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We evaluated the in vitro activity of olorofim against Coccidioides species. Olorofim demonstrated potent in vitro activity against all isolates tested with a minimum inhibitory concentration (MIC) range ≤0.008-0.06 µg/mL and geometric mean MIC of 0.010 µg/mL. This activity was also maintained against isolates with elevated fluconazole MICs (≥16 µg/mL), including strains with MICs ≥32 µg/mL (olorofim MIC range ≤0.008-0.06 µg/mL and geometric mean MICs of ≤0.009 and ≤0.013 µg/mL, respectively)., Competing Interests: This study and olorofim powder were provided by F2G, Ltd. N.P.W. has received research support to the UT Health San Antonio from bioMerieux, F2G, Mycovia, Sfunga, and Scynexis and has served on an advisory board for F2G. G.R.T. has served as a consultant and received research support from Astellas, Amplyx, Cidara, F2G, Mayne, Melinta, Mundipharma, Scynexis, and the DSMB for Pfizer. T.F.P. has served as a consultant and/or received research support from Cidara, F2G, Gilead, Scynexis, and Elion Therapeutics.

Infusion reactions (tachycardia, hypertension, fever, etc.) associated with liposomal amphotericin B are common. Animal models have found complement activation responsible, yet the pathophysiology has not been evaluated in human patients. We performed a prospective observational study and found complement activation-related pseudoallergy (CARPA) responsible in those with infusion reactions.

Background: Patients with pulmonary coccidioidomycosis often experience prolonged symptoms lasting weeks to months. Limited data exist regarding whether fluconazole prevents development of disseminated disease or shortens symptom duration. We describe factors associated with fluconazole receipt and assess its effect on outcomes among patients with pulmonary coccidioidomycosis., Methods: Using the MerativeTM MarketScan® Commercial Database, we identified immunocompetent patients ages 18-64 with incident pulmonary coccidioidomycosis during 2017-2023 and continuous enrollment in the 180 days before and after diagnosis. We examined demographic and clinical differences between patients treated vs. not treated with fluconazole and performed 1:1 greedy nearest neighbor propensity score matching to control for these differences. We performed bivariate analyses on the matched subset to evaluate patient outcomes by fluconazole receipt., Results: Among 1,448 patients with pulmonary coccidioidomycosis, 659 (46%) received fluconazole. Patients who received fluconazole more frequently had pre-diagnosis symptoms (95% vs. 72%, p<0.001) and antibiotic prescriptions (68% vs. 32%, p<0.001) than those who did not. Among the propensity score matched subset (n=696), hospitalization (4% vs. 1%, p=0.004) and disseminated coccidioidomycosis (3% vs. 0%, p=0.006) were more frequent among patients who received fluconazole. The median number of days from diagnosis to last visit for chest pain (50.0 vs. 46.5), cough (64.0 vs. 39.0), fatigue (63.0 vs. 65.5), myalgia (98.0 vs. 74.0), and joint pain (93.5 vs. 107.5) was not significantly different between treatment groups., Conclusions: Our results support existing guidelines that fluconazole may not be associated with improved outcomes for certain immunocompetent patients with pulmonary coccidioidomycosis., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2025.)

Background: Coccidioidomycosis (Valley Fever) is a dimorphic fungal infection endemic to the southwest United States, Mexico, Central and South America, which can lead to chronic debilitating illness and death., Objectives: This qualitative study was conducted to develop a bespoke patient-reported outcome measure for patients with chronic disseminated coccidioidomycosis to assess health-related quality of life (HRQoL) impacts., Patients and Methods: Online, first-person narratives of patient experiences of disseminated coccidioidomycosis were used to create a patient-centred conceptual model of symptoms and impacts of the condition. Interviews were conducted with expert clinicians, followed by concept elicitation interviews with patients, to generate key symptom and impact concepts from which an initial patient-reported outcome measure was developed. The draft measure was reviewed with clinicians for clinical relevance and further assessed in cognitive debriefing interviews with patients to refine the measure and establish content validity., Results: A total of 25 patients were interviewed, which identified impacts relating to physical function, activities of daily living, cognitive function, social/role function and emotional function of disseminated coccidioidomycosis. Twenty items were developed simultaneously in English and Spanish to capture the main impacts across these 5 areas. In general, items were clear and well understood by patients, and clinicians found the measure clinically relevant and appropriate for assessing the burden of disseminated coccidioidomycosis on HRQoL., Conclusions: Once fully validated, the Valley Fever-Patient Reported Outcome measure may be used in interventional studies to assess HRQoL outcomes, and in clinical practice to monitor patients' HRQoL., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Coccidioidomycosis, caused by the dimorphic fungi Coccidioides immitis and Coccidioides posadasii, is recognized as an increasing threat both nationally and worldwide. This is in large part secondary to the expanding range of Coccidioides species and increased international travel to endemic regions. Most individuals exposed to airborne Coccidioides organisms do not need medical attention, but approximately 30% will demonstrate primary pulmonary coccidioidomycosis with signs and symptoms that mimic community-acquired pneumonia or other respiratory illnesses. Further, 5% of those with a diagnosis of pulmonary coccidioidomycosis will demonstrate serious and even life-threatening manifestations, including extrapulmonary or disseminated coccidioidomycosis. Of those who demonstrate pulmonary coccidioidomycosis, past evidence suggests that approximately 5% to 15% will experience long-term pulmonary sequelae in the form of nodules, abscesses, or cavitary lesions. These lesions may not be easily distinguished from malignancy or other infections, such as TB, and they add a substantial burden to both patients and the health care system. Despite the long-term consequences of cavitary coccidioidomycosis in some individuals, the current literature review and practice guidelines demonstrate a paucity of clear management strategies to treat these patients. In this report, we focus on cavitary lesions in coccidioidomycosis with the goal of presenting a description of the evaluation and management of their various forms, manifestations, and complications. These recommendations are derived from a multidisciplinary group of experts., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

The taxonomy of the Cryptococcus gattii species complex continues to evolve, and has been divided into five pathogenic species. The objective of this systematic review was to summarise the geographical distribution of the C gattii species complex and the species within the C gattii species complex. We searched PubMed for articles related to human, animal, ecological, or laboratory-based studies of C gattii species complex isolates with traceable geographical origin published from January, 1970, until September, 2021. Having extracted their geographical origin, we used ArcMap to construct maps according to the highest degree of resolution allowed by their reported taxonomy, to reflect the most likely area of transmission on the basis of published reports of human isolates. 604 such articles were included in the study. This review indicated that although C gattii species complex isolates have been reported globally, understanding their heterogeneous geographical distribution by species can have implications for researchers and clinicians in formulating research questions and considering diagnostic quandaries., Competing Interests: Declaration of interests FH is the Vice President of the International Society for Human and Animal Mycology, treasurer of the Netherlands Society for Medical Mycology, chair of the Royal Netherlands Society for Microbiology, Microbial Genomic Division, and received molecular diagnostic kits from Bruker Molecular Diagnostics. NCB was the Data and Safety Monitoring Board chair for NCT04335123. All other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Despite the availability of multiple classes of lipoprotein-lowering medications, some high-risk patients have persistent hypercholesterolemia and may require nonpharmacologic therapy. Lipoprotein apheresis (LA) is a valuable but underused adjunctive therapeutic option for low-density lipoprotein cholesterol and lipoprotein(a) lowering, particularly in children and adults with familial hypercholesterolemia. In addition to lipid lowering, LA reduces serum levels of proinflammatory and prothrombotic factors, reduces blood viscosity, increases microvascular myocardial perfusion, and may provide beneficial effects on endothelial function. Multiple observational studies demonstrate strong evidence for improved cardiovascular outcomes with LA; however, use in the United States is limited to a fraction of its Food and Drug Administration-approved indications. In addition, there are limited data regarding LA benefit for refractory focal segmental glomerulosclerosis. In this scientific statement, we review the history of LA, mechanisms of action, cardiovascular and renal outcomes data, indications, and options for treatment.

