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Principles of Antibiotic Therapy
The fundamental principles in selection of antibiotics for bacterial meningitis are using agents that:
- Achieve bactericidal activity in the CSF: The CSF has impaired humoral immunity, so bacteriostatic agents are not reliable. Antibiotics must be bactericidal at CSF concentrations.
- Penetrate adequately into the CSF: Most antibiotics only achieve 10-20% of serum concentrations in CSF due to the blood-brain barrier. Small, lipid-soluble antibiotics penetrate best. Inflammation disrupts the blood-brain barrier, increasing permeability.
- Cover likely causative organisms based on patient age
Empiric Antibiotic Therapy
Empiric antibiotic therapy should be initiated immediately if bacterial meningitis is suspected clinically, even before lumbar puncture is performed. The regimen should provide coverage for S. pneumoniae and N. meningitidis, the leading causes of bacterial meningitis.
Neonates <1 month old
Likely pathogens: Group B streptococcus, Escherichia coli, Listeria monocytogenes
Recommended regimen:
- Ampicillin 50-100 mg/kg/dose IV every 6 hours
- Cefotaxime 50 mg/kg/dose IV every 6 hours
Or
- Ampicillin 50-100 mg/kg/dose IV every 6 hours
- Gentamicin 2.5 mg/kg/dose IV every 8 hours
Add acyclovir if risk factors for HSV present.
Children 1 month – 2 years old
Likely pathogens: S. pneumoniae, N. meningitidis, H. influenzae, Group B streptococcus
Recommended regimen:
- Vancomycin 15 mg/kg/dose IV every 6 hours (max 4 g/day)
- Ceftriaxone 50-100 mg/kg/dose IV every 12 hours (max 4 g/day)
Children >2 years old
Likely pathogens: S. pneumoniae, N. meningitidis
Recommended regimen:
- Vancomycin 15 mg/kg/dose IV every 6 hours (max 4 g/day)
- Ceftriaxone 50-100 mg/kg/dose IV every 12 hours (max 4 g/day)
Special populations may require additional coverage:
- Immunocompromised patients: add ampicillin to cover Listeria
- Penetrating trauma or neurosurgery: add metronidazole for anaerobes
- CSF shunt: add vancomycin for Staphylococci
Empiric antivirals like acyclovir should be added if HSV encephalitis is clinically suspected based on risk factors and presentation.
The empiric regimen should be continued until the CSF culture identifies the causative organism.
The CSF gram stain can guide therapy, but empiric antibiotics should not be narrowed based on gram stain alone due to potential misinterpretation.
Definitive Antibiotic Therapy
Once the organism is identified by CSF culture, antibiotics can be tailored accordingly:
Streptococcus pneumoniae
- Penicillin-sensitive: Penicillin G 300,000 units/kg/day IV divided q4-6h or ceftriaxone 100 mg/kg/day IV
- Penicillin-resistant, cephalosporin-sensitive: Ceftriaxone 100 mg/kg/day IV or cefotaxime 225-300 mg/kg/day IV
- Cephalosporin-resistant: Vancomycin 60 mg/kg/day IV plus ceftriaxone 100 mg/kg/day IV. Add rifampin if poor clinical response.
Neisseria meningitidis
- Ceftriaxone 100 mg/kg/day IV or cefotaxime 225-300 mg/kg/day IV
- Alternative: Penicillin G 300,000 units/kg/day in four divided doses
Haemophilus influenzae
- Ceftriaxone 100 mg/kg/day IV or cefotaxime 200-300 mg/kg/day IV
Group B streptococcus
- Penicillin G 450,000-500,000 units/kg/day IV divided q4-6h or ampicillin 300 mg/kg/day IV divided q6h
Listeria monocytogenes
- Ampicillin 300 mg/kg/day IV plus gentamicin 7.5 mg/kg/day IV. Can transition to ampicillin alone once stable.
Staphylococcus aureus
- Oxacillin or nafcillin 150-200 mg/kg/day IV for MSSA
- Vancomycin 60 mg/kg/day IV for MRSA
- Alt: Ceftaroline 45 mg/kg/day in three divided doses
Gram negative bacilli
- 3rd generation cephalosporin (e.g. ceftriaxone, cefotaxime) plus gentamicin for Enterobacteriaceae
- Ceftazidime or meropenem for Pseudomonas
- Meropenem for ESBL-producing organisms
Key Points in Definitive Therapy:
- Tailor therapy to pathogen and sensitivities – do not rely solely on empiric regimen
- Check local resistance patterns to guide antibiotic selection
- Combination therapy often required for resistant organisms
- Add rifampin if poor clinical response to first-line antibiotics
- Aminoglycosides do not achieve adequate CSF penetration – cannot be used alone
- Carbapenems like meropenem are second-line options for resistant organisms
Duration of Therapy
The duration of antibiotic therapy depends on the causative organism:
- Streptococcus pneumoniae: 10-14 days
- Neisseria meningitidis: 5-7 days
- Haemophilus influenzae: 7-10 days
- Group B streptococcus: 14-21 days
- Listeria monocytogenes: 21-28 days
- Staphylococcus aureus: ≥14 days
- Gram negative bacilli: ≥21 days
Shorter courses (4-7 days) have been proposed for certain common pathogens, but there are limited data, so standard durations are still recommended.
The duration is extended if:
- Repeat LP still shows positive culture
- Repeat LP still shows high CSF white count
- Complications like abscess are present
Adjunctive Therapy
Dexamethasone:
- Shown to improve neurological outcomes in pneumococcal meningitis
- Should be given just prior to or with the first antibiotic dose
- Reserved for children > 2 months old due to risk of gastrointestinal bleeding in young infants
- Dose: 0.15 mg/kg q6h x 4 days (maximum dose 10 mg q6h)
Response to Therapy and Monitoring
- Lack of clinical improvement within 24-48 hours warrants repeat LP to check sterility and tailor/adjust antibiotics
- Persistent fever >5 days occurs in 10-15% of cases, evaluate for complications or secondary infection
- Check repeat blood cultures to confirm sterility
- Daily neurologic assessment for new focal findings
- Repeat neuroimaging if signs of increased intracranial pressure
Prevention
Routine vaccination against H. influenzae type B and S. pneumoniae has dramatically reduced rates of meningitis.
Additional vaccines recommended for high risk groups:
- Meningococcal vaccine: adolescents 11-18 years old, college freshmen in dormitories, those with asplenia or complement deficiency. Protects against serogroups A, C, W, Y.
- Hib vaccine: Children with asplenia or sickle cell disease
- Pneumococcal vaccine: Children with immunocompromising conditions, cochlear implants
Post-exposure prophylaxis:
- Close contacts of meningococcal cases should receive antibiotic prophylaxis with rifampin, ciprofloxacin, or ceftriaxone.
- Household contacts of Hib cases should receive rifampin if unvaccinated children under 4 years old are present.
Clinical Pearls:
- Always initiate treatment promptly in suspected cases, even before confirmatory diagnostics.
- Adjust antibiotic choices based on local resistance patterns.
- In patients with a rash following ampicillin administration, consider viral meningitis, as this is a common reaction.
- Always consider potential drug-drug interactions, especially in patients on multiple medications.