RESUMEN
An adult female rhesus macaque presented during routine annual physical examination for evaluation of a 2.5-cm diameter superficial ulcerated dermal lesion that was subsequently diagnosed as a systemic fungal infection caused by Cryptococcus gattii. Cryptococcus gattii is one of several basidiomycetic yeasts responsible for pulmonary, neurologic, and disseminated infections in humans and animals. This report describes the diagnosis, management, and clinical resolution of a C. gattii infection in an immunocompetent 5-year-old female rhesus macaque.
Asunto(s)
Antifúngicos , Criptococosis , Cryptococcus gattii , Macaca mulatta , Enfermedades de los Monos , Animales , Cryptococcus gattii/aislamiento & purificación , Criptococosis/veterinaria , Criptococosis/tratamiento farmacológico , Criptococosis/diagnóstico , Criptococosis/microbiología , Femenino , Enfermedades de los Monos/microbiología , Enfermedades de los Monos/diagnóstico , Enfermedades de los Monos/tratamiento farmacológico , Antifúngicos/uso terapéutico , InmunocompetenciaRESUMEN
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.
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Criptococosis , Infecciones por VIH , Humanos , Femenino , Masculino , Adulto , Infecciones por VIH/complicaciones , Pronóstico , Criptococosis/mortalidad , Criptococosis/tratamiento farmacológico , Criptococosis/complicaciones , Persona de Mediana Edad , Estudios Retrospectivos , Adulto Joven , Infecciones Oportunistas Relacionadas con el SIDA/microbiología , Infecciones Oportunistas Relacionadas con el SIDA/mortalidad , Antifúngicos/uso terapéutico , Cryptococcus/aislamiento & purificación , Hospitales , China/epidemiologíaRESUMEN
Cryptococcosis is a systemic zoonotic disease that is challenging to diagnose based on clinical findings in cats and dogs due to the nonspecific nature of its clinical presentation. This case report aims to document the first confirmed case of disseminated cryptococcosis caused by Cryptococcus neoformans in a dog in Turkey and to highlight the potential link between natural disasters such as earthquakes and the emergence of zoonotic diseases in domestic animals. A two-and-a-half-year-old spayed female Cocker Spaniel presented with increased respiratory sounds, skin lesions, facial swelling and enlarged lymph nodes. These symptoms appear to be a complication of Demodex infestation due to the stress experienced by the dog following exposure to a severe earthquake. Diagnostic procedures including cytologic examination, fungal culture and DNA sequence analysis, which confirmed the infection was caused by C. neoformans. Due to the delay in the correct diagnosis of the disease, which, contrary to common data, started as an allergic reaction on the skin and was later diagnosed as a Demodex infestation, the dog died of severe respiratory failure during the treatment with itraconazole. The case highlights the critical role of veterinary emergency and critical care in the diagnosis and management of zoonotic diseases post-natural disasters. It also highlights the need for increased awareness and preparedness among veterinary professionals to address animal health challenges following such events.
Asunto(s)
Criptococosis , Enfermedades de los Perros , Zoonosis , Animales , Perros , Femenino , Criptococosis/diagnóstico , Criptococosis/veterinaria , Criptococosis/tratamiento farmacológico , Criptococosis/microbiología , Enfermedades de los Perros/microbiología , Enfermedades de los Perros/diagnóstico , Enfermedades de los Perros/parasitología , Enfermedades de los Perros/tratamiento farmacológico , Zoonosis/microbiología , Zoonosis/diagnóstico , Zoonosis/parasitología , Turquía , Cryptococcus neoformans/aislamiento & purificación , Desastres , Humanos , Resultado Fatal , Antifúngicos/uso terapéuticoRESUMEN
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.
Asunto(s)
Criptococosis , Cryptococcus neoformans , Mielitis , Humanos , Mielitis/microbiología , Mielitis/tratamiento farmacológico , Mielitis/diagnóstico , Criptococosis/tratamiento farmacológico , Criptococosis/microbiología , Criptococosis/diagnóstico , Cryptococcus neoformans/aislamiento & purificación , Masculino , Huésped Inmunocomprometido , Persona de Mediana Edad , Síndrome Nefrótico/complicaciones , Inmunosupresores/uso terapéutico , Imagen por Resonancia MagnéticaRESUMEN
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 Æ©FICI 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.
