Bacterial Infections Of Central Nervous System Research Articles

Meningitis a Listeria monocytogenes in a young, immunocompetent male

Listeria Monocytogenes (LM) is a gram-positive intracellular pathogen usually transmitted to humans by ingesting contaminated food. It typically infects immunocompromised individuals, such as pregnant women, newborns, alcoholics, and the elderly. LM is a rare cause of meningitis in immunocompetent, healthy adults. However, its clinical presentation is similar to that of other viral or bacterial central nervous system infections and its course can be rapid and aggressive. Physicians should therefore always consider LM as a possible etiologic agent of meningitis, especially in cases that do not respond to first-line empiric antibiotic therapy. We report a case of Listeria Monocytogenes meningitis in a previously healthy 16-year-old.

Epidemiology and diagnosis of viral and bacterial central nervous system infections in Sri Lanka: A Narrative review

Bacterial central nervous system (CNS) infections are life-threatening diseases with high mortality and long-term neurological sequels, while viral CNS infections are mild and self-limited. In Sri Lanka, 1000-1500 and 150-250 patients with meningitis and encephalitis respectively are reported annually to the Epidemiology Unit. Haemophilus influenzae, Group B Streptococcus, Streptococcus pneumoniae, Escherichia coli, Mycobacterium tuberculosis, Neisseria meningitidis, Group D Streptococcus, Leptospira borgpetersenii serovar Tarasssovi, Listeria monocytogenes, Streptococcus bovis biotype 2, enterovirus, Herpes Simplex Virus type 1 and type 2, Varicella zoster virus and cytomegalovirus have been reported up to 2022 in patients with meningitis while dengue virus, Japanese encephalitis virus, Varicella zoster virus, West Nile virus, Human Bocavirus Type 1, 2 and 3, human adenovirus type 41, Echovirus type 9 and 25, Herpes Simplex Virus type 1 and Mycoplasma pneumoniae have been reported in patients with encephalitis and meningoencephalitis. However less than 10% of cases have a definitive aetiological diagnosis with conventional bacterial culture methods routinely used to diagnose bacterial CNS infections, while molecular assays are used only for selected common viral pathogens in government hospitals in Sri Lanka. Use of antibiotics prior to cerebrospinal fluid collection, delay in sample collection, and low volume of samples have been identified as factors for low sensitivity of test results. Scientists, microbiologists and virologists are responsible for developing new test methods to identify current and previously unidentified causative microorganisms to extend the spectrum of neurotropic organisms in Sri Lanka to enhance the aetiological diagnosis.

Viral, Bacterial, Metabolic, and Autoimmune Causes of Severe Acute Encephalopathy in Sub-Saharan Africa: A Multicenter Cohort Study

To assess whether viral, bacterial, metabolic, and autoimmune diseases are missed by conventional diagnostics among children with severe acute encephalopathy in sub-Saharan Africa. One hundred thirty-four children (6 months to 18years) presenting with nontraumatic coma or convulsive status epilepticus to 1 of 4 medical referral centers in Uganda, Malawi, and Rwanda were enrolled between 2015 and 2016. Locally available diagnostic tests could be supplemented in 117 patients by viral, bacterial, and 16s quantitative polymerase chain reaction testing, metagenomics, untargeted metabolomics, and autoimmune immunohistochemistry screening. Fourteen (12%) cases of viral encephalopathies, 8 (7%) cases of bacterial central nervous system (CNS) infections, and 4 (4%) cases of inherited metabolic disorders (IMDs) were newly identified by additional diagnostic testing as the most likely cause of encephalopathy. No confirmed cases of autoimmune encephalitis were found. Patients for whom additional diagnostic testing aided causal evaluation (aOR 3.59, 90% CI 1.57-8.36), patients with a viral CNS infection (aOR 7.91, 90% CI 2.49-30.07), and patients with an IMD (aOR 9.10, 90% CI 1.37-110.45) were at increased risk for poor outcome of disease. Viral and bacterial CNS infections and IMDs are prevalent causes of severe acute encephalopathy in children in Uganda, Malawi, and Rwanda that are missed by conventional diagnostics and are associated with poor outcome of disease. Improved diagnostic capacity may increase diagnostic yield and might improve outcome of disease.

