Attenuated cerebrospinal fluid leukocyte count and sepsis in adults with pneumococcal meningitis: a prospective cohort study

BACKGROUND: A low cerebrospinal fluid (CSF) white-blood cell count (WBC) has been identified as an independent risk factor for adverse outcome in adults with bacterial meningitis. Whereas a low CSF WBC indicates the presence of sepsis with early meningitis in patients with meningococcal infections, the relation between CSF WBC and outcome in patients with pneumococcal meningitis is not understood. METHODS: We examined the relation between CSF WBC, bacteraemia and sepsis in a prospective cohort study that included 352 episodes of pneumococcal meningitis, confirmed by CSF culture, occurring in patients aged >16 years. RESULTS: CSF WBC was recorded in 320 of 352 episodes (91%). Median CSF WBC was 2530 per mm(3 )(interquartile range 531–6983 per mm(3)) and 104 patients (33%) had a CSF WBC <1000/mm(3). Patients with a CSF WBC <1000/mm(3 )were more likely to have an unfavourable outcome (defined as a Glasgow Outcome Scale score of 1–4) than those with a higher WBC (74 of 104 [71%] vs. 87 of 216 [43%]; P < 0.001). CSF WBC was significantly associated with blood WBC (Spearman's test 0.29), CSF protein level (0.20), thrombocyte count (0.21), erythrocyte sedimentation rate (-0.15), and C-reactive protein levels (-0.18). Patients with a CSF WBC <1000/mm(3 )more often had a positive blood culture (72 of 84 [86%] vs. 138 of 196 [70%]; P = 0.01) and more often developed systemic complications (cardiorespiratory failure, sepsis) than those with a higher WBC (53 of 104 [51%] vs. 69 of 216 [32%]; P = 0.001). In a multivariate analysis, advanced age (Odds ratio per 10-year increments 1.22, 95%CI 1.02–1.45), a positive blood culture (Odds ratio 2.46, 95%CI 1.17–5.14), and a low thrombocyte count on admission (Odds ratio per 100,000/mm(3 )increments 0.67, 95% CI 0.47–0.97) were associated with a CSF WBC <1000/mm(3). CONCLUSION: A low CSF WBC in adults with pneumococcal meningitis is related to the presence of signs of sepsis and systemic complications. Invasive pneumococcal infections should possibly be regarded as a continuum from meningitis to sepsis

Population genomics of Group B Streptococcus reveals the genetics of neonatal disease onset and meningeal invasion

Group B Streptococcus (GBS), or Streptococcus agalactiae, is a pathogen that causes preterm births, stillbirths, and acute invasive neonatal disease burden and mortality. Here, we investigate bacterial genetic signatures associated with disease onset time and meningeal tissue infection in acute invasive neonatal GBS disease. We carry out a genome-wide association study (GWAS) of 1,338 GBS isolates from newborns with acute invasive disease; the isolates had been collected annually, for 30 years, through a national bacterial surveillance program in the Netherlands. After controlling for the population structure, we identify genetic variation within noncoding and coding regions, particularly the capsule biosynthesis locus, statistically associated with neonatal GBS disease onset time and meningeal invasion. Our findings highlight the impact of integrating microbial population genomics and clinical pathogen surveillance, and demonstrate the effect of GBS genetics on disease pathogenesis in neonates and infants

Validation of a Dutch Risk Score Predicting Poor Outcome in Adults with Bacterial Meningitis in Vietnam and Malawi

We have previously developed and validated a prognostic model to predict the risk for unfavorable outcome in Dutch adults with bacterial meningitis. The aim of the current study was to validate this model in adults with bacterial meningitis from two developing countries, Vietnam and Malawi. Demographic and clinical characteristics of Vietnamese (n = 426), Malawian patients (n = 465) differed substantially from those of Dutch patients (n = 696). The Dutch model underestimated the risk of poor outcome in both Malawi and Vietnam. The discrimination of the original model (c-statistic [c] 0.84; 95% confidence interval 0.81 to 0.86) fell considerably when re-estimated in the Vietnam cohort (c = 0.70) or in the Malawian cohort (c = 0.68). Our validation study shows that new prognostic models have to be developed for these countries in a sufficiently large series of unselected patients