Coccidioidomycosis is the clinical disease caused by the dimorphic pathogenic fungi Coccidioides immitis and C posadasii. The number of clinically recognized coccidioidomycosis cases continues to increase yearly including in regions outside the traditional regions of endemicity. Following inhalation of Coccidioides spores, the course may range from asymptomatic exposure with resultant immunity, to a subacute pulmonary illness, to life-threatening disseminated infection. This review will summarize recent advances in our understanding of the infection and will include the ecology of Coccidioides, epidemiology and risk factors for infection, vaccine and novel antifungals in development, and management of immunosuppressed patients., Competing Interests: Disclosure N.M. Ampel has no conflicts of interest. F. M. Donovan has received research support from F2G, United Kingdom. G.R. Thompson has served as a consultant and received research support from Astellas, United States, Basilea, Cidara, United States, F2G, GSK, Melinta, Mundipharma, Germany, and Scynexis., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Invasive candidiasis/candidemia (IC/C) is associated with a substantial health economic burden driven primarily by prolonged hospital stay. The once-weekly IV echinocandin, rezafungin acetate, has demonstrated non-inferiority to caspofungin in the treatment of IC/C. This paper reports a post hoc pooled exploratory analysis of length of stay (LoS) for hospital and intensive care unit (ICU) stays in two previously published clinical trials (ReSTORE [NCT03667690] and STRIVE [NCT02734862], that compared rezafungin with daily IV caspofungin (stable patients in the caspofungin group who met relevant criteria could step down to fluconazole after 3 days or more)., Methods: LoS outcomes were analysed descriptively in the pooled modified intention to treat (mITT) population (all patients who had a documented Candida infection in line with trial requirements and received at least one dose of study drug). In addition, to adjust for an imbalance between treatment groups in the proportion receiving mechanical ventilation at baseline, a generalised linear model with mechanical ventilation as a binary covariate was applied. Responses to an exploratory question in the phase 3 trial on possible earlier discharge with weekly rezafungin are also reported., Results: 294 patients were included (rezafungin 139, caspofungin 155), of whom 126 (43%) had ICU admission. Patients treated with rezafungin had a numerically shorter LoS than with caspofungin in all analyses. Mean total LoS was 25.2 days, vs 28.3 days with caspofungin, and mean ICU LoS was 16.1 vs 21.6 days for rezafungin and caspofungin, respectively. After adjustment for mechanical ventilation status the difference in ICU LoS was 4.1 days, a relative difference of 24% (95% CI -11%, 72%). Physicians would have considered earlier discharge for 16% of patients (30/187) with weekly rezafungin, an average of 5-6 days earlier., Conclusions: Rezafungin may enable shorter hospital and ICU LoS in IC/C compared with daily IV caspofungin, with accompanying savings in resource use. Further research is needed to confirm this in the real-world setting., Trial Registration: NCT03667690 (ReSTORE; September 12, 2018); NCT02734862 (STRIVE; April 12, 2016)., Competing Interests: Declarations Data and availability of materials Data supporting the findings of this study are available on request from Sara Dickerson, Sara.Dickerson@mundipharma.com. Ethics approval and consent to participate Both the STRIVE and ReSTORE trials were in conducted in accordance with current country and local regulations, the International Conference on Harmonisation Good Clinical Practice, and the Declaration of Helsinki. Ethics committees or institutional review boards at participating sites approved the protocols and all amendments. All patients, or their legally authorised representative, provided written informed consent. Consent for publication Not applicable. Competing interests PMH reports grants or contracts from Baxter, Cytosorbents, and Pfizer; consulting fees from Baxter, Cytosorbents, and Pfizer; honoraria from Baxter, and Cytosorbents; and support for attending meetings from Mundipharma, and Pfizer, outside of the submitted work. MB reports honoraria from and membership of data safety monitoring board or advisory board for Angelini, Cidara, Gilead, Menarini, MSD, Pfizer, and Shionogi, outside of the submitted work. OAC reports grants or contracts from Amplyx, Basilea, Bundesministerium für Bildung und Forschung, Cidara, German Center for Infection Research, European Union Directorate-General for Research and Innovation (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, and Scynexis; consulting fees from AbbVie, Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, IQVIA, Janssen, Matinas, MedPace, Menarini, Molecular Partners, Noxxon, Octapharma, Pardes, Pfizer, Pharma Support America, Scynexis, and Seres; honoraria from Abbott, AbbVie, Al-Jazeera Pharmaceuticals, Astellas, Gilead, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, Merck/MSD, Mylan, Noscendo, Pfizer, and Shionogi; payment for expert testimony from Cidara; data safety monitoring board or advisory board membership for Actelion, Allecra, Cidara, Entasis, IQVIA, Janssen, MedPace, Paratek, Pharma Support America, Pulmocide, Shionogi, and The Prime Meridian Group; a patent at the German Patent and Trade Mark Office (DE 10 2021 113 007.7); stocks from CoRe Consulting; outside of the submitted work. HD reports consulting fees from Pfizer, Gilead, MSD, Mundipharma, Shionogi, Viatris, outside of the submitted work. JF was an advisor/consultant and received grant support and honoraria for talks on behalf of Astellas Pharma, Gilead Sciences, Merck Sharp & Dohme and Pfizer, outside of the submitted work. MK reports grants from Barnes-Jewish Hospital Foundation and consulting fees from Merck, Pfizer, and Shionogi, outside of the submitted work. PP reports grants from Astellas, Gilead, Scynexis, and Cidara; fees for scientific advisory board from F2G, Matinas, TFF, Basilea outside of the submitted work. JP Reports no conflict of interest. JV reports consulting fees from and membership of data safety monitoring board or advisory board for F2G and consulting fees from Cidara and Scynexis, outside of the submitted work. IB and NM report being employees of Mundipharma. TS reports being an employee of and holding stocks in Cidara Therapeutics. GRT reports grants and consulting fees from Amplyx, Astellas, Cidara, F2G, and Manye; grants from Merck; and data safety monitoring board membership for Pfizer, outside of the submitted work., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

