Search Results (59)

Introduction: Acute Myeloid Leukemia (AML) is a hematologic malignancy characterized by the clonal expansion of myeloid progenitors. While it primarily affects the bone marrow, extramedullary relapse occurs in 3–5% of cases, and it is linked to poor prognosis. Central nervous system (CNS) involvement presents diagnostic challenges due to nonspecific symptoms. CNS manifestations include leptomeningeal dissemination, nerve infiltration, parenchymal lesions, and myeloid sarcoma, occurring at any disease stage and frequently asymptomatic. Methods: A 62-year-old man with a recent history of AML in remission presented with diplopia and aching paresthesias in the left periorbital region spreading to the left frontal area. The diagnostic workup included neurological and hematological evaluation, lumbar puncture, brain CT, brain magnetic resonance imaging (MRI) with contrast, and dermatological evaluation with skin biopsy due to the appearance of nodular skin lesions on the abdomen and thorax. Results: Neurological evaluation showed hypoesthesia in the left mandibular region, consistent with left trigeminal nerve involvement, extending to the periorbital and frontal areas, and impaired adduction of the left eye with divergent strabismus in the primary position due to left oculomotor nerve palsy. Brain MRI showed an equivocal thickening of the left oculomotor nerve without enhancement. Cerebrospinal fluid (CSF) analysis initially showed elevated protein (47 mg/dL) with negative cytology; a repeat lumbar puncture one week later detected leukemic cells. Skin biopsy revealed cutaneous AML localization. A diagnosis of AML relapse with CNS and cutaneous localization was made. Salvage therapy with FLAG-IDA-VEN (fludarabine, cytarabine, idarubicin, venetoclax) and intrathecal methotrexate, cytarabine, and dexamethasone was started. Subsequent lumbar punctures were negative for leukemic cells. Due to high-risk status and extramedullary disease, the patient underwent allogeneic hematopoietic stem cell transplantation. Post-transplant aplasia was complicated by septic shock; the patient succumbed to an invasive fungal infection. Conclusions: This case illustrates the diagnostic complexity and poor prognosis of extramedullary AML relapse involving the CNS. Early recognition of neurological signs, including cranial nerve dysfunction, is crucial for timely diagnosis and management. Although initial investigations were negative, further analyses—including repeated CSF examinations and skin biopsy—led to the identification of leukemic involvement. Although neuroleukemiosis cannot be confirmed without nerve biopsy, the combination of clinical presentation, neuroimaging, and CSF data strongly supports the diagnosis of extramedullary relapse of AML. Multidisciplinary evaluation remains essential for detecting extramedullary relapse. Despite treatment achieving CSF clearance, the prognosis remains unfavorable, underscoring the need for vigilant clinical suspicion in hematologic patients presenting with neurological symptoms. Full article

Background: Exophiala dermatitidis is a dematiaceous, thermotolerant, yeast-like fungus increasingly recognized as an opportunistic pathogen in chronic airway diseases. While commonly associated with cystic fibrosis, its clinical significance in non-cystic fibrosis bronchiectasis (NCFB) remains unclear. Case Presentation: We report the case of a 66-year-old immunocompetent woman with a history of breast cancer in remission and NCFB, who presented with chronic cough and dyspnea. Chest CT revealed bilateral bronchiectasis with new pseudonodular opacities. Bronchoalveolar lavage cultures identified E. dermatitidis, along with Pseudomonas aeruginosa and methicillin-sensitive Staphylococcus aureus. Given clinical stability and the absence of systemic signs, initial therapy included oral voriconazole, levofloxacin, doxycycline, and inhaled amikacin. Despite persistent fungal isolation on repeat bronchoscopy, the patient remained asymptomatic with stable radiologic and functional findings. Antifungal therapy was discontinued, and the patient continued under close monitoring. The patient exhibited clinical and radiological stability despite repeated fungal isolation, reinforcing the hypothesis of persistent colonization rather than active infection. Discussion: This case underscores the diagnostic challenges in distinguishing fungal colonization from true infection in structurally abnormal lungs. In NCFB, disrupted mucociliary clearance and microbial dysbiosis may facilitate fungal persistence, even in the absence of overt immunosuppression. The detection of E. dermatitidis should prompt a comprehensive evaluation, integrating clinical, radiologic, and microbiologic data to guide management. Voriconazole is currently the antifungal agent of choice, though therapeutic thresholds and duration remain undefined. Conclusions: This report highlights the potential role of E. dermatitidis as an under-recognized respiratory pathogen in NCFB and the importance of a multidisciplinary, individualized approach to diagnosis and treatment. This case underscores the need for further research on fungal colonization in NCFB and the development of evidence-based treatment guidelines. Further studies are needed to clarify the pathogenic significance, optimal management, and long-term outcomes of E. dermatitidis in non-CF chronic lung diseases. Full article

