Antifungal and Antivirulence Activity of Vanillin and Tannic Acid Against Aspergillus fumigatus and Fusarium solani.

Aspergillus fumigatus and Fusarium solani infections have become severe health threat; both pathogens are considered a priority due to the increasing emergence of antifungal-resistant strains and high mortality rates. Therefore, the discovery of new therapeutic strategies has become crucial. In this study, we evaluated the antifungal and antivirulence effects of vanillin and tannic acid against Aspergillus fumigatus and Fusarium solani. The minimum inhibitory concentrations of the compounds were determined by the microdilution method in RPMI broth in 96-well microplates according to CLSI. Conidial germination, protease production, biofilm formation, and in vivo therapeutic efficacy assays were performed. The results demonstrated that vanillin and tannic acid had antifungal activity against Aspergillus fumigatus, while tannic acid only exhibited antifungal activity against Fusarium solani. We found that vanillin and tannic acid inhibited conidial germination and secreted protease production and biofilm formation of the fungal pathogens using sub-inhibitory concentrations. Besides, vanillin and tannic acid altered the fungal membrane permeability, and both compounds showed therapeutic effect against aspergillosis and fusariosis in an infection model in Galleria mellonella larvae. Our results highlight the antivirulence effect of vanillin and tannic acid against priority pathogenic fungi as a possible therapeutic alternative for human fungal infections.

Invasive fungal rhinosinusitis by Fusarium proliferatum/annulatum in a patient with acute myeloid leukemia: A case report and review of the literature.

Antifungal prophylaxis with a mold-effective agent has led to a substantial decrease in invasive infections caused by Aspergillus spp. in the management of patients with acute myeloid leukemia undergoing induction chemotherapy. However, difficult-to-treat infections caused by other molds, such as Fusarium, Lomentospora, and Scedosporium species may still complicate the neutropenic period. Here, we present a case of a 23-year-old woman with acute myeloid leukemia who developed a breakthrough invasive fungal rhinosinusitis caused by Fusarium proliferatum/annulatum on posaconazole prophylaxis. The infection was diagnosed using clinical, microbiological, and radiological criteria and the isolate was identified using Matrix Assisted Lazer Desorption Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS) and sequencing. We searched Pubmed with "Fusarium proliferatum", "Fusarium annulatum", "immunosuppression AND fusariosis", "rhinosinusitis AND Fusarium proliferatum" and summarized the English literature for similar rhinosinusitis cases infected with the same pathogen.

Multicenter Retrospective Study of Invasive Fusariosis in Intensive Care Units, France.

Invasive fusariosis can be life-threatening, especially in immunocompromised patients who require intensive care unit (ICU) admission. We conducted a multicenter retrospective study to describe clinical and biologic characteristics, patient outcomes, and factors associated with death and response to antifungal therapy. We identified 55 patients with invasive fusariosis from 16 ICUs in France during 2002----2020. The mortality rate was high (56%). Fusariosis-related pneumonia occurred in 76% of patients, often leading to acute respiratory failure. Factors associated with death included elevated sequential organ failure assessment score at ICU admission or history of allogeneic hematopoietic stem cell transplantation or hematologic malignancies. Neither voriconazole treatment nor disseminated fusariosis were strongly associated with response to therapy. Invasive fusariosis can lead to multiorgan failure and is associated with high mortality rates in ICUs. Clinicians should closely monitor ICU patients with a history of hematologic malignancies or stem cell transplantation because of higher risk for death.

Invasive fusariosis in patients with leukaemia in the era of mould-active azoles: increasing incidence, frequent breakthrough infections and lack of improved outcomes.

OBJECTIVES: Historically, patients with leukaemia and invasive fusariosis (IF) have experienced poor outcomes in the setting of persistent immunosuppression. Herein, we retrospectively reviewed the incidence, presentation and outcomes of IF that are scarcely studied in contemporary cohorts of leukaemia patients. METHODS: We identified adult leukaemia patients with proven or probable IF at MD Anderson Cancer Center during 2009-21. Independent risk factors for 42 day mortality after IF diagnosis were determined using a multivariable logistic regression model. Combined with historical data, the annual IF incidence density over the past 23 years was estimated using Poisson regression analysis. RESULTS: Among 140 leukaemia patients with IF (114 proven), 118 patients (84%) had relapsed/refractory leukaemia and 124 (89%) had neutropenia at IF diagnosis. One hundred patients (71%) had pulmonary IF, 88 (63%) had disseminated IF and 48 (34%) had fungaemia. Coinfections were common (55%). Eighty-nine patients (64%) had breakthrough IF to mould-active triazoles. Most patients (84%) received combination antifungal therapy. Neutrophil recovery [adjusted OR (aOR), 0.04; 95% CI, 0.01-0.14; P < 0.0001], pulmonary IF (aOR, 3.28; 95% CI, 1.11-9.70; P = 0.032) and high SOFA score (aOR, 1.91 per 1-point increase; 95% CI, 1.47-2.50; P < 0.0001) were independent predictors of 42 day mortality outcomes. From 1998 to 2021, IF incidence density increased significantly at an annual ratio of 1.03 (95% CI, 1.01-1.06; P = 0.04). CONCLUSIONS: IF is predominantly seen in patients with relapsed/refractory leukaemia and increasingly seen as a breakthrough infection to mould-active triazoles. Despite frequent combination antifungal therapy, high mortality rates have persisted in patients with lasting neutropenia.

