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1.
BMC Infect Dis ; 24(1): 747, 2024 Jul 29.
Article in English | MEDLINE | ID: mdl-39075375

ABSTRACT

BACKGROUND: As disseminated extrapulmonary tuberculosis infection can involve multiple systems and result in atypical clinical manifestations that mimic other diseases, the diagnosis may be difficult, especially in elderly patients. Delaying treatment can adversely affect the prognosis. And to achieve better prognosis, early detection and diagnosis are necessary, as well as early initiation of comprehensive treatment. CASE PRESENTATION: We present the case of a 78-year-old man with disseminated tuberculosis who developed the uncommon complication of urinary retention due to a psoas abscess, meningoencephalitis, and the rare secondary hemophagocytic lymphohistiocytosis syndrome. The patient achieved a favorable outcome following targeted therapy with antitubercular medications. CONCLUSIONS: This case highlights that disseminated extrapulmonary tuberculosis infection can present with a variety of manifestations, and may exhibit many rare and complex clinical presentations. Prompt and accurate diagnosis and treatment play a crucial role in improving prognosis for the patients with persistent fever.


Subject(s)
Antitubercular Agents , Lymphohistiocytosis, Hemophagocytic , Meningoencephalitis , Humans , Male , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/diagnosis , Aged , Meningoencephalitis/drug therapy , Meningoencephalitis/microbiology , Meningoencephalitis/complications , Antitubercular Agents/therapeutic use , Psoas Abscess/microbiology , Psoas Abscess/drug therapy , Tuberculosis/complications , Tuberculosis/drug therapy , Abscess/microbiology , Abscess/drug therapy
2.
J Infect Chemother ; 30(3): 263-265, 2024 Mar.
Article in English | MEDLINE | ID: mdl-37863259

ABSTRACT

A 37-year-old woman was hospitalized with fever and consciousness disturbance. She showed systemic inflammation with stress cardiomyopathy. Brain computed tomography showed diffuse brain edema. Cerebrospinal fluid (CSF) findings revealed markedly elevated cerebrospinal fluid pressure with pleocytosis, elevated protein, and elevated interleukin 6. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nicking enzyme amplification reaction test using a nasopharyngeal swab was positive, and the patient was diagnosed with SARS-CoV-2 infection. From the negative result of the CSF SARS-CoV-2 polymerase chain reaction test and no findings of bacterial or viral infection, we diagnosed meningoencephalitis by multisystem inflammation syndrome in adults (MIS-A). Intravenous methylprednisolone pulse therapy improved her symptoms and brain edema. There have been no cases of MIS-A with meningoencephalitis, and no initial treatment strategy has been established, especially in emergency cases of suspected MIS-A. The present case suggested Early intravenous methylprednisolone pulse with anti-coronaviral therapies after the exclusion of bacterial infection would be useful in suspected MIS-A with emergent meningoencephalitis cases.


Subject(s)
Brain Edema , COVID-19 , Connective Tissue Diseases , Meningoencephalitis , Humans , Adult , Female , COVID-19/complications , COVID-19/diagnosis , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/complications , Systemic Inflammatory Response Syndrome/diagnosis , Systemic Inflammatory Response Syndrome/drug therapy , Inflammation , Meningoencephalitis/diagnosis , Meningoencephalitis/drug therapy , Methylprednisolone/therapeutic use
3.
Antimicrob Agents Chemother ; 67(10): e0081823, 2023 10 18.
Article in English | MEDLINE | ID: mdl-37728934

ABSTRACT

Cryptococcal meningoencephalitis (CM) is a devastating fungal disease with high morbidity and mortality. The current regimen that is standard-of-care involves a combination of three different drugs administered for up to one year. There is a critical need for new therapies due to both toxicity and inadequate fungicidal activity of the currently available antifungal drugs. ATI-2307 is a novel aryl amidine that disrupts the mitochondrial membrane potential and inhibits the respiratory chain complexes of fungi-it thus represents a new mechanism for direct antifungal action. Furthermore, ATI-2307 selectively targets fungal mitochondria via a fungal-specific transporter that is not present in mammalian cells. It has very potent in vitro anticryptococcal activity. In this study, the efficacy of ATI-2307 was tested in a rabbit model of CM. ATI-2307 demonstrated significant fungicidal activity at dosages between 1 and 2 mg/kg/d, and these results were superior to fluconazole and similar to amphotericin B treatment. When ATI-2307 was combined with fluconazole, the antifungal effect was greater than either therapy alone. While ATI-2307 has potent anticryptococcal activity in the subarachnoid space, its ability to reduce yeasts in the brain parenchyma was relatively less over the same study period. This new drug, with its unique mechanism of fungicidal action and ability to positively interact with an azole, has demonstrated sufficient anticryptococcal potential in this experimental setting to be further evaluated in clinical studies.