Arthritis in adults with community-acquired bacterial meningitis: a prospective cohort study

BACKGROUND: Although the coexistence of bacterial meningitis and arthritis has been noted in several studies, it remains unclear how often both conditions occur simultaneously. METHODS: We evaluated the presence of arthritis in a prospective nationwide cohort of 696 episodes of community-acquired bacterial meningitis, confirmed by culture of cerebrospinal fluid, which occurred in patients aged >16 years. The diagnosis of arthritis was based upon the judgment of the treating physician. To identify differences between groups Fisher exact statistics and the Mann-Whitney U test were used. RESULTS: Arthritis was recorded in 48 of 696 (7%) episodes of community-acquired bacterial meningitis in adults. Joint-fluid aspirations were performed in 23 of 48 patients (48%) and joint-fluid cultures yielded bacteria in 6 of 23 patients (26%). Arthritis occurred most frequently in patients with meningococcal meningitis (12%). Of the 48 patients with bacterial meningitis and coexisting arthritis, four died (8%) and 10 (23%) had residual joint symptoms. CONCLUSION: Arthritis is a common manifestation in patients with community-acquired bacterial meningitis. Functional outcome of arthritis in bacterial meningitis is generally good because meningococcal arthritis is usually immune-mediated, and pneumococcal arthritis is generally less deforming than staphylococcal arthritis. Nevertheless, additional therapeutic measures should be considered if clinical course is complicated by arthritis. In patients with infectious arthritis prolonged antibiotic therapy is mandatory

Daptomycin in experimental murine pneumococcal meningitis

<p>Abstract</p> <p>Background</p> <p>Daptomycin, a lipopeptide antibiotic, could be an alternative to vancomycin for treatment of pneumococcal meningitis. We determined the activity of daptomycin versus vancomycin, with dexamethasone as an adjuvant, in a murine model of pneumococcal meningitis.</p> <p>Methods</p> <p>Ninety-six 25–30 gram mice were inoculated intracisternally with serotype 3 <it>Streptococcus pneumoniae </it>modified by the integration of a luminescent <it>lux </it>operon. All mice were treated with either dexamethasone 1 mg/kg intraperitoneally every 6 hours alone or in combination with either vancomycin or daptomycin, also administered intraperitoneally. Serum antimicrobial concentrations were selected to approximate those achieved in humans. Following treatment, bioluminescence and cerebrospinal fluid (CSF) bacterial concentrations were determined. Caspase-3 staining was used to assess apoptosis on brain histopathology.</p> <p>Results</p> <p>Sixteen hours post intracisternal inoculation, bacterial titers in CSF were 6.8 log₁₀cfu/ml. Amongst the animals given no antibiotic, vancomycin 50 mg/kg at 16 and 20 hours or daptomycin 25 mg/kg at 16 hours, CSF titers were 7.6, 3.4, and 3.9 log₁₀cfu/ml, respectively, at 24 hours post infection (p-value, < 0.001 for both vancomycin or daptomycin versus no antibiotic); there was no significant difference in bactericidal activity between the vancomycin and daptomycin groups (p-value, 0.18). CSF bioluminescence correlated with bacterial titer (Pearson regression coefficient, 0.75). The amount of apoptosis of brain parenchymal cells was equivalent among treatment groups.</p> <p>Conclusion</p> <p>Daptomycin or vancomycin, when given in combination with dexamethasone, is active in the treatment of experimental pneumococcal meningitis.</p

Update of the Preventive Antibiotics in Stroke Study (PASS): Statistical analysis plan

