Different categories of anti tuberculosis therapy
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WHO 2022 anti-tuberculosis drug classification groups first second line MDR-TB
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Categories of Anti-Tuberculosis (Anti-TB) Therapy
Anti-TB drugs are organized into two main categories - first-line and second-line - and for drug-resistant TB, the WHO further classifies second-line agents into Groups A, B, and C (updated 2022). Newer agents form a distinct group.
1. First-Line Drugs (for Drug-Susceptible TB)
These are the most effective, least toxic agents and form the backbone of standard treatment.
| Drug | Abbreviation | Mechanism | Daily Dose (adult) | Key Toxicities |
|---|---|---|---|---|
| Isoniazid | H (INH) | Inhibits mycolic acid synthesis (InhA) | 300 mg/day | Peripheral neuropathy, hepatitis, hypersensitivity |
| Rifampin (Rifampicin) | R (RIF) | Inhibits RNA polymerase (β-subunit) | 600 mg/day | Orange discoloration of secretions, hepatitis, drug interactions (CYP inducer) |
| Pyrazinamide | Z (PZA) | Disrupts membrane energy metabolism; active in acidic milieu | 25 mg/kg/day | Hyperuricemia, hepatotoxicity, arthralgias |
| Ethambutol | E (EMB) | Inhibits arabinosyltransferase (cell wall) | 15-25 mg/kg/day | Optic neuritis (dose-related, reversible) |
| Rifapentine | Rpt | Same as rifampin (RNA polymerase inhibitor) | 1200 mg/day (new 4-month regimen) | Similar to rifampin; rash, anemia |
| Rifabutin | Rfb | RNA polymerase inhibitor | 300 mg/day | Rash, leukopenia, uveitis; less CYP induction than rifampin |
| Moxifloxacin | Mfx | Inhibits DNA gyrase | 400 mg/day | QT prolongation, GI upset |
Standard 6-month regimen: 2 months HRZE (intensive phase) + 4 months HR (continuation phase).
New 4-month regimen (2022): Rifapentine + Moxifloxacin + Isoniazid + Pyrazinamide - shown non-inferior to the 6-month regimen in patients ≥12 years weighing ≥40 kg.
2. Second-Line Drugs
Used when first-line drugs fail, are not tolerated, or when drug resistance is documented.
WHO Group A - Fluoroquinolones (highest priority)
- Levofloxacin (Lfx)
- Moxifloxacin (Mfx)
- Gatifloxacin (Gfx)
- Mechanism: Inhibit DNA gyrase/topoisomerase II
WHO Group B - Second-Line Injectable Agents
- Amikacin (Am)
- Capreomycin (Cm)
- Kanamycin (Km)
- Streptomycin (S) - used only if no other Group B agent is available
- Mechanism: Aminoglycosides inhibit protein synthesis at the 30S ribosomal subunit; capreomycin is a cyclic peptide with similar action
- Toxicities: Ototoxicity, nephrotoxicity
WHO Group C - Core Second-Line Agents
- Ethionamide / Prothionamide (Eto/Pto) - structural analog of isoniazid; inhibits mycolic acid synthesis
- Cycloserine / Terizidone (Cs/Trd) - inhibits cell wall peptidoglycan synthesis; neurotoxicity
- Linezolid (Lzd) - oxazolidinone; inhibits 50S ribosome; myelosuppression, neuropathy
- Clofazimine (Cfz) - riminophenazine dye; mechanism not fully established; skin discoloration
- Aminosalicylic acid (PAS) - inhibits folate synthesis/uptake; GI intolerance
3. New/Novel Agents (for MDR-TB and XDR-TB)
These drugs represent a significant advance in treating drug-resistant TB.