Competing Interests: Potential conflicts of interest. J. W. B. reports payments from Up-to-Date for serving as an author or editor for sections on histoplasmosis. P. G. P. reports institutional support from Cidara, Amplyx, Pfizer, F2G, Mayne Pharmaceuticals, Merck & Co., Inc, and Astellas and personal payments for participation on a Data Safety Monitoring Board or Advisory Board from F2G, Matinas, and Cidara. G. R. T. III reports support (grants or contracts) from Cidara, Amplyx, Pfizer, F2G, Mayne Pharmaceuticals, and Merck & Co., Inc. L. A. T. reports grants from BMS and Novartis for a skin cancer health equity project in farmworker communities. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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., Competing Interests: Potential conflicts of interest. A. S.: grants from Pfizer and Gilead and honoraria for lectures and advisory boards from Pfizer, MSD, Shionogi, Angelini, and Menarini. P. M. H.: grants or contracts from Baxter, Cytosorbents, and Pfizer; consulting fees from Baxter, Cytosorbents, and Pfizer; honoraria from Baxter and Cytosorbents; and support for attending meetings from Mundipharma and Pfizer, outside of the submitted work. O. A. C.: grants or contracts from Cidara, F2G, Gilead, MedPace, MSD, Mundipharma, Pfizer, and Scynexis; consulting fees from AbbVie, AiCuris, Cidara, Gilead, IQVIA, Matinas, MedPace, Pfizer, PSI, and Scynexis; honoraria for lectures from Abbott, AbbVie, Al-Jazeera Pharmaceuticals/Hikma, Gilead, Grupo Biotoscana/United Medical/Knight, Medscape, medupdate, Merck/MSD, Noscendo, Pfizer, and Shionogi; payment for expert testimony from Cidara; participation on a Data and Safety Monitoring Board or advisory board from Cidara, IQVIA, Janssen, Medpace, PSI, Pulmocide, and Shionogi. M. C.: research funding from F2G, Cidara, Shionogi, Pfizer, AstraZeneca, and Janssen, and served as a speaker and advisory board membership for Gilead, Pfizer, and MSD. M. B.: consulting fees and payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from MSD, Pfizer, Menarini, Shionogi, Angelini, and Gilead; and Data and Safety Monitoring Board or advisory board participation for Cidara and Mundipharma. H. D.: fees from Mundipharma for serving on expert boards and conferences. M. K.: funding from the Barnes-Jewish Hospital Foundation. B. J. K.: served on the independent data review committee for Cidara. N. M.: is an employee of Mundipharma Research Ltd. P. P.: grants from and data review committee membership for Cidara and Melinta; grants from Astellas, Scynexis, and Merck; and advisory board membership for F2G and Matinas. T. S.: employee and shareholder of Cidara Therapeutics. J. A. V.: research and consulting for Astellas, Amplyx, Cidara, F2G, Melinta, and Scynexis and served on the Data and Safety Monitoring Board for F2G. G. R. T.: research and consulting for Astellas, Amplyx, Cidara, F2G, Mayne, Melinta, Mundipharma, and Scynexis and served on the Data and Safety Monitoring Board for Pfizer. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Respiratory fungal infections pose a significant threat to human health. Animal models do not fully recapitulate human disease, necessitating advanced models to study human-fungal pathogen interactions. In this study, we utilized primary human airway epithelial cells (hAECs) to recapitulate the lung environment in vitro and investigate cellular responses to two diverse, clinically significant fungal pathogens, Aspergillus fumigatus and Coccidioides posadasii . To understand the mechanisms of early pathogenesis for both fungi, we performed single-cell RNA sequencing of infected hAECs. Analysis revealed that both fungi induced cellular stress and cytokine production. However, the cell subtypes affected and specific pathways differed between fungi, with A. fumigatus and C. posadasii triggering protein-folding-related stress in ciliated cells and hypoxia responses in secretory cells, respectively. This study represents one of the first reports of single-cell transcriptional analysis of hAECs infected with either A. fumigatus or C. posadasii , providing a vital dataset to dissect the mechanism of disease and potentially identify targetable pathways.

Global epidemiological data show that the incidence of invasive fungal disease (IFD) has increased in recent decades, with the rising frequency of infections caused by Aspergillus and Mucorales order species. The number and variety of patients at risk of IFD has also expanded, owing in part to advances in the treatment of hematologic malignancies and other serious diseases, including hematopoietic stem cell transplantation (HCT) and other therapies causing immune suppression. Isavuconazonium sulfate (active moiety: isavuconazole) is an advanced-generation triazole antifungal approved for the treatment of invasive aspergillosis and mucormycosis that has demonstrated activity against a variety of yeasts, moulds, and dimorphic fungi. While real-world clinical experience with isavuconazole is sparse in some geographic regions, it has been shown to be effective and well tolerated in diverse patient populations, including those with multiple comorbidities who may have failed to respond to prior triazole antifungal therapy. Isavuconazole may be suitable for patients with IFD receiving concurrent QTc-prolonging therapy, as well as those on venetoclax or ruxolitinib. Data from clinical trials are not available to support the use of isavuconazole prophylactically for the prevention of IFD or for the treatment of endemic IFD, such as those caused by Histoplasma spp., but real-world evidence from case studies suggests that it has clinical utility in these settings. Isavuconazole is an option for patients at risk of IFD, particularly when the use of alternative antifungal therapies is not possible because of toxicities, pharmacokinetics, or drug interactions., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Microbial cell-free DNA (mcfDNA) sequencing is a promising tool to identify infectious pathogens when traditional methods fail to identify the causative agent. We performed a retrospective observational cohort study to evaluate clinical outcomes among pediatric and adult patients who underwent mcfDNA testing. 127 mcfDNA tests were reviewed from 112 patients. Baseline characteristics included 61 (54.5 %) adults, 52 (40.9 %) tests were from female patients, and 67 (52.8 %) tests were obtained from patients designated as immunocompromised. Of all tests obtained, 59 (46.4 %) were deemed clinically relevant. 41 (32.3 %) of tests also led to a change in antimicrobial management for the corresponding patient. No statistically significant association was ascertained between patient-specific factors and clinically relevant test results. Testing in certain clinical scenarios or high-risk settings may be useful, however further studies are needed to assess the cost-benefit of this approach., Competing Interests: Declaration of competing interest The authors declare there are no competing interests, (Copyright © 2024. Published by Elsevier Inc.)