Subject(s)
Cryptococcus neoformans , Meningitis, Cryptococcal , Meningoencephalitis , Animals , Rabbits , Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , Fluconazole/pharmacology , Fluconazole/therapeutic use , Meningitis, Cryptococcal/drug therapy , Meningitis, Cryptococcal/microbiology , Meningoencephalitis/drug therapy , Meningoencephalitis/microbiology , Mammals
4.
Antimicrob Agents Chemother ; 67(10): e0045923, 2023 10 18.
Article in English | MEDLINE | ID: mdl-37750714

ABSTRACT

Cryptococcus neoformans (Cn) is an encapsulated neurotropic fungal pathogen and the causative agent of cryptococcal meningoencephalitis (CME) in humans. Recommended treatment for CME is Amphotericin B (AmpB) and 5-fluorocytosine (5-FC). Though effective, AmpB has displayed numerous adverse side effects due to its potency and nephrotoxicity, prompting investigation into alternative treatments. Palmitoylethanolamide (PEA) is an immunomodulatory compound capable of promoting neuroprotection and reducing inflammation. To investigate the efficacy of PEA as a therapeutic alternative for CME, we intracerebrally infected mice with Cn and treated them with PEA or AmpB alone or in combination. Our results demonstrate that PEA alone does not significantly prolong survival nor reduce fungal burden, but when combined with AmpB, PEA exerts an additive effect and promotes both survivability and fungal clearance. However, we compared this combination to traditional AmpB and 5-FC treatment in a survivability study and observed lower efficacy. Overall, our study revealed that PEA alone is not effective as an antifungal agent in the treatment of CME. Importantly, we describe the therapeutic capability of PEA in the context of Cn infection and show that its immunomodulatory properties may confer limited protection when combined with an effective fungicidal agent.


Subject(s)
Cryptococcosis , Cryptococcus neoformans , Meningitis, Cryptococcal , Meningoencephalitis , Humans , Mice , Animals , Meningitis, Cryptococcal/drug therapy , Meningitis, Cryptococcal/microbiology , Antifungal Agents/therapeutic use , Cryptococcosis/drug therapy , Cryptococcosis/microbiology , Amphotericin B/therapeutic use , Flucytosine/therapeutic use , Meningoencephalitis/drug therapy
5.
J Clin Immunol ; 43(8): 2146-2155, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37814084

ABSTRACT

PURPOSE: Non-HIV cryptococcal meningoencephalitis (CM) in previously healthy individuals is often complicated by a post-infectious inflammatory response syndrome (c-PIIRS) characterized by neurologic deterioration after appropriate antifungal therapy with sterilization of CSF fungal cultures. c-PIIRS results from an excessive inflammatory response to fungal antigens released during fungal lysis, mediated by IFN-γ, IL-6, and activated T-helper cells, leading to immune-mediated host damage that responds to pulse-corticosteroid taper therapy (PCT). Typically, oral steroids may take up to a year to taper, and occasionally, patients will be refractory to steroid therapy or may demonstrate high-risk lesions such as those involving intracranial arteries. Also, patients can have problematic side effects from prolonged corticosteroids. Hence, appropriate adjunctive agents are needed to reduce corticosteroid doses in the treatment of c-PIIRS. Due to a possible role of IL-6 in pathogenesis, IL-6 receptor blockade by tocilizumab may be useful in the treatment of c-PIIRS. METHODS: Two previously healthy patients with non-HIV cPIIRS were seen at the NIH. Due to concerns for intracranial vascular rupture in an area of inflammation (Patient 1) and intractable symptoms on high-dose oral corticosteroids (Patient 2) with evidence of persistent CSF inflammation, patients were treated with 4-8 mg/kg tocilizumab every 2 weeks while maintained on a constant dose of prednisone. RESULTS: Two patients exhibited rapid immunological improvement following treatment with tocilizumab. Patient 1 remained vascularly stable, and Patient 2 had near resolution of headaches with improvement in mental status as evidenced by improved MOCA score. The two had improved CSF inflammatory parameters and no significant side effects. Both CSF cultures remained negative throughout treatment. CONCLUSIONS: Tocilizumab may be a safe adjunctive treatment for CM-related PIIRS suggesting further study.


