Novel Therapeutic Approaches to Invasive Candidiasis: Considerations for the Clinician

Introduction

Candida Infections

Yeasts of the genus Candida represent the most frequent cause of fungal diseases in Europe and North America.¹ Candida spp. are part of the commensal flora of the skin and gut in humans. They can cause localized infections, such as vulvovaginal or oral/esophageal candidiasis, as well as invasive infections in individuals with predisposing conditions, such as decreased immunity and/or rupture of the mechanical barriers (e.g., intravascular catheters, complicated abdominal surgery).² Invasive candidiasis (IC) includes candidemia (i.e., bloodstream infections) and non-candidemic deep-seated candidiasis, such as intra-abdominal candidiasis (IAC) or chronic disseminated (hepatosplenic) candidiasis.¹ IC can affect both immunocompromised patients (e.g., neutropenic patients) and apparently immunocompetent patients who are critically ill. It represents a major cause of healthcare-associated sepsis, in particular in the intensive care units (ICU).³ Candida albicans is the most frequent pathogenic Candida species in humans, followed by Candida glabrata and other non-albicans Candida spp. (e.g., C. parapsilosis, C. tropicalis, C. krusei).¹ Candida auris has recently emerged as a novel Candida species of concern.⁴

The Evolving Landscape of Invasive Candidiasis

While the global epidemiological trends of IC are difficult to assess and may vary between different geographical areas, its incidence remains high and data from North America and Europe suggest an increased burden of the disease among the elderly and immunocompromised populations.^1,5,6 As a consequence, a paradoxical increase of mortality rates of IC has been reported over time despite advances in diagnostic and therapeutic approaches.^5,7 The epidemiology of IC has also evolved in terms of microbiology, with a decreasing proportion of Candida albicans and a progressive predominance of non-albicans Candida spp., in particular Candida glabrata, that are less susceptible to azoles.^1,5 These epidemiological changes have not only been observed in Europe and in North America, but also in Asia and in the Southern hemisphere where azole-resistant C. glabrata and C. tropicalis isolates are increasingly reported.^8–10

Moreover, an emerging Candida species, Candida auris, has spread in all continents since 2009.^4,11 In addition to its ability to cause hospital outbreaks,^12,13 C. auris has the ability to rapidly develop resistance to all antifungal drug classes with increasing reports of multi-resistant isolates.^4,14,15 C. auris currently represents an important proportion of Candida bloodstream pathogens in some parts of the world, such as in South Asia and South Africa where it has been associated with an epidemiological shift.^16,17

Epidemiology of Azole and Echinocandin Resistance Among Candida spp

Currently, the treatment of IC relies on echinocandin drugs (caspofungin, anidulafungin and micafungin) as empirical or first-line therapy and azoles (mainly fluconazole) as second-line or step-down therapy for susceptible isolates.^2,18,19 Other triazoles (e.g., voriconazole) and amphotericin B formulations can be used in particular cases.^2,18,19

Echinocandins are active against most wild-type pathogenic Candida spp.²⁰ Although C. parapsilosis is less susceptible in vitro, echinocandins remain effective for the treatment of IC attributed to this pathogen.²¹ Echinocandin resistance is essentially acquired by mutations in the FKS genes, encoding for the (1,3)-beta-D-glucan synthase (the target of echinocandins).²⁰ Its overall rate is variable according to different geographical areas, but usually does not exceed 10%. The proportion of echinocandin resistant C. glabrata may reach 5% to 15% in some US centers, but remains below 3% in Europe.^22–27 Echinocandin resistance in C. albicans is much less frequent (<1%).^25,27 Among C. auris, echinocandin resistance is mainly observed in clade I with a prevalence varying between 0.5% and 4%.^14,15,28,29 Overall, the rate of echinocandin resistance among Candida spp. seems to increase over time.^15,23,30 Regarding fluconazole resistance, besides the Candida spp. exhibiting variable intrinsic level of resistance (e.g., C. glabrata, C. krusei), acquired resistance is reported at variable rates (1% to 20%) among C. albicans and C. tropicalis, and in the majority of C. auris isolates (>90%).^1,4

Current Gaps for the Treatment of Invasive Candidiasis

Limitations of the three current antifungal drug classes used for IC may be due to: 1) multiple resistance of the causative agent; 2) pharmacologic considerations, such as lack of oral formulations for outpatient treatment or poor penetration in some tissues (e.g., brain, eye); and 3) toxicity or drug-drug interactions.

