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Fungal infections present a significant health risk, particularly in immunocompromised individuals. Berberine, a natural isoquinoline alkaloid, has demonstrated broad-spectrum antimicrobial activity, though its antifungal potential and underlying mechanisms against both yeast-like and filamentous fungi are not fully understood. This study investigates the antifungal efficacy of berberine against Candida albicans , Cryptococcus neoformans , Trichophyton rubrum , and Trichophyton mentagrophytes in vitro, as well as its therapeutic potential in a murine model of cryptococcal infection. Berberine showed strong antifungal activity, with MIC values ranging from 64 to 128 µg/mL. SEM and TEM analyses revealed that berberine induced notable disruptions to the cell wall and membrane in C. neoformans . No signs of cell necrosis or apoptosis were observed in fungal cells treated with 2 × MIC berberine, and it did not increase intracellular ROS levels or affect mitochondrial membrane potential. Molecular docking and binding affinity assays demonstrated a strong interaction between berberine and the fungal enzyme CYP51, with a dissociation constant (KD) of less than 1 × 10 -12 M, suggesting potent inhibition of ergosterol biosynthesis. In vivo studies further showed that berberine promoted healing in guinea pigs infected with T. mentagrophytes , and in a murine cryptococcal infection model, it prolonged survival and reduced lung inflammation, showing comparable efficacy to fluconazole. These findings indicate that berberine exerts broad-spectrum antifungal effects through membrane disruption and CYP51 inhibition, highlighting its potential as a promising therapeutic option for fungal infections.

Background: Cryptococcus is an opportunistic infection acquired through inhalation from the environment, primarily affecting individuals with compromised immune systems. It typically leads to pneumonia upon passing through lung tissue. The infection can disseminate to various organs via the bloodstream, resulting in meningitis or encephalitis in the central nervous system. Disseminated Cryptococcus has been reported to involve the skin, liver, eyes, lymph nodes, bone marrow, spleen, kidneys, and intestines, significantly increasing morbidity and mortality. However, pancreatic involvement in Cryptococcus is relatively rare, and a few case reports have highlighted severe organ damage and high mortality rates., Case Presentation: In this case report, we present the case of a 36-year-old Asian man who presented with a 2-week history of headaches and blurred vision in his right eye. Brain magnetic resonance imaging revealed multiple brain masses, along with a mass in the lower left lung field and a tumor in the pancreatic tail, as detected by chest computed tomography. Endoscopic ultrasound-guided fine needle biopsy and computed tomography-guided lung biopsy confirmed the diagnosis of disseminated cryptococcal infection involving the pancreas, lung, and brain. The patient's clinical condition improved following antifungal therapy. Additionally, we identified anti-granulocyte-macrophage colony-stimulating factor antibody as a risk factor for disseminated cryptococcal infection in this patient., Conclusion: Disseminated cryptococcosis can be a potentially lethal condition, as highlighted by previous literature. However, early diagnosis using contrast-enhanced harmonic endoscopic ultrasound and endoscopic ultrasound-guided biopsies, as well as prompt treatment as demonstrated in our case, can improve outcomes and prevent mortality., (© 2024. The Author(s).)

Background: Cerebral venous sinus thrombosis (CVST), a serious cerebrovascular and neurological emergency, is common in pregnant individuals and accounts for approximately 0.5-1.0% of all cerebrovascular diseases. However, CVST with cryptococcal meningoencephalitis in immunocompetent pregnant patients is rare., Case Presentation: A 30-year-old woman who was 33 weeks pregnant presented with recurrent dizziness, headache, and vomiting as the main clinical manifestations, all of which were initially nonspecific. After assessment of the cerebrospinal fluid, skull computerized tomography, magnetic resonance imaging, and other laboratory and imaging examinations, the patient was diagnosed with secondary pregnancy-related CVST with cryptococcal meningoencephalitis. Despite receiving potent anticoagulant and antifungal treatment, the patient's condition deteriorated, and the patient's family opted to cease treatment., Conclusions: We present a rare case of CVST with cryptococcal meningoencephalitis in an immunocompetent pregnant patient. The difficulty of diagnosing and treating secondary pregnancy-related CVST caused by cryptococcal meningoencephalitis, as well as the great challenges faced at present are highlighted. One crucial lesson from the present case is that when clinical and imaging signs are unusual for CVST during pregnancy, it is essential to account for the possibility of other central nervous system (CNS) diseases, such as CNS infections with Cryptococcus, which may cause CVST., (© 2024. The Author(s).)

We report a case of disseminated cryptococcosis, an uncommon fungal infection predominantly affecting the lungs and central nervous system, with the rare involvement of adrenal cryptococcosis, compounded by meningitis and pneumonia. The patient, previously diagnosed with primary myelofibrosis and undergoing oral Ruxolitinib treatment, exhibited immunosuppression. Imaging via chest and abdominal CT scans revealed inflammation in the right lung's middle lobe, splenomegaly, a splenic lesion, and a left adrenal mass, initially prompting considerations of pheochromocytoma. However, unilateral adrenalectomy and subsequent pathological examination disclosed extensive infiltration by inflammatory and multinucleate giant cells, with Periodic acid-Schiff (PAS) staining confirming the diagnosis. The identification of adrenal cryptococcosis was further supported by positive adrenal pus culture and significantly elevated capsular antigens in both serum and cerebrospinal fluid, at titers of 1:2560. Following a month of oral antifungal treatment, marked reductions in capsular antigen levels were noted, to 1:640 and 1:160 in serum and cerebrospinal fluid, respectively. The patient was discharged on a regimen of oral amphotericin B, flucytosine, and fluconazole, with regular outpatient follow-ups showing no signs of recurrence or dissemination., (© 2024. The Author(s).)

Background: Cryptococcus neoformans causes cryptococcosis, primarily affecting immunocompromised individuals, including solid-organ transplant recipients, and, less frequently, immunocompetent people., Case: A 15-year-old male with congenital hepatic fibrosis, portal hypertension, and cirrhosis underwent orthotopic liver transplantation. He received perioperative antimicrobial and antifungal prophylaxis and continued immunosuppressive treatment. Thirty months post-transplant, he presented with fever, hypertension, and sacroiliac joint pain. Peripheral blood cultures showed C. neoformans, confirmed by pan-fungal polymerase chain reaction assay and latex agglutination tests. Despite initial treatment with intravenous (IV) fluconazole, his condition worsened, necessitating intubation for acute hypoxic respiratory failure. Magnetic resonance imaging and computed tomography scans indicated disseminated cryptococcosis with lymphadenitis, possible meningitis, and pneumonia. Treatment was escalated to IV liposomal amphotericin B and 5-flucytosine, while reducing immunosuppressive treatment. Despite negative fungal cultures on the tenth day, the patient deteriorated, developing pancreatitis, pneumonia, and massive gastrointestinal bleeding, leading to death on the 35th day of hospitalization., Conclusion: This case shows the severity and complexity of managing disseminated cryptococcosis in pediatric liver transplant recipients. Aggressive therapy and early identification are essential for improving outcomes in these high-risk patients., Competing Interests: The authors declare that there is no conflict of interest.

Pulmonary cryptococcosis is an uncommon invasive fungal infection of the lungs seen in immunocompromised individuals but increasingly reported among the immunocompetent. We report a rare case of pulmonary cryptococcosis in an immunocompetent host highlighting its unique clinical and radiological presentation.Clinical trial number: Not applicable., (© 2024. The Author(s).)

Pulmonary cryptococcosis is a fungal infection caused by Cryptococcus species, with Cryptococcus neoformans being the most common agent, affecting the lungs. While it commonly occurs in immunocompromised individuals, such as those with HIV/AIDS or undergoing immunosuppressive therapy, its presentation in patients with chronic kidney disease (CKD) is relatively rare. However, it should be considered in the differential diagnosis of respiratory infections in patients with CKD, particularly in the context of immunosuppression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ., (Copyright © 2024 Indian Association of Medical Microbiologists. Published by Elsevier B.V. All rights reserved.)

