Correspondence
Dexamethasone in Adults with Bacterial Meningitis
N Engl J Med 2003; 348:954-957March 6, 2003
- Article
To the Editor:
The study by de Gans and van de Beek and their colleagues (Nov. 14 issue)1 demonstrates the benefits of dexamethasone in adults with bacterial meningitis. The authors conclude by recommending dexamethasone for all adults with acute bacterial meningitis. How to operationalize this recommendation poses a problem. In addition to having suspected meningitis, patients in this study had to have cloudy cerebrospinal fluid, bacteria on Gram's staining, or a cerebrospinal fluid white-cell count of more than 1000. Thus, these patients were very likely to have acute bacterial meningitis. Most patients seeking medical attention with suspected meningitis, however, are unlikely to have a bacterial cause, and they typically receive empirical therapy pending complete evaluation. Is it clinically justifiable to wait for the confirmatory data before administering an antibiotic when waiting may constitute a delay in therapy? To avoid this pitfall, the clinical threshold for administering antibiotics is likely to be set much lower than that used in this study.
It is likely that the majority of potential candidates for dexamethasone will not have bacterial meningitis. As the target group becomes diluted by patients without bacterial meningitis, the benefit from dexamethasone will be correspondingly reduced, and the frequency of adverse outcomes may increase. Before recommending the routine use of adjunctive dexamethasone therapy for most adults with suspected bacterial meningitis,2 we must determine whether the benefits extend to initial empirical therapy.
2 ReferencesJeffrey A. Tabas, M.D.
Henry F. Chambers, M.D.
San Francisco General Hospital, San Francisco, CA 94110
jtabas@itsa.ucsf. edu 1
de Gans J ,van de Beek D . Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002;347:1549-1556
Full Text | Web of Science | Medline2
Tunkel AR ,Scheld WM . Corticosteroids for everyone with meningitis? N Engl J Med 2002;347:1613-1615
Full Text | Web of Science | Medline
To the Editor:
Because delaying treatment is associated with worse outcomes,1 the standard of emergency care in the United States is to administer antibiotics immediately to patients with suspected bacterial meningitis. The results of a culture of cerebrospinal fluid from a subsequent lumbar puncture should not be affected for several hours after the administration of antibiotics.2
Given that the interval between the arrival of the patient and the beginning of treatment probably varied and that the time to treatment may affect the outcome, it is disturbing that de Gans and van de Beek did not provide a record of time to treatment. In the absence of such data, one is left to wonder whether statistically significant differences in the time to treatment between the dexamethasone group and the placebo group might help to account for differences in outcome between the groups. Evidence of unusual delay would raise questions about the conclusions of the study.
2 ReferencesDavid N. Tancredi, M.D.
William D. Binder, M.D.
Massachusetts General Hospital, Boston, MA 02114
dtancredi@partners.org 1
Aronin SI ,Peduzzi P ,Quagliarello VJ . Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing. Ann Intern Med 1998;129:862-869
Web of Science | Medline2
Quagliarello VJ ,Scheld WM . Treatment of bacterial meningitis. N Engl J Med 1997;336:708-716
Full Text | Web of Science | Medline
To the Editor:
The study by de Gans and van de Beek and their colleagues provides important data on the use of dexamethasone in patients with acute bacterial meningitis. All pneumococci isolated in this study were sensitive to penicillin, although in many areas of the world, the reality is unfortunately different. A big issue of concern is the possibility of a negative interaction between dexamethasone and vancomycin in patients who require treatment with the latter drug.1 Thus, we might see more therapeutic failures with broader use of dexamethasone therapy. Vancomycin has been considered to be the best treatment for meningitis caused by pneumococci with reduced sensibility to cephalosporins. In spite of the widespread recommendation for its use, there is relatively little clinical research on vancomycin for the treatment of meningitis, and it has poor penetration in cerebrospinal fluid, where it often reaches only subtherapeutic concentrations.
1 ReferencesVicente Abril, M.D., Ph.D.
Enrique Ortega, M.D., Ph.D.
Hospital General Universitario, 46014 Valencia, Spain
vabrill@medynet.com 1
Cabellos C ,Martinez-Lacasa J ,Martos A , et al. Influence of dexamethasone on efficacy of ceftriaxone and vancomycin therapy in experimental pneumococcal meningitis. Antimicrob Agents Chemother 1995;39:2158-2160
Web of Science | Medline
To the Editor:
De Gans and van de Beek clearly show a beneficial effect of dexamethasone on outcome in adults with bacterial meningitis, particularly that due to penicillin-susceptible pneumococci. Could most of this effect be attributable to the beneficial effects of corticosteroids on mortality1 and hemodynamic stability1,2 in patients with septic shock? Hypotension was a predictor of an unfavorable outcome in this study (P=0.03). In addition, patients in the dexamethasone group were significantly less likely to have cardiorespiratory failure (10 percent vs. 20 percent, P=0.02). Moreover, from Table 3 of the article, it appears that most of the reduction in the risk of an unfavorable outcome can be accounted for by the difference in mortality between the groups. There was no reported difference in the frequency of neurologic sequelae, including hearing loss. Are there data on the cause of death — particularly, data differentiating refractory shock and multiple-organ dysfunction syndrome, which are typical of septic shock, from neurologic causes (e.g., brain death or withdrawal of care because of poor neurologic prognosis) suggesting sequelae of meningitis?