| Drug | Class | Mechanism | Key Feature |
|---|---|---|---|
| Bedaquiline (Bdq) | Diarylquinoline | Inhibits mycobacterial ATP synthase | Core drug in all MDR/RR-TB regimens; QT prolongation |
| Pretomanid (Pa) | Bicyclic nitroimidazole | (1) Inhibits mycolic acid synthesis (aerobic) and (2) generates toxic reactive nitrogen species (anaerobic) | FDA-approved for XDR/pre-XDR-TB |
| Delamanid (Dln) | Bicyclic nitroimidazole | Inhibits mycolic acid synthesis | Licensed in EU for MDR-TB |
| Linezolid (Lzd) | Oxazolidinone | 50S ribosomal inhibitor | Now classified as Group A in MDR-TB regimens |
4. Key Treatment Regimens by Drug Resistance Pattern
| TB Type | Preferred Regimen |
|---|---|
| Drug-susceptible (DS-TB) | 2HRZE / 4HR or 4-month rifapentine regimen |
| Isoniazid-resistant | 6 months Lfx + RZE |
| MDR/RR-TB | BPaLM: Bdq + Pa + Lzd + Mfx for 6 months (preferred) |
| Pre-XDR-TB / XDR-TB | BPaLM (drop Mfx if fluoroquinolone-resistant); or BPaL + extended linezolid |
| Latent TB (LTBI) | 3HP (3 months weekly isoniazid + rifapentine) or 6-9 months isoniazid |
5. Mnemonics
- RIPE - Rifampin, Isoniazid, Pyrazinamide, Ethambutol (standard 4-drug intensive phase)
- SHINE - Streptomycin, cycloserine, Highdose isoniazid, Injectables, Newer agents, Ethionamide (second-line memory aid)
Special Notes
- Pyridoxine (vitamin B6) is co-administered with isoniazid to prevent peripheral neuropathy, especially in at-risk groups (pregnant women, alcoholics, malnourished patients, diabetics).
- Streptomycin is contraindicated in pregnancy due to cranial nerve VIII damage in neonates.
- MDR-TB is defined as resistance to at least isoniazid AND rifampin. XDR-TB additionally requires resistance to a fluoroquinolone AND bedaquiline or linezolid.
- The WHO 2022 update established BPaLM as the preferred regimen for MDR/RR-TB, replacing older injectable-based regimens.
Sources: Katzung's Basic and Clinical Pharmacology 16e, Ch. 47; Harrison's Principles of Internal Medicine 22e; Goodman & Gilman's Pharmacological Basis of Therapeutics; WHO Consolidated Guidelines on TB Module 4, 2022 update
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Here is a comprehensive, up-to-date breakdown of all new and updated TB treatment regimens as of mid-2026.
Updated and New Anti-Tuberculosis Drug Regimens (2022-2026)
1. Drug-Susceptible TB (DS-TB) - Active Disease
Traditional Standard Regimen (Still Widely Used)
2HRZE / 4HR - Total 6 months
- Intensive phase (2 months): Isoniazid (H) + Rifampin (R) + Pyrazinamide (Z) + Ethambutol (E)
- Continuation phase (4 months): Isoniazid + Rifampin
- Extended to 9 months (2HRZE/7HR) if: cavitary disease, delayed sputum culture conversion at 2 months, or incomplete pyrazinamide course
NEW: 4-Month Regimen (Study 31/A5349 Trial, 2020; CDC Interim Guidance 2022)
2PaZMH / 9-week PaMH - Total ~17 weeks (~4 months)
| Phase | Duration | Drugs |
|---|---|---|
| Intensive | 8 weeks | Rifapentine 1200 mg daily + Moxifloxacin 400 mg + Isoniazid 300 mg + Pyrazinamide |
| Continuation | 9 weeks | Rifapentine + Moxifloxacin + Isoniazid |
- Shown non-inferior to the 6-month HRZE regimen in a large multinational RCT (including HIV+ patients with CD4 >100)
- WHO conditional recommendation; CDC interim guidance issued 2022
- Not recommended in: pregnancy, children <12 years, weight <40 kg, severe extrapulmonary TB, fluoroquinolone resistance
- Levofloxacin may replace moxifloxacin in patients at risk of QT prolongation (emerging evidence, levofloxacin carries lower QT risk)
2. Latent TB Infection (LTBI) - Updated Preferred Regimens
| Regimen | Duration | Schedule | Notes |
|---|---|---|---|
| 3HP - Isoniazid + Rifapentine | 3 months | Weekly (12 doses) | Preferred for adults & children >2 yrs including HIV+ |
| 1HP - Isoniazid + Rifapentine | 1 month | Daily | Non-inferior to 9H in HIV+ patients (2020 WHO update); avoid drug interactions |
| 4R - Rifampin alone | 4 months | Daily | Preferred over 6-9H for many adults |
| 3HR - Isoniazid + Rifampin | 3 months | Daily | Acceptable alternative |
| 6H / 9H - Isoniazid alone | 6-9 months | Daily or twice-weekly | Oldest regimen; still used where rifamycins unavailable |
3HP is currently the regimen of choice for children >2 years and most adults per Harrison's 22e (2025). Self-administered 3HP is non-inferior to DOT-administered 3HP.
