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Cryptococcal meningitis (CM) causes significant global morbidity and mortality. Current therapeutic strategies rely on deoxycholated or liposomal forms of the polyene amphotericin B. Nystatin is also a polyene with broad-spectrum antimicrobial activity. Treatment with systemic nystatin has been limited by toxicity, which is a consistent challenge with polyene therapeutics. One mechanism to improve the toxicity is usage of a liposomal form of the active agent. Previous data from a murine candidemia model indicated that liposomal nystatin may be an effective antifungal drug formulation. Since the rabbit model of CM is a highly predictive preclinical system for evaluating antifungal therapeutics, we tested the effectiveness of two doses of daily liposomal nystatin, 3 and 8 mg/kg in the rabbit model of CM. Treatment with liposomal nystatin in this model did not reduce the fungal burden in the cerebrospinal fluid. A subsequent clinical trial also did not find activity in a human population. These data indicate that liposomal nystatin in the current form and at the tested dosages is not an effective therapy for CM. The data provide further evidence for the predictive power of the rabbit model of CM as a vital preclinical system for testing novel antifungal therapeutics for CM. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Fusariosis of the central nervous system (CNS) is extremely uncommon. Treatment and outcome data from previously published cases may provide some guidance in light of the ongoing fungal meningitis outbreak in 2023 involving Fusarium spp. in the United States and Mexico. METHODS: We reviewed the published literature describing cases of invasive fusariosis of the (CNS) that included data on patient demographic characteristics, treatment, and outcome. RESULTS: Twenty-six cases met inclusion criteria. The mean age was 36 years, 55% involved females, 60% had underlying hematologic malignancy, and another 16% were on immunosuppressants. The majority of infections were from Fusarium solani species complex. Overall 72% of patients died. The majority received monotherapy with amphotericin B, although some received voriconazole monotherapy or combination therapy with amphotericin B plus voriconazole with or without adjuvant surgery. Among the survivors, 3 received amphotericin B monotherapy, 2 voriconazole monotherapy, 1 combination therapy of both, and one surgery only. CONCLUSION: The overall mortality rate in published cases of fusariosis of the CNS was high, although-unlike during the current outbreak-the preponderance of patients were severely immunocompromised. While historically the majority were treated with amphotericin B monotherapy, some recent patients were treated with voriconazole monotherapy or combination therapy with amphotericin B plus voriconazole. Current guidelines recommend monotherapy with voriconazole or lipid formulations of amphotericin B or combination of both for the treatment of invasive fusariosis, which is in line with the findings from our literature review and should be considered during the ongoing 2023 outbreak.

Cryptococcal meningitis is one of the most common fungal meningitis in adults and causes disabling morbidity and mortality worldwide. The occurrence of postinfectious inflammatory response syndrome during cryptococcal meningitis treatment presents a diagnostic challenge. This time course seems paradoxical because patients show worsening symptoms and imaging findings. However, laboratory data improve with antifungal treatments. Herein, we present a case of an older woman diagnosed with cryptococcal meningitis who later developed postinfectious inflammatory response syndrome. Despite the initial antifungal treatment and improvements in cerebrospinal fluid analysis results, the patient's neurological condition deteriorated; imaging findings worsened. Magnetic resonance imaging at the time of postinfectious inflammatory response syndrome showed more prominent meningeal enhancement and brain edema, consistent with postinfectious inflammatory response syndrome, combined with negative repeat cerebrospinal fluid cultures for cryptococcal species. This case highlights the importance of considering postinfectious inflammatory response syndrome when patients with cryptococcal meningitis show clinical worsening during treatment. Prompt corticosteroid therapy significantly improves patient outcomes. Radiologists and clinicians should be aware of postinfectious inflammatory response syndrome to provide appropriate therapeutic options and improve prognosis in patients with cryptococcal meningitis.

