Introduction
Tuberculosis (TB) remains a major global health threat, caused by Mycobacterium tuberculosis (M.tb), a slow-growing, aerobic, acid-fast bacillus with a unique, lipid-rich cell wall conferring virulence and intrinsic drug resistance. Diagnosis relies on acid-fast stains, culture, PCR, and clinical criteria. TB is primarily pulmonary but can affect any organ. Increased risk is seen in immunosuppressed individuals, with airborne human-to-human transmission.
Microbiology and Pathogenesis: Key Points
- M. tuberculosis cell wall: High mycolic acid content → acid-fast, waxy barrier, resistant to many antibiotics and host defenses.
- Pathogenicity: Intracellular survival in macrophages, granuloma formation; latent and active disease states.
Classification and Mechanisms of Anti-Tubercular Drugs
Anti-TB drugs are divided into first-line, second-line, and new drugs based on clinical efficacy, toxicity, and role in multidrug-resistant TB (MDR-TB).
First-Line Drugs
| Drug | Mechanism of Action | Bactericidal/Static | Site of Action | Major Side Effects |
|---|---|---|---|---|
| Isoniazid | Inhibits mycolic acid synthesis (cell wall) via InhA and KasA inhibition; activated by KatG | Cidal (rapid growers); static (resting) | All (intra/extracellular) | Hepatotoxicity, neuropathy, rash |
| Rifampicin | Inhibits DNA-dependent RNA polymerase (β-subunit) → blocks RNA synthesis | Cidal | All (intra/extracellular) | Hepatotoxicity, orange discoloration, drug interactions |
| Ethambutol | Inhibits arabinogalactan synthesis via EmbB inhibition (cell wall) | Static | All | Optic neuritis, gout |
| Pyrazinamide | Prodrug → pyrazinoic acid inhibits fatty acid synthase I, disrupts membrane transport and energy | Cidal (in acidic environments) | Intracellular mycobacteria | Hepatotoxicity, hyperuricemia, arthralgia |
| Streptomycin | Inhibits protein synthesis (30S ribosome), misreading of mRNA | Cidal (extracellular) | Extracellular | Ototoxicity, nephrotoxicity, contraindicated in pregnancy |
References: Goodman & Gilman’s 13th Ed., Katzung 15th Ed., Lecturio.
Second-Line and New Anti-Tubercular Agents
| Class/Drug | Mechanism of Action | Clinical Role | Adverse Effects |
|---|---|---|---|
| Aminoglycosides (amikacin, kanamycin) | 30S ribosome inhibitor (protein synthesis) | MDR-TB, XDR-TB | Nephro/ototoxicity |
| Capreomycin | 70S ribosome, initiator complex inhibitor | MDR-TB, XDR-TB | Similar to aminoglycosides |
| Fluoroquinolones (levofloxacin, moxifloxacin) | Inhibits DNA gyrase/topoisomerase IV | MDR-TB; MAC, XDR-TB | Tendinopathy, CNS effects |
| Ethionamide | Inhibits mycolic acid synthesis (like INH) | MDR-TB, leprosy | GI, neurotoxicity, hepatotoxicity |
| Cycloserine | Inhibits cell wall peptide synthesis (D-alanine racemase, ligase) | MDR-TB, neuropsychiatric | Neurotoxicity (depression, seizures) |
| PAS | Inhibits folic acid synthesis | MDR-TB | GI, liver, thyroid dysfunction |
| Linezolid | 50S ribosome inhibitor (protein synthesis) | MDR/XDR-TB, MAC | Myelosuppression, neuropathy |
| Clofazimine | DNA binding, membrane disruption, ROS generation | MDR/XDR-TB, leprosy | Skin discoloration, GI effects |
| Bedaquiline | ATP synthase inhibitor (energy metabolism) | MDR/XDR-TB (core new drug) | QT prolongation, hepatotoxicity |
| Delamanid | Inhibits mycolic acid synthesis, ATP generation (nitroimidazole group) | MDR/XDR-TB (core new drug) | QT prolongation |
| Pretomanid | Converted to reactive nitrogen species—DNA/protein/membrane damage | MDR/XDR-TB (combo regimens) | GI, QT prolongation |
References: Goodman & Gilman’s 13th Ed., WHO 2022 guidelines, newtbdrugs.org.
Pharmacology Details of Core Drugs
Isoniazid (INH)
- Pharmacokinetics: Well absorbed orally; distributed to all tissues including CSF. Metabolized by hepatic acetylation (fast/slow acetylators – genetic polymorphism). Excreted in urine.
- Adverse Effects: Hepatotoxicity (age-related), peripheral neuropathy (especially slow acetylators, diabetics, malnourished), treated/prevented with pyridoxine.
- Clinical Pearls: Backbone of all regimens, resistance via KatG/inhA mutations, always used in combination.
Source: Antitubercular drugs: possible role of natural products acting as antituberculosis medication in overcoming drug resistance and drug-induced hepatotoxicity – Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Mechanism-of-action-of-INH-on-Mycobacterium-tuberculosis_fig1_373657618 [accessed 8 Nov 2025]
Rifampicin (RIF)
- Pharmacodynamics: Oral, excellent tissue penetration, including CNS and intracellular compartments.
- Adverse Effects: Hepatotoxicity, potent CYP450 induction—multiple drug interactions, orange-red urine/fluids, thrombocytopenia.
- Clinical Pearls: Indispensable in TB, leprosy, MAC, and as a prophylactic. Resistance due to rpoB mutation.
Pyrazinamide (PZA)
- Pharmacokinetics: Absorbed orally; distributed widely. Metabolized hepatically; excreted renally.
