What is the difference between HRZE (Isoniazid, Rifampicin, Pyrazinamide, Ethambutol) and HRZES (Isoniazid, Rifampicin, Pyrazinamide, Ethambutol, Streptomycin) regimens in the treatment of Central Nervous System (CNS) tuberculosis?

HRZE vs HRZES in CNS Tuberculosis

For CNS tuberculosis (tuberculous meningitis), use HRZE (isoniazid, rifampicin, pyrazinamide, ethambutol) for 2 months followed by HR (isoniazid and rifampicin) for 10 months, for a total duration of 12 months. Streptomycin (the "S" in HRZES) is not necessary and offers no additional benefit for CNS TB, as it penetrates poorly into cerebrospinal fluid except when meninges are acutely inflamed. 1

Key Differences Between HRZE and HRZES

Drug Penetration into CNS

• Isoniazid, pyrazinamide, and ethionamide penetrate well into cerebrospinal fluid throughout treatment 1
• Rifampicin penetrates less effectively but still achieves therapeutic levels 1
• Ethambutol and streptomycin only penetrate adequately when meninges are inflamed in the early stages of treatment 1
• Intrathecal administration of streptomycin is unnecessary and not recommended 1

Standard Regimen for CNS TB

The recommended treatment consists of:

• Initial phase (2 months): HRZE given daily 1, 2
• Continuation phase (10 months): HR given daily 1, 2
• Total duration: 12 months 1, 2

When to Consider a Fourth Drug Beyond Ethambutol

Streptomycin or ethionamide can replace ethambutol as the fourth drug in the initial phase if: 1

• Drug resistance is suspected or proven
• The patient cannot tolerate ethambutol
• Visual acuity cannot be monitored (particularly in unconscious Stage III patients) 1

Ethionamide (15-20 mg/kg orally, max 1 g/day divided into 2-3 doses) should specifically be used for TB meningitis according to CDC guidelines for HIV-infected children, though this principle applies broadly 1

Critical Treatment Considerations

Corticosteroid Therapy

Adjunctive corticosteroids are mandatory for CNS tuberculosis and improve outcomes in moderate to severe disease (Stages II and III): 1, 3

• Dexamethasone 6-12 mg per day, OR
• Prednisone 60-80 mg per day
• Tapered over 4-8 weeks 3
• Do not taper too quickly as CNS inflammation symptoms may recur 3

Disease Staging and Prognosis

The British Medical Research Council staging system guides treatment intensity: 3

• Stage I: Fully conscious, rational, no neurologic signs
• Stage II: Confused or has neurologic signs (cranial nerve palsy, hemiparesis) - corticosteroids recommended
• Stage III: Comatose or stuporous with severe neurologic signs - corticosteroids mandatory

Drug Resistance Considerations

If isoniazid resistance is documented: 1

• Discontinue isoniazid
• Continue rifampicin + pyrazinamide + ethambutol + streptomycin for first 2 months
• Follow with rifampicin + pyrazinamide + ethambutol to complete 12-18 months total 1

If rifampicin resistance is documented: 1

• Discontinue rifampicin
• Use isoniazid + pyrazinamide + ethambutol + streptomycin for first 2 months
• Continue isoniazid + pyrazinamide + ethambutol to complete 12-18 months total

If multidrug resistance (resistance to both isoniazid and rifampicin): 4

• Consult a tuberculosis expert immediately
• Use at least 2 drugs to which the organism is susceptible
• Minimum of 3 drugs should be administered
• Treatment duration: 18-24 months after culture conversion 1

Monitoring Requirements

• Directly observed therapy (DOT) is standard of care for all tuberculosis patients, including CNS TB 1, 4
• Pyridoxine supplementation should be administered if isoniazid is used, particularly in HIV-infected patients, pregnant women, malnourished individuals, and those with diabetes or renal failure 1, 5
• Baseline and periodic liver function tests are essential, especially during the first 2 months 6

Common Pitfalls to Avoid

• Never use streptomycin as routine fifth drug in CNS TB - it adds no benefit beyond the initial weeks when meninges are inflamed and increases toxicity risk 1
• Never shorten treatment duration below 12 months for CNS TB - even if cultures become negative earlier, the full 12-month course is required 1, 4
• Never omit corticosteroids in Stage II or III disease - they significantly improve neurologic outcomes and survival 1, 3
• Never use ethambutol without caution in unconscious patients - visual acuity cannot be monitored, making streptomycin or ethionamide preferable as the fourth drug 1
• Never extend pyrazinamide beyond 2 months unless treating drug-resistant TB - prolonged use increases hepatotoxicity without additional benefit 5
• Never add a single drug to a failing regimen - this promotes drug resistance 6