Invasive fungal diseases (IFDs) are becoming increasingly acknowledged as a significant concern linked to heightened rates of morbidity and mortality. Regrettably, the available antifungal therapies for managing IFDs are constrained. Emerging evidence indicates that enolase holds promise as a potential target protein for combating IFDs; however, there is currently a deficiency in antifungal medications specifically targeting enolase. This study establishes that isobavachalcone (IBC) exhibits noteworthy antifungal efficacy both in vitro and in vivo. Moreover, our study has demonstrated that IBC effectively targets Eno1 in Candida albicans (CaEno1), resulting in the suppression of the glycolytic pathway. Additionally, our research has indicated that IBC exhibits a higher affinity for CaEno1 compared to human Eno1 (hEno1), with the presence of isoprenoid in the side chain of IBC playing a crucial role in its ability to inhibit enolase activity. These findings contribute to the comprehension of antifungal approaches that target Eno1, identifying IBC as a potential inhibitor of Eno1 in human pathogenic fungi.

Treatments for emerging and rare invasive fungal diseases (IFDs) represent a critical unmet medical need. For IFDs that occur less frequently than invasive aspergillosis, such as mucormycosis, hyalohyphomycosis, and phaeohyphomycosis, randomized controlled clinical trials are impractical and unlikely to meet urgent public health needs. Understanding regulatory approaches for approval of drugs for rare cancers and rare metabolic diseases could help meet the challenges of studying drugs for rare IFDs. A single-arm, controlled clinical trial with a high-quality external control(s), with confirmatory evidence from nonclinical studies, including pharmacokinetic/pharmacodynamic data in predictive animal models of the disease may support findings of effectiveness of new drugs and biologics. Control populations may include historical controls from published literature, patient registries, and/or contemporaneous external control groups. Continuous engagement among clinicians, industrial sponsors, and regulatory agencies to develop consensus on trial design and innovative development pathways for emergent and rare invasive fungal diseases is important.

Central nervous system (CNS) lesions, especially invasive fungal diseases (IFDs), in immunocompromised patients pose a great challenge in diagnosis and treatment. We report the case of a 48-year-old man with acute myeloid leukaemia and probable pulmonary aspergillosis, who developed hyposthenia of the left upper limb, after achieving leukaemia remission and while on voriconazole. Magnetic resonance imaging (MRI) showed oedematous CNS lesions with a haemorrhagic component in the right hemisphere with lepto-meningitis. After 2 weeks of antibiotics and amphotericin-B, brain biopsy revealed chronic inflammation with abscess and necrosis, while cultures were negative. Clinical recovery was attained, he was discharged on isavuconazole and allogeneic transplant was postponed, introducing azacitidine as a maintenance therapy. After initial improvement, MRI worsened; brain biopsy was repeated, showing similar histology; and 16S metagenomics sequencing analysis was positive (Veilonella, Pseudomonas). Despite 1 month of meropenem, MRI did not improve. The computer tomography and PET scan excluded extra-cranial infectious-inflammatory sites, and auto-immune genesis (sarcoidosis, histiocytosis, CNS vasculitis) was deemed unlikely due to the histological findings and unilateral lesions. We hypothesised possible IFD with peri-lesion inflammation and methyl-prednisolone was successfully introduced. Steroid tapering is ongoing and isavuconazole discontinuation is planned with close follow-up. In conclusion, the management of CNS complications in immunocompromised patients needs an interdisciplinary approach.

The incidence of invasive fungal diseases (IFDs) is on the rise globally, particularly among immunocompromised patients, leading to significant morbidity and mortality. Current clinical antifungal agents, such as polyenes, azoles, and echinocandins, face increasing resistance from pathogenic fungi. Therefore, there is a pressing need for the development of novel antifungal drugs. Marine-derived secondary metabolites represent valuable resources that are characterized by varied chemical structures and pharmacological activities. While numerous compounds exhibiting promising antifungal activity have been identified, a comprehensive review elucidating their specific underlying mechanisms remains lacking. In this review, we have compiled a summary of antifungal compounds derived from marine organisms, highlighting their diverse mechanisms of action targeting various fungal cellular components, including the cell wall, cell membrane, mitochondria, chromosomes, drug efflux pumps, and several biological processes, including vesicular trafficking and the growth of hyphae and biofilms. This review is helpful for the subsequent development of antifungal drugs due to its summary of the antifungal mechanisms of secondary metabolites from marine organisms.

