Meningitis

The Infectious Diseases Society of America (IDSA) has issued new guidelines for the diagnosis and treatment of bacterial meningitis. Recommendations are based on results from clinical trials and data from animal experimentation published through May 2004. The guidelines were published in the November 1 issue of Clinical Infectious Diseases, and can be accessed online at http:// www.journals.uchicago.edu/CID/journal/ issues/v39n9/34796/34796.text.html. Definitions of strength of recommendations and quality of evidence are listed in Table 1.

Initial Management Steps

When a patient presents with suspected acute bacterial meningitis, the physician should begin antimicrobial therapy as soon as possible. Bacterial meningitis is a neurologic emergency; progression to more severe disease reduces the patient's likelihood of a full recovery.

A blood culture and lumbar puncture should be performed immediately to confirm the diagnosis. Because complications associated with lumbar puncture include life-threatening brain herniation, at-risk patients (e.g., those who are immunocompromised, had a seizure within the previous week [adults only], have papilledema, or have a specific neurologic abnormality) should have a computed tomographic (CT) scan before undergoing the procedure (B-II). Lumbar puncture also may be delayed pending CT scan results if it may be likely that symptoms are caused by increased intracranial pressure from, for example, a central nervous system mass lesion. Blood samples still should be obtained from patients immediately, and appropriate empiric therapy administered. Once a negative CT scan result is obtained, patients can proceed to lumbar puncture.

Empiric therapy. Empiric therapy should begin as soon as bacterial meningitis is thought likely. Widespread resistance to penicillins and sulfonamides has forced a consideration of new agents for the treatment of bacterial meningitis, such as cephalosporins, vancomycin (Vancocin), rifampin (Rifadin), carbapenems, and fluoroquinolones. Choice of agents for empiric therapy should be determined by the patient's age and the presence of predisposing conditions, and should assume antimicrobial resistance. Recommendations are listed in Table 2 (A-III).

Adjunctive Dexamethasone Therapy. The addition of dexamethasone also should be considered. Adjunctive dexamethasone can reduce the subarachnoid space inflammatory response--a major factor in morbidity and mortality caused by bacterial meningitis--and may therefore alleviate many of the pathologic consequences of bacterial meningitis (e.g., cerebral edema, cerebral vasculitis, change in cerebral blood flow, increase in intracranial pressure, neuronal injury). There is some concern that adjunctive dexamethasone therapy may inhibit the efficacy of cerebrospinal fluid (CSF) vancomycin and would therefore be harmful to patients with penicillin- or cephalosporin-resistant strains. However, in the absence of data from clinical trials, adjunctive dexamethasone is recommended for all adults with suspected or proven pneumococcal meningitis, and in infants and children with Haemophilus influenzae type b meningitis (A-I), even if the isolate subsequently is found to be highly resistant to penicillin or a cephalosporin. Patients should be observed closely in follow-up to check for any adverse outcomes. Recommended dosage of dexamethasone is 0.15 mg per kg administered every six hours for two to four days, beginning 10 to 20 minutes before (or at least concomitant with) the first antimicrobial dose (A-I). Patients receiving adjunctive dexamethasone for the treatment of suspected pneumococcal meningitis may benefit from the addition of rifampin to the combination of vancomycin and a thirdgeneration cephalosporin.

The use of dexamethasone in infants and children with pneumococcal meningitis is controversial, and there are insufficient data to support its use in neonates or in adults with meningitis caused by other pathogens. Patients who already have received antimicrobial therapy should not be given dexamethasone therapy, as it is unlikely to improve their outcome (A-I). Dexamethasone therapy should be continued following test results only if gram-positive diplococci are found in the CSF Gram stain, or if cultures reveal Streptococcus pneumoniae.

Diagnosis

Diagnosis of bacterial meningitis is dependent on CSF examination following lumbar puncture. In bacterial meningitis, opening pressure generally is between 200 and 500 mm [H.sub.2]O (lower in children); white blood cell count and protein concentration are elevated; glucose concentration may be low; and there may be a neutrophil or lymphocyte predominance.

Because determining the bacterial etiology can take up to 48 hours with CSF cultures, an alternative diagnostic test should be considered.

Gram stain examination of CSF is recommended for all patients in whom meningitis is suspected (A-III). It is fast, inexpensive, and accurate in 60 to 90 percent of patients, although misinterpretation and contamination may cause false-positive results.

Polymerase Chain Reaction (PCR) is useful for excluding a diagnosis of bacterial meningitis and may eventually, with further refinement, be used for determining etiology (B-II).

Latex agglutination, while quick, simple, and sensitive, is not recommended for routine use as pathogens cannot be ruled out by a negative test result (D-II). It is most useful for patients who have begun therapy and have negative Gram stain and CSF culture results.

Limulus lysate assay, though sensitive, also is not recommended for routine use (D-II) as it does not distinguish between organisms or rule out gram-negative meningitis, and it is not widely available.

When CSF findings suggest bacterial meningitis but CSF Gram stain and culture results are negative, a combination of laboratory tests is necessary to distinguish bacterial from viral meningitis. (Although there is a validated CSF result model, its clinical utility has not yet been proven, and it should not be used to determine initiation of antimicrobial therapy.) The most strongly recommended tests are PCR, which is more sensitive than viral culture and faster than cell culture for the detection of enterovirus, and determination of C-reactive protein (CRP) concentration, which has a high negative predictive value for bacterial meningitis when results are normal (B-II).

