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Streptococcus pneumoniae is a common pathogen associated with community-acquired bacterial meningitis, characterized by high morbidity and mortality rates. While vaccination reduces the incidence of meningitis, many survivors experience severe brain damage and corresponding sequelae. The pathogenesis of pneumococcal meningitis has not been fully elucidated. Currently, meningitis requires bacterial disruption of the blood - brain barrier, a process that involves the interaction of bacterial surface components with host cells and various inflammatory responses. This review delineates the global prevalence, pathogenesis, and treatment strategies of pneumococcal meningitis. The objective is to enhance the thorough comprehension of the clinical manifestations and biological mechanisms of the disease, thereby enabling more efficient prevention, diagnosis, and therapeutic interventions.

Background: Streptococcus pneumoniae (S. pneumoniae), Haemophilus influenzae (H. influenzae), and Neisseria meningitidis (N. meningitidis) are leading causes of childhood bacterial meningitis and preventable by vaccines. The aim of this hospital-based sentinel surveillance is to describe the epidemiological characteristics of pneumococcal meningitis, including disease burden, and to provide baseline data on pneumococcal serotype distribution to support decision making for pneumococcal conjugate vaccine (PCV) introduction in Vietnam., Methods: Surveillance for probable bacterial meningitis in children 1-59 months of age is conducted in three tertiary level pediatric hospitals: one in Hanoi and two in Ho Chi Minh City. Cerebrospinal fluid (CSF) specimens were collected via lumbar puncture from children with suspected meningitis. Specimens were transferred immediately to the laboratory department of the respective hospital for cytology, biochemistry, and microbiology testing, including culture. PCR testing was conducted on CSF specimens for bacterial detection (S. pneumoniae, H. influenzae, and N. meningitidis) and pneumococcal serotyping., Results: During 2015-2018, a total of 1,803 children with probable bacterial meningitis were detected; 1,780 had CSF specimens available for testing. Of 245 laboratory-confirmed positive cases, the majority were caused by S. pneumoniae (229,93.5%). Of those with S. pneumoniae detected, over 70% were caused by serotypes included in currently available PCV products; serotypes 6 A/6B (27.1%), 14 (19.7%), and 23 F (16.2%) were the most common serotypes. Children with laboratory-confirmed pneumococcal meningitis were more likely to live in Hanoi (p < 0.0001) and children 12-23 months of age were at greater odds (OR = 1.65, 95% CI: 1.11, 2.43; p = 0.006) of having confirmed pneumococcal meningitis compared to children < 12 months of age when compared to those without laboratory-confirmed bacterial meningitis. Additionally, children with confirmed pneumococcal meningitis were more likely to exhibit signs and symptoms consistent with clinical meningitis compared to negative laboratory-confirmed meningitis cases (p < 0.0001) and had a greater odds of death (OR = 6.18, 95% CI: 2.98, 12.86; p < 0.0001)., Conclusions: Pneumococcal meningitis contributes to a large burden of bacterial meningitis in Vietnamese children. A large proportion are caused by serotypes covered by PCVs currently available. Introduction of PCV into the routine immunization program could reduce the burden of pneumococcal meningitis in Viet Nam., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Streptococcus pneumoniae is a major cause of meningitis in under developed countries with low vaccination rates and high antibiotic resistance. This study aimed to analyze 83 suspected meningitis patients in Karachi for the detection of S. pneumoniae followed by its whole genome sequencing and Pan Genome analysis. Out of the 83 samples collected, 33 samples with altered physical (turbidity), cytological (white blood cell count) and biochemical (total protein and total glucose concentrations) parameters indicated potential meningitis cases, while these parameters were within normal healthy ranges in remaining 50 samples. Latex particle agglutination (LPA) was performed on the 33 samples, revealing 20 positive cases of bacterial meningitis. The PCR and culturing methods revealed 5 S. pneumoniae isolates. Antibiotic susceptibility tests showed that one S. pneumoniae strain was resistant to erythromycin, levofloxacin, and tetracycline. Whole-genome sequencing of this resistant strain was performed and S. pneumoniae was confirmed with MLST analysis, while it had > 2.3 Mb genome and a single repUS43 plasmid. In CARD analysis, the strain had tet(M), ermB, RlmA(II), patB, pmrA, and patA ARGs, which could provide resistance against tetracycline, macrolide, fluoroquinolone, and glycopeptide antibiotics. Phylogenetic analysis revealed that the isolate was closely related to strains from Hungary and the USA. Pan-genome analysis with 144 genome assemblies from NCBI database showed that 1101 non-redundant core genes were shared between all strains. This study gives valuable understanding into the prevalence and characterization of meningitis-causing bacteria in Karachi, Pakistan  with prime focus on multi-drug resistant S. pneumoniae., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Bacterial meningitis is still a significant public health concern, with high morbidity and mortality rates. Despite this, it is still a rare event that requires the bacterial invasion of the meninges. However, some predisposing factors can trigger recurrent episodes of meningitis. This study is aimed at determining the clinical characteristics and the molecular epidemiology of episodes of recurrent community-acquired meningitis with and without predisposing factors. For this purpose, we performed a retrospective study of our laboratory database during the period of 2010 to 2020. Additionally, using molecular tools developed in our previous works, the epidemiology of the pathogens causing these episodes was analyzed using cerebrospinal fluid samples, especially in the absence of isolated strains. We observed a total of 1,779 meningitis cases and 230 were caused by Streptococcus pneumoniae. Of those, 16 were recurrent meningitis episodes (16/1,779; 0.9%) from seven patients. Pneumococcus was the main agent responsible in these recurrent episodes and only two episodes were caused by Haemophilus influenzae. The mean age of these patients was 20 years old and three had predisposing factors which could have led to contracting meningitis. The samples presented different pneumococcal serotypes. Most of them were non-vaccine-covered serotypes and antibiotic susceptible strains. Therefore, it was demonstrated how the practical employment of molecular tools, developed for research, when applied in the routine of diagnosis, can provide important information for epidemiological surveillance. Furthermore, it was shown how pneumococcus was the leading cause of recurrent community-acquired meningitis without predisposing factors, suggesting that pneumococcal vaccination may be necessary, even in those groups of individuals considered to be less susceptible., (© 2024. The Author(s) under exclusive licence to Sociedade Brasileira de Microbiologia.)

