Pediatric Central Nervous System Infections Research Articles

Ceftaroline Fosamil as a Potential Treatment for Central Nervous System Infections in Children

Abstract Ceftaroline has been reported to show efficacy in limited adult clinical case studies including a report of a patient with a methicillin-resistant Staphylococcus aureus (MRSA) infection of a ventriculopleural shunt, and in 2 reports for use as a salvage therapy in a case of an epidural abscess infected with MRSA, as well as a case of methicillin-resistant Staphylococcus epidermidis (MRSE) ventriculostomy-related infection. The pharmacokinetic (PK) and pharmacodynamic (PD) properties of ceftaroline in healthy adults and neurosurgical patients have been assessed to develop population PK models used to perform simulations to evaluate the probability of target attainment of different ceftaroline dosing regimens for central nervous system (CNS) infections. Results from the simulations indicated that the penetration of ceftaroline into the cerebrospinal fluid was dependent on the degree of meningeal inflammation, suggesting that inflammation associated with infection would provide adequate antibiotic exposure, similar to other β-lactam antibiotics. Ceftaroline has a potential, unique role as a β-lactam antibiotic in the treatment of MRSA and coagulase negative staphylococci causing CNS infections as an alternative to vancomycin, the current standard of care. Support for treatment of CNS infections may be derived from further cerebrospinal fluid PK studies followed by PK/PD modeling prior to the conduct of prospective phase 2/3 clinical studies aimed at assessing the efficacy and safety of ceftaroline for the treatment of pediatric CNS infections. Ceftaroline's penetration enhanced by meningeal inflammation suggests that the drug could be a candidate to treat MRSA CNS infections.

Pediatric central nervous system infections in the Amazon: clinical and laboratory profiles.

Central nervous system (CNS) infections are important causes of mortality and morbidity in children, and they are related to severe problems such as hearing loss, neurological sequelae, and death. The objective was to describe clinical and laboratory exam profiles of children who were diagnosed with CNS infections. We conducted a cross-sectional study based on medical records, which included pediatric patients aged from 3 months to 15 years, with a clinical suspicion of CNS infection between January 2014 to December 2019. The pathogens were confirmed in cerebrospinal fluid (CSF) samples using Gram staining, cell culture, molecular diagnostics (PCR and qPCR), and serology. Out of the 689 enrolled patients, 108 (15.6%) had laboratory-confirmed infections in CSF. The most common bacterial pathogens isolated from the culture were Neisseria meningitidis serogroup C in 19, Streptococcus pneumoniae in 11, and Haemophilus influenzae in seven samples. The viruses identified were Enterovirus, Cytomegalovirus, Varicella-zoster virus, Epstein-Barr virus, and arbovirus. No patient was found to be positive for Herpes simplex virus 1 and 2. Patients with viral infections showed altered levels of consciousness (p = 0.001) when compared to bacterial infections. This study shows the presence of important vaccine-preventable pathogens, and different families of viruses causing CNS infections in the pediatric patients of Manaus.

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.

Emergence of Parechovirus A3 as the Leading Cause of Central Nervous System Infection, Surpassing Any Single Enterovirus Type, in Children in Kansas City, Missouri, USA, from 2007 to 2016

Picornaviruses including Enterovirus species A-D (EV) and Parechovirus species A (PeV-A) are the leading reported causes of pediatric central nervous system infections in the United States. We investigated the molecular epidemiology of EV and PeV-A over 10 years, in cerebrospinal fluid (CSF) collected from children seen at Children's Mercy -Kansas City (CMKC) during 2007 through 2016. The overall prevalence for EV was 16% (862/5362) and 7% (271/4016) for PeV. Among all picornavirus CSF detections EV was 76% and PeV-A was 24%. Multiple EV types co-circulated each year with a total of 31 EV types detected in the 10-year period; majority belonged to EV-B species (96%). Two PeV-A types were detected; PeV-A3 was the dominant PeV-A type (95%). Top five picornaviruses (PeV-A3, 26%; E30, 11%; E6 10%; E18 9%, E9 7%) in the CSF of infants accounted for two-third of all detections and PeV-A3 was the leading picornavirus detected. Routine testing and reporting of PeV-A in addition to EV, especially in children under 6 months old with acute febrile illnesses, could reduce hospital stays and antibiotic usage.