Lactate concentration is not recommended (D-III) since results generally are nonspecific and may be confounded by other factors (although a CSF lactate concentration of 4.0 mmol per L or greater may be used as an indication for empirical therapy in postoperative neurosurgical patients [B-II]).

Procalcitonin concentration measurement is useful, but cannot be recommended until it becomes more widely available (C-II).

Management

Targeted antimicrobial therapy can begin in adults following a positive CSF Gram stain result. (Note that empiric antibiotic therapy should not be delayed pending the results of Gram stain or other diagnostic tests.) Children should not be given targeted therapy until blood culture results confirm the diagnosis, since CSF Gram stain interpretation is subject to expertise. In the meantime, they should receive empiric therapy with vancomycin plus either ceftriaxone (Rocephin) or cefotaxime (Claforan). Patients whose Gram stain result is negative also should continue with empiric therapy.

Antimicrobial therapy should be modified as soon as the pathogen has been isolated and in vitro tests have been performed. Duration of therapy depends on individual patient response, though generalized guidelines according to the responsible pathogen are as follows: Neisseria meningitidis or H. influenzae, seven days; S. pneumoniae, 10 to 14 days; Streptococcus agalactiae, 14 to 21 days; aerobic gram-negative bacilli, 21 days (two weeks beyond the first sterile CSF culture in neonates); Listeria monocytogenes, 21 days or longer. Intravenous therapy is recommended throughout to maintain sufficient CSF concentrations.

In neonates with meningitis caused by gram-negative bacilli, the duration of therapy should be determined in part by repeated lumbar punctures documenting CSF sterilization (A-III). Patients who have not responded clinically after 48 hours of appropriate therapy also should be monitored with repeated CSF analysis (A-III), particularly those with meningitis caused by resistant strains and those who have received adjunctive dexamethasone therapy. Repeated CSF analysis is not recommended on a routine basis.

Because any complications of bacterial meningitis usually occur within the first two or three days of treatment, carefully selected patients may be eligible for outpatient management, with close follow-up. Criteria for outpatient therapy are inpatient antimicrobial therapy for six or more days; no fever for at least 24 to 48 hours; no significant neurologic dysfunction, focal findings, or seizure activity; stable or improving condition; ability to take f luids by mouth; safe environment with access to a telephone, a refrigerator, food, utilities, and home health nursing; reliable intravenous line and infusion device, if necessary; physician available daily; and an established plan for physician and nurse visits, laboratory monitoring, and emergencies.

Antimicrobial Agents

Cephalosporins. Third-generation cephalosporins (cefotaxime or ceftriaxone) are recommended for the treatment of childhood bacterial meningitis (A-I) and for pneumococcal and meningococcal meningitis caused by penicillin- resistant strains (A-III). They are the drugs of choice for empiric therapy in the treatment of H. influenzae type b meningitis, because resistance to chloramphenicol has developed. Third-generation cephalosporins have shown greater efficacy than chloramphenicol (Chloromycetin) and the second-generation cephalosporin cefuroxime (Ceftin). They are effective in meningitis caused by aerobic gram-negative bacilli (A-II), but increasing resistance makes in vitro susceptibility testing crucial. Ceftazidime (Ceptaz) has proved effective in the treatment of Pseudomonas meningitis (A-II). Cefepime (Maxipime), a fourth-generation cephalosporin, has proved safe and effective in the treatment of infants and children with bacterial meningitis, and has been used successfully in patients with bacterial meningitis caused by Enterobacter species and Pseudomonas aeruginosa (A-II).

Vancomycin. The use of vancomycin is not recommended in patients with bacterial meningitis caused by non-resistant strains (E-II). In patients with meningitis caused by penicillin- or cephalosporin-resistant strains it may be used in combination with a third-generation cephalosporin but should not be used alone (A-III). If a patient is unresponsive to parenteral administration, intrathecal administration may be considered.

Rifampin. Rifampin should be used only in combination with other antimicrobial agents as resistance develops rapidly when it is used alone. It has been used in combination with a third-generation cephalosporin with or without vancomycin for treatment of pneumococcal meningitis caused by penicillin- or cephalosporin-resistant strains, though data on its efficacy are lacking. The addition of rifampin is recommended only if clinical or bacteriologic response to a susceptible pathogen is delayed (A-III).

Carbapenems. Imipenem (Primaxin) has proved successful, but is not recommended for treatment of meningitis in most patients because of the potential for seizure activity (D-II). Meropenem (Merrem) has less potential for seizure and is recommended as an alternative to cefotaxime and ceftriaxone in the treatment of patients with bacterial meningitis (A-I), and for use in the treatment of meningitis caused by certain gram-negative bacilli (A-III). Although meropenem is effective in treating patients with pneumococcal meningitis caused by penicillin- or cephalosporin-resistant strains, the prevalence of strains with shared resistance may undermine its usefulness (D-II).

Fluoroquinolones. The use of f luoroquinolones in the treatment of bacterial meningitis is recommended when patients are unresponsive to or cannot be given standard antimicrobial therapy, or when meningitis is caused by gram-negative bacilli that are resistant to multiple agents (A-III). Newer fluoroquinolones, such as gatifloxacin (Tequin) and moxifloxacin (Avelox), potentially are useful in treating bacterial meningitis, but should be used only as alternative agents until more evidence is produced (B-II). There are no data on the use of these agents in newborns and children, although they may be considered in these patients when standard therapy is ineffective. Trovafloxacin (Trovan) no longer is used owing to possible liver toxicity.

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