Promising agents in the pipeline for invasive fungal infections

An estimated 1 billion people worldwide develop a fungal infection each year. Of these, approximately 1.6 million will die because of their infection, a toll surpassing diseases such as malaria and tuberculosis.

The main fungi that infect humans include Aspergillus species, Candida species, Cryptococcus species and Pneumocystis species.

In the United States, invasive fungal infections (IFIs) are becoming more common and are associated with high financial burden, morbidity and mortality. Rare and difficult-to-treat invasive mycoses like Fusarium species and Scedosporium species are increasing in incidence with an increasing immunocompromised patient population.

The CDC’s 2019 Antibiotic Resistance Threats in the United States report noted many fungi of concern. Candida auris was listed as an urgent threat, drug-resistant Candida species were listed as a serious threat and azole-resistant Aspergillus fumigatus were on the watch list.

Over at least a 2-decade period, no new classes of antifungals were approved, making infections due to these organisms incredibly difficult to treat in the landscape of increasing resistance and limited options. As part of the 2020 U.S. National Action Plan, the CDC and partner agencies planned to address antifungal resistance through prevention, One Health Surveillance, advanced diagnostics, research and international collaboration.

Since the development of the first antifungals in the 1950s, four main antifungal classes have been indicated for the treatment of IFIs: polyenes, triazoles, echinocandins and pyrimidine analogues. The agents below have historically been safe and effective but also have gaps in their utility.

Polyenes

Amphotericin B is the only antifungal in the polyene class. It is one of the most potent and broadest spectrum antifungals available. It is given only through IV administration because of poor oral bioavailability, which limits its outpatient utility. It also has associated adverse reactions including infusion-related reactions, electrolyte disturbances and nephrotoxicity. The reformulation of liposomal amphotericin B helped to improve the nephrotoxicity, but it can still be toxic to patients.

Triazoles

The triazoles fluconazole, isavuconazole, itraconazole, posaconazole and voriconazole are the agents available for systemic infections, although there are more that can be administered topically. Most can be given orally or intravenously, whereas other antifungals are mostly IV only. Although there are benefits with ease of administration, there are limitations with azoles, including liver toxicity, drug interactions, teratogenicity and QTc prolongation.

Echinocandins

The echinocandins caspofungin, anidulafungin and micafungin inhibit formation of the fungal cell wall. They have a great safety profile, causing mostly nausea or vomiting. Limitations include that they are only available intravenously, and although they are a preferred empiric agent for most cases of candidemia and invasive candidiasis per Infectious Diseases Society of America guidelines, they are not distributed well in the central nervous system (CNS), eyes or urinary tract.

Pyrimidine analogues

Flucytosine is a pyrimidine analogue that is usually not used alone because it rapidly develops resistance. It has limited utility, often as part of a combination regimen like in cryptococcal meningitis.

Below is a summary of newer antifungals that highlights their benefits and potential places in therapy, as well as their FDA approval status as of June 2023.

Fosmanogepix

Fosmanogepix is a novel Gwt1 enzyme inhibitor which targets the fungal enzyme (Gwt1) essential for transferring proteins to the fungal cell wall. It has activity against Candida species (except C. krusei), Cryptococcus neoformans and C. gatti, azole-resistant Aspergillus species, Fusarium species, Scedosporium species, and other rare molds. It has variable in vitro activity against some Mucorales. It has been shown to be synergistic with amphotericin and has activity in the brain. Benefits of fosmanogepix include oral bioavailability of over 90%, available IV formulations, a broad spectrum of activity and a favorable side effect profile. It has not yet received FDA approval.

Ibrexafungerp

Similar to the echinocandins, ibrexafungerp inhibits 1,3-beta-D-glucan synthesis in the fungal cell wall. It is the first triterpenoid class agent and has in vitro activity against Aspergillus species, Candida species — including C. auris but not C. lusitaniae and C. krusei — and endemic fungi. It lacks activity for molds and has variable activity against echinocandin-resistant fungi. Ibrexafungerp may have a role as a step-down agent for IFIs because it is available orally and has been studied intravenously. It was approved by the FDA in June of 2021 as an oral medication with indications for vulvovaginal candidiasis (VVC) and recurrences of VVC. Like azoles, it is limited by its black box warning for embryo-fetal toxicity and numerous drug-drug interactions. One ongoing trial, the CARES study, is enrolling patients in the U.S. and India with C. auris infections, which may further highlight its activity against C. auris.

Olorofim

Olorofim is novel as a dihydroorotate dehydrogenase enzyme inhibitor that disrupts the synthesis of pyrimidine. It is not a broad-spectrum antifungal, having no activity against yeast or Mucorales group. It maintains activity against molds like Coccidioides species, Histoplasma species, Scedosporium species and Lomentospora prolificans. It has been studied as an oral and IV agent and has 45% bioavailability with tissue distribution into the kidney, liver, lung and CNS. It may play a niche role in the treatment of these less frequently encountered fungal infections and is well tolerated, with few drug interactions. It does not currently have FDA approval.

Opelconazole

Opelconazole is a triazole that was developed for inhalation. It is active against most of the common fungi causing infections, including Candida species, Aspergillus species and Cryptococcus species. Because of its optimization as an inhaled agent, it can achieve high concentrations in the lungs, helping to limit systemic adverse effects and drug interactions. It may play a key role in prophylaxis and treatment of invasive fungal airway infections but does not yet have FDA approval.

Rezafungin

Approved in March, rezafungin has benefits over other available agents. It is a once-weekly echinocandin and structural analog of anidulafungin. It has a half-life of over 130 hours with a favorable safety profile and is being studied in many forms, including IV, subcutaneous, oral and as an ointment/gel. It has similar in vitro activity to the other echinocandins, including higher minimum inhibitory concentrations for C. parapsilosis. Rezafungin is currently being studied in the ReSPECT trial for the prevention of invasive fungal disease caused by Candida species, Aspergillus species and Pneumocystis jirovecii in patients undergoing blood or marrow transplantation. It may play a role in prophylaxis after transplantation, as well as a more convenient outpatient parenteral antimicrobial therapy option with its unique once-weekly dosing. In the STRIVE and ReSTORE trials, it has shown comparable outcomes to caspofungin. It was approved for adults with limited or no alternative options for the treatment of candidemia and invasive candidiasis. Currently, it is available only intravenously and comes with warnings for infusion-related reactions, photosensitivity and hepatic adverse reactions.

Oteseconazole

Oteseconazole is a tetrazole that was approved by the FDA in April 2022 as an oral antifungal to reduce the incidence of recurrent vulvovaginal candidiasis. It is well tolerated, with minimal reports of headache and nausea. It was designed to have fewer drug-drug interactions and less toxicity compared with other agents, although it does have renal and hepatic dose limitations.

Encochleated amphotericin B

Encochleated amphotericin B is an oral dosage form of amphotericin B with the same broad spectrum created to improve the toxicities of IV amphotericin B. In studies such as the EnACT 1 trial, it has had comparable outcomes to other agents with limited traditional side effects seen.

Kira Voyer, PharmD, is a PGY2 infectious diseases pharmacy resident at Denver Health Medical Center.

Kati Shihadeh, PharmD, BCIDP, is a clinical pharmacy specialist in infectious diseases at Denver Health Medical Center. Shihadeh can be reached at [email protected].