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BACKGROUND: Rezafungin is an echinocandin approved in the US and EU to treat candidaemia and/or invasive candidiasis. This post-hoc, pooled analysis of the Phase 2 STRIVE and Phase 3 ReSTORE trials assessed rezafungin versus caspofungin in patients with candidaemia and/or invasive candidiasis (IC) in the intensive care unit (ICU) at randomisation. METHODS: STRIVE and ReSTORE were randomised double-blind trials in adults with systemic signs and mycological confirmation of candidaemia and/or IC in blood or a normally sterile site ≤ 96 h before randomisation. Data were pooled for patients in the ICU at randomisation who received intravenous rezafungin (400 mg loading dose then 200 mg once weekly) or caspofungin (70 mg loading dose then 50 mg once daily) for ≤ 4 weeks. Outcomes were Day 30 all-cause mortality (primary outcome), Day 5 and 14 mycological eradication, time to negative blood culture, mortality attributable to candidaemia/invasive candidiasis, safety, and pharmacokinetics. RESULTS: Of 294 patients in STRIVE/ReSTORE, 113 were in the ICU at randomisation (rezafungin n = 46; caspofungin n = 67). At baseline, ~ 30% of patients in each group had impaired renal function and/or an Acute Physiologic Assessment and Chronic Health Evaluation II score ≥ 20. One patient (in the caspofungin group) was neutropenic at baseline. Day 30 all-cause mortality was 34.8% for rezafungin versus 25.4% for caspofungin. Day 5 and 14 mycological eradication was 78.3% and 71.7% for rezafungin versus 59.7% and 65.7% for caspofungin, respectively. Median time to negative blood culture was 18 (interquartile range, 12.6-43.0) versus 38 (interquartile range, 15.9-211.3) h for rezafungin versus caspofungin (stratified log-rank P = 0.001; nominal, not adjusted for multiplicity). Candidaemia/IC-attributable deaths occurred in two rezafungin patients versus one caspofungin patient. Safety profiles were similar between groups. Overall, 17.4% (rezafungin) versus 29.9% (caspofungin) of patients discontinued due to treatment-emergent adverse events. Rezafungin exposure following the initial 400-mg dose was comparable between patients in the ICU at randomisation (n = 50) and non-ICU patients (n = 117). CONCLUSIONS: Rezafungin was well tolerated and efficacious in critically ill, mainly non-neutropenic patients with candidaemia and/or IC. This analysis provides additional insights into the efficacy and safety of rezafungin in the ICU population.

BACKGROUND: Rezafungin, a novel, once-weekly echinocandin for the treatment of candidemia and/or invasive candidiasis (IC) was noninferior to caspofungin for day 30 all-cause mortality (ACM) and day 14 global cure in the phase 3 ReSTORE trial (NCT03667690). We conducted preplanned subgroup analyses for patients with a positive culture close to randomization in ReSTORE. METHODS: ReSTORE was a multicenter, double-blind, double-dummy, randomized trial in patients aged ≥18 years with candidemia and/or IC treated with once-weekly intravenous rezafungin (400 mg/200 mg) or once-daily intravenous caspofungin (70 mg/50 mg). This analysis comprised patients with a positive blood culture drawn between 12 hours before and 72 hours after randomization or a positive culture from another normally sterile site sampled between 48 hours before and 72 hours after randomization. Efficacy endpoints included day 30 ACM, day 14 global cure rate, and day 5 and 14 mycological response. Adverse events were evaluated. RESULTS: This analysis included 38 patients randomized to rezafungin and 46 to caspofungin. In the rezafungin and caspofungin groups, respectively, day 30 ACM was 26.3% and 21.7% (between-group difference [95% confidence interval], 4.6% [-13.7%, 23.5%]), day 14 global response was 55.3% and 50.0% (between-group difference, 5.3% [-16.1%, 26.0%]), and day 5 mycological eradication was 71.1% and 50.0% (between-group difference, 21.1% [-0.2%, 40.2%]). Safety was comparable between treatments. CONCLUSIONS: These findings support the efficacy and safety of rezafungin compared with caspofungin for the treatment of candidemia and/or IC in patients with a positive culture close to randomization, with potential early treatment benefits for rezafungin.