Objectives: The objective of this study was to determine the role of cerebrospinal fluid (CSF) bacterial load in adults with pneumococcal meningitis., Methods: We quantified bacterial load in CSF samples from the diagnostic lumbar puncture of adults with community-acquired pneumococcal meningitis. We also measured CSF concentrations of complement component 5a (C5a), and determined associations between bacterial load, clinical characteristics, C5a and unfavourable outcome (Glasgow Outcome Scale score <5)., Results: Bacterial load was quantified in 152 CSF samples. Median age of these patients was 61 years (interquartile range [IQR] 51-68), and 69 of 152 (45%) were female. Median CSF bacterial load was 1.6 × 10 4 DNA copies/mL (IQR 3.4 × 10 3 -1.2 × 10 5 ), and did not correlate with CSF white cell count nor with CSF protein concentrations. Median CSF C5a concentration was 35.8 mg/L (IQR 15.9-105.6), and was moderately correlated with CSF bacterial loads (Spearman's rho = 0.42; p < 0001). High bacterial loads were associated with development of complications, such as circulatory shock (OR per logarithmic increase: 2.4, 95% CI: 2.0-2.9; p < 0.001) and cerebrovascular complications [OR: 1.9, 95% CI: 1.6-2.3; p < 0.001]). High bacterial loads were also associated with unfavourable outcome (OR: 2.8, 95% CI: 2.4-3.3; p < 0.001) and death (OR: 3.1, 95% CI: 2.6-3.8; p < 0.001). In a multivariable regression model including age, immunocompromised state, extrameningeal infection focus, admission Glasgow Coma Scale score and CSF C5a concentration, CSF bacterial load remained an independent predictor of unfavourable outcome (adjusted OR: 2.5, 95% CI: 1.6-3.9; p < 0.001)., Discussion: High CSF bacterial load predicts the development of complications and unfavourable outcome in adults with pneumococcal meningitis., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Despite effective antibiotic therapy, brain-destructive inflammation often cannot be avoided in pneumococcal meningitis. The causative signals are mediated predominantly through TLR-recruited myeloid differentiation primary response adaptor 88 (MyD88), as indicated by a dramatic pneumococcal meningitis phenotype of Myd88-/- mice. Because lipoproteins and single-stranded RNA are crucial for recognition of Gram-positive bacteria such as Streptococcus pneumoniae by the host immune system, we comparatively analyzed the disease courses of Myd88-/- and Tlr2-/- Tlr13-/- mice. Their phenotypic resemblance indicated TLR2 and -13 as master sensors of S. pneumoniae in the cerebrospinal fluid. A neutralizing anti-TLR2 antibody (T2.5) and chloroquine (CQ) - the latter applied here as an inhibitor of murine TLR13 and its human ortholog TLR8 - abrogated activation of murine and human primary immune cells exposed to antibiotic-treated S. pneumoniae. The inhibitory effect of the T2.5/CQ cocktail was stronger than that of dexamethasone, the current standard adjunctive drug for pneumococcal meningitis. Accordingly, TLR2/TLR13 blockade concomitant with ceftriaxone application significantly improved the clinical course of pneumococcal meningitis compared with treatment with ceftriaxone alone or in combination with dexamethasone. Our study indicates the importance of murine TLR13 and human TLR8, besides TLR2, in pneumococcal meningitis pathology, and suggests their blockade as a promising antibiotic therapy adjunct.

An eleven month old girl was referred to the pediatric emergency department at Landspitali Hospital due to fever and lethargy. On examination she was acutely ill with fluctuating level of conciousness. She deteriorated quickly after arrival at the emergency department and was diagnosed with pneumococcal meningitis. In the past year several cases of bacterial meningitis have been diagnosed with Streptococcus pneumoniae as the most common pathogen. The disease causing serotypes have been serotypes that were not in the vaccine that was used in iceland and the Icelandic health authorities have decided to change the vaccination programme accordingly.

Streptococcus pneumoniae (SPN) is a globally significant cause of meningitis, the pathophysiology of which involves damage to the brain by both bacterial virulence factors and the host inflammatory response. In most cases of SPN meningitis bacteria translocate from the blood into the central nervous system (CNS). The principal site of SPN translocation into the CNS is not known, with possible portals of entry proposed to be the cerebral or meningeal blood vessels or the choroid plexus. All require SPN to bind to and translocate across the vascular endothelial barrier, and subsequently the basement membrane and perivascular structures, including an additional epithelial barrier in the case of the blood-CSF barrier. The presence of SPN in the CNS is highly inflammatory resulting in marked neutrophilic infiltration. The secretion of toxic inflammatory mediators by activated neutrophils within the CNS damages pathogen and host alike, including the non-replicative neurons which drives morbidity and mortality. As with the translocation of SPN, the recruitment of neutrophils into the CNS in SPN meningitis necessitates the translocation of neutrophils from the circulation across the vascular barrier, a process that is tightly regulated under basal conditions - a feature of the 'immune specialization' of the CNS. The brain barriers are therefore central to SPN meningitis, both through a failure to exclude bacteria and maintain CNS sterility, and subsequently through the active recruitment and/or failure to exclude circulating leukocytes. The interactions of SPN with these barriers, barrier inflammatory responses, along with their therapeutic implications, are explored in this review., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gil, Wall, Noursadeghi and Brown.)

Pneumolysin is a major virulence factor of Streptococcus pneumoniae that plays a key role in interaction with the host during invasive disease. How pneumolysin influences these dynamics between host and pathogen interaction during early phase of central nervous system infection in pneumococcal meningitis remains unclear. Using a whole-animal in vivo dual RNA sequencing (RNA-seq) approach, we identify pneumolysin-specific transcriptional responses in both S. pneumoniae and zebrafish (Danio rerio) during early pneumococcal meningitis. By functional enrichment analysis, we identify host pathways known to be activated by pneumolysin and discover the importance of necroptosis for host survival. Inhibition of this pathway using the drug GSK'872 increases host mortality during pneumococcal meningitis. On the pathogen's side, we show that pneumolysin-dependent competence activation is crucial for intra-host replication and virulence. Altogether, this study provides new insights into pneumolysin-specific transcriptional responses and identifies key pathways involved in pneumococcal meningitis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

One-third of pneumococcal meningitis (PM) survivors suffer from neurological sequelae including learning disabilities and hearing loss due to excessive neuroinflammation. There is a lack of efficacious compounds for adjuvant therapy to control this long-term consequence of PM. One hallmark is the recruitment of leukocytes to the brain to combat the bacterial spread. However, this process induces excessive inflammation, causing neuronal injury. Maraviroc (MVC)-a CCR5 antagonist-was demonstrated to inhibit leukocyte recruitment and attenuate neuroinflammation in several inflammatory diseases. Here, we show that in vitro, MVC decreased nitric oxide production in astroglial cells upon pneumococcal stimulation. In vivo, infant Wistar rats were infected with 1 × 10 4  CFU/ml S. pneumoniae and randomized for treatment with ceftriaxone plus MVC (100 mg/kg) or ceftriaxone monotherapy. During the acute phase, neuroinflammation in the CSF was measured and histopathological analyses were performed to determine neuronal injury. Long-term neurofunctional outcome (learning/memory and hearing capacity) after PM was assessed. MVC treatment reduced hippocampal cell apoptosis but did not affect CSF neuroinflammation and the neurofunctional outcome after PM. We conclude that MVC treatment only exerted limited effect on the pathophysiology of PM and is, therefore, not sufficiently beneficial in this experimental paradigm of PM., (© 2022. The Author(s).)

