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Monday, August 11, 2025

Antituberculosis agents


Introduction

  • Antituberculosis agents are drugs used for the prevention and treatment of infections caused by Mycobacterium tuberculosis and related mycobacteria.

  • They can be divided into first-line (most potent, least toxic, standard regimen drugs) and second-line agents (used when resistance or intolerance occurs).

  • The goals of therapy:

    • Achieve rapid bacterial killing (bactericidal effect).

    • Sterilize dormant bacilli to prevent relapse.

    • Prevent emergence of resistance through combination therapy.

  • These agents are typically used in combination regimens according to WHO guidelines to maximize cure rates and minimize resistance.

Classification

1. First-Line Antituberculosis Agents

  • Used in standard treatment of drug-susceptible TB.

  • High efficacy, lower toxicity compared to second-line drugs.

Isoniazid (INH)

  • Mechanism: Inhibits synthesis of mycolic acids (essential components of mycobacterial cell wall).

  • Activity: Bactericidal against rapidly dividing bacilli; bacteriostatic against dormant organisms.

  • Adverse effects: Hepatotoxicity, peripheral neuropathy (prevent with pyridoxine), rash.

  • Notes: Resistance via mutations in katG or inhA.

Rifampicin (RIF)

  • Mechanism: Inhibits bacterial DNA-dependent RNA polymerase.

  • Activity: Bactericidal against rapidly dividing and semi-dormant bacilli.

  • Adverse effects: Hepatotoxicity, orange discoloration of body fluids, drug interactions (potent CYP450 inducer).

  • Notes: Cross-resistance with rifabutin and rifapentine possible.

Pyrazinamide (PZA)

  • Mechanism: Converted to pyrazinoic acid; disrupts membrane energetics and fatty acid synthesis in acidic conditions.

  • Activity: Bactericidal against semi-dormant bacilli in acidic environments (within macrophages).

  • Adverse effects: Hepatotoxicity, hyperuricemia, arthralgia.

Ethambutol (EMB)

  • Mechanism: Inhibits arabinosyl transferases, disrupting arabinogalactan polymerization in the cell wall.

  • Activity: Bacteriostatic; prevents emergence of resistance when combined with other drugs.

  • Adverse effects: Optic neuritis (red–green color vision loss), rash.

Streptomycin (SM) (less common in first-line use)

  • Mechanism: Aminoglycoside; inhibits protein synthesis by binding to 30S ribosomal subunit.

  • Activity: Bactericidal against extracellular bacilli.

  • Adverse effects: Ototoxicity, nephrotoxicity.

2. Second-Line Antituberculosis Agents

  • Used for multidrug-resistant TB (MDR-TB) or when first-line agents cannot be used due to toxicity/intolerance.

  • Generally less effective, more toxic, and more expensive.

Fluoroquinolones

  • Levofloxacin, Moxifloxacin, Ofloxacin.

  • Mechanism: Inhibit DNA gyrase and topoisomerase IV.

  • Adverse effects: QT prolongation, tendinopathy, GI upset.

Injectable Aminoglycosides and Polypeptides

  • Amikacin, Kanamycin, Capreomycin.

  • Mechanism: Inhibit protein synthesis.

  • Adverse effects: Ototoxicity, nephrotoxicity.

Ethionamide / Prothionamide

  • Mechanism: Inhibits mycolic acid synthesis (similar to INH).

  • Adverse effects: GI intolerance, hepatotoxicity, hypothyroidism.

Cycloserine / Terizidone

  • Mechanism: Inhibits cell wall synthesis by blocking D-alanine incorporation.

  • Adverse effects: CNS toxicity (depression, psychosis, seizures).

p-Aminosalicylic Acid (PAS)

  • Mechanism: Folate synthesis antagonist.

  • Adverse effects: GI upset, hypersensitivity reactions.

Clofazimine

  • Mechanism: Binds to mycobacterial DNA, interfering with replication and growth; anti-inflammatory properties.

  • Adverse effects: Skin discoloration, GI upset.

Bedaquiline

  • Mechanism: Inhibits mycobacterial ATP synthase.

  • Adverse effects: QT prolongation, hepatotoxicity.

Delamanid / Pretomanid

  • Mechanism: Inhibit mycolic acid synthesis; release reactive nitrogen species under anaerobic conditions.

  • Adverse effects: QT prolongation, GI upset.

Mechanisms of Action Overview

  • Cell wall synthesis inhibition: Isoniazid, Ethambutol, Ethionamide, Pretomanid, Delamanid.

  • RNA synthesis inhibition: Rifampicin.

  • Protein synthesis inhibition: Streptomycin, Amikacin, Kanamycin, Capreomycin, Cycloserine.

  • Energy metabolism disruption: Pyrazinamide (membrane energetics), Bedaquiline (ATP synthase inhibition).

  • DNA replication interference: Fluoroquinolones, Clofazimine.

Resistance Considerations

  • Monotherapy leads to rapid emergence of resistance; hence, always use in combination regimens.

  • Resistance mechanisms:

    • Mutation in drug targets (e.g., katG for INH, rpoB for RIF).

    • Drug inactivation.

    • Efflux pump overexpression.

Adverse Effect Monitoring

  • Hepatotoxicity: Monitor liver function with INH, RIF, PZA, Ethionamide.

  • Ocular toxicity: Regular vision testing with Ethambutol.

  • Renal toxicity: Monitor creatinine with aminoglycosides, Capreomycin.

  • Cardiac monitoring: QT prolongation with Bedaquiline, Delamanid, Moxifloxacin.

  • Neuropsychiatric monitoring: Cycloserine, high-dose INH without pyridoxine.

Special Populations

  • Pregnancy: Avoid Streptomycin (ototoxic to fetus); HRZE generally considered safe.

  • HIV co-infection: Manage drug–drug interactions (Rifampicin induces metabolism of many antiretrovirals).

  • Pediatric: Dose adjustments and liquid formulations often needed.

Future Directions

  • Shorter regimens for drug-susceptible TB (4-month courses with rifapentine and moxifloxacin).

  • All-oral MDR-TB regimens (Bedaquiline + Pretomanid + Linezolid ± Moxifloxacin).

  • Host-directed therapies to enhance immune clearance of M. tuberculosis.




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