Introduction
In-hospital morbidity and mortality continue to be significantly impacted by invasive candidiasis (IC), a condition caused by the yeast pathogen Candida. The emergence of multi-resistant Candida species, including Candida auris and certain Candida glabrata isolates, is a concerning factor due to the limited number of available antifungal drugs. However, recent advancements in antifungal drug development offer promising prospects for the treatment of IC. Three new antifungal agents, currently undergoing Phase II/III clinical trials, are anticipated to play a crucial role in the future management of IC. Rezafungin, a novel echinocandin with an extended half-life, is one of these agents. Additionally, ibrexafungerp and fosmanogepix, two first-in-class antifungal drugs, demonstrate broad spectrum activity against Candida spp., including C. auris and species resistant to echinocandins. These novel antifungal agents also present intriguing alternative options due to their acceptable oral bioavailability (ibrexafungerp and fosmanogepix) or their long interdose interval (once-weekly intravenous administration for rezafungin), allowing for prolonged and/or outpatient treatment of complicated IC.This review explores the potential role of these novel antifungal drugs in treating IC, taking into account their pharmacological properties as well as their preclinical and clinical data.
About Candida Infections
Candida yeasts are a common cause of fungal diseases in Europe and North America. They can cause localized infections and more serious invasive infections in individuals with weakened immune systems or compromised barriers. Invasive candidiasis (IC) includes bloodstream infections and deep-seated infections. IC is a significant cause of healthcare-associated sepsis, particularly in intensive care units. Candida albicans is the most common pathogenic species, followed by Candida glabrata and other non-albicans species. Candida auris, a concerning emerging species, has been spreading globally since 2009 and has shown resistance to multiple antifungal drugs. The incidence of IC remains high, particularly among the elderly and immunocompromised populations. Mortality rates of IC have been increasing despite advancements in diagnosis and treatment. The epidemiology of IC has also changed, with a decrease in Candida albicans and an increase in non-albicans species, including drug-resistant strains. Candida auris has caused hospital outbreaks and is now a significant pathogen in some regions.
Novel Antifungal Agents for Invasive Candidiasis
Rezafungin
Rezafungin (CD101) is a novel echinocandin drug that inhibits (1,3)beta-D-glucan synthase. It has enhanced stability, low clearance, and a prolonged half-life of 130 hours, allowing for a once-weekly dosing schedule. Rezafungin has a fungicidal effect and a similar spectrum of activity as other echinocandins. It is administered intravenously and does not reach therapeutic concentrations in the central nervous system, eye, and urine. The main advantage of rezafungin is its convenient once-weekly administration compared to the daily dosing of other echinocandins. In vitro susceptibility testing studies have established upper limits for wild-type isolates of various Candida species. Rezafungin has demonstrated comparable or superior efficacy to other echinocandins, including micafungin, in murine models of invasive candidiasis (IC), including infections caused by Candida auris. Rezafungin has shown higher concentrations in liver lesions compared to micafungin, potentially leading to improved outcomes and reduced development of resistance. Clinical trials have been conducted to evaluate the safety and efficacy of rezafungin in treating IC. The results of these trials have shown comparable cure rates between rezafungin and caspofungin, supporting the use of rezafungin as a potential treatment option for IC.
Ibrexafungerp
Ibrexafungerp (SCY-078, MK-3118) is a triterpenoid derived from enfumafungin that inhibits (1,3)-beta- D-glucan synthase, similar to echinocandins. However, it has a different binding site on the target enzyme, allowing it to maintain activity against most echinocandin- resistant isolates. Ibrexafungerp has acceptable oral bioavailability and can be administered orally, although its solubility and absorption can be affected by factors such as low pH and co-administration of food. It exhibits moderate MICs for Candida spp., except for C. parapsilosis where it has comparable MICs to other echinocandins. It also demonstrates good activity against pan-resistant C. auris isolates. In murine models, oral ibrexafungerp has shown effectiveness against IC caused by various Candida species, including FKS-mutant isolates. It achieves high concentrations in liver abscesses, surpassing those of micafungin. Ibrexafungerp has been FDA-approved for the treatment of vulvovaginal candidiasis, and preliminary efficacy has been observed as step-down therapy for IC. Phase III studies are ongoing to further evaluate its efficacy as second-line oral therapy and for the treatment of C. auris IC.
Fosmanogepix
Fosmanogepix (APX001, E1211) is a first-in-class antifungal agent that inhibits Gwt1, an enzyme involved in the GPI biosynthesis pathway necessary for cell wall integrity. It is converted to its active form, manogepix (APX001A, E1210), by systemic phosphatases. Fosmanogepix can be administered intravenously or orally with high oral bioavailability and has a prolonged half-life with excellent tissue distribution, including the brain and eye. Manogepix exhibits fungistatic activity against most pathogenic yeasts and molds, excluding Mucorales. It is particularly effective against multi-resistant C. auris isolates and echinocandin-resistant Candida strains. In vitro, manogepix inhibits biofilm formation and demonstrates prolonged post-antifungal effects. Acquired resistance to manogepix can occur through mutations in the Gwt1 gene or overexpression of ABC transporters. In animal models, fosmanogepix shows efficacy against IC caused by wild-type and resistant Candida strains, with superior effectiveness against FKS-mutant isolates compared to echinocandins. It exhibits good penetration in liver abscesses and variable penetration in the CNS and eye. In a phase II trial, fosmanogepix showed promising results for the treatment of candidemia, and further studies are underway, including a phase III trial comparing fosmanogepix to standard therapy for candidemia and other IC.