Diagnosis of Neurological Infections in Pediatric Patients from Cell-Free DNA Specimens by Using Metagenomic Next-Generation Sequencing.

Central nervous system (CNS) infections can cause significant morbidity and mortality, especially in children. Rapid and accurate pathogenic detection in suspected CNS infections is essential for disease control at the early stage of infection. To evaluate the performance of metagenomic next-generation sequencing (mNGS) of cell-free DNA (cfDNA) in cerebrospinal fluid (CSF) in pediatric patients, we retrospectively analyzed the efficiency of cfDNA mNGS in children with CNS infections (n = 257) or noninfectious neurological disorders (n = 81). The CSF samples of 124 random subjects were used to evaluate the accuracy between mNGS of cfDNA and whole-cell DNA (wcDNA). In total, cfDNA mNGS detected a wide range of microbes with a detection rate of 71.0%, and the sensitivity and total coincidence rate with clinical diagnosis reached 68.9% and 67.5%, respectively. Compared with wcDNA mNGS, cfDNA mNGS had a higher efficacy in detecting viruses (66 versus 13) and Mycobacterium (7 versus 1), with significantly higher reads per million. The dominant causative pathogens were bacteria and viruses in CNS infections, but these presented with different pathogen spectra in different age categories. The best timing for the mNGS test ranged from 1 to 6 days after the start of anti-infection therapy, and the earlier mNGS started, the better was identification of bacterial CNS infections. This study emphasized that cfDNA mNGS had overall superiority to conventional methods on causative pathogen detection in pediatric CNS infections, and it was even better than wcDNA mNGS. Furthermore, research needs to be better validated in large-scale clinical trials to improve the clinical applications of cfDNA mNGS. IMPORTANCE Our study emphasized that cfDNA mNGS had overall superiority to conventional methods on causative pathogen detection in CNS-infected children, and it was even better than wcDNA mNGS. cfDNA mNGS detected a wide range of pathogens with a high total coincidence rate (67.5%) against clinical diagnosis. The best timing for cfDNA mNGS detection ranged from 1 to 6 days, rather than 0 days, after the start of empirical anti-infection therapy. The earlier mNGS started, the better the identifications of bacterial CNS infections. To the best of our knowledge, this research is the first report evaluating the clinical utility of mNGS with different methods (cfDNA versus wcDNA) of extracting DNA from CSF specimens in diagnosing pediatric CNS infections. Meanwhile, this is the largest cohort study that has evaluated the performance of mNGS using cfDNA from CSF specimens in pediatric patients with CNS infections.

The Blood-Brain Barrier and Pharmacokinetic/Pharmacodynamic Optimization of Antibiotics for the Treatment of Central Nervous System Infections in Adults.

Bacterial central nervous system (CNS) infections are serious and carry significant morbidity and mortality. They encompass many syndromes, the most common being meningitis, which may occur spontaneously or as a consequence of neurosurgical procedures. Many classes of antimicrobials are in clinical use for therapy of CNS infections, some with established roles and indications, others with experimental reporting based on case studies or small series. This review delves into the specifics of the commonly utilized antibacterial agents, updating their therapeutic use in CNS infections from the pharmacokinetic and pharmacodynamic perspectives, with a focus on the optimization of dosing and route of administration that have been described to achieve good clinical outcomes. We also provide a concise synopsis regarding the most focused, clinically relevant information as pertains to each class and subclass of antimicrobial therapeutics. CNS infection morbidity and mortality remain high, and aggressive management is critical in ensuring favorable patient outcomes while averting toxicity and upholding patient safety.

