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Derek J Bays,1 Emily N Jenkins,2,3 Meghan Lyman,3 Tom Chiller,3 Nora Strong,4 Luis Ostrosky-Zeichner,4 Martin Hoenigl,5– 7 Peter G Pappas,8 George R Thompson III1,9 1Department of Internal Medicine, Division of Infectious Diseases, School of Medicine, University of California Davis, Sacramento, CA, USA; 2ASRT, Inc, Atlanta, GA, USA; 3Mycotic Disease Branch, Centers for Disease Control and Prevention, Atlanta, GA, USA; 4Division of Infectious Diseases, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA; 5Division of Infectious Diseases, Department of Internal Medicine, Medical University of Graz, Graz, Austria; 6Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, La Jolla, CA, USA; 7Clinical and Translational Fungal Working Group, University of California San Diego, La Jolla, CA, USA; 8Division of Infectious Diseases, Department of Internal Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; 9Department of Medical Microbiology and Immunology, University of California-Davis, Davis, CA, USACorrespondence: Derek J Bays; George R Thompson III, Email djbays@ucdavis.edu; grthompson@ucdavis.eduAbstract: Invasive candidiasis (IC) is an increasingly prevalent, costly, and potentially fatal infection brought on by the opportunistic yeast, Candida. Previously, IC has predominantly been caused by C. albicans which is often drug susceptible. There has been a global trend towards decreasing rates of infection secondary to C. albicans and a rise in non-albicans species with a corresponding increase in drug resistance creating treatment challenges. With advances in management of malignancies, there has also been an increase in the population at risk from IC along with a corresponding increase in incidence of breakthrough IC infections. Additionally, the emergence of C. auris creates many challenges in management and prevention due to drug resistance and the organism’s ability to transmit rapidly in the healthcare setting. While the development of novel antifungals is encouraging for future management, understanding the changing epidemiology of IC is a vital step in future management and prevention.Keywords: Candida, epidemiology, resistance, emerging, non-albicans Candida species

Introduction'Real-world' data for mold-active triazoles (MATs) in the treatment of invasive fungal infections (IFIs) are lacking. This study evaluated usage of MATs in a disease registry for the management of IFIs.MethodsData were collected for this multicenter, observational, prospective study from 55 US centers, between March 2017 and April 2020. Eligible patients received isavuconazole, posaconazole, or voriconazole as MAT monotherapy (one MAT) or multiple/sequenced MAT therapy (more than one MAT) for prophylaxis or treatment. Patients were enrolled within 60 days of MAT initiation. The primary objective was to characterize patients receiving a MAT and their patterns of therapy. The full analysis set (FAS) included eligible patients for the relevant enrollment protocol, and the safety analysis set (SAF) included patients who received ≥ 1 MAT dose.ResultsOverall, 2009 patients were enrolled in the SAF. The FAS comprised 1993 patients (510 isavuconazole; 540 posaconazole; 491 voriconazole; 452 multiple/sequenced MAT therapies); 816 and 1177 received treatment and prophylaxis at study index/enrollment, respectively. Around half (57.8%) of patients were male, and median age was 59 years. Among patients with IFIs during the study, the most common pathogens were Aspergillus fumigatus in the isavuconazole (18.2% [10/55]) and voriconazole (25.5% [12/47]) groups and Candida glabrata in the posaconazole group (20.9% [9/43]); the lungs were the most common infection site (58.2% [166/285]). Most patients were maintained on MAT monotherapy (77.3% [1541/1993]), and 79.4% (1520/1915) completed their MAT therapies. A complete/partial clinical response was reported in 59.1% (591/1001) of patients with a clinical response assessment. Breakthrough IFIs were reported in 7.1% (73/1030) of prophylaxis patients. Adverse drug reactions (ADRs) were reported in 14.7% (296/2009) of patients (3.9% [20/514] isavuconazole; 11.3% [62/547] posaconazole; 14.2% [70/494] voriconazole).ConclusionsIn this 'real-world' study, most patients remained on their initial therapy and completed their MAT therapy. Over half of patients receiving MATs for IFIs had a successful response, and most receiving prophylaxis did not develop breakthrough IFIs. ADRs were uncommon.

Background: Hospitalized patients are at increased risk for candidemia and invasive candidiasis (C/IC). Improved therapeutic regimens with enhanced clinical and pharmacoeconomic outcomes utilizing existing antifungal agents are still needed.Methods: An ope

