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This study investigates the diagnostic practices for mucormycosis among 30 French University Hospital mycology laboratories, in 2024. All laboratories perform both direct examination and culture, with fluorescent brighteners being the most commonly used method for direct examination. While 77 % of the participating laboratories routinely identify Mucorales to the species level, with 70 % having adopted Mucorales-specific quantitative PCR, primarily for the diagnosis of invasive fungal infections. Antifungal susceptibility testing practices varied between centers, with 36.7 % of laboratories consistently performing these tests, primarily using gradient concentration strips. Amphotericin B, posaconazole, and isavuconazole were the most frequently tested antifungals. These findings highlight variations in laboratory practices and emphasize the importance of establishing uniform diagnostic and susceptibility testing methods to optimize mucormycosis management., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Eric Dannaoui has received research grants from Biomérieux: travel grants from Gilead, Mundipharma, and Pfizer; speaker's fee from Mundipharma, Pfizer, and Gilead. Kévin Brunet has received travel grants from Pfizer and Gilead and speaker's fee from Gilead. Laurence Millon has received travel grants from Gilead and Pfizer; speaker's fee from Gilead and Pfizer. Marjorie Cornu received travel grants and speaker's fee from Gilead and Pfizer. The other authors have no conflicts of interest to disclose., (Copyright © 2024 SFMM. Published by Elsevier Masson SAS. All rights reserved.)

Background: Auranofin is an approved anti-rheumatic drug that has a broad-range inhibitory action against several microorganisms, including human pathogenic fungi. The auranofin activity against Histoplasma capsulatum, the dimorphic fungus that causes histoplasmosis, has not been properly addressed. Since there are few therapeutic options for this life-threatening systemic mycosis, this study evaluated the effects of auranofin on H. capsulatum growth and expression of virulence factors., Methodology/principal Findings: Minimal inhibitory and fungicidal concentrations (MIC and MFC, respectively) of auranofin against 15 H. capsulatum strains with distinct genetic backgrounds were determined using the yeast form of the fungus and a microdilution protocol. Auranofin activity was also assessed on a macrophage model of infection and on a Tenebrio molitor invertebrate animal model. Expression of virulence-related genes was compared between auranofin treated and untreated H. capsulatum yeast cells using a quantitative PCR assay. Auranofin affected the growth of different strains of H. capsulatum, with MIC and MFC values ranging from 1.25 to 5.0 μM and from 2.5 to >10 μM, respectively. Auranofin was able to kill intracellular H. capsulatum yeast cells and conferred protection against the fungus in the experimental animal model of infection. Moreover, the expression of catalase A, HSP70, superoxide dismutase, thioredoxin reductase, serine proteinase, cytochrome C peroxidase, histone 2B, formamidase, metallopeptidase, Y20 and YPS3 proteins were reduced after six hours of auranofin treatment. CONCLUSIONS/SIGNIFICANCE: Auranofin is fungicidal against H. capsulatum and reduces the expression of several virulence-related genes, which makes this anti-rheumatic drug a good candidate for new medicines against histoplasmosis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 de Abreu Almeida et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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.)

