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Rezafungin, a new US Food and Drug Administration-approved, long-acting echinocandin to treat candidaemia and invasive candidiasis, was efficacious with a similar safety profile to caspofungin in clinical trials. We conducted pooled analyses of the phase 2 STRIVE and phase 3 ReSTORE rezafungin trials. ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial conducted at 66 tertiary care centres in 15 countries. STRIVE was a multicentre, double-blind, double-dummy, randomised phase 2 trial conducted at 44 centres in 10 countries. Adults (≥18 years) with candidaemia or invasive candidiasis were treated with once-a-week intravenous rezafungin (400 mg and 200 mg) or once-a-day intravenous caspofungin (70 mg and 50 mg). Efficacy was evaluated in a pooled modified intent-to-treat (mITT) population. Primary efficacy endpoint was day 30 all-cause mortality (tested for non-inferiority with a pre-specified margin of 20%). Secondary efficacy endpoint was mycological response. Safety was also evaluated. The STRIVE and ReSTORE trials are registered with ClinicalTrials.gov, NCT02734862 and NCT03667690, and both studies are complete. ReSTORE was conducted from Oct 12, 2018, to Oct 11, 2021, and STRIVE from July 26, 2016, to April 18, 2019. The mITT population, pooling the data from the two trials, comprised 139 patients for rezafungin and 155 patients for caspofungin. Day 30 all-cause mortality rates were comparable between groups (19% [26 of 139] for the rezafungin group and 19% [30 of 155] for the caspofungin group) and the upper bound of the 95% CI for the weighted treatment difference was below 10% (−1·5% [95% CI −10·7 to 7·7]). Mycological eradication occurred by day 5 in 102 (73%) of 139 rezafungin patients and 100 (65%) of 155 caspofungin patients (weighted treatment difference 10·0% [95% CI −0·3 to 20·4]). Safety profiles were similar across groups. Rezafungin was non-inferior to caspofungin for all-cause mortality, with a potential early treatment benefit, possibly reflecting rezafungin's front-loaded dosing regimen. These findings are of clinical importance in fighting active and aggressive infections and reducing the morbidity and mortality caused by candidaemia and invasive candidiasis. Melinta Therapeutics and Cidara Therapeutics.

Rezafungin is a next-generation, once-a-week echinocandin in development for the treatment of candidaemia and invasive candidiasis and for the prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp after blood and marrow transplantation. We aimed to compare the efficacy and safety of intravenous rezafungin versus intravenous caspofungin in patients with candidaemia and invasive candidiasis. ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial done at 66 tertiary care centres in 15 countries. Adults (≥18 years) with systemic signs and mycological confirmation of candidaemia or invasive candidiasis were eligible for inclusion and randomly assigned (1:1) to receive intravenous rezafungin once a week (400 mg in week 1, followed by 200 mg weekly, for a total of two to four doses) or intravenous caspofungin (70 mg loading dose on day 1, followed by 50 mg daily) for no more than 4 weeks. The primary endpoints were global cure (consisting of clinical cure, radiological cure, and mycological eradication) at day 14 for the European Medical Agency (EMA) and 30-day all-cause mortality for the US Food and Drug Administration (FDA), both with a target non-inferiority margin of 20%, assessed in the modified intention-to-treat population (all patients who received one or more doses of study drug and had documented Candida infection based on a culture from blood or another normally sterile site obtained within 96 h before randomisation). Safety was evaluated by the incidence and type of adverse events and deaths in the safety population, defined as all patients who received any amount of study drug. The trial is registered with ClinicalTrials.gov, NCT03667690, and is complete. Between Oct 12, 2018, and Aug 29, 2021, 222 patients were screened for inclusion, and 199 patients (118 [59%] men; 81 [41%] women; mean age 61 years [SD 15·2]) were randomly assigned (100 [50%] patients to the rezafungin group and 99 [50%] patients to the caspofungin group). 55 (59%) of 93 patients in the rezafungin group and 57 (61%) of 94 patients in the caspofungin group had a global cure at day 14 (weighted treatment difference −1·1% [95% CI −14·9 to 12·7]; EMA primary endpoint). 22 (24%) of 93 patients in the rezafungin group and 20 (21%) of 94 patients in the caspofungin group died or had an unknown survival status at day 30 (treatment difference 2·4% [95% CI −9·7 to 14·4]; FDA primary endpoint). In the safety analysis, 89 (91%) of 98 patients in the rezafungin group and 83 (85%) of 98 patients in the caspofungin group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events that occurred in at least 5% of patients in either group were pyrexia, hypokalaemia, pneumonia, septic shock, and anaemia. 55 (56%) patients in the rezafungin group and 52 (53%) patients in the caspofungin group had serious adverse events. Our data show that rezafungin was non-inferior to caspofungin for the primary endpoints of day-14 global cure (EMA) and 30-day all-cause mortality (FDA). Efficacy in the initial days of treatment warrants evaluation. There were no concerning trends in treatment-emergent or serious adverse events. These phase 3 results show the efficacy and safety of rezafungin and support its ongoing development. Cidara Therapeutics and Mundipharma.

