BACTERIAL MENINGITIS

BACTERIAL MENINGITIS

Current Diagnosis

•   Patient age and epidemiology:

•   Clinical symptoms: Fever, headache, meningeal signs

•   CSF examination: High opening pressure (>300 mm Hg)

•   Elevated white blood cell count (>10–>5000)

•   >60% polymorphonuclear cells

•   Low CSF glucose (<40 mg/dL or <50% serum glucose)

•   High CSF protein (>50–>1.0 g/dL)

•   Bacteria present on Gram stain of CSF

Abbreviation: CSF = cerebrospinal fluid.

Current Therapy

•   Neonates <2 mo

•   Group B streptococcal infection: cefotaxime (Claforan) or ampicillin

•   Gram-negative rods, other than Pseudomonas: cefotaxime

•   Pseudomonas: cefepime (Maxipime), ceftazidime (Fortaz), or meropenem (Merrem)

•   Listeria: Ampicillin + gentamicin (Garamycin)

•   Children >2 mo

•   Empirical for unknown etiology: cefotaxime or ceftriaxone (Rocephin)

•   Streptococcus pneumoniae: cefotaxime or ceftriaxone

•   Haemophilus influenzae: cefotaxime or ceftriaxone

•   Neisseria meningitidis: ampicillin or cefotaxime

•   Older children and adults

•   Empirical for unknown etiology: cefotaxime or ceftriaxone

•   S. pneumoniae: cefotaxime or ceftriaxone

•   N. meningitidis: ampicillin or cefotaxime

•   Gram negative, postoperative, or Staphylococcus aureus (see Tables 1–4)

•   Add vancomycin if at risk for infection with resistant pneumococcus

Acute bacterial meningitis occurs in all age groups, but predominantly in children younger than 2 years and the elderly (older than 60 years). With the introduction of effective protein conjugate vaccines for Haemophilus and pneumococcal infection, the incidence of bacterial meningitis is rapidly declining in children, and adults are now the major population affected. Bacterial meningitis is a medical emergency requiring rapid and decisive action to prevent death or neurologic sequelae. Since the introduction of chloramphenicol (Chloromycetin) in the early 1950s, the mortality rate has remained between 5% and 40%, depending on the age of the patient and the etiology. Of the survivors, 10% to 30% suffer permanent neurologic deficits. Prognosis is affected by the timeliness of therapy, the age of the patient, and the etiology. Presumptive diagnosis and administration of therapy are critical.

Diagnosis

Acute bacterial meningitis must be considered in the differential diagnosis of persons of any age presenting with fever and headache or signs of meningeal irritation or acute central nervous system dysfunction. Presentations can be subtle at the extremes of age or in patients who have received partially effective antibiotic therapy. The diagnosis of bacterial meningitis requires the examination of the cerebrospinal fluid (CSF), which must be performed as expeditiously as possible. Studies indicate that lumbar puncture may be safely performed on patients who have normal mental status or are without focal neurologic signs or papilledema; clinical impressions are predictive of the computed tomography (CT) findings. If there are signs or symptoms suggesting the presence of an intracranial mass (e.g., tumor, cerebral hematoma, or brain abscess), blood cultures should be obtained and empirical antibiotics should be administered prior to the performance of a CT scan.

Characteristically, the CSF findings in bacterial meningitis include a cell count of greater than 500 to 5000 white blood cells (WBCs) per mm3 with a predominance of neutrophils, a protein concentration of greater than 150 mg/mL, and a low glucose (e.g., less than 35–40 mg/dL). No single value is absolute, and a single value may be normal in up to a third of the cases. The Gram-stained sediment of centrifuged CSF is the critical examination leading to a specific diagnosis. In patients who have not received antibiotics capable of reaching the CSF, the Gram stain is positive in 80% to 90% of culture- confirmed cases. In persons previously treated with antibiotics (e.g., β- lactam antibiotics, tetracycline, fluoroquinolones), the frequency of positive Gram stains is much reduced (e.g., 60% to 70%), but the cells, cell type, protein, and glucose concentrations are not significantly affected. CSF antigen tests are not reliable, and variable negative and positive predictive values direct against relying on the use of such tests. Clinical judgment is paramount, and antibiotics should be given in situations of ambiguous results of the CSF examination.

