https://orcid.org/0000-0003-1238-8199
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ABSTRACT
Introduction: Invasive fungal infections (IFIs) remain a significant cause of morbidity and mortality despite significant advancements in currently available therapy. With a flush pipeline of investigational antifungals, the clinician must identify appropriate roles of currently available therapies, potential advantages of emerging antifungals, and shortcomings in the evolving clinical evidence.
Areas covered: Standard and developing treatment approaches for IFIs with currently available antifungals are summarized with a focus on invasive candidiasis and invasive aspergillosis. Emerging investigational antifungals are discussed in depth, including mechanisms of action, fungal activity, clinical evidence, and ongoing research. An opinion on the impact and potential role of therapy for emerging antifungals of interest is also provided.
Expert opinion: Despite advances and clinical studies optimizing antifungal use, current therapies fall short in preventing IFI morbidity and mortality. Further optimization of currently available antifungals may improve outcomes; however, novel agents are required for historically difficult-to-treat infections, transitions to oral treatment, minimizing adverse drug effects, decreasing drug interactions, and ultimately improving patient quality of life. Emerging antifungals may positively revolutionize the treatment of IFIs.
List of abbreviations
| AmB: | = | Amphotericin B |
| ARAF: | = | Azole-resistant A. fumigatus |
| AUC: | = | Area under curve |
| CAmB: | = | Encochleated amphotericin B |
| CNS: | = | Central nervous system |
| DDIs: | = | Drug-drug interactions |
| DHODH: | = | Dihydroorotate dehydrogenase |
| EUCAST: | = | European Committee on Antimicrobial Susceptibility Testing |
| FDA: | = | Food and Drug Administration |
| GI: | = | Gastrointestinal |
| GPI: | = | Glycosylphosphatidylinositol |
| IA: | = | Invasive aspergillosis |
| IC: | = | Invasive candidiasis |
| ICU: | = | Intensive Care Unit |
| IDSA: | = | Infectious Disease Society of America |
| IFI: | = | Invasive Fungal Infections |
| IV: | = | Intravenous |
| MDR: | = | Multi-drug-resistant |
| MIC: | = | Minimum inhibitory concentration |
| PD: | = | Pharmacodynamic |
| PK: | = | Pharmacokinetic |
| RVVC: | = | Recurrent vulvovaginal candidiasis |
| SOC: | = | Standard of care |
| TDM: | = | Therapeutic drug monitoring |
| U.S.: | = | United States |
Article highlights
There is an unmet clinical need to address emerging antifungal resistance among invasive fungal infections (IFIs).
Significant advancements in the antifungal pipeline have resulted in promising agents with unique mechanisms of action, improved formulations, fewer toxicities, and drug–drug interactions compared to many current antifungal therapies.
Tetrazoles, specifically oral oteseconazole, VT-1129, and VT-1598, have increased specificity for fungal CYP51 and the potential to replace triazoles in many fungal infections (e.g., vulvovaginal candidiasis) as they are associated with minimal drug–drug interactions and fewer adverse effects. Tetrazoles can preserve excellent activity against some resistant IFIs and boast a broad spectrum of activity, particularly with VT-1598.
Rezafungin is a new echinocandin with an extended half-life allowing for once weekly intravenous dosing while maintaining a satisfactory pharmacokinetic/pharmacodynamic and safety profile against Candida, Aspergillus and Pneumocystis spp.
Ibrexafungerp is a novel oral and intravenous triterpenoid with a broad spectrum and has shown promising efficacy in triazole and echinocandin-resistant infections. In vivo and in vitro activity has been demonstrated for the treatment of invasive candidiasis, invasive aspergillosis and other fungal infections refractory to current standards of care.
Encochleated amphotericin B, pending clinical efficacy studies, is en route to be the first oral amphotericin maintaining a broad range of activity against yeasts and molds with reduced toxicity compared to intravenous formulations.
Fosmanogepix is formulated for both oral and intravenous administration against multidrug-resistant and difficult-to-treat infections including Candida spp., Aspergillus spp., and rare molds. It has a favorable safety profile and attains wide tissue distribution, making it a viable future option for empiric treatment and continuation as oral step-down therapy.
Olorofim offers a unique mechanism by inhibiting fungal growth via inhibition of dihydroorotate dehydrogenase. It has shown efficacy in targeting Aspergillus spp. and rare molds, but is limited in its yeast coverage. This agent has great promise as a targeted mold agent or for salvage therapy in refractory or difficult-to-treat IFIs.
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Declaration of interest
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer Disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.