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Abstract & Commentary
Synopsis: Adjunctive therapy with dexamethosone, initiated immediately before or with the first dose of antibiotic, significantly improved outcomes in adults with pneumococcal meningitis.
Source: de Gans J, et al. Dexamethasone in adults with bacterial meningitis. N Engl J Med. 2002;347:1549-1556.
De Gans and colleagues in the Netherlands randomized adults with suspected bacterial meningitis to receive, in addition to amoxicillin, dexamethasone (10 mg IV q.6h. for 4 d, initiated 15-20 min) before first antibiotic administration. After an interim analysis was conducted on approximately one half of the total enrollment, the protocol was amended to allow administration of the dexamethasone simultaneously with the antibiotic and to allow investigators to follow local guidelines for choice of empirical antibiotic therapy; both changes were made to accelerate enrollment.
Of the 301 patients enrolled, 159 were assigned dexamethasone and 144 assigned placebo were included in the final analysis of outcome at 8 weeks. The groups were comparable at the time of enrollment. Approximately one fifth of the patients had a negative-CSF culture but were included in the analysis because of other findings consistent with a bacterial etiology of their meningitis. Streptococcus pneumoniae and Neisseria meningitidis each accounted for approximately one-third of the positive cultures. CSF from 6 patients yielded Listeria monocytogenes, 4 Haemophilus influenzae, 3 Staphylococcus aureus, and 1 each of Escherichia coli, Klebsiella pneumoniae, Capnocytophaga canimorsus, and a Corynebacterium species.
A favorable outcome was defined as the presence of mild or no disability, with the patient able to return to work or school. Dexamethasone therapy was associated with a significant reduction in the risk of an unfavorable outcome (RR, 0.59; 95% CI, 0.37-0.93; P = 0.03), as well as a reduction in mortality (RR, 0.48; 95% CI, 0.24-0.96; P = 0.04). The effects were most striking in the patients with pneumococcal meningitis among whom assignment to dexamethasone therapy was associated with unfavorable outcome in 26% vs 52% in the placebo group (RR, 0.50; 95% CI, 0.30-0.83; P = 0.006). The mortality rate was reduced from 34% to 14%. In contrast, patients with meningococcal meningitis, with unfavorable outcomes in only 8% and 11%, derived no apparent benefit from dexathasone therapy; this was also true of those with other organisms on culture (although the number of these was quite small) and those with negative cultures.
Dexamethasone therapy was well tolerated, although 2 recipients of this drug were withdrawn from the study because of severe hyperglycemia, as were one each for suspected stomach perforation (that, in fact, was not present) and agitation and flushing. In addition, 1 dexamethasone recipient developed gastrointestinal bleeding and perforation of the stomach.
Susceptibility testing was performed on 77 of the 108 S pneumoniae isolates; all had a penicillin MIC < 0.1 mg/mL. One of 80 meningococcal isolates tested had intermediate resistance to penicillin. The initial empiric antibiotic therapy provided adequate coverage in 97% of the dexamethasone and 98% of the placebo group with positive cultures.
Comment by Stan Deresinski, MD, FACP
While some level of controversy has persisted regarding the benefit of adjunctive corticosteroid therapy in pediatric meningitis, there is reasonable evidence that dexamethasone administration is associated with a reduction in neurological sequelae in children, most particularly sensorineural hearing loss in H influenzae meningitis. The evidence of benefit in pneumococcal meningitis, now the most common form of this infection in the United States, and the evidence of benefit in adults has been much weaker. This study clearly demonstrates a benefit to dexamethasone therapy in adults with pneumococcal meningitis. In contrast, no benefit could be demonstrated in patients with meningococcal meningitis, an infection with a much better prognosis.
The choice of amoxicillin by de Gans et al at the initiation of the trial was based on the susceptibility data prevalent in The Netherlands at the time. The current recommendation in the United States for empiric treatment of bacterial meningitis, dictated by the increasing antibiotic resistance in S pneumoniae, is the use of ceftriaxone plus vancomycin. Some also recommend the addition of rifampin, particularly in patients given corticosteroids because of concerns about their potential negative effect on vancomycin accumulation in the CSF, a concern which, based on human data, may be unwarranted.
de Gans et al, as well as Tunkel and Scheld in an accompanying editorial, recommend the routine use of dexamethasone, given immediately before or with the first dose of antibiotic, as adjunctive therapy in adults with suspected pneumococcal meningitis.1 Tunkel and Scheld recommend against their use in patients who have already received antibiotics or those in septic shock. They further recommend that, if the meningitis is found to not be caused by S pneumoniae, administration of dexamethasone be discontinued. Tunkel and Scheld also raise concern regarding the applicability of these findings to treatment of infections caused by pneumococci that are ceftriaxone resistant. These seem reasonable recommendations and concerns, although the caveat against corticosteroid use in patients with septic shock, which is based on a study demonstrating a trend, not statistically significant, toward poorer outcomes in septic shock patients in the absence of reduced adrenalcortical reserve, may be questionable.2,3
Dr. Deresinski, Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor of Infectious Disease Alert.
1. Tunkel AR, Scheld AR. N Engl J Med. 2002;347:1613-1615.
2. Annane D, et al. JAMA. 2002; 288:862-871.
3. Deresinski S. Infectious Disease Alert. 2002;21:177-179.