Antibiotic Selection

The outcome of bacterial meningitis is closely related to the timely use of antibiotics. Hypotension, seizures, an altered mental status, and hypoglycorrhachia at the time of initial antibiotic administration are predictive of higher case fatality and neurologic sequelae. Because prompt administration of antibiotics is critical, the choice of antibiotics must be made before results of the CSF cultures are known. If organisms are seen on Gram stain, therapy may be directed by the probable bacterial etiology (Table 1). In the event the CSF Gram stain fails to reveal a possible pathogen, empirical antibiotic therapy should be begun based on the age of the patient for those persons who have acquired their infection in the community (Table 2). For those persons who are members of special risk groups, empirical therapy should be based on the likely etiology (Table 3). Once the CSF cultures are completed, therapy can be modified according to results of the culture and sensitivity data.

Table 1

Cerebrospinal Fluid Gram Stain Morphology and Antibiotic Recommendations

Table 2

Antibiotic Recommendations for Bacterial Meningitis Acquired in the Community, by Age Group and Probable Pathogen

Age Group Probable Pathogens Empirical Therapy
Neonate <1 mo Group B streptococcus; E. coli, or other gram-negative Ampicillin plus cefotaxime
enteric rod; occasionally L. monocytogenes (Claforan)
Infants 1–3 mo H. influenzae, N. meningitidis, S. pneumoniae, Group B streptococci Ceftriaxone (Rocephin) or cefotaxime (Claforan)
Children 3 mo–7 y and older children and adults 7–50 y H. influenzae, S. pneumoniae, N. meningitidis Ceftriaxone or cefotaxime plus vancomycin (Vancocin)
Older adults >50 y S. pneumoniae, N. meningitidis, L. monocytogenes Ceftriaxone plus ampicillin

Table 3

Antibiotic Recommendations for Presumed Bacterial Meningitis in Persons with Special Risks

Condition or Risk Factor Common Pathogens Antibiotic  Recommendations
Impaired immunity (e.g., HIV, early complement deficiency,  agammaglobulinemia) L. monocytogenes, S. pneumoniae, H. influenzae Ampicillin plus ceftriaxone (Rocephin) or cefotaxime (Claforan)
Closed head trauma with CSF leak S. pneumoniae, H. influenzae Ceftriaxone or cefotaxime plus vancomycin (Vancocin)
Asplenia S. pneumoniae, H. influenzae Ceftriaxone or cefotaxime plus vancomycin
Terminal  complement deficiency N. meningitidis Ceftriaxone or cefotaxime
Neurosurgical  procedures S. aureus Vancomycin plus ceftriaxone or cefotaxime
CSF shunt infections Coagulase-negative staphylococci, Gram-negative bacilli
Elderly patients (>65 y) S. pneumoniae, L. monocytogenes Ceftriaxone or cefotaxime plus vancomycin
Recurrent bacterial meningitis (see CSF leak) S. pneumoniae Ceftriaxone or cefotaxime plus vancomycin
Alcoholic patients S. pneumoniae and Gram-negative bacilli Ceftriaxone or cefotaxime plus vancomycin

Abbreviation: CSF = cerebrospinal fluid.

Antibiotics used in bacterial meningitis should be rapidly bactericidal and achieve high concentrations in the CSF. Antibiotics should be given in maximal doses (Table 4). Because the bactericidal activity of antibiotics in CSF is dose dependent, the fractional CSF-to- serum ratio is very small. Finally, the use of combinations of antibiotics should be minimized to avoid antagonizing the bactericidal activity.

Table 4

Antibiotic Doses for Adults and Children for Treatment of Bacterial Meningitis

Adapted from Bradley JS, Nelson JD: 2002–2003 Nelson’s Pocket Book of Pediatric Antimicrobial Therapy, 15th ed. Philadelphia, Lippincott Williams & Wilkins, 2002; Gilbert DN, Moellering RC, Sande MA. The Sanford Guide to Antimicrobial Therapy 2005. Hyde Park, Antimicrobial Therapy Inc., 2005.

Special Considerations for Antibiotic Therapy

During the past two decades, resistance to penicillin and some third- generation cephalosporins (e.g., ceftriaxone [Rocephin], cefotaxime [Claforan]) has steadily increased among strains of Streptococcus pneumoniae. Currently, approximately 30% to 50% of isolates are either intermediately (inhibitory concentration, 0.1–1.0 µg/mL) or fully (inhibitory concentration more than 2.0 µg/mL) resistant to Penicillin G and ampicillin. Resistance to ceftriaxone (Rocephin) and cefotaxime (Claforan) may occur as well in 10% to 15% of strains. Vancomycin (Vancocin) is recommended in those regimens for meningitis when pneumococci are considered. However, higher maximal doses are required for vancomycin because of its relatively poor penetration into the CSF. In general, lumbar puncture with CSF culture should be repeated in 48 hours in those cases where vancomycin therapy is the primary drug because of demonstrated penicillin or cephalosporin resistance.