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Abstract Background Isavuconazole was compared to caspofungin followed by oral voriconazole in a Phase 3, randomized, double-blind, multinational clinical trial for the primary treatment of patients with candidemia or invasive candidiasis. Methods Adult patients were randomized 1:1 to isavuconazole (200 mg intravenous [IV] three-times-daily [TID] for 2 days, followed by 200 mg IV once-daily [OD]) or caspofungin (70 mg IV OD on day 1, followed by 50 mg IV OD [70 mg in patients > 80 kg]) for a maximum of 56 days. After day 10, patients could switch to oral isavuconazole (isavuconazole arm) or voriconazole (caspofungin arm). Primary efficacy endpoint was successful overall response at the end of IV therapy (EOIVT) in patients with proven infections who received ≥1 dose of study drug (modified-intent-to-treat [mITT] population). The pre-specified noninferiority margin was 15%. Secondary outcomes in the mITT population were successful overall response at 2 weeks after the end of treatment, all-cause mortality at days 14 and 56, and safety. Results Of 450 patients randomized, 400 comprised the mITT population. Baseline characteristics were balanced between groups. Successful overall response at EOIVT was observed in 60.3% of patients in the isavuconazole arm and 71.1% in the caspofungin arm (adjusted difference -10.8, 95% confidence interval -19.9–-1.8). The secondary endpoints, all-cause mortality, and safety were similar between arms. Median time to clearance of the bloodstream was comparable between groups. Conclusions This study did not demonstrate non-inferiority of isavuconazole to caspofungin for primary treatment of invasive candidiasis. Secondary endpoints were similar between both groups. Clinical Trials Registration NCT00413218. In a Phase 3, randomized, double-blind, multinational clinical trial comparing isavuconazole to caspofungin for the primary treatment of patients with proven candidemia or invasive candidiasis, isavuconazole failed to demonstrate noninferiority compared with caspofungin.

Candida albicans (Ca), a prominent opportunistic fungal pathogen in humans, has garnered considerable attention due to its infectious properties. Herein, we have identified and characterized CaCDAP1 (Ca orf19.1034), a homolog of ScDAP1 found in Saccharomyces cerevisiae. CaCDAP1 encodes a 183-amino acid protein with a conserved cytochrome b5-like heme-binding domain. The deletion of CaDAP1 renders Ca cells susceptible to caspofungin and terbinafine. CaDAP1 deletion confers resistance to Congo Red and Calcofluor White, and sensitivity to sodium dodecyl sulfate. The deletion of CaDAP1 results in a 50% reduction in chitin content within the cell wall, the downregulation of phosphorylation levels in CaMkc1, and the upregulation of phosphorylation levels in CaCek1. Notably, CaDAP1 deletion results in the abnormal hyphal development of Ca cells and diminishes virulence in a mouse systemic infection model. Thus, CaDAP1 emerges as a critical regulator governing cellular responses to antifungal drugs, the synthesis of cell wall chitin, and virulence in Ca.

The cell wall of human fungal pathogens plays critical roles as an architectural scaffold and as a target and modulator of the host immune response. Although the cell wall of the pathogenic yeast Candida albicans is intensively studied, one of the major fibrillar components in its cell wall, [beta]-1,6-glucan, has been largely neglected. Here, we show that [beta]-1,6-glucan is essential for bilayered cell wall organization, cell wall integrity, and filamentous growth. For the first time, we show that [beta]-1,6-glucan production compensates the defect in mannan elongation in the outer layer of the cell wall. In addition, [beta]-1,6-glucan dynamics are also coordinated by host environmental stimuli and stresses with wall remodeling, where the regulation of [beta]-1,6-glucan structure and chain length is a crucial process. As we point out that [beta]-1,6-glucan is exposed at the yeast surface and modulate immune response, [beta]-1,6-glucan must be considered a key factor in host--pathogen interactions.

Mitotic anaphase onset is a key cellular process tightly regulated by multiple kinases. The involvement of mitogen-activated protein kinases (MAPKs) in this process has been established in Xenopus egg extracts. However, the detailed regulatory cascade remains elusive, and it is also unknown whether the MAPK-dependent mitotic regulation is evolutionarily conserved in the single-cell eukaryotic organisms such as fission yeast (Schizosaccharomyces pombe). Here, we show that two MAPKs in S. pombe indeed act in concert to restrain anaphase-promoting complex/cyclosome (APC/C) activity upon activation of the spindle assembly checkpoint (SAC). One MAPK, Pmk1, binds to and phosphorylates Slp1.sup.Cdc20, the co-activator of APC/C. Phosphorylation of Slp1.sup.Cdc20 by Pmk1, but not by Cdk1, promotes its subsequent ubiquitylation and degradation. Intriguingly, Pmk1-mediated phosphorylation event is also required to sustain SAC under environmental stress. Thus, our study establishes a new underlying molecular mechanism of negative regulation of APC/C by MAPK upon stress stimuli, and provides a previously unappreciated framework for regulation of anaphase entry in eukaryotic cells.

Candida auris has emerged as a significant fungal threat due to its rapid worldwide spread since its first appearance, along with its potential for antimicrobial resistance and virulence properties. This study was designed to examine virulence characteristics, the efficacy of ceragenins, and biofilm-derived drug resistance in seven C. auris strains isolated from Turkish intensive care patients. It was observed that none of the tested strains exhibited proteinase or hemolysis activity; however, they demonstrated weak phospholipase and esterase activity. In addition, all strains were identified as having moderate to strong biofilm formation characteristics. Upon determining the minimum inhibitory concentrations (MIC) of ceragenins, it was discovered that CSA-138 exhibited the highest effectiveness with a MIC range of 1–0.5 µg/mL, followed by CSA-131 with a MIC of 1 µg/mL. Also, antimicrobial agents destroyed mature biofilms at high concentrations (40–1280 µg/mL). The investigation revealed that the strains isolated from Türkiye displayed weak exoenzyme activities. Notably, the ceragenins exhibited effectiveness against these strains, suggesting their potential as a viable treatment option.