Antituberculosis Agents

Overview

Mycobacterium tuberculosis infection requires multi-drug therapy for 6-9+ months due to the organism's slow growth, ability to form metabolically dormant persister cells, and high risk of resistance emergence with single-drug therapy. Standard treatment uses the RIPE regimen: Rifampin, Isoniazid, Pyrazinamide, and Ethambutol.

First-Line Agents

Isoniazid (INH): Prodrug activated by mycobacterial catalase-peroxidase (KatG) to reactive species that inhibit InhA (enoyl-ACP reductase) in mycolic acid synthesis — a unique component of the mycobacterial cell wall. Bactericidal against rapidly dividing bacilli. Resistance via KatG mutations (most common) or InhA promoter mutations.

Toxicity: Hepatotoxicity (monitor LFTs; more common in slow acetylators, alcoholics); peripheral neuropathy from pyridoxine (vitamin B6) depletion — supplement B6 prophylactically in at-risk patients. Drug-drug interactions via CYP inhibition.

Rifampin (Rifampicin): Inhibits the beta subunit of bacterial DNA-dependent RNA polymerase, preventing transcription initiation. Bactericidal against all populations including semi-dormant organisms. Strong CYP3A4 inducer — dramatically reduces levels of many drugs (HIV antiretrovirals, warfarin, oral contraceptives, tacrolimus). Characteristic orange discoloration of body fluids (inform patients).

Toxicity: Hepatotoxicity, flu-like syndrome with intermittent dosing, hypersensitivity, thrombocytopenia.

Pyrazinamide (PZA): Prodrug converted to pyrazinoic acid by mycobacterial pyrazinamidase; targets fatty acid synthase I (FasI). Active only in acidic environments (phagolysosomes of macrophages) against semi-dormant organisms — critical for shortening treatment from 9-12 to 6 months by sterilizing the caseous/acidic compartment. Resistance via pncA mutations.

Toxicity: Hepatotoxicity, hyperuricemia (inhibits uric acid secretion), arthralgias.

Ethambutol (EMB): Inhibits arabinosyl transferases (EmbB), blocking arabinogalactan synthesis in the mycobacterial cell wall. Primarily bacteriostatic.

Toxicity: Optic neuritis (dose-dependent, reversible with early detection) — monthly visual acuity and color discrimination testing required.

MDR and XDR Tuberculosis

MDR-TB: Resistant to both INH and rifampin. Requires 18-24 months of second-line agents (fluoroquinolones, bedaquiline, linezolid, cycloserine). XDR-TB: Additionally resistant to fluoroquinolones and aminoglycosides. Treatment with bedaquiline (inhibits ATP synthase) + delamanid (inhibits mycolic acid synthesis) + pretomanid combinations.

Latent TB Treatment

INH alone for 9 months, or rifampin for 4 months, or INH + rifapentine once weekly for 3 months (3HP regimen — preferred for improved adherence).

Key Takeaways

• RIPE regimen for 6 months (2 months RIPE + 4 months RI) sterilizes all bacterial populations
• Pyrazinamide is critical for shortening treatment duration by killing semi-dormant organisms in acidic macrophages
• Rifampin is a strong CYP3A4 inducer with numerous drug interactions including antiretrovirals
• Ethambutol causes reversible optic neuritis; monthly visual monitoring is mandatory