Objectives: We aimed to describe features and outcomes of cryptococcosis among HIV-seronegative individuals in a large surveillance network for cryptococcosis in France., Methods: We included incident cases of cryptococcosis in HIV-seronegative individuals from 2005 to 2020. We compared patient characteristics, disease presentations, cryptococcal antigen results, and induction antifungal treatments according to underlying disease. We examined factors associated with 90-day mortality. Among patients with disseminated infections, we investigated whether receipt of flucytosine and polyene combination was associated with lower mortality., Results: Among 652 individuals, 209 (32.1%) had malignancy, 130 (19.9%) were solid-organ transplant recipients, 204 (31.3%) had other immunocompromising conditions, and 109 (16.7%) had no reported underlying factor. The commonest presentations were disseminated infections (63.3%, 413/652) and isolated pulmonary infections (25.3%, 165/652). Solid-organ transplant patients were most likely to have disseminated infections and a positive serum cryptococcal antigen result. Patients with malignancy were older and less likely to receive a flucytosine-containing regimen for disseminated infections than others (58.7%, 78/133 vs. 73.2%, 194/265; p 0.029). The crude 90-day case-fatality ratio was 27.2% (95% CI, 23.5%-31.1%). Age ≥60 years (aOR: 2.75 [1.78-4.26]; p < 0.001), meningitis/fungaemia (aOR: 4.79 [1.80-12.7]; p 0.002), and malignancy (aOR: 2.4 [1.14-5.07]; p 0.02) were associated with higher 90-day mortality. Receipt of flucytosine and polyene combination was associated with lower 90-day mortality (aOR: 0.40 [0.23-0.71]; p 0.002) in multivariable analysis and inverse probability of treatment weighted analysis (aOR: 0.45 [0.25-0.80]; p 0.006)., Discussion: HIV-seronegative individuals with cryptococcosis comprise a wide range of underlying conditions with different presentations and outcomes, requiring a tailored approach to diagnosis and management., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: To determine the epidemiological cut-off values (ECVs) of ten antifungal agents in a wide range of yeasts and Aspergillus spp. using gradient concentration strips., Methods: The minimum inhibitory concentrations for amphotericin B, anidulafungin, caspofungin, micafungin, flucytosine, fluconazole, itraconazole, isavuconazole, posaconazole, and voriconazole, determined with gradient concentration strips at 35 French microbiology laboratories between 2002 and 2020, were retrospectively collected. Then, the ECVs were calculated using the iterative method and a cut-off value of 97.5%., Results: Minimum inhibitory concentrations were available for 17 653 clinical isolates. In total, 48 ECVs (including 32 new ECVs) were determined: 29 ECVs for frequent yeast species (e.g. Candida albicans and itraconazole/flucytosine, and Candida glabrata species complex [SC] and flucytosine) and rare yeast species (e.g. Candida dubliniensis, Candida inconspicua, Saccharomyces cerevisiae, and Cryptococcus neoformans) and 19 ECVs for Aspergillusflavus SC, Aspergillusfumigatus SC, Aspergillusnidulans SC, Aspergillusniger SC, and Aspergillusterreus SC., Conclusions: These ECVs can be added to the already available gradient concentration strip-specific ECVs to facilitate minimum inhibitory concentration interpretation and streamline the identification of nonwild type isolates., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: The growing emergence of azole-resistant Aspergillus fumigatus strains worldwide is a major concern for current systemic antifungal treatment. Here we report antifungal activities of a novel inhaled triazole, PC1244, against a collection of multi-azole-resistant A. fumigatus strains., Methods: MICs of PC1244 were determined for A. fumigatus carrying TR34/L98H (n = 81), TR46/Y121F/T289A (n = 24), M220 (n = 6), G54 (n = 11), TR53 (n = 1), TR463/Y121F/T289A (n = 2), G448S (n = 1), G432C (n = 1) and P216S (n = 1) resistance alleles originating from either India, the Netherlands or France. The effects of PC1244 were confirmed in an in vitro model of the human alveolus and in vivo in temporarily neutropenic, immunocompromised mice., Results: PC1244 exhibited potent inhibition [geometric mean MIC (range), 1.0 mg/L (0.125 to >8 mg/L)] of growth of A. fumigatus strains carrying cyp51A gene mutations, showing much greater potency than voriconazole [15 mg/L (0.5 to >16 mg/L)], and an effect similar to those on other azole-susceptible Aspergillus spp. (Aspergillus flavus, Aspergillus terreus, Aspergillus tubingensis, Aspergillus nidulans, Aspergillus niger, Aspergillus nomius, Aspergillus tamarii) (0.18-1 mg/L). In TR34/L98H and TR46/Y121F/T289A A. fumigatus-infected in vitro human alveolus models, PC1244 achieved superior inhibition (IC50, 0.25 and 0.34 mg/L, respectively) compared with that of voriconazole (IC90, >3 mg/L and >10 mg/L, respectively). In vivo, once-daily intranasal administration of PC1244 (0.56-70 μg/mouse) to the A. fumigatus (AF91 with M220V)-infected mice reduced pulmonary fungal load and serum galactomannan more than intranasal posaconazole., Conclusions: PC1244 has the potential to become a novel topical treatment of azole-resistant pulmonary aspergillosis., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

The recent development of highly sensitive and specific point-of-care tests has made it possible to diagnose HIV-associated cryptococcal meningitis within minutes. However, diagnostic advances have not been matched by new antifungal drugs and treatment still relies on old off-patent drugs: amphotericin B, flucytosine and fluconazole. Cryptococcal meningitis treatment is divided in three phases: induction, consolidation and maintenance. The induction phase, aimed at drastically reducing cerebrospinal fluid fungal burden, is key for patient survival. The major challenge in cryptococcal meningitis management has been the optimisation of induction phase treatment using the limited number of available medications, and major progress has recently been made. In this review, we summarise data from key trials which form the basis of current treatment recommendations for HIV-associated cryptococcal meningitis., Competing Interests: No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed.