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Anfotericina B , Antifúngicos , Criptococosis , Sinergismo Farmacológico , Inhibidores de la Proteasa del VIH , Anfotericina B/farmacología , Anfotericina B/uso terapéutico , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Inhibidores de la Proteasa del VIH/uso terapéutico , Inhibidores de la Proteasa del VIH/farmacología , Animales , Criptococosis/tratamiento farmacológico , Humanos , Caenorhabditis elegans/microbiología , Caenorhabditis elegans/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Cryptococcus neoformans/efectos de los fármacos , Quimioterapia Combinada , Ritonavir/uso terapéutico , Ritonavir/farmacología , Cryptococcus/efectos de los fármacosRESUMEN
CASE: A 38-year-old woman presented to our clinic with right knee pain and difficulty ambulating. After cultures were obtained, a cryptococcal infection of the patella was identified. Subsequent workup revealed previously undiagnosed HIV/AIDS and a disseminated cryptococcal infection. CONCLUSION: Over a 20-month course, the patient was treated with fluconazole and antiretroviral therapy with very limited medication compliance. The disseminated infection caused cutaneous, hepatic, and cerebral complications. Eventually, compliance improved, and a final procedure to obtain post-treatment cultures and apply antifungal bone matrix was completed. The patient cleared the infection and will likely require lifetime antifungal treatment.
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Criptococosis , Osteomielitis , Rótula , Humanos , Femenino , Adulto , Criptococosis/tratamiento farmacológico , Criptococosis/diagnóstico por imagen , Rótula/diagnóstico por imagen , Rótula/microbiología , Osteomielitis/microbiología , Osteomielitis/diagnóstico por imagen , Osteomielitis/tratamiento farmacológico , Antifúngicos/uso terapéutico , Fluconazol/uso terapéuticoRESUMEN
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.
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Antifúngicos , Criptococosis , Cryptococcus neoformans , Fluconazol , Humanos , Femenino , Persona de Mediana Edad , Cryptococcus neoformans/aislamiento & purificación , Cryptococcus neoformans/efectos de los fármacos , Criptococosis/tratamiento farmacológico , Criptococosis/microbiología , Criptococosis/diagnóstico , Criptococosis/patología , Antifúngicos/uso terapéutico , Fluconazol/uso terapéutico , Dermatomicosis/tratamiento farmacológico , Dermatomicosis/microbiología , Dermatomicosis/diagnóstico , Dermatomicosis/patología , Piel/patología , Piel/microbiología , Resultado del Tratamiento , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/complicacionesRESUMEN
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.
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Criptococosis , Osteomielitis , Tuberculosis de la Columna Vertebral , Humanos , Femenino , Persona de Mediana Edad , Osteomielitis/diagnóstico , Osteomielitis/microbiología , Osteomielitis/tratamiento farmacológico , Criptococosis/diagnóstico , Criptococosis/tratamiento farmacológico , Diagnóstico Diferencial , Tuberculosis de la Columna Vertebral/diagnóstico , Vértebras Torácicas , Antifúngicos/uso terapéutico , Fluconazol/uso terapéutico , Tomografía Computarizada por Rayos XRESUMEN
C. neoformans, a life-threatening invasive fungal pathogen, can hijack the pulmonary macrophages as 'Trojan horse', leading to cryptococcal meningitis and recurrence. Combatting these elusive fungi has posed a long-standing challenge. Here, we report an inhaled cascade-targeting drug delivery platform that can sequentially target host cells and intracellular fungi. The delivery system involves encapsulating amphotericin B (AMB) into polymeric particles decorated with AMB, creating a unique surface pattern, denoted as APP@AMB. The surface topology of APP@AMB guides the efficient macrophages internalization and intracellular drugs accumulation. Following endocytosis, the surface-functionalized AMB specifically targets intracellular fungi by binding to ergosterol in the fungal membrane, as demonstrated through co-localization studies using confocal microscopy. Through on-site AMB delivery, APP@AMB displays superior efficacy in eliminating C. neoformans in the lungs and brain compared to free AMB following inhalation in infected mice. Additionally, APP@AMB significantly alleviates the nephrotoxicity associated with free AMB inhalation therapy. Thus, this biocompatible delivery system enabling host cells and intracellular fungi targeting in a cascade manner, provides a new avenue for the therapy of fungal infection.
