Incidence and Mortality of COVID-19-Associated Invasive Fungal Infections Among Critically Ill Intubated Patients: A Multicenter Retrospective Cohort Analysis.

Background: An association between coronavirus disease 2019 (COVID-19)-associated invasive fungal infections (CAIFIs) and high mortality among intubated patients has been suggested in previous research. However, some of the current evidence was derived from small case series and multicenter studies conducted during different waves of the COVID-19 pandemic. We examined the incidence of CAIFIs and their associated mortality using a large, multicenter COVID-19 database built throughout the pandemic. Methods: We conducted a retrospective analysis of the National COVID Cohort Collaborative (N3C) database collected from 76 medical centers in the United States between January 2020 and August 2022. Patients were 18 years or older and intubated after severe acute respiratory syndrome coronavirus 2 infection. The primary outcomes were incidence and all-cause mortality at 90 days. To assess all-cause mortality, we fitted Cox proportional hazard models after adjusting for confounders via inverse probability weighting. Results: Out of the 4 916 229 patients with COVID-19 diagnosed during the study period, 68 383 (1.4%) met our cohort definition. The overall incidence of CAIFI was 2.80% (n = 1934/68 383). Aspergillus (48.2%; n = 933/1934) and Candida (41.0%; n = 793/1934) were the most common causative organisms. The incidence of CAIFIs associated with Aspergillus among patients who underwent BAL was 6.2% (n = 83/1328). Following inverse probability weighting, CAIFIs caused by Aspergillus (hazard ratio [HR], 2.0; 95% CI, 1.8-2.2) and Candida (HR, 1.7; 95% CI, 1.5-1.9) were associated with increased all-cause mortality. Systemic antifungals reduced mortality in 17% of patients with CAIFI with Aspergillus and 24% of patients with CAIFI with Candida. Conclusions: The incidence of CAIFI was modest but associated with higher 90-day all-cause mortality among intubated patients. Systemic antifungals modified mortality.

MSG-15: Super-Bioavailability Itraconazole Versus Conventional Itraconazole in the Treatment of Endemic Mycoses-A Multicenter, Open-Label, Randomized Comparative Trial.

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.

Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM.

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.

Description of Cryptococcosis Following SARS-CoV-2 Infection: A Disease Survey Through the Mycosis Study Group Education and Research Consortium (MSG-19).

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.

Spatial Epidemiologic Analysis and Risk Factors for Nontuberculous Mycobacteria Infections, Missouri, USA, 2008-2019.

Nontuberculous mycobacteria (NTM) infections are caused by environmental exposure. We describe spatial distribution of NTM infections and associations with sociodemographic factors and flooding in Missouri, USA. Our retrospective analysis of mycobacterial cultures reported to the Missouri Department of Health and Social Services surveillance system during January 1, 2008-December 31, 2019, detected geographic clusters of infection. Multilevel Poisson regression quantified small-area geographic variations and identified characteristics associated with risk for infection. Median county-level NTM infection rate was 66.33 (interquartile range 51-91)/100,000 persons. Risk of clustering was significantly higher in rural areas (rate ratio 2.82, 95% CI 1.90-4.19) and in counties with >5 floodings per year versus no flooding (rate ratio 1.38, 95% CI 1.26-1.52). Higher risk for NTM infection was associated with older age, rurality, and more flooding. Clinicians and public health professionals should be aware of increased risk for NTM infections, especially in similar environments.

Single High Dose of Liposomal Amphotericin B in Human Immunodeficiency Virus/AIDS-Related Disseminated Histoplasmosis: A Randomized Trial.

BACKGROUND: Histoplasmosis is a major AIDS-defining illness in Latin America. Liposomal amphotericin B (L-AmB) is the drug of choice for treatment, but access is restricted due to the high drug and hospitalization costs of the conventional long regimens. METHODS: Prospective randomized multicenter open-label trial of 1- or 2-dose induction therapy with L-AmB versus control for disseminated histoplasmosis in AIDS, followed by oral itraconazole therapy. We randomized subjects to: (i) single dose 10 mg/kg of L-AmB; (ii) 10 mg/kg of L-AmB on D1, and 5 mg/kg of L-AmB on D3; (iii) 3 mg/kg of L-AmB daily for 2 weeks (control). The primary outcome was clinical response (resolution of fever and signs/symptoms attributable to histoplasmosis) at day 14. RESULTS: A total of 118 subjects were randomized, and median CD4+ counts, and clinical presentations were similar between arms. Infusion-related toxicity, kidney toxicity at multiple time-points, and frequency of anemia, hypokalemia, hypomagnesemia, and liver toxicity were similar. Day 14 clinical response was 84% for single-dose L-AmB, 69% 2-dose L-AmB, and 74% for control arm (P = .69). Overall survival on D14 was 89.0% (34/38) for single-dose L-AmB, 78.0% (29/37) for 2-dose L-AmB, and 92.1% (35/38) for control arm (P = .82). CONCLUSIONS: One day induction therapy with 10 mg/kg of L-AmB in AIDS-related histoplasmosis was safe. Although clinical response may be non-inferior to standard L-AmB therapy, a confirmatory phase III clinical trial is needed. A single induction dose would markedly reduce drug-acquisition costs (>4-fold) and markedly shorten and simplify treatment, which are key points in terms of increased access.