Background and Objectives: In 2020, a wide range of hygiene measures was implemented to mitigate infections caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In consequence, pulmonary infections due to other respiratory pathogens also decreased. Here, we evaluated the number of bacterial and viral meningitis and encephalitis cases during the coronavirus disease 2019 (COVID-19) pandemic., Methods: In a multicentre retrospective analysis of data from January 2016 until December 2020, numbers of patients diagnosed with bacterial meningitis and other types of CNS infections (such as viral meningitis and encephalitis) at 26 German hospitals were studied. Furthermore, the number of common meningitis-preceding ear-nose-throat infections (sinusitis, mastoiditis and otitis media) was evaluated., Results: Compared to the previous years, the total number of patients diagnosed with pneumococcal meningitis was reduced (n = 64 patients/year in 2020 vs. n = 87 to 120 patients/year between 2016 and 2019, all p < 0.05). Additionally, the total number of patients diagnosed with otolaryngological infections was significantly lower (n = 1181 patients/year in 2020 vs. n = 1525 to 1754 patients/year between 2016 and 2019, all p < 0.001). We also observed a decline in viral meningitis and especially enterovirus meningitis (n = 25 patients/year in 2020 vs. n = 97 to 181 patients/year between 2016 and 2019, all p < 0.001)., Discussion: This multicentre retrospective analysis demonstrates a decline in the number of patients treated for viral and pneumococcal meningitis as well as otolaryngological infections in 2020 compared to previous years. Since the latter often precedes pneumococcal meningitis, this may point to the significance of the direct spread of pneumococci from an otolaryngological focus such as mastoiditis to the brain as one important pathophysiological route in the development of pneumococcal meningitis., (© 2022. The Author(s).)

Background: Treatment of patients with penicillin-resistant S. pneumoniae (PRSP) is complicated because of the relatively poor blood-brain barrier penetration of effective antimicrobials. Our case: A previously healthy 70-year-old woman, a traveler from China to Japan, was admitted to our hospital with fever and loss of consciousness. She has no history of pneumococcal vaccination. She was diagnosed with bacterial meningitis due to penicillin-and third-generation cephalosporin-resistant strains of S. pneumoniae. The patient was successfully treated with a combination therapy of vancomycin (VCM) and levofloxacin (LVFX) and recovered without any neurological sequelae. As the treatment of penicillin-and third-generation cephalosporin-resistant strains of S. pneumoniae meningitis remains unclear, we conducted a review of the reported cases of meningitis caused by penicillin- and cephalosporin-resistant S. pneumoniae., Method: We performed a search using the keywords "penicillin-resistant Streptococcus pneumoniae," "meningitis," and "pneumococcal meningitis". We searched the electronic databases PubMed, Embase, and Ichushi from their inception to March 2020. Subsequently, two authors independently reviewed the resulting database records, retrieved full texts for eligibility assessment, and extracted data from these cases., Result: We identified 18 papers describing thirty-five cases of penicillin- and cephalosporin-resistant S. pneumoniae meningitis including our case. The patient's characteristics were; median age: 50 years, men:50%, 85% of cases received combination regimens of antibiotics: Ceftroriaxone (CTRX) plus VCM (20 cases), CTRX plus VCM plus rifampicin (RFP) (two cases), CTRX plus linezolid (one case), fluoroquinolones (two cases), carbapenems (six cases), Thirty-five percent received steroids. Twenty-four percent of patients died. Twenty-six percent of patients complicated neurological sequalae., Conclusion: Combination therapy including VCM plus LVFX could be a treatment option., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Treatment failure in pneumococcal meningitis due to antibiotic resistance is an increasing clinical challenge and alternatives to antibiotics warrant investigation. Phage-derived endolysins efficiently kill gram-positive bacteria including multi-drug resistant strains, making them attractive therapeutic candidates. The current study assessed the therapeutic potential of the novel endolysin PlyAZ3aT in an infant rat model of ceftriaxone-resistant pneumococcal meningitis., Methods: Efficacy of PlyAZ3aT was assessed in a randomized, blinded and controlled experimental study in infant Wistar rats. Meningitis was induced by intracisternal infection with 5 x 107 CFU/ml of a ceftriaxone-resistant clinical strain of S. pneumoniae, serotype 19A. Seventeen hours post infection (hpi), animals were randomized into 3 treatment groups and received either (i) placebo (phosphate buffered saline [PBS], n = 8), (ii) 50 mg/kg vancomycin (n = 10) or (iii) 400 mg/kg PlyAZ3aT (n = 8) via intraperitoneal injection. Treatments were repeated after 12 h. Survival at 42 hpi was the primary outcome; bacterial loads in cerebrospinal fluid (CSF) and blood were secondary outcomes. Additionally, pharmacokinetics of PlyAZ3aT in serum and CSF was assessed., Results: PlyAZ3aT did not improve survival compared to PBS, while survival for vancomycin treated animals was 70% which is a significant improvement when compared to PBS or PlyAZ3aT (p<0.05 each). PlyAZ3aT was not able to control the infection, reflected by the inability to reduce bacterial loads in the CSF, whereas Vancomycin sterilized the CSF and within 25 h. Pharmacokinetic studies indicated that PlyAZ3aT did not cross the blood brain barrier (BBB). In support, PlyAZ3aT showed a peak concentration of 785 μg/ml in serum 2 h after intraperitoneal injection but could not be detected in CSF., Conclusion: In experimental pneumococcal meningitis, PlyAZ3aT failed to cure the infection due to an inability to reach the CSF. Optimization of the galenic formulation e.g. using liposomes might enable crossing of the BBB and improve treatment efficacy., Competing Interests: The authors have declared that no competing interests exist.

Background: SARS-CoV-2 is the major cause of infections in humans since December 2019 and is top of the global health concern currently. Streptococcus pneumoniae is one of the leading pathogens of invasive bacterial diseases, including pneumonia, sepsis, and meningitis. Moreover, this bacteria is mostly responsible for secondary infections subsequent to post-viral respiratory disease. Co-infections with bacterial and viral pathogens are associated with severe course of the disease and are a major cause of mortality. In this report, we describe a rare case of COVID-19 patient with pneumococcal sepsis and meningitis of unsuccessful course., Case Presentation: A 89-year-old man, not vaccinated against SARS-CoV-2 infection, was diagnosed with COVID-19 pneumonia. Patient required oxygen therapy due to respiratory failure. The initial treatment of viral infection with tocilizumab and dexamethasone allowed for the stabilization of the patient's condition and improvement of laboratory parameters. On the 9th day of hospitalization the patient's condition deteriorated. Consciousness disorders and acute respiratory disorders requiring intubation and mechanical ventilation were observed. Brain computed tomography excluded intracranial bleeding. The Streptococcus pneumoniae sepsis with concomitant pneumoniae and meningitis was diagnosed based on microbiological culture of blood, bronchial wash, and cerebrospinal fluid examination. Despite targeted antibiotic therapy with ceftriaxone and multidisciplinary treatment, symptoms of multiple organ failure increased. On the 13th day of hospitalization, the patient died., Conclusions: Co-infections with bacterial pathogens appear to be not common among COVID-19 patients, but may cause a sudden deterioration of the general condition. Not only vascular neurological complications, but also meningitis should be always considered in patients with sudden disturbances of consciousness. Anti-inflammatory treatment with the combination of corticosteroids and tocilizumab (or tocilizumab alone) pose a severe risk for secondary lethal bacterial or fungal infections. Thus, treating a high-risk population (i.e. elderly and old patients) with these anti-inflammatory agents, require daily clinical assessment, regular monitoring of C-reactive protein and procalcitonin, as well as standard culture of blood, urine and sputum in order to detect concomitant infections, as rapidly as possible., (© 2022. The Author(s).)