Asunto(s)
Anfotericina B , Antifúngicos , Criptococosis , Cryptococcus neoformans , Sistemas de Liberación de Medicamentos , Cryptococcus neoformans/efectos de los fármacos , Animales , Anfotericina B/administración & dosificación , Antifúngicos/administración & dosificación , Antifúngicos/uso terapéutico , Antifúngicos/farmacología , Criptococosis/tratamiento farmacológico , Ratones , Polímeros/química , Polímeros/administración & dosificación , Pulmón/metabolismo , Pulmón/microbiología , Células RAW 264.7 , Ratones Endogámicos BALB C , Administración por Inhalación , Femenino , Encéfalo/metabolismo , Encéfalo/efectos de los fármacosRESUMEN
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.
RésuméObjectifs: Cette étude a étudié le potentiel anti-cryptocoque de certaines huiles essentielles (HE)/composés seuls et en combinaison avec fluconazole. Matériels et méthodes: Nous avons étudié l'activité antifongique des huiles de Cinnamomum verum, Cymbopogon citratus, Cymbopogon martini et Syzygium spiceum , et leurs principaux ingrédients actifs, le cinnamaldéhyde, le citral, l'eugénol et le géraniol, contre les normes cliniques et standards. souches de Cryptococcus neoformans (CN). Diffusion sur disque, microdilution en bouillon, méthodes en damier et microscopie électronique à transmission ont été utilisés pour déterminer l'inhibition de la croissance, l'interaction synergique et le mécanisme d'action des composés testés. Résultats: HE/composés a montré une efficacité antifongique prononcée contre les CN résistantes aux azoles dans l'ordre suivant: cinnamaldéhyde > eugénol > S. spiceum > C. verum > citral > C. citratus > géraniol ≥ C. martini , chacun présentant une zone d'inhibition > 15 mm. Ces huiles/composés étaient hautement cides par rapport au fluconazole. L'eugénol et le cinnamaldéhyde ont montré la synergie la plus forte avec le fluconazole contre le CN en abaissant leurs CMI jusqu'à 32 fois. La microscopie électronique à transmission a indiqué des dommages à la paroi cellulaire fongique, à la membrane cellulaire et à d'autres organites endomembranaires. Conclusion: Les huiles testées et leurs composés actifs ont montré une activité anti-cryptocoque potentielle contre les souches de CN résistantes aux azoles. De plus, l'eugénol et le cinnamaldéhyde ont significativement potentialisé l'activité anticryptococcique du fluconazole. Il est suggéré que plusieurs Les sites d'action des huiles/composés pourraient transformer le fluconazole statique en une combinaison médicamenteuse cide pour lutter contre la cryptococcose.
Asunto(s)
Acroleína , Antifúngicos , Cryptococcus neoformans , Cymbopogon , Farmacorresistencia Fúngica , Sinergismo Farmacológico , Eugenol , Fluconazol , Pruebas de Sensibilidad Microbiana , Aceites Volátiles , Cryptococcus neoformans/efectos de los fármacos , Cryptococcus neoformans/ultraestructura , Fluconazol/farmacología , Antifúngicos/farmacología , Aceites Volátiles/farmacología , Cymbopogon/química , Farmacorresistencia Fúngica/efectos de los fármacos , Acroleína/análogos & derivados , Acroleína/farmacología , Eugenol/farmacología , Humanos , Monoterpenos Acíclicos/farmacología , Syzygium/química , Cinnamomum zeylanicum/química , Terpenos/farmacología , Monoterpenos/farmacología , Microscopía Electrónica de Transmisión , Aceites de Plantas/farmacología , Criptococosis/tratamiento farmacológico , Criptococosis/microbiologíaRESUMEN
A 2-year-old Norwegian Forest cat was presented for evaluation of bilateral purulent nasal discharge and stertorous breathing. A computed tomography (CT) scan of the head revealed an intranasal mass of the left nasal cavity extending behind the tube openings and completely obstructing the nasopharynx. Rhinoscopy confirmed a pinkish, shiny mass. CT scan showed both compartments of the right middle ear filled with abnormal soft tissue attenuating material. There was no change in the bony outline of the middle ear. In the endoscopic examination, after endoscopically assisted tympanocentesis, this material in the accessible dorsolateral compartment proved to be classic polypous tissue in addition to highly viscous glue-like secretions. A secondary otitis media due to a drainage disorder was suspected.Using an endoscopic-interventional approach through the nostril, the nasopharyngeal mass was removed for histopathological examination, in order to restore the nasal airway, and to allow tube drainage. In contrast to cats with classical malignant nasal cavity masses, the cat showed several attachment points of the mass and multiple undulating elevations bilaterally in the nasopharyngeal mucosa.Cytological and histopathological examination identified the mass as a fungal granuloma in the context of a cryptococcus infection only rarely observed in Germany. Molecular genetic analysis confirmed an infection with Cryptococcus neoformans var. grubii.A single intranasal and nasopharyngeal endoscopic debridement resulted in a significant improvement of the clinical signs and a complete healing of the right middle ear (including the tympanic membrane) within 14 days, but not in a complete cure of the disease. The cat was therefore treated with oral itraconazole solution for several weeks.The case report shows that nasal cryptococcosis can also affect cats in Germany. Rhinoscopy reveals a nasopharyngeal mass with multiple attachment points, which is unusual for a neoplasia. In addition to the recommended removal of the mass, oral administration of systemic antimycotics is strongly advised.