Cryptococcal infection of central nervous system commonly involves meningitis or meningoencephalitis, but rarely mimics inflammatory myelitis. We present short segment myelitis as a dominant manifestation caused by Cryptococcus neoformans in a patient with nephrotic syndrome under immunosuppressive therapy. This case report highlights Cryptococcus neoformans as a potential etiological factor for short segment myelitis in immunocompromised hosts., (© 2024. The Author(s).)

Background: Cryptococcosis is an invasive infection that commonly affects immunosuppressed individuals, especially patients with HIV infection. Cryptococcal infection in HIV-infected patients should be considered a major health concern because it is associated with high morbidity and mortality rates. In this study, we aimed to evaluate the clinical characteristics and prognostic factors of cryptococcal infections in human immunodeficiency virus (HIV)-infected patients to facilitate effective clinical management and improve patient outcomes., Methods: We reviewed and analyzed the clinical data and relevant laboratory test results of HIV-infected patients with positive cryptococcal cultures and reserved strains between 2013 and 2023 from Beijing Youan Hospital affiliated to Capital Medical University. The clinical characteristics and laboratory test results of the patients were compared, and the correlation between parameters and the prognoses of the patients at different observation timepoints (3, 6, 9, and 12 months) was analyzed., Results: A total of 76 patients (70 males and six females; median age, 37 years) were included in this study. The results indicated that the later the initiation of antiretroviral therapy (ART) after the diagnosis of HIV infection (> 6 months), the higher the probability of death. Analysis of the correlation between the time of ART initiation and the timing of treatment for cryptococcal infections showed that the time of ART initiation was strongly related to survival at different timepoints. Initiation of ART time within 0-4 weeks, 4-6 weeks and more than 6weeks of starting treatment for Cryptococcus infection was associated with a lower mortality rate at 12-month, the 3-month, 6- and 9-month follow-up timepoint separately., Conclusions: Although cryptococcal infection in HIV-infected patients continues to be a challenging and intricate issue, ART is a key factor that affects its prognosis. The later ART is started, the worse the prognosis of the infection. The time of ART initiation and the timing of treatment for cryptococcal infections should be further refined and balanced based on different clinical courses. Thus, clinicians should pay closer attention to cryptococcal infections in patients with HIV infection and initiate ART based on the patient's clinical condition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Dai, Lou, Yu, Chen and Lu.)

Background: Cryptococcosis is an infectious disease caused by encapsulated heterobasidiomycete yeasts. As an opportunistic pathogen, cryptococcal inhalation infection is the most common. While Primary cutaneous cryptococcosis is extremely uncommon., Case Presentation: A 61-year-old woman with a history of rheumatoid arthritis on long-term prednisone developed a red plaque on her left thigh. Despite initial antibiotic treatment, the erythema worsened, leading to rupture and fever. Microbiological analysis of the lesion's secretion revealed Candida albicans, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus epidermidis. Skin biopsy showed thick-walled spores, and culture confirmed primary cutaneous infection with Cryptococcus neoformans. Histopathological stains were positive, and mass spectrometry identified serotype A of the pathogen. The patient was treated with oral fluconazole and topical nystatin, resulting in significant improvement and near-complete healing of the skin lesion within 2.5 months., Conclusions: Primary cutaneous cryptococcosis was a primary skin infection exclusively located on the skin. It has no typical clinical manifestation of cutaneous infection of Cryptococcus, and culture and histopathology remain the gold standard for diagnosing. The recommended medication for Primary cutaneous cryptococcosis is fluconazole. When patients at risk for opportunistic infections develop skin ulcers that are unresponsive to antibiotic, the possibility of primary cutaneous cryptococcosis needs to be considered., (© 2024. The Author(s).)

Cryptococcosis is a fungal infection that is becoming increasingly prevalent worldwide, particularly among individuals with compromised immune systems, such as HIV patients. Amphotericin B (AmB) is the first-line treatment mainly combined with flucytosine. The scarcity and the prohibitive cost of this regimen urge the use of fluconazole as an alternative, leading to increased rates of treatment failure and relapses. Therefore, there is a critical need for efficient and cost-effective therapy to enhance the efficacy of AmB. In this study, we evaluated the efficacy of the HIV protease inhibitors (PIs) to synergize the activity of AmB in the treatment of cryptococcosis. Five PIs (ritonavir, atazanavir, saquinavir, lopinavir, and nelfinavir) were found to synergistically potentiate the killing activity of AmB against Cryptococcus strains with ƩFICI ranging between 0.09 and 0.5 against 20 clinical isolates. This synergistic activity was further confirmed in a time-kill assay, where different AmB/PIs combinations exhibited fungicidal activity within 24 hrs. Additionally, PIs in combination with AmB exhibited an extended post-antifungal effect on treated cryptococcal cells for approximately 10 hrs compared to 4 hours with AmB alone. This promising activity against cryptococcal cells did not exhibit increased cytotoxicity towards treated kidney cells, ruling out the risk of drug combination-induced nephrotoxicity. Finally, we evaluated the efficacy of AmB/PIs combinations in the Caenorhabditis elegans model of cryptococcosis, where these combinations significantly reduced the fungal burden of the treated nematodes by approximately 2.44 Log10 CFU (92.4%) compared to the untreated worms and 1.40 Log10 ((39.4%) compared to AmB alone. The cost-effectiveness and accessibility of PIs in resource-limited geographical areas compared to other antifungal agents, such as flucytosine, make them an appealing choice for combination therapy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Alkashef, Seleem. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Cryptococcus neoformans causes cryptococcosis, one of the most prevalent fungal diseases, generally characterized by meningitis. There is a limited and not very effective number of drugs available to combat this disease. In this manuscript, we show the host defense peptide mimetic brilacidin (BRI) as a promising antifungal drug against C. neoformans . BRI can affect the organization of the cell membrane, increasing the fungal cell permeability. We also investigated the effects of BRI against the model system Saccharomyces cerevisiae by analyzing libraries of mutants grown in the presence of BRI. In S. cerevisiae , BRI also affects the cell membrane organization, but in addition the cell wall integrity pathway and calcium metabolism. In vivo experiments show BRI significantly reduces C. neoformans survival inside macrophages and partially clears C. neoformans lung infection in an immunocompetent murine model of invasive pulmonary cryptococcosis. We also observed that BRI interacts with caspofungin (CAS) and amphotericin (AmB), potentiating their mechanism of action against C. neoformans . BRI + CAS affects endocytic movement, calcineurin, and mitogen-activated protein kinases. Our results indicate that BRI is a novel antifungal drug against cryptococcosis., Importance: Invasive fungal infections have a high mortality rate causing more deaths annually than tuberculosis or malaria. Cryptococcosis, one of the most prevalent fungal diseases, is generally characterized by meningitis and is mainly caused by two closely related species of basidiomycetous yeasts, Cryptococcus neoformans and Cryptococcus gattii . There are few therapeutic options for treating cryptococcosis, and searching for new antifungal agents against this disease is very important. Here, we present brilacidin (BRI) as a potential antifungal agent against C. neoformans . BRI is a small molecule host defense peptide mimetic that has previously exhibited broad-spectrum immunomodulatory/anti-inflammatory activity against bacteria and viruses. BRI alone was shown to inhibit the growth of C. neoformans , acting as a fungicidal drug, but surprisingly also potentiated the activity of caspofungin (CAS) against this species. We investigated the mechanism of action of BRI and BRI + CAS against C. neoformans . We propose BRI as a new antifungal agent against cryptococcosis., Competing Interests: Gustavo H. Goldman is a member of the scientific advisory board of Innovation Pharmaceuticals, a company that is conducting clinical trials on brilacidin. Other authors have no conflict of interest.