Meningitis caused by gram-negative bacilli such as Pseudomonas aeruginosa, Escherichia coli, or Enterobacter cloacae should be treated with a cephalosporin with an extended spectrum of Gram-negative activity, such as ceftazidime (Fortaz) or cefepime (Maxipime). A carbapenem, such as imipenem (Primaxin) or meropenem (Merrem), can also be used for antibiotic-resistant gram-negative enteric and pseudomonas meningitis. Meropenem is associated with less risk of drug-induced seizures and may be a better choice for bacterial meningitis.

Patients with ventriculoatrial and ventriculoperitoneal shunt– associated meningitis and ventriculitis usually require removal of the shunt for cure, as well as the administration of antibiotics to clear the infection. Certain patients with infections caused by organisms of reduced virulence, such as coagulase-negative staphylococci, or those with exquisitely antibiotic-susceptible infections, can be treated with a trial of antibiotics alone.

Because of the extreme sensitivity of Neisseria meningitidis to antibiotics, uncomplicated meningitis may be treated with as little as 5 to 7 days of antibiotics. Pneumococcal meningitis may be treated with 10 to 14 days of antibiotics, and haemophilus infections are treated successfully with 7 to 10 days of antibiotics. Gram-negative meningitis was treated in the past with 3 weeks of aminoglycosides, but current experience with newer extended-spectrum cephalosporins (ceftriaxone, cefotaxime, carbapenems) suggests that 2 weeks of therapy is often sufficient in neonates as well as in some elderly patients and postoperative infections.

All patients with bacterial meningitis should be monitored carefully throughout the treatment period. Infectious disease consultation is recommended for most infections of the central nervous system.

Repeated lumbar punctures are not routinely recommended for patients with fully susceptible bacterial isolates or in those who show good response to therapy. Repeated sampling of the CSF with lumbar puncture or, when appropriate, shunt or ventricular reservoir puncture should be performed in those with known resistant bacterial isolates, in patients who have an inadequate response, in those patients who deteriorate on therapy, or in those for whom clinical response may correlate poorly with the microbiologic response (shunt infections, neonates, and elderly patients).

Adjunctive Therapy

Corticosteroids reduce the incidence of permanent neurologic sequelae in children with bacterial meningitis, particularly when caused by Haemophilus influenza type b. Data in support of steroids in either pneumococcal or meningococcal infections are less robust.

Dexamethasone (Decadron1), 0.15 mg/kg every 6 hours for the first 2 to 4 days of treatment, was evaluated in children older than 2 months with bacterial meningitis. The first dose of dexamethasone should be given before, at the start, or no later than 12 hours after beginning antibiotics.

Use of corticosteroids in adults is more controversial. Although doses of dexamethasone are recommended by some experts for adults with bacterial meningitis, its efficacy in adult meningitis has not been evaluated in a well-designed prospective trial. A recent study in adults found that corticosteroids significantly reduced the risk for unfavorable outcomes, particularly in patients with pneumococcal meningitis. There has been concern that the anti-inflammatory properties of dexamethasone may decrease the penetration of antibiotics, especially vancomycin, into the CSF. One study in children did not show this to be the case. Dexamethasone1 should be administered in adults with proven or suspected pneumococcal meningitis, but only if it can be given prior to the first dose of antibiotics in a dose of 10 mg every 6 hours for 4 days. In patients with meningitis caused by S. pneumoniae highly resistant to penicillin (minimum inhibitory concentration [MIC] >2.0 µg/mL) or cephalosporins (MIC >4.0 µg/mL), vancomycin should not be used as a single agent if corticosteroids are used. The addition of rifampin (Rifadin1) is often recommended in these situations.

Chemoprophylaxis for Bacterial Meningitis

Prophylactic antibiotics are recommended in case of meningitis caused by Neisseria meningitidis and H. influenzae type b. Prophylaxis is provided to eliminate the carriage of organisms among contacts and prevent spread to hosts susceptible to invasive disease. In cases of meningococcal meningitis, prophylaxis is indicated only for those with household or intimate contact with the index case. Administration of prophylaxis to large groups (e.g., college students, schoolchildren, or preschool classes) requires a special assessment and a recommendation of local or regional health departments.

Chemoprophylaxis is not necessary for casual contacts or medical personnel unless there is a direct exposure to respiratory secretions. The recommended dose of rifampin (Rifadin) is 10 mg/kg (600 maximal, adults) twice a day for 2 days; ciprofloxacin (Cipro1), 500 mg as single dose, is also effective for adults. Third-generation cephalosporins used in treatment of the index case of meningitis are sufficient to eliminate carriage of the organism.