Background: Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Africa despite increasing access to antiretroviral therapy (ART). Mortality is driven in part by limited availability of amphotericin-based treatment, drug-induced toxicities of amphotericin B deoxycholate and prolonged hospital admissions. A single, high-dose of liposomal amphotericin (L-AmB, Ambisome) on a fluconazole backbone has been reported as non-inferior to 14 days of standard dose L-AmB in reducing fungal burden. This trial examines whether single, high-dose L-AmB given with high-dose fluconazole and flucytosine is non-inferior to a seven-day course of amphotericin B deoxycholate plus flucytosine (the current World Health Organization [WHO] recommended treatment regimen)., Methods: An open-label phase III randomised controlled non-inferiority trial conducted in five countries in sub-Saharan Africa: Botswana, Malawi, South Africa, Uganda and Zimbabwe. The trial will compare CM induction therapy with (1) a single dose (10 mg/kg) of L-AmB given with 14 days of fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) to (2) seven days amphotericin B deoxycholate (1 mg/kg/day) given alongside seven days of flucytosine (100 mg/kg/day) followed by seven days of fluconazole (1200 mg/day). The primary endpoint is all-cause mortality at ten weeks with a non-inferiority margin of 10% and 90% power. Secondary endpoints are early fungicidal activity, proportion of grade III/IV adverse events, pharmacokinetic parameters and pharmacokinetic/pharmacodynamic associations, health service costs, all-cause mortality within the first two and four weeks, all-cause mortality within the first ten weeks (superiority analysis) and rates of CM relapse, immune reconstitution inflammatory syndrome and disability at ten weeks. A total of 850 patients aged ≥ 18 years with a first episode of HIV-associated CM will be enrolled (425 randomised to each arm). All patients will be followed for 16 weeks. All patients will receive consolidation therapy with fluconazole 800 mg/day to complete ten weeks of treatment, followed by fluconazole maintenance and ART as per local guidance., Discussion: A safe, sustainable and easy to administer regimen of L-AmB that is non-inferior to seven days of daily amphotericin B deoxycholate therapy may reduce the number of adverse events seen in patients treated with amphotericin B deoxycholate and shorten hospital admissions, providing a highly favourable and implementable alternative to the current WHO recommended first-line treatment., Trial Registration: ISRCTN, ISRCTN72509687 . Registered on 13 July 2017.

The antifungal effects of the novel triazole PC1244, designed for topical or inhaled administration, against Aspergillus fumigatus were tested in a range of in vitro and in vivo studies. PC1244 demonstrated potent antifungal activities against clinical A. fumigatus isolates ( n = 96) with a MIC range of 0.016 to 0.25 μg/ml, whereas the MIC range for voriconazole was 0.25 to 0.5 μg/ml. PC1244 was a strong tight-binding inhibitor of recombinant A. fumigatus CYP51A and CYP51B (sterol 14α-demethylase) enzymes and strongly inhibited ergosterol synthesis in A. fumigatus with a 50% inhibitory concentration of 8 nM. PC1244 was effective against a broad spectrum of pathogenic fungi (MIC range, <0.0078 to 2 μg/ml), especially Aspergillus terreus , Trichophyton rubrum , Candida albicans , Candida glabrata , Candida krusei , Cryptococcus gattii , Cryptococcus neoformans , and Rhizopus oryzae PC1244 also proved to be quickly absorbed into both A. fumigatus hyphae and bronchial epithelial cells, producing persistent antifungal effects. In addition, PC1244 showed fungicidal activity (minimum fungicidal concentration, 2 μg/ml) which indicated that it was 8-fold more potent than voriconazole. In vivo , once-daily intranasal administration of PC1244 (3.2 to 80 μg/ml) to temporarily neutropenic, immunocompromised mice 24 h after inoculation with itraconazole-susceptible A. fumigatus substantially reduced the fungal load in the lung, the galactomannan concentration in serum, and circulating inflammatory cytokine levels. Furthermore, 7 days of extended prophylaxis with PC1244 showed in vivo effects superior to those of 1 day of prophylactic treatment, suggesting accumulation of the effects of PC1244. Thus, PC1244 has the potential to be a novel therapy for the treatment of A. fumigatus infection in the lungs of humans., (Copyright © 2018 Colley et al.)

