Principles of chemotherapy of anti tb drugs
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Here is a comprehensive overview of the Principles of Chemotherapy of Anti-TB Drugs:
Principles of Chemotherapy of Anti-TB Drugs
1. Rationale for Combination Therapy
The cornerstone of anti-TB chemotherapy is the use of multiple drugs simultaneously. This is based on several key principles:
- Preventing drug resistance: M. tuberculosis undergoes spontaneous mutations that confer resistance to individual drugs. The frequency is low (~1 in 10⁶–10⁸ bacilli per drug), but in large bacterial populations (e.g., pulmonary cavities), resistant mutants pre-exist. Using ≥2 drugs ensures mutants resistant to one drug are killed by another.
- Single-drug therapy is never acceptable — it invariably leads to acquired resistance.
- Combination therapy exploits the principle that the chance of simultaneous resistance to two unrelated drugs is the product of each individual mutation rate (e.g., 10⁻⁶ × 10⁻⁸ = 10⁻¹⁴), making pan-resistance essentially impossible with a proper regimen.
2. Bacterial Populations in TB Lesions
Understanding why multiple drugs and a long duration are needed requires recognizing the four distinct bacterial populations:
| Population | Location | Metabolic State | Key Drug Active Against It |
|---|---|---|---|
| Rapidly dividing bacilli | Cavity walls (extracellular) | Active | Isoniazid (INH) |
| Slowly dividing/semi-dormant | Caseous material | Intermittently active | Rifampicin (RIF) |
| Intracellular bacilli | Inside macrophages (acidic pH) | Low activity | Pyrazinamide (PZA) |
| Dormant bacilli ("persisters") | Various lesions | Dormant | Rifampicin (sterilizing activity) |
This is why PZA is critical in the initial phase and RIF is the most important sterilizing drug.
3. Phases of Treatment
A. Initial (Intensive) Phase — 2 months
- Goal: Rapid bacterial kill — reduces the bacterial load dramatically, eliminates most susceptible organisms, prevents amplification of resistance.
- Standard regimen: INH + RIF + PZA + EMB (2HRZE)
- Reduces infectivity quickly (patients are usually non-infectious within 2 weeks of starting treatment).
B. Continuation (Maintenance) Phase — 4 months
- Goal: Sterilization — eliminates remaining dormant/semi-dormant bacilli and prevents relapse.
- Standard regimen: INH + RIF (4HR)
- Total duration for drug-susceptible TB: 6 months (minimum).
For TB meningitis or bone/joint TB, continuation phase is extended (total 9–12 months).
4. First-Line Anti-TB Drugs
| Drug | Abbreviation | Primary Mechanism | Key Role |
|---|---|---|---|
| Isoniazid | H (INH) | Inhibits mycolic acid synthesis (InhA) | Bactericidal (early kill) |
| Rifampicin | R (RIF) | Inhibits RNA polymerase (rpoB) | Bactericidal + sterilizing |
| Pyrazinamide | Z (PZA) | Disrupts membrane energy (at acidic pH) | Sterilizing (intracellular) |
| Ethambutol | E (EMB) | Inhibits arabinosyltransferase (embB) | Bacteriostatic; prevents resistance |
| Streptomycin | S | Inhibits 30S ribosome (protein synthesis) | Bactericidal (now rarely first-line) |
5. Key Chemotherapeutic Principles
a. Sterilizing Activity
The ability of a drug to eliminate persistent, slow-growing, or dormant bacilli (preventing relapse). Rifampicin and PZA are the most potent sterilizing drugs — this is why 6-month therapy became possible.
b. Bactericidal vs. Bacteriostatic Activity
- Bactericidal drugs (INH, RIF, PZA, Streptomycin): Kill bacilli — essential for reducing bacterial load.
- Bacteriostatic drugs (EMB): Suppress growth, prevent emergence of resistance.
c. Early Bactericidal Activity (EBA)
The rate of killing in the first 2 days of treatment. INH has the highest EBA of any anti-TB drug.
d. Prevention of Resistance
- Adequate drug regimen with ≥2 effective drugs at all times.
- Adequate dosing — subtherapeutic levels promote resistance.
- Adherence — the single most important factor.
6. Causes of Acquired Drug Resistance
Based on established guidelines (Treatment of Drug-Susceptible Tuberculosis, p. 38):
- Large bacillary burden (pulmonary cavities) — pre-existing resistant mutants
- Inadequate drug regimen — wrong drugs, wrong doses
- Poor adherence — patient and/or provider failure
- Malabsorption of one or more anti-TB drugs
- Sequential addition of single drugs to a failing regimen (amplifier effect)
7. Directly Observed Therapy (DOT)
- WHO-recommended strategy to ensure adherence.
- A healthcare worker observes each dose being swallowed.
- Reduces the risk of acquired resistance and treatment failure.
- The "DOTS strategy" (Directly Observed Treatment, Short-course) is the global standard.
8. Drug Resistance Patterns
| Type | Definition |
|---|---|
| MDR-TB | Resistant to at least INH + RIF |
| Pre-XDR-TB | MDR-TB + resistant to any fluoroquinolone |
| XDR-TB | MDR-TB + resistant to fluoroquinolone + bedaquiline or linezolid |
| Primary resistance | Resistance present before treatment begins (acquired from a resistant source case) |
| Acquired resistance | Resistance that develops during treatment (inadequate regimen) |
9. Special Situations
| Situation | Modification |
|---|---|
| HIV co-infection | Start ART within 2–8 weeks of TB treatment; use rifampicin-based regimen |
| Pregnancy | INH + RIF + EMB for 9 months if PZA excluded; PZA recommended by WHO in high-burden settings |
| Hepatic disease | Avoid PZA and RIF if severe; substitute with streptomycin/EMB |
| Renal impairment | Adjust EMB and streptomycin doses; INH and RIF are safe |
| CNS TB / Bone TB | Extend treatment to 9–12 months |
10. Principles Summary (Mnemonic: DOTS-C)
- D — Duration must be adequate (minimum 6 months)
- O — Observed therapy (DOT) to ensure adherence
- T — Two or more effective drugs always (never monotherapy)
- S — Sterilizing drugs (RIF, PZA) must be included
- C — Combination from the start (never add single drugs to failing regimens)
These principles form the backbone of effective TB control and are why, when properly applied, drug-susceptible TB is curable in >95% of cases.
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