Subject(s)
Cryptococcus , Meningitis, Cryptococcal , Meningoencephalitis , Humans , Meningitis, Cryptococcal/diagnosis , Meningitis, Cryptococcal/drug therapy , Interleukin-6 , Inflammation , Adrenal Cortex Hormones/therapeutic use , Meningoencephalitis/drug therapy
6.
Curr Opin Infect Dis ; 36(3): 186-191, 2023 06 01.
Article in English | MEDLINE | ID: mdl-37093056

ABSTRACT

PURPOSE OF REVIEW: Free-living amebae (FLA) including Naegleria fowleri , Balamuthia mandrillaris , and Acanthamoeba species can cause rare, yet severe infections that are nearly always fatal. This review describes recent developments in epidemiology, diagnosis, and treatment of amebic meningoencephalitis. RECENT FINDINGS: Despite similarities among the three pathogenic FLA, there are notable variations in disease presentations, routes of transmission, populations at risk, and outcomes for each. Recently, molecular diagnostic tools have been used to diagnose a greater number of FLA infections. Treatment regimens for FLA have historically relied on survivor reports; more data is needed about novel treatments, including nitroxoline. SUMMARY: Research to identify new drugs and guide treatment regimens for amebic meningoencephalitis is lacking. However, improved diagnostic capabilities may lead to earlier diagnoses, allowing earlier treatment initiation and improved outcomes. Public health practitioners should continue to prioritize increasing awareness and providing education to clinicians, laboratorians, and the public about amebic infections.


Subject(s)
Acanthamoeba , Amebiasis , Central Nervous System Protozoal Infections , Infectious Encephalitis , Meningoencephalitis , Humans , Central Nervous System Protozoal Infections/diagnosis , Central Nervous System Protozoal Infections/drug therapy , Central Nervous System Protozoal Infections/epidemiology , Amebiasis/diagnosis , Amebiasis/drug therapy , Amebiasis/epidemiology , Meningoencephalitis/diagnosis , Meningoencephalitis/drug therapy , Meningoencephalitis/epidemiology , Infectious Encephalitis/diagnosis , Infectious Encephalitis/drug therapy , Infectious Encephalitis/epidemiology
7.
J Antimicrob Chemother ; 78(4): 1015-1022, 2023 04 03.
Article in English | MEDLINE | ID: mdl-36857467

ABSTRACT

BACKGROUND: There are limited data describing clinical flucytosine pharmacokinetics (PK). The variability of flucytosine partitioning into the CNS is not known. We described the interindividual variability in flucytosine PK in patients with HIV-associated cryptococcal meningoencephalitis. In addition, we quantified the extent and variability of CSF partitioning of flucytosine. METHODS: A PK study was conducted in 64 patients with confirmed HIV-associated cryptococcal meningoencephalitis in Blantyre, Malawi. A four-compartment PK model was developed, and Monte Carlo simulations were performed with flucytosine administered at different doses and in different schedules. RESULTS: The estimated mean apparent volume of the central compartment was 17.50 (SD 9.99) L; mean apparent clearance was 5.88 (SD 3.35) L/h; mean apparent volume of the CNS compartment was 41.73 (SD 13.66) L. From the Bayesian posterior estimates, AUC24 values at steady state (144-168 h) with doses of 25 mg/kg q6h were median (IQR) 890.38 (603.81-1213.70) mg.h/L in plasma and 595.66 (425.69-776.64) mg.h/L in CSF. The ratio of CSF:plasma AUC24 was 0.69 (IQR 0.58-0.82). CONCLUSIONS: This study revealed significant interindividual variability in flucytosine PK in plasma and CSF in patients with HIV-associated cryptococcal meningoencephalitis. The population PK model is a first critical step for revised flucytosine regimens that maximize fungal killing and minimize toxicity and the emergence of resistance.


Subject(s)
Cryptococcus neoformans , HIV Infections , Meningitis, Cryptococcal , Meningoencephalitis , Humans , Adult , Flucytosine , Antifungal Agents/therapeutic use , Meningitis, Cryptococcal/drug therapy , Bayes Theorem , Meningoencephalitis/drug therapy , Meningoencephalitis/microbiology , HIV Infections/complications , HIV Infections/drug therapy
8.
BMC Infect Dis ; 23(1): 434, 2023 Jun 27.
Article in English | MEDLINE | ID: mdl-37365493