Fusarium oxysporum disseminated infection in a teenage patient with a relapse of acute lymphoblastic leukemia - Case report and review of the literature.

Infections are still a significant cause of mortality in children with hematologic malignancies. Fusariosis is a relatively rare and opportunistic infection, which may present dangerous course and a poor prognosis. Below, we describe the fatal course of a 15-years old patient with a combined bone marrow and testicular relapse of ALL and multisystemic Fusariosis oxysporum infection with fulminant evolution. Despite aggressive therapy, which included multiagent antifungal treatment and surgical debridement, patient succumbed to the disease. The review of the literature was conducted and the need for early detection of fusarium symptoms was emphasized. The case encourages further research in the prevention and treatment of the illness.

Fusariosis in Mexico: A 10-year retrospective series.

Fusarium species represent an opportunistic fungal pathogen. The data in Mexico about Fusarium infections in humans are scarce. Here, we present a retrospective series of patients with a confirmed diagnosis of fusariosis in eight different hospitals in Mexico from January 2010 to December 2019. The diagnosis of proven fusariosis was made according to the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORT/MSG) criteria. A total of 49 cases were identified in our series. Most patients had burn injuries (49%), and 37% had hematological malignancies. Most patients had fire injuries (40%), followed by electric injuries (8%), febrile neutropenia (10%), and pancytopenia (6%). Patients had skin and soft tissue involvement in 49%, followed by blood culture isolation and biopsies from different sites of the body (lung, sinuses, bone tissue, and eyes). Febrile neutropenia (10%) and fungemia (8%) were the most common clinical syndromes in immunosuppressed patients. Most patients received monotherapy (67%), where voriconazole was used in 30% of the cases, followed by conventional amphotericin B (16%), and lipidic formulations of amphotericin B in 10% (either liposomal amphotericin B or amphotericin B lipid complex). Combination therapy was used in 20% of the cases, and the most common combination therapy was triazole plus any lipidic formulation of amphotericin B (10%). Mortality related to Fusarium infection occurred in 22% of patients. Fusariosis is a serious threat. Burn injuries and hematologic malignancies represent the most common causes of infection in this small series from Mexico.

This study describes the epidemiological characteristics of patients with fusariosis from a multicenter cohort in Mexico. These findings provide information from this invasive fungal disease that threatens different countries in Latin America.

Practical issues related to non-Aspergillus invasive mold infections.

Infection by non-Aspergillus molds has been increasingly reported. The management of such infections is challenging both for diagnosis and treatment, including the need of well-trained mycologists to properly identify rare fungi, difficulties in distinguishing between contamination, colonization and infection, the lack of randomized studies comparing different drugs or regimens, poor activity of available antifungal agents, lack of correlation between in vitro antifungal susceptibility tests and clinical outcome, and poor prognosis. Mucormycosis and fusariosis are the most frequent non-Aspergillus mold infections. Mucormycosis occurs more frequently in four major groups of patients: solid organ transplant recipients, patients with hematologic malignancies receiving chemotherapy or hematopoietic cell transplantation, diabetic patients, and immunocompetent individuals who suffer various types of skin and soft tissue trauma. Invasive fusariosis occurs almost exclusively in patients with hematologic malignancies. In this review we discuss practical issues related to the management of these and other non-Aspergillus mold infections.

Invasive fusariosis.

Invasive fusariosis is a serious invasive fungal disease, affecting immunocompetent and, more frequently, immunocompromised patients. Localized disease is the typical clinical form in immunocompetent patients. Immunocompromised hosts at elevated risk of developing invasive fusariosis are patients with acute leukemia receiving chemotherapeutic regimens for remission induction, and those undergoing allogeneic hematopoietic cell transplant. In this setting, the infection is usually disseminated with positive blood cultures, multiple painful metastatic skin lesions, and lung involvement. Currently available antifungal agents have poor in vitro activity against Fusarium species, but a clear-cut correlation between in vitro activity and clinical effectiveness does not exist. The outcome of invasive fusariosis is largely dependent on the resolution of immunosuppression, especially neutrophil recovery in neutropenic patients.

