Tuberculosis and Its Treatment

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

References: Goodman & Gilman’s 13th Ed., Katzung 15th Ed., Lecturio.​

Second-Line and New Anti-Tubercular Agents

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

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

New Drug Table (MDR/XDR)

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​