ABSTRACT

BACKGROUND: The combined infection of actinomyces odontolyticus sepsis and cryptococcal encephalitis is rare in routine clinical practice. Thus, we presented this case report and literature review to provide clues to improve such patients' diagnoses and treatment processes. CASE PRESENTATION: The main clinical manifestations of the patient were high fever and intracranial hypertension. Then, we completed the routine cerebrospinal fluid examination, biochemical detection, cytological examination, bacterial culture, and India ink staining. Firstly, the blood culture suggested actinomyces odontolyticus infection, considering the possibility of actinomyces odontolyticus sepsis and intracranial actinomyces odontolyticus infection. Accordingly, the patient was administered penicillin for treatment. Although the fever was slightly relieved, the symptoms of intracranial hypertension did not relieve. After 7 days, the characteristics of brain magnetic resonance imaging and the results of pathogenic metagenomics sequencing and cryptococcal capsular polysaccharide antigen suggested that cryptococcal infection. Based on the above results, the patient was diagnosed with a combined infection of cryptococcal meningoencephalitis and actinomyces odontolyticus sepsis. Anti-infection therapy with 'penicillin, amphotericin, and fluconazole' was provided, improving the clinical manifestations and objective indexes. CONCLUSION: The combined infection of Actinomyces odontolyticus sepsis and cryptococcal encephalitis is first reported in this case report, and combined antibiotics with 'penicillin, amphotericin, and fluconazole' are effective.


Subject(s)
Actinomycosis , Cryptococcus neoformans , Intracranial Hypertension , Meningitis, Cryptococcal , Meningoencephalitis , Sepsis , Humans , Fluconazole/therapeutic use , Amphotericin B/therapeutic use , Actinomycosis/diagnosis , Actinomycosis/drug therapy , Actinomycosis/microbiology , Penicillins/therapeutic use , Sepsis/diagnosis , Sepsis/drug therapy , Meningoencephalitis/diagnosis , Meningoencephalitis/drug therapy , Actinomyces , Intracranial Hypertension/drug therapy , Antifungal Agents/therapeutic use , Antifungal Agents/pharmacology , Meningitis, Cryptococcal/diagnosis
9.
Neuropediatrics ; 54(1): 68-72, 2023 02.
Article in English | MEDLINE | ID: mdl-35817356

ABSTRACT

INTRODUCTION: Various neurologic manifestations have already been described in children during or after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. The central nervous system disorders reported in children are mainly encephalopathies during multisystem inflammatory syndrome. We present here an acute meningoencephalitis with cerebral vasculitis associated to a coronavirus disease 2019 (COVID-19) infection in a 13-year-old girl with a 1-year clinical, electroencephalogram (EEG), and magnetic resonance imaging (MRI) follow-up. CASE REPORT: A 13-year-old girl presented acute symptoms of consciousness impairment, frontal headache, hyperthermia, and aphasia, with moderate lymphopenia (900/mm3), elevated C-reactive protein (17 mg/L), cerebrospinal fluid (CSF) pleocytosis (15 cells/mm3), slow background with frontal focalization on EEG, a left frontal ischemic lesion, leptomeningeal enhancement, and bilateral limbic fluid-attenuated inversion recovery hyperintensity on cerebral MRI. Reverse transcription-polymerase chain reaction for SARS-CoV-2 was positive in nasopharyngeal swab and COVID serology was positive for immunoglobulin (Ig) M and G, whereas extensive autoimmune antibody investigation was negative except for a positive low titer of anti-myelin oligodendrocyte glycoprotein in CSF and blood. The diagnosis of probable encephalitis associated to cerebral vasculitis after COVID infection was suggested and steroids pulse were started. She recovered within a few days. Six months later, she had moderate clinical sequels including persistent intermittent headaches, an isolated spatial deficit, and focal spikes on the EEG without argument for epilepsia. CONCLUSION: A teenager without previous medical history presented with acute encephalitis with leptomeningitis and vasculitis after a recent COVID-19 infection. Steroids pulse therapy allowed clinical improvement. Cerebral MRI and EEG helped diagnosis, follow-up of the encephalitis, and evolution after treatment.


Subject(s)
COVID-19 , Encephalitis , Meningoencephalitis , Vasculitis, Central Nervous System , Female , Humans , COVID-19/complications , SARS-CoV-2 , Meningoencephalitis/complications , Meningoencephalitis/drug therapy , Encephalitis/drug therapy , Encephalitis/etiology , Adrenal Cortex Hormones , Vasculitis, Central Nervous System/complications , Vasculitis, Central Nervous System/drug therapy
10.
BMC Vet Res ; 19(1): 269, 2023 Dec 12.
Article in English | MEDLINE | ID: mdl-38087262

