不以善小而不为,不以恶小而为之

review article T h e n e w e ng l a nd j o u r na l o f m e dic i n e n engl j med 354;1 www.nejm.org january 5, 200644 current concepts Community-Acquired Bacterial Meningitis in Adults Diederik van de Beek, M.D., Ph.D., Jan de Gans, M.D., Ph.D., Allan R. Tunkel, M.D., Ph.D., and Eelco F.M. Wijdicks, M.D., Ph.D. From the Department of Neurology, Cen- ter of Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam (D.B., J.G.); the De- partment of Medicine, Monmouth Medi- cal Center, Long Branch, N.J. (A.R.T.); and the Department of Neurology, Division of Critical Care Neurology, Mayo Clinic College of Medicine, Rochester, Minn. (E.F.M.W.). Address reprint requests to Dr. van de Beek at the Department of Neurology H2, Aca- demic Medical Center, University of Am- sterdam, P.O. Box 22660, 1100 DD Amster- dam, the Netherlands, or at d.vandebeek@ amc.uva.nl. N Engl J Med 2006;354:44-53. Copyright © 2006 Massachusetts Medical Society. Bacterial meningitis is a medical, neurologic, and sometimes neurosurgical emergency that requires a multidisciplinary approach. Bacterial meningitis has an annual incidence of 4 to 6 cases per 100,000 adults (defined as patients older than 16 years of age), and Streptococcus pneumoniae and Neisseria meningitidis are responsible for 80 percent of all cases.1,2 A diagnosis of bacterial meningitis is often considered, but the disease can be difficult to recognize.1-8 Rec- ommendations for antimicrobial therapy are changing as a result of the emergence of antimicrobial resistance. In this review we summarize the current concepts of the initial approach to the treatment of adults with bacterial meningitis, highlighting adjunctive dexamethasone therapy and focusing on the management of neurologic complications. initial approach In adults presenting with community-acquired acute bacterial meningitis, the sen- sitivity of the classic triad of fever, neck stiffness, and altered mental status is low (44 percent), but almost all such patients present with at least two of four symptoms — headache, fever, neck stiffness, and altered mental status (as defined by a score below 14 on the Glasgow Coma Scale).1 Lumbar puncture is mandatory in any pa- tient in whom bacterial meningitis is suspected, although the procedure can be hazardous (Fig. 1 in the Supplementary Appendix, available with the full text of this article at www.nejm.org). Reports have emphasized the risk of brain herniation as a complication of diagnostic lumbar puncture in patients with meningitis.9-13 Pa- tients with expanding masses (e.g., subdural empyema, brain abscess, or necrotic temporal lobe in herpes simplex encephalitis) may present with symptoms that ap- pear to be identical with those of bacterial meningitis, and in these patients as well, lumbar puncture may be complicated by brain herniation.5,9 The withdrawal of cere- brospinal fluid reduces counterpressure from below, thereby adding to the effect of compression from above, increasing the brain shift that may already be present (Fig. 1).9 Neuroimaging — either cranial computed tomography (CT) or magnetic resonance imaging (MRI) — to detect brain shift is recommended as a precaution in selected patients before lumbar puncture.9,10 A prospective study involving 301 adults with suspected meningitis confirmed that clinical features can be used to identify patients who are unlikely to have abnormal findings on cranial CT (41 per- cent of the patients in this study).10 Of 235 patients who underwent cranial CT, in only 5 patients (2 percent) was bacterial meningitis confirmed, reflecting the hetero- geneity of the study group with clinically suspected bacterial meningitis. Cranial imaging should precede lumbar puncture in patients who have new-onset sei- zures, an immunocompromised state, signs that are suspicious for space-occupy- ing lesions, or moderate-to-severe impairment of consciousness.9,10,13 When these Copyright © 2006 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at EMORY UNIVERSITY on January 12, 2007 . current concepts n engl j med 354;1 www.nejm.org january 5, 2006 45 criteria are met, indications for cranial imaging before lumbar puncture are present in about 45 percent of patients with bacterial meningitis con- firmed by cerebrospinal fluid culture.1 Lumbar puncture may also be harmful in patients with coagulopathy, because of the chance of needle- induced subarachnoid hemorrhage or of the de- velopment of spinal subdural and epidural hema- tomas.14 When a diagnosis of bacterial meningitis is probable but neuroimaging is not available, lum- bar puncture should be given preference in patients with moderate-to-severe impairment of conscious- ness or in an immunocompromised state. How- ever, when warning signs of a space-occupying lesion (e.g., new-onset seizure, papilledema, or evolving signs of brain tissue shift) are present, lumbar