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.

Fusarium species central nervous system infection.

PURPOSE OF REVIEW: Fusarium species are an increasingly important cause of meningitis and invasive disease in immunocompromised patients as well as in otherwise healthy patients as observed in two recent healthcare-associated outbreaks. This review summarizes recently published information on treatment and diagnosis of this infection. RECENT FINDINGS: Incidence of Fusarium species meningitis and invasive fusariosis are increasing. Molecular techniques are improving the speed of diagnosis. New antifungal agents in development show good in vitro activity against some Fusarium species. New technologies, including cerebrospinal fluid (CSF) filtration, may play a role in treatment of central nervous system (CNS) disease. Due to the continued prime importance of the host immune system in recovery, immunomodulatory treatments may play a role in treatment. SUMMARY: The overall incidence of CNS fusariosis is increasing with a continued poor prognosis, but new diagnostic and treatment modalities are in development which may offer improvements.

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.

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.

Isolation and characterization of Fusarium spp. From unhatched eggs of Caretta caretta in Tuscany (Italy).

Sea Turtle Egg Fusariosis (STEF) is a worldwide emergent fungal disease affecting eggs and causing embryos mortality in turtle's nests such as those of Caretta caretta. It is caused by a complex of species belonging to Fusarium genus, particularly those included in the Fusarium Solani Species Complex (FSSC). During the samplings carried out in summer 2020 along the Tuscany coastlines (Italy), C. caretta eggs showed clinical signs resembling those caused by STEF. A total of 32 fungal isolates were obtained from lesioned eggs whose molecular characterization allowing identifying as belonging to FSSC / Neocosmospora spp., Fusarium oxysporum Species Complex (FOSC) / F. oxysporum and Fusarium nodosum, i.e., fungal genera and speciesincluding also well-known plant pathogens. Isolates inoculated on several plant hosts did not result in any pathogenic activity but F. nodosum causing, on wheat spikes, disease symptoms.This is the first time F. nodosum has been isolated from portions of eggs showing evident signs of fungal infection. This work represents the first report of Fusarium spp. isolated from C. caretta eggs showing lesions resembling those caused by STEF on Tuscan coast thus posing a significant concern to loggerhead sea turtle conservation also in this region.

Invasive fusariosis.

SUMMARYInvasive 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.

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.

Fusarium Keratitis From a Comprehensive Eye Health Care Facility in South India: Molecular Characterization by MALDI-TOF Versus Polymerase Chain Reaction Sequencing, Species Complex Distribution, and Clinical Correlation.

PURPOSE: Fusarium keratitis possesses significant diagnostic and therapeutic challenges. Medically relevant Fusaria belong to various species complexes and show prominent differences in their antifungal susceptibility profile which may influence the clinical outcome. Rapid diagnostic methods are warranted for precise identification of species complexes for prompt initiation of correct antifungals. The aim of the study was to compare between matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) and polymerase chain reaction sequencing for correct species-level identification and to analyze the clinical outcome among different Fusarium species complexes. METHODS: Twenty-nine culture-proven Fusarium keratitis cases were included in this study. A phylogenetic tree was constructed after TEF1α gene sequencing and isolates were subjected to MALDI-TOF MS, followed by database expansion and identification. Clinical outcome and risk association among species complexes were analyzed retrospectively. RESULTS: Maximum likelihood phylogeny categorized 68.9% isolates as Fusarium solani species complex (FSSC), 17.2% as Fusarium dimerum species complex (FDSC), followed by 13.7% as Fusarium fujikuroi species complex (FFSC). With extended database, MALDI-TOF MS could correctly speciate 96.5% (28/29) isolates. Previous antibiotic usage ( P = 0.034) and preoperative antifungal treatment with natamycin, voriconazole, or ketoconazole ( P = 0.025) were significantly higher in the FSSC group. The patients in the FFSC group had a significantly longer duration of symptoms at the time of clinical presentation to the clinic (15 days vs. 5 days, P = 0.030). Among 11 patients with a clinically poor outcome, 9 (31%) had FSSC infection. CONCLUSIONS: Patients infected with the FSSC had more aggressive infection with poor prognosis. MALDI-TOF MS can serve as the best alternative method to conventional molecular identification with reduced turnaround time, which may help the ophthalmologists to consider the appropriate antifungals or early surgical intervention for improved outcome.