ABSTRACT

BACKGROUND: Meningoencephalomyelitis of unknown etiology (MUE) is a comprehensive term for non-infectious inflammatory brain diseases of the central nervous system (CNS) caused by abnormal autoimmune responses. This study aims to compare the differences in survival and clinical response of MUE according to the adjuvant immunosuppressant use. Medical records of 82 dogs diagnosed with MUE were reviewed retrospectively. RESULTS: The overall survival time was 769 days (range 14-2687 days). The median survival time for each adjunctive was: leflunomide 1035 days (range 126-2163 days), mycophenolate mofetil 865 days (range 39-2191 days), cyclosporin 441 days (range 11-2176 days), cytosine arabinoside 754 days (range 6-1898 days) and a combination of mycophenolate mofetil and cytosine arabinoside 132 days (range 23-1227 days). There was no significant difference in the incidence rate of adverse events according to the immunosuppressants, but moderate to severe anemia was confirmed in 3 patients (18.7%) in the leflunomide group. CONCLUSIONS: The survival time and response rate of MUE dogs differed depending on which adjunctive immunosuppressants were used. Leflunomide showed a long survival time and a relatively good response rate in dogs with MUE. However, a large-scale further study with standardized doses of immunosuppressants and supportive treatment and constant monitoring interval is needed.


Subject(s)
Dog Diseases , Encephalomyelitis , Meningoencephalitis , Humans , Dogs , Animals , Immunosuppressive Agents/adverse effects , Retrospective Studies , Mycophenolic Acid/adverse effects , Leflunomide/therapeutic use , Prognosis , Meningoencephalitis/drug therapy , Meningoencephalitis/veterinary , Cytarabine/adverse effects , Encephalomyelitis/veterinary , Dog Diseases/diagnosis
11.
Pract Neurol ; 23(6): 512-515, 2023 Nov 23.
Article in English | MEDLINE | ID: mdl-37802650

ABSTRACT

A 21-year-old woman with multiple sclerosis (taking regular fingolimod) developed sudden-onset severe headache with nausea and malaise. Neurological examination was normal and she was afebrile. Blood results showed lymphocytes 0.53 x 109/L and C reactive protein 19 mg/L. CT scan of head and venogram were normal. CSF showed an opening pressure of 33 cm H2O and an incidental light growth of Cryptococcus neoformans, confirmed with positive India Ink stain and a positive cryptococcal antigen (1:100). She was treated for cryptococcal meningoencephalitis with amphotericin and flucytosine. Her presenting symptoms had closely mimicked subarachnoid haemorrhage. This atypical presentation of cryptococcal CNS infection highlights the need for vigilance in immunosuppressed patients.


Subject(s)
Meningitis, Cryptococcal , Meningoencephalitis , Multiple Sclerosis , Female , Humans , Young Adult , Adult , Meningitis, Cryptococcal/drug therapy , Fingolimod Hydrochloride/adverse effects , Amphotericin B , Meningoencephalitis/drug therapy
12.
Medicina (Kaunas) ; 59(12)2023 Dec 13.
Article in English | MEDLINE | ID: mdl-38138266

ABSTRACT

Behçet's disease (BD) is a systemic vasculitis that frequently presents with a relapsing-remitting pattern. CNS involvement (Neuro-Behçet) is rare, affecting approximately 10% of patients. Its etiological mechanisms are not yet fully understood. The most commonly accepted hypothesis is that of a systemic inflammatory reaction triggered by an infectious agent or by an autoantigen, such as heat shock protein, in genetically predisposed individuals. Mycobacterium tuberculosis is known to be closely interconnected with BD, both affecting cell-mediated immunity to a certain extent and probably sharing a common genetic background. We present the case of a 34-year-old Caucasian woman who had been diagnosed with tuberculous meningitis 15 months prior, with significant neurological deficits and lesional burden on MRI with repeated relapses whenever treatment withdrawal was attempted. These relapses were initially considered as reactivation of tuberculous meningoencephalitis, and symptoms improved after a combination of antituberculous treatment and corticosteroid therapy. After the second relapse, the diagnosis was reconsidered, as new information emerged about oral and genital aphthous lesions, making us suspect a BD diagnosis. HLA B51 testing was positive, antituberculous treatment was stopped, and the patient was started on high doses of oral Cortisone and Azathioprine. Consequently, the evolution was favorable, with no further relapses and slow improvements in neurological deficits. To our knowledge, this is the first report of Neuro-Behçet's disease onset precipitated by tuberculous meningitis. We include a review of the available literature on this subject. Our case reinforces the fact that Mycobacterium tuberculosis infection can precipitate BD in genetically predisposed patients, and we recommend HLA B51 screening in patients with prolonged or relapsing meningoencephalitis, even if an infectious agent is apparently involved.