The triazole antifungals posaconazole and itraconazole can cause pseudohyperaldosteronism with hypertension and hypokalemia, edema, and gynecomastia by inhibiting steroid synthesis and metabolism. Mechanisms underlying pseudohyperaldosteronism include inhibition of adrenal 11β-hydroxylase cytochrome-P450 (CYP) 11B1 and 17α-hydroxylase (CYP17A1) as well as peripherally expressed 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). To enhance specificity for fungal CYP51, tetrazoles have been developed. This study employed H295R adrenocortical cells and enzyme activity assays to assess the potential risk of oteseconazole and two other tetrazoles, VT-1598 and quilseconazole, to inhibit adrenal steroidogenesis or 11β-HSD2. Steroidomic footprint analyses of H295R cell supernatants using untargeted liquid-chromatography-high-resolution mass-spectrometry (LC-HRMS) indicated overall patterns common to oteseconazole, quilseconazole and itraconazole, as well as similarities between VT-1598 and isavuconazole. Additionally, more specific features of the steroid signatures were observed. Targeted quantification of nine adrenal steroids in supernatants from treated H295R cells revealed an overall inhibition of adrenal steroidogenesis by the three tetrazoles, itraconazole and isavuconazole, providing an explanation for their similar steroidomic pattern. Applying recombinant enzymes indicated that this effect is not due to direct inhibition of steroidogenic enzymes because no or only weak inhibition could be observed. Moreover, oteseconazole and the two other tetrazoles did not inhibit 11β-HSD2, suggesting that they do not pose a risk of pseudohyperaldosteronism. Furthermore, oteseconazole did not alter steroid concentrations in a recent clinical study. Nevertheless, follow-up studies should assess the mechanism underlying the observed overall steroidogenesis inhibition by tetrazoles, itraconazole and isavuconazole, and whether concentrations achievable in a subgroup of susceptible patients might cause adrenal insufficiency and hyperplasia., Competing Interests: Authors TD and SB were employed by the Mycovia Pharmaceuticals Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jäger, González-Ruiz, Joos, Winter, Boccard, Degenhardt, Brand, Rudaz, Thompson and Odermatt.)

Introduction: Ibrexafungerp is a new triterpenoid antifungal agent with activity against a variety of fungal species, including Aspergillus spp. and echinocandin-resistant Candida spp., Areas Covered: This evaluation will summarize currently available clinical evidence on the use of ibrexafungerp in the treatment/prevention of vulvovaginal candidiasis (VVC) and detail the mechanism of action, pharmacokinetic/pharmacodynamic parameters, and ongoing/latest research involving ibrexafungerp., Expert Opinion: The evidence involving the utilization of ibrexafungerp for the treatment of VVC shows that it is superior when compared to placebo and has comparable clinical cure rates when compared with fluconazole. Ibrexafungerp demonstrates reliable coverage against several Candida spp. including echinocandin-resistant strains, Candida auris , and Aspergillus spp. For VVC, a dose of 300 mg (two 150 mg tablets) twice daily is recommended and does not require dose adjustments based on renal or hepatic function. The use of ibrexafungerp outside of VVC is currently under study with several ongoing trials showing promising interim data.

Antibiotic treatment promotes the outgrowth of intestinal Candida albicans, but the mechanisms driving this fungal bloom remain incompletely understood. We identify oxygen as a resource required for post-antibiotic C. albicans expansion. C. albicans depleted simple sugars in the ceca of gnotobiotic mice but required oxygen to grow on these resources in vitro, pointing to anaerobiosis as a potential factor limiting growth in the gut. Clostridia species limit oxygen availability in the large intestine by producing butyrate, which activates peroxisome proliferator-activated receptor gamma (PPAR-γ) signaling to maintain epithelial hypoxia. Streptomycin treatment depleted Clostridia-derived butyrate to increase epithelial oxygenation, but the PPAR-γ agonist 5-aminosalicylic acid (5-ASA) functionally replaced Clostridia species to restore epithelial hypoxia and colonization resistance against C. albicans. Additionally, probiotic Escherichia coli required oxygen respiration to prevent a post-antibiotic bloom of C. albicans, further supporting the role of oxygen in colonization resistance. We conclude that limited access to oxygen maintains colonization resistance against C. albicans., Competing Interests: Declaration of interests G.R.T. is consulting for Astellas, Cidara, F2G, Immy, Mayne, Melinta, Mundipharma, Scynexis, and Pfizer on projects that are not related to this publication. G.R.T. receives research support from Astellas, Cidara, F2G, Mayne, Melinta, Merck, Mundipharma, Scynexis, and Pfizer for projects that are not related to this publication., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Public health officials are responding to an outbreak of fungal meningitis among patients who received procedures under epidural anesthesia at 2 clinics (River Side Surgical Center and Clinica K-3) in Matamoros, Mexico, during 1 January to 13 May 2023. This report describes outbreak epidemiology and outlines interim diagnostic and treatment recommendations., Methods: Interim recommendations for diagnosis and management were developed by the Mycoses Study Group Research Education and Consortium (MSGERC) based on the clinical experience of clinicians caring for patients during the current outbreak or during previous outbreaks of healthcare-associated fungal meningitis in Durango, Mexico, and the United States., Results: As of 7 July 2023, the situation has evolved into a multistate and multinational fungal meningitis outbreak. A total of 185 residents in 22 US states and jurisdictions have been identified who might be at risk of fungal meningitis because they received epidural anesthesia at the clinics of interest in 2023. Among these patients, 11 suspected, 10 probable, and 10 confirmed US cases have been diagnosed, with severe vascular complications and 8 deaths occurring. Fusarium solani species complex has been identified as the causative agent, with antifungal susceptibility testing of a single isolate demonstrating poor in vitro activity for most available antifungals. Currently, triple therapy with intravenous voriconazole, liposomal amphotericin B, and fosmanogepix is recommended., Conclusions: Efforts to understand the source of this outbreak and optimal treatment approaches are ongoing, but infectious diseases physicians should be aware of available treatment recommendations. New information will be available on the Centers for Disease Control and Prevention's (CDC's) website., Competing Interests: Potential conflicts of interest. L. O.-Z. is the president of the MSG-ERC, Vice-President of ICHS, and has received research funding, consulting and/or speaking honoraria from the following entities: Scynexis, Pulmocide, Gilead, Astellas, NIH, Pfizer, T2 biosystems, F2G, GSK, Melinta, Viracor, and Cidara. P. G. P. has received research funding from F2G, Cidara, CDC, Astellas, Melinta, Gilead, Mayne, Scynexis, participated on Data Safety Monitoring or Advisory Board for Melinta, Matinas, Cidara, and Scynexis; and serves as a consultant for Melinta, F2G, Matinas, and Scynexis. T. F. P. has served as a consultant, on data safety monitoring/data review committees, on a Scientific Advisory Board, or received research support from: Cidara, F2G, Gilead, Scynexis, and Sfunga, outside of the submitted work and royalties from Wolters Klower. A. N. M. serves as a consultant to the Michigan Department of Health & Human Services and is a shareholder of Pfizer pharmaceuticals. N. P. W. has received research support from bioMerieux, Bruker, F2G, Maxwell Biosciences, Mycovia, Scynexis, and Sfunga; payment or honoraria for speaking or educational events and travel support from American Society for Microbiology; a leadership or fiduciary role at Clinical and Laboratory Standards Institute; receipt of antifungal powders from F2G, Pfizer, and Scynexis; and has served as a consultant for F2G. G. R. T. reports grants or contracts and consulting fees from Astellas, Cidara, F2G, Mayne, Mundipharma, and Melinta; and participation on a Data Safety Monitoring or Advisory Board for Pfizer. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Coccidioidomycosis, histoplasmosis, and blastomycosis are underrecognized and frequently misdiagnosed fungal infections that can clinically resemble bacterial and viral community-acquired pneumonia. This guidance is intended to help outpatient clinicians test for these fungal diseases in patients with community-acquired pneumonia to reduce misdiagnoses, unnecessary antibacterial use, and poor outcomes., Competing Interests: Potential conflicts of interest. J. W. B. reports payments from Up-to-Date for serving as an author or editor for sections on histoplasmosis. P. G. P. reports institutional support from Cidara, Amplyx, Pfizer, F2G, Mayne Pharmaceuticals, Merck & Co., Inc, and Astellas and personal payments for participation on a Data Safety Monitoring Board or Advisory Board from F2G, Matinas, and Cidara. G. R. T. III reports support from Cidara, Amplyx, Pfizer, F2G, Mayne Pharmaceuticals, and Merck & Co., Inc. L. A. T. reports grants from BMS and Novartis for a skin cancer health equity project in farmworker communities. All other authors report no potential conflicts. All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. This activity was reviewed by the Centers for Disease Control and Prevention and was conducted consistent with applicable federal law and Centers for Disease Control and Prevention policy; see for example, 45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. §241(d); 5 U.S.C. §552a; 44 U.S.C. §3501 et seq., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