Abstract Cryptococcal meningitis (CM) is a severe fungal disease in immunocompromised patients affecting the central nervous system (CNS). Host response and immunological alterations in the cerebrospinal fluid (CSF) after invasion of Cryptococcus neoformans to the central nervous system have been investigated before but rigorous and comprehensive studies examining cellular changes in the CSF of patients with cryptococccal meningitis are still rare. We retrospectively collected CSF analysis and flow cytometry data of CSF and blood in patients with CM (n = 7) and compared them to HIV positive patients without meningitis (n = 13) and HIV negative healthy controls (n = 7). Within the group of patients with CM we compared those with HIV infection (n = 3) or other immunocompromised conditions (n = 4). Flow cytometry analysis revealed an elevation of natural killer cells and natural killer T cells in the CSF and blood of HIV negative patients with CM, pointing to innate immune activation in early stages after fungal invasion. HIV positive patients with CM exhibited stronger blood-CSF-barrier disruption. Follow-up CSF analysis over up to 150 days showed heterogeneous cellular courses in CM patients with slow normalization of CSF after induction of antifungal therapy.

Background Methods Results Conclusion Five organs (heart, right lung, liver, right, and left kidneys) from a deceased patient were transplanted into five recipients in four US states; the deceased patient was identified as part of a healthcare‐associated fungal meningitis outbreak among patients who underwent epidural anesthesia in Matamoros, Mexico.After transplant surgeries occurred, Fusarium solani species complex, a fungal pathogen with a high case‐mortality rate, was identified in cerebrospinal fluid from the organ donor by metagenomic next‐generation sequencing (mNGS) and fungal‐specific polymerase chain reaction and in plasma by mNGS.Four of five transplant recipients received recommended voriconazole prophylaxis; four were monitored weekly by serum (1‐3)‐β‐d‐glucan testing. All five were monitored for signs of infection for at least 3 months following transplantation. The liver recipient had graft failure, which was attributed to an etiology unrelated to fungal infection. No fungal DNA was identified in sections of the explanted liver, suggesting that F. solani species complex did not contribute to graft failure. The remaining recipients experienced no signs or symptoms suggestive of fusariosis.Antifungal prophylaxis may be useful in preventing donor‐derived infections in recipients of organs from donors that are found to have Fusarium meningitis. [ABSTRACT FROM AUTHOR]

Cryptococcal meningitis (CM) is a severe fungal disease in immunocompromised patients affecting the central nervous system (CNS). Host response and immunological alterations in the cerebrospinal fluid (CSF) after invasion of Cryptococcus neoformans to the central nervous system have been investigated before but rigorous and comprehensive studies examining cellular changes in the CSF of patients with cryptococccal meningitis are still rare. We retrospectively collected CSF analysis and flow cytometry data of CSF and blood in patients with CM (n = 7) and compared them to HIV positive patients without meningitis (n = 13) and HIV negative healthy controls (n = 7). Within the group of patients with CM we compared those with HIV infection (n = 3) or other immunocompromised conditions (n = 4). Flow cytometry analysis revealed an elevation of natural killer cells and natural killer T cells in the CSF and blood of HIV negative patients with CM, pointing to innate immune activation in early stages after fungal invasion. HIV positive patients with CM exhibited stronger blood-CSF-barrier disruption. Follow-up CSF analysis over up to 150 days showed heterogeneous cellular courses in CM patients with slow normalization of CSF after induction of antifungal therapy. [ABSTRACT FROM AUTHOR]