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Enfermedades de los Gatos , Criptococosis , Animales , Gatos , Enfermedades de los Gatos/diagnóstico , Enfermedades de los Gatos/microbiología , Enfermedades de los Gatos/patología , Criptococosis/veterinaria , Criptococosis/diagnóstico , Criptococosis/microbiología , Criptococosis/patología , Criptococosis/tratamiento farmacológico , Diagnóstico Diferencial , Neoplasias Nasofaríngeas/veterinaria , Neoplasias Nasofaríngeas/diagnóstico , Alemania , Tomografía Computarizada por Rayos X/veterinaria , Enfermedades Nasofaríngeas/veterinaria , Enfermedades Nasofaríngeas/diagnóstico , Enfermedades Nasofaríngeas/microbiología , Enfermedades Nasofaríngeas/patologíaRESUMEN
ABSTRACT: This article reports an elderly male patient with nodules and ulcers on the face and behind the left ear after trauma. Primary cutaneous cryptococcosis was confirmed using pathological biopsy, special staining, tissue culture, and fungal sequencing. The patient received a therapeutic intervention involving the administration of the antifungal agent itraconazole. Substantial amelioration of cutaneous manifestations was observed after a 3-month course of treatment. After an elapsed interval, the patient was diagnosed with esophageal tumor. Moreover, the literature on 33 patients with primary cutaneous cryptococcosis published in the past 10 years was also reviewed.
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Antifúngicos , Criptococosis , Dermatomicosis , Humanos , Criptococosis/tratamiento farmacológico , Criptococosis/patología , Criptococosis/microbiología , Criptococosis/diagnóstico , Masculino , Antifúngicos/uso terapéutico , Dermatomicosis/tratamiento farmacológico , Dermatomicosis/microbiología , Dermatomicosis/patología , Dermatomicosis/diagnóstico , Anciano , Itraconazol/uso terapéutico , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/microbiología , Neoplasias Esofágicas/tratamiento farmacológico , Resultado del Tratamiento , Biopsia , Cryptococcus neoformans/aislamiento & purificaciónRESUMEN
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.
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Antifúngicos , Criptococosis , Cryptococcus neoformans , Saccharomyces cerevisiae , Antifúngicos/farmacología , Cryptococcus neoformans/efectos de los fármacos , Animales , Ratones , Criptococosis/tratamiento farmacológico , Criptococosis/microbiología , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/genética , Modelos Animales de Enfermedad , Macrófagos/microbiología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Pruebas de Sensibilidad Microbiana , Caspofungina/farmacología , Femenino , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Anfotericina B/farmacologíaRESUMEN
Isobavachalcone (IBC) is a natural small molecule with various biological activities; however, its inhibitory effects on Cryptococcus neoformans remain unclear. In our study, IBC showed a good antifungal effect. Through in vitro experiments, its minimum inhibitory concentration was 0.5-1 µg/mL. It exhibited the same antifungal effect as Amphotericin B in brain and lung infections in in vivo experiments. IBC also showed a synergistic antifungal effect with emodin with lower toxicity, and C. neoformans did not develop drug resistance to IBC. In the mechanistic study, significantly damaged mitochondria of C. neoformans, a significant reduction in mitochondrial membrane potential and adenosine triphosphate production, and an increase in hydrogen peroxide (H2O2) caused by IBC were observed using transmission electron microscopy. Through drug affinity-responsive target stability combined with phenotype detection, riboflavin synthases of aconitase and succinate dehydrogenase were screened. Molecular docking, quantitative polymerase chain reaction experiments, target inhibitor and agonist intervention, molecular interaction measurements, and minimum inhibitory concentration detection of the constructed expression strains revealed that IBC targeted the activity of these two enzymes, interfered by the tricarboxylic acid cycle, inhibited the production of adenosine triphosphate, blocked electron transport, reduced mitochondrial membrane potential, and induced antioxidation imbalance and reactive oxygen species accumulation, thus producing an antifungal effect. Therefore, IBC is a promising lead drug and redox antifungal agent for C. neoformans.