3. MDR/RR-TB - The BPaLM Era (WHO 2022 Update - Major Change)
NEW Preferred: 6-Month BPaLM Regimen
| Drug | Abbreviation | Dose |
|---|---|---|
| Bedaquiline | B (Bdq) | 400 mg/day x 2 weeks, then 200 mg 3x/week |
| Pretomanid | Pa | 200 mg/day |
| Linezolid | L (Lzd) | 600 mg/day (often reduced to 300 mg to minimize toxicity) |
| Moxifloxacin | M (Mfx) | 400 mg/day |
- Duration: 6 months total (no separate intensive/continuation phases)
- Evidence: TB-PRACTECAL RCT (Lancet Resp Med 2024) - BPaLM showed only 12% unfavorable outcomes vs 41% in standard care (NNT = 7); serious adverse events were also far fewer (23% vs 48%) - TB-PRACTECAL trial
- A 2025 systematic review (PMID 39813501) confirmed BPaLM is more effective and safer than standard of care
- Drop moxifloxacin (use BPaL) if fluoroquinolone resistance is confirmed
Alternative: 9-Month All-Oral Regimen (WHO 2022)
For MDR/RR-TB without fluoroquinolone resistance, no prior second-line drug exposure
- Intensive phase (4-6 months): Bedaquiline + Levofloxacin or Moxifloxacin + Ethionamide + Ethambutol + Pyrazinamide + High-dose Isoniazid + Clofazimine
- Continuation phase (5 months): Levofloxacin or Moxifloxacin + Clofazimine + Pyrazinamide + Ethambutol
Extended Individualized Regimen (≥18 months - for XDR-TB / BPaLM failures)
Constructed using WHO group priority:
- Group A (all 3 must be included): Levofloxacin/Moxifloxacin, Bedaquiline, Linezolid
- Group B (≥1 required): Clofazimine, Cycloserine/Terizidone
- Group C (add if needed): Ethambutol, Delamanid, Pyrazinamide, Imipenem, Amikacin, Ethionamide, PAS
4. Isoniazid-Resistant TB (Hr-TB)
Regimen: 6 months - Rifampin + Ethambutol + Pyrazinamide + Levofloxacin (REZL)
- WHO 2022 recommendation; no isoniazid in this regimen
5. XDR-TB / Pre-XDR-TB
BPaL or BPaLM (6 months) - core preferred regimen
- FDA approved pretomanid specifically for XDR/pre-XDR-TB in combination with bedaquiline and linezolid
- ECG monitoring mandatory due to QT prolongation risk (bedaquiline + moxifloxacin)
- Routine liver enzyme monitoring for pretomanid
6. Drugs in the Pipeline (Phase 2-3 Trials, as of 2025-2026)
| Drug | Class | Status | Notes |
|---|---|---|---|
| Sorfequiline (TBAJ-876) | Diarylquinoline | Phase IIb | Next-gen bedaquiline; less QT prolongation |
| Ganfeborole (GSK-656) | DprE1 inhibitor | Phase 2 | |
| Sutezolid | Oxazolidinone | Phase 2 | Linezolid analog, potentially less myelosuppression |
| Delpazolid | Oxazolidinone | Phase 2 | |
| Telacebec (Q203) | Imidazopyridine | Phase 2 | Novel ATP synthase inhibitor |
| Sanfetrinem | Oral beta-lactam | Phase 2 | Repurposed; GSK/BMGF |
| Long-acting bedaquiline (LA-BDQ) | Injectable depot | Phase 3 | Monthly injection for adherence |
| TBAJ-587 | Diarylquinoline | Phase 1 | |
| BTZ-043 | DprE1 inhibitor | Phase 2b |
7. WHO 2025 Update - Nutrition
The October 2025 WHO guidelines (Module 6) added mandatory nutritional assessment and counseling for all TB patients and household contacts, recognizing undernutrition as a major driver of TB burden and poor outcomes.
Summary Comparison Table
| TB Type | Old Regimen | New/Updated Regimen | Duration Saved |
|---|---|---|---|
| DS-TB (pulmonary) | 2HRZE/4HR | 2PaZMH/9wk PaMH | 2 months |
| LTBI | 9H or 6H | 3HP (weekly) or 1HP (daily, HIV+) | 6-8 months |
| MDR/RR-TB | 18-24 months injectable | 6-month BPaLM (all oral) | 12-18 months |
| XDR-TB | 24+ months | 6-month BPaL | 18+ months |
| Hr-TB | 6H + others | 6 months REZL | Same duration, better outcomes |
The shift toward all-oral, shorter regimens is the defining trend of the 2022-2026 era, with BPaLM being the single most impactful change for drug-resistant TB. - Harrison's Principles of Internal Medicine 22e (2025); Katzung's Pharmacology 16e; WHO Module 4 2022; TB-PRACTECAL Lancet 2024 PMID 37980911
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