Multiple resistance (i.e., ≥2 antifungal drug classes) is mainly a concern for echinocandin and azole resistant C. glabrata and C. auris. Limited pharmacologic properties can be an issue for echinocandins because of their lack of oral bioavailability and very poor penetration in eye, central nervous system (CNS) and urine. Finally, liver toxicity and drug-drug interactions (with drugs interfering with cytochrome P450) may limit the use of azoles, which are currently the only antifungals with oral bioavailability. Amphotericin B formulations also exhibit important limitations, such as nephrotoxicity and their lack of oral formulation.

Novel antifungal agents are needed to fulfill these gaps.³¹ Ideally, these molecules should provide broad-spectrum activity against Candida spp. including those with azole and/or echinocandin resistance, to be available as both intravenous and oral formulations, to have large tissue distribution including in sanctuary sites (CNS, deep abscesses, urine) and to have few side effects and drug-drug interactions. This review will focus on novel antifungal agents that are currently in phase II/III clinical trials for the treatment of IC.

Novel Antifungal Agents for Invasive Candidiasis

Three antifungal agents, including two first-in-class molecules (ibrexafungerp and fosmanogepix) and one molecule of a pre-existing class with improved pharmacologic properties (rezafungin), have completed or are currently in phase II/III trials for the treatment of IC (Table 1). All of them are expected to palliate some of the above mentioned gaps and to represent important therapeutic options for IC in the future. Their potential advantages and limitations are summarized in Table 2.

Table 1 Characteristics and Stage of Development of Novel Antifungal Agents for the Treatment of IC

Table 2 Advantages and Limitations of Novel Antifungal Drugs for IC

Rezafungin

Rezafungin (CD101) is a novel echinocandin drug (inhibitor of the (1,3)beta-D-glucan synthase) with enhanced stability, low clearance and prolonged half-life (130h), which allows an interdose interval of one week.³² It is fungicidal and has the same spectrum of activity as other echinocandins and, similar to them, it can be administered by intravenous route only and does not reach therapeutic concentrations in the CNS, eye and urine.³² Therefore, its main advantage consists of the convenient mode of administration (once weekly instead of once daily for other echinocandins). In vitro susceptibility testing studies of rezafungin against pathogenic Candida spp. suggested the following wild-type upper limits (WT-UL) to distinguish the wild-type and non-wild type isolates: 0.06–0.125 mg/L for C. albicans, 0.125–0.25 mg/L for C. glabrata and C. krusei, 0.25 mg/L for C. tropicalis, 0.5 mg/L for C. auris and 4 mg/L for C. parapsilosis.^33,34 In murine models of IC, rezafungin demonstrated at least similar (or even better) efficacy compared to other echinocandins (e.g., micafungin) against the most relevant Candida spp. including C. auris.^35–39 Notably, the area under the curve (AUC) / minimal inhibitory concentration (MIC) ratio to achieve efficacy endpoints was lower for rezafungin compared to other echinocandins.³⁸ In a murine model of IAC, rezafungin could reach much higher concentrations in liver lesions compared to micafungin, which may be associated with improved outcomes and decreased risk of development of resistance due to suboptimal concentrations.⁴⁰

The safety and efficacy of rezafungin for the treatment of IC in humans have been tested in two double-blind randomized controlled-trials against caspofungin.^41,42 In a Phase II study of 207 patients (STRIVE), rezafungin was tested at two different dosing regimens (400 mg once weekly and 400 mg loading dose, then 200 mg once weekly) versus standard regimen of caspofungin.⁴¹ Overall cure rates at day 14 were comparable between the three treatment arms (60.5%, 76.1%, 67.2% for rezafungin high and low dose regimens, and caspofungin, respectively). In a Phase III study (ReSTORE), rezafungin (400 mg loading dose, then 200 mg once weekly) met non-inferiority criteria compared to caspofungin with a global cure at day 14 of 59.1% vs. 60.6%, respectively.⁴²