3D blood-brain barrier-organoids as a model for Lyme neuroborreliosis highlighting genospecies dependent organotropism

Lyme neuroborreliosis (LNB), a tick-borne infection caused by spirochetes within the Borrelia burgdorferi sensu lato (s.L.) complex, is among the most prevalent bacterial central nervous system (CNS) infections in Europe and the US. Here we have screened a panel of low-passage B. burgdorferi s.l. isolates using a novel, human-derived 3D blood-brain barrier (BBB)-organoid model. We show that human-derived BBB-organoids support the entry of Borrelia spirochetes, leading to swelling of the organoids and a loss of their structural integrity. The use of the BBB-organoid model highlights the organotropism between B. burgdorferi s.l.genospecies and their ability to cross the BBB contributing to CNS infection.

Aetiologies and clinical presentation of central nervous system infections in Vietnamese patients: a prospective study

Knowledge of the clinical presentation of central nervous system (CNS) infections and the causative pathogens is crucial for appropriate diagnosis and rapid initiation of appropriate treatment to prevent severe neurological sequelae. The aim of this study is to understand the aetiology of CNS infections based on the clinical presentation of Vietnamese patients. A prospective hospital-based cohort study was conducted between May 2014 and May 2017. We screened 137 patients with clinically suspected CNS infection for fungal, bacterial and viral pathogens using their cerebrospinal fluid (CSF) and blood cultures. In addition, DNA or RNA extracted from CSF samples were subjected to nucleic acid testing (NAT) with a selective panel of bacterial, viral and fungal pathogens. At least one pathogen could be detected in 41% (n = 56) of the patients. The main pathogens causing CNS infections were Streptococcus suis (n = 16; 12%) and Neisseria meningitidis (n = 9; 7%), followed by Herpes simplex virus 1/2 (n = 4; 3%) and Klebsiella pneumoniae (n = 4; 3%). Other pathogens were only identified in a few cases. Patients with bacterial CNS infections were significantly older, had a worse outcome, a lower Glasgow Coma Scale (GCS), a higher rate of speech impairment and neck stiffness than patients with viral or tuberculous CNS infections. In northern Vietnam, adults are mostly affected by bacterial CNS infections, which have a severe clinical course and worse outcomes compared to viral or tuberculous CNS infections. Clinicians should be aware of the regional occurrence of pathogens to initiate rapid and appropriate diagnosis and treatment.

Discriminating between Lyme neuroborreliosis and other central nervous system infections by use of biomarkers CXCL13 and IL-6

CXCL13 in cerebrospinal fluid has gradually become an established biomarker for Lyme neuroborreliosis (LNB), however the diagnostic performance of CXCL13 may be improved by the addition of IL-6, a non-specific infection biomarker. The aim of this study was to measure the concentrations of CXCL13 and IL-6 in cerebrospinal fluid, in the attempt to evaluate the diagnostic performance of these two biomarkers, in the differentiation between definite and possible LNB, as well as between LNB and other neuroinfections. This study used a cross-sectional design to quantify the levels of CXCL13 and IL-6 in cerebrospinal fluid (CSF) specimens from consecutive patients examined for central nervous system (CNS) infections at Lillebaelt Hospital in the Region of Southern Denmark. CXCL13 and IL-6 were measured simultaneously using the Bio-Plex 200 multiplex Cytokine Immunoassay System (Bio-Rad). Based on clinical and paraclinical findings, we grouped patients into six separate groups: definite LNB, possible LNB, Viral CNS infection, non-Borrelia Bacterial CNS infection, Other CNS disease (with pleocytosis) and Negative (without pleocytosis). A combined interpretation of four variables (leukocyte cell counts, protein concentration, CXCL13 and IL-6 concentrations in CSF) is presented using principal component cluster analysis. We included by chart review 390 patients discharged with definite LNB (n = 31), possible LNB (n = 10), confirmed Viral or non-Borrelia Bacterial CNS infection (n = 34), Other CNS disease (n = 58), and Negative (n = 257) for CXCL13 and IL-6 analysis. Principal component analysis (PCA) revealed three distinct clusters based on leukocyte cell counts, protein concentration, CXCL13 and IL-6 concentrations in CSF from 380 included patients (10 possible LNB patients excluded). The clusters clearly differentiate the groups: definite LNB, non-Borrelia Bacterial CNS infection and Negative (without pleocytosis). A receiver operating characteristic (ROC) curve comparing LNB patients (n = 31) and all non-LNB conditions with CSF pleocytosis (n = 99) indicated an optimal CXCL13 cut-off value of 50.7 pg/mL, resulting in a sensitivity and a specificity of 93.6 and 91.1%, respectively. The ROC analysis comparing patients with confirmed non-LNB CNS infection (n = 34) and all others with CSF pleocytosis (n = 97) resulted in an optimal IL-6 cut-off value of 111.5 pg/mL, yielding a sensitivity and a specificity of 78.8% and 82.5% respectively. Of the ten possible LNB patients, three cases (with CXCL13 levels above cut-off) fall within the LNB cluster, and one case is just outside, providing some laboratory support for the diagnosis of LNB. The remaining six possible LNB patients (with CXCL13 levels below the 50.7 cut-off) had little support for the diagnosis of LNB in the PCA-plot. The results of this study confirm that CXCL13 is a valuable supplement for diagnosis of LNB, and that the combination of CXCL13 and IL-6 may be used to differentiate cases of LNB from other CNS infections. Furthermore, IL-6 can be of differential diagnostic value when evaluating patients with possible LNB.