Liposome-based drug delivery systems have revolutionized modern pharmaceutics, offering unparalleled versatility and precision in therapeutic delivery. These lipid vesicles, capable of encapsulating hydrophilic, hydrophobic, and amphiphilic drugs, have demonstrated significant potential in addressing pharmacokinetic challenges such as poor solubility, systemic toxicity, and rapid clearance. This review provides a comprehensive exploration of the evolution of liposomes from laboratory models to clinically approved therapeutics, highlighting their structural adaptability, functional tunability, and transformative impact on modern medicine. We discuss pivotal laboratory-scale preparation techniques, including thin-film hydration, ethanol injection, and reverse-phase evaporation, along with their inherent advantages and limitations. The challenges of transitioning to industrial-scale production are examined, with emphasis on achieving batch-to-batch consistency, scalability, regulatory compliance, and cost-effectiveness. Innovative strategies, such as the incorporation of microfluidic systems and advanced process optimization, are explored to address these hurdles. The clinical success of Food and Drug Administration (FDA)-approved liposomal formulations such as Doxil^® and AmBisome^® underscores their efficacy in treating conditions ranging from cancer to fungal infections. Furthermore, this review delves into emerging trends, including stimuli-responsive and hybrid liposomes, as well as their integration with nanotechnology for enhanced therapeutic precision. As liposomes continue to expand their role in gene therapy, theranostics, and personalized medicine, this review highlights their potential to redefine pharmaceutical applications. Despite existing challenges, ongoing advancements in formulation techniques and scalability underscore the bright future of liposome-based therapeutics in addressing unmet medical needs. Full article

Scutellaria baicalensis Gorg is a medicinal herb of significant value in traditional Chinese medicine. Root rot is a major issue in S. baicalensis-producing areas. The aim of this study was to evaluate whether indole-3-carboxaldehyde, a metabolite derived from Purpureocillium lilacinum, has a significant effect on Fusarium solani (one of the main pathogenic fungi causing S. baicalensis root rot), and to clarify its antifungal mechanism. We evaluated the toxicity of indole-3-carboxaldehyde to F. solani using the growth rate assay and found that the EC₅₀ value was 59.563 μg/mL; we also performed additional pot experiments under greenhouse conditions. The effects of indole-3-carboxaldehyde on fungal hyphal morphology and ultrastructure were evaluated through scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Indole-3-carboxaldehyde was found to induce the disintegration of the mitochondrial double membrane in F. solani, as well as cause cell wall separation. Further probing into the effects of indole-3-carboxaldehyde on mitochondrial aspects was conducted using enzyme activity test kits and real-time quantitative PCR. The findings indicated that indole-3-carboxaldehyde decreases the mitochondrial membrane potential; reduces the activities of SOD, CAT, POD, and GR enzymes; and hampers the growth of F. solani by suppressing the activity of mitochondrial electron transport chain complex I, resulting in H₂O₂ accumulation. This disruption of the mitochondrial antioxidant pathway impedes the effective clearance of reactive oxygen species (ROS), ultimately leading to the death of F. solani. Future studies of indole-3-carboxaldehyde should focus on its effect on metabolic pathways, which could facilitate the development of innovative pesticides. Full article

Chronic granulomatous invasive fungal sinusitis (CGIFS) is an uncommon type of invasive sinusitis that is characteristically seen in immunocompetent individuals. Common clinical manifestations of this condition include proptosis, cheek swelling, and headache. The pathogenic organism is Aspergillus in the majority of reported cases. Diagnosis is made by histopathological and microbiological examination of tissue specimens. Due to its expansible nature, bone erosion is also associated with this condition. Treatment is surgical clearance/debulking followed by long-term antifungal therapy. Here, we report the case of a 31-year-old male presented with right-side cheek swelling. The patient underwent a medial maxillectomy and was diagnosed with CGIFS. The patient was put on oral voriconazole for 3 months. To conclude, CGIFS is a rare variant of invasive fungal sinusitis that may mimic malignancy or granulomatous diseases such as tuberculosis, rhinoscleroma, and syphilis. Accurate diagnosis is of utmost importance in providing management for CGIFS. Full article