Ibrexafungerp

Ibrexafungerp (SCY-078, MK-3118) is a triterpenoid derived from enfumafungin, which inhibits the (1,3)-beta-D-glucan synthase.⁴³ Therefore, it is structurally different from the echinocandins, but exerts its fungicidal antifungal activity via the same target.⁴³ Because its binding site on the target enzyme is not the same and only partially overlaps with that of echinocandins, ibrexafungerp can maintain antifungal activity against a majority of FKS-mutant echinocandin resistant isolates.⁴³ In terms of pharmacologic properties, ibrexafungerp has the advantage to exhibit acceptable oral bioavailability (35–50%) to be administered by oral route.⁴³ Its solubility and absorption is favored by low pH and co-administration of food and can be affected by clinical conditions, such as use of proton pump inhibitors, antacids, nausea, vomiting and loss of appetite.⁴³ Similar to echinocandins, ibrexafungerp has high rate of plasma protein binding and very poor penetration in CNS and urine.⁴³ In vitro, ibrexafungerp exhibits MICs for Candida spp. that are somewhat higher compared to other echinocandins, except for C. parapsilosis.^43,44 Reported WT-UL are: 0.5 mg/L for C. albicans, 1mg/L for C. tropicalis and C. parapsilosis, 2 mg/L for C. glabrata, 4 mg/L for C. krusei.⁴⁴ Relatively high MICs (≥4 mg/L) have been reported among C. lusitaniae and C. guilliermondii isolates.⁴⁴ For C. auris, MIC₅₀ and MIC₉₀ (i.e., encompassing 50% and 90% of tested isolates, respectively) were 0.5 and 1 mg/L, respectively.^45,46 Notably, ibrexafungerp demonstrated good activity against pan-resistant C. auris isolates.⁴⁷ The activity of ibrexafungerp against FKS-mutant Candida spp. is variable and this variation seems to be dependent on the site/type of mutation; overall it is conserved against approximately 75% of isolates.^43,44 In murine models, oral ibrexafungerp was effective in treating IC caused by different Candida spp. including C. auris and C. glabrata FKS-mutant isolates.^48–50 In a murine model of IAC, ibrexafungerp achieved high concentrations in liver abscesses (~100-fold higher than in serum), which were superior to a comparative echinocandin (more than 5-fold higher compared to micafungin).⁵¹

Ibrexafungerp has been approved by the Food and Drug Administration (FDA) for the treatment of vulvovaginal candidiasis following two phase III trials.^52,53 Its safety and preliminary efficacy as step-down therapy following initial echinocandin therapy for the treatment of IC was evaluated in a small (n = 27 patients) phase II study.⁵⁴ Two different dosing regimens of oral ibrexafungerp (1000 mg loading dose followed by 500 mg qd, and 1250 mg loading dose followed by 750 mg qd) were compared to a standard oral fluconazole regimen with similar response rates (71%, 86%, 71%, respectively) and rates of adverse events. The population pharmacokinetic model indicated that about 85% of patients receiving the ibrexafungerp high dose regimen would achieve the pharmacodynamics target (AUC_0-24 of 15.4 µM/h, based on previous murine models).^48,54,55 Two phase III studies are ongoing: one randomized double-blind trial evaluating ibrexafungerp versus fluconazole as second-line oral therapy following initial echinocandin therapy (MARIO, NCT05178862) and an open-label study evaluating the efficacy of ibrexafungerp for the treatment of C. auris IC (CARES, NCT03363841).⁵⁶

Fosmanogepix

Fosmanogepix (APX001, E1211), which is converted to its active moiety manogepix (APX001A, E1210) by systemic phosphatases, is a first-in-class antifungal agent that inhibits Gwt1, an enzyme localized in the endoplasmic reticulum and involved in the glycosylphosphatidylinositol (GPI) biosynthesis pathway.⁵⁷ Because GPI is required for anchorage of mannoproteins in the cell wall and membrane, this results in endoplasmic reticulum stress, altered cell wall integrity, impaired morphogenesis (germ tube formation, hyphal elongation) and inhibition of adhesion and biofilm formation.^57,58 Moreover, alterations in the cell wall may unmask (1,3)-beta-D-glucan and activate the host immune response.⁵⁹ Fosmanogepix can be administered intravenously or orally with an oral bioavailability of >90%, which is not altered by co-administration of food.⁵⁷ It has prolonged half-life (2.5 days) and excellent tissue distribution including in the brain and eye.⁵⁷ Some drug-drug interactions with inhibitors or inducers of cytochrome P450 isoenzymes are possible and are under investigation.⁵⁷