puncture should not be performed until after neuroimaging has been performed. Delay in the initiation of antimicrobial thera- py can result in poor outcome in this disease. In a retrospective study, patients were stratified as having a low, intermediate, or high risk of adverse Seizures Hydrocephalus Transtentorial herniation Infarct Figure 1. Major Intracranial Complications in Bacterial Meningitis in Adults. Transtentorial herniation is caused by diffuse swelling of the brain, or hydrocephalus; the herniation may be asym- metrical when lateral focal lesions are present. Hydrocephalus results from basal obstruction of the cerebrospinal fluid. Infarcts are caused by inflammatory occlusion of the basal arteries. Seizures, as indicated on encephalo- grams, are caused by cortical inflammation. Copyright © 2006 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at EMORY UNIVERSITY on January 12, 2007 . T h e n e w e ng l a nd j o u r na l o f m e dic i n e n engl j med 354;1 www.nejm.org january 5, 200646 outcome, according to baseline prognostic fac- tors.15 The median delay between the time of ar- rival at the emergency department and the admin- istration of antibiotics was four hours. Among patients whose condition worsened while they were in the emergency department to a category with a higher risk of having an adverse outcome, an association was found between the time of the start of antimicrobial therapy and outcome. Another retrospective study found an association between delays in administering antibiotics long- er than six hours after arrival in the emergency department and death.16 Delay was most frequent- ly due to the performance of cranial imaging be- fore diagnostic lumbar puncture and the transfer of patients to another hospital. If imaging is per- formed before lumbar puncture, therapy should be initiated before the patient is sent for neuro- imaging (Fig. 1 in the Supplementary Appendix). In patients who have not undergone prior imag- ing and in whom disease progression is apparent, therapy should be started directly after lumbar puncture, as well as in all patients with cloudy cerebrospinal fluid (suggesting the diagnosis of bacterial meningitis).14 The opening pressure of the cerebrospinal fluid is elevated in most patients with bacterial meningitis.1,5 In a prospective cohort study, 40 percent of the patients had very high opening pressures (>400 mm, as measured with the use of a water manometer), which were associated with lower levels of consciousness but not with adverse outcome.1 Cerebrospinal fluid findings are important in the differential diagnosis of pa- tients with suspected meningitis.17 In this disease, pleocytosis (100 to 10,000 white cells per cubic millimeter), elevated protein levels (>50 mg per deciliter [0.5 g per liter]), and decreased cerebro- spinal fluid glucose levels (<40 percent of simul- taneously measured serum glucose) are usually present.1,4-8,17 There is usually a predominance of neutrophils (range, 80 to 95 percent) in the cerebrospinal fluid, but a predominance of lym- phocytes can occur.1,4-8 Normal or marginally el- evated cerebrospinal fluid white-cell counts occur in 5 to 10 percent of patients and are associated with an adverse outcome.1 Gram’s staining of cerebrospinal fluid permits the rapid identification of the causative organ- ism (sensitivity, 60 to 90 percent; specificity, ≥97 percent).1,8 Bacterial antigen tests have a limited sensitivity, but they may be helpful in patients with findings consistent with bacterial meningi- tis and negative Gram’s staining and cultures of cerebrospinal fluid.8 New molecular techniques for detecting bacteria in the cerebrospinal fluid by polymerase chain reaction (PCR) have emerged as powerful tools in the diagnosis of patients with negative cultures of cerebrospinal fluid; such tools have high sensitivity and specificity, although further refinements are needed before PCR can be routinely recommended.18,19 Table 1. Recommendations for Empirical Antimicrobial Therapy in Adults with Community-Acquired Bacterial Meningitis.* Predisposing Factor Common Bacterial Pathogen Antimicrobial Therapy Age 16–50 yr Neisseria meningitidis, Streptococcus pneumoniae Vancomycin plus a third-generation cephalo- sporin†‡ >50 yr S. pneumoniae, N. meningitidis, Listeria monocy- togenes, aerobic gram-negative bacilli Vancomycin plus a third-generation cephalo- sporin plus ampicillin‡§ Presence of a risk factor¶ S. pneumoniae, L. monocytogenes, Haemophilus influenzae Vancomycin plus a third-generation cephalo- sporin plus ampicillin‡§ * For additional information, including alternative antimicrobial therapies, see Table 1 in the Supplementary Appendix, available with the full text of this article at www.nejm.org. † Only in regions with very low rates of penicillin resistance (<1 percent), monotherapy with penicillin may be