Background: Infections occur in 30% of stroke patients and are associated with unfavorable outcomes. Preventive antibiotic therapy lowers the infection rate after stroke, but the effect of preventive antibiotic treatment on functional outcome in patients with stroke is unknown. The PASS is a multicenter, prospective, phase three, randomized, open-label, blinded end-point (PROBE) trial of preventive antibiotic therapy in acute stroke. Patients are randomly assigned to either ceftriaxone at a dose of 2 g, given every 24 h intravenously for 4 days, in addition to standard stroke-unit care, or standard stroke-unit care without preventive antibiotic therapy. The aim of this study is to assess whether preventive antibiotic treatment improves functional outcome at 3 months by preventing infections. This paper presents in detail the statistical analysis plan (SAP) of the Preventive Antibiotics in Stroke Study (PASS) and was submitted while the investigators were st

Development and internal validation of a prediction rule for post-stroke infection and post-stroke pneumonia in acute stroke patients

Introduction Patients with acute stroke are at high risk for infection. These infections are associated with unfavourable outcome after stroke. A prediction rule can identify the patients at the highest risk for strategies to prevent infection. We aim to develop a prediction rule for post-stroke pneumonia and other infections in patients with acute stroke. Patients and methods We used data from the Preventive Antibiotics in Stroke Study, a multicentre randomised trial comparing preventive ceftriaxone vs. standard stroke care in patients with acute stroke. Possible predictors for post-stroke pneumonia or infection were selected from the literature. Backward elimination logistic regression analysis was used to construct prediction rules for pneumonia or infection. Internal validation was performed and a risk chart was constructed. We adjusted for preventive antibiotic use. Results Pneumonia was diagnosed in 159 of the 2538 included patients, and infection in 348. Pneumonia was predicted by higher age, male sex, pre-stroke disability, medical history of chronic obstructive pulmonary disease, more severe stroke, dysphagia and intracerebral haemorrhage (rather than ischaemic stroke). Infections were predicted by higher age, male sex, history of diabetes, chronic obstructive pulmonary disease, more severe stroke, dysphagia, use of bladder catheter, preventive antibiotic use and intracerebral

Increasing incidence of group B streptococcus neonatal infections in the Netherlands is associated with clonal expansion of CC17 and CC23

Abstract: Group B streptococcus (GBS) is the leading cause of neonatal invasive disease worldwide. In the Netherlands incidence of the disease increased despite implementation of preventive guidelines. We describe a genomic analysis of 1345 GBS isolates from neonatal (age 0–89 days) invasive infections in the Netherlands reported between 1987 and 2016. Most isolates clustered into one of five major lineages: CC17 (39%), CC19 (25%), CC23 (18%), CC10 (9%) and CC1 (7%). There was a significant rise in the number of infections due to isolates from CC17 and CC23. Phylogenetic clustering analysis revealed that this was caused by expansion of specific sub-lineages, designated CC17-A1, CC17-A2 and CC23-A1. Dating of phylogenetic trees estimated that these clones diverged in the 1960s/1970s, representing historical rather than recently emerged clones. For CC17-A1 the expansion correlated with acquisition of a new phage, carrying gene encoding a putative cell-surface protein. Representatives of CC17-A1, CC17-A2 and CC23-A1 clones were identified in datasets from other countries demonstrating their global distribution

Increasing incidence of group B streptococcus neonatal infections in the Netherlands is associated with clonal expansion of CC17 and CC23

Abstract: Group B streptococcus (GBS) is the leading cause of neonatal invasive disease worldwide. In the Netherlands incidence of the disease increased despite implementation of preventive guidelines. We describe a genomic analysis of 1345 GBS isolates from neonatal (age 0–89 days) invasive infections in the Netherlands reported between 1987 and 2016. Most isolates clustered into one of five major lineages: CC17 (39%), CC19 (25%), CC23 (18%), CC10 (9%) and CC1 (7%). There was a significant rise in the number of infections due to isolates from CC17 and CC23. Phylogenetic clustering analysis revealed that this was caused by expansion of specific sub-lineages, designated CC17-A1, CC17-A2 and CC23-A1. Dating of phylogenetic trees estimated that these clones diverged in the 1960s/1970s, representing historical rather than recently emerged clones. For CC17-A1 the expansion correlated with acquisition of a new phage, carrying gene encoding a putative cell-surface protein. Representatives of CC17-A1, CC17-A2 and CC23-A1 clones were identified in datasets from other countries demonstrating their global distribution