Intrathecal/Intraventricular Colistin for Antibiotic-Resistant Bacterial CNS Infections in Pediatric Population: A Systematic Review.

Central nervous system (CNS) infections constitute a life-threatening condition, especially in children. Treatment limitations exist for drug-resistant CNS bacterial infections. Inadequate CNS penetration and intravenous (IV) antibiotic treatment failure represent a major clinical challenge. However, patients with antibiotic-resistant bacterial CNS infections may benefit from intrathecal (IT) or intraventricular (IVT) colistin. The authors aimed to assess the safety and effectiveness of IT/IVT colistin therapy in the pediatric population, with or without other antibiotics, for the treatment of antibiotic-resistant CNS infections. A comprehensive literature search was conducted using the electronic databases of PubMed, Ovid, and Embase for relevant articles using the following terms: “Colistin”, “CNS infection”, and “Outcome”, as well as their combinations. The retrieved articles were filtered by age (Child), language (English), route of administration (IT/IVT), and species (Humans). The present systematic review comprised 20 articles that included 31 children (19; 61.2% were boys) with multidrug-resistant CNS infection. Their ages ranged from less than one month to 18 years (median: 9 months). Acinetobacter baumannii was the main causative organism in 22 patients (70.9%), and infection occurred mainly after neurosurgical interventions (83.8%). An external ventricular drain was inserted to administer colistin into the ventricular system in 29 cases (93.5%). The median duration for colistin therapy was 18 days. Twenty-three patients (74%) recovered, while five patients (16%) had residual disability, and three patients (10%) died. The authors concluded that IT/IVT colistin therapy is safe and effective as either the primary or adjunct treatment for antibiotic-resistant cases with CNS infection.

Efficacy and safety of mesenchymal stem cells treatment for multidrug-resistant graft-versus-host disease after haploidentical allogeneic hematopoietic stem cell transplantation.

Purpose:Graft-versus-host disease (GVHD) is an important complication after human leukocyte antigen (HLA) haploidentical donor (HID) hematopoietic stem cell transplantation (HSCT), which may lead to poor prognosis. Our study intends to identify the efficacy and safety of mesenchymal stem cells (MSCs) for multidrug-resistant (MDR)-GVHD after HID HSCT.Methods:MDR-GVHD was referring to GVHD remaining no response to at least two types of therapy, and hUCB-MSCs were given at the dose of (1.0–2.0) × 106/kg once a week.Results:A total of 21 patients were enrolled in this retrospective study (acute GVHD (aGVHD): n = 14, chronic GVHD (cGVHD): n = 7). The median dose of MSCs was 1.2 × 106 cells/kg (range, 0.8–1.8 × 106) cells/kg, and the median numbers of infusion were 2 (range, 1–7) and 3 (range, 2–12) for MDR-aGVHD and MDR-cGVHD patients, respectively. In MDR-aGVHD patients, the overall response rate (ORR) was 57.1%, including 50.0% complete response (CR) and 7.1% partial response (PR), and the median time to response was 49.5 days (range, 16–118) days. The 2-year probability of overall survival after MSCs was 64.3%. Five patients (35.7%) developed infections after MSCs, and no obvious hematologic toxicities were observed. Five MDR-aGVHD patients died after MSCs treatments because of GVHD progression (n = 1), severe infection (bacterial central nervous system infection: n = 1; fungal pneumonia: n = 2), and poor graft function (n = 1). In MDR-cGVHD patients, three patients (42.9%) achieved PR after MSCs and the median time to response was 56 days (22–84) days. The ORRs for moderate and severe cGVHD were 50.0% and 33.3%, respectively. Four MDR-cGVHD patients died after MSCs treatments because of GVHD progression (n = 2), severe fungal pneumonia (n = 1), and relapse (n = 1).Conclusion:MSCs treatment may be safe and effective for MDR-GVHD after HID HSCT.