Aspergillus spp. are ubiquitous fungi present in soil, organic debris, water, decaying vegetation and dust produced in renovation and/or building work. Several studies have shown the presence of aspergilli in various healthcare environments. Typically, thousands of fungal spores are inhaled every day, but if spore clearance fails (typically in immunocompromised patients), fungi can grow and invade lung tissue, causing invasive aspergillosis (IA) which is one of the most frequent infections in highly immunocompromised patients. Aspergillus fumigatus is the most common species involved; this species can be attributed to about 80% of the cases of aspergillosis. According to the WHO, Aspergillus fumigatus is one of four critical priority fungi. The first-line treatment of diseases caused by Aspergillus, in particular IA, is based on triazole antimycotics. Unfortunately, resistance to antimycotics is increasing, partly due to their widespread use in various areas, becoming a significant concern to clinicians who are charged with caring for patients at high risk of invasive mycoses. A recent WHO report emphasised the need for strategies to improve the response, and in particular strengthen laboratory capacity and surveillance, support investment in research and strengthen public health interventions for the prevention and control of fungal infections through a One Health approach. Full article

Fungal diseases, despite their low incidence in sharks and rays, are considered emerging diseases in this group of animals and can lead to high mortality rates despite treatment. The information available related to the treatment of fungal diseases in elasmobranchs is limited and is frequently based on the empirical knowledge provided by the professionals and clinicians working with these species. The use of azole antifungal drugs, especially voriconazole, has shown promise as a potential treatment option for fungal infections in elasmobranchs, with favorable outcomes in some registered cases. However, scientific knowledge regarding azole pharmacokinetics (PK) in fish remains limited, and despite the recent publication of a PK study with voriconazole in rays, there are still no published PK studies for azoles in sharks. In this study, voriconazole was administered at 4 mg/kg intravenously (IV) and intramuscularly (IM) to nursehound sharks (Scyliorhinus stellaris) (n = 6). Blood samples were collected before administration and at nine predetermined time intervals afterwards (0.25, 0.5, 1, 1.5, 2, 4,8,12, 24, and 36 h). Plasma concentrations were determined using a validated high-performance liquid chromatography (HPLC) method, and pharmacokinetic (PK) parameters were estimated using a non-compartmental model. The mean peak plasma concentrations (C_max) ± SEM after IM administration was 3.00 ± 0.23 µg/mL. The volume of distribution (Vd) after IV and IM administration resulted in 1.39 ± 0.09 L/kg and 1.50 ± 0.18 L/kg, respectively, showing no statistically significant differences between the two routes. Clearance (Cl) values were 0.12 ± 0.01 mL/min after IV administration and 0.29 ± 0.05 mL/min after IM administration. No adverse effects were detected during the study or four weeks after administration. These results support the administration of IV and IM voriconazole in sharks; however, additional studies on toxicity and pharmacodynamics are necessary. Moreover, further research on the susceptibility of fungal pathogens affecting elasmobranchs is needed to establish an optimal dosing regimen for IM voriconazole in the treatment of mycosis in sharks. Full article

Vascular catheter-related infections, primarily caused by Candida albicans and Candida parapsilosis, pose significant challenges due to the formation of biofilms on catheters, leading to refractory disease and considerable morbidity. We studied the efficacy of micafungin in systemic and lock therapies to eliminate catheter-based biofilms and deep tissue infections in experimental central venous catheter (CVC)-related candidemia in neutropenic rabbits. Silastic CVCs in rabbits were inoculated with 1 × 10³ CFU/mL of C. albicans or C. parapsilosis, establishing catheter-based biofilm, and subjected to various treatments. Neutropenic rabbits treated with a combination of lock therapy and systemic micafungin demonstrated the most significant reduction in fungal burden, from 5.0 × 10⁴ to 1.8 × 10² CFU/mL of C. albicans and from 5.9 × 10⁴ to 2.7 × 10² CFU/mL of C. parapsilosis (p ≤ 0.001), in the CVC after 24 h, with full clearance of blood cultures after 72 h from treatment initiation. The combination of lock and systemic micafungin therapy achieved eradication of C. albicans from all studied tissues (0.0 ± 0.0 log CFU/g) vs. untreated controls (liver 7.5 ± 0.22, spleen 8.3 ± 0.25, kidney 8.6 ± 0.07, cerebrum 6.3 ± 0.31, vena cava 6.6 ± 0.29, and CVC wash 2.3 ± 0.68 log CFU/g) (p ≤ 0.001). Rabbits treated with a combination of lock and systemic micafungin therapy demonstrated a ≥2 log reduction in C. parapsilosis in all treated tissues (p ≤ 0.05) except kidney. Serum (1→3)-β-D-glucan levels demonstrated significant decreases in response to treatment. The study demonstrates that combining systemic and lock therapies with micafungin effectively eradicates catheter-based biofilms and infections caused by C. albicans or C. parapsilosis, particularly in persistently neutropenic conditions, offering promising implications for managing vascular catheter-related candidemia and providing clinical benefits in cases where catheter removal is not feasible. Full article