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Antifúngicos , Chalconas , Criptococosis , Cryptococcus neoformans , Pruebas de Sensibilidad Microbiana , Cryptococcus neoformans/efectos de los fármacos , Antifúngicos/farmacología , Chalconas/farmacología , Animales , Criptococosis/tratamiento farmacológico , Criptococosis/microbiología , Simulación del Acoplamiento Molecular , Oxidación-Reducción , Proteínas Mitocondriales/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteínas Fúngicas/metabolismoRESUMEN
BACKGROUND: In July 2023, our hospital confirmed one case of lumbar spine infected complicated by Mycobacterium tuberculosis and Cryptococcus neoformans. The patient was admitted due to lower back pain for 1 year and a hard lump for 3 months. Symptoms and signs: Dressing can be seen fixed on the lower back, with severe bleeding. When the dressing is removed, a hard and protruding lump with a size of 6 cm x 8 cm, a sinus tract can be seen near the mass, with a slightly red wound and a sinus depth of about 3 cm. Light red fluid can be seen flowing out. There are no symptoms such as redness, swelling, or heat in the rest of the lower back, and the patient has no other underlying diseases or surgical history. METHODS: Lumbar magnetic resonance imaging and lumbar CT examination; Percutaneous puncture lumbar vertebral biopsy was performed, and the biopsy tissue was subjected to pathological examination, mNGS (metagenomic next-generation sequencing), and acid-fast staining; Extract pus from the lump for fungal culture and ink staining, and identify the fungi through MALDI-TOF MS. RESULTS: Bone destruction and bone marrow edema in the L5 vertebral body, compression of the spinal canal at the L5 vertebral body level; The pathological results of the biopsy tissue indicate granulomatous lesions. The acid-fast staining of the tissue is positive, and the mNGS of the tissue indicates infection with Mycobacterium tuberculosis. A single fungus was cultured from pus and identified by MALDI-TOF MS as Cryptococcus neoformans. Clinically, isoniazid 0.3 g ivgtt + rifampicin 0.45 g qd po + ethambutol 0.25 g qd po + pyrazinamide 0.75 g qd po + fluconazole 0.3 g qd po was administered for treatment. After 11 days, there was slight pain at the incision site, and the original symptoms were significantly relieved. The wound dressing was fixed in place, dry and without obvious exudation. Improved and discharged, followed up for 3 months with no recurrence of the lesion. CONCLUSIONS: mNGS is an effective identification technique that can be used to accurately diagnose suspected infection cases. MALDI-TOF MS has significant advantages over traditional detection methods in shortening detection time. This case achieved satisfactory treatment results for patients through a reasonable treatment plan, which is of great significance for exploring the diagnosis and treatment of similar disease infections.
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Criptococosis , Cryptococcus neoformans , Vértebras Lumbares , Mycobacterium tuberculosis , Humanos , Cryptococcus neoformans/aislamiento & purificación , Vértebras Lumbares/microbiología , Mycobacterium tuberculosis/aislamiento & purificación , Criptococosis/diagnóstico , Criptococosis/microbiología , Criptococosis/tratamiento farmacológico , Masculino , Tuberculosis de la Columna Vertebral/diagnóstico , Tuberculosis de la Columna Vertebral/microbiología , Imagen por Resonancia Magnética , Antituberculosos/uso terapéutico , Antituberculosos/administración & dosificación , Persona de Mediana Edad , Tomografía Computarizada por Rayos XRESUMEN
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.