An unusual presentation of invasive Fusarium aortitis in a patient who is immunocompromised: A case report.

Fusarium (F.) species are ubiquitous filamentous fungi that may cause various opportunistic infections, especially in patients who are immunocompromised. A rare manifestation of disseminated fusariosis affects the aortic valve and results in invasive aortitis, which poses a significant challenge for clinicians in diagnosis and treatment. Here, we report a case of a patient, aged 54 years, who is immunocompromised, presenting initially with Fusarium keratitis and chorioretinitis in both eyes and a new endovascular aortic mass. Positron emission tomography/computed tomography was performed, suggesting aortitis. Transoesophageal echocardiography and electrocardiogram-guided computed tomography-angiography confirmed a large intraluminal mass in the ascending aorta. The aortic mass and a part of the ascending aorta were resected surgically, and a filamentous fungus with the microscopic features of the genus Fusarium was isolated and later identified molecularly as F. petroliphilum. The course of the treatment was complicated by perioperative cerebral embolization and mesenteric ischemia. These complications could be attributed to a preoperatively existing occlusion of the superior and inferior mesenteric artery and a subtotal stenosis of the celiac trunk. This case report describes a rare manifestation of disseminated fusariosis, frequently characterized by protracted clinical courses with poor prognosis. Fusariosis may manifest at different sites at different times or persist as a long-lasting disease with reactivation. This case highlights the importance of the interdisciplinary approach for effectively treating invasive mycoses.

Invasive fusariosis in acute leukaemia patients-An outbreak in the haematology ward.

Fusarium, a common fungus, emerges as a pathogen in severely immunocompromised patients. We present a series of patients who developed invasive fusariosis (IF) during admission to an acute leukaemia ward: an outbreak of 12 cases in June and July 2018, followed by four sporadic cases until 2021. No case was reported earlier. All patients were clustered in the same location with indoor air and water installations found to be contaminated with Fusarium spp. thus a nosocomial outbreak was assumed. Following the water installation replacement, the number of Fusarium cases dramatically dropped to one or two isolated instances per year in the same location. All 16 patients had acute leukaemia and developed IF during severe neutropenia following induction therapy. IF diagnosis was based on positive blood cultures (14 patients) and/or on tissue biopsies (3 patients). The median time from admission to the IF onset was 20 days, and from the first day of severe neutropenia (≤500/mm3) was 11.5 days. All patients were febrile, eight had moderate-to-severe myalgias, eight had respiratory involvements: lung lesions and/or sinusitis and seven had characteristic skin lesions. Follow-up: 12 out of 16 (75%) were alive on Day 90; nine out of 15 (60%) were alive on Month 6. All with intractable neutropenia died. In severely neutropenic febrile patients, the triad of respiratory involvement/skin lesions/severe myalgia may suggest Fusarium aetiology. The ability to recover from neutropenia is critical to surmount IF. The indoor environment in immunocompromised dedicated settings must be constantly controlled.

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.

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.

In vitro antifungal susceptibility profile of Iranian Fusarium isolates: Emphasising on the potent inhibitory effect of efinaconazole compared to other drugs.

BACKGROUND: Fusarium species are opportunistic human pathogens that remarkably cause fungal infections ranging from superficial to fatal invasive disseminated infections. Fusarium species are notoriously resistant to the majority of antifungal agents. OBJECTIVES: Therefore, detailed studies regarding in vitro susceptibility are required and may lead to a better prognosis of severe infections. METHODS: We evaluated 25 antifungal drugs in vitro against 282 clinical and environmental Fusarium isolates. RESULTS: Fusarium species demonstrated high MICs/MECs values to the most commonly used antifungal drugs in clinical practice. The geometric mean (GM) MICs for luliconazole (0.004 µg/ml) and lanoconazole (0.012 µg/ml) were the lowest, followed by efinaconazole (0.98 µg/ml) and amphotericin B (1.04 µg/ml). CONCLUSIONS: Efinaconazole, a novel triazole, may be a promising candidate for the treatment of superficial Fusarium infections. Furthermore, the development of systemic formulations of these drugs as well as further in vitro and in vivo investigations could aid in the treatment of systemic fusariosis.