Aspergillosis is a fungal infection caused by various species of Aspergillus, most notably A. fumigatus. This fungus causes a spectrum of diseases, including allergic bronchopulmonary aspergillosis, aspergilloma, chronic pulmonary aspergillosis, and invasive aspergillosis. The clinical manifestations and severity of aspergillosis can vary depending on individual immune status and the specific species of Aspergillus involved. The recognition of Aspergillus involves pathogen-associated molecular patterns (PAMPs) such as glucan, galactomannan, mannose, and conidial surface proteins. These are recognized by the pathogen recognition receptors present on immune cells such as Toll-like receptors (TLR-1,2,3,4, etc.) and C-type lectins (Dectin-1 and Dectin-2). We discuss the roles of cytokines and pathogen recognition in aspergillosis from both the perspective of human and experimental infection. Several cytokines and chemokines have been implicated in the immune response to Aspergillus infection, including interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), CCR4, CCR17, and other interleukins. For example, allergic bronchopulmonary aspergillosis (ABPA) is characterized by Th2 and Th9 cell-type immunity and involves interleukin (IL)-4, IL-5, IL-13, and IL-10. In contrast, it has been observed that invasive aspergillosis involves Th1 and Th17 cell-type immunity via IFN-γ, IL-1, IL-6, and IL-17. These cytokines activate various immune cells and stimulate the production of other immune molecules, such as antimicrobial peptides and reactive oxygen species, which aid in the clearance of the fungal pathogen. Moreover, they help to initiate and coordinate the immune response, recruit immune cells to the site of infection, and promote clearance of the fungus. Insight into the host response from both human and animal studies may aid in understanding the immune response in aspergillosis, possibly leading to harnessing the power of cytokines or cytokine (receptor) antagonists and transforming them into precise immunotherapeutic strategies. This could advance personalized medicine. Full article

Mast cells (MCs) are abundant at sites exposed to the external environment and pathogens. Local activation of these cells, either directly via pathogen recognition or indirectly via interaction with other activated immune cells and results in the release of pre-stored mediators in MC granules. The release of these pre-stored mediators helps to enhance pathogen clearance. While MCs are well known for their protective role against parasites, there is also significant evidence in the literature demonstrating their ability to respond to viral, bacterial, and fungal infections. Vitamin D is a fat-soluble vitamin and hormone that plays a vital role in regulating calcium and phosphorus metabolism to maintain skeletal homeostasis. Emerging evidence suggests that vitamin D also has immunomodulatory properties on both the innate and adaptive immune systems, making it a critical regulator of immune homeostasis. Vitamin D binds to its receptor, called the vitamin D receptor (VDR), which is present in almost all immune system cells. The literature suggests that a vitamin D deficiency can activate MCs, and vitamin D is necessary for MC stabilization. This manuscript explores the potential of vitamin D to regulate MC activity and combat pathogens, with a focus on its ability to fight viruses. Full article

Antifungals are used in exotic avian and reptile species for the treatment of fungal diseases. Dose extrapolations across species are common due to lack of species-specific pharmacological data. This may not be ideal because interspecies physiological differences may result in subtherapeutic dosing or toxicity. This critical review aims to collate existing pharmacological data to identify antifungals with the most evidence to support their safe and effective use. In the process, significant trends and gaps are also identified and discussed. An extensive search was conducted on PubMed and JSTOR, and relevant data were critically appraised. Itraconazole or voriconazole showed promising results in Japanese quails, racing pigeons and inland bearded dragons for the treatment of aspergillosis and CANV-related infections. Voriconazole neurotoxicity manifested as seizures in multiple penguins, but as lethargy or torticollis in cottonmouths. Itraconazole toxicity was predominantly hepatotoxicity, observed as liver abnormalities in inland bearded dragons and a Parson’s chameleon. Differences in formulations of itraconazole affected various absorption parameters. Non-linearities in voriconazole due to saturable metabolism and autoinduction showed opposing effects on clearance, especially in multiple-dosing regimens. These differences in pharmacokinetic parameters across species resulted in varying elimination half-lives. Terbinafine has been used in dermatomycoses, especially in reptiles, due to its keratinophilic nature, and no significant adverse events were observed. The use of fluconazole has declined due to resistance or its narrow spectrum of activity. Full article

