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Isavuconazole is a novel triazole with broad-spectrum antifungal activity. The SECURE trial assessed efficacy and safety of isavuconazole versus voriconazole in patients with invasive mould disease. This was a phase 3, double-blind, global multicentre, comparative-group study. Patients with suspected invasive mould disease were randomised in a 1:1 ratio using an interactive voice–web response system, stratified by geographical region, allogeneic haemopoietic stem cell transplantation, and active malignant disease at baseline, to receive isavuconazonium sulfate 372 mg (prodrug; equivalent to 200 mg isavuconazole; intravenously three times a day on days 1 and 2, then either intravenously or orally once daily) or voriconazole (6 mg/kg intravenously twice daily on day 1, 4 mg/kg intravenously twice daily on day 2, then intravenously 4 mg/kg twice daily or orally 200 mg twice daily from day 3 onwards). We tested non-inferiority of the primary efficacy endpoint of all-cause mortality from first dose of study drug to day 42 in patients who received at least one dose of the study drug (intention-to-treat [ITT] population) using a 10% non-inferiority margin. Safety was assessed in patients who received the first dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00412893. 527 adult patients were randomly assigned (258 received study medication per group) between March 7, 2007, and March 28, 2013. All-cause mortality from first dose of study drug to day 42 for the ITT population was 19% with isavuconazole (48 patients) and 20% with voriconazole (52 patients), with an adjusted treatment difference of −1·0% (95% CI −7·8 to 5·7). Because the upper bound of the 95% CI (5·7%) did not exceed 10%, non-inferiority was shown. Most patients (247 [96%] receiving isavuconazole and 255 [98%] receiving voriconazole) had treatment-emergent adverse events (p=0·122); the most common were gastrointestinal disorders (174 [68%] vs 180 [69%]) and infections and infestations (152 [59%] vs 158 [61%]). Proportions of patients with treatment-emergent adverse events by system organ class were similar overall. However, isavuconazole-treated patients had a lower frequency of hepatobiliary disorders (23 [9%] vs 42 [16%]; p=0·016), eye disorders (39 [15%] vs 69 [27%]; p=0·002), and skin or subcutaneous tissue disorders (86 [33%] vs 110 [42%]; p=0·037). Drug-related adverse events were reported in 109 (42%) patients receiving isavuconazole and 155 (60%) receiving voriconazole (p<0·001). Isavuconazole was non-inferior to voriconazole for the primary treatment of suspected invasive mould disease. Isavuconazole was well tolerated compared with voriconazole, with fewer study-drug-related adverse events. Our results support the use of isavuconazole for the primary treatment of patients with invasive mould disease. Astellas Pharma Global Development, Basilea Pharmaceutica International.

Talaromyces marneffei is a dimorphic fungus that causes substantial disease in Asia, especially among persons infected with the human immunodeficiency virus. In this randomized, controlled trial, initial therapy with amphotericin B was found to be superior to itraconazole. The dimorphic fungus Talaromyces (previously Penicillium ) marneffei causes a life-threatening mycosis in immunocompromised persons living in or traveling to Southeast Asia, China, and India. 1 Talaromycosis (previously penicilliosis) is a major cause of human immunodeficiency virus (HIV)–related death; its prevalence is surpassed only by the prevalence of tuberculosis and cryptococcosis, 2 and it leads to 4 to 15% of HIV-related hospital admissions in regions in which the disease is endemic. 3 – 7 Talaromycosis is increasingly diagnosed among patients who are not infected with HIV but who have other immunodeficiency conditions 8 and is reported to be the second most common cause of all . . .

In this randomized trial of patients undergoing treatment for acute myelogenous leukemia or the myelodysplastic syndrome, prophylaxis with posaconazole resulted in fewer fungal infections and longer survival than did prophylaxis with fluconazole or itraconazole. The difference was primarily due to a lower rate of invasive aspergillosis in the posaconazole group. In patients undergoing treatment for acute myelogenous leukemia or the myelodysplastic syndrome, prophylaxis with posaconazole resulted in fewer fungal infections and longer survival than did prophylaxis with fluconazole or itraconazole. Invasive fungal infections remain a major cause of illness and death in patients with neutropenia who have hematologic cancers, despite the availability of new antifungal agents. The incidence of proven or probable mold and yeast infections can reach 24% among patients with leukemia. 1 , 2 Reported mortality from candidiasis or aspergillosis ranges from 40 to 50%, and mortality from fusariosis or zygomycosis is 70% or more. 3 – 8 Prophylaxis is a commonly used treatment strategy, because the diagnosis of fungal infection is often delayed or difficult to establish with certainty, and a delay in antifungal treatment increases mortality. 9 – 11 Antifungal prophylaxis with . . .