We assessed the impact of the pediatric 13-valent pneumococcal conjugate vaccine (PCV13) on pneumococcal meningitis in adults in Japan in 2014-2018 by comparing epidemiological characteristics of adults with invasive pneumococcal disease with (n = 222) and without (n = 1258) meningitis. The annual incidence of pneumococcal meningitis in 2016-2018 was 0.20-0.26 cases/100,000 population. Age (p < 0.001) and case fatality rate (p = 0.003) were significantly lower in patients with meningitis than in those without meningitis. The odds of developing meningitis were higher in asplenic/hyposplenic or splenectomized patients (adjusted odds ratio [aOR] 2.29, 95% CI 1.27-4.14), for serotypes 10A (aOR 3.26, 95% CI 2.10-5.06) or 23A (aOR 3.91, 95% CI 2.47-6.19), but lower for those aged ≥ 65 years (aOR 0.59, 95% CI 0.44-0.81). PCV13 had an indirect effect on nonmeningitis, but its impact on meningitis was limited because of an increase in non-PCV13 serotypes. Of meningitis isolates, 78 (35.1%) and 3 (1.4%) were penicillin G- or ceftriaxone-resistant, respectively. We also confirmed an association of the pbp1bA641C mutation with meningitis (aOR 2.92, 95% CI 1.51-5.65)., (© 2022. The Author(s).)

Streptococcus pneumoniae causes life-threatening meningitis. Its capsular polysaccharide determines the serotype and influences disease severity but the mechanism is largely unknown. Due to evidence of elevated cytokines levels in the meningeal inflammatory response, we measured 41 cytokines/chemokines and growth factors in cerebrospinal fluid (CSF) samples from 57 South African meningitis patients (collected in the period 2018-2019), with confirmed S. pneumoniae serotypes, using a multiplexed bead-based immunoassay. Based on multivariable Bayesian regression, using serotype 10A as a reference and after adjusting for HIV and age, we found IL-6 concentrations significantly lower in patients infected with serotypes 6D (undetectable) and 23A (1601 pg/ml), IL-8 concentrations significantly higher in those infected with 22A (40,459 pg/ml), 7F (32,400 pg/ml) and 15B/C (6845 pg/ml), and TNFα concentration significantly higher in those infected with serotype 18A (33,097 pg/ml). Although a relatively small number of clinical samples were available for this study and 28% of samples could not be assigned to a definitive serotype, our data suggests 15B/C worthy of monitoring during surveillance as it is associated with in-hospital case fatality and not included in the 13-valent polysaccharide conjugate vaccine, PCV13. Our data provides average CSF concentrations of a range of cytokines and growth factors for 18 different serotypes (14, 19F, 3, 6A, 7F, 19A, 8, 9N, 10A, 12F, 15B/C, 22F, 16F, 23A, 31, 18A, 6D, 22A) to serve as a basis for future studies investigating host-pathogen interaction during pneumococcal meningitis. We note that differences in induction of IL-8 between serotypes may be particularly worthy of future study., (© 2021. The Author(s).)

Over a 4-year study period from 2015 to 2018, altogether 183 isolates of bacterial meningitis were collected from 12 hospitals covering the entire Moroccan territory. Neisseria meningitidis represented 58.5%, Streptococcus pneumoniae 35.5%, and Haemophilus influenzae type b 6%. H. influenzae type b mainly affected 5-year-olds and unvaccinated adults. N. meningitidis serogroup B represented 90.7% followed by serogroup W135 with 6.5%. Decreased susceptibility to penicillin G (DSPG) for all isolates accounted for 15.7%, with 11.6% being resistant to penicillin G (PG) and 4.1% decreased susceptibility. Cumulative results of all strains showed 2.7% decreased susceptibility to amoxicillin and 3.3% resistant, 2.2% of isolates were resistant to third-generation cephalosporin and 2.2% were decreased susceptible, 5.5% were resistant to chloramphenicol and 2.7% were resistant to rifampin. The frequency of DSPG observed in our study is more common in S. pneumoniae than in N. meningitidis (P < 0.05). These isolates have been found to be highly susceptible to antibiotics used for treatment and prophylaxis chemotherapy and the observed resistance remains rare. The impact of introduction of conjugate vaccines against H. influenzae type b and S. pneumoniae (PCVs) is an advantage in reducing meningitis cases due to these two species.

Hyper-virulent Streptococcus pneumoniae serotype 1 strains are endemic in Sub-Saharan Africa and frequently cause lethal meningitis outbreaks. It remains unknown whether genetic variation in serotype 1 strains modulates tropism into cerebrospinal fluid to cause central nervous system (CNS) infections, particularly meningitis. Here, we address this question through a large-scale linear mixed model genome-wide association study of 909 African pneumococcal serotype 1 isolates collected from CNS and non-CNS human samples. By controlling for host age, geography, and strain population structure, we identify genome-wide statistically significant genotype-phenotype associations in surface-exposed choline-binding (P = 5.00 × 10 -08 ) and helicase proteins (P = 1.32 × 10 -06 ) important for invasion, immune evasion and pneumococcal tropism to CNS. The small effect sizes and negligible heritability indicated that causation of CNS infection requires multiple genetic and other factors reflecting a complex and polygenic aetiology. Our findings suggest that certain pathogen genetic variation modulate pneumococcal survival and tropism to CNS tissue, and therefore, virulence for meningitis.

Background: To describe the prevalence, clinical characteristics, impact of systemic steroids exposure and outcomes of delayed cerebral vasculopathy (DCV) in a cohort of adult patients with pneumococcal meningitis (PM)., Methods: Observational retrospective multicenter study including all episodes of PM from January 2002 to December 2015. DCV was defined as proven/probable/possible based upon clinical criteria and pathological-radiological findings. DCV-patients and non-DCV-patients were compared by univariate analysis., Results: 162 PM episodes were included. Seventeen (10.5%) DCV-patients were identified (15 possible, 2 probable). At admission, DCV-patients had a longer duration of symptoms (>2 days in 58% vs. 25.5% (p 0.04)), more coma (52.9% vs. 21.4% (p 0.03)), lower median CSF WBC-count (243 cells/uL vs. 2673 cells/uL (p 0.001)) and a higher proportion of positive CSF Gram stain (94.1% vs. 71% (p 0.07)). Median length of stay was 49 vs. 15 days (p 0.001), ICU admission was 85.7% vs. 49.5% (p 0.01) and unfavorable outcome was found in 70.6% vs. 23.8% (p 0.001). DCV appeared 1-8 days after having completed adjunctive dexamethasone treatment (median 2,5, IQR=1.5-5)., Conclusions: One tenth of the PM developed DCV. DCV-patients had a longer duration of illness, were more severely ill, had a higher bacterial load at admission and had a more complicated course. Less than one third of cases recovered without disabilities. The role of corticosteroids in DCV remains to be established., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Although the pneumococcal conjugate vaccine (PCV) has decreased the incidence of invasive pneumococcal disease (IPD) in children, cases of IPD caused by non-PCV serotypes have been increasing. Here, we report two cases of bacterial meningitis caused by meropenem-resistant Streptococcus pneumoniae; in both the cases, 13-valent PCV (PCV13) had been administered. The isolated S. pneumoniae strains were non-PCV13 serotype 35B and resistant to penicillin G, cefotaxime, and meropenem. In addition, multilocus sequence typing (MLST) revealed the sequence type (ST) to be 558. In case 1, a 6-month-old girl recovered without sequelae after antibiotic therapy comprising cefotaxime and vancomycin, whereas in case 2, a 9-month-old boy was treated with an empirical treatment comprising ceftriaxone and vancomycin administration. However, maintaining the blood concentration of vancomycin within the effective range was difficult, due to which the antibiotics were changed to panipenem/betamipron. During the treatment, he presented with seizures, which were effectively controlled with antiepileptic drugs. The rate of incidence of penicillin-susceptible IPD has been substantially increasing after the introduction of PCV. However, an upsurge in IPD cases due to multidrug-resistant (MDR) serotype 35B has been reported in countries where PCV13 was introduced before introducing in Japan. Moreover, an increase in the proportion of MDR serotype 35B and decrease in the susceptibility to broad-spectrum antimicrobials, including meropenem, have been reported. Hence, the number of meningitis cases caused by MDR serotype 35B/ST558 may increase in the future., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Mizrahi and colleagues present a well-described case of the emergence of drug resistance in Streptococcus pneumoniae meningitis during therapy with ceftriaxone monotherapy with a low bactericidal concentration in the cerebrospinal fluid. Adherence to international guidelines could possibly have prevented the emergence of this resistant isolate and the adverse outcome., (Copyright © 2020 American Society for Microbiology.)