Dose optimisation of antibiotics used for meningitis.

Central nervous system (CNS) infections such as ventriculitis and meningitis are associated with significant morbidity and mortality. In part, this may be due to increased difficulties in achieving a therapeutic antibiotic concentration at the site of infection due to both the pharmacokinetic (PK) changes observed during critical illness and the reduced antibiotic penetration through the blood brain barrier. This paper reviews the pharmacodynamics (PD) and CNS PKs of antibiotics used for Gram-negative bacterial CNS infections to provide clinicians with practical dosing advice. Recent PK studies have shown that currently used intravenous antibiotic dosing regimens may not achieve a therapeutic exposure within the CNS, even for reportedly 'susceptible' bacteria per the current clinical meningitis breakpoints. Limited data exist for new β-lactam antibiotic/β-lactamase inhibitor combinations, which may be required for multidrug resistant infections. Intraventricular antibiotic administration, although not a new concept, has further evidence demonstrating improved patient outcomes compared with intravenous therapy alone, despite the ongoing paucity of PK studies guiding dosing recommendations. Clinicians should obtain the bacterial minimum inhibitory concentration when treating patients with CNS Gram-negative bacterial infections and consider the underlying PK/PD principles when prescribing antibiotics. Therapeutic drug monitoring, where available, should be considered to guide dosing. Intraventricular therapy should also be considered for patients with ventricular drains to optimise clinical outcomes.

MR vessel wall imaging in cerebral bacterial and fungal infections.

PurposeCentral nervous system (CNS) bacterial and fungal infections can cause secondary vasculitis which worsens the prognosis due to development of complications like infarctions or hemorrhages. In this prospective study, we aim to study intracranial vessel wall imaging findings in bacterial and fungal infections.MethodsWe included 12 cases of nontubercular bacterial and fungal CNS infections each, in whom definitive microbiological diagnosis could be made. High-resolution vessel wall imaging (VWI) and time of flight MR angiography (TOF MRA) were incorporated in the routine imaging protocol. All cases were evaluated for the presence of vascular enhancement, pattern of enhancement, and stenosis on VWI. Statistical analysis was done to evaluate association between findings of vessel wall imaging and infarctions.ResultsWe found infarctions in 5 out of 12 cases (41.7%) of the bacterial group and 7 out of 12 cases (58.3%) of the fungal group. Vessel wall enhancement was seen in 5 cases (41.7%) of the bacterial group and 9 cases (75%) of the fungal group. There was a significant association between infarctions and vessel wall enhancement in the fungal group. However, pattern of enhancement or stenosis on VWI was not significantly associated with presence of infarction. VWI detected more cases of vascular involvement than TOF MRA.ConclusionSecondary infectious vasculitis in bacterial and fungal infections can be detected by VWI, which can play an important role in better patient management as detection of vascular involvement can prompt early treatment to prevent complications like infarctions or hemorrhages.