Patients with decreased levels of CD18 (β2 integrins) suffer from life-threatening bacterial and fungal infections. CD11b, the α subunit of integrin CR3 (CD11b/CD18, αMβ2), is essential for mice to fight against systemic Candida albicans infections. Live elongating C. albicans activates CR3 in immune cells. However, the hyphal ligands that activate CR3 are not well defined. Here, we discovered that the C. albicans Als family proteins are recognized by the I domain of CD11b in macrophages. This recognition synergizes with the β-glucan-bound lectin-like domain to activate CR3, thereby promoting Syk signaling and inflammasome activation. Dectin-2 activation serves as the outside-in signaling for CR3 activation at the entry site of incompletely sealed phagosomes, where a thick cuff of F-actin forms to strengthen the local interaction. In vitro, CD18 partially contributes to IL-1β release from dendritic cells induced by purified hyphal Als3. In vivo, Als3 is vital for C. albicans clearance in mouse kidneys. These findings uncover a novel family of ligands for the CR3 I domain that promotes fungal clearance.

Rezafungin is a long-acting, intravenously administered echinocandin for the treatment of candidemia and invasive candidiasis (IC). Non-inferiority of rezafungin vs caspofungin for the treatment of adults with candidemia and/or IC was demonstrated in the Phase 3 ReSTORE study based on the primary endpoints of day 14 global cure and 30-day all-cause mortality. Here, an analysis of ReSTORE data evaluating efficacy outcomes by baseline Candida species is described. Susceptibility testing was performed for Candida species using the Clinical and Laboratory Standards Institute reference broth microdilution method. There were 93 patients in the modified intent-to-treat population who received rezafungin; 94 received caspofungin. Baseline Candida species distribution was similar in the two treatment groups; C. albicans (occurring in 41.9% and 42.6% of patients in the rezafungin and caspofungin groups, respectively), C. glabrata (25.8% and 26.6%), and C. tropicalis (21.5% and 18.1%) were the most common pathogens. Rates of global cure and mycological eradication at day 14 and day 30 all-cause mortality by Candida species were comparable in the rezafungin and caspofungin treatment groups and did not appear to be impacted by minimal inhibitory concentration (MIC) values for either rezafungin or caspofungin. Two patients had baseline isolates with non-susceptible MIC values (both in the rezafungin group: one non-susceptible to rezafungin and one to caspofungin, classified as intermediate); both were candidemia-only patients in whom rezafungin treatment was successful based on the day 30 all-cause mortality endpoint. This analysis of ReSTORE demonstrated the efficacy of rezafungin for candidemia and IC in patients infected with a variety of Candida species.

Candida auris has become a serious threat to public health. The mechanisms of how this fungal pathogen adapts to the mammalian host are poorly understood. Here we report the rapid evolution of an adaptive C. auris multicellular aggregative morphology in the murine host during systemic infection. C. auris aggregative cells accumulate in the brain and exhibit obvious advantages over the single-celled yeast-form cells during systemic infection. Genetic mutations, specifically de novo point mutations in genes associated with cell division or budding processes, underlie the rapid evolution of this aggregative phenotype. Most mutated C. auris genes are associated with the regulation of cell wall integrity, cytokinesis, cytoskeletal properties, and cellular polarization. Moreover, the multicellular aggregates are notably more recalcitrant to the host antimicrobial peptides LL-37 and PACAP relative to the single-celled yeast-form cells. Overall, to survive in the host, C. auris can rapidly evolve a multicellular aggregative morphology via genetic mutations.