SUMMARYFungal infections are on the rise, driven by a growing population at risk and climate change. Currently available antifungals include only five classes, and their utility and efficacy in antifungal treatment are limited by one or more of innate or acquired resistance in some fungi, poor penetration into "sequestered" sites, and agent-specific side effect which require frequent patient reassessment and monitoring. Agents with novel mechanisms, favorable pharmacokinetic (PK) profiles including good oral bioavailability, and fungicidal mechanism(s) are urgently needed. Here, we provide a comprehensive review of novel antifungal agents, with both improved known mechanisms of actions and new antifungal classes, currently in clinical development for treating invasive yeast, mold (filamentous fungi), Pneumocystis jirovecii infections, and dimorphic fungi (endemic mycoses). We further focus on inhaled antifungals and the role of immunotherapy in tackling fungal infections, and the specific PK/pharmacodynamic profiles, tissue distributions as well as drug-drug interactions of novel antifungals. Finally, we review antifungal resistance mechanisms, the role of use of antifungal pesticides in agriculture as drivers of drug resistance, and detail detection methods for antifungal resistance.

The effects of climate change and natural disasters on fungal pathogens and the risks for fungal diseases remain incompletely understood. In this literature review, we examined how fungi are adapting to an increase in the Earth's temperature and are becoming more thermotolerant, which is enhancing fungal fitness and virulence. Climate change is creating conditions conducive to the emergence of new fungal pathogens and is priming fungi to adapt to previously inhospitable environments, such as polluted habitats and urban areas, leading to the geographical spread of some fungi to traditionally non-endemic areas. Climate change is also contributing to increases in the frequency and severity of natural disasters, which can trigger outbreaks of fungal diseases and increase the spread of fungal pathogens. The populations mostly affected are the socially vulnerable. More awareness, research, funding, and policies on the part of key stakeholders are needed to mitigate the effects of climate change and disaster-related fungal diseases., Competing Interests: Declaration of interests DS received speaker fees from Pfizer and Hikma Pharmaceuticals, all outside of the submitted work. AC is a Fellow of the CIFAR Program Fungal Kingdom: Threats & Opportunities. JDJ received research funding from Astellas, F2G, and Pfizer, all outside of the submitted work. J-PG received speaker fees and travel support from Gilead, Mundipharma, Pfizer, and Shionogi, all outside of the submitted work. RS received speaker fees from Akademie für Infektionsmedizin, Hikma, and Pfizer, and travel support from Pfizer, all outside of the submitted work. OC reports grants or contracts from Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, and Scynexis; consulting fees from AbbVie, Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, IQVIA, Janssen, Matinas, MedPace, Menarini, Molecular Partners, MSG-ERC, Noxxon, Octapharma, Pfizer, PSI, Scynexis, and Seres; honoraria for lectures from Abbott, AbbVie, Al-Jazeera Pharmaceuticals, Astellas, Gilead, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, Merck/MSD, Mylan, Noscendo, Pfizer, and Shionogi; payment for expert testimony from Cidara; participation on a Data Safety Monitoring Board (DSMB) or Advisory Board from Actelion, Allecra, Cidara, Entasis, IQVIA, Janssen, MedPace, Paratek, PSI, Pulmocide, Shionogi, and The Prime Meridian Group; a patent at the German Patent and Trade Mark Office (DE 10 2021 113 007.7); stocks from CoRe Consulting, and EasyRadiology; and other interests from DGHO, DGI, ECMM, EHA, ISHAM, MSG-ERC, and Wiley. GRT received research and consulting fees from Astellas, Amplyx, Cidara, F2G, Mayne, Melinta, Mundipharma, and Scynexis and served on the DSMB for Pfizer, all outside of the submitted work. MH received research funding from Gilead, Astellas, MSD, IMMY, Mundipharma, Scynexis, F2G, and Pfizer, all outside of the submitted work. DPK received honoraria and research support from Gilead Sciences and Astellas Pharma; received consultant fees from Astellas Pharma, MSD, and Gilead Sciences; and is a member of the Data Review Committee of Cidara Therapeutics, AbbVie, Scynexis, and the Mycoses Study Group, all unrelated to the submitted work. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: During the early stages of the coronavirus disease 2019 (COVID-19) pandemic, those with severe COVID-19 infection were at risk for a number of opportunistic infections including COVID-19-associated pulmonary aspergillosis (CAPA). We initiated a randomized clinical trial to evaluate whether isavuconazole, a triazole antifungal, could prevent CAPA and improve survival in patients admitted to the ICU with severe COVID-19 infection., Methods: We designed a phase III/IV randomized, double-blind, two-arm, placebo-controlled trial evaluating standard of care (SOC) plus isavuconazole versus SOC plus placebo and were to enroll participants admitted to the ICU with severe COVID-19 infection at three medical centers in California, United States. The projected sample size was 162 participants., Results: Due to poor enrollment and the declining number of COVID-19 cases over time, the study was terminated after 7 participants were enrolled, all enrolled at one study site (UC San Diego Health). CAPA was suspected in two participants and they were started on open-label isavuconazole. One was withdrawn due to possible isavuconazole-related adverse side effects., Conclusion: Enrollment was slower-than-expected due to multiple factors, including competing COVID-19-related studies and hesitancy from potential study participants or their families to join the study. Our experience highlights some of the difficulties in planning and running a clinical trial focused on fungal superinfections involving severely ill patients during the height of the COVID-19 pandemic. Lessons learned from this study will help in the design of proposed studies examining antifungal prophylaxis against aspergillosis following other severe respiratory viral infections., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This study was funded by 10.13039/100007705Astellas Pharma Global Development, Inc. All authors have received funding from Astellas but they did not influence the work reported in this paper., (© 2024 The Authors.)

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.

