Central Nervous System Infections

Laura M. Tormoehlen

Karen L. Roos

I. BACTERIAL MENINGITIS

The initial signs and symptoms of bacterial meningitis are fever, stiff neck, headache, lethargy, confusion or coma, nausea and vomiting, and photophobia. Examination of the CSF shows an elevated opening pressure (>180 mm H₂O), a decreased glucose concentration (<40 mg per dl), polymorphonuclear pleocytosis, and an elevated protein concentration. The diagnosis is made by demonstrating the organism with Gram’s stain or in culture. Polymerase chain reaction (PCR) to detect bacterial nucleic acid in CSF is available at some centers. Bacterial meningitis is a neurologic emergency, and initial treatment is empiric until a specific organism is identified.

A. Therapeutic approach

1. Dexamethasone therapy.

The American Academy of Pediatrics recommends consideration of dexamethasone in the treatment of infants and children 2 months of age and older with proven or suspected bacterial meningitis on the basis of findings on CSF examination, a Gram’s-stained smear of the CSF, or antigen test results. Dexamethasone is also recommended in adults with suspected bacterial meningitis and in proven pneumococcal meningitis (based on CSF gram-positive diplococci or blood or CSF cultures that are positive for Streptococcus pneumoniae). In clinical trials, dexamethasone improves the outcome of meningitis. In experimental models of bacterial meningitis, dexamethasone inhibits synthesis of the inflammatory cytokines, decreases leakage of serum proteins into the CSF, minimizes damage to the blood-brain barrier (BBB), and decreases CSF outflow resistance. Dexamethasone also decreases brain edema and intracranial pressure (ICP).

The recommended dosage of dexamethasone is 0.15 mg per kg intravenous (IV) every 6 hours for the first 4 days of therapy. The initial dose of dexamethasone should be given before or at least with the initial dose of antimicrobial therapy for maximum benefit. Dexamethasone is not likely to be of much benefit if started >24 hours or more after antimicrobial therapy has been initiated. The concomitant use of an histamine-2 receptor antagonist is recommended with dexamethasone to avoid gastrointestinal bleeding.

2. Antimicrobial therapy.

If bacterial meningitis is suspected, antimicrobial therapy must be initiated immediately. This should be done before the performance of CT or lumbar puncture. Initial antimicrobial therapy is empiric and is determined by the most likely meningeal pathogen according to the patient’s age and underlying condition or predisposing factors.

The most likely etiologic organisms of bacterial meningitis in neonates are group B streptococci, enteric gram-negative bacilli (Escherichia coli), and Listeria monocytogenes. Empiric therapy for bacterial meningitis in a neonate should include a combination of ampicillin and either a third or fourth generation cephalosporin (cefotaxime or cefepime).
Empiric therapy for community-acquired bacterial meningitis in infants and children should include coverage for S.pneumoniae and Neisseria meningitidis. A third or fourth generation cephalosporin (ceftriaxone, cefotaxime, or cefepime) and vancomycin are recommended as initial therapy for bacterial meningitis in children in whom the etiologic agent has not been identified. Cefuroxime, also a thirdgeneration cephalosporin, is not recommended for therapy for bacterial meningitis in children because of reports of delayed sterilization of CSF cultures associated with hearing loss in children treated with cefuroxime.
Empiric therapy for community-acquired bacterial meningitis in adults (15 to 50 years of age) should include coverage for 5. pneumoniae and N. meningitidis. A third-generation cephalosporin (ceftriaxone or cefotaxime) or a fourth-generation cephalosporin (cefepime) plus vancomycin is recommended for empiric therapy. All CSF isolates of pneumococci and meningococci should be tested for antimicrobial susceptibility. Cefotaxime, ceftriaxone, or cefepime is recommended for relatively resistant strains of pneumococci (penicillin minimal inhibitory concentrations [MIC], 0.1 to 1.0 µg per ml and MICs of cefotaxime or cefepime ≤0.5 µg per ml). For highly penicillin-resistant pneumococcal meningitis (MIC > 1.0 µg per ml), a combination of vancomycin and a third-generation or fourth-generation cephalosporin is recommended. Penicillin G or ampicillin can be used for meningococcal meningitis.
Initial therapy for meningitis in postneurosurgical patients should be directed against gram-negative bacilli, Pseudomonas aeruginosa, and Staphylococcus aureus. Ceftazidime or meropenem is recommended for management of gram-negative bacillary meningitis in neurosurgical patients. Ceftazidime is the only cephalosporin with sufficient activity against P. aeruginosa in the CNS. Vancomycin should be added until infection with staphylococci is excluded.
In infants, children, and adults with CSF ventriculoperitoneal shunt infections, initial therapy for meningitis should include coverage for coagulase-negative staphylococci and S. aureus. The assumption can be made that the organism will be resistant to methicillin; therefore, initial therapy for a shunt infection should include IV vancomycin. Intrashunt or intraventricular vancomycin may also be needed to eradicate the infection.
In immunocompromised patients, the infecting organism can be predicted on the basis of the type of immune abnormality. In patients with neutropenia, initial therapy for bacterial meningitis should include coverage for L. monocytogenes, staphylococci, and enteric gram-negative bacilli. Patients with defective humoral immunity and those who have undergone splenectomy are unable to mount an antibody response to a bacterial infection or to control an infection caused by encapsulated bacteria. These patients are at particular risk of meningitis caused by S. pneumoniae, Haemophilus influenzae type b (Hib), and N. meningitidis.
The most common organisms causing meningitis in the older adult (50 years or older) are S. pneumoniae and enteric gram-negative bacilli; however, meningitis caused by Listeria organisms and Hib are increasingly recognized. The recommended initial therapy for meningitis in the older adult is either ceftriaxone, cefotaxime, or cefepime in combination with vancomycin and ampicillin. Table 43.1 lists empiric antimicrobial therapy for bacterial meningitis by age group. Tables 43.2 and 43.3 list the recommended antimicrobial therapy for bacterial meningitis in neonates, infants and children, and adults by meningeal pathogen.