Aerosolized liposomal amphotericin B (L-AmB) has been investigated as prophylaxis against invasive aspergillosis. However, the clinical results are controversial and some trials suggest that toxicity could be a limitation for wider use. Our aim was to assess the dynamics of cell toxicity induced in a human alveolar epithelial cell line (A549) after exposure to L-AmB (50 to 400μg/ml) or amphotericin B deoxycholate (D-AmB; 50 to 200μg/ml) by monitoring real-time A549 cell viability using an impedance-based technology. Results were expressed as cell index values integrating cell adhesion, proliferation, and survival. In parallel, the gene expression of proinflammatory cytokines was quantified at 6 and 24h after drug addition by real-time RT-PCR on cell lysates. No sustained reduction of cell indexes was observed with L-AmB or empty liposomes, even at 400μg/ml. Only the highest concentration tested of L-AmB (400μg/ml) yielded transient significant 6-fold and 4-fold induction of TNF-α and IL-8 mRNAs, respectively. In contrast, D-AmB induced a decrease in cell indexes and only the 50μg/ml concentration of D-AmB was followed by cell recovery, higher concentrations leading to cell death. Significant 4-fold, 7-fold and 3-fold inductions of TNF-α, IL-8 and IL-33 mRNAs were also observed at 6h with 50μg/ml of D-AmB. In conclusion, continuous cell impedance measurement showed no toxicity on overall cellular behavior although a slight proinflammatory cytokine expression is possible after L-AmB challenge. Real-time kinetics of cell impedance is an interesting tool for initial screening of cell toxicity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The profile of PC945, a novel triazole antifungal designed for administration via inhalation, was assessed in a range of in vitro and in vivo studies. PC945 was characterized as a potent, tightly binding inhibitor of Aspergillus fumigatus sterol 14α-demethylase (CYP51A and CYP51B) activity (50% inhibitory concentrations [IC 50 s], 0.23 μM and 0.22 μM, respectively) with characteristic type II azole binding spectra. Against 96 clinically isolated A. fumigatus strains, the MIC values of PC945 ranged from 0.032 to >8 μg/ml, while those of voriconazole ranged from 0.064 to 4 μg/ml. Spectrophotometric analysis of the effects of PC945 against itraconazole-susceptible and -resistant A. fumigatus growth yielded IC 50 (determined based on optical density [OD]) values of 0.0012 to 0.034 μg/ml, whereas voriconazole (0.019 to >1 μg/ml) was less effective than PC945. PC945 was effective against a broad spectrum of pathogenic fungi (with MICs ranging from 0.0078 to 2 μg/ml), including Aspergillus terreus , Trichophyton rubrum , Candida albicans , Candida glabrata , Candida krusei , Cryptococcus gattii , Cryptococcus neoformans , and Rhizopus oryzae (1 or 2 isolates each). In addition, when A. fumigatus hyphae or human bronchial cells were treated with PC945 and then washed, PC945 was found to be absorbed quickly into both target and nontarget cells and to produce persistent antifungal effects. Among temporarily neutropenic immunocompromised mice infected with A. fumigatus intranasally, 50% of the animals survived until day 7 when treated intranasally with PC945 at 0.56 μg/mouse, while posaconazole showed similar effects (44%) at 14 μg/mouse. This profile affirms that topical treatment with PC945 should provide potent antifungal activity in the lung., (Copyright © 2017 Colley et al.)