Background: The polysaccharide capsule is a major virulence factor of S. pneumoniae in diseases such as meningitis. While some capsular serotypes are more often found in invasive disease, high case fatality rates are associated with those serotypes more commonly found in asymptomatic colonization. We tested whether growth patterns and capsule size in human cerebrospinal fluid depends on serotype using a clinical isolate of S. pneumoniae and its capsule switch mutants., Results: We found that the growth pattern differed markedly from that in culture medium by lacking the exponential and lysis phases. Growth in human cerebrospinal fluid was reduced when strains lost their capsules. When a capsule was present, growth was serotype-specific: high carriage serotypes (6B, 9 V, 19F and 23F) grew better than low carriage serotypes (7F, 14, 15B/C and 18C). Growth correlated with the case-fatality rates of serotypes reported in the literature. Capsule size in human cerebrospinal fluid also depended on serotype., Conclusions: We propose that serotype-specific differences in disease severity observed in meningitis patients may, at least in part, be explained by differences in growth and capsule size in human cerebrospinal fluid. This information could be useful to guide future vaccine design.

Austrian syndrome is a rare condition caused by invasive Streptococcus pneumoniae, comprising a triad of pneumococcal meningitis, endocarditis, and pneumonia. Herein, we report a 59-year-old male patient who presented with fever and tenderness of the right shoulder. Although the initial diagnosis was acromioclavicular joint septic arthritis, the present case showed a reduced level of consciousness, pulmonary infiltrates, cerebral infarcts, and destruction of the mitral valve. This case suggests that acromioclavicular joint arthritis could be an initial presentation of pneumococcal infection inclusive of Austrian syndrome, especially in patients with some risk factors of invasive pneumococcal infections, such as chronic alcoholism., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Streptococcus suis is an emerging agent of zoonotic bacterial meningitis in Asia. We describe the epidemiology of S. suis cases and clinical signs and microbiological findings in persons with meningitis in Bali, Indonesia, using patient data and bacterial cultures of cerebrospinal fluid collected during 2014-2017. We conducted microbiological assays using the fully automatic VITEK 2 COMPACT system. We amplified and sequenced gene fragments of glutamate dehydrogenase and recombination/repair protein and conducted PCR serotyping to confirm some serotypes. Of 71 cases, 44 were confirmed as S. suis; 29 isolates were serotype 2. The average patient age was 48.1 years, and 89% of patients were male. Seventy-seven percent of patients with confirmed cases recovered without complications; 11% recovered with septic shock, 7% with deafness, and 2% with deafness and arthritis. The case-fatality rate was 11%. Awareness of S. suis infection risk must be increased in health promotion activities in Bali.

Background: Streptococcus pneumonia meningitis (PM) is a major cause of childhood neurological deficits. Although the Notch1 signaling pathway regulates neurogenesis and neuroinflammation, we know little about its expression or influence on hippocampal neurogenesis and gliogenesis during PM., Methods: We used immunofluorescence and Western blots to detect Notch1 signaling expression during experimental PM. Through double-labeling immunofluorescence, we investigated proliferation and differentiation in the dentate gyrus (DG) in PM before and after treatment with exogenous Notch1 activator (Jagged1) and inhibitor (IMR-1)., Results: Our results showed that Notch1 was activated after 24 hours in PM. Compared with the phosphate-buffered saline (PBS) control, Jagged1 increased the proliferation of neural stem cells and progenitor cells (NS/PCs) in DG. After 14 and 28 days of meningitis, astrocyte differentiation increased compared with control. Astrocyte differentiation was higher in the Jagged1 versus the PBS group. In contrast, IMR-1 increased neuronal differentiation but decreased astrocyte differentiation compared with dimethyl sulfoxide treatment., Conclusions: Under PM, Notch1 signaling promotes NS/PC proliferation and astrocyte differentiation in DG, while decreasing neuronal differentiation. Transient activation of the Notch1 signaling pathway explains the reactive gliogenesis and limited neuronal differentiation observed in PM., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Abscess formation in the subscapularis muscle is a rare clinical condition. Few reports are available regarding the treatment methods and surgical approaches for subscapularis intramuscular abscesses. Here, we describe a case of subscapularis intramuscular abscess that was treated successfully via surgical drainage using a new approach, the "dorsal subscapularis approach"., Case Presentation: A 67-year-old woman presented to our hospital with complaints of fever and disturbance of consciousness. Two days prior to visiting our hospital, right shoulder pain and limited range of motion in the shoulder were noted. Cerebrospinal fluid examination and contrast-enhanced computed tomography (CT) imaging on admission revealed a right subscapularis intramuscular abscess with concomitant bacterial meningitis. The patient's clinical symptoms improved after antibiotic administration for 3 weeks, but the right shoulder pain persisted. Contrast-enhanced CT imaging performed after antibiotic administration revealed an abscess in the right shoulder joint space, in addition to a capsule of the abscess in the right subscapularis muscle. We performed open surgical drainage for the abscess, which had spread from the subscapularis muscle to the glenohumeral joint. Using the deltoid-pectoral approach, we detected exudate and infected granulation tissue in the joint cavity. Furthermore, we separated the dorsal side of the subscapularis muscle from the scapula using a raspatory and detected infected granulation tissue in the subscapularis muscle belly. We performed curettage and washed as much as possible. After surgery, antibiotic administration continued for 2 weeks. The patient's right shoulder pain subsided and CT performed 2 months after surgery revealed no recurrence of infection., Conclusions: The present case indicated that a subscapularis intramuscular abscess could lead to severe concomitant infections of other organs via the hematogenous route. Thus, early detection and treatment are necessary. Moreover, in this case, surgical drainage using a dorsal subscapularis approach was beneficial to treating the abscess, which had spread from the subscapularis muscle to the glenohumeral joint.

