Trichosporon spp. endocarditis is a severe and hard-to-treat infection. Immunosuppressed subjects and carriers of prosthetic valves or intracardiac devices are at risk. This article presents the case of an immunocompetent 74-year-old man affected by endocarditis of the prosthetic aortic valve. After Bentall surgery, cultures of the removed valve demonstrated Trichosporon ashaii as the etiological agent. The patient was treated with amphotericin B at first and subsequently with fluconazole. Given the fragility of the patient and the aggressiveness of the pathogen, life-long prophylactic therapy with fluconazole was prescribed. After 5 years follow-up, no drug-related toxicities were reported and the patient never showed any signs of recurrence. The review of the literature illustrates that Trichosporon spp. endocarditis may present even many years after heart surgery, and it is often associated with massive valve vegetations, severe embolic complications, and unfavorable outcome. Due to the absence of international guidelines, there is no unanimous therapeutic approach, but amphotericin B and azoles are usually prescribed. Additionally, a prompt surgical intervention seems to be of paramount importance. When dealing with a life-threatening disease, such as mycotic endocarditis of prosthetic valves, it is essential to consider and treat even rare etiological agents such as Trichosporon spp.

BACKGROUND: Fungal urinary tract infections (UTIs) are becoming increasingly common in hospitalized patients and Candida species are the most prevalent organisms. However, recurrent candiduria in young healthy outpatients is rare thus require further examination to find the etiologic factors.
METHODS: We described a case of recurrent asymptomatic c caused by azole-resistant C. glabrata in a healthy young female who only had previous use of antibiotics without other risk factors. However, after removal of the predisposing factor and the use of sensitive antifungal agents, the patient\'s urine cultures remained positive. This phenomenon indicated to us that the patient might have an immune-related genetic deficiency. We found a novel caspase-associated recruitment domain-containing protein 9 (CARD9) gene mutation (c.808-11G > T) which might be the cause of recurrent asymptomatic candiduria in this immune-competent young female without any underlying diseases.
CONCLUSIONS: We report a case of recurrent asymptomatic candiduria caused by azole-resistant Candida glabrata in a young healthy female with a novel CARD9 mutation. A functional study of this mutation should be performed in the future to determine its effect on asymptomatic fungal UTIs.

Although the treatment of aspergillosis has been studied for years, the optimal nonsurgical treatment of chronic cavitary pulmonary aspergillosis (CCPA) remains unsatisfactory, especially in lung cancer. We report two advanced non-small cell lung cancer (NSCLC) patients who recovered from CCPA following instillation of Amphotericin B (AmB) by bronchoscopy combined with systemic voriconazole. The first patient was diagnosed with lung adenocarcinoma after right upper lobe resection and was treated with anaplastic lymphoma kinase-targeted therapy. Chest computed tomography (CT) revealed a right pulmonary cavity containing solid materials. The second patient was diagnosed with squamous cell carcinoma and received immunotherapy following surgery, chemotherapy, and radiotherapy. Chest CT tomography revealed a mass in the right lung cavity. Both patients\' cultures and next-generation sequencing of their bronchoalveolar lavage (BAL) samples revealed presence of Aspergillus fumigatus. In addition, the galactomannan test of both patients BAL samples was positive. Systemic voriconazole was prescribed based on in vitro susceptibility testing. The chest images and clinical symptoms of both patients did not improve after one month of voriconazole therapy within the therapeutic blood concentration. Considering the low local concentrations of antifungals against CCPA, AmB instillation by bronchoscopy combined with systemic voriconazole was utilized. The chest CT images and clinical symptoms of both patients markedly improved in the following third month. Instillation of AmB combined with systemic voriconazole may be a promising treatment option for NSCLC patients with CCPA who fail voriconazole monotherapy.

Triazole fungicides such as propiconazole (Pi) or tebuconazole (Te) show hepatotoxicity in vivo, e.g., hypertrophy and vacuolization of liver cells following interaction with nuclear receptors such as PXR (pregnane-X-receptor) and CAR (constitutive androstane receptor). Accordingly, azoles affect gene expression associated with these adverse outcomes in vivo but also in human liver cells in vitro. Additionally, genes indicative of liver cholestasis are affected in vivo and in vitro. We therefore analyzed the capability of Pi and Te to cause cholestasis in an adverse outcome pathway (AOP)-driven approach in hepatic cells of human origin in vitro, considering also previous in vivo studies. Bile salt export pump (BSEP) activity assays confirmed that both azoles are weak inhibitors of BSEP. They alternate the expression of various cholestasis-associated target genes and proteins as well as the mitochondrial membrane function. Published in vivo data, however, demonstrate that neither Pi nor Te cause cholestasis in rodent bioassays. This discrepancy can be explained by the in vivo concentrations of both azoles being well below their EC50 for BSEP inhibition. From a regulatory perspective, this illustrates that toxicogenomics and human in vitro models are valuable tools to detect the potential of a substance to cause a specific type of toxicity. To come to a sound regulatory conclusion on the in vivo relevance of such a finding, results will have to be considered in a broader context also including toxicokinetics in a weight-of-evidence approach.

Fungal infections due to Fusarium species are serious albeit rare and mostly occur in severely immunocompromised patients. The prognosis of such infections, especially of disseminated manifestations, is poor as a result of multi-antifungal resistance, particularly to azoles. We report a case of a rapidly progressive necrotizing fasciitis of the foot secondary to Fusarium solani in a young female patient with acute lymphoblastic leukemia on consolidation therapy. Surgical debridement was undertaken and liposomal amphotericin was given as definitive therapy for a total of six weeks followed by secondary prophylaxis that resulted in remarked clinical and radiological improvement. High clinical suspicion, prompt surgical intervention, rapid diagnosis, and timely initiation of appropriate antifungal therapy are crucial for a favorable outcome in this relatively uncommon life-threatening infection.