2 ReferencesAri R. Joffe, M.D.
University of Alberta, Edmonton, AB T6G 2B7, Canada
ajoffe@cha.ab. ca 1
Annane D ,Sebille V ,Charpentier C , et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862-871
CrossRef | Web of Science | Medline2
Briegel J ,Forst H ,Haller M , et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med 1999;27:723-732
CrossRef | Web of Science | Medline
To the Editor:
The results of the study by de Gans and van de Beek and their colleagues are intriguing. We believe, however, that the recommendations in the accompanying editorial by Tunkel and Scheld1 regarding the use of dexamethasone in suspected pneumococcal meningitis are premature. A recent study in Malawi evaluated the use of corticosteroids in children with bacterial meningitis but came to different conclusions.2 In addition to possible differences between the pathogenesis of pneumococcal meningitis in the developing brains of children and that in adults, other differences between the studies include the rates of antimicrobial resistance and immunocompetence. These differences may modify the effect of corticosteroids.
In Malawi, 34 percent of the 459 patients tested for human immunodeficiency virus (HIV) were positive. In the report by de Gans and van de Beek, there was no reference to the immune status of the subjects. The increasing incidence of HIV and the fact that the HIV-infected population has a high incidence of invasive pneumococcal disease make representation of this group in any such efficacy studies vital.
Clearly, with such conflicting results, more studies are needed. Corticosteroids may have a role in treating bacterial meningitis, but exactly what that role is needs to be further elucidated.
2 ReferencesMichael Poshkus, M.D.
Stephen Obaro, M.B., B.S., Ph.D.
Brown University, Providence, RI 02903
sobaro@lifespan.org 1
Tunkel AR ,Scheld WM . Corticosteroids for everyone with meningitis? N Engl J Med 2002;347:1613-1615
Full Text | Web of Science | Medline2
Molyneux EM ,Walsh AL ,Forsyth H , et al. Dexamethasone treatment in childhood bacterial meningitis in Malawi: a randomised controlled trial. Lancet 2002;360:211-218
CrossRef | Web of Science | Medline
Author/Editor Response
Tabas and Chambers ask whether it is clinically justifiable to wait for confirmatory data before administering antibiotics. Although prospective data are lacking on the relation between the timing of administration of antimicrobial agents and the clinical outcome in adults with suspected bacterial meningitis,1 in our opinion, dexamethasone and antibiotics should be administered as soon as possible. However, in some patients, waiting for confirmatory data seems to be justifiable, especially in patients with a low level of clinical severity (53 percent of our study population).2 In addition, “dilution” of the target group is not relevant to the effect of dexamethasone in patients with bacterial meningitis; it is analogous to the dilution of the effect of antibiotic therapy in this group. The rate of side effects will be minimal with the administration of 10 mg of dexamethasone, and therapy should be discontinued if the patient is found not to have bacterial meningitis.
Tancredi and Binder ask about the absence of data concerning the time of treatment. Although we did not record the duration of the delay, the treatment groups were similar in terms of all base-line characteristics. Therefore, it is unlikely that the results are confounded.
We agree with Abril and Ortega that decreased cerebrospinal fluid vancomycin levels are a matter of concern. Therefore, patients receiving dexamethasone should not be treated with vancomycin as the sole antimicrobial agent and should be observed carefully.3
Joffe would like us to provide more data on the cause of death. At this time, we are analyzing these data and will present them when we have finished doing so.
Poshkus and Obaro state that consideration of persons with HIV, a population that is growing and is at increased risk for pneumococcal disease, is crucial to any evaluation of adjunctive dexamethasone in bacterial meningitis. According to our prospective data from a nationwide cohort of adults with bacterial meningitis (1998 through 2002), however, only 5 of 336 patients with pneumococcal meningitis (1.5 percent) were HIV-positive. We disagree that the results of the Malawian trial preclude a recommendation for adults with bacterial meningitis.4 The Malawian study included mainly children in whom treatment began late, HIV-positive children, and children receiving inappropriate antibiotic therapy. Therefore, the results are not representative for patients with bacterial meningitis in developed countries. Moreover, results of our meta-analysis are pending. Four randomized trials are included, so that we summarize the results in 508 adults with bacterial meningitis. Relative risks of death reported in various studies have been consistent, ranging from 0.32 to 0.56, with an overall relative risk of 0.43 (95 percent confidence interval, 0.26 to 0.70). The results of our randomized, controlled trial and this meta-analysis support routine use of dexamethasone in adults with acute bacterial meningitis.5
5 ReferencesJan de Gans, M.D.
Diederik van de Beek, M.D.