consid- ered, although many experts recommend combination therapy for all patients until the results of in vitro susceptibility testing are available. ‡ Cefotaxime and ceftriaxone are the third-generation cephalosporins recommended. § Only in regions with very low rates of penicillin resistance and cephalosporin resistance, combination therapy with amoxicillin (ampicillin) and a third-generation cephalosporin may be considered. ¶ Risk factors include alcoholism and altered immune status. Copyright © 2006 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at EMORY UNIVERSITY on January 12, 2007 . current concepts n engl j med 354;1 www.nejm.org january 5, 2006 47 The choice of initial antimicrobial therapy is based on the most common bacteria causing the disease according to the patient’s age and the clinical setting and on patterns of antimicrobial susceptibility (Table 1).20,21 After the results of culture and susceptibility testing are available, antimicrobial therapy can be modified for optimal treatment (Table 1 in the Supplementary Appen- dix).20,21 With the worldwide increase in the prevalence of penicillin-resistant pneumococci, combination therapy with vancomycin plus a third- generation cephalosporin (either ceftriaxone or cefotaxime) has become the standard approach to empirical antimicrobial therapy.22,23 Although clinical data on the efficacy of rifampin in pa- tients with pneumococcal meningitis are lacking, some authorities would use this agent in combi- nation with a third-generation cephalosporin, with or without vancomycin, in patients with pneu- mococcal meningitis caused by bacterial strains that, on the basis of local epidemiology, are likely to be highly resistant to penicillin or cephalospo- rin. Such patients should also receive adjunctive dexamethasone therapy. Respiratory isolation for 24 hours is indicated for patients with suspected meningococcal infec- tion. Isolation is not required for those with signs of pneumococcal infection (otitis or pneumonia) or with bacteria other than N. meningitidis identi- fied by Gram’s staining. Persons who have close contact with the patient must receive chemopro- phylaxis to eradicate meningococcal carriage (Ta- ble 1 in the Supplementary Appendix).8,23 adjunctive dexamethasone therapy A recent randomized, placebo-controlled trial in- volving 301 adults with suspected meningitis in combination with cloudy cerebrospinal fluid, bac- teria in the cerebrospinal fluid on Gram’s staining, or a cerebrospinal f luid leukocyte count of more than 1000 per cubic millimeter showed that ad- junctive treatment with dexamethasone before or with the first dose of antimicrobial therapy re- duced the risk of unfavorable outcome from 25 percent to 15 percent (number needed to treat, 10 patients).24 Mortality was reduced from 15 per- cent to 7 percent. The benefit was greatest in pa- tients with intermediate disease severity, as defined by a score on the Glasgow Coma Scale on admis- sion of 8 to 11 (scores can range from 3 to 15, with 15 indicating a normal level of consciousness), and in those with pneumococcal meningitis, in whom unfavorable outcomes declined from 52 percent to 26 percent (number needed to treat, four). In patients with pneumococcal meningitis, mortality was reduced from 34 percent to 14 per- cent. This benefit was a result of reduced mortality from systemic causes.25 In addition, the benefits of dexamethasone were not offset by any apparent side effects of treatment with dexamethasone. What are the practical implications of the re- sults of this study?24 First, in all patients whose condition fulfills the inclusion criteria of the study, dexamethasone (at a dose of 10 mg) should be initiated before or with the first dose of antibi- otics and continued for four days (at a dose of 10 mg every six hours). Second, in patients with suspected meningitis, the results of the study sup- port the administration of adjunctive dexameth- asone with or before the first dose of empirical antibiotics, although the study did not specifically address this issue. This course may result in the unnecessary treatment of patients who do not have bacterial meningitis, but the potential ben- efits outweigh any potential risks associated with dexamethasone therapy. Therapy should be dis- continued if the patient is found not to have bacte- rial meningitis. Third, dexamethasone should be continued for four days in patients with bacte- rial meningitis, regardless of microbial cause or clinical severity. The absence of a significant clinical benefit in some subgroups of patients does not rule out a beneficial effect of dexamethasone in these subgroups, because the study was not powered to analyze all subgroups of interest. Some experts, however, would discontinue dexametha- sone if the meningitis is found to be caused by a bacterium other than S. pneumoniae.21 In