessReview

Fosmanogepix: A Review of the First-in-Class Broad Spectrum Agent for the Treatment of Invasive Fungal Infections

by Karen Joy Shaw and Ashraf S. Ibrahim

J. Fungi 2020, 6(4), 239; https://doi.org/10.3390/jof6040239 - 22 Oct 2020

Cited by 147 | Viewed by 12982

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 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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15 pages, 300 KiB

Open AccessReview

Isavuconazole—Animal Data and Clinical Data

by Livio Pagano, Chiara Cattaneo, Martina Quattrone, Margherita Oberti, Maria Mazzitelli and Enrico Maria Trecarichi

J. Fungi 2020, 6(4), 209; https://doi.org/10.3390/jof6040209 - 6 Oct 2020

Cited by 9 | Viewed by 3093

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.

(This article belongs to the Special Issue Antifungal Agents Recently Approved or Under Development)

9 pages, 383 KiB

Open AccessReview

Review of the Novel Echinocandin Antifungal Rezafungin: Animal Studies and Clinical Data

by Yanan Zhao and David S. Perlin

J. Fungi 2020, 6(4), 192; https://doi.org/10.3390/jof6040192 - 28 Sep 2020

Cited by 37 | Viewed by 6013

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 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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11 pages, 419 KiB

Open AccessReview

Review of the Novel Investigational Antifungal Olorofim

by Nathan P. Wiederhold

J. Fungi 2020, 6(3), 122; https://doi.org/10.3390/jof6030122 - 30 Jul 2020

Cited by 96 | Viewed by 8394

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 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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7 pages, 261 KiB

Open AccessReview

Encochleated Amphotericin B: Is the Oral Availability of Amphotericin B Finally Reached?

by Maria Aigner and Cornelia Lass-Flörl

J. Fungi 2020, 6(2), 66; https://doi.org/10.3390/jof6020066 - 18 May 2020

Cited by 61 | Viewed by 4673

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 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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