A 53-year-old man was referred to our hospital because of fever and disturbed consciousness with a left-sided toothache from 5 days ago. Neurological examinations revealed a low level of consciousness, nuchal rigidity, bilateral mydriasis, and positive Babinski sign. A lumbar puncture yielded clouded fluid with a WBC 22,698/μl (polynuclear cell 98%), 681 mg/dl of protein and 0 mg/dl of glucose. The antigen of Streptococcus pneumoniae in urine and cerebrospinal fluid (CSF) were positive. Streptococcus pneumoniae was isolated from CSF culture. Brain CT on admission showed a communicating hydrocephalus. Diagnosis of pneumococcal meningitis with hydrocephalus was made and we treated with ceftriaxone and dexamethasone. The lumbar drainage placed at L 3/4 level became occluded, thus, extra-ventricular drainage was performed. Intracranial pressure (ICP) was 20 cmH 2 O upon insertion of the ICP sensor. At Day 2, the ICP decreased to 10 cmH 2 O and never increased during his course of hospitalization. Repeat brain CT showed no hydrocephalus. He responded to antimicrobial therapy and became lucid and afebrile. At Day 4, the extra-ventricular drainage was removed because of bleeding from right choroid plexus on brain CT. We treated with antimicrobial therapy until Day 21. He was transferred to another hospital for rehabilitation with mild neurological sequelae at Day 31. The cases presenting with hydrocephalus in the acute phase of bacterial meningitis has a high mortality rate. The presence of hydrocephalus is a poor prognostic factor. Although the therapeutic value of extra-ventricular drainage for hydrocephalus has been unclear, his report represents a case for neurologists to consider performing extra-ventricular drainage for hydrocephalus.

Streptococcus pneumoniae is the leading cause of adult bacterial meningitis. Differing from Neisseria meningitidis (the second most common cause of acute bacterial meningitis), contact tracing and chemoprophylaxis are not required. At postmortem, the differentiation between S. pneumoniae and N. meningitidis is traditionally done by culture and polymerase chain reaction performed on blood or cerebrospinal fluid, but may take hours, if not days, to analyze. We present a death from bacterial meningitis in a 73-year-old woman in which a rapid urinary pneumococcal antigen testing was able to identify S. pneumoniae as the causative organism within 1 hour. This was confirmed by subsequent brain swab culture. The rapid urinary pneumococcal antigen test in the case prevented the need for contact tracing and chemoprophylaxis. This case highlights the potential use of this test to rapidly identify the culprit organism at postmortem examination when acute bacterial meningitis is detected.

Background: Pneumococcal meningitis (PM) is a serious disease that can rarely recur at a later time after the initial episode., Methods: A retrospective multicenter case-control study was conducted with data for children 18 years of age or younger obtained from the National Observatory of Bacterial Meningitis in Children between January 2001 and September 2015. Cases were all patients with RPM. Each case was matched with 2 randomized controls with a single PM episode in the year of the first episode of PM in the case and born the same year. Case and control data were compared., Results: Among the 1634 PM episodes in children 18 years of age or younger, 24 (1.5%) children had RPM. RPM cases were significantly less frequent than single PM cases in winter (27% vs. 48%; P=0.03) and showed significantly less concomitant ear, nose and throat infections when considering the first episode (30% vs. 56%, P = 0.04) and all episodes (28% vs. 56%, P < 0.01). Cerebrospinal fluid leakage was frequent in RPM cases versus controls (83% vs. 10%, P < 0.01), including 25% discovered after the third PM episode. Immune deficiency was absent in cases and present in 15% of controls. Cases and controls did not differ in death rate or neurologic outcome., Conclusions: RPM is rare in children. Cerebrospinal fluid leakage must be considered.

Objective: To determine the resistance rate of penicillin and ceftriaxone amongst invasive meningitis and nonmeningitis isolates of streptococcus pneumoniae., Methods: The prospective cross-sectional study was conducted from January 2011 to March 2014 at the Clinical Microbiology Laboratory of Aga Khan University, Karachi, and comprised all invasive strains of streptococcus pneumoniae. Penicillin and ceftriaxone susceptibilities were performed and interpreted based on minimum inhibitory concentration breakpoints recommended by Clinical and Laboratory Standards Institute guidelines. Data was analysed using Stata 12., Results: There were 163 strains isolated from sterile body fluids of 109 patients. Of the total, 46(28%) samples were meningitic while 117(72%) were non-meningitic. Of the meningeal isolates, 12(26%) were resistant to penicillin, while none was resistant to ceftriaxone and vancomycin. None of non meningeal isolates showed resistance to penicillin, ceftriaxone or vancomycin., Conclusion: There was considerable penicillin resistance among meningeal strains of streptococcus pneumoniae, but here appeared to be no need to add vancomycin for empirical treatment of invasive streptococcus pneumonia infection.

Streptococcus pneumoniae (pneumococci) is a leading cause of severe bacterial meningitis in many countries worldwide. To characterize the repertoire of fitness and virulence factors predominantly expressed during meningitis we performed niche-specific analysis of the in vivo proteome in a mouse meningitis model, in which bacteria are directly inoculated into the cerebrospinal fluid (CSF) cisterna magna. We generated a comprehensive mass spectrometry (MS) spectra library enabling bacterial proteome analysis even in the presence of eukaryotic proteins. We recovered 200,000 pneumococci from CSF obtained from meningitis mice and by MS we identified 685 pneumococci proteins in samples from in vitro filter controls and 249 in CSF isolates. Strikingly, the regulatory two-component system ComDE and substrate-binding protein AliB of the oligopeptide transporter system were exclusively detected in pneumococci recovered from the CSF. In the mouse meningitis model, AliB-, ComDE-, or AliB-ComDE-deficiency resulted in attenuated meningeal inflammation and disease severity when compared to wild-type pneumococci indicating the crucial role of ComDE and AliB in pneumococcal meningitis. In conclusion, we show here mechanisms of pneumococcal adaptation to a defined host compartment by a proteome-based approach. Further, this study provides the basis of a promising strategy for the identification of protein antigens critical for invasive disease caused by pneumococci and other meningeal pathogens., Competing Interests: The authors have declared that no competing interests exist.

Background: Streptococcus pneumoniae causes many human diseases including bacterial meningitis. Previous study proposed that pneumolysin (PLY), a cytotoxin from pneumococcus, is related to the infection across blood-brain barrier (BBB). However, the mechanism of how PLY break through BBB remains elusive. The present study showed that PLY can increase the permeability of BBB both in vitro and in vivo in our experiments., Results: Further we found out that PLY leads to the high expression of CERB-binding protein (CBP) which can lead to releasing of tumor necrosis factor α then enhance apoptosis of cells which is a significant factor leading to permeabilization of BBB., Conclusion: Our findings demonstrate that CBP plays an important role in the pneumococcus infection in the brain and could be a potential therapeutic target against pneumococcal meningitis., (© 2019 Wiley Periodicals, Inc.)

Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life-threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. In a genome-wide association study of human and pathogen we show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity, identifying variants in CCDC33 associated with susceptibility. Pneumococcal genetic variation explains a large amount of invasive potential (70%), but has no effect on severity. Serotype alone is insufficient to explain invasiveness, suggesting other pneumococcal factors are involved in progression to invasive disease. We identify pneumococcal genes involved in invasiveness including pspC and zmpD, and perform a human-bacteria interaction analysis. These genes are potential candidates for the development of more broadly-acting pneumococcal vaccines.