Invasive Fusarium rhinosinusitis in COVID-19 patients: report of three cases with successful management.

Invasive fungal rhinosinusitis (IFRS) is a life-threatening infection that can occur in immunocompromised patients, including those with COVID-19. Although Mucorales and Aspergillus species are the most common causes of IFRS, infections caused by other fungi such as Fusarium are rare. In this report, we present three cases of proven rhinosinusitis fusariosis that occurred during or after COVID-19 infection. The diagnosis was confirmed through microscopy, pathology, and culture, and species identification of the isolates was performed by DNA sequencing the entire ITS1-5.8 rRNA-ITS2 region and translation elongation factor 1-alpha (TEF-1α). Antifungal susceptibility testing was conducted according to CLSI guidelines. The causative agents were identified as Fusarium proliferatum, F. oxysporum + Aspergillus flavus, and F. solani/falciforme. Treatment involved the administration of antifungal medication and endoscopic sinus surgery to remove the affected mucosa, leading to the successful resolution of the infections. However, one patient experienced a recurrence of IFRS caused by A. flavus 15 months later. Early diagnosis and timely medical and surgical treatment are crucial in reducing mortality rates associated with invasive fusariosis. Additionally, the cautious use of corticosteroids in COVID-19 patients is highly recommended.

Fusariosis in cancer patients: 13 case series report and literature review / Fusariosis en pacientes con cáncer: serie de 13 casos y revisión de la literatura

The fusariosis is an opportunistic mycosis caused by Fusarium spp. Its clinical presentation depends on the immunological status of the host, especially in patients with hematooncological diseases, whose manifestations vary from localized to invasive fungal infections. Skin or blood culture helps to guide combined antifungal treatment with amphotericin B and voriconazole. Here, we present 13 cases in a period of eleven years of patients with cancer who developed disseminated fusariosis and their outcomes, together with a review of the related literature. In this series of cases, mortality was 61.5 % (8/13), despite the use of the antifungal. Out of the 13 cases, 11 had hematological neoplasia and 2 solid neoplasia. The most determinant risk factor was profound neutropenia. Skin involvement and positive blood cultures in most cases allowed combined treatment prescription. Persistent febrile neutropenia associated with skin lesions, onychomycosis, nodules, or lung masses lead to suspicion of Fusarium spp. fungal invasive infection. The aim of this series of cases is to remind healthcare professionals that oncological patients with deep and persistent febrile neutropenia can develop fusariosis.

La fusariosis es una micosis oportunista producida por Fusarium spp. Su presentación clínica depende del estado inmunológico del huésped, especialmente, el de aquellos con enfermedades hematooncológicas, cuyas manifestaciones varían desde formas localizadas hasta infección fúngica invasora. El cultivo de piel o de sangre permite orientar el tratamiento antifúngico combinado con anfotericina B y voriconazol. Se presentan 13 casos de pacientes con cáncer en un periodo de once años que desarrollaron fusariosis diseminada; asimismo, se hizo con una revisión extensa de la literatura. En esta serie de casos, la mortalidad fue del 61,5 % (8/13), a pesar del uso del antifúngico. De los 13 pacientes, 11 tenían neoplasia hematológica y 2 neoplasia sólida. El factor de riesgo más importante fue la neutropenia profunda. El compromiso de la piel y los hemocultivos positivos facilitaron la prescripción del tratamiento combinado en la mayoría de los casos. La neutropenia febril persistente asociada a lesiones cutáneas, la onicomicosis, los nódulos o las masas pulmonares permitieron sospechar una infección fúngica invasora por Fusarium spp. El objetivo de la presentación de esta serie de casos es recordar el diagnóstico de fusariosis a la comunidad médica en contacto con pacientes oncológicos, con neutropenia febril profunda y persistentes.

Treatment of Fusarium Infection of the Central Nervous System: A Review of Past Cases to Guide Therapy for the Ongoing 2023 Outbreak in the United States and Mexico.