Corticosteroids Increase the Risk of Invasive Fungal Infections More Than Tumor Necrosis Factor-Alpha Inhibitors in Patients With Inflammatory Bowel Disease.

Background: Invasive fungal infections are a devastating complication of inflammatory bowel disease (IBD) treatment. We aimed to determine the incidence of fungal infections in IBD patients and examine the risk with tumor necrosis factor-alpha inhibitors (anti-TNF) compared with corticosteroids. Methods: In a retrospective cohort study using the IBM MarketScan Commercial Database we identified US patients with IBD and at least 6 months enrollment from 2006 to 2018. The primary outcome was a composite of invasive fungal infections, identified by ICD-9/10-CM codes plus antifungal treatment. Tuberculosis (TB) infections were a secondary outcome, with infections presented as cases/100 000 person-years (PY). A proportional hazards model was used to determine the association of IBD medications (as time-dependent variables) and invasive fungal infections, controlling for comorbidities and IBD severity. Results: Among 652 920 patients with IBD, the rate of invasive fungal infections was 47.9 cases per 100 000 PY (95% CI 44.7-51.4), which was more than double the TB rate (22 cases [CI 20-24], per 100 000 PY). Histoplasmosis was the most common invasive fungal infection (12.0 cases [CI 10.4-13.8] per 100 000 PY). After controlling for comorbidities and IBD severity, corticosteroids (hazard ratio [HR] 5.4; CI 4.6-6.2) and anti-TNFs (HR 1.6; CI 1.3-2.1) were associated with invasive fungal infections. Conclusions: Invasive fungal infections are more common than TB in patients with IBD. The risk of invasive fungal infections with corticosteroids is more than double that of anti-TNFs. Minimizing corticosteroid use in IBD patients may decrease the risk of fungal infections.

The Geographic Distribution of Dimorphic Mycoses in the United States for the Modern Era.

BACKGROUND: The dimorphic mycoses (DMs) of the United States-Histoplasma, Coccidioides, and Blastomyces-commonly known as endemic mycoses of North America (in addition to Paracoccidioides) are increasingly being diagnosed outside their historical areas of endemicity. Despite this trend, the maps outlining their geographic distributions have not been updated in more than half a century using a large, nationwide database containing individual-patient-level data. METHODS: This was a retrospective analysis of >45 million Medicare fee-for-service beneficiaries from 1 January 2007 through 31 December 2016. Diagnoses of histoplasmosis, coccidioidomycosis, and blastomycosis were defined by International Classification of Diseases, Ninth/10th Revision, codes. The primary outcome was the incidence of histoplasmosis, coccidioidomycosis, and blastomycosis for each US county. Clinically meaningful thresholds for incidence were defined as 100 cases/100 000 person-years for histoplasmosis and coccidioidomycosis and 50 cases/100 000 person-years for blastomycosis. RESULTS: There were 79 749 histoplasmosis, 37 726 coccidioidomycosis, and 6109 blastomycosis diagnoses in unique persons from 2007-2016 across 3143 US counties. Considering all US states plus Washington, DC, 94% (48/51) had ≥1 county above the clinically relevant threshold for histoplasmosis, 69% (35/51) for coccidioidomycosis, and 78% (40/51) for blastomycosis. CONCLUSIONS: Persons with histoplasmosis, coccidioidomycosis, and blastomycosis are diagnosed in significant numbers outside their historical geographic distributions established >50 years ago. Clinicians should consider DM diagnoses based on compatible clinical syndromes with less emphasis placed on patients' geographic exposure. Increased clinical suspicion leading to a subsequent increase in DM diagnostic testing would likely result in fewer missed diagnoses, fewer diagnostic delays, and improved patient outcomes.

Novel agents in the treatment of invasive fungal infections in solid organ transplant recipients.

PURPOSE OF REVIEW: Recipients of solid organ transplants (SOTs) suffer a significant burden of invasive fungal infections (IFIs). The emergence of drug-resistant fungi and toxicities of currently used antifungal agents as well as drug-drug interactions with immunosuppressants make their treatment challenging. This review discusses selected novel antifungal agents in the development pipeline that can currently be used through clinical trials or may be commercially available in the near future. RECENT FINDINGS: These agents in development have novel pharmacokinetics and pharmacodynamics, expanded spectra of activity and excellent safety profiles. SUMMARY: The properties of novel antifungal agents have the potential to expand the therapeutic options for IFIs in recipients of SOTs.