Voriconazole is a triazole antifungal used empirically for the treatment of complicated meningitis associated with Cryptococcus neoformans. Biopsy studies show that the drug exhibits adequate brain penetration although levels of cerebral spinal fluid (CSF) are highly variable. Considering that CSF is one of the main surrogates for CNS exposure, the present work proposed the building of a population pharmacokinetic modeling (popPK) model able to describing the exposure achieved by voriconazole in the plasma, interstitial cerebral fluid and CSF of healthy and infected rats. The developed popPK model was described by four compartments, including total plasma, free brain and total CSF concentrations. The following PK parameters were determined: K_m = 4.76 mg/L, V_max = 1.06 mg/h, Q₁ = 2.69 L, Q_in = 0.81 h⁻¹ and Q_out = 0.63 h⁻¹. Infection was a covariate in the Michaelis–Menten constant (K_m) and intercompartmental clearance from the brain tissue compartment to central compartment (Q_out). Simulations performed with the popPK model to determine the probability of reaching the therapeutic target of fAUC > MIC showed that VRC has sufficient tissue exposure in the interstitial fluid and in the CSF for the treatment of fungal infections in these tissues at prevalent minimum inhibitory concentrations. Full article

Cryptococcus neoformans is an opportunistic fungal pathogen that causes over 180,000 annual deaths in HIV/AIDS patients. Innate phagocytes in the lungs, such as dendritic cells (DCs) and macrophages, are the first cells to interact with the pathogen. Neutrophils, another innate phagocyte, are recruited to the lungs during cryptococcal infection. These innate cells are involved in early detection of C. neoformans, as well as the removal and clearance of cryptococcal infections. However, C. neoformans has developed ways to interfere with these processes, allowing for the evasion of the host’s innate immune system. Additionally, the innate immune cells have the ability to aid in cryptococcal pathogenesis. This review discusses recent literature on the interactions of innate pulmonary phagocytes with C. neoformans. Full article

The use of radiolabeled glucose for PET imaging resulted in the most commonly used tracer in the clinic, 2-deoxy-2-[¹⁸F]fluoroglucose (FDG). More recently, other radiolabeled sugars have been reported for various applications, including imaging tumors and infections. Therefore, in this study, we developed a series of fluorine-18-labeled L-rhamnose derivatives as potential PET tracers of various fungal and bacterial strains. Acetyl-protected triflate precursors of rhamnose were prepared and radiolabeled with fluorine-18 followed by hydrolysis to produce L-deoxy [¹⁸F]fluororhamnose. The overall radiochemical yield was 7–27% in a 90 min synthesis time with a radiochemical purity of 95%. In vivo biodistribution of the ligands using PET imaging showed that 2-deoxy-2-[¹⁸F]fluoro-L-rhamnose is stable for at least up to 60 min in mice and eliminated via renal clearance. The tracer also exhibited minimal tissue or skeletal uptake in healthy mice resulting in a low background signal. Full article

Candida lipolytica is an uncommon Candida species causing invasive fungemia. This yeast is mainly associated with the colonisation of intravascular catheters, complicated intra-abdominal infections, and infections in the paediatric population. Here, we report a case of C. lipolytica bloodstream infection in a 53-year-old man. He was admitted for an alcohol withdrawal syndrome and mild COVID-19. Among the primary risk factors for candidemia, only the use of broad-spectrum antimicrobials was reported. The empiric treatment was commenced with caspofungin and then targeted with intravenous fluconazole. Infective endocarditis was ruled out using echocardiography, and PET/TC was negative for other deep-seated foci of fungal infection. The patient was discharged after blood culture clearance and clinical healing. To the best of our knowledge, this is the first case of C. lipolytica candidemia in a patient with COVID-19 and alcohol use disorder. We performed a systematic review of bloodstream infections caused by C. lipolytica. Clinicians should be aware of the possibility of C. lipolytica bloodstream infections in patients with alcohol use disorder, especially in a COVID-19 setting. Full article