Background: Emerging risk factors highlight the need for an updated understanding of cryptococcosis in the United States., Objective: Describe the epidemiological trends and clinical outcomes of cryptococcosis in three patient groups: people with HIV (PWH), non-HIV-infected and non-transplant (NHNT) patients, and patients with a history of solid organ transplantation., Methods: We utilized data from the Merative Medicaid Database to identify individuals aged 18 and above with cryptococcosis based on the International Classification of Diseases, Tenth Revision diagnosis codes from January 2017 to December 2019. Patients were stratified into PWH, NHNT patients, and transplant recipients according to Infectious Diseases Society of America guidelines. Baseline characteristics, types of cryptococcosis, hospitalization details, and in-hospital mortality rates were compared across groups., Results: Among 703 patients, 59.7% were PWH, 35.6% were NHNT, and 4.7% were transplant recipients. PWH were more likely to be younger, male, identify as Black, and have fewer comorbidities than patients in the NHNT and transplant groups. Notably, 24% of NHNT patients lacked comorbidities. Central nervous system, pulmonary, and disseminated cryptococcosis were most common overall (60%, 14%, and 11%, respectively). The incidence of cryptococcosis fluctuated throughout the study period. PWH accounted for over 50% of cases from June 2017 to June 2019, but this proportion decreased to 47% from July to December 2019. Among the 52% of patients requiring hospitalization, 61% were PWH and 35% were NHNT patients. PWH had longer hospital stays. In-hospital mortality at 90 days was significantly higher in NHNT patients (22%) compared to PWH (7%) and transplant recipients (0%). One-year mortality remained lowest among PWH (8%) compared to NHNT patients (22%) and transplant recipients (13%)., Conclusion: In this study, most cases of cryptococcosis were PWH. Interestingly, while the incidence remained relatively stable in PWH, it slightly increased in those without HIV by the end of the study period. Mortality was highest in NHNT patients., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Invasive candidiasis is an important fungal disease caused by Candida albicans and, increasingly, non-albicans Candida pathogens. Invasive Candida infections originate most frequently from endogenous human reservoirs and are triggered by impaired host defences. Signs and symptoms of invasive candidiasis are non-specific; candidaemia is the most diagnosed manifestation, with disseminated candidiasis affecting single or multiple organs. Diagnosis poses many challenges, and conventional culture techniques are frequently supplemented by non-culture-based assays. The attributable mortality from candidaemia and disseminated infections is ~30%. Fluconazole resistance is a concern for Nakaseomyces glabratus, Candida parapsilosis, and Candida auris and less so in Candida tropicalis infection; acquired echinocandin resistance remains uncommon. The epidemiology of invasive candidiasis varies in different geographical areas and within various patient populations. Risk factors include intensive care unit stay, central venous catheter use, broad-spectrum antibiotics use, abdominal surgery and immune suppression. Early antifungal treatment and central venous catheter removal form the cornerstones to decrease mortality. The landscape of novel therapeutics is growing; however, the application of new drugs requires careful selection of eligible patients as the spectrum of activity is limited to a few fungal species. Unanswered questions and knowledge gaps define future research priorities and a personalized approach to diagnosis and treatment of invasive candidiasis is of paramount importance., (© 2024. Springer Nature Limited.)

Background: Cryptococcal meningitis (CM), an opportunistic fungal infection affecting immunocompromised hosts, leads to high mortality. The role of previous exposure to glucocorticoids as a risk factor and as an outcome modulator has been observed, but systematic studies are lacking., Objective: The primary aim of this study is to evaluate the impact of glucocorticoid use on the clinical outcomes, specifically mortality, of non-HIV and non-transplant (NHNT) patients diagnosed with CM., Methods: We queried a global research network to identify adult NHNT patients with CM based on ICD codes or recorded specific Cryptococcus CSF lab results with or without glucocorticoid exposure the year before diagnosis. We performed a propensity score-matched analysis to reduce the risk of confounding and analysed outcomes by glucocorticoid exposure. We used a Cox proportional hazards model for survival analysis., Results: We identified 764 patients with a history of glucocorticoid exposure and 1267 patients without who developed CM within 1 year. After propensity score matching of covariates, we obtained 627 patients in each cohort. The mortality risk in 1 year was greater in patients exposed to prior glucocorticoids (OR: 1.3, CI: 1.2-2.0, p = 0.002). We found an excess of 45 deaths among CM patients with previous glucocorticoid use (7.4% increased absolute risk of dying within 1 year of diagnosis) compared to CM controls without glucocorticoid exposure. Hospitalisation, intensive care unit admission, emergency department visits, stroke and cognitive dysfunction also showed significant, unfavourable outcomes in patients with glucocorticoid-exposed CM compared to glucocorticoid-unexposed CM patients., Conclusions: Previous glucocorticoid administration in NHNT patients seems to associate with 1-year mortality after CM adjusted for possible confounders related to demographics, comorbidities and additional immunosuppressive medications. Serial CrAg screening might be appropriate for higher-risk patients on glucocorticoids after further cost-benefit analyses., (© 2024 Wiley-VCH GmbH. Published by John Wiley & Sons Ltd.)

Background: 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., Methods: 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., Findings: 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., Interpretation: 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., Funding: Melinta Therapeutics and Cidara Therapeutics., Competing Interests: Declaration of interests AFD reports consulting fees from Cidara. AS reports a grant from Gilead Sciences and, outside of the submitted work, grant from Pfizer; consulting fees and honoraria from Angelini, Gilead, Menarini, MSD, Pfizer, and Shionogi; and support for attending meetings from Pfizer. BJK reports independent data review committee membership for Cidara. GRT reports grants and consulting fees from Astellas, Cidara, F2G, Mayne, Mundipharma, and Scynexis. JAA reports being an employee of Melinta Therapeutics. JAV reports grants from Cidara and Scynexis; consulting fees from Cidara and F2G; and data safety monitoring board or advisory board participation for F2G and Scynexis, outside of the submitted work. JPH reports consulting fees from Angelini, Menarini, MSD, Pfizer, Tillots, and Zambon; honoraria from Angelini, Menarini, and Pfizer; support for attending meetings from MSD and Pfizer; and data safety monitoring board or advisory board participation for TFT Pharmaceuticals, outside of the submitted work. MB reports honoraria from, and data safety monitoring board or advisory board membership for, Angelini, Astellas, Bayer, Biomerieux, Cidara, Gilead, Menarini, MSD, Nabriva, and Shionogi, outside of the submitted work. MH reports grants from Cidara; and outside of the submitted work, honoraria from Gilead and Pfizer; support for attending meetings from Gilead, MSD, and Pfizer; and is President of the Belgian Society of Infectious Diseases. MK reports a grant from Barnes-Jewish Hospital Foundation, and data safety monitoring board or advisory board membership for Melinta Therapeutics, outside of the submitted work. OAC reports grants or contracts from Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, and Scynexis; consulting fees from AbbVie, Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, IQVIA, Janssen, Matinas, MedPace, Menarini, Molecular Partners, MSG-ERC, Noxxon, Octapharma, Pfizer, PSI, Scynexis, and Seres; honoraria from Abbott, AbbVie, Al-Jazeera Pharmaceuticals, Astellas, Gilead, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, Merck/MSD, Mylan, Noscendo, Pfizer, and Shionogi; payment for expert testimony from Cidara; a patent at the German Patent and Trade Mark Office (DE 10 2021 113 007.7); data safety monitoring board or advisory board participation for Actelion, Allecra, Cidara, Entasis, IQVIA, Janssen, MedPace, Paratek, PSI, Pulmocide, Shionogi, and The Prime Meridian Group; stocks from CoRe Consulting and EasyRadiology; and other interests with Wiley (Editor-in-Chief for Mycoses), outside of the submitted work. PGP reports grants from Cidara and Scynexis; consulting fees from Cidara; and data safety monitoring board or advisory board participation for Cidara, outside of the submitted work. PMH reports grants or contracts from Baxter, Cytosorbents, and Pfizer; consulting fees from Baxter, Cytosorbents, and Pfizer; honoraria from Baxter and Cytosorbents; and support for attending meetings from Mundipharma and Pfizer, outside of the submitted work. TS reports being an employee of Cidara Therapeutics; and, outside of the submitted work, reports being a shareholder in Cidara Therapeutics. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