Trichosporon spp. are a constituent of the normal flora of humans that can cause both superficial and invasive infections, mainly in immunocompromised and immunocompetent hosts, respectively. Herein, we a report of Trichosporon asahii causing subcutaneous fungal infection (SFI) in an immunocompetent patient after carpal tunnel surgery. Although susceptible to fluconazole, the treatment of SFI failed even using high doses of this azole. The skin lesion improved following the administration of voriconazole. We conducted a literature minireview searching reports on SFI in immunocompetent patients to check for epidemiological, diagnostic, therapeutic, and outcome characteristics. A total of 32 cases were reported. Despite being uncommon, the clinical suspicion and early diagnosis of SFI in immunocompetent patients undergoing previous surgery are important. Our study indicated that the azoles are the most active antifungal agents against Trichosporon spp., except for fluconazole, and voriconazole can be considered the first therapeutic option.

Aspergillus calidoustus is an emerging, azole-resistant, cryptic Aspergillus species in immunosuppressed patients that often features extrapulmonary involvement and carries high mortality. The case presented by J. F. Camargo, R. Jabr, A. D. Anderson, L. Lekakis, et al. (Antimicrob Agents Chemother 66:e02206-21, 2022, https://doi.org/10.1128/aac.02206-21) describes a transplant recipient with disseminated A. calidoustus infection who was successfully treated with surgical source control, tapering of immunosuppression, and long-term, combination antifungal treatment that included the first-in-class fosmanogepix, which targets fungal mannoprotein trafficking and anchoring.

In this study, we examined the toxicities, including poisoning and overdoses, with polyene, azole, flucytosine and echinocandin antifungals reported to the Swiss National Poison Centre.
An observational cross-sectional study on antifungals was performed based on reports between 1995 and 2016 to Tox Info Suisse. Patient demographic and clinical characteristics were summarised among all reported calls, stratified by age group. In secondary analyses, we evaluated cases with clinical follow-up information.
In total, 149 cases were reported to the National Poison Centre during the study period, of which 49 (32.9%) were male and 91 (61.1%) were female, and 95 (63.8%) were adults and 54 (36.2%) were children (age ≤16 years). The most frequently reported drug class was azoles (136; 91.3%). In 31 cases (20.8%) reported by treating physicians, further clinical follow-up information was available. Nearly one-half of these patients were asymptomatic (15/31; 48.4%). In 11 patients (35.5%) among those with symptoms, the symptoms of toxicity were categorised with a strong causality to the respective antifungal. Clinical findings caused by triazoles were effects in the gastrointestinal tract, hallucinations and predelirium state. Clinical findings caused by polyenes were mostly minor symptoms with infusion-related effects or hypokalaemia. The severity was categorised as minor in 6 (54.5%) of 11 cases and as moderate in 5 cases (45.5%).
Despite high administered doses, no severe or fatal cases occurred within the study period. Although various toxicities can occur with antifungal administration and overdoses, they showed a favourable safety profile.

Infections with Scedosporium and Lomentospora species, in particular Lomentospora (previously Scedosporium) prolificans, are nearly universally fatal and rapidly-progressive in the transplant population. We report a case of a patient with diffuse large B-cell lymphoma undergoing myelosuppressive chemotherapy who developed disseminated L. prolificans infection which afterward persisted in his knee joint. The infection was treated with early empiric triple antifungal therapy tailored to synergy studies, growth factors to quickly resolve neutropenia, and aggressive debridement (where possible) of infection sites, including amputation. He achieved an 11-month remission until undergoing autologous hematopoietic stem cell transplantation with deep myelosuppression, wherein recrudescent L. prolificans infection occurred, causing death. We highlight the importance of early treatment, synergy studies, and especially recovery of neutropenia in treating this devastating condition.

BACKGROUND: The recent increase in cases of azole-resistant Aspergillus fumigatus (ARAf) infections is a major clinical concern owing to its treatment limitations. Patient-derived ARAf occurs after prolonged azole treatment in patients with aspergillosis and involves various cyp51A point mutations or non-cyp51A mutations. The prognosis of patients with chronic pulmonary aspergillosis (CPA) with patient-derived ARAf infection remains unclear. In this study, we reported the case of a patient with ARAf due to HapE mutation, as well as the virulence of the isolate.
METHODS: A 37-year-old male was presented with productive cough and low-grade fever. The patient was diagnosed with CPA based on the chronic course, presence of a fungus ball in the upper left lobe on chest computed tomography (CT), positivity for Aspergillus-precipitating antibody and denial of other diseases. The patient underwent left upper lobe and left S6 segment resection surgery because of repeated haemoptysis during voriconazole (VRC) treatment. The patient was postoperatively treated with VRC for 6 months. Since then, the patient was followed up without antifungal treatment but relapsed 4 years later, and VRC treatment was reinitiated. Although an azole-resistant isolate was isolated after VRC treatment, the patient did not show any disease progression in either respiratory symptoms or radiological findings. The ARAf isolated from this patient showed slow growth, decreased biomass and biofilm formation in vitro, and decreased virulence in the Galleria mellonella infection model compared with its parental strain. These phenotypes could be caused by the HapE splice site mutation.
CONCLUSIONS: This is the first to report a case demonstrating the clinical manifestation of a CPA patient infected with ARAf with a HapE splice site mutation, which was consistent with the in vitro and in vivo attenuated virulence of the ARAf isolate. These results imply that not all the ARAf infections in immunocompetent patients require antifungal treatment. Further studies on the virulence of non-cyp51A mutations in ARAf are warranted.