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Commentary on the paper by McIntyre et al (see page 391)
Bacterial meningitis continues as a major cause of morbidity and mortality among children throughout the world. McIntyre et al report on a six year experience in Australia with 122 cases of pneumococcal meningitis; 89% of cases occurred in children less than 5 years of age.1 Fifteen (13%) children died and 23 (22%) suffered severe neurological outcomes including paresis, hydrocephalus with shunting, visual loss, and marked intellectual impairment. Only 55% recovered without any identified sequelae. How can we improve the outcome of pneumococcal meningitis?
Early antibiotic treatment appears appealing as a fundamental for improving outcome, yet not all cases treated early have a good outcome. The report of McIntyre et al shows once again that children presenting “in extremis” (shock, respiratory failure, etc) are frequently beyond the full benefits of intervention regardless of whether their course was one with rapid onset or more slowly progressive after a prodromal illness. However, the authors report that delay in admission to the hospital is likely to contribute to poor outcome. Yet, once at the hospital, the time to antibiotic administration (either 4–12 hours or later) was not associated with enhanced morbidity in survivors. These observations support the practice of complete evaluation including blood and cerebrospinal fluid (CSF) cultures, when not contraindicated, prior to initiation of therapy as there is no evidence that short delays resulting from transport and/or performance of a lumbar puncture or computed tomography (to rule out increased intracranial pressure) results in increased morbidity.
Lebel and McCracken reported excess morbidity among children whose cerebral spinal fluid culture remained positive for the causative pathogen 18 to 36 hours after initiating therapy compared to children with more rapid sterilisation.2 Short term complications such as seizures and subdural effusion were observed in a greater proportion of cases with delayed sterilisation, as well as greater likelihood of neurological disabilities and moderate or profound hearing loss. Although patient age, severity at presentation, and bacterial pathogens all contribute to morbidity in bacterial meningitis, there is no debate about the benefit of early sterilisation. Current antimicrobial strategies usually result in rapid sterilisation of Neisseria meningitis in the CSF (within 4–6 hours), while Streptococcus pneumoniae requires as long as 48 hours when children are treated with third generation cephalosporins.3 Is it possible that, in part, the morbidity of pneumococcal meningitis is related to slower sterilisation of the central nervous system by currently recommended therapy (cefotaxime plus vancomycin)?
Even with rapid sterilisation and administration of potent antimicrobial agents, the inflammatory reaction within the central nervous system and its effects on cerebral blood flow as well as direct action of bacterial toxins on the nervous system can still cause severe morbidity.4 In 1990, Mustafa et al reported that children with detectable markers of inflammation (cytokines) within the CSF had a higher prevalence of neurological sequelae.5 These insights led to a renewed interest in corticosteroids as adjunctive therapy for bacterial meningitis because of the potential to modulate cytokines, thus reducing the inflammatory response and decreasing intracranial pressure. Early studies of dexamethasone supported a reduction in sensorineural hearing loss with early administration; however, the effect appeared pathogen specific (Haemophilus influenzae type b) and limited to hearing loss.6,7 The current report of McIntyre et al adds one more perspective to the controversy over whether, in fact, dexamethasone administered to children with pneumococcal meningitis improves the outcome. To support this conclusion, McIntyre et al reference a meta-analysis7 and a randomised clinical trial (RCT) in children that showed trends favouring the dexamethasone treated group for sensorineural hearing loss (at 3 months).8 There are several reasons to question whether these citations resolve the ongoing controversy. In McIntyre et al’s meta-analysis of dexamethasone as adjunctive therapy in bacterial meningitis, the authors concluded that the evidence was only suggestive for a benefit in pneumococcal disease.7 In addition, one study in particular9 had an unusually high mortality (28%), and hearing loss was not assessed in younger children. The study included patients from 3 months to 60 years of age and did not specify if the observed effects of dexamethasone occurred in adults or children (or both). Even the authors of the meta-analysis concluded that this study “differed from others” and that statistical evidence of protection from early dexamethasone (for pneumococcal meningitis) is lost if this study is excluded. The RCT cited included children older than 2 years of age and the differences in mortality, neurological outcome, and moderate to severe hearing loss (between 27 patients who received dexamethasone and 26 who received placebo) were “statistically insignificant” at the 6 week follow up.8 Statistical significance was achieved only at the 3 month follow up for hearing loss when one child in the dexamethasone treated group was found to have significantly improved hearing compared to the earlier measurement. For several clinical studies that failed to show improved outcomes with dexamethasone,6,10,11 McIntyre et al suggest the lack of multivariate analysis as the reason for failing to show the benefit. Unfortunately, their current study will not resolve the conflicting views among those who believe and those who do not that dexamethasone is effective as adjunctive therapy.12 What approach should the clinician use?