Background Public health officials are responding to an outbreak of fungal meningitis among patients who received procedures under epidural anesthesia at 2 clinics (River Side Surgical Center and Clinica K-3) in Matamoros, Mexico, during 1 January to 13 May 2023. This report describes outbreak epidemiology and outlines interim diagnostic and treatment recommendations. Methods Interim recommendations for diagnosis and management were developed by the Mycoses Study Group Research Education and Consortium (MSGERC) based on the clinical experience of clinicians caring for patients during the current outbreak or during previous outbreaks of healthcare-associated fungal meningitis in Durango, Mexico, and the United States. Results As of 7 July 2023, the situation has evolved into a multistate and multinational fungal meningitis outbreak. A total of 185 residents in 22 US states and jurisdictions have been identified who might be at risk of fungal meningitis because they received epidural anesthesia at the clinics of interest in 2023. Among these patients, 11 suspected, 10 probable, and 10 confirmed US cases have been diagnosed, with severe vascular complications and 8 deaths occurring. Fusarium solani species complex has been identified as the causative agent, with antifungal susceptibility testing of a single isolate demonstrating poor in vitro activity for most available antifungals. Currently, triple therapy with intravenous voriconazole, liposomal amphotericin B, and fosmanogepix is recommended. Conclusions Efforts to understand the source of this outbreak and optimal treatment approaches are ongoing, but infectious diseases physicians should be aware of available treatment recommendations. New information will be available on the Centers for Disease Control and Prevention's (CDC's) website. [ABSTRACT FROM AUTHOR]

The field of infectious diseases saw numerous exciting advances in 2023. Trials of new antibiotics and treatment regimens sought to address rising rates of antimicrobial resistance. Other studies focused on the most appropriate use of currently available treatments, balancing the dual goals of providing effective treatment and impactful antimicrobial stewardship. Improvements in disease prevention were made through trials of both new vaccines and new chemoprophylaxis approaches. Concerning trends this year included increasing rates of invasive group A streptococcal infections, medical tourism-associated cases of fungal meningitis, and the return of locally acquired malaria to the United States. This review covers some of these notable trials and clinical developments in infectious diseases in the past year. [ABSTRACT FROM AUTHOR]

Background: Fungal infections of the central nervous system usually affect immunocompromised patients. Primary Aspergillus myelitis has never been described. Report: A 45-year-old immunocompetent male with subacute paraplegia was treated for inflammatory myelitis before clinical deterioration requiring mechanical ventilation. Purulent meningitis preceded the formation of a paraspinal nodule biopsied by neurosurgery. Histopathological analysis revealed the presence of fungal hyphae, and polymerase chain reaction was positive for Aspergillus fumigatus. No cause of immunodeficiency was identified in this patient. Discussion: Primary Aspergillus myelitis may be confused with inflammatory myelitis and should be considered even in the absence of apparent immunosuppression. [ABSTRACT FROM AUTHOR]

A 78-year-old woman presented to hospital with altered mental status. Hyponatremia was diagnosed and treated. She maintained mental confusion despite normal sodium. No headache, fever or focal signs were present. CSF analysis showed chronic meningitis; MRI demonstrated basilar enhancement. She was empirically treated for tuberculosis, with no improvement. PCR for Sporothrix in the CSF was positive. After treatment with Amphotericin followed by oral itraconazole, she completely recovered her cognitive abilities. Follow-up CSF was normal. This report illustrates the need to consider sporotrichosis in the differential diagnosis of chronic meningitis in immunocompetent, and the importance of PCR as a diagnostic tool.

OBJECTIVE: To analyze the patients who underwent surgery in two private clinics, from January 2023 to date, in Matamoros, Tamaulipas, Mexico, and to establish the possibility of having contracted fungal meningitis. MATERIALS AND METHODS: Observational, descriptive study using statistical analysis technique, including all patients who met any of the three predictions established of the entering protocol with a probability of fungal meningitis. A clinical record was kept for all cases and a database was created at the time of admission including: age, sex, age group, clinical data, characterization of fungal meningitis, type of surgery, date of surgery and type of anaesthesia. RESULTS: Of 405 patients identified, 50 were from Matamoros, Tamaulipas, and all of them were asked to undergo their medical check-up at the general hospital of this town; only 26 attended: 24 were female and 2 were male. Of them, 4/26 were PCR positive for Fusarium solani, with cosmetic surgery and epidural anesthesia being predominant factors. The clinical picture appeared within a period of 30 to 60 days, stiff neck was the main symptom in 3/26 patients. Tomography scans were reported to have no morphological alterations upon admission. CONCLUSIONS: In fungal infection of the central nervous system the cabinet images are very non-specific; thus the faster and more reliable diagnostic method is PCR in cerebrospinal fluid. The inoculation of the fungus with contaminated drugs, in healthy patients, is perhaps the most accepted cause in this research. [ABSTRACT FROM AUTHOR]

