Could Recommending Dexamethasone in Bacterial Meningitis Improve Patient Outcomes?

The Infectious Disease Society of America (IDSA) guidelines for meningitis, published more than a decade ago in 2004, outline a variety of aspects of bacterial meningitis from diagnostic evaluation to treatment strategies.¹ Obtaining bacterial cultures and initiating early, empiric antibiotic therapy are the cornerstones of meningitis treatment. Unlike in almost all other infections, however, there’s a critically important adjunct to meningitis treatment that actually improves mortality: the corticosteroid dexamethasone.

Despite high-quality evidence demonstrating benefit with a favorable adverse effect profile, dexamethasone is commonly forgotten as an early adjunct in bacterial meningitis, yet it’s a simple clinical intervention for pharmacists to make in order to improve patient outcomes.

The mechanism of benefit of corticosteroids in bacterial meningitis¹

When antibiotics are given in meningitis, bacterial lysis triggers a profound inflammatory response in the subarachnoid space of the brain. This inflammation leads to cerebral edema, which in turn generates a cascade of events including intracranial hypertension, reduced cerebral perfusion pressure, and eventually neuronal injury causing morbidity and mortality.

The landmark trial demonstrating dexamethasone benefit in adults

Prior to 2002, there was a paucity of data regarding the role of corticosteroids in bacterial meningitis. On the basis of animal studies and mostly uncontrolled trials, there was a signal of potential benefit, which prompted the European Dexamethasone in Adulthood Bacterial Meningitis study in 2002.²

This large, multicenter, randomized controlled trial enrolled 301 adult patients with suspected bacterial meningitis. Patients were randomized to receive dexamethasone (10 mg IV every 6 hours) or placebo for 4 days. Importantly, this treatment was initiated either before (within 20 minutes) or concurrently with antibiotic therapy. Given the proposed mechanism of benefit regarding the reduction in inflammatory response, the timing of administration with respect to antibiotic therapy is likely a critical aspect of corticosteroid therapy.

The primary endpoint of the trial was an “unfavorable” score on the Glasgow Outcome Scale measured after 8 weeks. This outcome scale measures morbidity and mortality with a score of 1 (death), 2 (vegetative), 3 (severe disability), 4 (moderate disability), or 5 (mild or no disability). For the primary endpoint, “unfavorable” was defined as patients having moderate disability (a score of 4) or lower.

Patients receiving dexamethasone were less likely to have an unfavorable outcome compared to those receiving placebo (15% vs 25%). Impressively, dexamethasone even demonstrated a reduction in mortality (7% vs 15%). Subgroup analysis by bacteria type suggested that meningitis due to Streptococcus pneumoniae demonstrated benefit, whereas other bacterial types (such as Neisseria meningitidis) did not show benefit, although the latter subgroup was dramatically underpowered and at risk for a type II statistical error.

Why is dexamethasone the corticosteroid of choice in bacterial meningitis?

Although theoretically any corticosteroid should reduce inflammation secondary to bacterial lysis, there are 2 important reasons to prefer dexamethasone. First, dexamethasone is supported by a large clinical trial in which a specific dose was proven to be efficacious.² Second, compared to other corticosteroids, dexamethasone (and betamethasone) have the most potent anti-inflammatory properties and the longest biological half-lives.³

Adverse effects of dexamethasone in bacterial meningitis

The dexamethasone dose studied in the landmark 2002 article is substantial—the 40 mg per day of dexamethasone is equivalent to prednisone 250 mg per day.³ Keeping in mind that the dose is only given for 4 days, the most common adverse effect is hyperglycemia. Because many patients will likely be admitted to an intensive care unit, an IV insulin infusion will often be required to maintain normoglycemia. In addition to hyperglycemia, other risks of high-dose corticosteroids include gastrointestinal bleeding and secondary infections, although both adverse effects are very uncommon and usually associated with longer-term therapy.

Efficacy of corticosteroids in pediatric bacterial meningitis¹

The IDSA guidelines don’t recommend corticosteroids in neonates (due to a lack of clinical data supporting efficacy). Among infants (>6 weeks of age) and children, the preponderance of evidence supports the use of dexamethasone (0.15 mg/kg IV every 6 hours for 2 to 4 days), particularly in patients with Haemophilus influenzae meningitis, and is recommended in the IDSA guidelines.

A simple call to action for pharmacists

Pharmacists can play an important role in the management of bacterial meningitis by ensuring that dexamethasone is given in patients with suspected bacterial meningitis. Because dexamethasone iisn’t an antibiotic, it’s frequently overlooked in the acute treatment of meningitis. Key aspects of this recommendation include the following:

• Dexamethasone reduces morbidity and mortality in bacterial meningitis by blunting the inflammatory response secondary to bacterial lysis, which frequently causes detrimental physiologic effects.
• Dexamethasone should be given prior (20 minutes before) or concurrently with antibiotics. There’s probably no benefit if the corticosteroid is given after antibiotics are initiated.
• Dexamethasone is given intravenously as 10 mg (or 0.15 mg/kg in pediatrics) IV Q6hr for up to 4 days.
• Evidence exists of benefit in both pediatrics and adults patients with bacterial meningitis.

References

• Tunkel AR, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39(9):1267-1284.
• de Gans J, et al.; European Dexamethasone in Adulthood Bacterial Meningitis Study Investigators. Dexamethasone in adults with bacterial meningitis. N Engl J Med. 2002;347(20):1549-1556.
• Chrousos GP, Chapter 39. Adrenocorticosteroids & adrenocortical antagonists. In: Katzung BG, et al. Basic & Clinical Pharmacology. 11th ed. NY:McGraw Hill; 2011.