A vaccine for coccidioidomycosis is likely to undergo trials in the near future. In this paper, we raise 4 questions that should be answered before its use and offer our solutions to these questions. These include defining the goals of vaccination, determining who should be vaccinated, how to measure vaccine immunity and protection, and how to address vaccine hesitancy and denial., Competing Interests: Potential conflicts of interest. The authors have no financial interests or connections, direct or indirect, or any other situations that might raise the question of bias in the work reported or the conclusions, implications, or opinions stated., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Severe coccidioidomycosis presenting with respiratory failure is an uncommon manifestation of disease. Current knowledge of this condition is limited to case reports and small case series., Methods: A retrospective multicenter review of patients with coccidioidomycosis-associated acute respiratory distress syndrome (CA-ARDS) was conducted. It assessed clinical and laboratory variables at the time of presentation, reviewed the treatment course, and compared this cohort with a national database of patients with noncoccidioidomycosis ARDS. Survivors and nonsurvivors of coccidioidomycosis were also compared to determine prognostic factors., Results: In this study, CA-ARDS (n = 54) was most common in males, those of Hispanic ethnicity, and those with concurrent diabetes mellitus. As compared with the PETAL network database (Prevention and Early Treatment of Acute Lung Injury; n = 1006), patients with coccidioidomycosis were younger, had fewer comorbid conditions, and were less acidemic. The 90-day mortality was 15.4% for patients with coccidioidomycosis, as opposed to 42.6% ( P < .0001) for patients with noncoccidioidomycosis ARDS. Patients with coccidioidomycosis who died, as compared with those who survived, were older, had higher APACHE II scores (Acute Physiology and Chronic Health Evaluation), and did not receive corticosteroid therapy., Conclusions: CA-ARDS is an uncommon but morbid manifestation of infection. When compared with a national database, the overall mortality appears favorable vs other causes of ARDS. Patients with CA-ARDS had a low overall mortality but required prolonged antifungal therapy. The utility of corticosteroids in this condition remains unconfirmed., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The epidemiology of invasive aspergillosis (IA) is evolving. To define the patient groups who will most likely benefit from primary or secondary Aspergillus prophylaxis, particularly those whose medical conditions and IA risk change over time, it is helpful to depict patient populations and their risk periods in a temporal visual model. The Sankey approach provides a dynamic figure to understand the risk of IA for various patient populations. While the figure depicted within this article is static, an internet-based version could provide pop-up highlights of any given flow's origin and destination nodes. A future version could highlight links to publications that support the color-coded incidence rates or other actionable items, such as bundles of applicable pharmacologic or non-pharmacologic interventions. The figure, as part of the upcoming Infectious Diseases Society of America's aspergillosis clinical practice guidelines, can guide decision-making in clinical settings., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: Prior studies have demonstrated that patients presenting for elective surgery may have higher-than-expected residual anti-Xa level activity at or beyond 24 hours following their last treatment dose of enoxaparin. Given that 24 hours of abstinence is currently recommended by both European and American societies before the performance of neuraxial or deep anesthetic/analgesic procedures, determining the actual timeframe at which residual anti-Xa level activity reliably falls below 0.2 IU/mL, the lower limit of the target range for thromboprophylaxis, is critical., Methods: This was a prospective observational trial. Consenting patients on treatment-dose enoxaparin were randomized to either a 24-hour group (last dose at 07:00 the day prior to surgery) or a 36-hour group (last dose at 19:00 2 days prior to surgery). On arrival for surgery, blood samples were obtained to assess residual anti-Xa level activity and renal function. The primary outcome was residual anti-Xa level activity following the last treatment dose of enoxaparin. Incorporating all patients, linear regression modeling was performed to predict the timepoint at which the level of anti-Xa activity reliably fell below 0.2 IU/mL., Results: 103 patients were analyzed. Time from the last dose at which residual anti-Xa activity fell below 0.2 IU/mL, based on the upper bound of the 95% CI, was 31.5 hours. No correlation overall between age, renal function, or sex was found., Conclusion: Residual levels of anti-Xa activity do not reliably fall below 0.2 IU/mL 24 hours following discontinuation of treatment-dose enoxaparin. Therefore, current time-based guidelines are not conservative enough. Routine anti-Xa testing should be strongly considered, or current time-based guidelines should be reassessed., Trial Registration Number: NCT03296033., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Invasive fungal disease caused by dimorphic fungi is associated with significant morbidity and mortality. Super-bioavailability itraconazole (SUBA-itra) is a novel antifungal agent with pharmacokinetic advantages over currently available formulations. In this prospective comparative study, we report the outcomes of patients with endemic fungal infections (histoplasmosis, blastomycosis, coccidioidomycosis, and sporotrichosis)., Methods: This open-label randomized trial evaluated the efficacy, safety, and pharmacokinetics SUBA-itra compared with conventional itraconazole (c-itra) treatment for endemic fungal infections. An independent data review committee determined responses on treatment days 42 and 180., Results: Eighty-eight patients were enrolled for IFD (SUBA-itra, n = 42; c-itra, n = 46) caused by Histoplasma (n = 51), Blastomyces (n = 18), Coccidioides (n = 13), or Sporothrix (n = 6). On day 42, clinical success was observed with SUBA-itra and c-itra on day 42 (in 69% and 67%, respectively, and on day 180 (in 60% and 65%). Patients treated with SUBA-itra exhibited less drug-level variability at days 7 ( P = .03) and 14 ( P = .06) of randomized treatment. The concentrations of itraconazole and hydroxyitraconazole were comparable between the 2 medications ( P = .77 and P = .80, respectively). There was a trend for fewer adverse events (AEs; 74% vs 87%, respectively; P = .18) and serious AEs (10% vs 26%; P = .06) in the SUBA-itra-treated patients than in those receiving c-itra. Serious treatment-emergent AEs were less common in SUBA-itra-treated patients (12% vs 50%, respectively; P < .001)., Conclusions: SUBA-itra was bioequivalent, well tolerated, and efficacious in treating endemic fungi, with a more favorable safety profile than c-itra., Clinical Trials Registration: NCT03572049., Competing Interests: Potential conflicts of interest. A. S. reports research funding from Astellas and Mayne and consulting fees from GSK and F2G. As deputy editor for Open Forum Infectious Diseases, per journal policy, A. S. was not involved in the peer review or editorial decision process for this article. G. R. T. reports research support and consulting fees from Astellas, Cidara, F2G, Mayne, Melinta, Merck, and Scynexis and served as a consultant for Pfizer. M. H. M. has received research funding from Mayne, F2G, and Scynexis and consulting fees from Astellas, Scynexis, and PSI. J. H. reports research funding from Mayne. L. A. M. is an employee of Mayne Pharma. P. G. P reports research funding from Mayne, Astellas, Scynexis, Melinta, and Cidara and consulting fees from Matinas, Melinta, and F2G. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The incidence of coccidioidomycosis continues to increase. The diagnosis frequently relies on non-invasive diagnostic testing with immunodiffusion and complement fixation (CF) testing the current gold standard. A direct comparison of quantitative immunodiffusion and CF for IgG antibodies has not been previously reported. In a comparison of 368 samples, there was close concordance observed (360/368 = 97.8%) (P-value < .001). These tests can be considerably interchangeable in the reference laboratory setting., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Coccidioidomycosis is a potentially fatal fungal disease of humans and animals that follows inhalation of Coccidioides spp. arthroconidia in the environment. The disease in dogs resembles that in people, and because dogs may be at increased risk of exposure due to their proximity to the ground and digging behavior, they are valuable models for the disease in humans. Dogs have been sentinels for identification of new regions of endemicity in Washington and Texas. Canine serosurveillance has also been used to predict variables associated with environmental presence of Coccidioides spp. Expansion of the endemic region of coccidioidomycosis with climate change-along with predicted population increases and increased development in the southwest United States-may result in 45.4 million additional people at risk of infection by 2090. Here we provide an overview of the value of dogs as sentinels for the disease and encourage the routine reporting of coccidioidomycosis cases in dogs to public health agencies. We also highlight the value of dogs as naturally occurring models for studying novel treatment options and preventatives, such as a novel live avirulent coccidioidomycosis vaccine., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