Copyright of Gaceta Médica de Caracas is the property of Academia Nacional de Medicina and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The article discusses a study by J. Bigot and colleagues on β-D-glucan in the cerebrospinal fluid (CSF) as a biomarker for the diagnosis of hematogenous Candida meningoencephalitis (HCME) and mold infections of the central nervous system (CNS). Topics include potential clinical utility of β-D-glucan and other polysaccharides, factors associated with mold infections of the CNS, and difficulty of diagnosing mucormycosis, which causes devastating damage to the CNS.

ABSTRACT The casein kinase 2 (CK2) complex has garnered extensive attention over the past decades as a potential therapeutic target for diverse human diseases, including cancer, diabetes, and obesity, due to its pivotal roles in eukaryotic growth, differentiation, and metabolic homeostasis. While CK2 is also considered a promising antifungal target, its role in fungal pathogens remains unexplored. In this study, we investigated the functions and regulatory mechanisms of the CK2 complex in Cryptococcus neoformans, a major cause of fungal meningitis. The cryptococcal CK2 complex consists of a single catalytic subunit, Cka1, and two regulatory subunits, Ckb1 and Ckb2. Our findings show that Cka1 plays a primary role as a protein kinase, while Ckb1 and Ckb2 have major and minor regulatory functions, respectively, in growth, cell cycle control, morphogenesis, stress response, antifungal drug resistance, and virulence factor production. Interestingly, triple mutants lacking all three subunits (cka1Δ ckb1Δ ckb2Δ) exhibited more severe phenotypic defects than the cka1Δ mutant alone, suggesting that Ckb1/2 may have Cka1-independent functions. In a murine model of systemic cryptococcosis, cka1Δ and cka1Δ ckb1Δ ckb2Δ mutants showed severely reduced virulence. Transcriptomic, proteomic, and phosphoproteomic analyses further revealed that the CK2 complex controls a wide array of effector proteins involved in transcriptional regulation, cell cycle control, nutrient metabolisms, and stress responses. Most notably, CK2 disruption led to dysregulation of key signaling cascades central to C. neoformans pathogenicity, including the Hog1, Mpk1 MAPKs, cAMP/PKA, and calcium/calcineurin signaling pathways. In summary, our study provides novel insights into the multifaceted roles of the fungal CK2 complex and presents a compelling case for targeting it in the development of new antifungal drugs.IMPORTANCEThe casein kinase 2 (CK2) complex, crucial for eukaryotic growth, differentiation, and metabolic regulation, presents a promising therapeutic target for various human diseases, including cancer, diabetes, and obesity. Its potential as an antifungal target is further highlighted in this study, which explores CK2’s functions in C. neoformans, a key fungal meningitis pathogen. The CK2 complex in C. neoformans, comprising the Cka1 catalytic subunit and Ckb1/2 regulatory subunits, is integral to processes like growth, cell cycle, morphogenesis, stress response, drug resistance, and virulence. Our findings of CK2’s role in regulating critical signaling pathways, including Hog1, Mpk1 MAPKs, cAMP/PKA, and calcium/calcineurin, underscore its importance in C. neoformans pathogenicity. This study provides valuable insights into the fungal CK2 complex, reinforcing its potential as a target for novel antifungal drug development and pointing out a promising direction for creating new antifungal agents.