Academic Medical Center, 1100 DE Amsterdam, the Netherlands
j.degans@amc. uva. nl 1
Tunkel AR, Scheld WM. Bacterial meningitis. Philadelphia: Lippincott Williams & Wilkins, 2001.
2
Aronin SI ,Peduzzi P ,Quagliarello VJ . Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing. Ann Intern Med 1998;129:862-869
Web of Science | Medline3
Tunkel AR ,Scheld WM . Corticosteroids for everyone with meningitis? N Engl J Med 2002;347:1613-1615
Full Text | Web of Science | Medline4
Molyneux EM ,Walsh AL ,Forsyth H , et al. Dexamethasone treatment in childhood bacterial meningitis and Malawi: a randomised controlled trial. Lancet 2002;360:211-218
CrossRef | Web of Science | Medline5
de Gans J ,van de Beek D . Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002;347:1549-1556
Full Text | Web of Science | Medline
Author/Editor Response
Tabas and Chambers raise the question of how to operationalize the recommendation to administer adjunctive dexamethasone to adults with bacterial meningitis, given the importance of prompt administration of antimicrobial therapy when the diagnosis is suspected. Although the study by de Gans et al. did not specifically address this issue, their results support the administration of adjunctive dexamethasone concomitant with or just before the first dose of empirical antimicrobial therapy. This approach may result in the unnecessary treatment of some patients who do not have bacterial meningitis, but the potential benefits (reduction in the rate of unfavorable outcomes and lower mortality) for patients with pneumococcal meningitis outweigh any potential risks associated with dexamethasone therapy. Previous prospective studies of adjunctive dexamethasone in bacterial meningitis, with the exception of one study involving 200 infants and children in which gastrointestinal hemorrhages requiring blood transfusion developed in 2 patients,1 have failed to demonstrate any serious adverse effects from the administration of dexamethasone.
Poshkus and Obaro cite an important study from Malawi that did not show a benefit of adjunctive dexamethasone in children with bacterial meningitis.2 However, many patients in that study had severe disease associated with malnutrition and concomitant HIV infection, and delays in presentation for medical care were common.3 In these patients, it is unlikely that adjunctive dexamethasone would have ameliorated the central nervous system damage that had already resulted from the consequences of bacterial meningitis (e.g., cerebral edema, increased intracranial pressure, and vascular thrombosis). Furthermore, more than one third of the children in that study received antimicrobial therapy before admission, and more than 30 percent were given second-line antimicrobial therapy because of an inadequate clinical or microbiologic response. No adverse effects were related to the administration of adjunctive dexamethasone in this trial.
We acknowledge that there are inadequate data regarding the use of adjunctive dexamethasone in HIV-infected patients and in patients with meningitis caused by pneumococcal strains that are highly resistant to penicillin or cephalosporins; careful monitoring is essential if these patients are treated with dexamethasone.
The study by de Gans et al. supports the use of adjunctive dexamethasone in adults with pneumococcal meningitis.4 Although more studies are desirable, it took almost nine years to complete this trial, which suggests that new information on the use of adjunctive dexamethasone will most likely not be available in the near future. Dexamethasone will not benefit all patients with bacterial meningitis, but there is the potential for improvement in outcome in selected patients without evidence of substantial harm from this adjunctive treatment.
4 ReferencesAllan R. Tunkel, M.D., Ph.D.
Drexel University College of Medicine, Philadelphia, PA 19129
allan.tunkel@drexel. edu W. Michael Scheld, M.D.
University of Virginia Health System, Charlottesville, VA 229801
Lebel MH ,Freij BJ ,Syrogiannopoulos GA , et al. Dexamethasone therapy for bacterial meningitis: results of two double-blind, placebo-controlled trials. N Engl J Med 1988;319:964-971
Full Text | Web of Science | Medline2
Molyneux EM ,Walsh AL ,Forsyth H , et al. Dexamethasone treatment in childhood bacterial meningitis in Malawi: a randomised controlled trial. Lancet 2002;360:211-218
CrossRef | Web of Science | Medline3
McCracken GH Jr . Rich nations, poor nations, and bacterial meningitis. Lancet 2002;360:183-183
CrossRef | Web of Science | Medline4
Tunkel AR ,Scheld WM . Corticosteroids for everyone with meningitis? N Engl J Med 2002;347:1613-1615
Full Text | Web of Science | Medline
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