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Dexamethasone Adjunctive Therapy in Bacterial Meningitis Improves Global Outcome and Decreases Mortality

Question

  • In patients with bacterial meningitis, does adjunctive treatment with steroids, in addition to antibiotics, alter mortality and overall outcome?

Clinical Bottom Lines

  1. Early treatment with dexamethasone in adults with bacterial meningitis improves clinical outcome and decreases mortality, without a significant increase in adverse events.


Summary of Key Evidence

  1. Prospective, randomized, double-blinded, placebo-controlled multicenter trial conducted in European countries (Netherlands, Belgium, Germany, Denmark, Austria) from June 1993 through December 2001.
  2. 301 patients were randomly assigned to a treatment group: 157 received dexamethasone and 144 received placebo. Analysis was by intention-to-treat.
  3. Patients received 10 mg of dexamethasone or placebo, given 15 to 20 minutes before or with the first dose of antibiotic, and continued every 6 hours for 4 days.
  4. Inclusion criteria: age 17 or older;clinical suspicion of meningitis;at least one of: cloudy CSF, +bacteria on Gram stain, CSF WBC count >1000/mm3.
  5. Exclusion criteria: hypersensitivity to beta-lactam antibiotics or corticosteroids; pregnant; CSF shunt; antibiotic treatment in previous 48 hours; history of active TB or fungal infection; recent head trauma, neurosurgery, or peptic ulcer disease; participating in another trial.
  6. Primary outcome measure: Glasgow Outcome Scale, a measure of independent functional status, at 8 weeks from initial randomization. Secondary outcomes: death, focal neurologic abnormalities (aphasia, cranial nerve palsy, monoparesis, hemiparesis, severe ataxia), hearing loss, GI bleeding, fungal infections, hyperglycemia.
  7. Subgroup analysis, according to causative organism (S. pneumoniae, N. meningitidis, other bacteria, negative cultures), was performed.
  8. Treatment with dexamethasone was associated with a reduction in the risk of an unfavorable outcome (RR 0.59; P = 0.03). Treatment with dexamethasone was also associated with a reduction in mortality (RR 0.48; P = 0.04).
  9. Dexamethasone was not associated with increased risk for adverse side effects.

Additional Comments

  • Validity assessment was positive: groups were randomized and similar at the inception, patients and investigators were blinded, follow-up was complete, analysis was by intention-to-treat.
  • Study protocol was altered after enrollment of approximately ½ of the patients; changes made (liberalization of antibiotic choices and allowing for administration of steroids with, rather than before antibiotics) may have had an impact on results.
  • These results are in agreement with a meta-analysis of similar studies in children, which showed reduction in hearing loss as sequelae of bacterial meningitis when steroids were administered as an adjunct to antibiotics.2
  • European countries have pathogens with different antibiotic resistance patterns, and possibly differing virulence (most isolates in these studies were sensitive to penicillin). The antibiotics necessary for treatment of resistant S. pneumoniae may have poor CSF penetration when administered with steroids, since they rely on meningeal inflammation.

Citation

  1. de Gans J, van de Beek D. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002; 347: 1549-1556.
  2. McIntyre P, et al. Dexamethasone as adjunctive therapy in bacterial meningitis: A meta-analysis of randomized clinical trials since 1988. JAMA 1997; 278: 925-931.

CAT Author: Kimberly S. Reynhout, MD

CAT Appraisers: Alex Kemper , MD

Date appraised: January 20, 2003

Last updated June 14, 2003
Department of Pediatrics and Communicable Diseases
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