BACKGROUND Cryptococcosis is an opportunistic fungal infection that typically occurs in patients with compromised immune systems, primarily affecting the respiratory and central nervous systems. However, cryptococcal osteomyelitis is a rare manifestation of cryptococcal infection, characterized by nonspecific clinical features. Here, we present a case of vertebral cryptococcal osteomyelitis in a middle-aged woman and discuss diagnostic approaches. CASE REPORT A 56-year-old woman presented with lower back pain and limited mobility, without fever, and with a history of pulmonary tuberculosis. Physical examination revealed enlarged lymph nodes and tenderness in the thoracic vertebrae. A computed tomography-guided biopsy confirmed granulomatous inflammation caused by Cryptococcus, with abundant 10 μm spherical microbial spores. After 4 weeks of treatment with amphotericin B and fluconazole, symptoms and lesions improved. Upon discharge, the patient was prescribed oral fluconazole. Follow-up examinations showed a stable condition and a negative serum cryptococcal capsular polysaccharide antigen test. CONCLUSIONS Given the rarity and lack of specificity of clinical features of cryptococcal spondylitis, clinicians encountering similar presentations should consider tuberculous spondylitis and spinal tumors as differential diagnoses. Additionally, tissue biopsy of the affected vertebral bodies should be performed early to establish the type of vertebral infection, aiding in diagnosis, treatment, and prognosis.

Objectives: This study investigated the anti-cryptococcal potential of certain essential oils (EOs)/compounds alone and in combination with fluconazole., Materials and Methods: We investigated the antifungal activity of oils of Cinnamomum verum, Cymbopogon citratus, Cymbopogon martini, and Syzygium aromaticum, and their major active ingredients cinnamaldehyde, citral, eugenol, and geraniol against clinical and standard strains of Cryptococcus neoformans (CN). Disc diffusion, broth microdilution, checkerboard methods, and transmission electron microscopy were employed to determine growth inhibition, synergistic interaction, and mechanism of action of test compounds., Results: EOs/compounds showed pronounced antifungal efficacy against azole-resistant CN in the order of cinnamaldehyde > eugenol > S. aromaticum > C. verum > citral > C. citratus > geraniol ≥ C. martini, each exhibiting zone of inhibition >15 mm. These oils/compounds were highly cidal compared to fluconazole. Eugenol and cinnamaldehyde showed the strongest synergy with fluconazole against CN by lowering their MICs up to 32-fold. Transmission electron microscopy indicated damage of the fungal cell wall, cell membrane, and other endomembranous organelles., Conclusion: Test oils and their active compounds exhibited potential anti-cryptococcus activity against the azole-resistant strains of CN. Moreover, eugenol and cinnamaldehyde significantly potentiated the anti-cryptococcal activity of fluconazole. It is suggested that multiple sites of action from oils/compounds could turn static fluconazole into a cidal drug combination in combating cryptococcosis., (Copyright © 2024 Copyright: © 2024 Annals of African Medicine.)

Background: Hepatitis B virus (HBV) infection can cause liver failure, while individuals with Acquired Immunodeficiency Virus Disease (AIDS) are highly susceptible to various opportunistic infections, which can occur concurrently. The treatment process is further complicated by the potential occurrence of immune reconstitution inflammatory syndrome (IRIS), which presents significant challenges and contributes to elevated mortality rates., Case Presentation: The 50-year-old male with a history of chronic hepatitis B and untreated human immunodeficiency virus (HIV) infection presented to the hospital with a mild cough and expectoration, revealing multi-drug resistant pulmonary tuberculosis (MDR-PTB), which was confirmed by XpertMTB/RIF PCR testing and tuberculosis culture of bronchoalveolar lavage fluid (BALF). The patient was treated with a regimen consisting of linezolid, moxifloxacin, cycloserine, pyrazinamide, and ethambutol for tuberculosis, as well as a combination of bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) for HBV and HIV viral suppression. After three months of treatment, the patient discontinued all medications, leading to hepatitis B virus reactivation and subsequent liver failure. During the subsequent treatment for AIDS, HBV, and drug-resistant tuberculosis, the patient developed disseminated cryptococcal disease. The patient's condition worsened during treatment with liposomal amphotericin B and fluconazole, which was ultimately attributed to IRIS. Fortunately, the patient achieved successful recovery after appropriate management., Conclusion: Enhancing medical compliance is crucial for AIDS patients, particularly those co-infected with HBV, to prevent HBV reactivation and subsequent liver failure. Furthermore, conducting a comprehensive assessment of potential infections in patients before resuming antiviral therapy is essential to prevent the occurrence of IRIS. Early intervention plays a pivotal role in improving survival rates., (© 2024. The Author(s).)

Invasive fungal infections are a significant public health concern, with mortality rates ranging from 20% to 85% despite current treatments. Therefore, we examined whether a ketogenic diet could serve as a successful treatment intervention in murine models of Cryptococcus neoformans and Candida albicans infection in combination with fluconazole-a low-cost, readily available antifungal therapy. The ketogenic diet is a high-fat, low-carbohydrate diet that promotes fatty acid oxidation as an alternative to glycolysis through the production of ketone bodies. In this series of experiments, mice fed a ketogenic diet prior to infection with C. neoformans and treated with fluconazole had a significant decrease in fungal burden in both the brain (mean 2.66 ± 0.289 log 10 reduction) and lung (mean 1.72 ± 0.399 log 10 reduction) compared to fluconazole treatment on a conventional diet. During C. albicans infection, kidney fungal burden of mice in the keto-fluconazole combination group was significantly decreased compared to fluconazole alone (2.37 ± 0.770 log 10 -reduction). Along with higher concentrations of fluconazole in the plasma and brain tissue, fluconazole efficacy was maximized at a significantly lower concentration on a keto diet compared to a conventional diet, indicating a dramatic effect on fluconazole pharmacodynamics. Our findings indicate that a ketogenic diet potentiates the effect of fluconazole at multiple body sites during both C. neoformans and C. albicans infection and could have practical and promising treatment implications.IMPORTANCEInvasive fungal infections cause over 2.5 million deaths per year around the world. Treatments for fungal infections are limited, and there is a significant need to develop strategies to enhance antifungal efficacy, combat antifungal resistance, and mitigate treatment side effects. We determined that a high-fat, low-carbohydrate ketogenic diet significantly potentiated the therapeutic effect of fluconazole, which resulted in a substantial decrease in tissue fungal burden of both C. neoformans and C. albicans in experimental animal models. We believe this work is the first of its kind to demonstrate that diet can dramatically influence the treatment of fungal infections. These results highlight a novel strategy of antifungal drug enhancement and emphasize the need for future investigation into dietary effects on antifungal drug activity., Competing Interests: J.R.P. received grants/consulting support from Appili, Pfizer, Matinas, Cidara, Scynexis, and F2G. C.D.G. received past salary support from projects funded by Appili, Astellas, Amplyx, Interventional Analgesix, Minnetronix, Pfizer, and Sfunga Therapeutics. He owns common stock totaling less than $5,000 of the following: GSK, Actinium, Nkarta, and Bristol Myers Squibb. W.H. holds or has recently held research grants with UKRI, EU (FP7, IMI-1, and IMI-2), Wellcome, F2G, Spero Therapeutics, Antabio, Pfizer, Allecra, Bugworks, Phico Therapeutics, BioVersys, and Global Antimicrobial Research and Development Partnership (GARDP). He is (or has recently been) a consultant for Appili Therapeutics, F2G, Spero Therapeutics, Pfizer, GSK, Phico Therapeutics, Pulmocide, and Mundipharma Research Ltd. He was a member of the Specialist Advisory Committee for GARDP (2020–2023), a member of the British Society for Antimicrobial Chemotherapy Breakpoint Committee (2020–2023), and a member of NIHR Health Technology Appraisal (HTA) Prioritisation Committee for hospital care and is the Specialty National Co-lead for Infection for the National Institute of Health Research (NIHR) (2020–current).