Concerns about the use of dexamethasone focus on four issues: the need for administration either prior to or concurrent with antibiotic therapy; penetration of antimicrobials in the CSF in the presence of decreased inflammation; potential for dexamethasone to mask signs such as fever that would identify the non-responsive patient; and potential for adverse events. First, there is general agreement that if effective, there is a narrow window for administration of steroids that either proceeds or is concurrent with the initial administration of antimicrobials. Second, the CSF concentrations of vancomycin, ceftriaxone, and rifampin in adults may be reduced when administered with dexamethasone. Although vancomycin appears to penetrate into CSF more reliably in children, and both ceftriaxone and cefotaxime achieve CSF concentrations that result in bactericidal activity against susceptible pneumococci, direct comparisons of CSF concentrations and rapidity of sterilisation in dexamethasone treated and untreated children have not been reported.13–15 Furthermore, the potential for diminished CNS penetration of vancomycin in patients receiving adjunctive corticosteroids led to US and UK recommendations, in adults, that rifampin be preferred to vancomycin to achieve optimal antimicrobial activity in the CSF for cephalosporin resistant Streptococcus pneumoniae.16,17 Third, clinical signs or symptoms may be decreased in the presence of dexamethasone and the clinician will need to both be vigilant for subtle clinical clues of inadequate response as well as be willing to document that sterilisation of the CSF has occurred when clinical concerns warrant such an approach. Furthermore, two recent studies (using different animal models) showed increased hippocampal neuronal apoptosis and reduced learning capacity and spatial memory when dexamethasone was added to treatment of experimental pneumococcal meningitis.18,19 Lastly, some gastrointestinal bleeding has been observed in up to 1–2% of children with bacterial meningitis administered dexamethasone. The current US recommendations advocate the use of dexamethasone for infants and children with meningitis due to Haemophilus influenzae but only advise consideration for children with pneumococcal meningitis in infants older than 6 weeks of age, reflecting the belief that current studies have not established a clear benefit.20
Early diagnosis and administration of antimicrobial therapy that is rapidly bactericidal in the central nervous system is the first principle for optimising the outcome of pneumococcal meningitis. Optimising cerebral blood flow by attention to fluid administration and strategies for reducing intracranial inflammation are attractive adjuncts; however, the optimal strategy for achieving these goals is unclear. Viewing dexamethasone as a first generation approach that reduces markers of CNS inflammation and likely ameliorates some of the morbidity of pneumococcal infection in some children places its use in perspective. Adjunctive approaches employing hypothermia, nitrous oxide inhibitors, or anti-inflammatory molecules such as IL-10 or anti-tumour necrosis factor-alpha antibody are under evaluation in experimental models. Thus, broad recommendations regarding dexamethasone treatment should be made with caution. Further research of mechanisms of CNS damage and strategies for abating the inflammatory response as well as its direct toxic effects are needed.
Commentary on the paper by McIntyre et al (see page 391)
Competing interests: Dr Pelton has acted as an expert witness regarding the outcome of bacterial meningitis during the last five years