Cryptococcal meningitis (CM) causes significant global morbidity and mortality. Current therapeutic strategies rely on deoxycholated or liposomal forms of the polyene amphotericin B. Nystatin is also a polyene with broad-spectrum antimicrobial activity. Treatment with systemic nystatin has been limited by toxicity, which is a consistent challenge with polyene therapeutics. One mechanism to improve the toxicity is usage of a liposomal form of the active agent. Previous data from a murine candidemia model indicated that liposomal nystatin may be an effective antifungal drug formulation. Since the rabbit model of CM is a highly predictive preclinical system for evaluating antifungal therapeutics, we tested the effectiveness of two doses of daily liposomal nystatin, 3 and 8 mg/kg in the rabbit model of CM. Treatment with liposomal nystatin in this model did not reduce the fungal burden in the cerebrospinal fluid. A subsequent clinical trial also did not find activity in a human population. These data indicate that liposomal nystatin in the current form and at the tested dosages is not an effective therapy for CM. The data provide further evidence for the predictive power of the rabbit model of CM as a vital preclinical system for testing novel antifungal therapeutics for CM.

Background: Cryptococcus neoformans is a leading cause of adult fungal meningitis and mortality in HIV/AIDS patients. The onset of fungal meningitis typically precedes the detection of serum/plasma cryptococcal antigen (CrAg) by several weeks. Screening for Cryptococcal Antigen (CrAg) and early treatment can significantly prevent the development of fungal meningitis in HIV/AIDS patients. Method: This descriptive cross-sectional study involved 100 antiretroviral therapy (ART) naive patients, comprising 65 males and 35 females, from both ART clinics and Medicine Indoor facilities. Serum/CSF cryptococcal positivity was determined using the Latex agglutination test (Pastorex TM Cryptoplus, BIO-RAD, France) and the Lateral flow assay by IMMY Kit (US FDA approved). CD4 counts were measured using a flow cytometer (Becton- Dickinson FACS count flow cytometer). Results: The prevalence of CrAg positivity in the study was 7% (7/100), with 4% (4/100) exhibiting features of meningitis. Statistical analysis revealed a significant association of antigenemia with demographic features such as age, inpatient status, and symptomatic groups (p-value ≤ 0.05). A low CD4 count (<50) was correlated with a higher seropositivity rate of 33.3% (5/100). Clinical symptoms like headache, vomiting, and fever showed a statistically significant association with cryptococcal antigenemia. Conclusion: The study concludes that cryptococcal antigenemia is more prevalent in ART-naive HIV patients with lower CD4 counts, emphasizing the need for urgent screening and the substitution of antifungal treatment to reduce morbidity and mortality associated with cryptococcal meningitis. [ABSTRACT FROM AUTHOR]

Primary intestinal lymphangiectasia (Waldmann's disease) is a rare exudative enteropathy without precisely assessed infectious risk. We report the case of a 49-year-old male patient with meningitis and cerebral vasculitis due to Cryptococcus neoformans complicating Waldmann's disease diagnosed 12 years ago. The treatment combined liposomal amphotericin B, 3 mg/kg daily plus flucytosine 25 mg/kg/6 h, both intravenously during 15 days, then fluconazole 800 mg daily during 8 weeks, and finally 200 mg daily indefinitely. Dexamethasone 0.4 mg/kg daily during the first week was gradually decreased over 2 months. The outcome was good, and the patient is still followed 3 years later without any recurrence. [ABSTRACT FROM AUTHOR]

Introduction: Mechanical methods aimed at the filtration of the cerebrospinal fluid (CSF) are a group of therapies that have been proposed to treat neurological conditions where pathogens are present in the CSF. Even though the industry of medical devices has not been very active in this field, there is a lack of systematization of the different systems and procedures that can be applied. Areas covered: First, we systematize the classification and definitions of procedures and systems for mechanical filtration of the CSF. Then, we made a literature review in search of clinical or preclinical studies where any system of mechanical CSF clearance was proposed or applied. Expert opinion: We found mechanical filtration of the CSF has been explored in subarachnoid hemorrhage, CNS infections (bacterial, viral, and fungal), meningeal carcinomatosis, multiple sclerosis, autoimmune encephalitis, and polyradiculomyelitis. Brain aging and neurodegenerative diseases are additional potential conditions of interest. While there is some preliminary positive evidence for many of these conditions, more advanced systems, detailed descriptions of procedures, and rigorous validations are needed to make these therapies a reality in the next decades. [ABSTRACT FROM AUTHOR]