Subject(s)
Behcet Syndrome , Meningoencephalitis , Tuberculosis, Meningeal , Female , Humans , Adult , Behcet Syndrome/complications , Behcet Syndrome/diagnosis , Behcet Syndrome/drug therapy , HLA-B51 Antigen , Tuberculosis, Meningeal/complications , Tuberculosis, Meningeal/diagnosis , Tuberculosis, Meningeal/drug therapy , Neoplasm Recurrence, Local , Meningoencephalitis/complications , Meningoencephalitis/diagnosis , Meningoencephalitis/drug therapy , Recurrence
13.
Clin Infect Dis ; 75(Suppl 3): S451-S458, 2022 10 17.
Article in English | MEDLINE | ID: mdl-36251558

ABSTRACT

The neurological sequelae of Bacillus anthracis infection include a rapidly progressive fulminant meningoencephalitis frequently associated with intracranial hemorrhage, including subarachnoid and intracerebral hemorrhage. Higher mortality than other forms of bacterial meningitis suggests that antimicrobials and cardiopulmonary support alone may be insufficient and that strategies targeting the hemorrhage might improve outcomes. In this review, we describe the toxic role of intracranial hemorrhage in anthrax meningoencephalitis. We first examine the high incidence of intracranial hemorrhage in patients with anthrax meningoencephalitis. We then review common diseases that present with intracranial hemorrhage, including aneurysmal subarachnoid hemorrhage and spontaneous intracerebral hemorrhage, postulating applicability of established and potential neurointensive treatments to the multimodal management of hemorrhagic anthrax meningoencephalitis. Finally, we examine the therapeutic potential of minocycline, an antimicrobial that is effective against B. anthracis and that has been shown in preclinical studies to have neuroprotective properties, which thus might be repurposed for this historically fatal disease.


Subject(s)
Anthrax , Bacillus anthracis , Meningoencephalitis , Anthrax/complications , Anthrax/drug therapy , Anthrax/epidemiology , Cerebral Hemorrhage/complications , Humans , Meningoencephalitis/complications , Meningoencephalitis/drug therapy , Meningoencephalitis/microbiology , Minocycline/therapeutic use
14.
Antimicrob Agents Chemother ; 66(4): e0218121, 2022 04 19.
Article in English | MEDLINE | ID: mdl-35315689

ABSTRACT

Neonatal sepsis is an underrecognized burden on health care systems throughout the world. Antimicrobial drug resistance (AMR) is increasingly prevalent and compromises the use of currently recommended first-line agents. The development of new antimicrobial agents for neonates and children is mandated by regulatory agencies. However, there remains uncertainty about suitable development pathways, especially because of the propensity of premature babies to develop meningoencephalitis as a complication of neonatal sepsis and difficulties studying this disease in clinical settings. We developed a new platform and approach to accelerate the development of antimicrobial agents for neonatal bacterial meningoencephalitis using Pseudomonas aeruginosa as the challenge organism. We defined the pharmacodynamics of meropenem and tobramycin in these models. The percentage of partitioning of meropenem and tobramycin into the cerebrospinal fluid was comparable at 14.3 and 13.7%, respectively. Despite this similarity, there were striking differences in their pharmacodynamics. Meropenem resulted in bactericidal activity in both the cerebrospinal fluid and cerebrum, whereas tobramycin had minimal antibacterial activity. A hollow fiber infection model (HFIM) using neonatal CSF concentration time profiles yielded pharmacodynamics comparable to those observed in the rabbit model. These new experimental models can be used to estimate the pharmacodynamics of currently licensed agents and those in development and their potential efficacy for neonatal bacterial meningoencephalitis.


Subject(s)
Meningoencephalitis , Neonatal Sepsis , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Drug Resistance, Bacterial , Meningoencephalitis/drug therapy , Meropenem/pharmacology , Microbial Sensitivity Tests , Neonatal Sepsis/drug therapy , Pseudomonas aeruginosa , Rabbits , Tobramycin/pharmacology , Tobramycin/therapeutic use
15.
J Antimicrob Chemother ; 78(1): 276-283, 2022 12 23.
Article in English | MEDLINE | ID: mdl-36411251

