This article is part of a larger clinical practice guideline on the management of histoplasmosis in adults, children, and pregnant people, developed by the Infectious Diseases Society of America. In this article, the panel provides recommendations for treatment of mild and moderate acute pulmonary histoplasmosis. The panel's recommendations are based upon evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach.

Background:There is no prospective, US multicenter study of COVID-19-associated pulmonary aspergillosis (CAPA). CAPA definitions do not differentiate invasive aspergillosis (IPA) from colonization. Validity of single mycologic test results is unclear. Methods:We performed a prospective 7-center US study of mechanically ventilated adults with COVID-19 (April 2021-May 2022). Mycoses Study Group (MSGERC) CAPA criteria include host and clinical factors, imaging and test results (histopathology; bronchoalveolar lavage [BAL] culture and/or BAL or serum galactomannan-immunoassay). Proven, putative, and unlikely IPA were defined by clinical criteria. CAPA-unlikely IPA criteria included survival or negative autopsy following no/limited antifungal treatment. IPA likelihood was estimated using sensitivity/specificity of tests from autopsy data. Results:CAPA incidence was 7% (14/212). Independent CAPA risk factors were EORTC/MSGERC host factor and cavitary lesions. Seven percent, 79%, and 14% of CAPA patients had proven, putative, and unlikely IPA, respectively. Respective estimated IPA likelihoods were 84%, 7%-99%, and 1%-8%. Overall, median estimated IPA likelihood was 30%. Patients with CAPA-unlikely IPA had a single positive BAL galactomannan-immunoassay with other negative tests. CAPA mortality (71%) was not impacted by antifungal treatment or significantly different than without CAPA. CAPA incidence was 10% and 16% by European Confederation of Medical Mycology and Public Health Wales definitions, respectively. IPA was unlikely in 75% (6/8) and 57% (13/23) diagnosed by these definitions but not MSGERC. Conclusions:CAPA is associated with high mortality, but IPA's contribution is unclear. Single positive tests are insufficient for diagnosing CAPA-IPA. IPA likelihood is best estimated by combining test results (both positive and negative).

Chronic granulomatous fungal sinusitis is a rare, debilitating infection characterized by an enlarging mass affecting the orbit, nose, palate, and paranasal sinuses, with occasional intraorbital and intracranial extension. Most cases are reported in subtropical regions, with rare reports from the United States and Europe. Globally, Aspergillus flavus is the primary causative agent in >60% of cases, followed by other Aspergillus species and dematiaceous molds. This study highlights the histopathologic, microbiologic, and molecular diagnostic features of 6 cases with chronic granulomatous fungal sinusitis caused by the emerging pathogen Curvularia, predominantly affecting healthy African Americans in the Southeastern United States. Histopathological examination revealed multinucleated giant cells and noncaseating granulomatous inflammation. Short septate hyphae with bulbous swelling predominated, but there was significant variation in size, shape, and color, with half the cases lacking hyphal pigmentation. Lack of awareness of this emerging entity and variable morphology led to initial misidentification in 3 cases as hyaline septate hyphae (Fusarium), yeasts, and Blastomyces. All cases showed extracellular and intracellular (within multinucleated giant cells) hyphae and round forms with thick refractile cell walls lacking intracellular contents, yielding a characteristic “ghost shell” morphology, indicating fungal nonviability. Consistent with this finding, only 1 culture yielded a live isolate of Curvularia. In addition, 28S rRNA gene sequencing of formalin-fixed paraffin-embedded tissue was required for identification and identified Curvularia lunata (n = 4), Curvularia spicifera (n = 1), and Curvularia spp. (n = 1). One case with 2 hyphal morphologies also grew Aspergillus fumigatus, indicating coinfection. Chronic granulomatous fungal sinusitis, caused by the understudied and persistent pathogen Curvularia, is an emerging threat in immunocompetent hosts, characterized by pathogen persistence in critical facial and cranial structures, despite a significant host response. To accurately diagnose and guide treatment, surgical pathologists must be aware of its expanded geographic range, affected populations, and key histopathologic features, as described herein.