Molecular Epidemiology of Enterovirus in Children with Central Nervous System Infections.

Limited recent molecular epidemiology data are available for pediatric Central Nervous System (CNS) infections in Europe. The aim of this study was to investigate the molecular epidemiology of enterovirus (EV) involved in CNS infections in children. Cerebrospinal fluid (CSF) from children (0–16 years) with suspected meningitis–encephalitis (ME) who were hospitalized in the largest pediatric hospital of Greece from October 2017 to September 2020 was initially tested for 14 common pathogens using the multiplex PCR FilmArray® ME Panel (FA-ME). CSF samples positive for EV, as well as pharyngeal swabs and stools of the same children, were further genotyped employing Sanger sequencing. Of the 330 children tested with FA-ME, 75 (22.7%) were positive for EV and 50 different CSF samples were available for genotyping. The median age of children with EV CNS infection was 2 months (IQR: 1–60) and 44/75 (58.7%) of them were male. There was a seasonal distribution of EV CNS infections, with most cases detected between June and September (38/75, 50.7%). EV genotyping was successfully processed in 84/104 samples: CSF (n = 45/50), pharyngeal swabs (n = 15/29) and stools (n = 24/25). Predominant EV genotypes were CV-B5 (16/45, 35.6%), E30 (10/45, 22.2%), E16 (6/45, 13.3%) and E11 (5/45, 11.1%). However, significant phylogenetic differences from previous described isolates were detected. No unusual neurologic manifestations were observed, and all children recovered without obvious acute sequelae. Specific EV circulating genotypes are causing a significant number of pediatric CNS infections. Phylogenetic analysis of these predominant genotypes found genetic differences from already described EV isolates.

342. Clinical Utility of a Next Generation Sequencing Test for Pathogen Detection in Pediatric Central Nervous System Infections

BackgroundPediatric central nervous system (CNS) infections are potentially life-threatening and may incur significant morbidity. Identifying a pathogen is important, both in terms of guiding therapeutic management, but also in characterizing prognosis. However, standard care testing by culture, serology, and PCR is often unable to identify a pathogen. We examined use of next generation sequencing (NGS) of cerebrospinal fluid (CSF) in detecting an organism in children with CNS infections.MethodsWe prospectively enrolled children with CSF pleocytosis and suspected CNS infection admitted to 3 tertiary pediatric hospitals. After standard care testing had been performed, the remaining CSF was submitted for analysis by NGS.ResultsWe enrolled 70 subjects over a 12-month recruitment period. A putative organism was isolated from CSF in 24 (34.3%) subjects by any diagnostic modality. NGS of the CSF samples identified a pathogen in 20 (28.6%) subjects. False positive results by NGS were identified in 2 patients. There were no cases in which NGS alone identified a pathogen. In 4 cases, a putative organism was recovered by standard care testing of the CSF, but not by CSF NGS. CSF culture recovered a putative organism in 12 cases (12.1%). A CSF PCR multiplex panel was utilized for 51 subjects. An organism was detected in 15 of these (29.4%). Using a reference composite of standard care testing, we determined the sensitivity and specificity of CSF NGS to be 83.3% (95% CI, 62.6–95.3%) and 91.3% (95% CI, 79.2–97.6%) respectively.ConclusionSequencing of CSF has the potential to rapidly and comprehensively identify infection with a single test. Further studies are needed to determine the optimal use of NGS for diagnosis of CNS infections.Disclosures All Authors: No reported disclosures

Multi-assay investigation of viral etiology in pediatric central nervous system infections.

