Search

The activity of liposomal nystatin against invasive pulmonary aspergillosis was investigated in persistently neutropenic rabbits. Treatment groups included liposomal nystatin at dosages of 1, 2 and 4 mg/kg/day intravenously, or amphotericin B deoxycholate 1 mg/kg/day administered intravenously after normal saline loading. As compared with untreated controls, liposomal nystatin administered at 2 and 4 mg/kg/day prolonged survival and reduced fungus-mediated tissue injury and excess lung weight at post-mortem in a similar manner to amphotericin B. Although amphotericin B was superior in clearing infected lung tissue, treatment with all regimens of liposomal nystatin led to a significant reduction in pulmonary fungal tissue burden. During treatment, ultrafast CT-scan demonstrated ongoing resolution of pulmonary lesions at 2 and 4 mg/kg/day, but not at 1 mg/kg/day. With the exception of mild increases in blood urea nitrogen (BUN) and serum creatinine values during treatment at 2 and 4 mg/kg/day, which were similar to those found in amphotericin B-treated rabbits, liposomal nystatin was well tolerated. Preliminary pharmacokinetic studies in non-infected animals established linear drug disposition of liposomal nystatin in plasma over the investigated dosage range and peak plasma levels above the MIC for the test strain after multiple daily dosing for 7 days. Liposomal nystatin increased survival and provided reduced tissue injury, effective microbiological clearance and tolerable side effects in experimental pulmonary aspergillosis in persistently neutropenic rabbits, thus providing a rational basis for further investigations in clinical trials. [ABSTRACT FROM AUTHOR]

Background: Infections are a major cause of morbidity in children with primary or secondary immunodeficiency, and have a negative impact on overall outcome., Objectives: This narrative review presents select paediatric-specific aspects regarding the clinical impact, diagnosis, management, and follow-up of infectious complications in patients with primary and secondary immunodeficiencies., Sources: PubMed until January 2024 and searched references in identified articles including the search terms: infection, immunodeficiency or cancer, diagnostics, antimicrobial agents, bacteria or fungus or virus, and follow-up., Content: Major advances have been made in the early detection and management of patients with primary immunodeficiency, and multiple analyses report in children with cancer on risk groups and periods of risk for infectious complications. Although many diagnostic tools are comparable between children and adults, specific considerations have to be applied, such as minimizing the use of radiation. Antimicrobial drug development remains a major challenge in the paediatric setting, which includes the establishment of appropriate dosing and paediatric approval. Last, long-term follow-up and the impact of late effects are extremely important to be considered in the management of immunocompromised paediatric patients., Implications: Although infectious disease supportive care of immunocompromised children and adolescents has considerably improved over the last three decades, close international collaboration is needed to target the specific challenges in this special population., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Invasive fungal disease (IFD) causes morbidity and mortality in immunocompromised hosts (ICHs). Based on increasing recognition of the impact of IFD on human disease, a recent WHO priority list identified key areas of need., Objectives: This review examines changes in the epidemiology of IFD, in particular the emergence of antifungal-resistant pathogens and the current availability of rapid diagnostic tests and antifungal treatment options., Sources: Literature between 2000 and January 2024 regarding fungal epidemiology, diagnostic tests, antifungal resistance, emerging fungal pathogens, and novel antifungal agents in both adult and paediatric ICH were reviewed., Content: We describe the changing epidemiology and continued burden and mortality of IFD in ICH. Furthermore, we discuss the emergence of antifungal-resistant organisms driven by new immunosuppressed populations, climate change, and antifungal exposure in the individual and environment. We highlight novel antifungal agents and how they will address current unmet needs., Implications: The changing epidemiology and increased population at risk for IFD, lack of recognition or quantification of risks for IFD with new therapies, current gaps in the availability of rapid diagnostic tests, and the imminent availability of novel antifungals with distinct spectra of activity argue for improved availability of and access to rapid diagnostics, antifungal stewardship programmes, and global access to antifungal agents., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Medically important pathogenic fungi invade vertebrate tissue and are considered primary when part of their nature life cycle is associated with an animal host and are usually able to infect immunocompetent hosts. Opportunistic fungal pathogens complete their life cycle in environmental habitats or occur as commensals within or on the vertebrate body, but under certain conditions can thrive upon infecting humans. The extent of host damage in opportunistic infections largely depends on the portal and modality of entry as well as on the host's immune and metabolic status. Diseases caused by primary pathogens and common opportunists, causing the top approximately 80% of fungal diseases [D. W. Denning, Lancet Infect Dis, 24:e428-e438, 2024, https://doi.org/10.1016/S1473-3099(23)00692-8], tend to follow a predictive pattern, while those by occasional opportunists are more variable. For this reason, it is recommended that diseases caused by primary pathogens and the common opportunists are named after the etiologic agent, for example, histoplasmosis and aspergillosis, while this should not be done for occasional opportunists that should be named as [causative fungus] [clinical syndrome], for example, Alternaria alternata cutaneous infection. The addition of a descriptor that identifies the location or clinical type of infection is required, as the general name alone may cover widely different clinical syndromes, for example, "rhinocerebral mucormycosis." A list of major recommended human and animal disease entities (nomenclature) is provided in alignment with their causative agents. Fungal disease names may encompass several genera of etiologic agents, consequently being less susceptible to taxonomic changes of the causative species, for example, mucormycosis covers numerous mucormycetous molds., Competing Interests: The authors declare no conflict of interest.