Background: Paediatric focal intracranial suppurative infections are uncommon but cause significant mortality and morbidity. There are no uniform guidelines regarding antibiotic treatment. This study reviewed management in a tertiary healthcare centre in the United Kingdom and considers suggestions for empirical treatment., Methods: A retrospective, single-centre cohort review of 95 children (< 18 years of age) with focal intracranial suppurative infection admitted between January 2001 and June 2016 in Newcastle upon Tyne, United Kingdom. Microbiological profiles and empirical antibiotic regimens were analysed for coverage, administration and duration of use. Mortality and neurological morbidity were reviewed. Data was analysed using t-tests, Mann-Whitney U tests, independent-samples median tests, and χ 2 -tests where appropriate. P-values < 0.05 were considered statistically significant., Results: Estimated annual incidence was 8.79 per million. Age was bimodally distributed. Predisposing factors were identified in 90.5%, most commonly sinusitis (42.1%) and meningitis (23.2%). Sinusitis was associated with older children (p < 0.001) and meningitis with younger children (p < 0.001). The classic triad was present in 14.0%. 43.8% of 114 isolates were Streptococcus spp., most commonly Streptococcus milleri group organisms. Twelve patients cultured anaerobes. Thirty one empirical antibiotic regimens were used, most often a third-generation cephalosporin plus metronidazole and amoxicillin (32.2%). 90.5% would have sufficient cover with a third generation cephalosporin plus metronidazole. 66.3% converted to oral antibiotics. Median total antibiotic treatment duration was 90 days (interquartile range, 60-115.50 days). Mortality was 3.2, 38.5% had short-term and 24.2% long-term neurological sequelae., Conclusions: Paediatric focal intracranial suppurative infection has a higher regional incidence than predicted from national estimates and still causes significant mortality and morbidity. We recommend a third-generation cephalosporin plus metronidazole as first-choice empirical treatment. In infants with negative anaerobic cultures metronidazole may be discontinued.

Neutrophils are crucial mediators of host defense that are recruited to the central nervous system (CNS) in large numbers during acute bacterial meningitis caused by Streptococcus pneumoniae. Neutrophils release neutrophil extracellular traps (NETs) during infections to trap and kill bacteria. Intact NETs are fibrous structures composed of decondensed DNA and neutrophil-derived antimicrobial proteins. Here we show NETs in the cerebrospinal fluid (CSF) of patients with pneumococcal meningitis, and their absence in other forms of meningitis with neutrophil influx into the CSF caused by viruses, Borrelia and subarachnoid hemorrhage. In a rat model of meningitis, a clinical strain of pneumococci induced NET formation in the CSF. Disrupting NETs using DNase I significantly reduces bacterial load, demonstrating that NETs contribute to pneumococcal meningitis pathogenesis in vivo. We conclude that NETs in the CNS reduce bacterial clearance and degrading NETs using DNase I may have significant therapeutic implications.

A 68-year-old man visited our hospital emergency department with consciousness disturbance. He was diagnosed as bacterial meningitis with septic shock, and initial empirical antibacterial therapy was initiated immediately. Streptococcus pneumoniae. was cultured from the cerebrospinal fluid (CSF), and brain MRIs showed pyogenic ventriculitis. Even though CSF findings improved, he was still in coma and finally died with pneumonia. It is unknown how pyogenic ventriculitis affects the course of bacterial meningitis. We analyzed total 11 inpatients with bacterial meningitis associated with or without the pyogenic ventriculitis, including the present patient, in our hospital. Severity of clinical symptoms and CSF findings might determine the duration of antimicrobial administration, regardless of whether pyogenic ventriculitis existed or not.

Bacterial meningitis is a public health crisis in the northern part of Ghana, where it contributes to very high mortality and morbidity rates. Early detection of the causative organism will lead to better management and effective treatment. Our aim was to evaluate the diagnostic accuracy of Pastorex and Wellcogen latex agglutination tests for the detection of bacterial meningitis in a resource-limited setting. CSF samples from 330 suspected meningitis patients within the northern zone of Ghana were analysed for bacterial agents at the zonal Public Health Reference Laboratory in Tamale using polymerase chain reaction (PCR) and two latex agglutination test kits; Pastorex and Wellcogen. The overall positivity rate of samples tested for bacterial meningitis was 46.4%. Streptococcus pneumoniae was the most common cause of bacterial meningitis within the sub-region, with positivity rate of 25.2%, 28.2% and 28.8% when diagnosed using Wellcogen, Pastorex and PCR respectively. The Pastorex method was 97.4% sensitive while the Wellcogen technique was 87.6% sensitive. Both techniques however produced the same specificity of 99.4%. Our study revealed that the Pastorex method has a better diagnostic value for bacterial meningitis than the Wellcogen method and should be the method of choice in the absence of PCR., Competing Interests: The authors have declared that no competing interests exist.

Bacterial mutations predisposing pneumococcus to causing meningitis, a more severe form of invasive pneumococcal disease (IPD), are largely unknown. Knowledge of such mutations may improve our understanding of pathogenesis and inform preventive strategies. Here we report a pneumococcal pbp1b gene mutation (pbp1bA641C causing N214T change in PBP1b transglycosylase domain) that is associated with meningitis in an exploratory cohort of IPD patients (n = 2054, p = 6.8 × 10 -6 ), in an independent confirmatory cohort (n = 2518, p = 2.3 × 10 -6 ), and in a combined analysis (n = 4572, p = 3.0 × 10 -10 ). Patients infected by the pbp1b641C genotype pneumococci show 2.8-fold odds (95% CI 1.7 to 4.8) of meningitis compared to those infected by non-pbp1b641C pneumococci, after controlling for pneumococcal serotype, antibiotic resistance, and patient age. The pbp1bA641C change results in longer time needed for bacterial killing by antibiotic treatment and shows evidence of being under positive selection. Thus, a pneumococcal mutation conferring increased antibiotic tolerance is associated with meningitis among IPD patients.

Recently, we have identified an extensively drug-resistant (XDR) Streptococcus pneumoniae serotype 15A isolate from a patient with bacterial meningitis. It belonged to sequence type 8279 (ST8279), a clone identified as XDR serotype 11A isolated in South Korea. We obtained and compared the genome sequences of an XDR 15A and an XDR 11A isolate. The genomes of two XDR isolates were highly identical, except for the capsular polysaccharide (cps) locus and another small region. Capsular switching from 11A to 15A may have occurred via recombination of the cps locus. The emergence of a new XDR clone via capsular switching would be a great concern for public health and in clinical settings., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Streptococcus pneumoniae is a major meningitis-causing pathogen globally, bringing about significant morbidity and mortality, as well as long-term neurological sequelae in almost half of the survivors. Subsequent to nasopharyngeal colonisation and systemic invasion, translocation across the blood‒brain barrier (BBB) by S. pneumoniae is a crucial early step in the pathogenesis of meningitis. The BBB, which normally protects the central nervous system (CNS) from deleterious molecules within the circulation, becomes dysfunctional in S. pneumoniae invasion due to the effects of pneumococcal toxins and a heightened host inflammatory environment of cytokines, chemokines and reactive oxygen species intracranially. The bacteria‒host interplay within the CNS likely determines not only the degree of BBB pathological changes, but also host survival and the extent of neurological damage. This review explores the relationship between S. pneumoniae bacteria and the host inflammatory response, with an emphasis on the BBB and its roles in CNS protection, as well as both the acute and long-term pathogenesis of meningitis.

