Treatment of bacterial meningitis and prediction of disease outcomes in children

Bacterial meningitis remains a significant cause of childhood morbidity and mortality, despite reductions to the global meningitis burden resulting from immunisations against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae. Meningitis poses a threat to child health especially in resource-limited settings, where mortality rates can reach up to 50%, even with the use of effective broad-spectrum antibiotics. The extent of the host’s immune response associates with bacterial meningitis outcomes. Consequently, new treatment modalities have focused on controlling the initial inflammatory burst. This doctoral thesis project evaluated the use of a continuous antibiotic infusion, in contrast to conventional boluses, combined with paracetamol as a treatment for childhood bacterial meningitis. In addition, this research attempted to identify new prognostic markers in the cerebrospinal fluid (CSF) of children with meningitis and examined the impact of children’s vitamin D status on disease outcomes. The use of a continuous four-day cefotaxime infusion combined with oral paracetamol was evaluated in a prospective, randomised, double-blind parallel-group trial conducted at the Paediatric Hospital of Luanda in Angola between 2012 and 2017. The control intervention consisted of conventional cefotaxime boluses four times daily and an oral placebo, using mortality by day 7 from treatment initiation as the primary outcome. The prognostic role of matrix metalloproteinases (MMPs), myeloperoxidase (MPO) and the antimicrobial protein cathelicidin in the CSF and vitamin D levels in serum were analysed retrospectively using a cohort from Latin America of children with bacterial meningitis. Our prospective clinical trial showed no benefit from using a continuous cefotaxime infusion combined with paracetamol as a treatment for childhood bacterial meningitis in Angola. By day 7, 61 of 187 (32.6%) children in the intervention group and 64 of 186 (34.4%) children in the control group died (absolute risk difference 1.8%, 95% confidence interval -7.8% to 11.4%). Similarly, no differences emerged between the study groups in terms of neurological sequelae. In addition, the retrospective studies identified MMP-8 as a promising prognostic marker for bacterial meningitis: upon admission, a CSF MMP-8 level greater than the median value increased the odds of death 4.9-fold. The other analysed MMP, MPO and cathelicidin were also expressed in the CSF of children with bacterial meningitis, but did not predict disease outcomes to a similar extent. Furthermore, children’s vitamin D status upon admission did not associate with survival. In conclusion, the prognosis of childhood bacterial meningitis in Angola could not be improved by using a continuous cefotaxime infusion and oral paracetamol. Many of the children in our study were severely ill when presenting at hospital, likely contributing to the poor outcomes and warranting further attention. CSF MMP-8, however, presented as a potential prognostic marker for the disease.