Background:Rezafungin is approved for use in adults with candidemia and/or invasive candidiasis (IC) based on data from the ReSTORE trial (NCT03667690), which demonstrated noninferior efficacy to caspofungin. For regulatory purposes, an additional cohort of patients from China was recruited to ReSTORE. Here, we compared rezafungin and caspofungin in patients with candidemia and/or IC through analysis of the ReSTORE global data plus the China extension study. Methods:Adults with candidemia/IC were randomized (1:1) to receive weekly rezafungin (400/200 mg) or daily caspofungin (70/50 mg) for ≤28 days. Noninferiority was concluded for primary efficacy endpoints if the upper bound of the 95% confidence interval (CI) was below 20% for Day 30 all-cause mortality and if the weighted lower bound was above -20% for Day 14 global cure. Additional efficacy outcomes and safety were evaluated. Results:Overall, 246 patients were randomized (122 rezafungin and 124 caspofungin). Noninferiority was demonstrated for both primary endpoints. Day 30 all-cause mortality was 25.2% and 24.8% (treatment difference 0.4%; 95% CI -10.8, 11.6) and Day 14 global cure was 56.5% and 57.3% (weighted treatment difference -1.0%; 95% CI -13.5, 11.6) with rezafungin versus caspofungin, respectively. Day 5 mycological eradication was numerically higher (68.7% vs 63.2%) and time to negative blood culture was numerically shorter (median 26.5 vs 38.8 h). Safety was comparable between groups; 53.3% (64/120; rezafungin) and 53.7% (66/123; caspofungin) of patients experienced serious adverse events. Conclusions:This analysis confirmed the overall efficacy and safety of rezafungin demonstrated in ReSTORE, with early efficacy related to front-loaded exposure.

Fungal endocarditis is an uncommon and challenging condition diagnostically and with respect to management. Medical literature on this topic is limited to case series, meta-analysis, review articles, and expert opinion. This brief review aims to describe major themes across the broad array of potential pathogens, but with a focus on nuanced points relating to the most common etiologies. The emphasis of this review will be clinical, focusing on general and species-specific risk factors, epidemiology, diagnosis, and management. The presentation of fungal endocarditis is non-specific and requires a high degree of clinical suspicion to make the diagnosis. Candida, Aspergillus, and Histoplasma are the most common causative agents, and while they share common trends, they have very distinct differences in epidemiology, diagnosis, and management.

Candida is a leading cause of hospital-acquired bloodstream infections, particularly in patients admitted to intensive care units. Nonculture-based molecular diagnostic assays improve time to treatment, thereby potentially influencing morbidity and mortality. Echinocandins are the treatment of choice for most cases of invasive candidiasis (IC) that do not involve the central nervous system and/or the eyes. Targeted antifungal prophylaxis decreases rates of IC and may influence mortality. Candida auris represents an emerging public health concern worldwide due to its inherent antifungal resistance and lethality, and its ability to persist on inanimate material.

BACKGROUND:Infection by Cryptococcus gattii can lead to pulmonary or central nervous system (CNS) disease, or both. Whether the sites of infection and disease severity are associated with C. gattii species and lineages or with certain underlying medical conditions, or both is unclear. We conducted a retrospective cohort study to identify factors associated with site of infection and mortality among C. gattii cases. METHODS:We extracted data on 258 C. gattii cases from Australia, Canada, and the United States reported from 1999 to 2011. We conducted unadjusted and multivariable logistic regression analyses to evaluate factors associated with site of infection and C. gattii mortality among hospitalized cases (N = 218). RESULTS:Hospitalized C. gattii cases with CNS and other extrapulmonary disease were younger, more likely to reside in Australia, and be infected with variety gattii I (VGI) lineage but less likely to have comorbidities and die as compared to cases with pulmonary disease. The odds of having CNS and/or other extrapulmonary disease were 9 times higher in cases with VGI infection (adjusted odds ratio [aOR] = 9.21, 95% confidence interval [CI] = 3.28-25.89). Age ≥70 years (aOR = 6.69, 95% CI = 2.44-18.30), chronic lung disease (aOR = 2.62, 95% CI = 1.05-6.51) and an immunocompromised status (aOR = 2.08, 95% CI = 1.05-6.51) were associated with higher odds of C. gattii mortality. CONCLUSIONS:Among hospitalized cases, C. gattii species and lineage are associated with site of infection but not with the risk of death, whereas older age and comorbidities increase the risk of death.

