Primary cerebral phaeohyphomycosis is a life-threatening disease caused by neurotropic dematiaceous fungi. At present, there are no consensus guidelines regarding optimal antifungal therapy in such cases. Generally, a combination of antifungal agents is recommended for treatment. However, the activities of antifungal combinations against these fungi have not been investigated. In this study, we evaluated the in vitro activities of 13 double and five triple antifungal combinations against clinical isolates of Cladophialophora bantiana (n = 7), Fonsecaea monophora (n = 2), and Cladosporium cladosporioides (n = 1), using a simplified checkerboard procedure. The minimum inhibitory concentrations (MICs) of nine antifungal drugs were determined by the broth microdilution method, and the interaction between antifungal agents in each combination was assessed by the fractional inhibitory concentration index. Excellent activity was observed for posaconazole and itraconazole. Flucytosine had potent activity against C. bantiana but was ineffective against F. monophora, and C. cladosporioides. The echinocandins demonstrated high MICs for all the isolates. Synergistic interactions were observed for all the double combinations, except when itraconazole was combined with either amphotericin B or flucytosine. The combination of amphotericin B with caspofungin showed synergistic interactions against 40% of the isolates. Antagonism was observed with isavuconazole-flucytosine combination against two C. bantiana isolates. The triple combinations of caspofungin and flucytosine with amphotericin B or posaconazole were synergistic against one isolate of F. monophora. For C. cladosporioides, synergy was observed for the triple combination of amphotericin B with caspofungin and flucytosine. Our results indicate that combination of caspofungin with amphotericin B or a triazole, with or without 5-flucytosine has great potential against neurotropic dematiaceous fungi.IMPORTANCEThis research uses a modified version of the checkerboard assay to standardize the in vitro testing of double and triple combinations of antifungal agents against neurotropic dematiaceous fungi. Antifungal combination therapy is associated with improved outcomes in cerebral phaeohyphomycosis. In this study, we demonstrate that posaconazole is the single most active antifungal drug against this group of fungi. The double combination of amphotericin B with caspofungin or a trizole, and the triple combinations of caspofungin and flucytosine with amphotericin B or posaconazole might hold promise in the treatment of cerebral phaeohyphomycosis. Our findings will guide in developing optimal therapeutic strategies for these refractory infections.

Fonsecaea monophora is a species of Fonsecaea that belongs to Chaetothyriales. It is usually isolated from tropical and subtropical regions, causing reactive inflammation, skin abscesses, and pain. Cerebral infection caused by F. monophora is rare but often fatal. Diagnosing this disease at an early stage is difficult, and appropriate antifungal therapy is often delayed as a result. We report the case of a 53-year-old woman with type 2 diabetes who presented with a headache 2 months ago and progressive right-sided weakness of 1 month\'s duration. Magnetic resonance imaging revealed a space-occupying lesion in the left frontal lobe and corpus callosum. The cystic mass was removed by surgical intervention, and the identification of the sample based on sequencing of the internal transcribed spaced region in BLAST-N search showed that the sequences producing most significant alignments were F. monophora or similar (query cover 99%, E value 0.0, per ident 99.84). The patient was treated with a 3-month course of twice daily voriconazole, leading to complete recovery.

Cerebral phaeohyphomycosis (CP) is a serious form of phaeohyphomycosis. We report a case of CP caused by Fonsecaea species in a 66-year-old immunocompromised renal transplant recipient female. Craniotomy was performed on an irregularly enhancing right cerebellar hemisphere lesion and abscess and tissue samples collected for microbiological and histological evaluation, showing fungal elements and Fonsecaea species was isolated. Antifungal treatment with voriconazole & liposomal amphotericin B was initiated with a temporary improvement in the patient\'s condition. Deep vein thrombosis jeopardized patient\'s prognosis. Despite aggressive surgical and medical intervention, our patient succumbed to the disease. Historically, CP has been linked with fatality rates as high as 65 %, despite surgical intervention and systemic antifungal medication.