Fosmanogepix [FMGX, APX001; active form: manogepix (MGX), APX001A] is a first-in-class, intravenous (IV)/oral antifungal currently being evaluated for invasive fungal disease treatment. Data from two phase 1, placebo-controlled studies [IV-oral switch (study 1) and multiple IV doses (study 2)] evaluating FMGX tolerability, and pharmacokinetics (PK) are presented. Healthy adults (study 1: 18-65 years; study 2: 18-55 years) were eligible (randomized 3:1 to FMGX: placebo). Eleven participants completed study 1. In study 2, 51 participants (48 planned + 3 replacement) were enrolled in six cohorts (8 participants each; 34 completed the study). In study 1, overall MGX systemic exposures were comparable from day 1 to day 42 of dosing; steady-state plasma concentrations were achieved in ≤24 h following two IV loading doses (1,000 mg) and exposures maintained after switching [IV (600 mg) to daily oral doses (800 mg)]. FMGX was safe and well-tolerated. In study 2, FMGX IV doses (loading doses twice daily/maintenance doses once daily; 3-h infusion) of 1,500/900 mg (cohort A), 900/900 mg (cohort B), and 1,000/900 mg (cohort C: with ondansetron) were not well-tolerated; most participants reported nausea and infrequent vomiting. FMGX IV doses of 1,000/750 mg (cohort D), 1,000/850 mg (cohort E), and 1,000/900 mg (cohort F: ondansetron prn) were relatively better tolerated. Steady-state systemic exposures were achieved between days 2 and 4. All cohorts had similar geometric mean (GM) concentrations during maintenance dosing and similar GM PK parameters. Dosing regimen evaluated in study 1 was safe, well-tolerated, and may be used for future clinical evaluations.

OBJECTIVE: The aim of this document was to develop standardized research definitions of invasive fungal diseases (IFD) in non-neutropenic, adult patients without classical host factors for IFD, admitted to intensive care units (ICUs).
METHODS: After a systematic assessment of the diagnostic performance for IFD in the target population of already existing definitions and laboratory tests, consensus definitions were developed by a panel of experts using the RAND/UCLA appropriateness method.
RESULTS: Standardized research definitions were developed for proven invasive candidiasis, probable deep-seated candidiasis, proven invasive aspergillosis, probable invasive pulmonary aspergillosis, and probable tracheobronchial aspergillosis. The limited evidence on the performance of existing definitions and laboratory tests for the diagnosis of IFD other than candidiasis and aspergillosis precluded the development of dedicated definitions, at least pending further data. The standardized definitions provided in the present document are aimed to speed-up the design, and increase the feasibility, of future comparative research studies.

Invasive fungal diseases (IFDs) still represent a relevant cause of mortality in patients affected by hematological malignancies, especially acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) undergoing remission induction chemotherapy, and in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Mold-active antifungal prophylaxis (MAP) has been established as a standard of care. However, breakthrough IFDs (b-IFDs) have emerged as a significant issue, particularly invasive aspergillosis and non-Aspergillus invasive mold diseases. Here, we perform a narrative review, discussing the major advances of the last decade on prophylaxis, the diagnosis of and the treatment of IFDs in patients with high-risk neutropenic fever undergoing remission induction chemotherapy for AML/MDS and allo-HSCT. Then, we present our single-center retrospective experience on b-IFDs in 184 AML/MDS patients undergoing high-dose chemotherapy while receiving posaconazole (n = 153 induction treatments, n = 126 consolidation treatments, n = 60 salvage treatments). Six cases of probable/proven b-IFDs were recorded in six patients, with an overall incidence rate of 1.7% (6/339), which is in line with the literature focused on MAP with azoles. The incidence rates (IRs) of b-IFDs (95% confidence interval (95% CI), per 100 person years follow-up (PYFU)) were 5.04 (0.47, 14.45) in induction (n = 2), 3.25 (0.0013, 12.76) in consolidation (n = 1) and 18.38 (3.46, 45.06) in salvage chemotherapy (n = 3). Finally, we highlight the current challenges in the field of b-IFDs; these include the improvement of diagnoses, the expanding treatment landscape of AML with molecular targeted drugs (and related drug-drug interactions with azoles), evolving transplantation techniques (and their related impacts on IFDs\' risk stratification), and new antifungals and their features (rezafungin and olorofim).