Detection of circulating DNA for the diagnosis of invasive fusariosis: retrospective analysis of 15 proven cases.

Fusarium spp. are plant pathogens and opportunistic pathogens in severely immunocompromised (hematological malignancy, neutropenia, solid organ transplantation, etc.) and severely burned patients. Invasive fusariosis often disseminates and mortality remains high partly due to delayed diagnosis in the absence of a positive culture. The aim of our study is to design a quantitative PCR (qPCR) assay and evaluate the detection of Fusarium spp. DNA for early diagnosis of invasive infection. A qPCR assay was designed and optimized to identify all Fusarium species complex and secondarily evaluated on patient samples. A total of 81 blood samples from 15 patients diagnosed with proven invasive fusariosis from 9 centers in France were retrospectively tested. Circulating DNA was detected in 14 patients out of 15 (sensitivity of 93% [95% Confidence Interval (CI95), 70.1-99.7]). Detection was possible up to 18 days (median 6 days) before the diagnosis was confirmed by positive blood culture or biopsy. By comparison serum galactomannan and ß-D-glucan were positive in 7.1 and 58.3% of patients respectively. qPCR was negative for all patients with other invasive fungal diseases (IFD) tested (n = 12) and IFD-free control patients (n = 40). No cross-reactions were detected using DNA extracted from 81 other opportunistic fungi. We developed and validated a pan-Fusarium qPCR assay in serum/plasma with high sensitivity, specificity, and reproducibility that could facilitate early diagnosis and treatment monitoring of invasive fusariosis. LAY ABSTRACT: Fusariosis ranks third among invasive mould infections. It is frequently diagnosed late due to the lack of specific tools. We designed and evaluated a new qPCR assay with high sensitivity and specificity allowing detection of Fusarium DNA in serum samples up to 18 days before conventional diagnosis.

A chloroacetamide derivative as a potent candidate for fusariosis treatment.

Fusariosis has presented a significant increase in their incidence in the last years. This epidemiological panorama probably is due to the increasing profile of refractory susceptibility of Fusarium spp. to available drugs, especially in immunocompromised individuals. Thus, the development of new compounds with effectiveness on these organisms is a necessity. This study evaluated the antifungal potential of a chloroacetamide derivative (4-BFCA) against resistant Fusarium strains. As a result, the compound was effective against all strains (MIC range 12.5-50 µg/mL). The time kill assay demonstrated that 4-BFCA presents a concentration-dependent fungicidal action. Although its action mechanism has not yet been elucidated, it was possible to observe its efficacy through damages and alterations provoked along the hyphae of Fusarium spp. 4-BFCA maintained a high survival rate of Tenebrio molitor larvae, suggesting that it does not cause acute systemic toxicity on this host at the concentration evaluated. In addition, 4-BFCA was 83.33% effective in combating a fungal infection in vivo on the chorioallantoid membrane of embryonated eggs. Our results are very promising and arouse interest to investigate the action of 4-BFCA on Fusarium strains since it acts as a possible candidate for the development of new therapies for the treatment of fusariosis.

A case of mycotic keratitis due to Fusarium sp. with an undesirable outcome.

Fungal keratitis, an infective disease of the cornea, represents a serious diagnostic and therapeutic problem that, if not recognized on time, could lead to irreversible eye damage. Herein we report a case of fungal keratitis due to Fusarium spp. infection. The 60-year-old man was admitted to our clinic due to an atraumatic acute onset of the disease, with a decrease in the visual acuity, photophobia, redness, and severe pain in the right eye. Clinical observation revealed an ulcer that affected 1/3 of the cornea and a hypopion in the anterior chamber. After the first results of microbiological analyzes, local and systemic antifungal therapy was applied. Due to the fact that the patient voluntarily left the treatment, there was a drastic worsening of the local findings as a full thickness total corneal infiltrate with more intense anterior chamber reaction. Finally, evisceration was performed. Given the fact that fungal keratitis is more prevalent in developing countries, official protocols and available effective antifungals are crucial for adequate treatment and a favorable outcome of this infection.

