Search Results (7)

Invasive pulmonary aspergillosis (IPA), traditionally associated with severe immunosuppression and neutropenia, is increasingly reported among non-neutropenic patients. This epidemiological shift highlights the need for a revised understanding of IPA’s pathogenesis, clinical presentation, and management strategies. The rising incidence in these populations likely reflects improved diagnostic capabilities and recognition of additional predisposing factors. Although profound immunosuppression remains a key risk, even moderate alterations in innate or adaptive immunity can promote Aspergillus spp. invasion. This review summarizes current knowledge and recent advances in the diagnosis and treatment of IPA. Specifically, treatment strategies must be tailored to comorbidities, infection severity, and drug tolerance. Early diagnosis and prompt antifungal therapy are crucial for improving outcomes. Voriconazole remains the first-line treatment, though therapeutic drug monitoring is essential to ensure efficacy and minimize toxicity. Isavuconazole represents an effective alternative, offering comparable efficacy, improved safety, predictable pharmacokinetics, and convenient once-daily dosing. Liposomal amphotericin B serves as a valuable option in severe or refractory cases due to its broad-spectrum activity and reduced nephrotoxicity. Supportive measures—such as respiratory optimization, comorbidity management, and immunomodulatory therapies—are integral to care. Prognosis depends on infection extent, immune status, and timeliness of therapy. Emerging antifungal agents, including olorofim, ibrexafungerp, and fosmanogepix, show promise against resistant Aspergillus species, expanding treatment options. Overall, IPA management in non-neutropenic patients requires a multidisciplinary, patient-centered approach integrating established antifungals, supportive care, and novel therapeutic advances. Full article

Candidemia is a highly prevalent invasive fungal infection caused primarily by C. albicans, C. parapsilosis, C. glabrata (currently Nakaseomyces glabratus), C. tropicalis, and C. krusei (currently Pichia kudriavzevii). Risk factors for the development of candidemia include steroid-induced immunosuppression used in solid organ or hematopoietic transplantation, and neutropenia secondary to infectious or tumorous processes. Alterations in the gut microbiota in people living with HIV, caused by antiretroviral therapy, increase the possibility of colonization by C. albicans. Likewise, the presence of a central venous catheter, parenteral nutrition, and abdominal surgery stand out as the main risk factors for the development of candidemia. New diagnostic tools have been developed for the diagnosis of this mycosis that allow the identification of the main species, from improvements in conventional stains such as calcofluor white, which increases sensitivity, as well as technologies such as T2 Candida, MoiM assay, biomarker panel (1,3 β-D-glucan, C-reactive protein, presepsin, and procalcitonin), and, more recently, the development of biosensors for the identification of Candida spp. Regarding treatment, the use of micafungin and anidulafungin in patients with obesity defined by a BMI > 30 kg/m² has shown higher survival rates and therapeutic success. Meanwhile, newer antifungals such as rezafungin and fosmanogepix have demonstrated excellent results in the treatment of these patients. Therefore, this review aims to update the epidemiology and risk factors of candidemia, as well as analyze the diagnostic tools and treatments currently available. Full article

This mini-review summarizes the clinical outcomes and antifungal susceptibility results, where available, for three new antifungals, including fosmanogepix, ibrexafungerp, and rezafungin, against Candida isolates cultured from patients in clinical trials. When reported, most of the data were generated by the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method or by both the CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) methodologies. For fosmanogepix, we summarize the in vitro data for C. auris isolates from 9 patients and for Candida spp. cultured from 20 patients in two clinical trials. Ibrexafungerp has also been evaluated in several clinical trials. From conference proceedings, a total of 176 Candida isolates were evaluated in the FURI and CARES studies, including 18 C. auris isolates (CARES study). However, MIC data are not available for all clinical isolates. Results from the ReSTORE rezafungin phase 3 clinical study also included in vitro results against Candida spp., but no patients with C. auris infections were included. In conclusion, this mini-review summarizes insights regarding clinical outcomes and the in vitro activity of three new antifungals against Candida spp. cultured from patients in clinical trials. Full article

The alarming spread and impact of multidrug-resistant Candida auris infections alongside the limited therapeutic options have prompted the development of new antifungals. These promising agents are currently in different stages of development, offering novel dosing regimens and mechanisms of action. A systematic search in MEDLINE, EMBASE, Web of Science, and Scopus up to 27 June 2022 was conducted to find relevant articles reporting data of in vitro activity and in vivo efficacy of investigational antifungals against C. auris. These included new additions to existing antifungal classes (rezafungin and opelconazole), first-in-class drugs such as ibrexafungerp, manogepix/fosmanogepix, olorofim and tetrazoles (quilseconazole, oteseconazole and VT-1598), as well as other innovative agents like ATI-2307, MGCD290 and VL-2397. From 592 articles retrieved in the primary search, 27 met the eligibility criteria. The most studied agent was manogepix/fosmanogepix (overall MIC₉₀: 0.03 mg/L), followed by ibrexafungerp (overall MIC₉₀: 1 mg/L) and rezafungin (overall MIC mode: 0.25 mg/L), while VT-1598 and ATI-2307 were the least explored drugs against C. auris. All these compounds demonstrated significant improvements in survival and reduction in tissue fungal burden on neutropenic animal models of candidemia due to C. auris. Continual efforts towards the discovery of new treatments against this multidrug-resistant fungus are essential. Full article