TABLE 43.1 Empirie Antimicrobial Therapy for Bacterial Meningitis

Age Group		Antimicrobial Agent
Neonates		Ampicillin plus cefotaxime or cefepime
Infants and children		Ceftriaxone, cefotaxime, or cefepime plus vancomycin
	Adults (15-50 y)
	Community acquired	Ceftriaxone, cefotaxime, or cefepime plus vancomycin
	Otitis, mastoiditis, sinusitis	Ceftriaxone plus vancomycin plus metronidazole
	Postneurosurgical	Ceftazidime or meropenem plus vancomycin
	Immunocompromised	Ceftazidime or meropenem plus ampicillin
Older adults		Ceftriaxone, cefotaxime, or cefepime plus vancomycin plus ampicillin

TABLE 43.2 Recommended Antimicrobial Therapy for Bacterial Meningitis in Neonates, Infants and Children by Organism

Total Daily Dose
Organism	Neonates (< 1 wk)	Neonates (1-4 wk)	Infants and Children (>4 wk)
Hib	Cefotaxime 100 mg/kg a day q12h or Cefepime 100 mg/kg a day q12h	Cefotaxime 150-200 mg/kg a day q8h or cefepime 100 mg/kg a day q12h	Ceftriaxone 100 mg/kg a day IV in a once or twice daily dosing regimen, or cefotaxime 225 mg/kg a day IV in divided doses q6h or cefepime 150 mg/kg a day in divided doses q8h
S. pneumoniae^a	Cefotaxime	Cefotaxime	Ceftriaxone or cefotaxime or cefepime
Group B streptococci	Ampicillin 100-150 mg/kg a day q8h	Ampicillin 200 mg/kg a day q8h	Ampicillin 200-300 mg/kg a day q4-6h
L. monocytogenes^b	Ampicillin with or without gentamicin 5 mg/kg a day q8h	Ampicillin with or without gentamicin 7.5 mg/kg a day q8h	Ampicillin with or without gentamicin 5 mg/kg a day q8h
N. meningitidis	Penicillin G 50,000-150,000 U/kg a day q8h, or ampicillin 100-150 mg/kg a day q12h	Penicillin G 150,000-200,000 U/kg a day q6h, or ampicillin 200 mg/kg a day q8h	Penicillin G 250,000-400,000 U/kg a day q4h, or ampicillin IV in divided doses q4-6h
Enteric gram-negative bacilli^a	Cefotaxime or cefepime	Cefotaxime or cefepime	Ceftriaxone or cefotaxime or cefepime
S. aureus	Oxacillin 50-100 mg/kg a day q6h	Oxacillin 100-200 mg/kg a day q6h	Oxacillin 200-300 mg/kg a day q4h
Methicillin-resistant staphylococci	Vancomycin 20-30 mg/kg a day q12h	Vancomycin 40 mg/kg a day q6h	Vancomycin 40-60 mg/kg a day q6h, may also add intrashunt or intraventricular vancomycin 10 mg once a day
^aDosages are the same as for Hib. ^bDosages are the same as for group B streptococci.

TABLE 43.3 Recommended Antimicrobial Therapy for Bacterial Meningitis in Adults by Organism

Organism	Antimicrobial Agent
S. pneumoniae	Ceftriaxone 4 g/d (q 12h) or cefotaxime 12 g/d (q4h) or cefepime 6 g/d (q8h) plus vancomycin 45-60 mg/kg/d (q6-12h)
N. meningitidis	Penicillin G 20-24 miU/kg a day (q4h) or ampicillin 12 g/d (q4h)
Gram-negative bacilli (except P. aeruginosa)	Ceftriaxone 4 g/d (q12h) or cefotaxime 12 g/d (q4h) or cefepime 6 g/d (q8h)
P. aeruginosa	Ceftazidime 8 g/d (q8h) or meropenem 6 g/d (q8h)
H. influenzae type b	Ceftriaxone or cefotaxime or cefepime
S. aureus (methicillin-sensitive)	Oxacillin 9-12 g/d (q4h) or nafcillin 12 g/d (q4h)
Staphylococcus aureus (methicillin-resistant)	Vancomycin 45-60 mg/kg/d (q6-12h)
L. monocytogenes	Ampicillin 12 g/d (q4h) with or without gentamicin
Enterobacteriaceae	Ceftriaxone or cefotaxime or cefepime