Background: The emergence of multidrug resistant Candida species to available drugs has led to renewed interest in the use of herbal medicines globally. This study scientifically verified antifungal effectiveness of five commonly used plant species in Pader district, against selected pathogenic candida strains. Methods: Powdered roots of Momordica foetida, Sansevieria dawei and Distimake dissectus; and stem barks of Khaya anthotheca and Mitragyna rubrostipulata were extracted sequentially using petroleum ether and methanol, respectively; and total water extraction at 24.4 °C (maceration), 60 °C (decoction) and boiling water at 87 °C (hot water infusion). Extracts and their combinations, positive controls (amphotericin B, and fluconazole) and negative control (80% dimethyl sulfoxide, verified to be tolerable concentration to the tested Candida species) were screened and verified for their antifungal activity against Candida albicans (ATCC: American Type Culture Collection reference strain 10231, ATCC 90028, 0770a and 0796), C. glabrata (VVc 004, ATCC 2950) and C. tropicalis (ATCC 750 and 0210) using agar well diffusion and broth micro-dilution, respectively. Results: Aqueous extract (24.4 °C) of M. rubrostipulata (ZOI: 18.00 ± 1.00 to 38.33 ± 0.17; MIC: 3.13 ± 0.00 to 20.83 ± 4.17; MFC: 12.50 ± 0.00 to 200.00 ± 0.00), methanol extract of K. anthotheca (10.11 ± 0.31 to 15.11 ± 0.65; 1.04 ± 0.26 to 12.50 ± 0.00; 12.50 ± 0.00 to 100.00 ± 0.00), and combination of aqueous extract (60 °C) of D. dissectus + methanol extract of K. anthotheca (7.89 ± 0.26 to 19.67 ± 0.37; 0.78 ± 0.00 to 50.00 ± 0.00; 12.50 ± 0.00 to 200.00 ± 0.00) exhibited broad spectrum antifungal activities and were fungistatic against all tested Candida species, which comprised 8 clinical/control and susceptible/resistant strains. None of the conventional drugs used demonstrated broad spectrum antifungal activity across all tested Candida species/strains. Conclusion: Methanol extract of K. anthotheca, aqueous extract (24.4 °C) of M. rubrostipulata, and combination of aqueous extract (60 °C) of D. dissectus + methanol extract of K. anthotheca could be effective in the treatment of candidiasis. They demonstrated potential broad spectrum antifungal activity against different species and strains of tested Candida than the fluconazole and amphotericin B drugs. Their fungistatic nature showed their ability to inhibit fungal growth. Hence, these extracts/extract combination can offer better treatment option for candidiasis if they are standardized and also their active curative compounds isolated and made into antifungal drugs. [ABSTRACT FROM AUTHOR]

ABSTRACT Pathogenic fungi must appropriately sense the host availability of essential metals such as Fe. In Candida albicans and other yeasts, sensing of Fe involves mitochondrial Fe‐S clusters. Yeast mutants for Fe‐S cluster assembly sense Fe limitation even when Fe is abundant and hyperaccumulate Fe. We observe this same disrupted Fe sensing with C. albicans mutants of SMF11, a NRAMP transporter of divalent metals. Mutants of smf11 hyperaccumulate both Mn and Fe and the elevated Mn is secondary to Fe overload. As with Fe‐S biogenesis mutants, smf11∆/∆ mutants show upregulation of ferric reductases that are normally repressed under high Fe, and Fe import is activated. However, unlike Fe‐S biogenesis mutants, smf11∆/∆ mutants show no defects in mitochondrial Fe‐S enzymes. Intriguingly, this exact condition of disrupted Fe sensing without inhibiting Fe‐S clusters occurs with C. albicans fre1∆/∆ mutants encoding a ferric reductase. Mutants of fre1 and smf11 display similar perturbations in the cell wall, in filamentation and in the ROS burst of morphogenesis, a Fe‐dependent process. As with FRE1, SMF11 is important for virulence in a mouse model for disseminated candidiasis. We propose a model in which FRE1 and SMF11 operate outside the mitochondrial Fe‐S pathway to donate ferrous Fe for Fe sensing. [ABSTRACT FROM AUTHOR]

