Dexamethasone in the Management of Bacterial Meningitis
Dexamethasone in the Management of Bacterial Meningitis
By Hal B. Jenson, MD, FAAP
The first trials of corticosteroids as adjunctive therapy for bacterial meningitis in 1969 concluded that they provided no benefit, and these studies did not include evaluations of hearing outcome.1 In 1988, the first studies that suggested the benefit of corticosteroids in bacterial meningitis prompted a series of additional studies that resulted in the 1994 recommendations by the American Academy of Pediatrics for the routine use of dexamethasone for Haemophilus influenzae type b meningitis to decrease the incidence of associated hearing loss. Nevertheless, several concerns remained unsettled. The use of suboptimal treatment with cefuroxime for H. influenzae type b meningitis may have affected the conclusions of one study. The largest numbers of patients with meningitis caused by Streptococcus pneumoniae and Neisseria meningitides were reported in two noncontrolled trials. One of these was a noncontrolled retrospective review. The second study was conducted in Egypt in adults and childrenthe majority of whom were comatose upon admission and were treated with intramuscular ampicillin and chloramphenicoland provided no formal evaluation of hearing in children younger than 4 years of age.
Dramatic changes in the epidemiology of bacterial meningitis in recent years have raised two dilemmas that require critical re-examination of defining the precise role of corticosteroids in the treatment of bacterial meningitis. First, H. influenzae type b meningitis has virtually vanished following the use of H. influenzae type b vaccines in 1990 and the recommendations for universal immunization of infants beginning at 2 months of age in 1992. Because of the vaccine-related decline in H. influenzae type b meningitis, bacterial meningitis in the United States is now a disease predominantly affecting adults rather than infants and young children, with S. pneumoniae being the major cause.2 Adjunctive corticosteroid use has not been specifically recommended by the American Academy of Pediatrics for S. pneumoniae meningitis. Second, the relatively recent emergence of penicillin- and cephalosporin-resistant S. pneumoniae, with a prevalence of resistance of 10-20% in many areas of the United States, has necessitated the addition of vancomycin as empiric therapy for bacterial meningitis.3 Vancomycin has good activity against virtually all pneumococcal isolates but has poor penetration into the central nervous systemespecially in the absence of inflammation. Clinical failures with the use of vancomycin in adults with pneumococcal meningitis suggested that concomitant dexamethasone therapy may have contributed to these failures. These developments pose important considerations for 1998. Is dexamethasone therapy appropriate for non-H. influenzae type b meningitis, and is it appropriate for routine empiric use for bacterial meningitis? Does the anti-inflammatory effect of corticosteroid therapy actually impair the transit of antibiotics across the blood-brain barrier and, hence, diminish the effectiveness of vancomycin? Fortunately, we have several lines of evidence to address these questions. All studies since 1988 have shown favorable trends in the course and outcome of adjunctive dexamethasone for meningitis-associated hearing loss and other neurologic deficits, although the effectiveness for S. pneumoniae and N. meningitides meningitis has not reached statistical significance. Meta-analysis, a powerful analytical tool, is useful to discern differences between study groups that are not apparent with small individual studies. A 1989 meta-analysis of the use of dexamethasone in meningitis showed a suggestion of benefit of dexamethasone for risk of bilateral moderate or severe hearing loss from H. influenzae type b meningitis but found inadequate cases of meningitis due to other organisms to demonstrate any benefit.4
A recent meta-analysis of 11 studies conducted from 1996 to 1998 provides further insight into these issues.5 This confirmed the beneficial effect of dexamethasone to reduce severe hearing loss associated with H. influenzae type b. The benefit was found, regardless of the timing of administration of dexamethasone (before or with antibiotics vs later) or of the antibiotic (cefuroxime vs other), suggesting that the difference that had been reported with cefuroxime in one study was consistently observed in other studies. For pneumococcal meningitis, the meta-analysis showed a benefit of dexamethasone only when given early to protect against severe hearing loss and possibly other neurological deficits. The importance of timing of dexamethasone administration explains the absence of benefit with dexamethasone given after antibiotics in a multicenter, randomized, controlled trial of 143 children that showed only a trend but not a statistically significant difference in outcome for pneumococcal meningitis.6 There were still too few cases even by meta-analysis of hearing loss with meningococcal meningitis to assess the benefit of dexamethasone. For all cases of bacterial meningitis, there was a suggestion of protection against neurologic deficits other than hearing loss. The outcomes were similar for studies that used two vs. more than two days of dexamethasone therapy. The only adverse effect from dexamethasone therapy was fever recurring after initial defervescence. The incidence of gastrointestinal bleeding increased with longer duration of dexamethasone therapy.
