Short Course Chemotherapy for Tuberculosis
Introduction
- Short-course chemotherapy (SCC) represents a paradigm shift in the management of tuberculosis (TB), reducing treatment duration from the historical 12–18 months to 6 months while maintaining high cure rates and minimizing relapse.
- The strategy relies on the synergistic use of potent bactericidal and sterilizing drugs to rapidly reduce the bacillary load and eliminate persistent organisms.
- Current pediatric management under the National Tuberculosis Elimination Programme (NTEP) 2022 guidelines emphasizes Universal Drug Susceptibility Testing (U-DST) to stratify patients upfront into Rifampicin-Sensitive (RS-TB) or Drug-Resistant (DR-TB) categories.
1. Scientific Basis of Short Course Chemotherapy
The success of SCC depends on the ability of drug combinations to target distinct subpopulations of Mycobacterium tuberculosis within the host:
- Rapidly Multiplying Bacilli: Found in cavity walls (neutral pH, high oxygen). Killed effectively by Isoniazid (H) and Rifampicin (R).
- Intracellular Bacilli (Slow Growing): Located inside macrophages (acidic pH). Pyrazinamide (Z) is the most potent sterilizing agent against this population.
- Extracellular Slowly Growing Bacilli (Spurters): Found in solid caseous necrosis (neutral pH, low oxygen). Rifampicin is the most effective drug here.
- Dormant Bacilli: Metabolic inactivity makes them resistant to most drugs; the host immune system typically eliminates these, though they are a source of relapse.
Key Principles:
- Bactericidal Action: Rapid killing of dividing bacilli to render the patient non-infectious (Intensive Phase).
- Sterilizing Action: Elimination of "persisters" to prevent relapse (Continuation Phase).
- Prevention of Resistance: Use of multiple drugs prevents the selection of naturally occurring drug-resistant mutants.
2. Phases of Chemotherapy
Treatment is biphasic to ensure both rapid clearance and prevention of relapse.
A. Intensive Phase (IP)
- Duration: 2 months.
- Goal: Rapidly kill M. tb to prevent deterioration and death, and reduce infectivity. Sputum conversion is achieved in 80–90% of cases.
- Regimen: Four drugs—Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), and Ethambutol (E) are used daily.
B. Continuation Phase (CP)
- Duration: 4 months.
- Goal: Elimination of residual/dormant bacilli to prevent relapse.
- Regimen: Three drugs—Isoniazid (H), Rifampicin (R), and Ethambutol (E).
- Note on Ethambutol: Previously, only H and R were used in CP. However, due to the high prevalence of background Isoniazid resistance in India (approx. 13% in new cases), Ethambutol is now mandated in the CP for all new cases to prevent the amplification of resistance.
3. Current Recommended Regimen (NTEP 2022)
The "Category II" (Retreatment) regimen has been withdrawn. All children, including those previously treated, are tested upfront for Rifampicin resistance. If sensitive, they are treated with the standard RS-TB regimen.
| Type of Patient | Regimen | Drugs | Duration |
|---|---|---|---|
| Drug Sensitive TB (New & Previously Treated) | 2 HRZE + 4 HRE | IP: Isoniazid, Rifampicin, Pyrazinamide, Ethambutol CP: Isoniazid, Rifampicin, Ethambutol | 6 Months |
Modifications:
- CNS / Spinal / Osteoarticular TB: The continuation phase is extended to 10 months, making the total duration 12 months.
- HIV Co-infection: Treatment is the same, but daily therapy is mandatory. Pyridoxine is strictly recommended.
4. Drug Dosages and Administration
NTEP recommends daily therapy using Fixed Drug Combinations (FDCs) to improve adherence and reduce prescription errors. Dispersible FDCs are available for children.
| Drug | Daily Dose (mg/kg) | Max Dose | Key Adverse Effects |
|---|---|---|---|
| Isoniazid (H) | 10 (7–15) | 300 mg | Hepatotoxicity, Peripheral neuropathy |
| Rifampicin (R) | 15 (10–20) | 600 mg | Hepatotoxicity, Red urine, Flu-like syndrome |
| Pyrazinamide (Z) | 35 (30–40) | 2000 mg | Hepatotoxicity, Arthralgia, Hyperuricemia |
| Ethambutol (E) | 20 (15–25) | 1200 mg | Optic neuritis (Dose-dependent) |
Adjunct Therapy:
- Pyridoxine (Vit B6): 10 mg/day is recommended for all children on INH regimens (previously only for high risk) to prevent neuropathy, given the high prevalence of malnutrition.
- Corticosteroids: Indicated for TB meningitis (reduces mortality/sequelae) and pericarditis.
5. Monitoring and Follow-up
- Clinical: Monthly assessment of weight, symptoms, and adherence.
- Microbiological: Follow-up sputum/gastric aspirate at the end of the Intensive Phase (2 months) and at completion (6 months).
- Response: If a child is non-responsive after 4 weeks of compliant therapy, they should be evaluated for drug resistance (using NAAT/LPA) rather than empirically extending the intensive phase.