The aim of this study was to identify baseline prognostic factors for poor clinical outcome of HIV-associated cryptococcal meningitis. We conducted a trial in Thailand and the USA comparing low- and high-dose concomitant use of amphotericin B and fluconazole for HIV-associated cryptococcal meningitis to amphotericin B followed by fluconazole. Subjects who were either alive and cerebrospinal fluid (CSF) culture-positive or dead were considered to have a poor outcome. At day 14, baseline characteristics associated with poor outcome included: low weight, high CSF cryptococcal antigen (CrAg) titre and low CSF white blood cell (WBC) count. At day 70, the associated baseline characteristics included: CSF CrAg titre >1:1024 and low Karnofsky performance status. Overall, consistent with published findings, low weight, high CSF CrAg titre and low CSF WBC counts at baseline were predictors for poor clinical outcome. In addition, we found that low Karnofsky performance status was predictive of poor outcome. Prompt management with appropriate antifungal therapy for this particular group of patients may improve the outcomes. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To review epidemiologic trends, advances in diagnosis and susceptibility testing, therapeutic options and guidelines, and management strategies for invasive candidiasis as relevant to the intensive care unit physician. DATA SOURCES, STUDY SELECTION, DATA EXTRACTION, DATA SYNTHESIS: Nonstructured review of peer-reviewed original articles, review articles, abstracts, guidelines, and consensus statements appearing in Medline, major scientific journals, and conference proceedings. CONCLUSIONS: Invasive candidiasis is a problem associated with substantial morbidity and mortality that is highly prevalent in the intensive care unit setting. Recent epidemiologic studies have shown a trend toward increasing numbers of infections and a shift toward infections caused by non-albicans Candida species. Guidelines for the management of these diseases have been published and recommend amphotericin B, fluconazole, or caspofungin as the primary therapeutic option. The choice of agent should depend on local epidemiology and patient factors. The role of newer antifungal agents for this population, such as the new azoles and echinocandins, remains to be determined. Priority areas of research include diagnostics, risk identification, and management strategy assessment such as prophylactic, preemptive, and empirical therapy. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the use of single-dose azithromycin for empirical treatment of nongonococcal urethritis.Design: Randomized, double-blind, multicenter trial comparing azithromycin vs doxycycline therapy, with a 2:1 randomization ratio. Patients were evaluated clinically and microbiologically for Chlamydia trachomatis and Ureaplasma urealyticum infection before therapy and at 2 and 5 weeks after study entry.Setting: Eleven sexually transmitted disease clinics throughout the United States.Patients: A total of 452 men aged 18 years or older with symptomatic nongonococcal urethritis of less than 14 days' duration.Intervention: Patients were treated with either 1.0 g of azithromycin as a single oral dose or 100 mg of doxycycline taken orally twice daily for 7 days.Main Outcome Measures: Clinical resolution of symptoms and signs of nongonococcal urethritis, microbiological cure of C trachomatis and U urealyticum, and occurrence of adverse experiences.Results: Of the 452 patients enrolled, 248 in the azithromycin-treated group and 123 in the doxycycline-treated group were evaluable for clinical response. The two treatment groups were comparable in terms of age, weight, ethnic distribution, sexual preference, sexual activity, and history of prior nongonococcal urethritis or gonorrhea. Sixteen percent of the azithromycin group and 24% of the doxycycline group were culture positive for C trachomatis before therapy, while 38% and 28%, respectively, were culture positive for U urealyticum. The cumulative clinical cure rate was 81% (95% confidence interval [CI], 75% to 85%) in the azithromycin-treated group and 77% (95% CI, 69% to 84%) in the doxycycline-treated group. Clinical cure rates in the two groups were also comparable when patients were stratified by presence or absence of infection with C trachomatis or U urealyticum prior to therapy. Among those infected with C trachomatis, overall microbiological cure rates were 83% (95% CI, 65% to 94%) for azithromycin-treated patients (n = 30) and 90% (95% CI, 68% to 98%) for doxycycline-treated patients (n = 21). Among those infected with U urealyticum, overall microbiological cure rates were 45% (95% CI, 34% to 57%) for azithromycin-treated patients (n = 75) and 47% (95% CI, 30% to 65%) for doxycycline-treated patients (n = 32). Adverse reactions were generally mild to moderate and occurred in 23% of the azithromycin-treated group and 29% of the doxycycline-treated group.Conclusions: For empirical treatment of the acute nongonococcal urethritis syndrome in men, a single oral dose of azithromycin was as effective as a standard 7-day course of doxycycline in achieving clinical cure. Further, clinical cure rates were comparable with either regimen, regardless of the presence or absence of Chlamydia or Ureaplasma infection. [ABSTRACT FROM AUTHOR]

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.