Invasive aspergillosis (IA) and mucormycosis (IM) cause significant morbidity and mortality in immunocompromised and/or hospitalized patients. Isavuconazonium sulfate, a prodrug of the antifungal triazole isavuconazole, has been approved for treatment of IA and IM in adults; and was recently approved in children. This study describes the outcomes, safety, and pharmacokinetics of isavuconazole for the treatment of proven, probable, or possible IA or IM in children. In this phase 2, open-label, non-comparative study, patients aged 1 to <18 years with at least possible invasive mold disease were enrolled across 10 centers in the US, Spain, and Belgium from 2019 to 2022. Patients received 10 mg/kg isavuconazonium sulfate daily (maximum 372 mg; equivalent to 5.4 mg/kg or 200 mg isavuconazole) for up to 84 (IA) or 180 days (IM). Outcomes included rates of all-cause case fatality, overall response, treatment-emergent adverse events (TEAEs), and pharmacokinetics. Of 31 patients enrolled, 61.3% were 1-<12 years old; 58.1% had underlying hematologic malignancies. The successful overall response rate at the end of treatment was 54.8%. Day 42 all-cause case fatality was 6.5%; 93.5% experienced TEAEs, and two patients discontinued treatment due to drug-related TEAEs. Dosing at 10 mg/kg (maximum dose: 372 mg) met the pre-defined exposure threshold of above the 25th percentile for the area under the concentration-time curve (≥60 mg·h/L). Simulated doses of 15 mg/kg improved drug exposures in patients aged 1-<3 years. Isavuconazole was well tolerated in children, with exposure consistent with adult studies. Successful response was documented in 54.8% of patients.CLINICAL TRIALSThis study is registered at ClinicalTrials.gov as NCT03816176., Competing Interests: The authors declare a conflict of interest (see Acknowledgments).

Background : Empirical antibacterial therapy for febrile neutropenia reduces mortality due to Gram-negative blood stream infections (BSIs). Pediatric guidelines recommend monotherapy with an antipseudomonal beta-lactam or a carbapenem and to add a second anti-Gram-negative agent in selected situations. We evaluated the changes in the proportions of resistance of beta-lactam monotherapies vs. their combination with amikacin, and the possible impact on ICU admission or death. Results : 797 BSIs due to Gram-negative bacteria in 685 patients were included. Combination therapies with amikacin had a lower percentage of isolates resistant to one or to both drugs compared with the respective monotherapy. The highest OR for ICU admission was observed when both drugs of the combination of meropenem-amikacin were resistant. Mortality was significantly associated with relapse or the progression of the underlying malignancy, and resistance to both drugs of the combinations of cefepime-amikacin or meropenem-amikacin. Methods : This study was based on data collected for a large multinational study, in which the susceptibility of Gram-negative bloodstream isolates was categorized following either EUCAST or CLSI according to local laboratory standards. An escalation antibiogram was generated for each selected drug. For resistant bacteria, the conditional susceptibility probability on resistance was calculated. Conclusions : In pediatric cancer patients with Gram-negative BSIs, the proportion of the resistant organism correlates with ICU admission or death, which may be reduced by combination therapy. In patients with suspected or confirmed Gram-negative BSIs that are not-improving or deteriorating under monotherapy, escalation to meropenem may represent the best option. Amikacin should be preferred when combination therapy is considered with ciprofloxacin as an alternative in the case of impaired renal function.