- Adverse Effects: Hepatotoxicity, hyperuricemia, arthralgia.
- Pearl: Essential for intensive phase, sterilizing action in acidic environments.
Ethambutol (EMB)
- Pharmacodynamics: Oral admin. Bacteriostatic. 20% fecal, 50% renal excretion.
- Adverse Effects: Optic neuritis (monitor vision), rare hepatotoxicity.
- Pearl: Included to prevent resistance during initial phase.
Streptomycin
- Administration: IM only, not oral.
- Adverse Effects: Ototoxicity, nephrotoxicity.
- Pearl: Used less frequently—MDR/XDR regimen adjunct, contraindicated in pregnancy.
New TB Drugs: Bedaquiline, Delamanid, Pretomanid
- Bedaquiline and delamanid are now WHO Group A core drugs for MDR/XDR regimens, typically used with linezolid and other agents for 6–9 month oral short-course regimens—improving cure rates, decreasing toxicity, and offering more convenient therapy.
WHO/India National TB Guidelines: Treatment Algorithms
Drug-Sensitive TB (Category I)
- Intensive Phase: 2 months—HRZE (isoniazid, rifampicin, pyrazinamide, ethambutol)
- Continuation Phase: 4 months—HR (isoniazid, rifampicin)
- Total Duration: 6 months minimum
Category II (Previously treated/relapse):
- Intensive Phase: 2(HRZES) / 1(HRZE)
- Continuation Phase: 5(HRE)
Drug-Resistant TB (MDR/XDR)
- MDR-TB (18–20 month regimen): 5 active drugs minimum: pyrazinamide, a fluoroquinolone (e.g., levofloxacin), an injectable aminoglycoside (e.g., amikacin/kanamycin/capreomycin), and a core drug (bedaquiline/delamanid).
- WHO Short-Course Regimen (BPaLM/BPaL): Bedaquiline, pretomanid, linezolid ± moxifloxacin; 6–9 months
- XDR-TB: Fewer options—combination regimens based on susceptibility (often includes all new drugs).
Adverse Effects & Monitoring
| Drug | Common Side Effects | Key Monitoring |
|---|---|---|
| Isoniazid | Hepatitis, neuropathy | LFTs, neuropathy |
| Rifampicin | Hepatitis, rash, drug interaction | LFTs, DDI review |
| Pyrazinamide | Arthritis, hepatitis, hyperuricemia | LFTs, serum uric acid |
| Ethambutol | Optic neuritis, rash | Baseline and periodic vision |
| Streptomycin | Ototoxicity, nephrotoxicity | Hearing, renal function |
| Injectable aminoglycosides | Nephro-, oto-toxicity | Renal, hearing |
| Fluoroquinolones | Tendinopathy, CNS | Tendon/CNS symptoms |
| Bedaquiline | QT prolongation, hepatotoxicity | ECG, LFTs |
| Delamanid | QT prolongation | ECG |
| Pretomanid | GI, QT prolongation | ECG, GI symptoms |
References: Goodman & Gilman’s 13th Ed., newtbdrugs.org, WHO.
Treatment of Atypical Mycobacterial Infections
- MAC (Mycobacterium avium complex): Prophylaxis: clarithromycin/azithromycin for low CD4 (<50) HIV patients.
- REC regimen: Rifabutin + ethambutol + clarithromycin/azithromycin.
- Quinolones and aminoglycosides: Additional roles; use in resistant cases.
Key Principles of Anti-TB Therapy
- Always use multiple drugs—monotherapy leads to resistance
- Directly Observed Therapy (DOTS): Ensures compliance, prevents resistance
- Adjust therapy based on susceptibility, previous treatment, and patient tolerance
Summary Tables
Main Characteristics of First-Line Drugs
| Drug | Dose (adult) | Main Mechanism | Critical Adverse Effects |
|---|---|---|---|
| Isoniazid | 5 mg/kg | InhA mycolic acid inhibition | Hepatitis, neuropathy |
| Rifampicin | 10 mg/kg | RNA polymerase inhibition | Hepatitis, CYP induction |
| Pyrazinamide | 20–25 mg/kg | Fatty acid synthase inhibition | Hepatitis, hyperuricemia |
| Ethambutol | 15–25 mg/kg | Arabinosyl transferase inhibition | Optic neuritis |
| Streptomycin | 15 mg/kg (IM) | 30S ribosome inhibition | Ototoxicity, nephrotoxicity |
New Drug Table (MDR/XDR)
| Drug | Group/Class | Standard Adult Dose | Principal Use | Side Effects/Monitoring |
|---|---|---|---|---|
| Bedaquiline | Diarylquinoline | 400 mg daily x 2w, then 200 mg 3x/wk | MDR/XDR core drug | QT, LFTs |
| Delamanid | Nitroimidazole | 100 mg bid | MDR/XDR core drug | QT, LFTs |
| Pretomanid | Nitroimidazole | 200 mg daily (in BPaL) | XDR regimens | QT, GI, LFTs |
References & Further Reading
- Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th Edition
- Katzung BG, Trevor AJ. Basic & Clinical Pharmacology, 15th Edition
- WHO TB Treatment Guidelines, 2022 Update
- newtbdrugs.org: Bedaquiline & Delamanid/Drug Pipeline
- Lecturio: Antimycobacterial Drugs
- Frontiers: New TB Pipeline Review
- CUTM Courseware: Antitubercular Drug
- MSF Medical Guidelines: Drug-resistant TB
- Indian National Guidelines, tbcindia.mohfw.gov.in
- EndTB.org Guide for New TB Drugs
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