BACKGROUND: Limited reports exist regarding invasive fungal diseases (IFDs) in inflammatory bowel disease (IBD) patients.
OBJECTIVE: This study aims to investigate the incidence and risk factors of IFDs, specifically invasive candidiasis, aspergillosis and pneumocystosis, in IBD patients in South Korea using nationwide data.
METHODS: A population-based retrospective cohort of 42,913 IBD patients between January 2010 and December 2018 was evaluated using the Health Insurance Review and Assessment database. The primary outcome was the incidence of IFDs, including invasive candidiasis, aspergillosis and pneumocystosis, while the secondary outcome involved analysing the risk factors associated with each specific infection.
RESULTS: The study included a total of 42,913 IBD patients, with 29,909 (69.7%) diagnosed with ulcerative colitis (UC) and 13,004 (30.3%) diagnosed with Crohn\'s disease (CD). IFDs occurred in 166 IBD patients (0.4%), with 93 cases in UC patients and 73 cases in CD patients. The incidence rates of invasive candidiasis, aspergillosis and pneumocystosis in IBD patients were 0.71 per 1000 person-years (PYs), 0.15 per 1000 PYs and 0.12 per 1000 PYs, respectively. The cumulative incidence of invasive candidiasis (adjusted p-value <.001) and Pneumocystosis (adjusted p-value = .012) was found to be higher in CD patients than in UC patients. Each IFD had different risk factors, including IBD subtypes, age at diagnosis, anti-tumour necrotic factor agents or the Charlson comorbidity index.
CONCLUSIONS: Based on nationwide data in South Korea, this study shows that IFDs occur consistently in patients with IBD, albeit with a low frequency.

Acute leukemia accounts for more than 30% of all pediatric cancer cases, and of these, 15-20% are acute myeloid leukemia (AML). Children who super from AML are more likely to develop infections due to the humoral and cellular immune deficits generated by the disease and its treatment. The incidence of fungal infections is underestimated; reports show that up to 75% of fungal infections go undiagnosed until autopsy. In only 30 years, the incidence of invasive candidiasis has increased by 40-fold. Thus, the high morbidity and mortality associated with fungal infections in hematological patients make it necessary to adopt preventive measures.
This work aimed to retrospectively identify pediatric patients with acute myeloid leukemia and invasive fungal diseases (IFDs) in a Latin American tertiary care hospital. A retrospective analysis of 36 clinical records of pediatric patients diagnosed with AML from 2007 to 2017 was carried out.
One hundred and twenty-nine hospitalizations were associated with infectious events. Thirteen patients in our study presented 15 infectious events associated with IFDs (11.6%). Two patients died because of complications related to IFDs (15.3%). The most frequent IFD type was aspergillosis, which was observed in 7 cases, followed by Candidemia, which was observed in 4 cases. The most frequent clinical manifestations were fever and respiratory distress.
Mortality due to IFD can be prevented with effective pharmacotherapy. An appropriate antifungal prophylaxis strategy still needs to be developed through larger prospective studies in Latin America.

We investigated single nucleotide polymorphisms (SNPs) possibly involved in immune reconstitution inflammatory syndrome of chronic disseminated candidiasis (IRIS-CDC) through a candidate gene approach and a prospective matched-control study. We found that an SNP located in interleukin-1B at rs1143627 was significantly associated with the risk of developing IRIS-CDC.