Clinical utility of cerebrospinal fluid vitamin D-binding protein as a novel biomarker for the diagnosis of viral and bacterial CNS infections

BackgroundRapid and accurate diagnosis of central nervous system (CNS) infections is important, and laboratory tests help diagnose CNS infections. Even when the patient has symptoms, laboratory tests often do not reveal any specific findings. The potential of vitamin D-binding protein (VDBP) to be used as a biomarker for viral and bacterial CNS infections was studied.MethodsA total of 302 subjects with suspected CNS infection who underwent lumbar puncture were included. Clinical and laboratory data were collected retrospectively. VDBP levels were measured in the cerebrospinal fluid (CSF) samples. Genotyping for the GC gene encoding VDBP was also performed. VDBP levels were analyzed and compared by CNS infection, pathogen, CSF opening pressure, and GC genotype.ResultsA CNS infection group (n = 90) and a non-CNS infection group (n = 212) were studied. In terms of its receiver operating characteristic, CSF VDBP showed an area under the curve of 0.726 for the diagnosis of CNS infection. CSF VDBP levels were significantly different between the CNS infection and non-infection groups. The CNS infection group with enterovirus showed a statistically lower distribution of CSF VDBP levels than the other virus groups. The group with CSF opening pressure > 25 cmH2O showed higher CSF VDBP levels than the other groups. There was no significant difference in GC gene allele distribution between the CNS infection and non-infection groups.ConclusionsCSF VDBP levels were increased in patients with CNS infection. The CSF VDBP showed potential as a new biomarker for viral and bacterial CNS infections.

Bibliometric analysis of bacterial central nervous system infection research in Southeast Asia

BackgroundThe status of research and scientific outputs with regards to bacterial central nervous system (CNS) infection in southeast Asia (SEA) is unknown. This study aimed to analyze and compare bacterial CNS infection research output of SEA countries in terms of bibliometric indices.MethodsThe major electronic databases (MEDLINE, Scopus, Embase, CENTRAL, Clinicaltrials.gov and WPRIM) were searched for studies on bacterial CNS infection in SEA until August 31, 2020. Frequencies, percentages and Spearman’s rho correlations were used.ResultsThere was a total of 648 unique studies on bacterial CNS infection in SEA and it was 657 when double-counted (collaborative studies between SEA countries). Thailand (n=148, 22.5%) and Vietnam (n=142, 21.6%) had the highest number of publications. The most common type of research publication was the case report / case series (n=160, 24.7%). Tuberculous meningitis/tuberculoma (n=176, 26.7%) was the most common topic. This study showed that the %GDP for research and development (R&D) was associated with a higher number of research output. However, the GDP per capita was not associated with any of the bibliometric indices. The total number of neurologists was associated with all of the bibliometric analysis.ConclusionBacterial CNS infection research output in SEA countries was low in terms of quantity. The %GDP for R&D was associated with the number of research publications. The total number of neurologists was associated with all of the bibliometric indices.

Cerebral phaeohyphomycosis due to Cladophialophora bantiana in an immunocompetent individual: A case report and brief review of literature

Background and Purpose: Fungal infections of the central nervous system (CNS) are life-threatening conditions that are frequently misdiagnosed with bacterial and viral CNS infections. Cerebral phaeohyphomycosis is a cerebral infection caused by dematiaceous fungi, especially Cladophialophora bantiana. Very few cases of fungal CNS infection have been reported across the world. High clinical suspicion should be cast for the patients with brain abscess that do not respond to conventional antibiotic therapy.Case report: We report a case of a 21-year-old male presenting with headache, seizures and weakness in the limbs. Radiological examination revealed multiple brain abscesses. After surgical excision and laboratory evaluation, it was found to be caused by C. bantiana. The patient’s outcome was good with surgical excision and voriconazole therapy.Conclusion: Brain abscess caused by C. bantiana is on rise, especially in immunocompromised groups. Thus, high clinical suspicion, accurate diagnosis and management are the fundamentals for good prognosis.