Intorduction: Pathogens drive the evolution of host defence strategies, with both innate and adaptive immune systems playing key roles. Priming enhances the innate immune system's readiness by functionally reprogramming immune cells after initial exposure to stimuli, like β-glucans. In this sense, Drosophila melanogaster is a valuable model to evaluate the role of innate immunity to control infections. Objectives: In this study we aimed to set light on the immune priming effect of oral treatment with heat-killed M. manresensis and two different heat-killed C. albicans isolates upon systemic infection by C. albicans in the D. melanogaster model. Methods: A clinical and a control ATCC 90028 Candida albicans strain were used. Flies were primed through oral administration of heat-killed C. albicans (hkCa), both clinical and control, and hk- Mycolicibacterium manresensis. After priming, flies were systemically infected with both C. albicans isolates. Host survival, pathogen load, and immune response in response to treatment and infection were evaluated. Results: Both treatments showed a significant capacity to enhance the expression of antimicrobial peptides, in particular Diptericin, and Drosomycin in males. This response had a marked sexual dimorphism due to the difference in Upd3, Nox, and Duox expression. Surprisingly, even when priming was able to avoid the growth of both C. albicans strains, survival was not improved in the case of the clinical isolate, causing an unexpected mortality rate in hours, regardless of the host's sex. Gene expression analysis 24 hours post-infection showed an exacerbated increase in Diptericin, Drosomycin and Upd3 expression upon infection with the clinical strain. Conclusion: Data herein suggests the presence of a strain-specific component in C. albicans as the booster of a "stormy" innate immune response, which must be further investigated, and position D. melanogaster as a useful model for evaluating virulent factors related to the modulation of the innate immunity. [ABSTRACT FROM AUTHOR]

Despite the increasing morbidity and mortality associated with fungal diseases in low-income and sub-Saharan Africa countries, it is apparent that most of the fungal pathogens involved have been omitted from the dilated list of neglected and emerging tropical diseases (NETDs). Because most of these pathogens are inextricably linked with other underlying diseases such as tuberculosis and AIDS, the main fungal pathogens causing diseases viz. Pneumocyctosis and meningitis are categorized as deadly AIDS-associated opportunistic infections, and they most often coexist with tuberculosis. In addition, other infections like candidiasis, keratitis, histoplasmosis, and mycetoma often cause deforming and debilitating illnesses that affect the working class in rural communities, largely due to underlying comorbidities. Inadequate diagnostic tests prevent easy identification of the burden associated with these diseases making treatment very difficult. Likewise, the rise of resistance to most antifungal medications currently accessible in Africa is still extremely concerning, as observed in other locations. To expatiate on the destructive impact of fungal infections on the socioeconomic and health status of sub-Saharan Africa's skint populace and to improve the menace posed by these pathogens, there is a need to stop trivializing and underestimating fungal pathogens of health importance. This viewpoint is intended to revisit threats associated with neglected, emerging, and re-emerging fungal pathogens (NEFPs) in sub-Saharan Africa. As a result, information needed to prioritize strategies for the diagnosis, prevention, and control of neglected fungal pathogens and emerging superbugs will be presented. Revisiting threats and possible diagnoses associated with NEFPs could serve as a better leverage toward curbing the effects of opportunistic pathogens on individuals living with either an underlying health condition or impaired immunological status in sub-Saharan Africa/ low-income countries. Article Highlights: Structural presentation of deforming and debilitating illnesses associated with NEFPs. Reassessment of important therapeutic antibodies against NEFPs. Improved diagnostic methods for the diagnosis, prevention, and control of neglected fungal pathogens and emerging superbugs. [ABSTRACT FROM AUTHOR]

Background: Candida glabrata is the second most common cause of invasive candidiasis worldwide. In this study, we determined the clinical characteristics and drug sensitivity of C. glabrata isolates and investigated the associations between MSH2 gene mutations, sequence types (ST), and drug resistance. Methods: A total of 154 C. glabrata isolates were collected from patients being treated in three hospitals in China. The antifungal sensitivity of the strains was assessed using the broth microdilution method. Multilocus sequence typing (MLST) was also performed, followed by MSH2 sequencing. The clinical features and outcomes of C. glabrata infection were analysed for a total of 49 strains, which were collected from patients with invasive Candida infection at Longhua Hospital. Results: All 154 isolates were found to be susceptible to amphotericin, 5-fluorocytosine, anidulafungin, caspofungin, and micafungin, whereas 11.7% were fluconazole-resistant, 18.8% were itraconazole non-wild type, and 35.7% were voriconazole non-wild type. ST7 (62.34%) was the most common ST genotype, followed by ST10 (16.88%) and ST15 (7.79%). The total azole resistance rates for all isolates, ST7, ST10, and other STs were 36.4, 42.7, 34.6, and 18.8%, respectively. The ST7 and ST10 isolates were characterised by a higher drug resistance rate than the other minor ST isolates. Moreover, 59.09% of isolates had one or more MSH2 non-synonymous mutations, with V239L being the most commonly detected mutation. The frequency of MSH2 mutations was significantly higher in azole-resistant isolates than in other isolates, whereas P6L or L87P mutations were associated with the highest azole resistance rates of up to 87.5% and 80%, respectively. Our results indicated that ST7 and ST15 are independent predictors of mortality caused by C. glabrata infection and revealed a higher 30-day mortality in patients infected with these strains than in those infected with other ST isolates. Conclusions: Our findings revealed the relationships between MLST, MSH2 gene mutations, and drug resistance in the common pathogenic fungus C. glabrata, and thereby enabled us to identify strains that are associated with higher rates of mortality. These findings will contribute to enhancing our understanding of the pathogenesis of C. glabrata infection. [ABSTRACT FROM AUTHOR]