This randomized, double-blind trial of prophylaxis to prevent invasive fungal infections was conducted in 600 patients with severe graft-versus-host disease after hematopoietic stem-cell transplantation. Posaconazole, an extended-spectrum triazole, was as effective as fluconazole in preventing invasive fungal infections (incidence, 5.3% and 9.0%, respectively). With posaconazole, there were fewer cases of invasive aspergillosis infections. In patients with severe graft-versus-host disease, posaconazole was as effective as fluconazole in preventing invasive fungal infections. With posaconazole, there were fewer cases of invasive aspergillosis infections. Invasive fungal infections remain one of the leading causes of death among recipients of hematopoietic stem-cell transplants. 1 – 3 In these patients, factors associated with complications resulting from transplantation, such as prolonged neutropenia, graft failure, immunosuppression, and graft-versus-host disease (GVHD), increase the risk of an invasive fungal infection. 4 – 6 Randomized, controlled trials have shown the superiority of fluconazole over placebo for the prevention of fungal infections, primarily those caused by candida species, after hematopoietic stem-cell transplantation. Fluconazole prophylaxis reduces both fungal-infection–related and overall mortality 7 , 8 and has become a standard of care for antifungal prophylaxis after the first 100 days of . . .

Current estimates of fungal disease incidence and mortality are imprecise. Population at risk denominators were used to estimate annual incidence for 2019–21. Extensive literature searches from 2010 to 2023 were combined with over 85 papers on individual country and global disease burden. Crude and attributable mortality were estimated using a combination of untreated mortality, the proportion of patients who are treated, and percentage survival in treated patients. Awareness, guidelines, and accessibility of diagnostics and therapies informed the ratio of treated to untreated cases. Estimates do not include influenza or COVID-19 outbreaks. Data from more than 120 countries were included. Annually, over 2 113 000 people develop invasive aspergillosis in the context of chronic obstructive pulmonary disease, intensive care, lung cancer, or haematological malignancy, with a crude annual mortality of 1 801 000 (85·2%). The annual incidence of chronic pulmonary aspergillosis is 1 837 272, with 340 000 (18·5%) deaths. About 1 565 000 people have a Candida bloodstream infection or invasive candidiasis each year, with 995 000 deaths (63·6%). Pneumocystis pneumonia affects 505 000 people, with 214 000 deaths (42·4%). Cryptococcal meningitis affects 194 000 people, with 147 000 deaths (75·8%). Other major life-threatening fungal infections affect about 300 000 people, causing 161 000 deaths (53·7%). Fungal asthma affects approximately 11·5 million people and might contribute to 46 000 asthma deaths annually. These updated estimates suggest an annual incidence of 6·5 million invasive fungal infections and 3·8 million deaths, of which about 2·5 million (68%; range 35–90) were directly attributable.

The recovery of other pathogens in patients with SARS-CoV-2 infection has been reported, either at the time of a SARS-CoV-2 infection diagnosis (co-infection) or subsequently (superinfection). However, data on the prevalence, microbiology, and outcomes of co-infection and superinfection are limited. The purpose of this study was to examine the occurrence of co-infections and superinfections and their outcomes among patients with SARS-CoV-2 infection. We searched literature databases for studies published from October 1, 2019, through February 8, 2021. We included studies that reported clinical features and outcomes of co-infection or superinfection of SARS-CoV-2 and other pathogens in hospitalized and non-hospitalized patients. We followed PRISMA guidelines, and we registered the protocol with PROSPERO as: CRD42020189763. Of 6639 articles screened, 118 were included in the random effects meta-analysis. The pooled prevalence of co-infection was 19% (95% confidence interval [CI]: 14%-25%, I2 = 98%) and that of superinfection was 24% (95% CI: 19%-30%). Pooled prevalence of pathogen type stratified by co- or superinfection were: viral co-infections, 10% (95% CI: 6%-14%); viral superinfections, 4% (95% CI: 0%-10%); bacterial co-infections, 8% (95% CI: 5%-11%); bacterial superinfections, 20% (95% CI: 13%-28%); fungal co-infections, 4% (95% CI: 2%-7%); and fungal superinfections, 8% (95% CI: 4%-13%). Patients with a co-infection or superinfection had higher odds of dying than those who only had SARS-CoV-2 infection (odds ratio = 3.31, 95% CI: 1.82-5.99). Compared to those with co-infections, patients with superinfections had a higher prevalence of mechanical ventilation (45% [95% CI: 33%-58%] vs. 10% [95% CI: 5%-16%]), but patients with co-infections had a greater average length of hospital stay than those with superinfections (mean = 29.0 days, standard deviation [SD] = 6.7 vs. mean = 16 days, SD = 6.2, respectively). Our study showed that as many as 19% of patients with COVID-19 have co-infections and 24% have superinfections. The presence of either co-infection or superinfection was associated with poor outcomes, including increased mortality. Our findings support the need for diagnostic testing to identify and treat co-occurring respiratory infections among patients with SARS-CoV-2 infection.

The ability to detect and appropriately treat candidaemia differs across geography2—yet the mortality estimate presented used only the mean case fatality rate (CFR) and a global ratio of treated to untreated cases. [...]the author makes several anti-conservative assumptions that risk overestimation of burden. [...]we are concerned that many of the results would not be reproducible if another group was tasked with the same methodological approach, because many of the key steps rely on expert opinion from a single expert.