Background: Cryptococcal osteomyelitis is a rare and potentially serious condition, typically encountered in individuals with compromised immune systems. This case underscores the unusual occurrence of disseminated Cryptococcosis in an immunocompetent person, involving multiple bones and lungs, with Cryptococcus neoformans identified as the causative agent., Case Presentation: An Indonesian man, previously in good health, presented with a chief complaint of successive multiple bone pain lasting for more one month, without any prior history of trauma. Additionally, he reported a recent onset of fever. On physical examination, tenderness was observed in the left lateral chest wall and right iliac crest. Laboratory findings indicated mildly elevated inflammatory markers. A computed tomography (CT) scan of the chest revealed an ovoid solid nodule in the right lower lung and multifocal osteolytic lesions in the sternum, ribs, and humeral head. A magnetic resonance imaging (MRI) study of the sacrum showed multiple lesions in the bilateral iliac bone and the lower L4 vertebral body. Confirmation of Cryptococcal osteomyelitis involved a fine-needle biopsy and culture, identifying Cryptococcus neoformans in the aspirate. The patient responded positively to targeted antifungal treatments, leading to a gradual improvement in his condition., Conclusions: This case emphasizes the need to consider Cryptococcus neoformans osteomyelitis in immunocompetent patients with bone pain. A definitive diagnosis involves a fine-needle biopsy for pathology and culture, and prompt initiation of appropriate antifungal treatment has proven effective in preventing mortality., (© 2024. The Author(s).)

Abstract: Cryptococcosis usually occurs in immunocompromised patients and presents as meningitis and lung disease. Adrenal gland involvement may be observed, yet primary adrenal insufficiency by cryptococcal infection is infrequent. We present a case of a middle-aged immunocompetent man with primary adrenal insufficiency and bilateral adrenal lesions, splenomegaly, and miliary mottling in the lungs on imaging. No evidence of meningitis was witnessed. The clinico-radiological findings led toward the differential diagnosis of disseminated tuberculosis or fungal infection. Detection of cryptococcus organism was done on fine-needle aspiration cytology and biopsy on periodic acid-Schiff stain and Gomori`s methenamine silver stain. Thus, it is recommended to keep the possibility of cryptococcosis in mind while dealing with instances that have a tuberculosis-like clinico-radiological presentation. The detection of the causal organism on Fine needle aspiration (FNA)/biopsy examination may be useful in confirming the diagnosis and determining the appropriate medical treatment., (Copyright © 2023 Copyright: © 2023 Indian Journal of Pathology and Microbiology.)

Rationale: Cryptococcosis presenting as endobronchial obstruction and lung collapse is an extremely rare occurrence. While these patients were treated with antifungal agents, unfortunately, half of them showed a suboptimal response., Patient Concerns: A 45-year-old immunocompetent male was admitted to the hospital due to a cough, yellow phlegm, and dyspnea persisting for 5 months. Chest computer tomography revealed a mass in the right main bronchus accompanied by right lower lobe atelectasis., Diagnoses: Endobronchial cryptococcosis presenting as endobronchial obstruction and lung collapse., Interventions: Early rigid bronchoscopic therapy was performed to resect endobronchial obstruction, which combined with antifungal agent., Outcomes: The patient recovered well with completely clinical and radiologic resolution at 1 year follow-up., Lessons: This case provides a good example of successful utilization of the early respiratory interventional therapy combined with antifungal agent in obstructive endobronchial cryptococcosis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: The relationship between antifungal susceptibility and mortality of cryptococcal meningitis (CM) in HIV-negative patients is poorly understood., Methods: We conducted a retrospective analysis of 1-year follow-up of 200 HIV-negative CM patients with an initial cerebrospinal fluid (CSF) culture for Cryptococcus neoformans. According to the cut-off values of minimum inhibitory concentration (MIC), two groups of five antifungal agents were classified: amphotericin B (AmB), ≤0.5 µg/mL, >0.5 µg/mL; 5-flucytosine (5-FC), ≤4 µg/mL, >4 µg/mL; fluconazole (FLU), ≤4 µg/mL, >4 µg/mL; itraconazole (ITR), ≤0.125 µg/mL, >0.125 µg/mL; and voriconazole (VOR), <0.25 µg/mL, ≥0.25 µg/mL. Comparisons were performed to analyse clinical features, laboratory, modified Rankin Scale (mRS) scores, and CSF findings under different prognosis outcomes in 1-year., Results: All of Cryptococcus neoformans isolates were sensitive to AmB and VOR, most of them were sensitive to 5-FC and FLU (95.5% and 90.5%, respectively) while only 55.0% of them were susceptible to ITR. Minimum inhibitory concentrations of ITR and VOR were significantly related to baseline mRS scores. All-cause mortality was not significantly related to MICs in Cryptococcus neoformans strains. The combination of actual antifungal agents and two groups of the MICs values for antifungal agents had no significant effects on all-cause mortality., Conclusion: Most Cryptococcus neoformans isolates were sensitive to AmB, VOR, 5-FC, and FLU. Because of the small number of deaths, we are not able to comment on whether MIC is associated with mortality of CM in HIV-negative patients., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Bacterial persisters, a subpopulation of genetically susceptible cells that are normally dormant and tolerant to bactericides, have been studied extensively because of their clinical importance. In comparison, much less is known about the determinants underlying fungicide-tolerant fungal persister formation in vivo. Here, we report that during mouse lung infection, Cryptococcus neoformans forms persisters that are highly tolerant to amphotericin B (AmB), the standard of care for treating cryptococcosis. By exploring stationary-phase indicator molecules and developing single-cell tracking strategies, we show that in the lung, AmB persisters are enriched in cryptococcal cells that abundantly produce stationary-phase molecules. The antioxidant ergothioneine plays a specific and key role in AmB persistence, which is conserved in phylogenetically distant fungi. Furthermore, the antidepressant sertraline (SRT) shows potent activity specifically against cryptococcal AmB persisters. Our results provide evidence for and the determinant of AmB-tolerant persister formation in pulmonary cryptococcosis, which has potential clinical significance., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Pulmonary cryptococcosis is a lung infection caused by the Cryptococcus yeast. It is rare in pediatrics, especially in immunocompetent children. The diagnosis of pulmonary cryptococcosis can be challenging due to the low specificity of symptoms, low index of suspicion, and limited diagnostic resources., Objective: To describe a clinical case of pulmonary cryptococcosis in an immunocompetent adolescent, detailing the diagnostic approach., Clinical Case: A 15-year-old patient, previously healthy, from a rural town, who consulted due to cough and a 1-month rib stitch pain, without fever or associated respiratory difficulty, with two images of condensation in the left lung on the chest x-ray. In the Computed Tomography, the images showed a nodular appearance. Due to suspicion of neoplastic pathology, a Positron Emission Tomography was performed, which showed hypermetabolic nodular lesions. The tomographic characteristics could correspond to fungal or granulomatous involvement. Considering the images and epidemiological risk factors such as rural origin and contact with bird droppings, the possibility of a mycosis was considered. A lung needle biopsy was performed under tomographic guidance. Cryptococcus neoformans was identified in the microbiology laboratory culture. The patient received treatment with itraconazole and fluconazole with good clinical and imaging response after 10 months of therapy and follow-up., Conclusion: In immunocompetent patients with a nonspecific clinical presentation, images can guide the diagnosis of pulmonary cryptococcosis, and an etiological search is essential to confirm it. In our case, the CT-guided needle biopsy was of great diagnostic utility.

Background/objective: With the development of society, pulmonary fungal diseases, represented by pulmonary aspergillosis and pulmonary cryptococcosis, have become increasingly common. However, there is a lack of clear understanding regarding coinfection by these two types of fungi in immunocompetent individuals., Methods: A retrospective study from 2014 to 2022 and a systematic literature review of original articles published in English were performed. Patients with pulmonary cryptococcosis complicated with pulmonary aspergillosis including 5 in the retrospective study and 6 in the systematic literature review., Result: The diagnosis of concurrent pulmonary cryptococcosis and pulmonary aspergillosis in patients was confirmed through repeated biopsies or surgical resection. Pulmonary cryptococcosis is often diagnosed initially (6/11, 55%), while the diagnosis of pulmonary aspergillosis is established when the lesions become fixed or enlarged during treatment. Transbronchial lung biopsy (3/11, 27%), thoracoscopic lung biopsy (2/11, 18%), and percutaneous aspiration biopsy of the lung (1/11, 9%) were the main methods to confirm concurrent infection. Most patients were treated with voriconazole, resulting in a cure for the coinfection (6/11, 55%)., Conclusion: Pulmonary cryptococcosis complicated with pulmonary Aspergillus is an easily neglected mixed fungal infection. During the treatment of lesion enlargement in clinical cryptococcus, we need to watch out for Aspergillus infection., (© 2024. The Author(s).)