Rapid Identification of Four Fusarium spp. Complex by High-Resolution Melting Curve Analysis and their Antifungal Susceptibility Profiles.

Fusarium species are globally distributed filamentous ascomycete fungi that are frequently reported as plant pathogens and opportunistic human pathogens, leading to yield loss of crops, mycotoxin contamination of food and feed products as well as damage to human and livestock. Human infections of Fusarium spp. are difficult to treat due to broad antifungal resistance by members of this genus. Their role as disease-causing agents in crops and humans suggests a need for antifungal resistance profiles as well as a simple, rapid, and cost effective identification method. Fusarium strains were isolated from food and clinical samples. High-resolution melting curve (HRM) analysis was performed using specific primers targeting internal transcribed spacer (ITS) region, followed with evaluation of specificity and sensitivity. The antifungal susceptibility of four Fusarium species was studied using the Sensititre YeastOne method. HRM analysis revealed reproducible, unimodal melting profiles specific to each of the four Fusarium strains, while no amplification of the negative controls. The minimum detection limits were 100-120 copies based on a 2 µl volume of template. Clear susceptibility differences were observed against antifungal agents by different Fusarium isolates, with amphotericin B and voriconazole displayed strongest antifungal effects to all the tested strains. We developed a simple, rapid, and low-cost qPCR-HRM method for identification of four Fusarium spp. (F. oxysporum, F. lateritium, F. fujikuroi, and F. solani). The antifungal susceptibility profiles supplied antifungal information of foodborne and clinical Fusarium spp. and provided guidance for clinical treatment of human infections.

Transcending sea turtles: First report of hatching failure in eggs of an Amazonian freshwater turtle with symptoms of the fungal emerging disease fusariosis.

During the last few decades, fungal pathogens have caused devastating population declines across a broad range of taxa. A newly emerging fungal disease, sea turtle egg fusariosis, caused by members of the Fusarium solani species complex (FSSC), has been reported to be responsible for hatching failure in sea turtles worldwide. However, this has not been detected in fresh water turtle species. Here, using relocated clutches and artificial incubation, we report high hatching failure in eggs symptomatic of fusariosis in the yellow-spotted Amazon River turtle (Podocnemis unifilis) inhabiting a pristine environment in the Ecuadorian Amazon. In 2020, we screened 680 eggs of the yellow-spotted Amazon River turtle, relocated from wild nesting areas to artificial nests, for visual symptoms of fusariosis and to estimate hatchability despite infection. We selected 68 eggs sampled in 2019 to confirm Fusarium infection by PCR amplification of the TEF-1α gene and sequenced seven of those amplicons on an Illumina Miseq to assess FSSC membership. We observed fusariosis symptoms in 42% of the 680 eggs. The proportion of symptomatic eggs within nests was negatively linked to the proportion of eggs that hatched. Hatchability was 8% for symptomatic eggs compared with 72% of asymptomatic eggs. Through PCR testing, 58% of symptomatic and 8% of asymptomatic eggs sampled in 2019 tested positive for Fusarium spp., and sequencing revealed that nine sequence variants from three asymptomatic and four symptomatic eggs corresponded to F. keratoplasticum, F. solani and F. falciforme, the three major FSSC pathogens reported in sea turtle egg fusariosis. Our study suggests that hatching failure in eggs linked to symptoms of fusariosis appears to be partially caused by Fusarium pathogens within FSSC in a freshwater turtle. Thus, fusariosis is more widespread among the Testudines than previously reported and is not limited to sea environments, findings of particular conservation concern.

Nosocomial disseminated fusariosis in a hematopoietic stem cell transplant recipient.

We report a case of nosocomial disseminated Fusarium in a stem cell transplant recipient. Identification of hospital fungal water reservoirs with routine surveillance cultures could potentially decrease rates of invasive infection.