The 5th European Conference on Infections in Leukaemia (ECIL-5) meeting aimed to establish evidence-based recommendations for the prophylaxis of Pneumocystis jirovecii pneumonia (PCP) in non-HIV-infected patients with an underlying haematological condition, including allogeneic HSCT recipients. Recommendations were based on the grading system of the IDSA. Trimethoprim/sulfamethoxazole given 2-3 times weekly is the drug of choice for the primary prophylaxis of PCP in adults ( A-II: ) and children ( A-I: ) and should be given during the entire period at risk. Recent data indicate that children may benefit equally from a once-weekly regimen ( B-II: ). All other drugs, including pentamidine, atovaquone and dapsone, are considered second-line alternatives when trimethoprim/sulfamethoxazole is poorly tolerated or contraindicated. The main indications of PCP prophylaxis are ALL, allogeneic HSCT, treatment with alemtuzumab, fludarabine/cyclophosphamide/rituximab combinations, >4 weeks of treatment with corticosteroids and well-defined primary immune deficiencies in children. Additional indications are proposed depending on the treatment regimen., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Given reports showing a high prevalence of azole resistance in Aspergillus fumigatus, alternatives to azole therapy are discussed when a threshold of 10% of azole-resistant environmental isolates is reached. This raises the issue of calculation of this threshold, either on the prevalence of azole-resistant isolates as a whole or on the prevalence of azole-resistant cases in populations at risk of invasive aspergillosis (IA). For isolate evaluation, there are high disparities in routine microbiological procedures for the isolation of A. fumigatus and azole resistance detection. There are also huge differences between the microbiological work-up for diagnosing IA. Some centres rely on galactomannan detection alone without actively trying to culture appropriate samples, which affects reliability of the figures on the prevalence of resistance and thus the threshold of resistance. Moreover, reports from the laboratory could mix up figures from completely different patient populations: frequent azole-resistant isolates from pneumology patients and rare azole-resistant isolates from haematology patients. Therefore, to sum isolates from different specimens and different wards can lead to erroneous calculations for the restricted populations at risk of developing IA. In conclusion, assessing the incidence of azole resistance in A. fumigatus should be based on harmonized consensual microbiological methods and reports should be restricted to IA episodes in identified populations at risk of IA when the issue is to define an operational threshold for modifying recommendations., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Mucormycosis is a rare, though increasingly prevalent, life-threatening fungal disease caused by Mucorales. The incidence has increased over the last decade and its mortality remains high at around 50%. Mucormycosis occurs mostly in patients with diabetes mellitus and/or in the context of immunosuppression resulting from chemotherapy for hematological malignancy, hematopoietic stem cell transplantation, or solid-organ transplantation. In this situation, lung and rhino-orbito-cerebral infections are the most frequent localizations of the disease. Prompt initiation of an effective treatment is essential to decrease mortality. However, mucormycosis and aspergillosis share close clinical and radiological features. Invasive procedures such as bronchial endoscopy and/or lung biopsy are necessary to confirm diagnosis, as no indirect tests are yet validated. Therefore, the challenge is to minimize the delay in diagnosis. When present, the reversed halo sign on CT scan is suggestive of mucormycosis. Quantitative polymerase chain reaction is a new promising approach to detect Mucorales DNA in serum and new molecular tools are available to detect Mucorales in tissues as well as to specify species. Recommendations from ECIL and ECMM/ESCMID have recently been published on management of mucormycosis. The recommended treatment is an amphotericin B lipid formulation in combination with surgery and modification of risk factors. High-dose (10 mg/kg) of liposomal amphotericin B is recommended in case of neurological involvement and posaconazole for maintenance therapy. Place of isavuconazole as well as posaconazole new formulations (tablets and intravenous) in first line treatment have to be defined. Improved radiologic descriptions of mucormycosis and new molecular tools may be key elements to help with rapid diagnosis in the future. Clinical trials are warranted to improve therapeutic success and hopefully survival., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Purpose of Review: This study focuses on the epidemiology and management of mucormycosis in hematopoietic stem cell transplant patients, a life-threatening mold infection whose incidence has increased over the past decades., Recent Findings: Mucormycosis may occur in hematopoietic stem cell transplant recipients with severe graft-versus-host disease, steroids, neutropenia, iron overload, diabetes, and malnutrition, or those who received antifungals not active against Mucorales. Its incidence in allogeneic hematopoietic stem cell transplant is around 0.3%. As Mucorales are not susceptible to voriconazole and candins, and as mucormycosis often mimics aspergillosis, it is extremely important to have a precise diagnostic to correctly manage the patient. The reversed halo sign on chest computed tomography has been associated to mucormycosis in neutropenic patients, but is not pathognomonic. Direct fungal identification is crucial. Molecular approaches are developed that may be extremely useful for early diagnosis., Summary: Although randomized trials are quite impossible to run, due to the rarity of the disease, the recent numerous data have allowed the elaboration of European guidelines for the management of mucormycosis. Lipid formulations of amphotericin B, and especially liposomal amphotericin B at high doses (5-10 mg/kg/day), are the standard treatment, combined with surgery and control of favoring factors. The prognosis is poor, and any delay in the initiation of therapy may impact on outcome.