Antifungal infections are becoming a major concern to human health due to antimicrobial resistance. Echinocandins have been promising agents against resistant fungal infections, primarily caspofungin, which has a more effective mechanism of action than azoles and polyenes. However, fungi such as Cryptococcus neoformans appear to be inheritably resistant to these drugs, which is concerning due to the high clinical importance of C. neoformans . In this review, we review the history of C. neoformans and the treatments used to treat antifungals over the years, focusing on caspofungin, while highlighting the C. neoformans problem and possible explanations for its inherent resistance.

Rationale: Pulmonary cryptococcal infections occur mainly in immunocompromised individuals, such as those with malignancies. Preoperative diagnosis of pulmonary cryptococcosis (PC) can be challenging for both clinicians and radiologists because of nonspecific clinical manifestations and variable radiologic features, as it is easily misdiagnosed as metastatic lung cancer., Patient Concerns: In case 1, a 76-year-old woman with a history of cervical cancer presented with lung nodules detected on chest computed tomography (CT) 13 months after completing concurrent chemoradiotherapy. In case 2, a 56-year-old woman with a history of ovarian cancer presented with pulmonary nodules on chest CT 19 months after completing chemotherapy. Both patients were clinically asymptomatic, and tumor markers were not elevated., Diagnoses: In case 1, chest CT revealed multiple enhanced nodules with lobulated margins in the left lower lobe, and positron emission tomography (PET)-CT showed uptake in the nodule with a standardized uptake value of 3.7. In case 2, chest CT revealed several nodules in the right upper lobe abutting the right major fissure, and PET-CT revealed fluorodeoxyglucose uptake in the nodules. Pathology revealed granulomatous inflammation with cryptococcal infection, and mucicarmine and periodic acid-Schiff staining confirmed cryptococcal infection in both cases., Interventions: Presumptive diagnoses of lung metastases were made in both cases and thoracoscopic lobectomy was performed. Postoperatively, the patients received antifungal therapy with fluconazole., Outcomes: PC was differentially diagnosed and effectively managed. The patients remained disease-free for both PC and gynecological cancers during subsequent follow-ups., Lessons: Recognition that PC can mimic lung metastasis is important for managing gynecological cancers. PC should be considered in the differential diagnosis when single or multiple nodules are detected on chest radiography without elevation of tumor markers in patients with gynecological cancer., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Cryptococcus neoformans is a ubiquitous environmental organism found worldwide. Infection with this organism occurs predominantly in immunocompromised hosts, including persons living with HIV or those with impaired cellular immunity. Cryptococcal pleural effusions have been described in cases with extensive pulmonary involvement. Here we present the case of a woman receiving temozolomide and steroids for glioblastoma multiforme, who developed cough and dyspnoea and was found to have an uncomplicated pleural effusion. Pleural fluid culture grew Cryptococcus neoformans with negative culture on bronchoalveolar lavage. High serum cryptococcal antigen titre of 1:64 prompted lumbar puncture which demonstrated positive cerebrospinal fluid for Cryptococcus neoformans She was treated with liposomal amphotericin B and flucytosine, followed by consolidation and maintenance therapy with fluconazole. Pleural involvement in the absence of pulmonary involvement has rarely been reported. We review pulmonary and radiographic manifestations of cryptococcal infection, when to assess for disseminated infection, and management principles., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Cryptococcus neoformans is an encapsulated yeast. It is a significant pathogen among immunocompromised people with HIV & Non-HIV vulnerable populations. These conditions include cancer, corticosteroid usage, immunosuppression following sarcoidosis, organ transplantation, immunosuppressive medication, and liver cirrhosis. In cirrhotic, it accounts for 6-21% of systemic infections., Methods: The retrospective study was conducted in tertiary care hepatobiliary center in New Delhi, India. Samples of blood, cerebrospinal fluid (CSF), urine, body fluids, and serum were processed for gram stain, India ink, fungal culture and identification, and cryptococcal antigen. Antifungal susceptibility was assessed using the micro-broth dilution technique., Results: 30 patients with cryptococcal infection were analysed, and 40 isolates from various samples were recovered. Out of 40 samples, C. neoformans was isolated from blood (62.5%), urine (15%), ascitic fluid (10%), MiniBAL (5%), bone marrow, CSF, and pleural fluid in one sample each. India ink positivity was 56% and all samples were positive for Cryptococcal antigen. Alcoholic liver disease & Hepatitis B & C associated chronic liver disease were seen in 43% & 20% of patients. Other underlying conditions were diabetes mellitus (20%), TB (10%), autoimmune hepatitis (6.6%), autoimmune disease (autoimmune hemolytic anemia, Sjogren syndrome) (6.6%), sarcoidosis (3.3%), hepatocellular carcinoma (3.3%). 7.5%, 5%, 2.5%, 7.5%, and 2.5% of C. neoformans strains were the non-wild type to fluconazole, 5-fluorocytosine, amphotericin B, posaconazole, and itraconazole respectively, but all strains were wildtype to voriconazole., Conclusion: According to the study liver conditions are a significant risk factor for cryptococcal infection. Therefore, cryptococcal isolation and antifungal susceptibility testing, as well as appropriate antifungal drug use, should be studied and paid attention too., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Indian Association of Medical Microbiologists. Published by Elsevier B.V. All rights reserved.)

Cryptococcus neoformans ( Cn ) is an encapsulated neurotropic fungal pathogen and the causative agent of cryptococcal meningoencephalitis (CME) in humans. Recommended treatment for CME is Amphotericin B (AmpB) and 5-fluorocytosine (5-FC). Though effective, AmpB has displayed numerous adverse side effects due to its potency and nephrotoxicity, prompting investigation into alternative treatments. Palmitoylethanolamide (PEA) is an immunomodulatory compound capable of promoting neuroprotection and reducing inflammation. To investigate the efficacy of PEA as a therapeutic alternative for CME, we intracerebrally infected mice with Cn and treated them with PEA or AmpB alone or in combination. Our results demonstrate that PEA alone does not significantly prolong survival nor reduce fungal burden, but when combined with AmpB, PEA exerts an additive effect and promotes both survivability and fungal clearance. However, we compared this combination to traditional AmpB and 5-FC treatment in a survivability study and observed lower efficacy. Overall, our study revealed that PEA alone is not effective as an antifungal agent in the treatment of CME. Importantly, we describe the therapeutic capability of PEA in the context of Cn infection and show that its immunomodulatory properties may confer limited protection when combined with an effective fungicidal agent., Competing Interests: The authors declare no conflict of interest.

Background: Cryptococcosis is one of the most frequent fungal eye infections in patients with immunosuppression. Currently, treatment approaches for non-meningeal, non-pulmonary cryptococcosis are based on those used for cryptococcal meningitis or pneumonia., Case Presentation: We present a rare case of non-meningeal, non-pulmonary cryptococcosis with clinical manifestations limited to one eye of a cadaveric kidney transplant recipient with chronic-active antibody-mediated rejection. Typical manifestations, diagnosis, and treatments, including antifungal therapies, adjunctive therapies, and immunosuppression reduction, are discussed. After timely diagnosis and treatment, her visual acuity recovered to baseline without recurrence or sequelae of cryptococcosis., Conclusions: Clinicians should be aware of rare presentations of fungal infections, especially when a kidney transplant recipient with rejection has been treated with intensive immunosuppressants. Early diagnosis with individualized therapies may have a favorable prognosis., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The aim of this study was to evaluate the efficacy and non-toxicity of ciclopirox olamine-loaded liposomes against Cryptococcus neoformans clinical isolates. Initially, 24-1 fractional experimental design was carried out to obtain an optimized formulation of liposomes containing CPO (CPO-LipoC), which were then used to prepare stealth liposomes (CPO-LipoS). Liposomal formulations were characterized by their mean size diameter, polydispersity index (PDI), and drug encapsulation efficiency (EE%). Immunosuppressed mice were exposed to CPO-LipoS at 0.5 mg/kg/day for 14 days to verify possible histopathological alterations in the liver and kidneys. Immunosuppressed mice infected with C. neoformans were treated with CPO-LipoS at 0.5 mg/kg/day for 14 days to quantify the fungal burden in spleen, liver, lungs, and brain. CPO-LipoS presented a mean size diameter, PDI, and EE% of 101.4 ± 0.7 nm, 0.307, and 96.4 ± 0.9%, respectively. CPO-LipoS was non-toxic for the liver and kidneys of immunosuppressed mice. At the survival curve, all infected animals submitted to treatment with CPO-LipoS survived until the end of the experiment. Treatment with CPO-LipoS reduced C. neoformans cells in the spleen (59.3 ± 3.4%), liver (75.0 ± 3.6%), lungs (75.7 ± 6.7%), and brain (54.2 ± 3.2%). CPO-LipoS exhibit antifungal activity against C. neoformans, and the encapsulation of CPO into stealth liposomes allows its use as a systemic drug for treating cryptococcosis., (© 2023. The Author(s) under exclusive licence to Sociedade Brasileira de Microbiologia.)