Brain Exposure to Piperacillin in Acute Hemorrhagic Stroke Patients Assessed by Cerebral Microdialysis and Population Pharmacokinetics

BackgroundThe broad antibacterial spectrum of piperacillin/tazobactam makes the combination suitable for the treatment of nosocomial bacterial central nervous system (CNS) infections. As limited data are available regarding piperacillin CNS exposure in patients without or with low-grade inflammation, a clinical study was conducted (1) to quantify CNS exposure of piperacillin by cerebral microdialysis and (2) to evaluate different dosing regimens in order to improve probability of target attainment (PTA) in brain.MethodsTen acute hemorrhagic stroke patients (subarachnoid hemorrhage, n = 6; intracerebral hemorrhage, n = 4) undergoing multimodality neuromonitoring received 4 g piperacillin/0.5 g tazobactam every 8 h by 30-min infusions for the management of healthcare-associated pneumonia. Cerebral microdialysis was performed as part of the clinical neuromonitoring routine, and brain interstitial fluid samples were retrospectively analyzed for piperacillin concentrations after the first and after multiple doses for at least 5 days and quantified by high-performance liquid chromatography. Population pharmacokinetic modeling and Monte Carlo simulations with various doses and types of infusions were performed to predict exposure. A T>MIC of 50% was selected as pharmacokinetic/pharmacodynamic target parameter.ResultsMedian peak concentrations of unbound piperacillin in brain interstitial space fluid were 1.16 (range 0.08–3.59) and 2.78 (range 0.47–7.53) mg/L after the first dose and multiple doses, respectively. A one-compartment model with a transit compartment and a lag time (for the first dose) between systemic and brain exposure was appropriate to describe the brain concentrations. Bootstrap median estimates of the parameters were: transfer rate from plasma to brain (0.32 h−1), transfer rate from brain to plasma (7.31 h−1), and lag time [2.70 h (coefficient of variation 19.7%)]. The simulations suggested that PTA would exceed 90% for minimum inhibitory concentrations (MICs) up to 0.5 mg/L and 1 mg/L at a dose of 12–16 and 24 g/day, respectively, regardless of type of infusion. For higher MICs, PTA dropped significantly.ConclusionLimited CNS exposure of piperacillin might be an obstacle in treating patients without general meningeal inflammation except for infections with highly susceptible pathogens. Brain exposure of piperacillin did not improve significantly with a prolongation of infusions.

Determination of pentraxin 3 levels in cerebrospinal fluid during central nervous system infections.

Pentraxin 3 (PTX3) is an acute phase protein; its plasmatic levels significantly rise during severe infections. Data on PTX3 levels in cerebrospinal fluid (CSF) of patients with central nervous system (CNS) infections are lacking. We aimed (a) to assess the diagnostic potential of measuring CSF PTX3 levels in patients with CNS infections and (b) to establish CSF PTX3 cutoffs to distinguish between bacterial and aseptic meningoencephalitis (ROC curve). PTX3 levels were measured in CSF from 19 patients admitted to Trieste Hospital, Italy, with CNS infection. A diagnosis of bacterial infection and aseptic meningoencephalitis was made in 7 (37%) and 12 (63%) patients, respectively. Subjects with bacterial infections showed significantly higher PTX3 levels (13.5 vs 1.27ng/mL in aseptic meningoencephalitis, p = 0.010). We identified two different CSF PTX3 levels cutoffs. (1) The best cutoff to maximise Youden's J was 9.6ng/mL with a sensitivity, specificity, positive predictive value and negative predictive value (NPV) of 71.4%, 91.4%, 83.3%, 84.6%, respectively. (2) The cutoff with higher NPV (100%) was 3.6ng/mL; a diagnosis of bacterial infections was obtained in 0% patients with CSF PTX3 levels < 3.6ng/mL vs 58% of those with CSF PTX3 levels ≥ 3.6ng/mL (p = 0.017). CSF PTX3 levels are higher in bacterial meningitis than aseptic meningoencephalitis. A cutoff of 3.6ng/mL of CSF PTX3 has a high NPV and can be used to exclude bacterial CNS infections.

Management of Central Nervous System Infections, Vientiane, Laos, 2003-2011.