INTRODUCTION: Fusariosis of the central nervous system (CNS) is extremely uncommon. Treatment and outcome data from previously published cases may provide some guidance in light of the ongoing fungal meningitis outbreak in 2023 involving Fusarium spp. in the United States and Mexico. METHODS: We reviewed the published literature describing cases of invasive fusariosis of the (CNS) that included data on patient demographic characteristics, treatment, and outcome. RESULTS: Twenty-six cases met inclusion criteria. The mean age was 36 years, 55% involved females, 60% had underlying hematologic malignancy, and another 16% were on immunosuppressants. The majority of infections were from Fusarium solani species complex. Overall 72% of patients died. The majority received monotherapy with amphotericin B, although some received voriconazole monotherapy or combination therapy with amphotericin B plus voriconazole with or without adjuvant surgery. Among the survivors, 3 received amphotericin B monotherapy, 2 voriconazole monotherapy, 1 combination therapy of both, and one surgery only. CONCLUSION: The overall mortality rate in published cases of fusariosis of the CNS was high, although-unlike during the current outbreak-the preponderance of patients were severely immunocompromised. While historically the majority were treated with amphotericin B monotherapy, some recent patients were treated with voriconazole monotherapy or combination therapy with amphotericin B plus voriconazole. Current guidelines recommend monotherapy with voriconazole or lipid formulations of amphotericin B or combination of both for the treatment of invasive fusariosis, which is in line with the findings from our literature review and should be considered during the ongoing 2023 outbreak.

Fosmanogepix Therapy of Disseminated Fusarium Infection.

Invasive Fusarium infections cause high mortality. Fosmanogepix, a first-in-class antifungal agent, has potent activity against Fusarium. A patient with acute leukemia with invasive fusariosis, probably involving the central nervous system and caused by Fusarium lactis resistant to currently available antifungal agents, was cured of her infection with fosmanogepix. Fosmanogepix was well tolerated.

Fusarium solani species complex infection treated with posaconazole in a liver transplantation patient; a case report.

Although Fusarium spp. rarely cause infections in healthy people, they can cause fusariosis, particularly in neutropenic hematological malignancies, bone marrow transplant patients, and immunocompromised patients, such as those with acquired immune deficiency syndrome (AIDS), and rarely in solid organ transplant recipients. Here, we present a case of a liver transplant recipient with F. solani species complex (FSSC) infection treated with posaconazole. A 61-year-old man presented with multiple itchy, painful, palpable, irregular, subcutaneous nodules on the right leg and total dystrophic onychomycosis in the right toenails. Incisional skin biopsies of the lesions were performed, and the samples were sent to the pathology and mycology laboratories for analysis. The clinical isolate was identified as FSSC using phenotypic, matrix-assisted laser desorption/ionization-time of flight mass spectrometry, and genotypic methods. Liposomal amphotericin B could not be administered owing to the development of side effects; hence, the patient was treated with posaconazole for 4 months. While some nodular lesions disappeared completely under this treatment, the others showed dimensional regression. This is the first case of FSSC infection with skin and nail involvement in a non-neutropenic, liver transplant patient in Turkey. Fusariosis may develop with rare species, such as FSSC, as first reported in this case of a liver transplant patient. Regardless of the species, amphotericin B is the first choice for treating fusariosis; however, posaconazole is an effective and safe alternative to amphotericin B.

Primary Invasive Cutaneous Fusariosis in Patients with STAT3 Hyper-IgE Syndrome.

Dominant negative (DN) mutations in signal transducer and activator of transcription 3 (STAT3) are known to cause hyper-IgE syndrome, a rare primary immunodeficiency. STAT3 DN patients are prone to develop fungal infections, including chronic mucocutaneous candidiasis due to impaired IL-17-mediated immunity, and pulmonary aspergillosis. Despite having preserved phagocyte functions, STAT3 DN patients present connective tissue abnormalities and a defect in the immunological skin barrier. Fusarium species are ubiquitous molds, whose potential to infect humans depends on the host's innate and cellular immune status. Our aim was to describe four STAT3 DN patients with fusariosis confined to the skin. Medical records were reviewed and summarized. Four patients, aged 4, 11, 30, and 33 years, presented with chronic skin lesions which started in the extremities. Two patients had remote lesions, and none had systemic involvement. Skin biopsies showed mycelial threads with deep inflammatory-occasionally granulomatous-infiltrates, reaching the dermis; cultures grew Fusarium solani. Response to treatment was heterogeneous, often requiring multimodal therapies, including topical antifungal preparations. In this work, we describe primary invasive cutaneous fusariosis as a syndromic entity in four STAT3 DN patients.

Clinical characteristics and outcomes of invasive and non-invasive fusariosis in South Korea.