In vitro, manogepix has fungistatic activity with a broad spectrum against most pathogenic yeasts and molds (with the exception of Mucorales).⁵⁷ MIC endpoints for yeasts are defined at 50% growth inhibition.⁵⁷ The WT-UL values were 0.03 mg/L for C. albicans, 0.03–0.06 mg/L for C. parapsilosis, 0.016–0.06 mg/L for C. tropicalis, 0.03–0.12 mg/L for C. auris and 0.125–0.25 mg/L for C. glabrata, while C. krusei is considered as intrinsically resistant (MIC >2 mg/L) and C. kefyr exhibits decreased susceptibility (MIC₉₀ 0.5 mg/L).^60–64 Manogepix was notably active against virtually all tested multi-resistant C. auris isolates and against echinocandin-resistant (FKS-mutant) C. glabrata and C. albicans.^63–65 In vitro, manogepix also demonstrated very potent inhibition of C. albicans adherence to polystyrene and biofilm formation, which was greater compared to that of fluconazole, micafungin and amphotericin B.⁵⁸ Manogepix also demonstrated prolonged post-antifungal effect in vitro and in vivo.⁵⁷ While acquired resistance to manogepix was not yet reported in vivo, in vitro studies showed that resistance can be acquired following manogepix exposure by mutations in the Gwt1 gene (V162A and V163A in C. albicans and C. glabrata, respectively) or overexpression of the ATP-binding cassette (ABC) transporters CDR11 and SNQ2 resulting from a gain-of-function mutation in the transcription factor gene ZCF29.^66,67

In in vivo animal models, the efficacy of fosmanogepix for IC treatment is hampered by the shorter half-life of its active moiety (manogepix) in mice compared to that in humans, which can be overcome by pre-treatment with a cytochrome P450 inhibitor.⁶⁸ The 24h free-drug AUC/MIC ratio was the pharmacokinetic/pharmacodynamics (PK/PD) index correlating with efficacy in mice.⁶⁹ Fosmanogepix or manogepix administered by intraperitoneal or oral routes had significant impact on kidney fungal burdens and survival in murine models of IC with wild-type C. albicans and C. glabrata compared to the untreated arms.^68,70 It is noteworthy that the comparator echinocandin in these studies demonstrated better results, although the differences did not reach statistical significance.^68,70 However, (fos-)manogepix was effective against echinocandin-resistant (FKS-mutant) C. albicans and C. glabrata, while the comparator echinocandin was not.^68,71 (Fos-)manogepix was also effective in murine models of C. auris IC.^72,73 In a murine model of IAC, repeated doses of fosmanogepix could achieve good penetration in liver abscesses after 3 days and its efficacy in reducing liver fungal burden was superior to that of micafungin.⁷⁴ The penetration of fosmanogepix into the CNS was analyzed in one rabbit model of C. albicans IC and one murine model of C. auris IC.^73,75 In rabbits, the CNS tissue / plasma concentration ratio was 1 and fosmanogepix treatment achieved significant reduction in CNS fungal burden (C. albicans) for concentrations ranging from 25 to 100 mg/kg bid.⁷⁵ In mice, a significant decrease of CNS fungal burden (C. auris) was only achieved at high concentrations of fosmanogepix (260 mg/kg bid).⁷³ In a rabbit model of C. albicans endophthalmitis, fosmanogepix displayed variable penetration in the different parts of the eye with liquid / plasma ratios of 0.09–0.12 in the vitreous humor and 0.02–0.04 in the choroid, which was sufficient to induce a significant decrease in fungal burden in both vitreous and choroid.⁷⁵

The efficacy of fosmanogepix as first-line treatment of candidemia (all Candida spp. except C. krusei) in non-neutropenic patients was tested in a non-comparative “proof of concept” phase II trial (N = 21 patients).⁷⁶ The drug was administered for 14 days with initial intravenous dosing (1000 mg bid on day 1, then 600 mg qd), with possibility for oral switch from day 4 (700 mg qd). The success rate at the end of treatment was 80% (16/20) and survival at day 30 was 85% (17/21). Fosmanogepix was well tolerated and the cases of death were not attributed to the drug. Another open label non comparative phase II study is evaluating the efficacy of fosmanogepix for the treatment of C. auris IC (APEX, NCT04148287).⁵⁶ A phase III randomized controlled trial comparing fosmanogepix (initial intravenous followed by oral therapy) versus standard therapy (initial intravenous caspofungin followed by oral fluconazole therapy) for the treatment of candidemia and other IC is expected to start soon (NCT05421858).