Creation and Internal Validation of a Clinical Predictive Model for Fluconazole Resistance in Patients With Candida Bloodstream Infection.

Background: Fluconazole is recommended as first-line therapy for candidemia when risk of fluconazole resistance (fluc-R) is low. Lack of methods to estimate resistance risk results in extended use of echinocandins and prolonged hospitalization. This study aimed to develop a clinical predictive model to identify patients at low risk for fluc-R where initial or early step-down fluconazole would be appropriate. Methods: Retrospective analysis of hospitalized adult patients with positive blood culture for Candida spp from 2013 to 2019. Multivariable logistic regression model was performed to identify factors associated with fluc-R. Stepwise regression was performed on bootstrapped samples to test individual variable stability and estimate confidence intervals (CIs). We used receiver operating characteristic curves to assess performance across the probability spectrum. Results: We identified 539 adults with candidemia and 72 Candida isolates (13.4%) were fluc-R. Increased risk of fluc-R was associated with older age, prior bacterial bloodstream infection (odds ratio [OR], 2.02 [95% CI, 1.13-3.63]), myelodysplastic syndrome (OR, 3.09 [95% CI, 1.13-8.44]), receipt of azole therapy (OR, 5.42 [95% CI, 2.90-10.1]) within 1 year of index blood culture, and history of bone marrow or stem cell transplant (OR, 2.81 [95% CI, 1.41-5.63]). The model had good discrimination (optimism-corrected c-statistic 0.771), and all of the selected variables were stable. The prediction model had a negative predictive value of 95.7% for the selected sensitivity cutoff of 90.3%. Conclusions: This model is a potential tool for identifying patients at low risk for fluc-R candidemia to receive first-line or early step-down fluconazole.

Metabolic syndrome in people with HIV from Guatemala: analysis of components and risk factors.

BACKGROUND: People with HIV (PWH) in Latin America are at a greater risk of developing comorbidities due to the increasing burden of obesity and metabolic syndrome in the region. We explored the associations between social, cardiovascular and HIV-related risk factors with metabolic syndrome in PWH from Guatemala. METHODS: Cross-sectional study analyzing demographic, clinical and laboratory data from PWH. Metabolic syndrome diagnosis and components are defined by the harmonized Joint Scientific Statement criteria. Data were collected from July 2019 to March 2020 and analyzed using correlations and logistic regression. RESULTS: Median age was 39 years [IQR 31-48], 56.8% of participants were male and 31.5% (n = 266, 95% CI 0.28-0.34) had metabolic syndrome. Age (adjusted odds ratio (aOR): 1.03, 95% CI 1.02-1.05, p <0.001), urban dweller (aOR: 1.48, 95% CI 1.00-2.18, p = 0.049), low physical activity (aOR: 1.45, 95% CI 1.01-2.08, p = 0.046), hyperuricemia (aOR: 3.31, 95% CI 1.93-5.67, p <0.001), current CD4+ T cell count < 200 cells/mm3 (aOR: 1.96, 95% CI 1.19-3.23, p = 0.009), 6 months of efavirenz (aOR: 1.89, 95% CI 1.29-2.77, p = 0.001), and obesity (aOR: 37.0, 95% CI 7.70-178.2, p < 0.001) were independently associated with metabolic syndrome. CONCLUSIONS: Prevalence of metabolic syndrome in this study was high and driven mainly by social and cardiovascular risk factors such as age, urban dwelling, obesity, hyperuricemia and low physical activity. Efavirenz use and CD4 count were the only HIV-related factors associated with metabolic syndrome.

Management of Histoplasmosis by Infectious Disease Physicians.

Background: The Infectious Diseases Society of America (IDSA) guidelines for the management of histoplasmosis were last revised 15 years ago. Since those guidelines were compiled, new antifungal treatment options have been developed. Furthermore, the ongoing development of immunomodulatory therapies has increased the population at increased risk to develop histoplasmosis. Methods: An electronic survey about the management practices of histoplasmosis was distributed to the adult infectious disease (ID) physician members of the IDSA's Emerging Infections Network. Results: The survey response rate was 37% (551/1477). Only 46% (253/551) of respondents reported seeing patients with histoplasmosis. Regions considered endemic had 82% (158/193) of physicians report seeing patients with histoplasmosis compared to 27% (95/358) of physicians in regions not classically considered endemic (P < 0.001). Most ID physicians follow IDSA treatment guidelines recommending itraconazole for acute pulmonary (189/253 [75%]), mild-moderate disseminated (189/253 [75%]), and as step-down therapy for severe disseminated histoplasmosis with (232/253 [92%]) and without (145/253 [57%]) central nervous system involvement. There were no consensus recommendations observed for survey questions regarding immunocompromised patients. Conclusions: Though there are increased reports of histoplasmosis diagnoses outside regions classically considered endemic, a majority of ID physicians reported not seeing patients with histoplasmosis. Most respondents reported adherence to IDSA guidelines recommending itraconazole in each clinical situation. New histoplasmosis guidelines need to reflect the growing need for updated general guidance, particularly for immunocompromised populations.