In an attempt to identify a wide spectrum of viral infections, cerebrospinal fluid (CSF) specimens were collected from pediatric cases with the preliminary diagnosis of viral encephalitis/meningoencephalitis in two reference hospitals, from October 2011 to December 2015. A combination of nucleic acid-based assays, including in house generic polymerase chain reaction (PCR) assays for enteroviruses, flaviviruses and phleboviruses, a commercial real-time PCR assay for herpesviruses and a commercial real time multiplex PCR, enabling detection of frequently-observed viral, bacterial and fungal agents were employed for screening. The microbial agent could be characterized in 10 (10%) of the 100 specimens. Viral etiology could be demonstrated in 7 (70%) specimens, which comprises Human Herpesvirus 6 (4/7), Herpes Simplex virus type1 (2/7) and Enteroviruses (1/7). In 3 specimens (30%), Streptococcus pneumoniae, Listeria monocytogenes and Staphylococcus aureus were detected via the multiplex PCR, which were also isolated in bacteriological media. All specimens with detectable viral nucleic acids, as well as unreactive specimens via nucleic acid testing remained negative in bacteriological cultures. Herpes and enteroviruses were identified as the primary causative agents of central nervous system infections in children. Enterovirus testing must be included in the diagnostic work-up of relevant cases.

Utility of cerebrospinal fluid analysis in pediatric central nervous system infections

Utility of cerebrospinal fluid analysis in pediatric central nervous system infections

Expressions of Brain-Derived Neurotrophic Factor (BDNF) in Cerebrospinal Fluid and Plasma of Children With Meningitis and Encephalitis/Encephalopathy

ABSTRACTMany reports in the field of childhood brain disorders have documented that brain-derived neurotrophic factor (BDNF) affects central nervous system (CNS) functions. In this clinical study, BDNF levels were evaluated in association with pediatric CNS infections. BDNF levels in the serum and cerebrospinal fluid (CSF) of 42 patients admitted during 5-year period, due to CNS infections, were measured by enzyme-linked immunosorbent assays (ELISAs). Control samples were collected from 108 patients with non-CNS infections (urinary tract infection, acute upper respiratory infection, acute gastroenteritis, etc.). Mean values of BDNF levels, at various ages, were determined and compared. BDNF levels were below the sensitivity of the ELISA in most CSF samples from the control group, but were significantly elevated in the patients with bacterial meningitis. The serum BDNF levels were elevated in all subgroups of patients with CNS infections, and the elevation was particularly notable in those with bacterial meningitis. BDNF expression in the CSF was correlated with CSF interleukin (IL)-6 levels as well as with blood platelet counts and neurological prognoses in those with bacterial meningitis. No correlation was found between BDNF levels and serum leukocyte numbers or C-reactive protein (CRP) levels. BDNF levels were found to be elevated in the serum and CSF of pediatric patients with CNS infections, particularly those with bacterial meningitis. Monitoring the changes in serum and CSF levels of BDNF may facilitate the diagnosis of acute meningitis and acute encephalopathy and allow the differential diagnosis of specific CNS infections.

Diffusion imaging in pediatric central nervous system infections.

Our purpose was to investigate the role of diffusion imaging (DI) in central nervous system (CNS) infections in pediatric patients. It was anticipated that DI would be more sensitive than conventional MRI in the detection of the infarctive complications of infection, and possibly, in the detection of the infectious process as well. Seventeen pediatric patients, eight having meningitis,, five with herpes encephalitis, three with brain abscess or cerebritis and one with sepsis, were evaluated at 1.5-T with DI. All herpes patients had positive DI at the site of herpetic involvement, and two had the addition of watershed infarctions. DI demonstrated more lesions in three of the four cases of herpetic encephalitis. Half the meningitis cases had watershed infarction where DI was better and half had vasculitic infarctions in which DI was equal to or better than conventional MRI. Diffusion imaging was more sensitive than conventional MRI alone in detection of changes due to infections and ischemic lesions, but did not differentiate between them by DI or apparent diffusion coefficient (ADC), although anatomic distribution of lesions proved useful.