Invasive fungal infections have mortality rates of 30–90%, depending on patient co-morbidities and the causative pathogen. The frequent emergence of drug resistance reduces the efficacy of currently approved treatment options, highlighting an urgent need for antifungals with new modes of action. Addressing this need, fosmanogepix (N-phosphonooxymethylene prodrug of manogepix; MGX) is the first in a new class of gepix drugs, and acts as a broad-spectrum, orally bioavailable inhibitor of the essential fungal glycosylphosphatidylinositol (GPI) acyltransferase Gwt1. MGX inhibits the growth of diverse fungal pathogens and causes accumulation of immature GPI-anchored proteins in the fungal endoplasmic reticulum. Relevant to the ongoing clinical development of fosmanogepix, we report a synergistic, fungicidal interaction between MGX and inhibitors of the protein phosphatase calcineurin against important human fungal pathogens. To investigate this synergy further, we evaluated a library of 124 conditional expression mutants covering 95% of the genes encoding proteins involved in GPI-anchor biosynthesis or proteins predicted to be GPI-anchored. Strong negative chemical-genetic interactions between the calcineurin inhibitor FK506 and eleven GPI-anchor biosynthesis genes were identified, indicating that calcineurin signalling is required for fungal tolerance to not only MGX, but to inhibition of the GPI-anchor biosynthesis pathway more broadly. Depletion of these GPI-anchor biosynthesis genes, like MGX treatment, also exposed fungal cell wall (1→3)-β-D-glucans. Taken together, these findings suggest the increased risk of invasive fungal infections associated with use of calcineurin inhibitors as immunosuppressants may be mitigated by their synergistic fungicidal interaction with (fos)manogepix and its ability to enhance exposure of immunostimulatory glucans. Full article

Fosmanogepix is a first-in-class antifungal currently in Phase 2 clinical trials for the treatment of invasive fungal infections caused by Candida, Aspergillus and rare molds. Fosmanogepix is the N-phosphonooxymethylene prodrug of manogepix, an inhibitor of the fungal enzyme Gwt1. Manogepix demonstrates broad spectrum in vitro activity against yeasts and molds, including difficult to treat pathogens. Because of its novel mechanism of action, manogepix retains potency against many resistant strains including echinocandin-resistant Candida and azole-resistant Aspergillus. Manogepix is also active against pathogens that demonstrate intrinsic resistance to other drug classes, such as Scedosporium, Lomentospora prolificans, and Fusarium with variable activity against Mucorales. Fosmanogepix demonstrates significant in vivo efficacy in mouse and rabbit disseminated infection models due to C. albicans, C. glabrata, C. auris, C. tropicalis, Coccidioides immitis, and F. solani as well as pulmonary infection models of A. fumigatus, A. flavus, S.prolificans, S. apiospermum and Rhizopus arrhizus. Clinical trials demonstrated high oral bioavailability (>90%), enabling switching between fosmanogepix intravenous and oral formulations without compromising blood levels. Favorable drug-drug interaction, tolerability, and wide tissue distribution profiles are observed making fosmanogepix an attractive option for the treatment of invasive fungal infections. This systematic review summarizes the findings of published data on fosmanogepix. Full article

Invasive fungal infections are associated with significant morbidity and mortality, and their management is restricted to a variety of agents from five established classes of antifungal medication. In practice, existing antifungal agents are often constrained by dose-limiting toxicities, drug interactions, and the routes of administration. An increasing prevalence of invasive fungal infections along with rising rates of resistance and the practical limitations of existing agents has created a demand for the development of new antifungals, particularly those with novel mechanisms of action. This article reviews antifungal agents currently in various stages of clinical development. New additions to existing antifungal classes will be discussed, including SUBA-itraconazole, a highly bioavailable azole, and amphotericin B cochleate, an oral amphotericin formulation, as well as rezafungin, a long-acting echinocandin capable of once-weekly administration. Additionally, novel first-in-class agents such as ibrexafungerp, an oral glucan synthase inhibitor with activity against various resistant fungal isolates, and olorofim, a pyrimidine synthesis inhibitor with a broad spectrum of activity and oral formulation, will be reviewed. Various other innovative antifungal agents and classes, including MGCD290, tetrazoles, and fosmanogepix, will also be examined. Full article