The Päivikki and Sakari Sohlberg, the Sigrid Jusélius, and the Paediatric Research Foundations, and the daily newspaper Helsingin Sanomat.

Background In our previous study in Luanda, Angola, initial continuous β-lactam infusion for 24 hours combined with oral acetaminophen for 48 hours showed promising results as a new treatment for childhood bacterial meningitis. We investigated whether extending this treatment regimen to 4 days would improve the outcomes further. Methods We conducted a randomized, double-blind, parallel-group study at the same hospital in Luanda. Children aged 2 months to 15 years presenting to hospital with symptoms and signs of bacterial meningitis were randomized to receive, for the first 4 days, a continuous infusion of cefotaxime (250 mg/kg/day) with simultaneous oral acetaminophen (first dose 30 mg/kg, then 20 mg/kg every 6 hours), or cefotaxime conventionally as boluses (62.5 mg/kg, 4 times per day) with placebo orally. All children received also glycerol orally. The primary outcome was mortality by day 7. Results In all, 375 patients were included in the study between 22 January 2012 and 21 January 2017. As 2 children succumbed before treatment initiation, 187 vs 186 participants remained in the intervention and control groups, respectively. On day 7, 61 of 187 (32.6%) children in the intervention group vs 64 of 186 (34.4%) in the control group had died (risk ratio, 0.95 [95% confidence interval {CI}, .71–1.26]; absolute risk difference, 1.8% [95% CI, −7.8 to 11.4]). At discharge from hospital, the corresponding numbers were 71 of 187 (38.0%) and 75 of 186 (40.3%), respectively. Conclusions Prolonged continuous β-lactam infusion combined with oral acetaminophen did not improve the gloomy outcomes of childhood bacterial meningitis in Angola. Clinical Trials Registration NCT01540838.

Adding laboratory parameters to a simple scoring system, such as the SLS, improves the prognostic accuracy only little in bacterial meningitis.

We explored the changes of the initially highly upgraded cerebrospinal fluid matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of MMP 1 (TIMP-1) response during recovery of childhood bacterial meningitis and their association with outcome. The sizes of these changes varied substantially, but a steeper decrease in the MMP-9 and an increase of the TIMP-1 concentrations augured a better outcome. Matrix metalloproteinases (MMPs) are a group of zinc-dependent enzymes which, through their ability to degrade extracellular matrix and nonmatrix bioactive substances, can direct and modify multiple diverse biological and pathological processes, among them the inflammatory and immune responses (1). The MMP activities are inhibited by their specific endogenous inhibitors, the tissue inhibitors of MMPs (TIMPs). Under physiological conditions, MMP activity is precisely regulated, whereas in disease, MMP activity is unbalanced (1).In childhood bacterial meningitis (BM), the initial concentrations of MMP-9 and TIMP-1 in the cerebrospinal fluid (CSF), and their molar ratio (MR), are highly upgraded, and the highest values are associated with adverse outcomes (2-6). We studied how the response was shut down and whether this process influenced the outcome. A better understanding of the response kinetics may open novel opportunities for therapeutic interventions (1, 7).The changes in the concentrations of MMP-9 and TIMP-1 and their MR from admission to 1 week of treatment (day 7) were analyzed using paired CSF samples taken, whenever enough CSF was available, on those days from patients of a previous BM study (8) ( Table 1; see also Fig. S1 in the supplemental material). All patients were treated with intravenous cefotaxime but were randomized to receive it during the first 24 h either as a continuous infusion or as an every-6-hour bolus (8). No adjuvant dexamethasone was given, but all the patients received oral glycerol (9). The audiological outcome was tested on day 7 by brain stem auditory evoked potentials (Madsen Octavus). Deafness was defined as a hearing threshold Ͼ80 dB in the better ear. Severe neurological sequelae were defined as blindness, quadriplegia or paresis, hydrocephalus requiring a shunt, or severe psychomotor retardation at discharge.The MMP-9 and TIMP-1 concentrations were determined by enzyme-linked immunosorbent assay (ELISA), as described previously (4). The changes in percent were compared with other data using the Spearman correlation for quantitative variables and the Mann-Whitney U test or Kruskal-Wallis test for nominal variables. The day-7 values also were examined in the same manner (see Tables S2 and S4 in the supplemental material). A P value of Ͻ0.05 was taken as significant.Within 1 week, the MMP-9 concentration fell by 90% (interquartile range [IQR], 28%) ( Fig. 1) from 476 ng/ml (IQR, 752 ng/ml) to 38 ng/ml (IQR, 62 ng/ml) (P Ͻ 0.0001). The children who later died (n ϭ 3) (Table 1) had a smaller decrease of 26% (IQR, 10%; P ϭ 0.02), and their day-7 MMP-9 concentration (see Table S2 in th...

The immunological response in bacterial meningitis (BM) causes the formation of reactive oxygen and nitrogen species (ROS, RNS) and activates myeloperoxidase (MPO), an inflammatory enzyme. Thus, structural oxidative and nitrosative damage to proteins and DNA occurs. We aimed to asses these events in the cerebrospinal fluid (CSF) of pediatric BM patients. Phenylalanine (Phe), para-tyrosine (p-Tyr), nucleoside 2′-deoxiguanosine (2dG), and biomarkers of ROS/RNS-induced protein and DNA oxidation: ortho-tyrosine (o-Tyr), 3-chlorotyrosine (3Cl-Tyr), 3-nitrotyrosine (3NO₂-Tyr) and 8-oxo-2′-deoxyguanosine (8OHdG), concentrations were measured by liquid chromatography coupled to tandem mass spectrometry in the initial CSF of 79 children with BM and 10 without BM. All biomarkers, normalized with their corresponding precursors, showed higher median concentrations (p < 0.0001) in BM compared with controls, except 8OHdG/2dG. The ratios o-Tyr/Phe, 3Cl-Tyr/p-Tyr and 3NO₂-Tyr/p-Tyr were 570, 20 and 4.5 times as high, respectively. A significantly higher 3Cl-Tyr/p-Tyr ratio was found in BM caused by Streptococcus pneumoniae, than by Haemophilus influenzae type b, or Neisseria meningitidis (p = 0.002 for both). In conclusion, biomarkers indicating oxidative damage to proteins distinguished BM patients from non-BM, most clearly the o-Tyr/Phe ratio. The high 3Cl-Tyr/p-Tyr ratio in pneumococcal meningitis suggests robust inflammation because 3Cl-Tyr is a marker of MPO activation and, indirectly, of inflammation.