Cladophialophora bantiana is a filamentous fungus, known as a dematiaceous fungus because of the presence of melanin. This fungus is of clinical importance because it is neurotropic and causes cerebral phaeohyphomycosis.
The available scientific information on the development of cerebral phaeohyphomycosis caused by Cladophialophora bantiana was analysed by selecting articles from the PubMed, Scopus and Google Scholar databases that describe case reports of fungal infection by C. bantiana in adults, taking into account the analysis of the patients\' symptomatology, clinical history and neuroanatomical damage, in addition to considering the mortality of the condition.
India and United States were the countries with most case reports, with 32 and 11 cases respectively. Moreover, in terms of neuroanatomical lesions, the majority of patients suffered mixed lesions (29%) and frontal lobe lesions (22%). In accordance with the patients\' condition, the pathology has a mortality rate of 62%.
It is concluded that cerebral phaeohyphomycosis has a high mortality rate, there is no standardised treatment and, in most cases, the fungal infection of the brain is mixed and affects several different parts of it. Furthermore, if not diagnosed and treated in time, it can lead to the patients\' death.
Infección micótica por Cladophialophora bantiana y desarrollo de feohifomicosis cerebral. Revisión sistemática de 58 informes de caso.
Introducción. Cladophialophora bantiana es un hongo filamentoso, denominado hongo dematiáceo por la presencia de melanina. Este hongo tiene importancia clínica por ser neurotrópico y causar feohifomicosis cerebral. Material y métodos. Se analizó la información científica disponible sobre el desarrollo de feohifomicosis cerebral provocada por Cladophialophora bantiana, seleccionando artículos de las bases de PubMed, Scopus y Google Scholar, que describen informes de caso sobre infección micótica de C. bantiana en adultos, considerando el análisis de la sintomatología, el historial clínico y los daños neuroanatómicos de los pacientes, además de considerar la mortalidad de la patología. Resultados. La India y Estados Unidos fueron los países con más informes de caso, 32 y 11 casos, respectivamente. Asimismo, en cuanto a las lesiones neuroanatómicas, en su mayoría, los pacientes sufrieron lesiones mixtas (29%) y del lóbulo frontal (22%). De acuerdo con el estado de los pacientes, la patología tiene una mortalidad del 62%. Conclusiones. Se concluye que la feohifomicosis cerebral tiene una alta mortalidad, no existe un tratamiento estandarizado y, en la mayoría de los casos, la infección fúngica del cerebro es mixta y afecta a varias partes del cerebro; además, si no se diagnostica y trata a tiempo, puede ocasionar la muerte de los pacientes.

A right-handed man in his early 60s with hypertension controlled by a single prescription medication presented with left-sided heaviness and intermittent right occipital headache. Initial diagnostic workup was unremarkable. CT revealed an enhancing lesion located in the right parietal lobe, with mild mass effect on the right occipital horn, indicative of a brain abscess. The patient was initially treated with a course of empirical antibiotics, including ceftriaxone, vancomycin, metronidazole and dexamethasone. The neurosurgery team aspirated the abscess the following day and extracted yellow pus that was sampled for bacterial and fungal cultures. These cultures returned positive for Rhinocladiella mackenziei, prompting a discontinuation of the empirical antibiotics and initiation of intravenous liposomal amphotericin B for 4 weeks. Intravenous posaconazole was added to the patient\'s existing therapy regimen, which was substituted with oral isavuconazole on discharge. The patient continues to take isavuconazole, and follow-up imaging has demonstrated regression of the abscess.