Bats with a nose for trouble Hibernating wild bat populations in eastern North America have suffered catastrophic decline in recent years as a result of white-nose syndrome (WNS). Colonization of the skin — on the eponymous nose — with the fungus Geomyces destructans has been linked to the disease, but other factors have been suggested as alternative causes. In a controlled experiment, it is now shown that G. destructans does infect bats, that it can be transmitted between animals and that infection causes WNS. This contrasts with recent reports that G. destructans is widespread among bats in Europe, where it seems to have no detrimental effects on carriers. White-nose syndrome (WNS) has caused recent catastrophic declines among multiple species of bats in eastern North America 1 , 2 . The disease’s name derives from a visually apparent white growth of the newly discovered fungus Geomyces destructans on the skin (including the muzzle) of hibernating bats 1 , 3 . Colonization of skin by this fungus is associated with characteristic cutaneous lesions that are the only consistent pathological finding related to WNS 4 . However, the role of G. destructans in WNS remains controversial because evidence to implicate the fungus as the primary cause of this disease is lacking. The debate is fuelled, in part, by the assumption that fungal infections in mammals are most commonly associated with immune system dysfunction 5 , 6 , 7 . Additionally, the recent discovery that G. destructans commonly colonizes the skin of bats of Europe, where no unusual bat mortality events have been reported 8 , 9 , 10 , has generated further speculation that the fungus is an opportunistic pathogen and that other unidentified factors are the primary cause of WNS 11 , 12 . Here we demonstrate that exposure of healthy little brown bats ( Myotis lucifugus ) to pure cultures of G. destructans causes WNS. Live G. destructans was subsequently cultured from diseased bats, successfully fulfilling established criteria for the determination of G. destructans as a primary pathogen 13 . We also confirmed that WNS can be transmitted from infected bats to healthy bats through direct contact. Our results provide the first direct evidence that G. destructans is the causal agent of WNS and that the recent emergence of WNS in North America may represent translocation of the fungus to a region with a naive population of animals 8 . Demonstration of causality is an instrumental step in elucidating the pathogenesis 14 and epidemiology 15 of WNS and in guiding management actions to preserve bat populations against the novel threat posed by this devastating infectious disease.

We evaluated the cost-effectiveness of posaconazole compared with standard azole therapy (SAT; fluconazole or itraconazole) for the prevention of invasive fungal infections (IFI) and the reduction of overall mortality in high-risk neutropenic patients with acute myelogenous leukaemia (AML) or myelodysplastic syndromes (MDS). The perspective was that of the Spanish National Health Service (NHS). A decision-analytic model, based on a randomised phase III trial, was used to predict IFI avoided, life-years saved (LYS), total costs, and incremental cost-effectiveness ratio (ICER; incremental cost per LYS) over patients' lifetime horizon. Data for the analyses included life expectancy, procedures, and costs associated with IFI and the drugs (in euros at November 2009 values) which were obtained from the published literature and opinions of an expert committee. A probabilistic sensitivity analysis (PAS) was performed. Posaconazole was associated with fewer IFI (0.05 versus 0.11), increased LYS (2.52 versus 2.43), and significantly lower costs excluding costs of the underlying condition (€6,121 versus €7,928) per patient relative to SAT. There is an 85% probability that posaconazole is a cost-saving strategy compared to SAT and a 97% probability that the ICER for posaconazole relative to SAT is below the cost per LYS threshold of €30,000 currently accepted in Spain. Posaconazole is a cost-saving prophylactic strategy (lower costs and greater efficacy) compared with fluconazole or itraconazole in high-risk neutropenic patients.

Deaths from AIDS (1 500 000 in 2013) have been falling more slowly than anticipated with improved access to antiretroviral therapy. Opportunistic infections account for most AIDS-related mortality, with a median age of death in the mid-30s. About 360 000 (24%) of AIDS deaths are attributed to tuberculosis. Fungal infections deaths in AIDS were estimated at more than 700 000 deaths (47%) annually. Rapid diagnostic tools and antifungal agents are available for these diseases and would likely have a major impact in reducing deaths. Scenarios for reduction of avoidable deaths were constructed based on published outcomes of the real-life impact of diagnostics and generic antifungal drugs to 2020. Annual deaths could fall for cryptococcal disease by 70 000, Pneumocystis pneumonia by 162 500, disseminated histoplasmosis by 48 000 and chronic pulmonary aspergillosis by 33 500, with approximately 60% coverage of diagnostics and antifungal agents; a total of >1 000 000 lives saved over 5 years. If factored in with the 90–90–90 campaign rollout and its effect, AIDS deaths could fall to 426 000 annually by 2020, with further reductions possible with increased coverage. Action could and should be taken by donors, national and international public health agencies, NGOs and governments to achieve the UNAIDS mortality reduction target, by scaling up capability to detect and treat fungal disease in AIDS. This article is part of the themed issue ‘Tackling emerging fungal threats to animal health, food security and ecosystem resilience’.