Cryptococcus neoformans is an important opportunistic human fungal pathogen that causes cryptococcosis in immunocompromised patients. However, the number of drugs for the treatment of cryptococcosis is restricted, and the development of novel antifungal drugs and innovative strategies for the treatment of cryptococcosis is urgently needed. In this study, we validated that DvAMP is a novel antimicrobial peptide with antimicrobial activity and that it was obtained by pre-screening from the UniProt database of more than three million unknown functional sequences based on the quantitative structure-activity relationships (QSARs) protocol (http://www.chemoinfolab.com/antifungal). The peptide exhibited satisfactory biosafety and physicochemical properties, and relatively rapid fungicidal activity against C. neoformans. Meanwhile, DvAMP was able to inhibit the static biofilm of C. neoformans and cause a reduction in the thickness of the capsule. In addition, DvAMP exerts antifungal effects through membrane-mediated mechanisms (membrane permeability and depolarization) and mitochondrial dysfunction, involving a hybrid multi-hit mechanism. Furthermore, by using the C. neoformans-Galleria mellonella infection model, we demonstrated that DvAMP has significant therapeutic effects in vivo and that it significantly reduces the mortality and fungal burden of infected larvae. These results suggest that DvAMP may be a potential antifungal drug candidate for the treatment of cryptococcosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Cryptococcus neoformans and Cryptococcus gattii cause cryptococcosis, a life-threatening fungal infection affecting mostly immunocompromised patients. In fact, cryptococcal meningitis accounts for about 19% of AIDS-related deaths in the world. Because of long-term azole therapies to treat this mycosis, resistance to fluconazole leading to treatment failure and poor prognosis has long been reported for both fungal species. Among the mechanisms implicated in resistance to azoles, mutations in the ERG11 gene, encoding the azole target enzyme lanosterol 14-α-demethylase, have been described. This study aimed to establish the amino acid composition of ERG11 of Colombian clinical isolates of C. neoformans and C. gattii and to correlate any possible substitution with the in vitro susceptibility profile of the isolates to fluconazole, voriconazole, and itraconazole. Antifungal susceptibility testing results showed that C. gattii isolates are less susceptible to azoles than C. neoformans isolates, which could correlate with differences in the amino acid composition and structure of ERG11 of each species. In addition, in a C. gattii isolate with high MICs for fluconazole (64 μg/mL) and voriconazole (1 μg/mL), a G973T mutation resulting in the substitution R258L, located in substrate recognition site 3 of ERG11, was identified. This finding suggests the association of the newly reported substitution with the azole resistance phenotype in C. gattii. Further investigations are needed to determine the exact role that R258L plays in the decreased susceptibility to fluconazole and voriconazole, as well as to determine the participation of additional mechanisms of resistance to azole drugs. IMPORTANCE The fungal species Cryptococcus neoformans and C. gattii are human pathogens for which drug resistance or other treatment and management challenges exist. Here, we report differential susceptibility to azoles among both species, with some isolates displaying resistant phenotypes. Azoles are among the most commonly used drugs to treat cryptococcal infections. Our findings underscore the necessity of testing antifungal susceptibility in the clinical setting in order to assist patient management and beneficial outcomes. In addition, we report an amino acid change in the sequence of the target protein of azoles, which suggests that this change might be implicated in resistance to these drugs. Identifying and understanding possible mechanisms that affect drug affinity will eventually aid the design of new drugs that overcome the global growing concern of antifungal resistance., Competing Interests: The authors declare no conflict of interest.

Patients receiving the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib have an increased likelihood of fungal infections. The objectives of this study were to determine if Cryptococcus neoformans infection severity was isolate dependent with BTK inhibition and whether blocking BTK impacted infection severity in a mouse model. We compared four clinical isolates from patients on ibrutinib to virulent (H99) and avirulent (A1-35-8) reference strains. BTK knockout (KO) and wild-type (WT) C57 mice and WT CD1 mice were infected by intranasal (i.n.), oropharyngeal aspiration (OPA), and intravenous (i.v.) routes. Infection severity was assessed by survival and fungal burden (CFU per gram of tissue). Ibrutinib (25 mg/kg) or vehicle was administered daily through intraperitoneal injections. In the BTK KO model, no isolate-dependent effect on fungal burden was observed, and infection severity was not significantly different from that of the WT with i.n., OPA, and i.v. routes. Ibrutinib treatment did not impact infection severity. However, when the four clinical isolates were compared to H99, two of these isolates were less virulent, with significantly longer survival and reduced rates of brain infection. In conclusion, C. neoformans infection severity in the BTK KO model does not appear to be isolate dependent. BTK KO and ibrutinib treatment did not result in significantly different infection severities. However, based on repeated clinical observations of increased susceptibility to fungal infections with BTK inhibitor therapy, further work is needed to optimize a mouse model with BTK inhibition to better understand the role that this pathway plays in susceptibility to C. neoformans infection., Competing Interests: The authors declare no conflict of interest.

There is a consensus that the antifungal repertoire for the treatment of cryptococcal infections is limited. Standard treatment involves the administration of an antifungal drug derived from natural sources (i.e., amphotericin B) and two other drugs developed synthetically (i.e., flucytosine and fluconazole). Despite treatment, the mortality rates associated with fungal cryptococcosis are high. Amphotericin B and flucytosine are toxic, require intravenous administration, and are usually unavailable in low-income countries because of their high cost. However, fluconazole is cost-effective, widely available, and harmless with regard to its side effects. However, fluconazole is a fungistatic agent that has contributed considerably to the increase in fungal resistance and frequent relapses in patients with cryptococcal meningitis. Therefore, there is an unquestionable need to identify new alternatives or adjuvants to conventional drugs for the treatment of cryptococcosis. A potential antifungal agent should be able to kill cryptococci and "bypass" the virulence mechanism of the yeast. Furthermore, it should have fungicidal action, low toxicity, high selectivity, easily penetrate the central nervous system, and widely available. In this review, we describe cryptococcosis, its conventional therapy, and failures arising from the use of drugs traditionally considered to be the reference standard. Additionally, we present the approaches used for the discovery of new drugs to counteract cryptococcosis, ranging from the conventional screening of natural products to the inclusion of structural modifications to optimize anticryptococcal activity, as well as drug repositioning and combined therapies.

Cryptococcosis is an infectious fungal disease widely studied for its epidemiological importance in the context of public health, given the high morbidity and mortality associated with this invasive fungal infection. Many cases of the disease present clinical resistance and progress to death, even in the presence of antifungal therapy. The prolonged use of triazole drugs to maintain the treatment of cryptococcosis in AIDS patients, can lead to selective pressure from mutant strains, among other resistance mechanisms, justifying the poor clinical evolution of some cases. In this study, a narrative review of the literature on the occurrence of antifungal resistance in cryptococcosis agents was performed. Publications from 2010 to 2022 that address this topic were selected using Google Scholars and Scopus website. Data from the studies were analyzed for the values of minimum inhibitory concentration (MIC) of drugs used in the management of cryptococcosis. The review showed that the highest MIC values occurred for voriconazole, especially against C. neoformans. It is concluded that there is a lack of studies with statistical analysis of the data obtained, in order to provide a better dimensioning of the resistance rates of cryptococcosis agents to different antifungal agents, both in geographical and temporal context.