Other Novel Antifungal Drugs Under Development

Some other antifungal drug candidates deserve mention, although they have not yet been assessed in phase II/III trials for IC. The tetrazoles (VT-1161, VT-1129 and VT-1598) are novel azole compounds that have much lower affinity for human cytochrome P450 isoenzymes (CYP2C9, CYP2C19, and CYP3A4), which results in lower potential for drug-drug interactions.^77,78 Moreover, they may exhibit distinct susceptibility patterns compared to triazoles and have conserved in vitro activity against some fluconazole-resistant isolates, such as C. glabrata, C. krusei and C. auris.^79–82 VT-1161 (oteseconazole) demonstrated safety and efficacy for the treatment of acute and recurrent vulvovaginal candidiasis in phase II and III trials.^83–85 Its efficacy for the treatment of IC has not yet been evaluated.

Structurally modified molecules derived from fluconazole, such as aryl-1,2,4-triazol-3-ylthio analogues of fluconazole (ATTAFs), or other benzylthio analogues demonstrated some improved in vitro activity (lower MIC) compared to fluconazole, as well as some synergistic interactions, against both fluconazole-susceptible and -resistant Candida isolates.^86,87

Other potential antifungal drug candidates for IC include T-2307, an arylamidine (close to pentamidine) targeting the mitochondrial membrane, which demonstrated potent in vitro activity against Candida spp. including C. auris and echinocandin-resistant C. glabrata and C. albicans, as well as in vivo efficacy in murine models of IC.^88–90

The Place of Novel Antifungal Agents in the Prevention and Treatment of Invasive Candidiasis

Prophylaxis

Indications for anti-Candida prophylaxis are limited.^2,18 It is recommended for some hematologic cancer patients, such as allogeneic hematopoietic stem cell transplant (HSCT) recipients during the neutropenic phase or early non-neutropenic phase and should be expanded to provide anti-mold protection in some circumstances (e.g., graft versus host disease after allogeneic HSCT or for patients with acute leukemia and prolonged chemotherapy-induced neutropenia). Fluconazole (anti-Candida only) or posaconazole (for both yeast and mold prevention) are currently the drugs of choice. One phase III randomized controlled study is currently evaluating rezafungin versus posaconazole or fluconazole prophylaxis in allogeneic HSCT recipients (ReSPECT, NCT04368559).⁵⁶ The role of antifungal prophylaxis to prevent IC in non-hematologic cancer patients is more controversial and should be limited to high-risk patients (e.g., complicated abdominal surgery with anastomotic leakage).^2,18 Novel antifungals seem to have little place for this indication, but might be considered in the future (e.g., ibrexafungerp) in the case of high prevalence of C. auris or azole resistance.

Empiric and Pre-Emptive Therapy

Antifungal therapy can be started empirically in patients at risk of IC with sepsis or pre-emptively in the case of a positive fungal biomarker (e.g., beta-glucan in serum). In these situations, the antifungal agent should ensure broad coverage of the most prevalent Candida spp. according to the local epidemiological context. Because of their broad spectrum of activity, echinocandins currently represent the privileged option. Because of its prolonged half-life, rezafungin does not appear to be a good candidate, as antifungal therapy should be reassessed or adapted quickly following receipt of microbiological results. Novel antifungal agents ensuring coverage of C. auris, such as ibrexafungerp and fosmanogepix, may be considered in the case of hospital outbreaks or high prevalence of this species. The poor activity of fosmanogepix against C. krusei should be kept in mind, although this species is a relatively rare cause of IC.

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). However, they should be initially reserved for indications where they provide an additional value compared to current antifungal drugs. These advantages may be related to their antifungal spectrum and/or their pharmacologic properties.

Figure 1 Potential place of novel antifungal agents for the treatment of IC. Abbreviations: FKS, genes encoding the (1,3)-beta-D-glucan synthase; CNS, central nervous system; O (green), good candidate; X (red), not an option.