Cryptococcosis is a major worldwide disseminated invasive fungal infection. Cryptococcosis, particularly in its most lethal manifestation of cryptococcal meningitis, accounts for substantial mortality and morbidity. The breadth of the clinical cryptococcosis syndromes, the different patient types at-risk and affected, and the vastly disparate resource settings where clinicians practice pose a complex array of challenges. Expert contributors from diverse regions of the world have collated data, reviewed the evidence, and provided insightful guideline recommendations for health practitioners across the globe. This guideline offers updated practical guidance and implementable recommendations on the clinical approaches, screening, diagnosis, management, and follow-up care of a patient with cryptococcosis and serves as a comprehensive synthesis of current evidence on cryptococcosis. This Review seeks to facilitate optimal clinical decision making on cryptococcosis and addresses the myriad of clinical complications by incorporating data from historical and contemporary clinical trials. This guideline is grounded on a set of core management principles, while acknowledging the practical challenges of antifungal access and resource limitations faced by many clinicians and patients. More than 70 societies internationally have endorsed the content, structure, evidence, recommendation, and pragmatic wisdom of this global cryptococcosis guideline to inform clinicians about the past, present, and future of care for a patient with cryptococcosis., Competing Interests: Declaration of interests AA reports grants from the Agence Nationale de la Recherche; serving as a consultant to Gilead Sciences; receiving speaking honoraria from Gilead Sciences and PR Edition; travel support from Gilead sciences and Pfizer; and patents with the Institut Pasteur. J-WA reports grants or contracts from WHO (fungal priority pathogens list) and receipt of equipment and materials from the Westmead Hospital Foundation. JB reports support from the Australian National Health and Medical Research Council and receipt of honoraria from Gilead. TAB reports a personal research fellowship from Gilead Sciences; investigator-led research grant from Pfizer; lecture honoraria and participation in advisory boards for Gilead Sciences, Mundipharma, and Pfizer; and participation in the Trial Steering Committee for a phase 2 trial of inhaled opelconazole (Pulmocide). FC reports speaker honoraria from, and being part of, an advisory board for Pfizer and United Medical. CCC reports receipt of an Early Career Fellowship from the Australian National Health and Medical Research Foundation, receipt of a speaker travel support for IDweek 2024, being a principal investigator in an early phase clinical trial unit, and was a recipient of the Australian National Health and Medical Research Council Early Career Fellowship (APP 1092160). MC reports grants from Cidara, F2G, Pfizer, and Janssen; receipt of honoraria from Pfizerm MSD and Gilead; and travel support from Pfizer. SCC reports untied educational grants from MSD Australia and F2G and is on the antifungal advisory boards of MSD Australia, Gilead Sciences, and F2G. OAC reports grants or contracts from BMBF, Cidara, EU-DG RTD (101037867), F2G, Gilead, MedPace, MSD, Mundipharma, Octapharma, Pfizer, and Scynexis; consulting fees from AbbVie, AiCuris, Biocon, Cidara, Gilead, IQVIA, Janssen, Matinas, MedPace, Menarini, Moderna, Molecular Partners, MSG-ERC, Noxxon, Octapharma, Pfizer, PSI, Scynexis, and Seres; honoraria for lectures from Abbott, AbbVie, Al-Jazeera Pharmaceuticals, Hikma, Gilead, Grupo Biotoscana/United Medical/Knight, MedScape, MedUpdate, Merck/MSD, Noscendo, Pfizer, Shionogi, and streamedup!; payment for expert testimony from Cidara; participation on a data safety monitoring board or advisory board from Boston Strategic Partners, Cidara, IQVIA, Janssen, MedPace, 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; other interests from Wiley; support from the German Federal Ministry of Research and Education; and funding by the Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy (Cologne Cluster of Excellence on Cellular Stress Responses in Aging-associated Diseases, EXC 2030—390661388). J-PG reports speaker honoraria from Gilead, MundiPharma, and Pfizer. NPG reports grants from National Institutes of Health (USA), National Institute of Health and Care Research (UK), Medical Research Council (MRC; UK), Centers for Disease Control and Prevention (CDC; USA), and National Health Laboratory Service Research Trust (South Africa); participation in the ACACIA trial as part of the data safety monitoring board, project committee of DREAMM, project advisory committee for 5FC Crypto, and leadership roles in the Federation of Infectious Diseases Societies of Southern Africa. AHG reports grants from Gilead Sciences; personal fees from Amplyx, Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp & Dohme, Mundipharma, Pfizer, and Scynexis; speaker honoraria from Gilead Sciences and MSD; and participation in an advisory board for Astellas, Mundipharma, Partner Therapeutics, and Pfizer. FH reports grants from Health Holland and European Society for Clinical Microbiology and Infectious Diseases; leadership roles as treasurer of the Netherlands Society for Medical Mycology, Chair of the Division Microbial Genomics of the Royal Netherlands Society for Microbiology, Vice-President International Society for Human and Animal Mycology (ISHAM); and receipt of evaluation kits from Bruker and Pathonostics. TSH reports receipt of an investigator award from Gilead Sciences, honoraria from Pfizer and Gilead Sciences, and participation in a data safety monitoring board or advisory board for Viamet and F2G. MH reports receipt of an European and Developing Countries Clinical Trials Partnership. JNJ reports support from the National Institute for Health Research; grants from European and Developing Countries Clinical Trials Partnership, joint global health trials (Wellcome Trust, MRC, and UK aid) and CDC; speaker fees from Gilead Sciences; participation on a data safety and monitoring board for the HARVEST, ARTIST, CASTLE, and ACACIA trials. GJ reports travel support to attend a meeting at ISHAM. NK was a speaker and advisor for Gilead Sciences, Merck/MSD, and Pfizer and a speaker for Astellas. MSL reports support from the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), and National Institutes of Health (NIH). OL reports receipt of consulting fees and honoraria from Gilead Science and patents with INSERM APHP. OMM reports travel support for ISHAM meeting in India and being the country ambassador for Kenya for ISHAM. BJM reports being chair of the Australia and New Zealand Paediatric Infectious Diseases Group. DBM reports leadership role in the Crypto Meningitis advocacy group. RO reports receiving research and educational grant funding from Gilead Sciences, CDC Atlanta, and Pfizer Specialties and travel support from the CDC foundation. PGP reports grants from Mayne, Astellas, Scynexis, and Cidara and receipt of consulting fees from F2G and Cidara. AKP reports speaker honoraria for Gilead Science, Pfizer India, and Intas pharmaceutical. JRP reports grants from NIH, Appili, and Sfunga; royalties from Up-To-Date; and participation on a data safety monitoring board or advisory board from Pulmocide, EFFECT trial, and IMPRINT trial. FQ-TF reports receipt of speaker honoraria from Pfizer and United Medical, travel support and laboratory diagnostic kits from IMMY, and leadership roles in Infocus Latin America. JS-G reports speaker honoraria from Gilead and Pfizer and is on an advisory committee for Pfizer. AS reports grants from Astellas and receiving consulting fees from Scynexis. RSp has received speaker honoraria from Pfizer and reports being chair of Young European Confederation of Medical Mycology. TT reports receipt of honoraria from Pfizer, MSD, Asahikasei pharma, and Sumitomo pharma. AW reports a grant from UK Research and Innovation; receipt of consultant fees from Gilead and MundiPharma; speaker fees from F2G and Gilead; and participation as a data safety monitoring board member for the RECOVERY trial. All declarations are outside the submitted work. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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.)

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.)

