A 42 year old female with type 2 diabetes presented to hospital with fevers, malaise and headache. She had become unwell 7 days earlier with coryzal symptoms, feverishness, and cough with green sputum. On examination she was unwell and intermittently drowsy but gas exchange was adequate and she was haemodynamically stable with lactate 1.5 units. Temperature was 39.6^oC and glucose was 15.8 units. Chest x-ray showed bibasal consolidation. CRP was 35 units and white cell count was 12.9. She received ceftriaxone 2 g, clarithromycin 500 mg, intravenous crystalloid 1000 mL and an insulin sliding scale.

One hour after admission the patient deteriorated with GCS 6 and non-purposeful shaking movements of the right arm and leg, which resolved with diazepam 5 mg intravenously. Her airway became partially obstructed despite nasopharyngeal and oral airways and she was urgently intubated. Aciclovir 900 mg was given and the patient was transferred to the ICU.

CT head showed no abnormality. A lumbar puncture revealed turbid yellow-tinged cerebrospinal fluid (CSF). Dexamethasone 10 mg was given. A phenytoin infusion was started. Sedation was maintained with propofol and fentanyl.

The CSF showed Gram positive cocci and a white cell count of 1274 units with neutrophils 1248 units. CSF glucose was 0.3 units and protein was 5.5 g. Ceftriaxone twice daily and dexamethasone four times daily were continued and acyclovir was discontinued. Blood cultures and CSF both grew Streptococcus pneumoniae. Viral PCR was negative. After 48 hours the patient was extubated and then discharged to the ward without any neurological deficit. She went home 5 days after admission. Ceftriaxone was given for a total of 14 days, facilitated by the outpatient parenteral antibiotic therapy team. She was advised not to drive for 6 months.

What adjunctive therapies, if any, are effective in the treatment of bacterial meningitis?

Joel Meyer

Bacterial meningitis occurs in about 3000 infants, children and adults in the UK each year. In community-dwelling adults, the most common causative organisms are Streptococcus pneumoniae and Neisseria meningitidis. Adult bacterial meningitis has a significant mortality despite effective antibiotic therapy, with a fatality rate of around 15% ¹. Systemic complications which contribute to this mortality include septic shock, disseminated intravascular coagulation and ARDS. The morbidity is also high, with a pooled prevalence of long term neurological sequelae – which include hearing loss, seizures, hydrocephalus, paresis, cranial nerve palsies and visual impairment – in excess of 30% ². Both mortality and morbidity increase with advancing age¹. Hypotension, obtunded mental state at presentation, and seizures within the first 24 hours (as in this case) are also associated with worse outcome³.

Bacterial meningitis necessitates early and appropriate antibiotics, and delays cost lives⁴. Unfortunately the timeliness of meningitis recognition and antibiotic administration in UK hospitals is inadequate and variable⁵.

Adjuvant therapy with dexamethasone has been extensively evaluated for its ability to reduce neurological complications and mortality in bacterial meningitis. The rationale is provided by animal models demonstrating glucocorticoid-induced reduction in CSF inflammation and oedema. Adults with meningitis randomised to dexamethasone had lower CSF pressures and lower concentrations of IL6, IL8 and IL10 than those randomised to placebo⁶.

The efficacy of adjuvant dexamethasone in meningitis has been studied in both developed and developing countries. In a randomised multicentre European trial of 301 adult patients, early intravenous dexamethasone 10 mg every 6 hours for 4 days reduced 8-week mortality (RR 0.48) and unfavourable outcomes (RR 0.56) compared to placebo⁷. Interestingly, the benefit was confined to those patients with S. pneumoniae meningitis. The subgroup with non-pneumococcal meningitis (usually meningococcal) did not benefit from dexamethasone, although this group was small and had a much more favourable mortality than the pneumococcal group (3 vs 23%) making a treatment effect harder to demonstrate.

Results from efficacy trials in the developing world contrast with those from Europe. A randomised controlled trial in 465 Malawian adults failed to demonstrate any benefit from dexamethasone compared to placebo (56% vs 53% mortality)⁸. A similarly sized trial in Vietnam did show a significant one month survival benefit of dexamethasone. But this benefit was limited to the 70% of patients who had microbiologically-confirmed bacterial meningitis, where as the 30% with unconfirmed disease had an increased risk of death with dexamethasone⁹. There has been considerable debate about the relevance of these findings to European practice. Important differences include: much poorer outcomes overall; treatment delay due to late presentation; much less pneumococcal disease: increased rates of tuberculous meningitis and HIV.