Other Novel Antifungal Drugs Under Development
Several antifungal drug candidates show promise for the treatment of invasive candidiasis (IC), although they have not yet undergone phase II/III trials. The tetrazoles (VT-1161, VT-1129, and VT-1598) are novel azole compounds with lower affinity for human cytochrome P450 isoenzymes, reducing the potential for drug-drug interactions. These tetrazoles may exhibit distinct susceptibility patterns compared to triazoles and have demonstrated in vitro activity against some fluconazole-resistant Candida strains. VT-1161 (oteseconazole) has shown efficacy in treating acute and recurrent vulvovaginal candidiasis but has not been evaluated for IC treatment. Structurally modified molecules derived from fluconazole, such as aryl-1,2,4-triazol-3-ylthio analogues (ATTAFs) and other benzylthio analogues, display improved in vitro activity and synergistic interactions against both fluconazole-susceptible and -resistant Candida isolates. Another potential candidate is T-2307, an arylamidine compound similar to pentamidine, which targets the mitochondrial membrane. T-2307 has exhibited potent in vitro activity against various Candida species, including C. auris and echinocandin-resistant C. glabrata and C. albicans. Furthermore, it has shown efficacy in murine models of IC.
The Place of Novel Antifungal Agents in the Prevention and Treatment of Invasive Candidiasis
Prophylaxis
The use of anti-Candida prophylaxis is limited and mainly recommended for specific groups, such as allogeneic hematopoietic stem cell transplant (HSCT) recipients during certain phases and patients with high-risk factors. Fluconazole or posaconazole are the preferred drugs for prophylaxis, depending on the need for protection against both yeast and mold. The effectiveness of rezafungin is currently being evaluated in a phase III study for HSCT recipients. Antifungal prophylaxis in non-hematologic cancer patients is more controversial and should be reserved for high-risk individuals. While novel antifungals have limited use in this context, they might be considered in the future, particularly for situations involving C. auris or azole resistance.
Empiric and Pre-Emptive Therapy
Antifungal treatment can be initiated empirically in high-risk patients with sepsis or preemptively based on positive fungal biomarkers, such as serum beta-glucan. In these cases, the chosen antifungal agent should provide broad coverage against the most common Candida species based on local epidemiology. Currently, echinocandins are the preferred option due to their broad spectrum of activity. Rezafungin, with its prolonged half-life, may not be suitable as therapy needs to be promptly adjusted based on microbiological results. Novel antifungal agents like ibrexafungerp and fosmanogepix, which offer coverage against C. auris, can be considered during hospital outbreaks or when there is a high prevalence of this species. However, it is important to note that fosmanogepix has limited activity against C. krusei, although this species is relatively uncommon as a cause of invasive candidiasis.
Targeted Therapy
Because of their broad spectrum of activity against Candida spp., these novel antifungal agents (i.e., rezafungin, ibrexafungerp and fosmanogepix) are expected to have an important place for the treatment of IC in the future (Figure 1).
Ibrexafungerp and fosmanogepix show activity against echinocandin-resistant Candida species, particularly C. glabrata and C. auris that are often resistant to azoles. However, cross-resistance may occur in some cases depending on the FKS mutation. Further research is needed to determine their efficacy against C. parapsilosis, C. krusei, C. lusitaniae, and C. guilliermondii. These novel antifungal agents have unique pharmacological properties such as oral bioavailability, prolonged half-life, intra-abdominal abscess penetration, and the ability to cross the blood-brain barrier. They offer potential advantages over conventional echinocandins. In areas with high fluconazole resistance, these drugs may be particularly useful.
Conclusion
Three novel antifungal drugs, including ibrexafungerp and fosmanogepix, are progressing through phase II and III trials for the treatment of IC. They show an extended antifungal spectrum, particularly against echinocandin- resistant Candida species like C. auris. These drugs offer advantages over current antifungal options, especially for patients requiring prolonged and ambulatory treatment or those with sanctuary sites of infection. However, their actual role and guidelines for their use need further clarification. Concerns include uncertain efficacy against rare Candida species, such as C. krusei, and potential limitations in oral bioavailability. The emergence of resistant species like C. auris highlights the importance of using these novel agents judiciously. Additionally, alternative approaches to IC treatment, such as enhancing the immune response with interferon-gamma, are being explored. For complicated abdominal surgery-related infections, the novel drugs are promising due to their excellent intra-abdominal abscess penetration and suitability for outpatient therapy. In the treatment of Candida meningitis or chorioretinitis, fosmanogepix could be an alternative to current options like liposomal amphotericin B and fluconazole.
Source: Lamoth, Frederic. “Novel therapeutic approaches to invasive candidiasis: Considerations for the clinician.” Infection and Drug Resistance (2023): 1087-1097.