a recent quantitative review of this topic that included the results of five clinical trials,26 treatment with corticosteroids was associated with a significant reduction in mortality and neuro- logic sequelae. In the subgroup of patients with meningococcal meningitis, mortality (relative risk, 0.9; 95 percent confidence interval, 0.3 to 2.1) and neurologic sequelae (relative risk, 0.5; 95 percent confidence interval, 0.1 to 1.7) were both reduced, although the results were not statistically signi- ficant. For some adults with suspected meningitis, however, adjunctive dexamethasone can be harm- ful (Fig. 1 in the Supplementary Appendix). Pa- Copyright © 2006 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at EMORY UNIVERSITY on January 12, 2007 . T h e n e w e ng l a nd j o u r na l o f m e dic i n e n engl j med 354;1 www.nejm.org january 5, 200648 tients with septic shock and adrenal insufficiency benefit from corticosteroid therapy in physio- logic doses and for longer than four days; how- ever, when there is no evidence of relative adrenal insufficiency, therapy with corticosteroids may be detrimental.27,28 There are no controlled stud- ies of the effects of corticosteroid therapy in a substantial number of patients with both men- ingitis and septic shock, and therefore corticoste- roid therapy cannot be unequivocally recom- mended for such patients, although the use of low doses, as used by Annane et al.27 (hydrocor- tisone, 50 mg every 6 hours, and fludrocortisone, 50 μg daily), seems reasonable at present. Start- ing corticosteroids before or with the first dose of parenteral antimicrobial therapy appears to be more effective than starting corticosteroids af- ter the first dose of antimicrobial therapy.29 In experimentally induced pneumococcal meningi- tis in animals, bacterial concentrations in the cerebrospinal f luid at the start of therapy ap- peared to be a more important factor influencing the antimicrobial-induced inflammatory response than the time dexamethasone therapy was initi- ated.30 There is a point after the first (parenteral) administration of an antimicrobial agent be- yond which dexamethasone loses its effective- ness, but this point has not been clearly defined. intensive care management Monitoring in a neurologic–neurosurgical inten- sive care unit is recommended in order to recog- nize changes in the patient’s consciousness and the development of new neurologic signs, moni- tor for subtle seizures, and treat severe agitation effectively.31 Practical recommendations and ad- mission criteria are given in Table 2 (and Fig. 1 in the Supplementary Appendix). Bacterial meningi- tis is often associated with septic shock, which is an important predictor of outcome.1,32 Patients with meningitis and septic shock may require in- sertion of a Swan–Ganz catheter, to measure car- diac output, the cardiac index, systemic vascular resistance, and pulmonary wedge pressures in or- der to assess intravascular volume and cardiac function.31 Adrenocorticoid insufficiency in pa- tients with septic shock must be treated with low doses of corticosteroids.27 Care should be taken to estimate and replace imperceptable fluid loss through the skin and lungs in patients who are febrile.31 Patients with bacterial meningitis are at risk of acute hyponatremia, although most cases are mild.1,8,32 Hyponatremia may be a result of cere- bral salt wasting, the syndrome of inappropriate antidiuretic hormone secretion, or exacerbation by aggressive fluid resuscitation.31,33,34 This lack of clarity about the mechanism has resulted in the clinical dilemma with regard to whether in- travenous fluids should be restricted in bacterial meningitis.34 In children with bacterial meningi- tis, fluid restriction does not improve either brain edema or outcome.33,35 Therefore, adult patients with meningitis should be treated with the goal of a normovolemic state. A core body tempera- ture of more than 40°C probably would need to be treated with techniques of cooling by conduction or antipyretic agents to avoid excessive fluid loss. In experimentally induced meningitis in animals, moderate hypothermia ameliorates inflamma- tory changes, although no clinical studies have been performed.36,37 decline in consciousness For patients with a decline in consciousness, or those whose condition fails to improve after the initiation of appropriate antimicrobial therapy, brain imaging is indicated. The indication for re- peated imaging is often arbitrarily based on the clinical status of the patient, the time between the decline in consciousness and the initiation of adequate therapy, and the results of previous im- aging studies. A common cause of a decline in consciousness in bacterial meningitis is clinical evidence of me- ningoencephalitis (Table 3). The release of proin- flammatory mediators in the subarachnoid space leads to