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: Recently, increasing focus on patient input into research and healthcare improvements has fostered expanded patient-centered advocacy efforts. This first pan-fungal disease summit, part of the MYCology Advocacy, Research, & Education effort, brought together patients, caregivers, and mycology experts to better document patient experiences with invasive fungal disease (IFD) and establish priorities for mycology education, advocacy, and research., Methods: Patients who had suffered from IFD, their caregivers, clinicians, industry representatives, government officials, and patient advocacy professionals were invited. Patients and caregivers shared their stories and struggles with IFD. Breakout sessions separated mycology experts from patients and caregivers for further discussions to identify commonalities and perceived gaps and to formulate recommendations. The 2 groups then reconvened to develop consensus recommendations., Results: IFD patients and their caregivers shared experiences reflecting the typically lengthy prediagnosis, acute treatment, long-term treatment, and posttreatment recovery stages of IFD. They reported substantial physical, psychological, and financial burdens associated with the IFD experience, particularly related to delayed diagnoses. They reaffirmed a need for coordinated patient-centered education, peer support, and advocacy to document the burden of serious fungal infections. Mycology experts discussed strategies to address gaps in the mycology field, such as insufficient training, inadequate workforce support, and a need to partner more with patient groups., Conclusions: A summit involving patients with IFD, family caregivers, and mycology experts identified a substantial nonclinical burden of disease associated with IFD. Patients and mycology experts prioritized several goals for education, advocacy, and research to raise awareness of IFD and improve outcomes., Competing Interests: Potential conflicts of interest. R. P. receives grant support from the Centers for Disease Control and Prevention and the Department of Labor; received consulting fees from Clinical Outcomes Solutions, a travel stipend from the World Health Organization to attend the annual Taskforce of AMR Survivors meeting and the European Confederation of Medical Mycology to speak at TIMM 2023; unpaid Board of Directors positions with MyCARE, Integrita Healthcare Foundation, and Valley Fever Americas Foundation. L. A. T. received research grant support from Bristol Myers Squibb and Novartis; support from Astellas Pharma US; F2G; IMMY; Melinta Therapeutics, Inc; and the Mycoses Study Group Education & Research Consortium for the 2023 Patient/Provider Summit that was the basis for this manuscript, a travel stipend from the International Alliance of Dermatology Patient Organizations to attend GlobalSkin2023; an unpaid nonvoting membership with MSGERC. G. C. received honoraria and travel assistance from Integrita Healthcare Foundation to attend the 2023 Patient Summit. J. M. received honoraria and travel assistance from Integrita Healthcare Education Foundation to attend the 2023 Patient Summit. T. D. received travel assistance from Integrita Healthcare Foundation to attend the 2023 Patient Summit; unpaid Board of Directors position with Integrita Healthcare Foundation. A. S. has received honoraria and travel assistance from Integrita Healthcare Foundation to attend the 2023 Patient/Provider Summit; an unpaid role as co-chair of the Patient Advocacy Committee at Integrita Healthcare Foundation. C. T. J. receives grant support from National Center for Advancing Translational Sciences and the Centers for Disease Control and Prevention; a paid position as the Executive Director of the Mycoses Study Group Education and Research Consortium; a paid role as faculty at The Ohio State University. T. J. W. receives support from the Henry Schueler Foundation and Save Our Sick Kids Foundation for this manuscript; grants or contracts with Astellas, F2G, Gilead, Leadiant, T2 Biosystems, and Scynexis; received consulting fees from Abbott Laboratories, Partner Therapeutics, Scynexis, Statera, T2 Biosystems, Shionogi, Omeros, and Leadiant; Advisory Board positions with Scynexis, Abbott Laboratories, Partner Therapeutics, T2 Biosystems, Gilead, and Leviant; leadership positions with Medical Mycology Societies of the Americas, Center for Innovative Therapeutics and Diagnostics, ECMM, Henry Schueler Foundation, Save Our Sick Kids Foundation, and Mycoses Study Group Education and Research Consortium. P. G. P. receives research support from Melinta, Astellas, and Scynexis; and consulting fees from F2G, Melinta, Matinas, and Scynexis. A. S. received consulting fees from Scynexis, F2G and GSK. All remaining authors: 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. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Abstract: Crowdsourced registries have been used to quickly gather information, especially during emerging public health concerns. Registries that began during the COVID-19 pandemic were used to rapidly answer key questions on coinfections, experimental treatments, and morbidity and mortality outcomes. Registries are also used more frequently to support clinical trials and track long-term outcomes in patient populations. This article reviews registry methodology, including the collection of data from crowdsourcing and real-world sources, that can be applied to nurse researcher and clinical research nurse skill sets. The authors illustrate a recently reported crowdsourced COVID-19 and cryptococcal disease registry that followed project management strategies and the Agency for Healthcare Research and Quality registry guidelines for planning, execution, and analysis of registries and other research methods., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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.)