Ibrexafungerp and fosmanogepix are active against most echinocandin-resistant Candida spp. and may become the first choice for the treatment of IC caused by these species, in particular C. glabrata and C. auris that often exhibits concomitant resistance to azoles. It should be noted that cross-resistance between echinocandins and ibrexafungerp may be observed in some cases according to the type of FKS mutation.⁴⁴ Whether ibrexafungerp or fosmanogepix may be more effective than echinocandins for the treatment of C. parapsilosis, which exhibits some decreased echinocandin susceptibility, should be investigated. Fosmanogepix should not be considered for the treatment of C. krusei IC because of high in vitro MICs, and some more data are needed to assess the actual efficacy of fosmanogepix against C. kefyr and of ibrexafungerp against C. krusei, C. lusitaniae and C. guilliermondii because of their decreased in vitro susceptibility to these respective drugs.

The major pharmacologic properties of these novel antifungal agents, which may provide diverse advantages over conventional echinocandins, are: 1) oral bioavailability (ibrexafungerp, fosmanogepix); 2) prolonged half-life (rezafungin, and to a lesser extend fosmanogepix); 3) better penetration in intra-abdominal abscesses according to murine models (rezafungin, ibrexafungerp, fosmanogepix); and 4) ability to cross the blood-brain barrier (fosmanogepix).

Novel antifungal drugs with acceptable oral bioavailability are particularly welcome for prompt hospital discharge of patients with uncomplicated IC due to azole-resistant Candida isolates (e.g. C. glabrata). They may be of particular interest in some areas, such as South Asia, where the rate of fluconazole resistance is particularly high due to the high prevalence of C. auris and the increasing rate of fluconazole-resistant C. tropicalis.^9,10,16

IAC is relatively frequent among patients with complicated abdominal surgery and often requires prolonged antifungal therapy in case of incomplete source control.^91,92 All three novel drugs appear as ideal candidates for the treatment of IAC as they seem to achieve excellent penetration in intra-abdominal abscesses and are convenient for outpatient therapy (i.e., once weekly intravenous administration for rezafungin or oral administration for ibrexafungerp and fosmanogepix). Whether these drugs could achieve improved penetration in abscesses compared to fluconazole should be further investigated. Albeit rare, Candida meningitis or chorioretinitis are difficult to treat because of the lack of penetration of echinocandins in the CNS and eye. Fosmanogepix may represent an alternative to liposomal amphotericin B and fluconazole, which are currently recommended for these infections.^2,18

Conclusions

Three novel antifungal drugs are currently progressing through phase II and III trials in order to be approved for the treatment of IC. Two of them (ibrexafungerp and fosmanogepix) are first-in-class molecules and display an extended antifungal spectrum, in particular against echinocandin-resistant Candida spp. (including C. auris), and all of them have interesting pharmacologic properties that may provide advantages over current antifungal drugs, in particular for patients requiring prolonged and ambulatory treatment or those with sanctuary sites of infection (e.g., deep abscesses, CNS infection). While all of them are expected to have a place for the treatment of IC, their actual role will need to be further defined and guidelines modified accordingly.

Some caveats should be outlined regarding their future use in clinical practice. In the absence of clinical breakpoints for MIC interpretation, there may be some doubt about their actual efficacy against some rare Candida spp. exhibiting MIC values falling within a putative intermediate range. In particular, C. krusei is supposed to be resistant to fosmanogepix and also exhibits relatively high MICs to ibrexafungerp. While the possibility of oral administration for fosmanogepix and ibrexafungerp may represent a major advantage considering the very limited current options (i.e.,only azoles), there might be some concern about their oral bioavailability, in particular for ibrexafungerp under specific circumstances (e.g., concomitant administration of proton pump- inhibitors or antacids, poor appetite, gastro-intestinal disturbances).

Because IC remains a major cause of healthcare-associated infection and emergence of resistant species (e.g., C. auris) is concerning, this expansion of the antifungal armamentarium may change the epidemiology and outcome of IC in the future. Because of the ability of Candida to develop resistance to antifungal drugs, a parsimonious use of these novel agents is warranted and their indications should be restricted to situations where they provide advantages over current antifungal classes. Indeed, some in vitro data suggest the ability of Candida spp. to develop resistance to some of them (e.g., fosmanogepix) and clinical data are currently insufficient to assess their potential to induce in vivo resistance.

Finally, it is important to mention that novel therapeutic approaches of IC are not restricted to the development of novel antifungal drugs, but also include strategies to enhance the immune response.⁹³ Interferon-gamma (IFN-γ) has been used as adjunctive therapy of standard antifungal agents in a small open-label case series with promising results.⁹⁴ This approach will be evaluated in a randomized clinical trial (NCT04979052).