Evaluation of Cerebrospinal Fluid Concentration of Daptomycin (Cubicin¬) in Pediatric Patients With Gram-positive Bacterial Meningitis, Concurrently Receiving Standard Antimicrobial Therapy

Background

Acute bacterial meningitis is a severe infection, which leads to persistent neurological deficits in up to 50% of patients, despite optimal medical treatment. Although, the incidence of acute bacterial meningitis has declined in developed countries since the advent of vaccines against Haemophilus influenzae and Streptococcus pneumoniae, this is not yet true for developing countries. Also, the impact of serotype replacement in invasive pneumococcal disease cannot be estimated to date.

Acute bacterial meningitis causes brain injury most prominently in the cerebral cortex, the inner ear and in the hippocampus. In the hippocampus, a brain region functionally important for learning and memory, the brain damage is characterized by apoptosis of cells in the hippocampal dentate gyrus. Autopsy studies demonstrated the occurrence of apoptosis in neurons of the hippocampal dentate gyrus in the majority (> 75%) of human autopsy cases, who died of acute bacterial meningitis. Children are particularly vulnerable to this form of brain damage because of ongoing development of neurological functions and they have a higher risk of neurologic deficits after bacterial meningitis than adults. The 3 most common pathogens in childhood meningitis are Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis. Streptococcus pneumoniae is associated with the greatest risk for fatal outcome or persistent neurological deficits. In the most recent prospective study hearing loss was the most common major sequelae in half of the patients, followed by cognitive deficits (40.0%), seizures (21.2%), and motor deficits (21.2%); one third of these patients had multiple defects.The pathogenesis of brain damage in meningitis is driven by the host's owns inflammatory reaction to the invading pathogens in the subarachnoid space. This inflammatory reaction is triggered by the release of subcapsular bacterial components. Unfortunately, β-lactam antibiotics, current standard of care in bacterial meningitis, induce bacteriolysis leading to a brisk accumulation of subcapsular bacterial components in the cerebrospinal fluid (CSF), which in turn trigger an over-shooting inflammatory reaction contributing to brain damage.

First evaluated more than 50 years ago, adjunctive corticosteroids still are the only approved therapy to minimize this inflammatory reaction in humans.

In children the benefit of a combination therapy with dexamethasone and ceftriaxone has only been proven in the reduction of permanent hearing loss after Haemophilus influenzae type b meningitis, a pathogen that today is virtually eradicated in regions that implemented the vaccination. Furthermore, the beneficial effects of dexamethasone administration in meningitis have been challenged repeatedly. A recent prospective study and two meta-analyses show conflicting results considering the benefit of adjuvant corticosteroid treatment for neurological outcome in children with acute bacterial meningitis. Furthermore, adjunctive corticosteroid treatment does not seem to benefit patients with acute bacterial meningitis in developing countries. Even more worrying are results in experimental meningitis, which indicate that dexamethasone might lead to neuronal injury.