A study of children with gram-positive or gram-negative bacterial meningitis treated with dexamethasone in addition to vancomycin showed a mean vancomycin CSF concentration of 3.3 g/mL.7 This higher dose is sufficient to overcome the relatively poor penetration of vancomycin across the blood-brain barrier. These results validate the use of vancomycin (in addition to cefotaxime or ceftriaxone) in the empiric treatment of bacterial meningitis even in areas with high rates of cephalosporin resistance and of vancomycin for treatment of penicillin and cephalosporin-resistant pneumococcal meningitis. Serum vancomycin concentrations should be monitored, and the dosage should be adjusted to maintain peak serum concentrations between 30-40 g/mL.8
There is no evidence to suggest that adjunctive dexamethasone therapy is detrimental to ultimate clinical outcome. Because two days of dexamethasone therapy appears to be as effective as four days and because of the increased incidence of adverse events (e.g., gastrointestinal bleeding, secondary fever) with four days of therapy, a duration of two days of dexamethasone is recommended for bacterial meningitis. The benefit for dexamethasone for partially treated bacterial meningitis is unknown. However, I recommend that corticosteroids be given with the first doses of parenteral antibiotics even if the patient has received prior doses of oral antibiotics. There is no evidence of adverse outcome if dexamethasone is administered to patients who are subsequently diagnosed with viral meningitis or meningoencephalitis.
The 1997 Red Book (Committee on Infectious Diseases of the American Academy of Pediatrics) states that dexamethasone is "recommended" for H. influenzae type b meningitis and "should be considered" for pneumococcal or meningococcal meningitis. The available evidence, including this recent meta-analysis, indicates that dexamethasone is appropriate and should be given for suspected pneumococcal meningitis. The recommended regimen for adjunctive dexamethasone is 0.6 mg/kg/d in four divided doses for the first two days of antibiotic treatment. A regimen of 0.8 mg/kg/d in two divided doses is also acceptable.
The timing of dexamethasone administration is very important for benefit of dexamethasone with pneumococcal meningitis. Because S. pneumoniae is now the major cause of bacterial meningitis, the first dose of dexamethasone should be administered empirically immediately before or with antibiotics to all patients with suspected bacterial meningitis. It is doubtful that dexamethasone has any beneficial effect if given more than four hours after the first parenteral dose of antibiotics, and it probably has diminished benefit if given even as little as 30-60 minutes after antibiotics. Regardless of the use of dexamethasone, all children with bacterial meningitis should have follow-up audiologic evaluation and other neurologic evaluations as indicated.
References
1. Girgis NI, et al. Dexamethasone treatment for bacterial meningitis in children and adults. Pediatr Infect Dis J 1989;8:848-851.
2. Schuchat A, et al. Bacterial meningitis in the United States in 1995. N Engl J Med 1997;337:970-976.
3. Friedland IR, McCracken GH. Management of infections caused by antibiotic-resistant Streptococcus pneumoniae. N Engl J Med 1994;331:377-382.
4. Havens PL, et al. Corticosteroids as adjunctive therapy in bacterial meningitis. A meta-analysis of clinical trials. Am J Dis Child 1989;143:1051-1055.
5. McIntyre PB, et al. Dexamethasone as adjunctive therapy in bacterial meningitis. A meta-analysis of randomized clinical trials since 1988. JAMA 1997; 278:925-931.
6. Wald ER, et al. Dexamethasone therapy for children with bacterial meningitis. Pediatrics 1995;95:21-28.
7. Klugman KP, et al. Bactericidal activity against cephalosporin-resistant Streptococcus pneumoniae in cerebrospinal fluid of children with acute bacterial meningitis. Antimicrob Agents Chemother 1993;37: 1630-1636.
8. Ahmed A. A critical evaluation of vancomycin for treatment of bacterial meningitis. Pediatr Infect Dis J 1997;16:895-903.
Dexamethasone treatment in cases of presumed bacterial meningitis:
a. has adverse effects if given to a patient with viral meningitis.
b. has no efficacy in reducing the incidence of hearing loss in pneumococcal meningitis.
c. increases the CSF concentration of antibiotics such as vancomycin.
d. is effective independent of the time of administration in relation to antibiotic administration in pneumococcal meningitis.
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