Introduction:
There are four classes of antifungal medicines for invasive fungal disease, and most drugs in these classes are toxic, even at low doses, infectious-disease experts say. A new class to treat severe diseases hasn’t been approved in over 20 years. Fungal infections receive less than 1.5% of all infectious-disease research funding. Four main drug groups currently in use are the macrolide polyene antibiotics, the azoles, the echinocandins and allylamines.
Major classes of antifungals include polyenes, azoles, echinocandins, antimetabolites
such as flucytosine, and allylamines such as terbinafine. (Ciccozzi, “Antifungal Agents in the 21st Century: Advances, Challenges, and Future Perspectives”)
Macrolide polyenes
Macrolide polyene such as Amphoteric B bind to fungal membranes, cuasing loss of selective permeability. They can be used to treat skin, mucous membrane lesiones cuase by Candida albicans. Injectable form of the drug can be used to treat histoplasmosis and Cryptococcus meningitis.
Polyenes, discovered in the 1950s, include Amphotericin B (AmB), Nystatin and Natamycin. AmB, available in conventional (deoxycholate, AmB-d) and lipid formulations (ABLC lipid complex, liposomal L-AmB), acts by binding to ergosterol, an essential component of the fungal
cell membrane, causing it to destabilize and form pores. Lipid formulations of AmB have
been developed to mitigate its toxicity, particularly the nephrotoxicity associated with the
deoxycholate formulation. A meta-analysis showed that lipid formulations significantly
reduced nephrotoxicity compared with conventional formulation. (Ciccozzi, “Antifungal Agents in the 21st Century: Advances, Challenges, and Future Perspectives”)
Azoles:
Azones such as Ketoconazole, flucanozole, micronazole and clotrimazole interfere with sterol synthesis to fungi. Ketoconazole is used for cutaneous mycoses, vaginal and oral candidiasis and systemic mycoses. Fluconazole has been used for AIDS related mycoses aspergillosis and Crytococcus meningitis. Clotrimazole and miconazole can be used to treat infections in the skin, mouth and vagina.
Azoles, introduced since the 1960s, are subdivided into Imidazoles (e.g., Miconazole, Ketoconazole), used mainly topically or with limited systemic use, and Triazoles (e.g., Fluconazole, Itraconazole, Voriconazole, Posaconazole, Isavuconazole), widely used systemically. They inhibit ergosterol synthesis by blocking the cytochrome P450-dependent enzyme lanosterol 14α-demethylase, leading to the accumulation of toxic methylated sterols and depletion of ergosterol, altering membrane function. Azoles are generally fungistatic against yeasts and fungicidal against Aspergillus spp. but have a high risk of drug interactions and potential hepatotoxicity. (Ciccozzi, “Antifungal Agents in the 21st Century: Advances, Challenges, and Future Perspectives”)
Echinocandins:
Echnicandins such as micafungin and caspofungin inhibit fungal cell wall synthesis. They can be used against Candida and strains and aspergillosis.
Echinocandins are the frist line treatment for candidemia. Flucytosine, also known as 5-fluorocytosine (5-FC), is used to treat severe invasive candidiasis, which can cause endocarditis, endopthalmitis, or meningitis. (“emergence of flucytosin-resistant Candida tropicalis clade, the Netherlands” 31(7) -July 2025)
Echinocandins, introduced in the early 2000s, include Caspofungin, Micafungin and
Anidulafungin. They act by inhibiting the synthesis of β-(1,3)-D-glucan, an essential structural
component of the fungal cell wall, through blocking the enzyme β-(1,3)-D-glucan synthase. They are fungicidal against Candida species and fungistatic against Aspergillus spp., generally well tolerated, with a more favorable drug interaction profile than azoles, although potential
hepatotoxicity is reported. Echinocandins are considered the first-line therapy for invasive
candidiasis in most current guidelines. (Ciccozzi, “Antifungal Agents in the 21st Century: Advances, Challenges, and Future Perspectives”)
Allylamines:
Allylamines such as Terbinafine and naftifine inhibt enzyem critical for ergosterol syntehsis. They have been used to treat ringworm and other cutaneous mycoses.
Drugs in Development:
Several antifungal drugs in development, including Scynexis’ ibrexafungerp and Pfizer’s fosmanogepix, have been shown in clinical trials to be effective against Aspergillus and Candida infections. Cidara Therapeutics Inc. has submitted its drug rezafungin for Food and Drug Administration approval to treat Candida infections, including severe disease; and F2G Ltd. said its antifungal olorofim had been found effective at eradicating Aspergillus and other rare molds in a Phase 2 clinical trial.
Ambisome (amphotericin B liposome for injection) (Gilead): is a proprietary liposomal formulation of amphotericin B, an antifungal agent, for teh treatment of serious invasive fungal infections caused by various fungal species in adults.
Noxafil (which refers to injection, delayed-release tablets, and oral suspension–Merk) and Noxafil PowderMix (for delayedrelease oral suspension –Merk) are prescription medicines used in adults and children to help prevent or treat fungal infections that can spread throughout your body (invasive fungal infections). These infections are caused by fungi called Aspergillus or Candida.
Agrobodies:
Biotalys developed EVOCA, one of the first protein-based biofungicides to be presented to regulators in the US and EU. It targets botrytis, also called gray mold, a fungus that afects grapes, strawberries, cucumbers and manother other crops and ornamental plants. It targets one or mroe antigens on fungal cell walls to affect the cells’ function. In developing its biofungicides, Biotalys identified the target first, a specific antigen on the fungal cell wall and then went after a mitigant for that target, using H chain antibodies derived from the camelid immune system.
Statins:
Statins have been shown to augment a number of antifungal drug classes, for example, the azoles and polyenes. Synthetic statins are generally considered more potent than the first generation of fungal metabolites. Fluvastatin is considered the most effective statin with the broadest and most potent fungal inhibitory activity, including fungicidal and/or fungistatic properties. This has been demonstrated with plasma concentrations that can easily be achieved in a clinical setting. Additionally, statins can potentiate the efficacy of available antifungal drugs in a synergistic fashion. Although only a limited number of animal and human studies have been reported to date, observational cohort studies have confirmed that patients using statins have a reduced risk of candidemia-related complications.
Antifungal Reistance:
Understanding the geographic spread and prevalence of antifungal resistance is critical to guide empirical treatment strategies, implement infection control measures, and inform health policies. The past few decades have witnessed the emergence and alarming spread of antifungal-resistant fungal pathogens, a growing threat to global public health that is acquiring a severity comparable to that of antibacterial pathogens. In particular, Candida auris, which has emerged almost simultaneously in different parts of the world since 2009 (first described isolation in Japan), has become a formidable nosocomial pathogen, reported in more than 60 countries. This yeast is characterized by multi-resistance to multiple classes of antifungals, with almost universal resistance to fluconazole (>90%) and significant rates of resistance to amphotericin B (20-35%), as well as echinocandins. Its transmission in hospitals is facilitated by its ability to spread rapidly, causing epidemic outbreaks that are difficult to control, especially in contaminated environments. (Ciccozzi, “Antifungal Agents in the 21st Century: Advances, Challenges, and Future Perspectives”)