Background: Data on antifungal prescribing in neonatal patients are limited to either single-center or single-country studies or to 1-day recording. Therefore, we assessed antifungal longitudinal usage in neonatal units (NUs) within Europe., Methods: CALYPSO, a prospective weekly point prevalence study on antifungal drug usage in NUs in 18 hospitals (8 European countries), was conducted in 2020 during a 12-week period. All patients receiving systemic antifungals were included. Ward demographics were collected at the beginning; ward and patient data including indication, risk factors and antifungal regimen were weekly collected prospectively., Results: Among 27 participating NUs, 15 (56%) practiced antifungal prophylaxis for neonates with birth weight <1000 g or <1500 g and additional risk factors. In total, 174 patients received antifungals with a median frequency per week of 10.5% ranging from 6.9% to 12.6%. Indication for antifungal prescribing was prophylaxis in 135/174 (78%) courses and treatment in 22% [39 courses (69% empirical, 10% preemptive, 21% targeted)]. Fluconazole was the most frequent systemic agent used both for prophylaxis (133/135) and treatment (15/39, 39%). Among neonates receiving prophylaxis, the most common risk factors were prematurity (119/135, 88%), mechanical ventilation (109/135, 81%) and central vascular catheters (89/135, 66%). However, gestational age <28 weeks was only recorded in 55/135 (41%) courses and birth weight <1000 g in 48/135 (35%). Most common reason for empirical treatment was late-onset sepsis; all 8 targeted courses were prescribed for invasive candidiasis., Conclusion: Antifungal usage in European NUs is driven by prophylaxis and empirical treatment with fluconazole being the most prescribed agent for both indications., Competing Interests: E.C.: Speaker at sponsored symposia for Pfizer and F2G. C.G. is funded by the Spanish Ministry of Science and Innovation—Instituto de Salud Carlos III and Fondos FEDER (Contrato Juan Rodés JR22/00044). A.H.G. has received grants from Gilead, Merck, Sharp & Dohme and Pfizer and has served as a consultant to Amplyx, Astellas, Basilea, F2G, Gilead. Merck, Sharp & Dohme, Pfizer, Scynexis and Mundipharma. T.L. has received a grant from Gilead Sciences, has served as a consultant to Gilead Sciences, Merck/MSD, Pfizer, Astellas, AstraZeneca, Recordati and Roche and served at the speaker´s bureau of Gilead Sciences, Merck/MSD, Astellas, Pfizer and GSK and Recordati. E.R. has received research grants from Merck, Abvie, Shionogi, Cidara and Pfizer Inc. to his institution and is a scientific advisor and member of the speaker bureaux for Gilead, Merck, Shionogi, Mundipharma and Pfizer Inc. For the remaining authors, there are no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Recent ECIL-guidelines recommend a quantitative PCR (qPCR) guided pre-emptive treatment approach to toxoplasmosis in seropositive recipients of allogeneic hematopoietic cell transplantation (allo-HCT). While qPCR might serve as a sensitive tool for early Toxoplasma detection, its role in treatment follow-up remains unknown., Methods: We analyzed the qPCR kinetics of allo-HCT recipients experiencing either Toxoplasma infection (TI, n=71) or disease (TD, n=14) in relation to different parameters. We included 85 patients with available qPCR values expressed as quantitative cycle (Cq) from four large hematological centers from 2009 to 2023, and kinetic analysis was performed in a selection of 74 patients screened at least weekly with blood qPCR. Day 0 (D0) was the day of anti-Toxoplasma treatment start or (when untreated) day of diagnosis., Results: Time to qPCR negativity was inversely proportional to the Cq value at D0 (p=0.0063). Not reaching negativity at D10 was associated with a significantly higher mortality at D30 (p=0.023). Patients with a high D0-parasitic load and patients with TD showed slower clearance (p<0.001, p=0.032). Time to negativity was not significantly different for patients started on prophylactic vs curative doses as first-line treatment regimen (p=0.16)., Conclusions: This study underscores the predictive value of qPCR kinetics monitoring in allo-HCT patients with toxoplasmosis. With the aforementioned risk factors, clinicians can identify patients at high-risk for worse outcome. Our results support to consider a therapeutic change or reinforcement if the parasitic load does not decrease after 10 days, supplementing existing clinical guidelines., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

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.)