Invasive fungal disease (IFD) is a morbid superinfection that can arise in critically ill patients with COVID-19 infection. Studies evaluating the full spectrum of COVID-19-associated fungal infections remain limited. Single-center retrospective study assessing IFD in patients with COVID-19, hospitalized for ≥ 72 h in the intensive care unit (ICU) between 02/25/20 and 02/28/22 (n = 1410). IFD was assessed using consensus criteria (EORTC/MSGERC or ISHAM/ECMM criteria). T- and chi-square tests compared demographic/clinical characteristics between IFD and non-IFD patients. Cox proportional hazards regression estimated risk factors for in-hospital mortality. Of 1410 patients with severe COVID-19, 70 (5

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.

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.

OBJECTIVES: Telecritical care (TCC) refers to the delivery of critical care using telehealth technologies. Despite increasing utilization, significant practice variation exists and literature regarding efficacy remains sparse. The Telecritical Care Collaborative Network sought to provide expert, consensus-based best practice recommendations for the design and delivery of TCC. DESIGN: We used a modified Delphi methodology. Following literature review, an oversight panel identified core domains and developed declarative statements for review by an expert voting panel. During three voting rounds, voters agreed or disagreed with statements and provided open-ended feedback, which the oversight panel used to revise statements. Statements met criteria for consensus when accepted by greater than or equal to 85% of voters. SETTING/SUBJECTS: The oversight panel included 18 multidisciplinary members of the TCC Collaborative Network, and the voting panel included 32 invited experts in TCC, emphasizing diversity of discipline, care delivery models, and geography. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified ten core domains: definitions/terminology; care delivery models; staffing and coverage models; technological considerations; ergonomics and workplace safety; licensing, credentialing, and certification; trust and relationship building; quality, safety, and efficiency, research agenda; and advocacy, leading to 79 practice statements. Of 79 original statements, 67 were accepted in round 1. After revision, nine were accepted in round 2 and two in round 3 (two statements were merged). In total, 78 practice statements achieved expert consensus. CONCLUSIONS: These expert consensus recommendations cover a broad range of topics relevant to delivery of TCC. Experts agreed that TCC is most effective when delivered by care teams with specific expertise and by programs with explicit protocols focusing on effective communication, technical reliability, and real-time availability. Interventions should be tailored to local conditions. Although further research is needed to guide future best practice statements, these results provide valuable and actionable recommendations for the delivery of high-quality TCC.

The Mycoses Study Group Education and Research Consortium is a collective of clinicians, researchers, and educators with the common goal to advance awareness, diagnosis, and management of invasive fungal diseases. Clinical Mycology Today, the Mycoses Study Group Education and Research Consortium's biennial meeting, is dedicated to discussing the most pressing contemporary issues facing the field of clinical mycology, promoting clinical, translational, and basic science collaborations, and mentoring the next generation of clinical mycologists. Here, we review the current opportunities and challenges facing the field of mycology that arose from discussions at the 2022 meeting, with emphasis on novel host risk factors, emerging resistant fungal pathogens, the evolving antifungal pipeline, and critical issues affecting the advancement of mycology research. Clinical mycology is at a pivotal inflection point, with expanding patient populations at risk of fungal infections, emerging drug-resistant pathogens, and promising new antifungals on the horizon.

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. This preplanned subgroup analysis of the ReSTORE trial supports rezafungin efficacy and safety versus caspofungin for the treatment of candidemia and/or invasive candidiasis in patients with a positive culture close to randomization, who may represent patients with more serious infections. Graphical Abstract

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

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. 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. Of 294 patients in STRIVE/ReSTORE, 113 were in the ICU at randomisation (rezafungin n = 46; caspofungin n = 67). At baseline, 30

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.