Cryptococcosis is a worldwide-distributed fungal disease affecting humans and animals and is considered the most common systemic mycosis in cats. Classically, the clinical presentation of cryptococcal infection in cats consists of solitary or multiple nodules located on the planum nasale or the bridge of the nose. Bone involvement as cryptococcal osteomyelitis is a rare clinical entity of cryptococcosis. Herein, this case report describes a domestic shorthair cat with osteomyelitis of the mandibular bone resulting from Cryptococcus spp. infection. During the physical examination, a subcutaneous mass measuring approximately 6 cm in diameter was identified at the mandibular region. Cytological evaluation revealed numerous encapsulated yeasts resembling Cryptococcus spp. Histopathological examination revealed multifocal to coalescent subcutaneous granulomatous inflammation with a large number of spherical yeasts surrounded by a clear capsule. These yeasts were positive for periodic acid-Schiff (PAS) staining. The cat was successfully treated with a combination of itraconazole therapy and surgical management. To the author's knowledge, this is the first clinical report of oral cryptococcal osteomyelitis in a cat., (© 2023. The Author(s) under exclusive licence to Sociedade Brasileira de Microbiologia.)

Introduction: Osteomyelitis is a bone inflammation that can be related to various infectious agents. As with any other type of inflammation, the prevailing symptoms and signs may include redness, swelling, pain, and heat. Fungal osteomyelitis is rare and usually found in immune-compromised patients., Case Presentation: A non-human immunodeficiency virus immunocompromised Greek female patient, 82 years old, visited the emergency department due to a 3 day pain located mainly over the left tibia's anterior surface, accompanied by swelling and redness. There was also a subcutaneous lesion of her left breast. Medical history revealed that the patient had an unmasked close contact with pigeons, a main host of the disease. Initial x-ray imaging showed an osteolytic area in the upper third of the tibial diaphysis. The patient was admitted and underwent a computed tomography-guided biopsy. The specimen revealed a Cryptococcus neoformans infection of the bone and the breast. She was treated with 400 mg fluconazole twice a day for 3 weeks while in hospital and 200 mg twice a day upon discharge for 9 months. After that, she underwent surgical debridement because of lasting local irritation. She was closely monitored in our outpatient office, and in her last visit, 1 year after the initial admission, inflammatory signs had regressed vastly., Conclusions: To our knowledge, this is the ninth cryptococcal osteomyelitis of the tibia to be recorded since 1974, and the most unusual finding was the bifocal nature of the infection, affecting both the tibia and the breast., (© 2023. The Author(s).)

Objective: Cryptococcal meningitis (CM) threatens people's health and is the main cause of opportunistic fungus-related death in acquired immune deficiency syndrome (AIDS) patients. Herein, we investigate the clinical characteristics and prognostic factors of AIDS patients with Cryptococcus neoformans in Wenzhou, Zhejiang Province, China., Methods: Our study enrolled AIDS patients diagnosed with Cryptococcus neoformans infection who were hospitalised in our hospital. They were divided into Group A (32 patients with CM) and Group B (28 patients without CM) according to their diagnosis. The differences between the two groups of patients' clinical symptoms, imaging examinations and laboratory examinations were observed. Statistical methods were used to analyse the difference in prognosis between the two groups., Results: Headache and fever were the most common clinical characteristics for patients with CM, while respiratory symptoms and fever were the most common clinical characteristics for patients without CM. The positive rate of cryptococcal capsular antigen, India ink staining and culture in the cerebrospinal fluid examination was higher in the CM patients than in the non-CM patients. The overall morbidity and mortality rate after systemic antifungal therapy was higher in the CM patients than in the non-CM patients. A higher incidence of headache, impaired consciousness, nuchal rigidity, first intracranial pressure > 200 mmH 2 O and mortality was observed in the CM patients than in the non-CM patients. Multifactorial logistic regression analysis showed that headache risk factors affecting the patient's prognosis at 12 weeks., Conclusion: Patients with AIDS diagnosed with Cryptococcus neoformans infection have insidious clinical symptoms in the early stage, and their manifestation is often non-specific, resulting in poor prognosis and high mortality among CM patients compared to patients without CM. Therefore, early identification and timely antifungal therapy before the disease progresses to meningitis are of great value in improving the survival rate of patients., (© 2023. The Author(s).)

Background: Cryptococcosis is one of the most common fungal infections in immunocompromised patients, which is caused by Cryptococcus neoformans . However, relatively little is known about the virulence factors of C. neoformans and the incidence of antifungal drug resistance in C. neoformans is rapidly increasing. This study was undertaken to investigate the virulence factors in C. neoformans , thymol, curcumin, piperine, gallic acid, eugenol, and plumbagin for their potential antimicrobial activity against C. neoformans ., Methods: The production of phospholipase and proteinase was detected using standard methods. Biofilm formation was determined using the microtiter plate method. The broth microdilution method was used to determine the antifungal activity. The antibiofilm activity was assessed using the safranin staining method., Results: All isolates of C. neoformans produced biofilms with optical density values ranging from 0.16 to 0.89. A majority of C. neoformans isolates that were tested exhibited strong phospholipase (7/8) and proteinase (5/8) production. Plumbagin (with minimum inhibitory concentration values ranging from 4 to 16  μ g/mL) showed the highest antifungal activity followed by thymol (with minimum biofilm inhibitory concentration values ranging from 8 to 64  μ g/mL). In addition, plumbagin showed the highest antibiofilm activity with minimum biofilm inhibitory concentration and minimum biofilm eradication concentration values ranging from 4 to 16  μ g/mL and 32 to 256  μ g/mL, respectively., Conclusion: Plumbagin, compared to other natural products studied, was the most efficient in terms of antifungal and antibiofilm activities. Hence, plumbagin could be used in combination with antifungals for the development of new anticryptococcal drugs., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Borel Ndezo Bisso et al.)

The human fungal pathogen, Cryptococcus neoformans, is responsible for deadly infections among immunocompromised individuals with the evolution of antifungal resistance driving the solution to discover new compounds that inhibit fungal virulence factors rather than kill the pathogen. Recently, exploration into natural sources (e.g., plants, invertebrates, microbes) of antifungal agents has garnered attention by integrating a One Health approach for new compound discovery. Here, we explore extracts from three mollusk species (freshwater and terrestrial) and evaluate effects against the growth and virulence factor production (i.e., thermotolerance, melanin, capsule, and biofilm) in C. neoformans. We demonstrate that clarified extracts of Planorbella pilsbryi have a fungicidal effect on cryptococcal cells comparable to fluconazole. Similarly, all extracts of Cipangopaludina chinensis affect cryptococcal thermotolerance and impair biofilm and capsule production, with clarified extracts of Cepaea nemoralis also conveying the latter effect. Next, inhibitory activity of extracts against peptidases related to specific virulence factors, combined with stress assays and quantitative proteomics, defined distinct proteome signatures and proposed proteins driving the observed anti-virulence properties. Overall, this work highlights the potential of compounds derived from natural sources to inhibit virulence factor production in a clinically important fungal pathogen., (© 2023. The Author(s).)