ABSTRACT

BACKGROUND: Single, high-dose liposomal amphotericin B (LAmB; AmBisome, Gilead Sciences) has demonstrated non-inferiority to amphotericin B deoxycholate in combination with other antifungals for averting all-cause mortality from HIV-associated cryptococcal meningitis. There are limited data on the pharmacokinetics (PK) of AmBisome. The aim of this study was to describe population PK of AmBisome and conduct a meta-analysis of the available studies to suggest the optimal dosing for cryptococcal meningoencephalitis. METHODS: Data from a Phase II and Phase III trial of high-dose, short-course AmBisome for cryptococcal meningoencephalitis were combined to develop a population PK model. A search was conducted for trials of AmBisome monotherapy and meta-analysis of clinical outcome data was performed. RESULTS: A two-compartment model with first-order clearance of drug from the central compartment fitted the data best and enabled the extent of inter-individual variability in PK to be quantified. Mean (SD) population PK parameter estimates were: clearance 0.416 (0.363)  L/h; volume of distribution 4.566 (4.518) L; first-order transfer of drug from central to peripheral compartments 2.222 (3.351)  h-1, and from peripheral to central compartment 2.951 (4.070)  h-1. Data for the meta-analysis were insufficient to suggest optimal dosing of AmBisome for cryptococcal meningoencephalitis. CONCLUSIONS: This study provides novel insight into the PK of AmBisome at the population level and the variability therein. Our analysis also serves to highlight the paucity of data available on the pharmacodynamics (PD) of AmBisome and underscores the importance of thorough and detailed PK/PD analysis in the development of novel antifungals, by demonstrating the challenges associated with post hoc PK/PD analysis.


Subject(s)
Cryptococcus neoformans , HIV Infections , Meningitis, Cryptococcal , Meningoencephalitis , Humans , Antifungal Agents/pharmacology , Meningitis, Cryptococcal/drug therapy , Meningoencephalitis/drug therapy , HIV Infections/complications , HIV Infections/drug therapy
16.
Eur J Neurol ; 29(10): 3117-3123, 2022 10.
Article in English | MEDLINE | ID: mdl-35763378

ABSTRACT

BACKGROUND AND PURPOSE: Enterovirus infections pose a serious threat for patients with humoral deficiencies and may be lethal, whilst the efficacy of proposed treatment options such as corticosteroids, intravenous immunoglobulins and fluoxetine remains debated. METHODS: Viral clearance was investigated in a patient with rituximab-induced B-cell depletion and chronic echovirus 13 (E13) meningoencephalitis/myofasciitis in response to intravenous immunoglobulins and fluoxetine using sequential semi-quantitative E13 viral load measurements by real-time reverse transcription polymerase chain reaction. Fluoxetine concentrations in plasma and cerebrospinal fluid were determined by liquid chromatography mass spectrometry. RESULTS: Intravenous immunoglobulins appeared ineffective in this case of E13 infection, whereas virus clearance in cerebrospinal fluid was obtained after 167 days of oral fluoxetine. Since treatment with corticosteroids resulted in a flare of symptoms, rechallenge with viral load measurements was not attempted. CONCLUSION: In this report of a patient with rituximab-associated chronic echovirus 13 meningoencephalitis, viral clearance in response to single treatment options is assessed for the first time. Our observations further support the in vivo efficacy of fluoxetine against enteroviral infections. More research is needed to establish its efficacy in different enterovirus strains.


Subject(s)
Echovirus Infections , Enterovirus Infections , Meningitis, Aseptic , Meningoencephalitis , Myositis , Antiviral Agents , Echovirus Infections/cerebrospinal fluid , Enterovirus B, Human , Fluoxetine/therapeutic use , Humans , Immunoglobulins, Intravenous/therapeutic use , Meningoencephalitis/cerebrospinal fluid , Meningoencephalitis/drug therapy , Rituximab/therapeutic use
17.
Infection ; 50(4): 1023-1027, 2022 Aug.
Article in English | MEDLINE | ID: mdl-35112322

ABSTRACT

Meningoencephalitis can be a diagnostic dilemma and one of its etiology are infectious causes including fungal agents. Fusarium species have attracted much attention as one of the invasive fungal infections. Major clinical manifestations of infections due to Fusarium spp. are broad such as keratitis, endophthalmitis, sino-pulmonary and central nervous system (CNS) infections. However, CNS fusariosis is rare and often happens due to hematogenous dissemination from other sites. Herein, we describe an unusual case of meningoencephalitis caused by Fusarium proliferatum, in a patient with rheumatoid arthritis.