SUMMARYFungal infections are on the rise, driven by a growing population at risk and climate change. Currently available antifungals include only five classes, and their utility and efficacy in antifungal treatment are limited by one or more of innate or acquired resistance in some fungi, poor penetration into "sequestered" sites, and agent-specific side effect which require frequent patient reassessment and monitoring. Agents with novel mechanisms, favorable pharmacokinetic (PK) profiles including good oral bioavailability, and fungicidal mechanism(s) are urgently needed. Here, we provide a comprehensive review of novel antifungal agents, with both improved known mechanisms of actions and new antifungal classes, currently in clinical development for treating invasive yeast, mold (filamentous fungi), Pneumocystis jirovecii infections, and dimorphic fungi (endemic mycoses). We further focus on inhaled antifungals and the role of immunotherapy in tackling fungal infections, and the specific PK/pharmacodynamic profiles, tissue distributions as well as drug-drug interactions of novel antifungals. Finally, we review antifungal resistance mechanisms, the role of use of antifungal pesticides in agriculture as drivers of drug resistance, and detail detection methods for antifungal resistance.

Systemic antifungal therapy is critical for reducing the mortality from many invasive and chronic fungal infections. Triazole antifungals are the most frequently prescribed antifungals but require attention to dosing and drug interactions. Nearly 600 severe drug-drug interactions and over 1100 moderate interactions requiring dose modifications are described or anticipated with systemic antifungal agents (see https://www.aspergillus.org.uk/antifungal-drug-interactions/). In this article, we address the common and less common, but serious, drug interactions observed in clinical practice with triazole antifungals, including a group of drugs that cannot be prescribed with all or most triazole antifungals (ivabradine, ranolazine, eplerenone, fentanyl, apomorphine, quetiapine, bedaquiline, rifampicin, rifabutin, sirolimus, phenytoin and carbamazepine). We highlight interactions with drugs used in children and new agents introduced for the treatment of haematological malignancies or graft versus host disease (midostaurin, ibrutinib, ruxolitinib and venetoclax). We also summarize the multiple interactions between oral and inhaled corticosteroids and triazole antifungals, and the strategies needed to optimize the therapeutic benefits of triazole antifungal therapy while minimizing potential harm to patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Pneumocystis jirovecii can cause life-threatening pneumonia (PjP), and patients with haematological malignancies are at high risk of this infection. Prophylactic measures have significantly decreased morbidity and mortality, but there is a paucity of contemporary data on the incidence and clinical course of PjP in well-defined and homogenous patient populations, such as children suffering from acute lymphoblastic leukaemia (ALL). In the multi-international trial AIEOP-BFM ALL2009, PjP was diagnosed in six children (incidence 1/1000) and was associated with insufficient prophylaxis in five of them. Although none of the patients died of PjP, the long-term impact of the infection is unclear., (© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Introduction: In Germany, the growing incidence of invasive fungal infections (IFIs) is a significant health concern, particularly impacting individuals with compromised immune systems due to factors like increasing transplant recipients, an ageing population, and heightened use of immunosuppressive medications. Diagnosing IFI remains challenging, and the integration of biomarker assays into clinical practice is difficult. Antifungal resistance, exemplified by pan-antifungal-resistant Candida auris cases, adds complexity to treatment. This study aims to provide a concise overview of the diagnostic and treatment landscape for IFI in Germany, identifying areas for improvement and paving the way for targeted interventions., Methods: Data were collected using an online electronic case report form from October 2021 to February 2023. The survey included questions about institutional practices related to fungal infection diagnosis and treatment, with invitations extended to researchers nationwide., Results: The study surveyed 58 hospitals across Germany. Notably, 77.6% managed high-risk patients for IFI. While 86% had onsite microbiology labs, a significant difference was noted for high-risk patients (93% in specialized hospitals versus 62% in others). Microscopy services had 96% coverage, while overall access to culture was 96%. Antigen tests had 96% coverage, and antibody access was reported at 98%. PCR testing was available at 98%. Imaging access showed no significant access differences. Variability existed in amphotericin B formulations based on patient profiles. Therapeutic drug monitoring was more common in high-risk patient institutions (89.5% versus 50.0%). All analysed institutions reported access to surgery (100%)., Conclusions: Addressing identified disparities in diagnostic and therapeutic resources for IFI is crucial to improving patient outcomes. The study calls for ongoing research and collaboration to optimize strategies for the prevention and treatment of IFI, emphasizing the importance of equitable access to resources, especially in high-risk patient populations., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Patients with haematological malignancies might develop life-threatening toxoplasmosis, especially after allogeneic haematopoietic stem-cell transplantation (HSCT). Reactivation of latent cysts is the primary