Introduction: Coccidioidal meningitis (CM) is the most lethal form of disseminated coccidioidomycosis. Current guidelines recommend fluconazole as initial therapy but there has been a paucity of data regarding failure of fluconazole and optimal fluconazole dosage in the treatment of CM. We conducted this study to understand risk factors for fluconazole failure. Methods: We conducted a single-center retrospective chart review of patients diagnosed with coccidioidal meningitis between 1 January 1988 and 15 May 2021. Relevant demographic and clinical variables were collected, along with outcomes including treatment failure and death at any point. Univariate tests were conducted using the chi-squared goodness of fit test and analysis of variance. Results: Among 71 patients who began treatment for CM with fluconazole, 22 (31%) developed worsening meningitis at a median time of 206 days. Longer time from symptom onset to diagnosis of CM was a risk factor for fluconazole failure. Although the absolute failure rate of fluconazole starting dose of 400 mg daily was higher than that of 800 mg daily, the differences did not achieve statistical significance (p = 0.39). Conclusion: Fluconazole failure is not uncommon in the treatment of CM. A dose of 800 mg daily was not superior to a dose of 400 mg daily. All patients on fluconazole for CM require close monitoring. [ABSTRACT FROM AUTHOR]

A 78-year-old woman presented to hospital with altered mental status. Hyponatremia was diagnosed and treated. She maintained mental confusion despite normal sodium. No headache, fever or focal signs were present. CSF analysis showed chronic meningitis; MRI demonstrated basilar enhancement. She was empirically treated for tuberculosis, with no improvement. PCR for Sporothrix in the CSF was positive. After treatment with Amphotericin followed by oral itraconazole, she completely recovered her cognitive abilities. Follow-up CSF was normal. This report illustrates the need to consider sporotrichosis in the differential diagnosis of chronic meningitis in immunocompetent, and the importance of PCR as a diagnostic tool. [ABSTRACT FROM AUTHOR]

In 2012, the US Centers for Disease Control and Prevention reported a fungal meningitis outbreak due to Exserohilum rostratum , caused by methylprednisolone administration. Twelve years later, an iatrogenic outbreak of Fusarium meningitis was documented in Mexico after epidural anesthesia., Competing Interests: Potential conflict of interest. All authors: No reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

A 57-year old man with uncontrolled diabetes presented with features suggestive of chronic meningitis. Cerebrospinal fluid (CSF) analysis revealed a polymorphonuclear pleocytosis with low glucose and high protein levels in the CSF. Bacterial and fungal cultures and tests for M. tuberculosis were negative. MRI spine showed leptomeningeal enhancement. On ruling out other causes, fungal meningitis was considered. The patient developed paraparesis in the hospital. MRI showed peripherally enhancing subdural lesion with dorsal cord involvement at the level of D4 and D5 vertebrae. On laminectomy and exploration, an intradural extramedullary abscess and a granuloma were noticed at T4--T5 spinal levels causing compression of the cord below. Histopathological examination of the lesions revealed acute on chronic inflammatory infiltrates interspersed by broad, aseptate, ribbon-like fungal elements highlighted by PAS stain, diagnostic of mucormycosis. Intravenous amphotericin B and oral posaconazole were administered for more than 8 weeks. On follow-up, he had complete neurological recovery without sequelae., Competing Interests: Patient consentBefore manuscript preparation, written informed consent was granted by the patient for the publication of his clinical data and the figures. Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Cryptococcal meningitis is one of the most common fungal meningitis in adults and causes disabling morbidity and mortality worldwide. The occurrence of postinfectious inflammatory response syndrome during cryptococcal meningitis treatment presents a diagnostic challenge. This time course seems paradoxical because patients show worsening symptoms and imaging findings. However, laboratory data improve with antifungal treatments. Herein, we present a case of an older woman diagnosed with cryptococcal meningitis who later developed postinfectious inflammatory response syndrome. Despite the initial antifungal treatment and improvements in cerebrospinal fluid analysis results, the patient's neurological condition deteriorated; imaging findings worsened. Magnetic resonance imaging at the time of postinfectious inflammatory response syndrome showed more prominent meningeal enhancement and brain edema, consistent with postinfectious inflammatory response syndrome, combined with negative repeat cerebrospinal fluid cultures for cryptococcal species. This case highlights the importance of considering postinfectious inflammatory response syndrome when patients with cryptococcal meningitis show clinical worsening during treatment. Prompt corticosteroid therapy significantly improves patient outcomes. Radiologists and clinicians should be aware of postinfectious inflammatory response syndrome to provide appropriate therapeutic options and improve prognosis in patients with cryptococcal meningitis., (Published by Elsevier Inc. on behalf of University of Washington.)