A woman in her 60s with suspected multicentric Castleman's disease, who was receiving treatment with oral prednisolone, presented to our hospital with mild cough and malaise. Chest CT showed diffuse infiltrative and granular shadows, indicating exacerbation of lung lesions caused by steroid-resistant multicentric Castleman's disease. A video-assisted thoracoscopic lung and mediastinal lymph node biopsy was performed. The biopsy revealed mediastinal lymph node tissue consistent with multicentric Castleman's disease, as well as presence of Cryptococcus neoformans in the alveolar space. C. neoformans infection in immunocompromised individuals may present with diffuse lung lesions and should be noted as a mimicker of acute exacerbation of Castleman's disease., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cryptococcus is the causal agent of cryptococcosis, a disease with high mortality mainly related to HIV immunosuppression and usually manifests with pneumonia and/or meningoencephalitis. There are very few therapeutic options; thus, innovative approaches are required. Herein, We examined the interaction of everolimus (EVL) with amphotericin B (AmB) and azoles [fluconazole (FLU), posaconazole (POS), voriconazole (VOR), itraconazole (ITR)] against Cryptococcus . Eighteen Cryptococcus neoforman clinical isolates were analyzed. Following the guidelines of the Clinical and Laboratory Standards Institute (CLSI) M27-A4, we conducted a broth microdilution experiment to determine the minimum inhibitory concentrations (MICs) of azoles, EVL, and AmB for assessing antifungal susceptibility. A fractional inhibitory concentration index (FICI) of less than and equal to 0.5 indicated synergy, with a range of 0.5 to 4.0 indicated indifference and a value more than 4.0 indicated antagonism. These experiments revealed that EVL had antifungal activity against C. neoforman . Moreover, EVL, POS, AmB, FLU, ITR, and VOR exhibited MIC values ranging from 0.5-2 μg/mL, 0.03125-2 μg/mL, 0.25-4 μg/mL, 0.5-32μg/mL, 0.0625-4μg/mL and 0.03125-2μg/mL, respectively. The combination of EVL with AmB and azoles (POS, FLU, ITR, and VOR) exhibited synergistic antifungal effects against 16 (88.9%), 9 (50%), 11 (61.1%), 10 (55.6%) or 6 (33.3%) of analyzed Cryptococcus strains. In the presence of EVL, the MIC values of AmB and azoles were significantly lowered. No antagonism was observed. Subsequently, in vivo analyses conducted using the G. mellonella model further confirmed that combination EVL+ POS, EVL+ FLU, and EVL+ITR treatment were associated with significantly improved larval survival following Cryptococcus spp. infection. These findings provide the first published evidence suggesting that a combination of EVL and AmB or azoles exhibit a synergistic effect and may be an effective antifungal disease treatment strategy for infections caused by Cryptococcus spp., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liang, Song and Liu.)

Background: Pulmonary cryptococcosis (PC) is a fungal infection that can have a variable prognosis depending on several factors. The objective of this study was to analyse the characteristics of pulmonary lesions and identify prognostic factors in patients with PC who were human immunodeficiency virus (HIV) -negative and underwent antifungal treatment., Methods: The study enrolled patients diagnosed with PC who were negative for HIV. Symptoms, CT characteristics of pulmonary lesions, serum cryptococcal capsular antigen (CrAg) titre, underlying diseases, and duration of antifungal treatment were evaluated over a 2-year follow-up., Results: A total of 63 patients (40 men and 23 women) with a mean age of 50.4 years were included. Half of the patients (50.8%) were asymptomatic, and the most common symptoms were cough (44.4%), expectoration (27.0%), and fever (17.5%). Pulmonary lesions were mainly present in the peripheral and lower lobes of the lung, with 35 cases classified as nodular-type lesions and 28 cases classified as mass-type lesions. At the first, third, sixth, 12th, and 24th-month follow-ups, the median proportion of residual pulmonary lesions were 59.6%, 29.9%, 12.2%, 9.6%, and 0.0%, respectively. During antifungal treatment, the lesions of 33 patients achieved complete response, while the remaining 30 patients did not. Compared with the non-CR group, the CR group had a lower baseline serum CrAg titre (median, 1:20 vs 1:80, P < 0.01), smaller pulmonary lesion size (median area, 1.6 cm 2 vs 6.3 cm 2 , P < 0.01), lower Hounsfield-units (HU) radiodensity (median, - 60.0 HU vs - 28.5 HU, P < 0.05), more nodular-type lesions (72.7% vs 36.7%, P < 0.01), and fewer air-bronchogram signs (18.2% vs 43.3%, P < 0.05). Multivariate logistic regression analysis showed that a larger lesion size on chest CT scans was associated with a lower likelihood of achieving complete response [OR: 0.89; 95% CI (0.81-0.97); P < 0.05]., Conclusions: PC was more commonly observed in HIV-negative men, and chest CT scans mostly revealed nodular-type lesions. After antifungal treatment, patients with smaller lesions had a better prognosis., (© 2023. The Author(s).)

Background: Cryptococcus gattii is a globally endemic pathogen causing disease in apparently immune-competent hosts. We describe a 22-year cohort study from Australia's Northern Territory to evaluate trends in epidemiology and management, and outcome predictors., Methods: A retrospective cohort study of all C. gattii infections at the northern Australian referral hospital 1996-2018 was conducted. Cases were defined as confirmed (culture-positive) or probable. Demographic, clinical and outcome data were extracted from medical records., Results: 45 individuals with C. gattii infection were included: 44 Aboriginal Australians; 35 with confirmed infection; none HIV positive out of 38 tested. Multifocal disease (pulmonary and central nervous system) occurred in 20/45 (44%). Nine people (20%) died within 12 months of diagnosis, five attributed directly to C. gattii. Significant residual disability was evident in 4/36 (11%) survivors. Predictors of mortality included: treatment before the year 2002 (4/11 versus 1/34); interruption to induction therapy (2/8 versus 3/37) and end-stage kidney disease (2/5 versus 3/40). Prolonged antifungal therapy was the standard approach in this cohort, with median treatment duration being 425 days (IQR 166-715). Ten individuals had adjunctive lung resection surgery for large pulmonary cryptococcomas (median diameter 6cm [range 2.2-10cm], versus 2.8cm [1.2-9cm] in those managed non-operatively). One died post-operatively, and 7 had thoracic surgical complications, but ultimately 9/10 (90%) treated surgically were cured compared with 10/15 (67%) who did not have lung surgery. Four patients were diagnosed with immune reconstitution inflammatory syndrome which was associated with age <40 years, brain cryptococcomas, high cerebrospinal fluid pressure, and serum cryptococcal antigen titre >1:512., Conclusion: C. gattii infection remains a challenging condition but treatment outcomes have significantly improved over 2 decades, with eradication of infection the norm. Adjunctive surgery for the management of bulky pulmonary C. gattii infection appears to increase the likelihood of durable cure and likely reduces the required duration of antifungal therapy., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests:Dr. KH has received advisory board fees and grant support from Gilead Sciences. The authors have no other conflicts to declare., (Copyright: © 2023 O’Hern et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Few therapeutic drugs and increased drug resistance have aggravated the current treatment difficulties of Cryptococcus in recent years. To better understand the antifungal drug resistance mechanism and treatment strategy of cryptococcosis. In this review, by combining the fundamental features of Cryptococcus reproduction leading to changes in its genome, we review recent research into the mechanism of four current anti-cryptococcal agents, coupled with new therapeutic strategies and the application of advanced technologies WGS and CRISPR-Cas9 in this field, hoping to provide a broad idea for the future clinical therapy of cryptococcosis.

A 77-year-old woman with seronegative rheumatoid arthritis who was being treated with prednisolone (8 mg/day) and methotrexate (12 mg/week) visited our hospital with an 11-day history of a fever and dyspnea. Chest computed tomography showed infiltration in the right lower lobe. A transbronchial lung cryobiopsy (TBLC) showed cryptococcal cells, and bronchoalveolar lavage fluid later showed growth of Cryptococcus neoformans. She was treated with amphotericin B and flucytosine for about four weeks, and the pulmonary shadows improved. The treatment was then changed to fluconazole as outpatient consolidation and maintenance therapy. A rare case of pulmonary cryptococcosis diagnosed by a TBLC is reported.

Cryptococcosis is an opportunistic mycosis that mainly affects immunosuppressed patients. The treatment is a combination of three antifungal agents: amphotericin B, 5-flucytosine and fluconazole. However, these drugs have many disadvantages, such as high nephrotoxicity, marketing bans in some countries and fungal resistance. One of the solutions to find possible new drugs is pharmacological repositioning. This work presents repositioned drugs as an alternative for new antifungal therapies for cryptococcosis. All the studies here were performed in vitro or in animal models, except for sertraline, which reached phase III in humans. There is still no pharmacological repositioning approval for cryptococcosis in humans, though this review shows the potential of repurposing as a rapid approach to finding new agents to treat cryptococcosis.