Background: Invasive fungal infections have been described throughout the COVID-19 pandemic. Cryptococcal disease after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported in several isolated case reports and 1 larger case series. We sought to describe cryptococcal infections following SARS-CoV-2 through establishing a database to investigate underlying risk factors, disease manifestations, and outcomes., Methods: We created a crowdsourced call for cases solicited through the Mycoses Study Group Education and Research Consortium, the Centers for Disease Control and Prevention Emerging Infectious Diseases Network, and infectious diseases Twitter groups. Data were collected in a web-based and secure REDCap survey without personal identifiers., Results: Sixty-nine cases were identified and submitted by 29 separate institutional sites. Cryptococcosis was diagnosed a median of 22 days (interquartile range, 9-42 days) after SARS-CoV-2 infection. Mortality among those with available follow-up was 72% (26/36) for the immunocompetent group and 48% (15/31) for the immunocompromised group (likelihood ratio, 4.01; P = .045). We observed a correlation between disease manifestation (central nervous system infection, proven/probable disseminated disease, and respiratory) and mortality (P = .002)., Conclusions: The mortality rate of 59% for patients with cryptococcosis following SARS-CoV-2 is higher than that of modern Cryptococcus cohorts. There was an association between immunocompromised status and cryptococcal disease manifestations as well as mortality. Moreover, our series emphasizes the need for clinical and laboratory assessment of opportunistic infections beyond 30 days when concerning symptoms develop., Competing Interests: Potential conflicts of interest. J. M. reports royalties or licenses from UpToDate. L. O.-Z. reports grants or contracts to institution from Pfizer, Scynexis, and Pulmocide; consulting fees to author from Pfizer, Gilead, Cidara, and F2G; and roles as President of MSGERC and Vice-President of ICHS. P. G. P. reports grants or contracts from Astellas, Scynexis, Gilead, Cidara, Melinta, and F2G, and consulting fees from Melinta, Matinas, F2G, and Cidara. J. P. reports royalties or licenses from UpToDate and Pulmocide (data review). A. S. reports grants or contracts from Astellas and Mayne, and consulting fees from F2G and GSK. P. V. reports grants or contracts paid to Mayo Clinic from Cidara, Scynexis, and Ansun; payment or honoraria paid to author from Merck Manual (author of chapter on fungi); and participation on a data and safety monitoring board or advisory board for AbbVie and Scynexis (payments to Mayo Clinic). 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) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

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.)

Competing Interests: Shari Lipner has served as a consultant for Ortho‐Dermatologics, Moberg Pharmaceuticals, Hoth Therapeutics, and BelleTorus Corporation. Lisa Tushla has received research grant support from Bristol Myers Squibb and Novartis in the area of skin cancer. These financial relationships were not involved with this study. The remaining authors declare no conflict of interest.

The rapid pace of name changes of medically important fungi is creating challenges for clinical laboratories and clinicians involved in patient care. We describe two sources of name change which have different drivers, at the species versus the genus level. Some suggestions are made here to reduce the number of name changes. We urge taxonomists to provide diagnostic markers of taxonomic novelties. Given the instability of phylogenetic trees due to variable taxon sampling, we advocate to maintain genera at the largest possible size. Reporting of identified species in complexes or series should where possible comprise both the name of the overarching species and that of the molecular sibling, often cryptic species. Because the use of different names for the same species will be unavoidable for many years to come, an open access online database of the names of all medically important fungi, with proper nomenclatural designation and synonymy, is essential. We further recommend that while taxonomic discovery continues, the adaptation of new name changes by clinical laboratories and clinicians be reviewed routinely by a standing committee for validation and stability over time, with reference to an open access database, wherein reasons for changes are listed in a transparent way., Competing Interests: The authors declare no conflict of interest.

Invasive fungal infections cause significant morbidity and mortality in hematopoietic stem cell transplant recipients. In order to minimize these infections, prophylaxis has become routine, although the agents used have changed over time. This presents new challenges as we consider an approach to breakthrough infections and recognize the epidemiologic shift toward isolates with higher rates of drug resistance. This review outlines the management of the most common pathogens (Candida, Aspergillus, Mucorales) as well as rarer pathogens that have higher rates of resistance (Trichosporon, Fusarium, Scedosporium, and Lomentospora). We discuss potential approaches to proven or possible breakthrough infections with yeast and pulmonary mold disease. Finally, we outline the role for combination therapy and newer antifungals, acknowledging current knowledge gaps and areas for future exploration., (© 2023 Wiley Periodicals LLC.)

Cryptococcosis is an invasive fungal infection found worldwide that causes significant morbidity and mortality among a broad range of hosts. There are approximately 223,000 new cases of cryptococcosis annually throughout the world, and at least 180,000 deaths are attributed to this infection each year. Most of these are due to complications of cryptococcal meningoencephalitis among HIV-infected patients in resource-limited environments. The majority of individuals diagnosed with cryptococcosis have underlying conditions associated with immune dysfunction such as HIV, solid organ transplant, hematologic malignancy, organ failure syndromes, and/or the use of immunosuppressive agents such as glucocorticosteroids and biologic agents. In most clinical series, there is a small proportion of patients with cryptococcosis who are phenotypically normal; that is, they have no clinically obvious predisposition to disease. Cryptococcal meningoencephalitis (CME) presentation and management differ substantially between these normal individuals and their immunocompromised counterparts. In this review, we will focus on CME in the phenotypically normal host and underscore differences in the clinical presentation, management, outcome, and potential risk factors for these patients compared to immunocompromised persons who develop this potential devastating invasive fungal infection.