OBJECTIVE: To report cases of cerebral phaeohyphomycosis at a tertiary hospital in Riyadh, Saudi Arabia. Phaeohyphomycetes are a widely distributed group of fungi whose cell walls contain 1,8 dihydroxynaphthalene-melanin. Cerebral infections caused by these fungi are uncommon and primarily associated with neurotrophic phaeohyphomycetes.
METHODS: In January of 2020 we looked back to identify cases of culture-positive cerebral phaeohyphomycosis from our medical records at King Faisal Specialist Hospital and Research Center in Riyadh, Saudi Arabia. Data on demographics, potential risk factors, clinical presentation, treatment, and outcomes were analyzed.
RESULTS: Twelve cases of cerebral phaeohyphomycosis were identified, of which 4 were caused by Rhinocladiella mackenziei and the other 8 were caused by various phaeohyphomycetes. There were 2 cases caused by Neoscytalidium dimidiatum, and one case each caused by the following: Acrophialophora fusispora, Chaetomium atrobrunneum, Exophiala dermatitidis, Exerohilum rostratum, Fonsecaea pedrosoi, and Cladophialophora bantiana. Most patients (10 of 12) had underlying immunosuppression. R. mackenziei caused a brain-only infection manifesting as abscess formation. Four patients survived for more than a year after therapy. Surgical evacuation and triazole therapy with posaconazole or itraconazole, alone or in combination with other antifungal agents, were associated with success.
CONCLUSIONS: Cerebral phaeohyphomycosis is an uncommon fungal infection that primarily affects immunocompromised patients and is associated with poor prognosis. R. mackenziei is the most prevalent fungus in our facility and has been linked to a universal mortality.

BACKGROUND: Cladophialophora bantiana, a neurotropic phaeoid fungus, is the primary agent of cerebral phaeohyphomycosis. The disease more commonly affects immunocompetent males and is associated with a high mortality rate.
METHODS: We report a case of brain abscess caused by Cladophialophora bantiana in a 50-year-old immunocompetent male who presented with headache for two months, weakness of both lower limbs for 15 days, and altered sensorium and aphasia for one day. Contrast-enhanced MRI of the brain showed multiple coalescent abscesses in the right basal ganglia and corpus callosum. Based on clinical and radiological suspicion of tuberculoma, treatment with antitubercular drugs was initiated. A month after discharge, the patient was re-admitted with history of loss of consciousness, altered sensorium, respiratory distress and aphasia. Brain CECT revealed multiple ring-enhancing lesions in the right basal ganglia with mass effect and a leftward midline shift. The patient underwent craniotomy and evacuation of abscess. Direct microscopy of pus aspirated from the lesions showed pigmented septate fungal hyphae, which was identified as C. bantiana in fungal culture. The patient was administered intravenous liposomal amphotericin B and voriconazole. However, he died due to multiple organ failure on day 19 after surgery.
CONCLUSIONS: Fungal etiology should be considered in the differential diagnosis of intracranial space occupying lesions, regardless of the host immune status. An early diagnosis, together with aggressive medical and neurosurgical interventions are imperative for improving the survival in such patients.

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Phaeohyphomycosis, previously known as chromoblastomycosis, is a chronic mycosis, usually affecting the skin. It is caused by dematiaceous fungi, which are a group of fungi that produce melanin in their cell walls. Cerebral phaeohyphomycosis occurs as a part of invasive presentation of the fungi, which usually affects immunocompromised patients, but may affect immunocompetent individuals as well. Cerebral infection in phaeohyphomycosis is associated with a poor prognosis regardless of the immune status of the patient. COVID-19 SARS-CoV-2 infection and/or medications used for its treatment may compromise the immune system, including in the post-COVID-19 period, resulting in invasive fungal infections, which have frequently been reported recently during the COVID-19 pandemic. We report a case of Fonsecaea associated cerebral phaeohyphomycosis in a recently diagnosed diabetic Omani lady, who presented to our hospital 6 weeks after recovery and discharge from hospitalization for moderate COVID-19 pneumonia.

Rhinocladiella mackenziei cerebral phaeohyphomycosis is a rare severe disease that has been typically described in the Middle East. Here, we report 2 cases of R. mackenziei cerebral phaeohyphomycosis in patients from Morocco, diagnosed and treated in France, and raise a concern about the ever-going extension of the area at risk for this devastating invasive fungal infection.