Background Outpatient parenteral antimicrobial therapy (OPAT) can deliver extended parenteral treatment of fungal infections in an ambulatory setting, whilst minimizing treatment burden and cost. The extended dosing interval of rezafungin may potentiate the benefits of OPAT. Methods This retrospective cohort study includes all adult patients who received echinocandin therapy in a large OPAT programme between 2012 and 2022. Patient characteristics, treatment and outcomes were studied. Data were analysed to determine the effects of replacing daily dosing with weekly dosing of echinocandin. Results Across the study period, 11% (44/386) of all patients in our Health Service treated with ≥7 days of echinocandin were managed via OPAT. All were Candida and related 'yeast-like' species infections. Nakaseomyces glabrata (20/41; 49%) was the most common pathogen, fungaemia the most common presentation (17/41; 41%) and azole resistance the most frequent indication for echinocandin use (21/41; 51%). In total, 633 days of echinocandin were administered as OPAT. Thirteen patients (13/41; 32%) received concurrent parenteral antibacterials. Treatment success was achieved in 30/41 (73%) patients. If daily echinocandin dosing was replaced with weekly dosing, a potential 52% (633 to 326) reduction in the total number of treatments (for any therapy) delivered by the OPAT team is possible. The ongoing need for daily antibacterial administration mitigated the benefit in some of this cohort. Conclusions Echinocandin therapy can be safely delivered via OPAT with outcomes equivalent to bed-based care. The extended dosing interval of rezafungin will allow for a substantial reduction in the number of treatments required across the patient cohort. [ABSTRACT FROM AUTHOR]

Background: Globally, sexually transmitted infections (STIs) collectively cause 2.3 million deaths and 1.2 million cases of cancer annually. However, the epidemiology of STIs in the Middle East and North Africa (MENA) is not well assessed because of various social and cultural factors. Methods: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and covering 23 MENA countries, 19 STIs, and data from 20,435,971 participants. PubMed, Embase, regional and international databases, and country-level reports were searched up to May 2024. Results: The analysis revealed significant regional variations in the prevalence of STIs within the MENA region. In North Africa, the most common STIs were bacterial vaginosis (31%), human papillomavirus (HPV, 23%), and Candida spp. (15%). In the Gulf Cooperation Council region and Yemen, Ureaplasma (25%), nongonococcal urethritis (NGU, 16%), and Mycoplasma spp. (12%) were the predominant infections. In the Levant region, the top STIs were HPV (20%), hepatitis B virus (HBV, 9%), and Candida spp. (9%). In Iran, Ureaplasma spp. (18%), HPV (17%), and cytomegalovirus (8%) were the most prevalent infections, whereas Ureaplasma spp. (20%), Candida spp. (18%), and HPV (16%) were most frequently detected in Türkiye. Gender-based disparities were observed, with a higher prevalence of Ureaplasma spp., Neisseria gonorrhoeae, and herpes in men and higher rates of Mycoplasma spp., HPV, HBV, and Candida spp. in women. Overall, high rates of nongonococcal urethritis (16.3%), Ureaplasma spp. (13.7%), HPV (12.7%), and Candida spp. (9.4%) were recorded in the MENA region. Conclusions: Most MENA countries lack national STI screening programs, and the reported data are primarily from symptomatic individuals. Establishing robust surveillance systems, addressing stigma and barriers to healthcare access, and expanding STIs screening and vaccination programs are crucial for accurately capturing the true burden of STIs in MENA countries. [ABSTRACT FROM AUTHOR]