Background: Fosmanogepix is a first-in-class antifungal targeting the fungal enzyme Gwt1, with broad-spectrum activity against yeasts and moulds, including multidrug-resistant fungi, formulated for intravenous (IV) and oral administration., Methods: This global, multicenter, non-comparative study evaluated the safety and efficacy of fosmanogepix for first-line treatment of candidaemia in non-neutropenic adults. Participants with candidaemia, defined as a positive blood culture for Candida spp. within 96 h prior to study entry, with ≤2 days of prior systemic antifungals, were eligible. Participants received fosmanogepix for 14 days: 1000 mg IV twice daily on Day 1, followed by maintenance 600 mg IV once daily, and optional switch to 700 mg orally once daily from Day 4. Eligible participants who received at least one dose of fosmanogepix and had confirmed diagnosis of candidaemia (<96 h of treatment start) composed the modified intent-to-treat (mITT) population. Primary efficacy endpoint was treatment success at the end of study treatment (EOST) as determined by the Data Review Committee. Success was defined as clearance of Candida from blood cultures with no additional antifungal treatment and survival at the EOST., Results: Treatment success was 80% (16/20, mITT; EOST) and Day 30 survival was 85% (17/20; 3 deaths unrelated to fosmanogepix). Ten of 21 (48%) were switched to oral fosmanogepix. Fosmanogepix was well tolerated with no treatment-related serious adverse events/discontinuations. Fosmanogepix had potent in vitro activity against baseline isolates of Candida spp. (MICrange: CLSI, 0.002-0.03 mg/L)., Conclusions: Results from this single-arm Phase 2 trial suggest that fosmanogepix may be a safe, well-tolerated, and efficacious treatment for non-neutropenic patients with candidaemia, including those with renal impairment., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Fungal endocarditis accounts for 1% to 3% of all infective endocarditis cases, is associated with high morbidity and mortality (>70%), and presents numerous challenges during clinical care. Candida spp. are the most common causes of fungal endocarditis, implicated in over 50% of cases, followed by Aspergillus and Histoplasma spp. Important risk factors for fungal endocarditis include prosthetic valves, prior heart surgery, and injection drug use. The signs and symptoms of fungal endocarditis are nonspecific, and a high degree of clinical suspicion coupled with the judicious use of diagnostic tests is required for diagnosis. In addition to microbiological diagnostics (e.g., blood culture for Candida spp. or galactomannan testing and PCR for Aspergillus spp.), echocardiography remains critical for evaluation of potential infective endocarditis, although radionuclide imaging modalities such as 18 F-fluorodeoxyglucose positron emission tomography/computed tomography are increasingly being used. A multimodal treatment approach is necessary: surgery is usually required and should be accompanied by long-term systemic antifungal therapy, such as echinocandin therapy for Candida endocarditis or voriconazole therapy for Aspergillus endocarditis.

Background: Antifungal prophylaxis can prevent invasive fungal diseases (IFDs) in high-risk, immunocompromised patients. This study assessed the real-world use of mold-active triazoles (MATs) for the prevention of IFDs., Methods: This subgroup analysis of a multicenter, observational, prospective registry in the United States from March 2017 to April 2020 included patients who received MATs for prophylaxis (isavuconazole, posaconazole, and voriconazole) at study index/enrollment. The primary objective was to describe patient characteristics and patterns of MAT use. Exploratory assessments included the frequency of breakthrough IFDs and MAT-related adverse drug reactions (ADRs)., Results: A total of 1177 patients (256 isavuconazole, 397 posaconazole, 272 voriconazole, and 252 multiple/sequenced MATs at/after index/enrollment) were included in the prophylaxis subgroup analysis. Patient characteristics were similar across MAT groups, but risk factors varied. Hematological malignancy predominated (76.5%) across all groups. Breakthrough IFDs occurred in 7.1% (73/1030) of patients with an investigator's assessment (5.0% [11/221] isavuconazole; 5.3% [20/374] posaconazole; 4.0% [9/226] voriconazole; and 15.8% [33/209] multiple/sequenced MATs). Aspergillus (29.5% [18/61]) and Candida (36.1% [22/61]) species were the most common breakthrough pathogens recovered. ADRs were reported in 14.1% of patients, and discontinuation of MATs due to ADRs was reported in 11.1% of patients (2.0% [5/245] isavuconazole; 8.2% [30/368] posaconazole; and 10.1% [27/267] voriconazole)., Conclusions: Breakthrough IFDs were uncommon in patients who received MATs for prophylaxis. Candida and Aspergillus species were the most commonly reported breakthrough pathogens. The discontinuation of MATs due to ADRs was infrequent. These findings support prophylactic strategies with isavuconazole, posaconazole, and voriconazole in high-risk patients., Competing Interests: Potential conflicts of interest. M.H.N. reports grants from Astellas Pharma Global Development, Inc., Scynexis, Mayne Pharma, Pulmocide, and T2 Biosystems and serves as consultant to T2 Biosystems and MiraVista. L.O.Z. reports grants from Gilead, Pfizer, Scynexis, Cidara, and Pulmocide; payment or honoraria from Pfizer and F2G; and participation on boards for Cidara, F2G, Pfizer, Eurofins, and Appili. P.G.P. reports grants from Scynexis, Mayne Pharma, Astellas, and Cidara and consulting fees from F2G, Matinas, and Cidara. T.J.W. reports grants for experimental and clinical antimicrobial pharmacology, therapeutics, and diagnostics to his institution from Allergan, Amplyx, Astellas, Lediant, Merck, The Medicines Company, Scynexis, Shionogi, T2 Biosystems, Tetraphase, and Viosera and has served as consultant to Amplyx, Astellas, Allergan, ContraFect, Gilead, Karyopharm, Leadiant, The Medicines Company, Merck, Methylgene, Partner Therapeutics, Pfizer, Scynexis, Shionogi, Statera, and T2 Biosystems. J.B. reports payment or honoraria from medSynergy and participation on an advisory board for Pfizer. B.D.A. reports grants from Leadiant; royalties from UpToDate; participation on advisory boards for HealthTrackRx, Merck, and ThermoFisher; leadership or fiduciary roles on other boards for the IDSA; and acting as principal investigator for clinical trial sites for F2G, Scynexis, Cidara, and Shire/Takeda. M.H.M. reports grants and consulting fees from Astellas; grants from F2G and Scynexis; and consulting fees from Scynexis and PSI. J.J. and Y.S. are/were employees of Astellas Pharma Global Development, Inc. G.R.T. has nothing to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Fosmanogepix (FMGX), a novel antifungal available in intravenous (IV) and oral formulations, has broad-spectrum activity against pathogenic yeasts and molds, including fungi resistant to standard of care antifungals. This multicenter, open-label, single-arm study evaluated FMGX safety and efficacy for treatment of candidemia and/or invasive candidiasis caused by Candida auris. Eligible participants were ≥18 years, with established candidemia and/or invasive candidiasis caused by C. auris, (cultured within 120 h [for candidemia] or 168 h [for invasive candidiasis without candidemia] with accompanying clinical signs) and limited treatment options. Participants were treated with FMGX (≤42 days; loading dose: 1000 mg IV twice daily [Day 1], followed by 600 mg IV once daily [QD]). Switching to oral FMGX 800 mg QD was permitted from Day 4. Primary endpoint was treatment success (survival and clearance of C. auris from blood/tissue cultures without additional antifungals) at the end of the study treatment (EOST), assessed by an independent data review committee (DRC). Day 30 survival was a secondary endpoint. In vitro susceptibility of Candida isolates was assessed. Nine participants with candidemia (male:6, female:3; 21 to 76 years) in intensive care units in South Africa were enrolled; all received IV FMGX only. DRC-assessed treatment success at EOST and Day 30 survival were 89% (8/9). No treatment related adverse events or study drug discontinuations were reported. FMGX demonstrated potent in vitro activity against all C. auris isolates (MIC range: 0.008 to 0.015 μg/mL [CLSI]; 0.004-0.03 μg/mL [EUCAST]), with the lowest MICs compared to other antifungals tested. Thus, the results showed that FMGX was safe, well-tolerated, and efficacious in participants with candidemia caused by C. auris., Competing Interests: The authors declare a conflict of interest. Jose A. Vazquez received grant support from Cidara, Scynexis and was a consultant for Cidara, Scynexis, F2G, Amplyx. Michael R. Hodges, Eric Ople, Pamela Wedel were employees of Amplyx (now a Pfizer Inc subsidiary). Michael R. Hodges was previously an employee of Pfizer and holds Pfizer stock. Paul A. Bien and Margaret Tawadrous are employees of Pfizer and hold Pfizer stock. Iwona Oborska was a consultant for Amplyx, previously a Pfizer employee, and Pfizer shareholder. Fathima Paruk has served on the speaker bureaus for Thermofischer Scientific, Pfizer, Biomerieux, MSD and Dr Reddy's. Peter G. Pappas received grant support from Astellas, Gilead, Mayne, Cidara, Scynexis and provided advisory and consultancy services to Amplyx, Mayne, Scynexis. Kenneth Boffard has no conflicts of interest to declare.

