Treatment of Tuberculosis Meningitis
TB meningitis requires a 9-12 month treatment regimen with isoniazid, rifampicin, pyrazinamide, and ethambutol (or streptomycin) for the first 2 months, followed by isoniazid and rifampicin for 7-10 additional months, plus adjunctive corticosteroids tapered over 6-8 weeks. 1
Initial Intensive Phase (First 2 Months)
The four-drug regimen for adults consists of: 1
- Isoniazid (INH): 5 mg/kg up to 300 mg daily 2
- Rifampicin (RIF): 10 mg/kg up to 600 mg daily 3
- Pyrazinamide (PZA): 40 mg/kg 4
- Fourth drug - Ethambutol (EMB): 15 mg/kg daily (preferred for adults) OR Streptomycin: 15 mg/kg daily 1, 3
The ATS/CDC/IDSA guidelines specifically state that for adults, ethambutol is preferred as the fourth drug based on expert opinion, though both ethambutol and streptomycin are acceptable options. 1 The rationale is that streptomycin and ethambutol only penetrate adequately when meninges are inflamed during early treatment stages. 5, 3
Continuation Phase (7-10 Additional Months)
After completing 2 months of four-drug therapy for drug-susceptible TB meningitis: 1
The British Thoracic Society recommends the full 12-month duration, while ATS/CDC/IDSA guidelines allow 9-12 months depending on clinical response. 3, 1 Given the devastating consequences of treatment failure, the 12-month duration represents the safer approach in clinical practice. 3
Adjunctive Corticosteroid Therapy
Corticosteroids are strongly recommended for all patients with TB meningitis based on mortality benefit demonstrated in systematic reviews: 1
- Dexamethasone: 6-12 mg/day OR Prednisolone: 60-80 mg/day 3, 6
- Duration: Tapered over 6-8 weeks 1, 5
- Evidence strength: Strong recommendation with moderate certainty in evidence 1
The systematic review found clear mortality benefit from adjuvant corticosteroids, making this a non-negotiable component of treatment. 1 Corticosteroids are particularly beneficial in Stage II and III disease (patients with confusion, neurologic signs, or coma). 6
Pediatric Considerations
For children with TB meningitis, the regimen differs slightly: 1
- Initial phase: INH (10-15 mg/kg up to 300 mg), RIF (10 mg/kg), PZA (40 mg/kg), and ethionamide or aminoglycoside (instead of ethambutol) for 2 months 1, 5
- Continuation phase: INH and RIF for 7-10 months 1, 5
- Total duration: Minimum 12 months recommended by British Thoracic Society 3
The AAP recommends ethionamide or an aminoglycoside rather than ethambutol in children because ethambutol should not be used when visual acuity cannot be monitored. 1, 2
Monitoring Requirements
Clinical and laboratory monitoring should include: 1, 5
- Repeated lumbar punctures to monitor CSF cell count, glucose, and protein, especially early in therapy 1, 5
- Regular neurological assessment for improvement or deterioration 5, 3
- Hepatotoxicity monitoring given the hepatotoxic potential of INH, RIF, and PZA 3
Neurosurgical Referral Indications
Immediate neurosurgical consultation is warranted for: 1, 5
Ventriculoperitoneal or ventriculoatrial shunting may be required for symptomatic hydrocephalus. 6
Critical Pitfalls to Avoid
Inadequate treatment duration is the most common error - TB meningitis requires 9-12 months, not the 6 months used for pulmonary TB. 5, 3 Premature discontinuation leads to relapse and drug resistance.
Insufficient drug penetration into CSF can occur if the wrong drugs are selected. 5 Isoniazid, pyrazinamide, and ethionamide penetrate well into CSF, while rifampicin penetrates less well but remains essential. 5, 3 Streptomycin and ethambutol only penetrate adequately when meninges are inflamed. 5, 3
Corticosteroid taper that is too rapid or discontinued too early may cause recurrence of CNS inflammation symptoms. 6 The full 6-8 week taper must be completed. 1
Failure to add a fourth drug when local resistance rates are >4% or unknown risks treatment failure with resistant organisms. 2, 6
Special Populations
HIV-infected patients: 1
- May have malabsorption requiring drug level monitoring 2
- May need longer treatment courses 6
- Higher rates of drug-resistant TB 7
- Drug interactions with antiretroviral therapy require careful management 7
Pregnant women: 2
- Avoid streptomycin (causes congenital deafness) 2
- Pyrazinamide not routinely recommended due to inadequate teratogenicity data 2
- Use INH, RIF, and ethambutol unless primary INH resistance is likely 2
Emerging Evidence
Higher doses of intravenous rifampicin (30 mg/kg) and fluoroquinolones (particularly levofloxacin 20 mg/kg) are being evaluated in ongoing trials to potentially improve outcomes and shorten treatment duration. 1, 5, 4 However, these remain investigational and should not replace standard therapy outside of clinical trials.