Digital Strategy and Social Media for Infectious Diseases.

This supplement demonstrates the profound reach of social media across several domains: improved clinical care and advocacy, data analysis, broad reach to diverse patient populations, educational access, best practices in medical education, peer review, digital strategy for individuals and institutions, and combating misinformation.

Noninvasive Testing and Surrogate Markers in Invasive Fungal Diseases.

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.

Attributable Mortality of Candida Bloodstream Infections in the Modern Era: A Propensity Score Analysis.

BACKGROUND: This study quantifies the mortality attributable to Candida bloodstream infections (BSI) in the modern era of echinocandins. METHODS: We conducted a retrospective cohort study of adult patients admitted to Barnes Jewish Hospital, a 1368-bed tertiary care academic hospital, in Saint Louis, Missouri, from 1 February 2012 to 30 April 2019. We identified 626 adult patients with Candida BSI that were frequency-matched with 6269 control patients that had similar Candida BSI risk-factors. The 90-day all-cause mortality attributable to Candida BSI was calculated using three methods-propensity score matching, matching by inverse weighting of propensity score, and stratified analysis by quintile. RESULTS: The 90-day crude mortality was 42.4% (269 patients) for Candida BSI cases and 17.1% (1083 patients) for frequency-matched controls. Following propensity score-matching, the attributable risk difference for 90-day mortality was 28.4% with hazard ratio (HR) of 2.12 (95% confidence interval [CI], 1.98-2.25, P < .001). In the stratified analysis, the risk for mortality at 90 days was highest in patients in the lowest risk quintile to develop Candida BSI (hazard ratio [HR] 3.13 (95% CI, 2.33-4.19). Patients in this lowest risk quintile accounted for 81(61%) of the 130 untreated patients with Candida BSI. Sixty-nine percent of untreated patients (57/83) died versus 35% of (49/127) of treated patients (P < .001). CONCLUSIONS: Patients with Candida BSI continue to experience high mortality. Mortality attributable to Candida BSI was more pronounced in patients at lowest risk to develop Candida BSI. A higher proportion of these low-risk patients went untreated, experienced higher mortality, and should be the target of aggressive interventions to ensure timely, effective treatment.

Systemic antifungal therapy with isavuconazonium sulfate or other agents in adults with invasive mucormycosis or invasive aspergillosis (non-fumigatus): A multicentre, non-interventional registry study.

BACKGROUND: Isavuconazole, administered as isavuconazonium sulfate (ISAVUSULF), is a broad-spectrum triazole agent for the treatment of invasive fungal disease. In phase 3 studies, ISAVUSULF showed comparable efficacy to voriconazole and amphotericin B for the treatment of invasive aspergillosis (IA) and invasive mucormycosis (IM), respectively. OBJECTIVES: The objective of this study is to determine all-cause mortality and safety outcomes among adults with IM and/or IA non-fumigatus (nf) treated with ISAVUSULF or other antifungal therapies (AFT). PATIENTS AND METHODS: This multicentre, non-interventional registry enrolled patients aged ≥18 years with IM or IA-nf who received systemic AFT from January 2016 to November 2018. Patients received primary ISAVUSULF, non-primary ISAVUSULF, or other AFT, as monotherapy or combination therapy. The primary end point was all-cause mortality at Days 42 and 84; safety outcomes were adverse drug reactions (ADRs) to ISAVUSULF. RESULTS: Of 204 patients enrolled, 74 received primary ISAVUSULF, 30 non-primary ISAVUSULF, and 100 other AFT. All-cause mortality through Day 42 was numerically lower in the non-primary ISAVUSULF group than in the primary ISAVUSULF and other AFT groups, for patients with IM (20.0% vs. 33.3% and 41.3%, respectively) or IA-nf (0% vs. 14.8% and 17.8%, respectively). All-cause mortality tended to be lower with combination therapy than with monotherapy, except for patients with IM receiving primary ISAVUSULF. Of 111 patients receiving ISAVUSULF, 14 (12.6%) reported ADRs, of whom three (2.7%) developed serious ADRs. There were no drug-related deaths. CONCLUSIONS: This study supports the effectiveness and tolerability of ISAVUSULF in clinical practice. Further research is required to confirm the value of ISAVUSULF combination therapy over monotherapy.