Pneumococcal meningitis, caused by Streptococcus pneumoniae, is the most common type of bacterial meningitis. The clinical management of this disease has been challenged by the emergence of multidrug-resistant Streptococcus pneumoniae, requiring the urgent development of new therapeutic alternatives. Over the course of bacterial meningitis, pathogen invasion is accompanied by a massive recruitment of peripheral immune cells, especially neutrophil granulocytes, which are recruited under the coordination of several cytokines and chemokines. Here, we used chemokine (C-C motif) ligand 3 (Ccl3)-deficient mice to investigate the functional role of CCL3 in a mouse model of pneumococcal meningitis. Following intrathecal infection with Streptococcus pneumoniae Ccl3-deficient mice presented a significantly shorter survival and higher bacterial load than wildtype mice, paralleled by an ameliorated infiltration of neutrophil granulocytes into the CNS. Blood sample analysis revealed that infected Ccl3-deficient mice showed a significant decrease in erythrocytes, hemoglobin and hematocrit as well as in the number of banded neutrophils. Moreover, infected Ccl3-deficient mice showed an altered cytokine expression profile. Glial cell activation remained unchanged in both genotypes. In summary, this study demonstrates that CCL3 is beneficial in Streptococcus pneumoniae-induced meningitis. Pharmacological modulation of the CCL3 pathways might, therefore, represent a future therapeutic option to manage Streptococcus pneumoniae meningitis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Increases in pneumococcal meningitis were reported from Ghanaian regions that lie in the meningitis belt in 2016-2017, despite introduction of 13-valent pneumococcal conjugate vaccine (PCV13) in 2012 using a 3-dose schedule (6, 10, and 14 weeks). We describe pneumococcal meningitis epidemiology in the Ghanaian Northern and Upper West regions across two meningitis seasons., Methods: Suspected meningitis cases were identified using World Health Organization standard definitions. Pneumococcal meningitis was confirmed if pneumococcus was the sole pathogen detected by polymerase chain reaction, culture, or latex agglutination in cerebrospinal fluid collected from a person with suspected meningitis during December 2015-March 2017. Pneumococcal serotyping was done using PCR. Annual age-specific pneumococcal meningitis incidence (cases per 100,000 population) was calculated, adjusting for suspected meningitis cases lacking confirmatory testing., Findings: Among 153 pneumococcal meningitis cases, 137 (89.5%) were serotyped; 100 (73.0%) were PCV13-type, including 85 (62.0%) that were serotype 1, a PCV13-targeted serotype. Persons aged ≥5 years accounted for 96.7% (148/153) of cases. Comparing 2015-2016 and 2016-2017 seasons, the proportion of non-serotype 1 PCV13-type cases decreased from 20.0% (9/45) to 4.1% (3/74) (p = 0.008), whereas the proportion that was serotype 1 was stable (71.1% (32/45) vs. 58.1% (43/74); p = 0.16). Estimated adjusted pneumococcal meningitis incidence was 1.8 in children aged <5 years and ranged from 6.8-10.5 in older children and adults., Conclusions: High pneumococcal meningitis incidence with a large proportion of serotype 1 disease in older children and adults suggests infant PCV13 vaccination has not induced herd protection with this schedule in this high-transmission setting., Competing Interests: The authors have declared that no competing interests exist.

Colombia introduced mass pneumococcal conjugate vaccination at the end of 2011. Using 2005-2015 surveillance data, we conducted a retrospective interrupted time-series analysis. A significant trend towards reduced monthly was observed in the post-vaccination period (2012-2015) compared with the expected rate, reaching in 2015 a reduction of 90.5% of pneumococcal meningitis. This trend was not observed for control diseases.

Background: In March 2010, the 10-valent pneumococcal conjugate vaccine (PCV10) was introduced into the routine immunization program in Brazil. We describe the pneumococcal serotypes that caused invasive pneumococcal diseases (IPD) before and after the introduction of PCV10 using data from a national laboratory-based surveillance system., Method: We compared the prevalence of vaccine types (VT) and non-vaccine types (NVT) of Streptococcus pneumoniae in three periods, pre-PCV10 (January/2005-December/2009), early post-PCV10 (January/2010-December/2013), and late post-PCV10 (January/2014-December/2015), by episode in meningitis and non-meningitis cases and by age group. Changes in serotype prevalence in the early and late post-PCV10 periods were determined using pre-PCV10 period as a reference., Results: A total of 8971 IPD isolates from patients aged 2 months to 99 years were analyzed. In the late post-PCV10 period, the VT-IPD reduction in the 2-month to 4-year age group was 83.4% for meningitis and 87.4% for non-meningitis cases; in the age groups 5-17 years, 18-64 years, and ≥65 years, VT declined by 56.1%, 54.1%, and 47.4%, respectively, in meningitis cases, and by 60.9%, 47.7%, and 53.4%, respectively, in non-meningitis cases. NVT-IPD increased throughout the study period, driven mainly by serotypes 3, 6C, and 19A, which remained the predominant types causing IPD in the late post-PCV10 period., Conclusion: We observed direct and indirect PCV10 protection against IPD caused by VT and a shift in the distribution of serotypes 5 years after the introduction of PCV10. Continued IPD surveillance is needed to evaluate the sustainability of the high prevalence of serotypes 3, 6C, and 19A, which were not included in PCV10., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The present study aimed to determine the cost of childhood pneumococcal infections under 5 years of age and to provide further data for future health economy studies. Electronic medical records of children diagnosed with meningitis caused by S. pneumoniae and all-cause pneumonia, and acute otitis media (AOM) between January 2013-April 2014 were retrospectively evaluated. Direct costs for the treatments of hospitalized patients (pneumonia and pneumococcal meningitis) including costs of healthcare services consisted of costs of hospital bed, examination, laboratory analyses, scanning methods, consultation, vascular access procedures, and infusion and intravenous treatments. Direct costs for patients (AOM) treated in outpatient setting included constant price paid for the examination and cost of prescribed antibiotics. Indirect costs included cost of work loss of parents and their transportation expenses. Data of 130 children with pneumococcal meningitis (n = 10), pneumonia (n = 53), and AOM (n = 67) were analyzed. The total median cost was €4,060.38 (direct cost: €3,346.38 and indirect cost: €829.18) for meningitis, €835.91 (direct cost: €480.66 and indirect cost: €330.09) for pneumonia, and €117.32 (direct cost: €17.59 and indirect cost: €99.73) for AOM. The medication cost (p = 0.047), indirect cost (p = 0.032), and total cost (p = 0.011) were significantly higher in pneumonia patients aged ≥36 months than those aged <36 months; however, direct cost of AOM were significantly higher in the patients aged <36 months (p = 0.049). Results of the present study revealed that the treatment cost was significantly enhanced for hospitalization and for advanced disease. Thus, preventive actions, mainly vaccination, should be conducted regularly.