BACKGROUND: Invasive fusariosis mainly affects immunocompromised patients including haematopoietic stem cell transplant recipients and those with haematologic malignancy. There are limited studies on invasive fusariosis in the Asia-Pacific region. OBJECTIVE: To describe the clinical characteristics and outcomes of invasive and non-invasive fusariosis in South Korea. PATIENTS/METHODS: From 2005 to 2020, patients with fusariosis who met the revised European Organisation for Research and Treatment of Cancer and the Mycoses Study Group criteria for the definition of proven or probable invasive fusariosis, and those with non-invasive fusariosis were retrospectively reviewed in a tertiary medical centre in Seoul, South Korea. RESULTS: Overall, 26 and 75 patients had invasive and non-invasive fusariosis, respectively. Patients with invasive fusariosis commonly had haematologic malignancy (62%), were solid organ transplant recipients (23%), and had a history of immunosuppressant usage (81%). In non-invasive fusariosis, diabetes mellitus (27%) and solid cancer (20%) were common underlying conditions. Disseminated fusariosis (54%) and invasive pulmonary disease (23%) were the most common clinical manifestations of invasive fusariosis; skin infection (48%) and keratitis (27%) were the most common manifestations of non-invasive fusariosis. Twenty-eight-day and in-hospital mortalities were high in invasive fusariosis (40% and 52%, respectively). In multivariate analysis, invasive fusariosis (adjusted odds ratio, 9.6; 95% confidence interval 1.3-70.8; p = .03) was an independent risk factor for 28-day mortality. CONCLUSIONS: Patients with invasive fusariosis were frequently immunocompromised, and more than half had disseminated fusariosis. Invasive fusariosis was associated with poor prognosis.

Disseminated Bisifusarium infection following toxic epidermal necrolysis in a child with B-cell acute lymphoblastic leukemia.

Fusarium is a polyphyletic genus of plant pathogens, members of which can cause opportunistic human infections with varying superficial and systemic presentations, including disseminated infections which typically occur in immunocompromised patients and have a poor prognosis. Treatment is challenging due to intrinsic resistance to many antifungal agents, and antifungal susceptibility testing is therefore essential. Early suspicion, isolation of the organism, and prompt initiation of management are crucial to improving survival. We present a case of disseminated Bisifusarium infection following toxic epidermal necrolysis in a child with B-cell acute lymphoblastic leukemia, successfully treated with liposomal amphotericin B, voriconazole, flucytosine, and terbinafine.

Successful treatment of disseminated amphotericin-resistant fusariosis in a paediatric patient with acute lymphoblastic leukaemia: a case report and literature review

Background: Disseminated fusariosis is a rare and fatal infection in immunocompromised patients. Objectives: We report a case of disseminated amphotericin-resistant fusariosis in a paediatric patient with acute lymphoblastic leukaemia and review the features of reported disseminated fusariosis in China. Materials & Methods: Case reports of disseminated fusariosis were searched from the Chinese literature over the last two decades. Results: The presented case is a 15-year-old female who developed fever and multiple painful purple plaques with black necrotic centres and blood blisters. Fusarium was detected in blood and skin lesions with a high minimum inhibitory concentration (MIC) of amphotericin B (AMB) (>32 µg/mL) and a low MIC of voriconazole (VRC) (0.25 µg/mL). The Fusarium fujikuroi species complex was finally identified by rRNA gene analysis. Combination therapy of VRC and terbinafine (TRF) successfully resolved the disease after more than four months of treatment. Based on the review, the most common manifestations of disseminated fusariosis were fever, skin lesions and positive blood cultures, comprising nine cases (64.3%). Other sites of infection, including the lungs, eyes, sinuses or bone marrow, occurred in eight cases (57.1%). Seven patients (50%) were cured after monotherapy or combination therapy with AMB and VRC. Conclusion: In view of this case and the review of the literature, early identification of Fusarium infection and the appropriate antifungal drugs are critical for successful treatment. Primary therapy should consist of VRC or liposomal amphotericin B (L-AMB), with salvage therapy consisting of posaconazole (PSC). The combination of antifungals is probably necessary and more effective.

Disseminated fusarium infection after allogeneic hematopoietic stem cell transplantation after CART: A case report.

BACKGROUND: Fusarium is a conditional pathogen that can cause invasive infection in patients with hematological diseases under immune function. METHODS: A case of recurrent and refractory Philadelphia chromosome-positive acute lymphoblastic leukemia was treated with allogeneic hematopoietic stem cell transplantation after chimeric antigen receptor-modified T cells treatment. RESULTS: During transplantation, disseminated Fusarium infection occurred, involving the skin, liver, spleen and central nervous system, and the patient eventually died. CONCLUSIONS: Early identification of Fusarium infection based on the characteristic rash and timely antifungal treatment can improve the cure rate.