Neuroimaging of postnatal pediatric central nervous system infections

Pediatric neuroimaging plays an important role in the timely diagnosis of postnatal central nervous system (CNS) infections, and in some patients the imaging findings are sufficiently specific to suggest a cause. The sequela of CNS infection, including hydrocephalus, subdural collections, ischemia/infarction, cerebral abscess, demyelination, and vascular thrombosis, can be accurately depicted and serially followed with current imaging techniques. The purpose of this review is to describe the spectrum of pediatric postnatal CNS infections, emphasizing key pathological and neuroimaging features, and to outline the strengths, weaknesses, and applications of current neuroimaging technology. The prenatal and perinatal infections falling under the designation of TORCH (toxoplasmosis, other [e.g., syphilis, HIV], rubella, cytomegalovirus, and herpes simplex II) are not covered.

Treatment of pediatric central nervous system infections

Treatment of pediatric central nervous system infections

Economic impact of diagnosis-related groups and severity of illness on reimbursement for central nervous system infections

Because the federal government's diagnosis-related group (DRG) classification system for prospective payment has not been widely applied to hospitalized pediatric patients, we analyzed the effectiveness of one DRG category (central nervous system infections) for a single year at a medium-sized children's hospital to control for patients' severity of illness and for hospital reimbursement. Several independent measures of severity of illness (length of stay, duration of fever, Physiologic Severity Index) showed that patients with bacterial meningitis and those with encephalitis (DRG 20) were more ill than those with aseptic meningitis (DRG 21) (p less than 0.001 for each measure). Cost analysis revealed that the hospital was only partially reimbursed for its charges (shortfall of $95,547) and that patients with Medicaid or no insurance accounted for 22% of discharges but 88% of losses. Reimbursement by DRG would have increased payment for DRG 21 but decreased that for DRG 20. If DRGs were applied to pediatric central nervous system infections and used in a prospective payment system, they would accurately predict disease severity between but not within groups, and significant financial losses for children's hospitals would still occur.

Cerebrospinal fluid penetration of imipenem and cilastatin (primaxin) in children with central nervous system infections.

Cerebrospinal fluid (CSF) penetration of imipenem-cilastatin was evaluated in 20 children (aged 4 months to 11 years) with central nervous system infections. A total of 10 children received a single 25-mg/kg intravenous dose, and 10 received three 25-mg/kg intravenous doses at 6-h intervals. Blood and CSF were obtained 1.5 to 2.5 h after the last dose during the early (days 1 to 3) and the late (days 7 to 10) stages of infection. Imipenem concentrations after single-dose infusion in serum and CSF during the early phase of treatment (8.59 +/- 0.95 and 1.36 +/- 0.32 micrograms/ml, respectively) were similar to those during the late phase (9.96 +/- 2.36 and 2.08 +/- 1.14 micrograms/ml, respectively). Concentrations of imipenem in serum and CSF after multiple-dose infusion during the early phase (11.97 +/- 2.03 and 1.87 +/- 0.29 micrograms/ml, respectively) were similar to those during the late phase (9.57 +/- 1.76 and 1.22 +/- 0.11 micrograms/ml, respectively). There were no significant differences in the serum or CSF imipenem concentrations between the single- and multiple-dose groups during the early or late treatment stages. Cilastatin concentrations in serum and CSF were similar in all groups with the exception of the multiple-dose, early- versus late-phase evaluation of CSF cilastatin concentration. There was no correlation between age or absolute CSF neutrophil count and the serum or CSF concentrations of imipenem or cilastatin. We found a mean CSF penetration of 15 to 27% for imipenem and 16 to 66% for cilastatin in children. These findings suggest that imipenem-cilastatin sufficiently penetrates into CSF in children to warrant further investigation of this compound in pediatric central nervous system infections.