Background and Purpose: The COVID-19 pandemic resulted in an overload of health services and healthcare professionals. The result is a setback in health promotion and prevention, delays in diagnosis, and deaths from other diseases that are currently receiving inadequate attention. This article illustrates the risk of this negligence.Case report: This study aimed to report a case of coinfection of disseminated cryptococcosis and BK virus in a patient without a previous diagnosis of human immunodeficiency virus infection and COVID-19 negative in the context of the COVID-19 pandemic. Despite receiving antifungal therapy, the patient died.Conclusion: This fatal case is a warning regarding delay of diagnosis and neglect ofother serious illnesses owing to the current pandemic, including fungal diseases and neglected diagnoses.

ABSTRACT Cryptococcus neoformans is a major fungal pathogen that often causes life-threatening meningitis in immunocompromised populations. This yeast pathogen is highly resistant to the echinocandin drug caspofungin. Previous studies showed that Cryptococcus lipid translocase (flippase) is required for the caspofungin resistance of that fungus. Mutants with a deleted subunit of lipid flippase, Cdc50, showed increased sensitivity to caspofungin. Here we designed an antifungal peptide targeting the P4-ATPase function. We synthesized stable peptides based on the Cdc50 loop region to identify peptides that can sensitize caspofungin by blocking flippase function and found that myristylated peptides based on the “AS15 sequence” was effective at high concentrations. A modified peptide, “AW9-Ma” showed a MIC of 64 μg/mL against H99 wild type and a fractional inhibitory concentration (FIC) index value of 0.5 when used in combination with caspofungin. Most notably, in the presence of the AW9-Ma peptide, C. neoformans wild type was highly sensitive to caspofungin with a MIC of 4 μg/mL, the same as the cdc50Δ mutant. Further assays with flow cytometry showed inhibition of the lipid flippase enzyme activity and significant accumulation of phosphatidylserine on the cell membrane surface. Using a fluorescently labeled peptide, we confirmed that the peptide co-localized with mCherry-tagged P4-ATPase protein Apt1 in C. neoformans. Structure-activity relationship studies of the AW9 sequence showed that two lysine residues on the peptide are likely responsible for the interaction with the P4-ATPase, hence critical for its antifungal activity. IMPORTANCE The authors have developed a lead compound peptide antifungal drug targeting a protein from the organism Cryptococcus neoformans. Binding of the drug to the target fungal protein causes charged lipid molecules to be retained on the surface. This peptide works in synergy with the existing antifungal drug caspofungin. Echinocandin drugs like caspofungin are one of the few classes of existing antifungals. Due to the high concentrations needed, caspofungin is rarely used to treat C. neoformans infections. The authors believe that their new compound provides a way to lower the concentration of caspofungin needed to treat such infections, thus opening the possibility for greater utility of these antifungal.