During 2003–2011, we recruited 1,065 patients of all ages admitted to Mahosot Hospital (Vientiane, Laos) with suspected central nervous system (CNS) infection. Etiologies were laboratory confirmed for 42.3% of patients, who mostly had infections with emerging pathogens: viruses in 16.2% (mainly Japanese encephalitis virus [8.8%]); bacteria in 16.4% (including Orientia tsutsugamushi [2.9%], Leptospira spp. [2.3%], and Rickettsia spp. [2.3%]); and Cryptococcus spp. fungi in 6.6%. We observed no significant differences in distribution of clinical encephalitis and meningitis by bacterial or viral etiology. However, patients with bacterial CNS infection were more likely to have a history of diabetes than others. Death (26.3%) was associated with low Glasgow Coma Scale score, and the mortality rate was higher for patients with bacterial than viral infections. No clinical or laboratory variables could guide antibiotic selection. We conclude that high-dependency units and first-line treatment with ceftriaxone and doxycycline for suspected CNS infections could improve patient survival in Laos.

Kynurenine Is a Cerebrospinal Fluid Biomarker for Bacterial and Viral Central Nervous System Infections.

The tryptophan-kynurenine-nicotinamide adenine dinucleotide (oxidized; NAD+) pathway is closely associated with regulation of immune cells toward less inflammatory phenotypes and may exert neuroprotective effects. Investigating its regulation in central nervous system (CNS) infections would improve our understanding of pathophysiology and end-organ damage, and, furthermore, open doors to its evaluation as a source of diagnostic and/or prognostic biomarkers. We measured concentrations of kynurenine (Kyn) and tryptophan (Trp) in 221 cerebrospinal fluid samples from patients with bacterial and viral (due to herpes simplex, varicella zoster, and enteroviruses) meningitis/encephalitis, neuroborreliosis, autoimmune neuroinflammation (due to anti-N-methyl-D-aspartate receptor [NMDA] encephalitis and multiple sclerosis), and noninflamed controls (ie, individuals with Bell palsy, normal pressure hydrocephalus, or Tourette syndrome). Kyn concentrations correlated strongly with CSF markers of neuroinflammation (ie, leukocyte count, lactate concentration, and blood-CSF-barrier dysfunction), were highly increased in bacterial and viral CNS infections, but were low or undetectable in NMDA encephalitis, multiple sclerosis, and controls. Trp concentrations were decreased mostly in viral CNS infections and neuroborreliosis. Multiple logistic regression analysis revealed that combinations of Kyn concentration, Trp concentration, and Kyn/Trp concentration ratio with leukocyte count or lactate concentration were accurate classifiers for the clinically important differentiation between neuroborreliosis, viral CNS infections, and autoimmune neuroinflammation. The Trp-Kyn-NAD+ pathway is activated in CNS infections and provides highly accurate CSF biomarkers, particularly when combined with standard CSF indices of neuroinflammation.

Age does not influence the disease course in a mouse model of Streptococcus pneumoniae serotype 3 meningitis

In order to elucidate the causes for the increased mortality of aged patients with bacterial central nervous system (CNS) infections, we compared the course of Streptococcus pneumoniae (S. pneumoniae) meningitis in aged and young mice. Aged (21.2 ± 3.1 months, n = 40) and young (3.2 ± 0.9 months, n = 42) C57BL/6N and B6/SJL mice were infected by intracerebral injection of 50–70 CFU S. pneumoniae serotype 3 and monitored for 15 days. Aged and young mice did not differ concerning mortality (35% versus 38%), weight loss, development of clinical symptoms, bacterial concentrations in cerebellum and spleen as well as the number of leukocytes infiltrating the CNS. In contrast to results from our geriatric mouse model of Escherichia coli (E. coli) meningitis, where aged mice showed a higher mortality and an impaired elimination of bacteria, we did not find any differences between aged and young mice after intracerebral infection with S. pneumoniae serotype 3. This indicates that the increased susceptibility of aged mice to bacterial CNS infections is pathogen-specific: It appears less prominent in infections caused by hardly phagocytable pathogens with thick capsules like S. pneumoniae serotype 3, where the age-related decline of the phagocytic capacity of microglia and macrophages has a minor influence on the disease course.