Sequential meta-analyses have attempted to resolve the uncertainty. These have variously included adults and/or children, in the developed and/or developing world. The most recent and largest of these is the 2013 Cochrane meta-analysis of 4121 patients in 25 randomised trials¹⁰. The findings were:

• No overall benefit of glucocorticoids, though there was a non-significant trend towards reduced mortality with dexamethasone (RR 0.74, CI 0.53-1.05) which remained non-significant when low and high income groups were sub-analysed.
• When analysed by pathogen, dexamethasone was found to be beneficial in S. pneumoniae meningitis (mortality RR 0.84, CI 0.72-0.98) but not N. meningitidis or H. influenzae.
• Lower rates of hearing loss and short-term neurological sequelae were observed with dexamethasone, especially in high-income countries.
• Excess adverse events attributable to dexamethasone have not been reported in any of the randomised controlled trials.

On the basis that S. pneumoniae is a major cause of community-acquired bacterial meningitis in UK adults, these findings favour the initiation of dexamethasone in all patients with suspected pneumococcal bacterial meningitis. The dose is 0.15 mg/kg six-hourly (10 mg qds for a typical adult). This should be continued for 4 days if S. pneumoniae is confirmed but discontinued if another organism is identified or if the diagnosis of bacterial meningitis is excluded. Timing may be important: guidelines advise the initiation of dexamethasone prior to or concurrently with the first antibiotic dose, and the avoidance of dexamethasone in patients who have already received antibiotics¹¹.

Adequate CSF levels of bactericidal antibiotics are a crucial element of meningitis treatment. For time-dependent antibiotics like beta-lactams and vancomycin, this means maximising the time during which the CSF concentration is above the minimum inhibitory concentration (hence twice-daily ceftriaxone). Penetration of antimicrobials into the CSF relies on the fact that the blood brain barrier is disrupted by inflammation. In a pre-clinical model, the anti-inflammatory effect of dexamethasone was shown to attenuate the penetration of vancomycin into CSF. Further research is needed but clinicians should be aware of this phenomenon when managing cephalosporin-resistant pneumococcal meningitis.

Dexamethasone is the only proven adjunctive therapy to date in bacterial meningitis. A negative trial of induced hypothermia was recently published¹². Glycerol and paracetamol have been investigated in African children and found to be ineffective¹³. N-acetylcysteine and other types of antioxidants have not progressed beyond early phase investigations. Future research is likely to identify new treatment paradigms based on a deeper immunological understanding of host and pathogen factors.

Undoubtedly the most cost effective intervention against meningitis is preventative vaccination. The incidence of bacterial meningitis in the UK has halved between 1989 and 2013, largely due to prophylactic vaccine-induced reduction in haemophilus and meningococcal A and C meningitis in infants and children. The pneumococcal polysaccharide vaccine was introduced in the UK in 1983, is non-immunogenic in children, and is indicated in over 65s and high risk adult patients. The heptavalent pneumococcal conjugate vaccine was introduced for infants in 2006 (superseded in 2010 by a 13-valent vaccine). Although the vaccine is given in infancy, the attributable reduction in invasive pneumococcal disease is clearly evident in both children and adults (independent of the polysaccharide vaccine), demonstrating the impact of herd immunity. A new meningococcal B vaccine has been approved in Europe but, despite considerable controversy, is not yet recommended by the UK’s Joint Committee on Vaccination and Immunisation¹⁴.

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Lessons learnt

Patients presenting with symptoms suggestive of bacterial meningitis must be treated promptly with appropriate CSF-penetrating bactericidal antibiotics. Reviewing the accumulated evidence and the most recent meta-analysis, it is clear that adjunctive dexamethasone confers a survival benefit in Streptococcus pneumoniae meningitis, and also a morbidity benefit which may be less pathogen-specific. This patient received appropriate investigation and treatment and fortunately made a full recovery, despite the adverse features on admission including seizures and reduced GCS. Vaccinations are a crucial tool in the prevention of meningitis.

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References

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11. van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med. 2004;351(18):1849.
12. Mourvillier B, Tubach F, van de Beek D, et al. Induced hypothermia in severe bacterial meningitis: a randomized clinical trial. JAMA. 2013 Nov 27;310(20):2174-83.
13. Molyneux EM, Kawaza K, Phiri A, et al. Glycerol and acetaminophen as adjuvant therapy did not affect the outcome of bacterial meningitis in malawian children. Pediatr Infect Dis J. 2014 Feb;33(2):214-6.
14. http://www.hpa.org.uk/Topics/InfectiousDiseases/InfectionsAZ/