Metagenomic next-generation sequencing is a novel diagnostic test with the potential to revolutionize the diagnosis of pediatric meningitis and encephalitis through unbiased detection of bacteria, viruses, parasites, and fungi in cerebrospinal fluid. Current literature is mostly observational with variable indications, populations, and timing of testing with resulting variability in diagnostic yield and clinical impact. Diagnostic stewardship strategies are needed to direct testing toward high-impact pediatric populations, to optimize timing of testing, to ensure appropriate interpretation of results, and to guide prompt optimization of antimicrobials. This review highlights the high clinical potential of this test, though future studies are needed to gather clinical impact and cost-effectiveness data for specific indications in pediatric populations. [ABSTRACT FROM AUTHOR]

Introduction: Coccidioidal meningitis (CM) is the most lethal form of disseminated coccidioidomycosis. Current guidelines recommend fluconazole as initial therapy but there has been a paucity of data regarding failure of fluconazole and optimal fluconazole dosage in the treatment of CM. We conducted this study to understand risk factors for fluconazole failure. Methods: We conducted a single-center retrospective chart review of patients diagnosed with coccidioidal meningitis between 1 January 1988 and 15 May 2021. Relevant demographic and clinical variables were collected, along with outcomes including treatment failure and death at any point. Univariate tests were conducted using the chi-squared goodness of fit test and analysis of variance. Results: Among 71 patients who began treatment for CM with fluconazole, 22 (31%) developed worsening meningitis at a median time of 206 days. Longer time from symptom onset to diagnosis of CM was a risk factor for fluconazole failure. Although the absolute failure rate of fluconazole starting dose of 400 mg daily was higher than that of 800 mg daily, the differences did not achieve statistical significance (p = 0.39). Conclusion: Fluconazole failure is not uncommon in the treatment of CM. A dose of 800 mg daily was not superior to a dose of 400 mg daily. All patients on fluconazole for CM require close monitoring.

The article describes the case of neuropsychiatric systemic lupus erythematosus (SLE) in a girl with neurocutaneous melanosis with congenital giant melanocytic nevus and intracranial melanosis due to a somatic activating mutation in NRAS. Topics include explanation on mutant NRAS protein expressed in the areas of skin and brain tissue with melanosis, clinical features of neuropsychiatric SLE in neurocutaneous melanosis, and the need to include neuropsychiatric SLE in a differential diagnosis.

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Background: The pathogenic fungus Schizophyllum sp. can cause allergic fungal rhinosinusitis and allergic bronchopulmonary mycosis in humans. Sinus and lung infections due to Schizophyllum sp. have been reported globally; however, no case of hypertrophic pachymeningitis due to this pathogen has been reported yet. Herein, we describe for the first time, a case of hypertrophic pachymeningitis due to Schizophyllum sp. Case presentation: A 69-year-old woman visited the hospital with chief complaints of headache, right trigeminal neuralgia (third branch), ataxic gait, and deafness in the right ear. Magnetic resonance imaging revealed a tumor in the right sphenoidal sinus and thickening of the dura mater surrounding the right porus acusticus internus. Endoscopic sinus surgery and neuroendoscopic biopsy were performed to remove sinus lesions and intracranial lesions, respectively. Both pathological specimens showed findings indicative of filamentous fungi on Grocott's staining. DNA sequencing with the sinus specimen revealed Schizophyllum sp. as the causative pathogen, consistent with the diagnosis of fungal sinusitis and hypertrophic pachymeningitis. Intravenous liposomal amphotericin B was started, but owing to lack of improvement, the treatment was switched to intravenous voriconazole. We observed improvements in both radiological findings and symptoms. However, the symptoms exacerbated again when the trough level of voriconazole decreased. Upon increasing the voriconazole dose, a higher trough level was obtained and the symptoms improved. Conclusion: Our study suggests that when symptoms of central nervous system infection due to Schizophyllum sp. do not improve with liposomal amphotericin B, voriconazole can be administered at high trough levels to improve the symptoms. [ABSTRACT FROM AUTHOR]