Chemoprophylaxis for H. influenzae type b is recommended for all household contacts of an index case if one of the contacts is an unvaccinated child younger than 4 years. If the index case is treated with ceftriaxone (Rocephin) or cefotaxime (Claforan), prophylaxis is not required, but if treated with ampicillin or chloramphenicol (Chloromycetin), prophylaxis is recommended to eliminate carriage. The recommended regimen for prophylaxis is rifampin,1 20 mg/kg (or 600 mg in adults) once a day for 4 days. With the near elimination of invasive infections caused by H. influenzae type b with the use of routine immunization of children with conjugate haemophilus vaccines, H. influenzae types A, F, and (rarely) other serotypes have emerged, and the use of prophylaxis is not recommended in these situations because sufficient data are not available to support its efficacy, nor has spread within contacts been documented.

Vaccines for Bacterial Meningitis

The universal recommendation for the use of protein-polysaccharide conjugate H. influenzae type b (HIB) vaccines in 1987 reduced the incidence of bacterial meningitis by this organism by greater than 97%. Three HIB vaccines (PedvaxHIB, ActHIB, HibTITER), licensed in the United States, are routinely given to children in dosage schedules employing three to four doses by 12 to 18 months of age (see www.cdc.gov).

A pneumococcal protein-polysaccharide conjugate vaccine (Prevnar) licensed in 2000 is routinely recommended for children and has markedly reduced the incidence of invasive infections with seven serotypes of pneumococci in children. This vaccine is also recommended for children at high risk of pneumococcal infections (e.g., HIV infection, asplenia, sickle cell disease, and others). A new Prevnar 13 with thirteen serotypes is now recommended to replace Prevnar 7 for routine use and is also recommended for persons over 50 years of age with high-risk conditions. The full recommendations for the use of this vacccine alone and in combination with the polysaccharide vaccine (Pneumovax 23) are available from the CDC. A pneumococcal polysaccharide vaccine (Pneumovax 23) is recommended for adults older than 65 years or for those over 50 years with risk factors (e.g., alcoholism, diabetes or other metabolic or renal disease, chronic pulmonary or cardiac disease). A polysaccharide conjugate vaccine (Prevnar) has been recently approved for limited adult use in high-risk patients; please see recommendations for use in adults and children at www.vaccines.gov. Although clear evidence for prevention of bacterial meningitis is lacking, evidence supports its efficacy against invasive pneumococcal diseases, many of which are the preceding infections leading to bacteremia and meningitis.

Three vaccines are available in the United States for prevention of meningococcal disease. All available vaccines provide protection against four serotypes: A, C, Y, and 1-135. Either of two protein- conjugate vaccines (Menactra and Menveo) are currently recommended for routine administration to all children at 11 to 12 years of age with a repeated dose at 5 years after the first dose. These vaccines are also recommended for persons at high risk for meningococcal disease (e.g., those with complement deficiencies, or asplenia, as well as microbiology technologists or travelers and workers in endemic areas) as early as 9 months of age, to be repeated at 12 months (Menactra) or equal to those who are 2 years of age or older (Menactra and Menveo) up to 55 years of age. It is recommended that younger patients at high risk be given a two-dose primary series and that all high-risk persons be given a second dose at 3 to 5 years depending upon risk and age at first dose (see the package inserts for dosing details). In addition, a single polysaccharide vaccine (Menomune) remains available for high-risk persons over 55 years of age.

References

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3.     Centers for Disease Control and Prevention. Use of 13-valent pneumococcal conjugate vaccine and 23 valent pneumococcal polysaccharide vaccine among children aged 6–18 years with immunocompromising conditions. MMWR. 2012;61:816–819.

4.    Centers for Disease Control and Prevention. Use of 13-valent pneumococcal conjugate vaccine and 23 valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2013;62:521–524.

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9.       Klinger G., Chin C.-Y., Beyene J., et al. Predicting the outcome of neonatal bacterial meningitis. Pediatrics. 2000;106:477–482.

10.       Odio C.M., Faingezicht I., Paris M., et al. The beneficial effects of early dexamethasone administration in infants and children with bacterial meningitis. N Engl J Med. 1991;324:1525–1531.

11.    Ronan A., Hogg G.G., Klug C.L. Cerebrospinal fluid shunt infections in children. Pediatr Infect Dis J. 1995;14:782–786.

12.     Schuchat A., Robinson K., Wenger J.D., et al. Bacterial meningitis in the United States in 1995. N Engl J Med. 1997;337:970–976. Unhanand M., Mustapha M.M., McCracken G.H., et al. Gram-negative enteric bacillary meningitis: A twenty-one year experience. J Pediatr. 1993;122:15–17.

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1  Not FDA approved for this  indication.

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