The relationship between the azole preexposure of 86 patients and the genotype, azole susceptibility, and cyp51A polymorphisms of 110 corresponding Aspergillus fumigatus isolates was explored. Isolates carrying serial polymorphisms (F46Y and M172V with or without N248T with or without D255E with or without E427K) had higher itraconazole MICs (P = 0.04), although <2 μg/ml using the EUCAST methodology, were associated with two genetic clusters (P < 0.001) and with voriconazole preexposure of patients (P = 0.016). Voriconazole preexposure influences the distribution of A. fumigatus isolates with selection of isolates carrying cyp51A polymorphisms and higher itraconazole MICs.

In vitro interaction of anidulafungin with voriconazole was tested by a microdilution broth checkerboard technique and an agar diffusion method against 30 Aspergillus clinical isolates belonging to five different species. By using a complete inhibition endpoint, indifferent interactions were observed for 97% of the isolates by the checkerboard technique (FIC index from 0.5 to 2) and for 100% of the isolates by the agar diffusion method (variation of -2 to +1 log(2) dilutions).

Objectives: An increase in invasive aspergillosis (IA) due to azole-resistant Aspergillus fumigatus isolates has been reported for 10 years. Our study aimed to estimate the prevalence of azole resistance in isolates prospectively collected in patients with haematological diseases., Methods: One hundred and eighteen isolates were collected from 89 consecutive patients over 4 years. Fifty-one patients had proven or probable IA. Species identification was ascertained based on β-tubulin gene sequencing. The MICs of azole drugs were determined using Etest(®), and the cyp51A gene and its promoter were sequenced to detect mutations., Results: All isolates were identified as A. fumigatus and all of them but one had itraconazole and voriconazole MICs of ≤ 2 mg/L and posaconazole MICs of ≤ 0.25 mg/L. An isolate for which the itraconazole MIC was high (itraconazole MIC = 16 mg/L; voriconazole MIC = 0.38 mg/L; and posaconazole MIC = 0.25 mg/L) was recovered from a patient naive to azole treatment and had a new G432S substitution. To establish whether this mutation existed in other isolates, the 1426-2025 bp cyp51A locus was sequenced for all. G432S was not found., Conclusions: In A. fumigatus, the prevalence of azole resistance is currently low in the haematological population in the Paris area. Surveillance programmes for azole resistance to adapt antifungal treatments are warranted for clinical isolates of A. fumigatus.

MALDI-TOF MS can be used for the identification of microorganism species. We have extended its application to a novel assay of Candida albicans susceptibility to fluconazole, based on monitoring modifications of the proteome of yeast cells grown in the presence of varying drug concentrations. The method was accurate, and reliable, and showed full agreement with the Clinical Laboratory Standards Institute's reference method. This proof-of-concept demonstration highlights the potential for this approach to test other pathogens.

Trichoderma longibrachiatum, a filamentous fungus, was recently described as an emerging pathogen in immunocompromised patients. Here, we report the first case, to our knowledge, of isolated invasive lung infection by T. longibrachiatum in a patient with hematologic malignancy. The infection mimicked invasive pulmonary aspergillosis and was successfully treated with a combination of voriconazole and caspofungin.

Cryptococcus neoformans is an opportunistic yeast that is present worldwide and interacts with various organisms. In humans, it is responsible for cryptococcosis, a deadly invasive fungal infection that represents around 220,000 cases per year worldwide. Starting from the natural history of the disease in humans, there is accumulating evidence on the capacity of this organism to enter dormancy. In response to the harsh host environment, the yeast is able to adapt dramatically and escape the vigilance of the host's immune cells to survive. Indeed, the yeast exposed to the host takes on pleiotropic phenotypes, enabling the generation of populations in heterogeneous states, including dormancy, to eventually survive at low metabolic cost and revive in favorable conditions. The concept of dormancy has been validated in C. neoformans from both epidemiological and genotyping data, and more recently from the biological point of view with the characterization of dormancy through the description of viable but nonculturable cells., Cryptococcus neoformans is a basidiomycetous opportunistic yeast that is widely present in the environment. It causes human cryptococcosis, which mainly affects immunocompromised patients and presents as a meningoencephalitis (1) that [...]

The article discusses a study which examined the diffusion of liposomal amphotericin B (L-AMB) and posaconazole (PSC) in the skeletal muscles of critically ill burn patients who received continuous venovenous hemodialysis. Topics discussed include subcutaneous mucormycosis caused by Mucor circinelloides, good tissue diffusion of L-AMB, and the poor bioavailability of PSC.