A southern sea otter (Enhydra lutris nereis) stranded dead in central California, USA, with a distended pericardial sac containing thousands of free-floating proteinaceous masses. Serology, fungal culture, PCR, and sequencing confirmed the etiology of this novel lesion as Coccidioides immitis. Range expansion of this zoonotic pathogen is predicted with climate change., (© Wildlife Disease Association 2024.)

Introduction: Fusariosis of the central nervous system (CNS) is extremely uncommon. Treatment and outcome data from previously published cases may provide some guidance in light of the ongoing fungal meningitis outbreak in 2023 involving Fusarium spp. in the United States and Mexico., Methods: We reviewed the published literature describing cases of invasive fusariosis of the (CNS) that included data on patient demographic characteristics, treatment, and outcome., Results: Twenty-six cases met inclusion criteria. The mean age was 36 years, 55% involved females, 60% had underlying hematologic malignancy, and another 16% were on immunosuppressants. The majority of infections were from Fusarium solani species complex. Overall 72% of patients died. The majority received monotherapy with amphotericin B, although some received voriconazole monotherapy or combination therapy with amphotericin B plus voriconazole with or without adjuvant surgery. Among the survivors, 3 received amphotericin B monotherapy, 2 voriconazole monotherapy, 1 combination therapy of both, and one surgery only., Conclusion: The overall mortality rate in published cases of fusariosis of the CNS was high, although-unlike during the current outbreak-the preponderance of patients were severely immunocompromised. While historically the majority were treated with amphotericin B monotherapy, some recent patients were treated with voriconazole monotherapy or combination therapy with amphotericin B plus voriconazole. Current guidelines recommend monotherapy with voriconazole or lipid formulations of amphotericin B or combination of both for the treatment of invasive fusariosis, which is in line with the findings from our literature review and should be considered during the ongoing 2023 outbreak., (© 2023. The Author(s).)

This contemporary, international, evidence-informed guidance aims to achieve the greatest good for the greatest number of people with familial hypercholesterolaemia (FH) across different countries. FH, a family of monogenic defects in the hepatic LDL clearance pathway, is a preventable cause of premature coronary artery disease and death. Worldwide, 35 million people have FH, but most remain undiagnosed or undertreated. Current FH care is guided by a useful and diverse group of evidence-based guidelines, with some primarily directed at cholesterol management and some that are country-specific. However, none of these guidelines provides a comprehensive overview of FH care that includes both the lifelong components of clinical practice and strategies for implementation. Therefore, a group of international experts systematically developed this guidance to compile clinical strategies from existing evidence-based guidelines for the detection (screening, diagnosis, genetic testing and counselling) and management (risk stratification, treatment of adults or children with heterozygous or homozygous FH, therapy during pregnancy and use of apheresis) of patients with FH, update evidence-informed clinical recommendations, and develop and integrate consensus-based implementation strategies at the patient, provider and health-care system levels, with the aim of maximizing the potential benefit for at-risk patients and their families worldwide., (© 2023. Springer Nature Limited.)

Purpose of Review: The endemic fungi are a significant cause of morbidity and mortality in effected patients. The range of endemicity for these are expanding with infections observed outside of traditional locations. Enhanced diagnostic and treatment practices may significantly alter patient outcomes., Recent Findings: Recently completed clinical trials have focused on an assessment of improving efficacy while minimizing patient toxicity. Practice changing trials have been completed in histoplasmosis showing the utility of a single up-front liposomal amphotericin B dose followed by standard itraconazole dosing. The recent evaluation of several antifungal options including isauvconazole in the treatment of coccidioidomycosis also show promise for additional therapeutic agents. A recently conducted trial has also shown the superiority of amphotericin B therapy over itraconazole in the treatment of talaromycosis., Summary: The increased range of endemic mycoses coupled with the growing immunocompromised patient population mandates continued investigation of improved diagnostic and therapeutic options. Advances in these areas have led to more rapid diagnosis and more efficacious antifungal therapy., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

A wide array of clinical manifestations follow infection with Coccidioides immitis or Coccidioides posadasii , ranging from asymptomatic infection to life-threatening pulmonary disease or extrapulmonary dissemination and meningitis. Epidemiological studies require consistent definitions of cases and their comparative clinical features. Understanding host and pathogen determinants of the severity of coccidioidomycosis also requires that specific clinical features (such as coccidioidal meningitis) and their overlap be precisely defined and quantified. Here we propose a system for categorization of outcomes of coccidioidomycosis in individuals who are not overtly immunocompromised that harmonizes clinical assessments during translational research of this increasingly common disease., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)