Background: Rezafungin is a next-generation, once-a-week echinocandin in development for the treatment of candidaemia and invasive candidiasis and for the prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp after blood and marrow transplantation. We aimed to compare the efficacy and safety of intravenous rezafungin versus intravenous caspofungin in patients with candidaemia and invasive candidiasis., Methods: ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial done at 66 tertiary care centres in 15 countries. Adults (≥18 years) with systemic signs and mycological confirmation of candidaemia or invasive candidiasis were eligible for inclusion and randomly assigned (1:1) to receive intravenous rezafungin once a week (400 mg in week 1, followed by 200 mg weekly, for a total of two to four doses) or intravenous caspofungin (70 mg loading dose on day 1, followed by 50 mg daily) for no more than 4 weeks. The primary endpoints were global cure (consisting of clinical cure, radiological cure, and mycological eradication) at day 14 for the European Medical Agency (EMA) and 30-day all-cause mortality for the US Food and Drug Administration (FDA), both with a target non-inferiority margin of 20%, assessed in the modified intention-to-treat population (all patients who received one or more doses of study drug and had documented Candida infection based on a culture from blood or another normally sterile site obtained within 96 h before randomisation). Safety was evaluated by the incidence and type of adverse events and deaths in the safety population, defined as all patients who received any amount of study drug. The trial is registered with ClinicalTrials.gov, NCT03667690, and is complete., Findings: Between Oct 12, 2018, and Aug 29, 2021, 222 patients were screened for inclusion, and 199 patients (118 [59%] men; 81 [41%] women; mean age 61 years [SD 15·2]) were randomly assigned (100 [50%] patients to the rezafungin group and 99 [50%] patients to the caspofungin group). 55 (59%) of 93 patients in the rezafungin group and 57 (61%) of 94 patients in the caspofungin group had a global cure at day 14 (weighted treatment difference -1·1% [95% CI -14·9 to 12·7]; EMA primary endpoint). 22 (24%) of 93 patients in the rezafungin group and 20 (21%) of 94 patients in the caspofungin group died or had an unknown survival status at day 30 (treatment difference 2·4% [95% CI -9·7 to 14·4]; FDA primary endpoint). In the safety analysis, 89 (91%) of 98 patients in the rezafungin group and 83 (85%) of 98 patients in the caspofungin group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events that occurred in at least 5% of patients in either group were pyrexia, hypokalaemia, pneumonia, septic shock, and anaemia. 55 (56%) patients in the rezafungin group and 52 (53%) patients in the caspofungin group had serious adverse events., Interpretation: Our data show that rezafungin was non-inferior to caspofungin for the primary endpoints of day-14 global cure (EMA) and 30-day all-cause mortality (FDA). Efficacy in the initial days of treatment warrants evaluation. There were no concerning trends in treatment-emergent or serious adverse events. These phase 3 results show the efficacy and safety of rezafungin and support its ongoing development., Funding: Cidara Therapeutics and Mundipharma., Competing Interests: Declaration of interests AFD reports consulting fees from Cidara. AS reports a grant from Gilead Sciences; consulting fees and honoraria from Angelini, Gilead, Menarini, MSD, and Shionogi, outside of the submitted work; and grants, consulting fees, honoraria, and support attending meetings from Pfizer, outside of the submitted work. BJK reports independent data review committee membership for Cidara. 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. 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. TS reports being an employee of and stocks in Cidara. MC reports grants and study materials from Cidara; grants from Siam Pharmaceuticals; honoraria from Gilead and MSD; and consulting fees, honoraria, and support to attend meetings from Pfizer. 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. MK reports grants from Barnes-Jewish Hospital Foundation and consulting fees from Merck, Pfizer, and Shionogi, outside of the submitted work. PGP reports grants from and data review committee membership for Cidara; grants from Astellas, Scynexis, and Merck; and advisory board membership for F2G, 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; and is a board member of German Society for Haematology and Medical Oncology, Deutsche Gesellschaft für Information und Wissen, ECMM European Confederation of Medical Mycology, International Society for Human & Animal Mycology, Mycoses Study Group–Education and Research Consortium, and Wiley, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: In March 2020, the World Health Organization declared COVID-19, caused by the SARS-CoV-2 virus, a pandemic. Patients with severe cases resulting in hospitalization and mechanical ventilation are at risk for COVID-19-associated pulmonary aspergillosis, an invasive fungal infection, and should be screened for aspergillosis if they have persistent hemodynamic instability and fever. Early detection and treatment of this fungal infection can significantly reduce morbidity and mortality in this population., Objective: To develop an evidence-based care step pathway tool to help intensive care unit clinicians assess, diagnose, and treat COVID-19-associated pulmonary aspergillosis., Methods: A panel of 18 infectious disease experts, advanced practice registered nurses, pharmacists, and clinical researchers convened in a series of meetings to develop the Care Step Pathway tool, which was modeled on a tool developed by advanced practice nurses to evaluate and manage side effects of therapies for melanoma. The Care Step Pathway tool addresses various aspects of disease management, including assessment, screening, diagnosis, antifungal treatment, pharmacological considerations, and exclusion of other invasive fungal coinfections., Results: The Care Step Pathway tool was applied in the care of a patient with COVID-19-associated aspergillosis. The patient was successfully treated., Conclusion: The Care Step Pathway is an effective educational tool to help intensive care unit clinicians consider fungal infection when caring for COVID-19 patients receiving mechanical ventilation in the intensive care unit, especially when the clinical course is deteriorating and antibiotics are ineffective., (©2022 American Association of Critical-Care Nurses.)