Subject(s)
Eye Infections, Fungal , Fusariosis , Fusarium , Keratitis , Meningoencephalitis , Antifungal Agents/therapeutic use , Fusariosis/diagnosis , Fusariosis/drug therapy , Fusariosis/microbiology , Humans , Keratitis/microbiology , Meningoencephalitis/diagnosis , Meningoencephalitis/drug therapy
18.
J Infect Chemother ; 28(8): 1168-1171, 2022 Aug.
Article in English | MEDLINE | ID: mdl-35370079

ABSTRACT

A neonatal patient with Herpes simplex virus type-2 meningoencephalitis was treated by high-dose intravenous acyclovir therapy. Serum and cerebrospinal fluid (CSF) concentrations were measured retrospectively, showing that the CSF-to-serum concentration ratio was 0.67-0.71, which was higher than the previously reported values in other age groups.


Subject(s)
Herpes Simplex , Meningoencephalitis , Acyclovir/therapeutic use , Antiviral Agents/therapeutic use , Cerebrospinal Fluid , Herpes Simplex/drug therapy , Herpesvirus 2, Human , Humans , Infant, Newborn , Meningoencephalitis/drug therapy , Retrospective Studies
19.
No Shinkei Geka ; 50(5): 952-960, 2022 Sep.
Article in Japanese | MEDLINE | ID: mdl-36128810

ABSTRACT

This review describes cryptococcal meningoencephalitis, tuberculous meningitis, neurosyphilis, and toxoplasma encephalitis. Central nervous system infections are neurological emergencies associated with mortality or other outcomes. Therefore, early diagnosis and treatment are critical. Fungal or gondii infections are rare and affect compromised hosts who are HIV positive, have diabetes, or take immunosuppressive or anticancer drugs. Cryptococcal antigens in the serum and cerebrospinal fluid are useful for the diagnosis of cryptococcal meningoencephalitis. RPR and TPHA tests are useful for the diagnosis of neurosyphilis. Cryptococcal meningoencephalitis and tuberculous meningitis often develop into hydrocephalus, making VP shunt necessary. Antifungal drugs for cryptococcal meningitis are limited by the blood-brain barrier, making a full recovery difficult; in such situations, intraventricular antifungal treatment is required.


Subject(s)
Meningoencephalitis , Mycoses , Neurosyphilis , Parasitic Diseases , Tuberculosis, Meningeal , Antifungal Agents/therapeutic use , Humans , Meningoencephalitis/drug therapy , Mycoses/drug therapy , Neurosyphilis/drug therapy , Parasitic Diseases/drug therapy , Tuberculosis, Meningeal/drug therapy
20.
Clin Infect Dis ; 73(9): e2789-e2798, 2021 11 02.
Article in English | MEDLINE | ID: mdl-33383587

ABSTRACT

BACKGROUND: Cryptococcal meningoencephalitis (CM) is a major cause of mortality in immunosuppressed patients and previously healthy individuals. In the latter, a post-infectious inflammatory response syndrome (PIIRS) is associated with poor clinical response despite antifungal therapy and negative cerebrospinal fluid (CSF) cultures. Data on effective treatment are limited. METHODS: Between March 2015 and March 2020, 15 consecutive previously healthy patients with CM and PIIRS were treated with adjunctive pulse corticosteroid taper therapy (PCT) consisting of intravenous methylprednisolone 1 gm daily for 1 week followed by oral prednisone 1 mg/kg/day, tapered based on clinical and radiological response plus oral fluconazole. Montreal cognitive assessments (MOCA), Karnofsky performance scores, magnetic resonance imaging (MRI) brain scanning, ophthalmic and audiologic exams, and CSF parameters including cellular and soluble immune responses were compared at PIIRS diagnosis and after methylprednisolone completion. RESULTS: The median time from antifungal treatment to steroid initiation was 6 weeks. The most common symptoms at PIIRS diagnosis were altered mental status and vision changes. All patients demonstrated significant improvements in MOCA and Karnofsky scores at 1 month (P < .0003), which was accompanied by improvements in CSF glucose, white blood cell (WBC) count, protein, cellular and soluble inflammatory markers 1 week after receiving corticosteroids (CS) (P < .003). All patients with papilledema and visual field deficits also exhibited improvement (P < .0005). Five out of 7 patients who underwent audiological testing demonstrated hearing improvement. Brain MRI showed significant improvement of radiological findings (P = .001). CSF cultures remained negative. CONCLUSIONS: PCT in this small cohort of PIIRS was associated with improvements in CM-related complications with minimal toxicity in the acute setting.


Subject(s)
Cryptococcus , Meningitis, Cryptococcal , Meningoencephalitis , Adrenal Cortex Hormones/therapeutic use , Antifungal Agents/therapeutic use , Fluconazole , Humans , Meningitis, Cryptococcal/drug therapy , Meningoencephalitis/drug therapy
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