mechanism of toxoplasmosis following HSCT; hence, patients at high risk are those who were seropositive before transplantation. The lack of trimethoprim-sulfamethoxazole prophylaxis and various immune status parameters of the patient are other associated risk factors. The mortality of toxoplasma disease-eg, with organ involvement-can be particularly high in this setting. We have developed guidelines for managing toxoplasmosis in haematology patients, through a literature review and consultation with experts. In allogeneic HSCT recipients seropositive for Toxoplasma gondii before transplant, because T gondii infection mostly precedes toxoplasma disease, we propose weekly blood screening by use of quantitative PCR (qPCR) to identify infection early as a pre-emptive strategy. As trimethoprim-sulfamethoxazole prophylaxis might fail, prophylaxis and qPCR screening should be combined. However, PCR in blood can be negative even in toxoplasma disease. The duration of prophylaxis should be a least 6 months and extended during treatment-induced immunosuppression or severe CD4 lymphopenia. If a positive qPCR test occurs, treatment with trimethoprim-sulfamethoxazole, pyrimethamine-sulfadiazine, or pyrimethamine-clindamycin should be started, and a new sample taken. If the second qPCR test is negative, clinical judgement is recommended to either continue or stop therapy and restart prophylaxis. Therapy must be continued until a minimum of two negative PCRs for infection, or for at least 6 weeks for disease. The pre-emptive approach is not indicated in seronegative HSCT recipients, after autologous transplantation, or in non-transplant haematology patients, but PCR should be performed with a high level of clinical suspicion., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Seroprevalence studies have shown that 70% of children are exposed to Cryptococcus , the most common cause of meningitis in people living with human immunodeficiency virus (HIV), but reported pediatric disease prevalence is much lower than in adults., Methods: PubMed and Ovid Global Health databases were searched with the terms "cryptococcosis," "cryptococcal meningitis," " Cryptococcus neoformans " or " Cryptococcus gattii ." All studies reporting pediatric specific data in the English language from 1980 up until December 2022 were included., Results: One hundred sixty-eight publications were reviewed totaling 1469 children, with the majority reported from Africa (54.2%). Sixty-five percent (961) were HIV positive, 10% (147) were non-HIV immunocompromised and 19% (281) were immunocompetent. Clinical signs and symptoms were only reported for 458 children, with fever (64%), headache (55%) and vomiting (39%) being the most common. Most children (80%) suffered from meningoencephalitis. Lung involvement was rarely described in HIV-positive children (1%), but significantly more common in the non-HIV immunocompromised (36%) and immunocompetent (40%) groups ( P < 0.0001). Only 22% received the recommended antifungal combination therapy, which was significantly higher in immunocompetent children than those with HIV (39% vs. 6.8%; P < 0.0001). Overall mortality was 23%. A significant higher mortality was observed in children with HIV compared with immunocompetent children (32% vs. 16%; P < 0.001), but not compared with children with non-HIV immunosuppression (25)., Conclusions: This is the largest review of pediatric cryptococcosis with new observations on differences in clinical presentation and outcome depending on the underlying condition. The lack of granular clinical data urges prospective clinical epidemiological studies for improved insight in the epidemiology, management and outcome of cryptococcosis in children., Competing Interests: A.W. has received consultant fees from Gilead and Mundipharma and payment for educational events from Gilead and F2G. The other authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Melanomas of the central nervous system (CNS) based on neurocutaneous melanocytosis (NCM) are exceptionally rare in childhood and have been described only sporadically. Rapidly progressive disease may represent a major challenge for treating physicians, especially given the limited knowledge about this condition. This analysis aimed to increase knowledge about the occurrence and treatment of these malignancies., Procedure: Data on diagnosis, treatment, and outcome of patients aged 0-18 years with CNS melanoma based on NCM recorded in the German Registry for Rare Pediatric Tumors (STEP registry) were analyzed. Additionally, published case reports on this condition were analyzed., Results: In STEP, five patients with leptomeningeal melanoma based on NCM were identified, with a median age at melanoma diagnosis of 3.7 years. Various multimodal treatments were performed: (partial) resection (n = 4), irradiation (n = 2), trametinib (n = 3), different cytostatics (n = 2), and anti-GD2 immunotherapy (n = 1). All patients died between 0.3 and 0.8 years after diagnosis. Including published case reports, 27 patients were identified with a median age of 2.8 years at melanoma diagnosis (range: 0.2-16.6). Fourteen of 16 cases with reported data had a NRAS alteration (88%), particularly NRAS p.Q61K (85%). In the expanded cohort, no patient survived longer than 1 year after diagnosis despite multimodal therapy (including trametinib; n = 9), with a median survival of 0.4 years (range 0.1-0.9)., Conclusions: CNS melanomas based on NCM in childhood are aggressive malignancies without curative treatment to date. Therapeutic approaches must be individualized. Genetic tumor sequencing is essential to improve understanding of tumorigenesis and potentially identify new therapeutic targets., (© 2023 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)