Asunto(s)
Criptococosis , Tuberculosis Resistente a Múltiples Medicamentos , Tuberculosis Pulmonar , Humanos , Masculino , Persona de Mediana Edad , Criptococosis/tratamiento farmacológico , Criptococosis/microbiología , Criptococosis/complicaciones , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/complicaciones , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/complicaciones , Fallo Hepático/virología , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Coinfección/tratamiento farmacológico , Coinfección/microbiología , Coinfección/virología , Antituberculosos/uso terapéutico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Infecciones Oportunistas Relacionadas con el SIDA/microbiologíaRESUMEN
Cryptococcus neoformans and Cryptococcus gattii are the predominant etiological agents of cryptococcosis, a particularly problematic disease in immunocompromised individuals. The increased clinical use of immunosuppressive drugs, the inherent ability of Cryptococcus species to suppress and evade host immune responses, and the emergence of drug-resistant yeast support the need for model systems that facilitate the design of novel immunotherapies and antifungals to combat disease progression. The mouse model of cryptococcosis is a widely used system to study Cryptococcus pathogenesis and the efficacy of antifungal drugs in vivo. In this chapter, we describe three commonly used strategies to establish cryptococcosis in mice: intranasal, intratracheal, and intravenous inoculations. Also, we discuss the methodology for delivering drugs to mice via intraperitoneal injection.
Asunto(s)
Criptococosis , Cryptococcus neoformans , Modelos Animales de Enfermedad , Animales , Criptococosis/microbiología , Criptococosis/tratamiento farmacológico , Criptococosis/inmunología , Ratones , Cryptococcus neoformans/patogenicidad , Cryptococcus gattii/patogenicidad , Antifúngicos/farmacología , Antifúngicos/uso terapéuticoRESUMEN
Elevation of arginase enzyme activity in the lung contributes to the pathogenesis of various chronic inflammatory diseases and infections. Inhibition of arginase expression and activity is able to alleviate those effects. Here, we investigated the immunomodulatory effect of arginase inhibitor in C. neoformans infection. In the pulmonary cryptococcosis model that was shown to recapitulate human infection, we found arginase expression was excessively induced in the lung during the late stage of infection. To inhibit the activity of arginase, we administered a specific arginase inhibitor, nor-NOHA, during C. neoformans infection. Inhibition of arginase reduced eosinophil infiltration and level of IL-13 secretion in the lungs. Whole lung transcriptome RNA-sequencing analysis revealed that treatment with nor-NOHA resulted in shifting the Th2-type gene expression patterns induced by C. neoformans infection to the Th1-type immune profile, with higher expression of cytokines Ifng, Il6, Tnfa, Csf3, chemokines Cxcl9 and Cxcl10 and transcription factor Stat1. More importantly, mice treated with arginase inhibitor had more infiltrating brain leukocytes and enhanced gene expression of Th1-associated cytokines and chemokines that are known to be essential for protection against C. neoformans infection. Inhibition of arginase dramatically attenuated spleen and brain infection, with improved survival. Taken together, these studies demonstrated that inhibiting arginase activity induced by C. neoformans infection can modulate host immune response by enhancing protective type-1 immune response during C. neoformans infection. The inhibition of arginase activity could be an immunomodulatory target to enhance protective anti-cryptococcal immune responses.
Asunto(s)
Arginasa , Arginina/análogos & derivados , Criptococosis , Cryptococcus neoformans , Ratones Endogámicos C57BL , Animales , Arginasa/metabolismo , Arginasa/antagonistas & inhibidores , Arginasa/genética , Criptococosis/inmunología , Criptococosis/tratamiento farmacológico , Cryptococcus neoformans/inmunología , Cryptococcus neoformans/efectos de los fármacos , Ratones , Pulmón/inmunología , Pulmón/patología , Pulmón/efectos de los fármacos , Citocinas/metabolismo , Citocinas/inmunología , Femenino , Modelos Animales de Enfermedad , Enfermedades Pulmonares Fúngicas/inmunología , Enfermedades Pulmonares Fúngicas/tratamiento farmacológico , Humanos , Células Th2/inmunología , Células Th2/efectos de los fármacos , Células TH1/inmunología , Células TH1/efectos de los fármacos , Encéfalo/inmunología , Encéfalo/efectos de los fármacos , Encéfalo/patología , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéuticoRESUMEN
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 log10 reduction) and lung (mean 1.72 ± 0.399 log10 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 log10-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.