Introduction: The epidemiology of invasive Candida infections is evolving. Infections caused by non- albicans Candida spp. are increasing; however, the antifungal pipeline is more promising than ever and is enriched with repurposed drugs and agents that have new mechanisms of action. Despite progress, unmet needs in the treatment of invasive candidiasis remain, and there are still too few antifungals that can be administered orally or that have CNS penetration., Areas Covered: The authors shed light on those antifungal agents active against Candida that are in early- and late-stage clinical development. Mechanisms of action and key pharmacokinetic and pharmacodynamic properties are discussed. Insights are offered on the potential future roles of the investigational agents MAT-2203, oteseconazole, ATI-2307, VL-2397, NP-339, and the repurposed drug miltefosine., Expert Opinion: Ibrexafungerp and fosmanogepix have novel mechanisms of action and will provide effective options for the treatment of Candida infections (including those caused by multiresistant Candida spp). Rezafungin, an echinocandin with an extended half-life allowing for once weekly administration, will be particularly valuable for outpatient treatment and prophylaxis. Despite this, there is an urgent need to garner clinical data on investigational drugs, especially in the current rise of azole-resistant and multidrug-resistant Candida spp.

Invasive fungal diseases cause significant morbidity and mortality, in particular affecting immunocompromised patients. Resistant organisms are of increasing importance, yet there are many notable differences in the ability to both perform and interpret antifungal susceptibility testing compared with bacteria. In this review, we will highlight the strengths and limitations of resistance data of pathogenic yeasts and moulds that may be used to guide treatment and predict clinical outcomes., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Antibody immunity has not been studied in organ transplant recipients (OTRs) with cryptococcosis. We determined serum antibody levels in OTRs: 23 cryptococcosis cases and 21 controls. Glucuronoxylomannan immunoglobulin M (IgM) and laminarin IgM were lower in cases than controls, were inversely associated with cryptococcosis status, and may hold promise as markers of cryptococcosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Invasive fungal infections continue to increase as at-risk populations expand. The high associated morbidity and mortality with fungal diseases mandate the continued investigation of novel antifungal agents and diagnostic strategies that include surrogate biomarkers. Biologic markers of disease are useful prognostic indicators during clinical care, and their use in place of traditional survival end points may allow for more rapid conduct of clinical trials requiring fewer participants, decreased trial expense, and limited need for long-term follow-up. A number of fungal biomarkers have been developed and extensively evaluated in prospective clinical trials and small series. We examine the evidence for these surrogate biomarkers in this review and provide recommendations for clinicians and regulatory authorities., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)