Pharmacology of Antitubercular Drugs
First-Line Drugs for Drug-Susceptible TB
For drug-susceptible tuberculosis, use a 6-month regimen consisting of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) for 2 months, followed by INH and RIF for 4 months. 1, 2, 3
Initial Phase (2 months):
- Isoniazid (INH): 5 mg/kg daily (max 300 mg) or 15 mg/kg twice weekly (max 900 mg). Mechanism: inhibits mycolic acid synthesis in bacterial cell wall. Requires pyridoxine 25-50 mg daily to prevent peripheral neuropathy. 1
- Rifampin (RIF): 10 mg/kg daily (max 600 mg). Mechanism: inhibits bacterial DNA-dependent RNA polymerase. Exhibits excellent sterilizing activity against persisters. 1, 3, 4
- Pyrazinamide (PZA): 15-30 mg/kg daily (max 2 g for <50 kg, 2.5 g for 50-75 kg, 3 g for >75 kg). Mechanism: disrupts membrane energetics and transport in acidic pH environments. Critical for shortening treatment duration. 1, 2
- Ethambutol (EMB): 15-25 mg/kg daily. Mechanism: inhibits arabinosyl transferases involved in cell wall arabinogalactan synthesis. Primarily prevents emergence of resistance. 1, 5
Continuation Phase (4 months):
- INH + RIF at same doses as initial phase 1
Fixed-Dose Combinations:
- Rifamate®: Contains RIF 300 mg + INH 150 mg per capsule; dose is 2 capsules daily (600 mg RIF + 300 mg INH). Minimizes inadvertent monotherapy and reduces pill burden. 1
- Rifater®: Contains RIF 120 mg + INH 50 mg + PZA 300 mg per tablet. Weight-based dosing: 4 tablets if ≤44 kg, 5 tablets if 45-54 kg, 6 tablets if ≥55 kg. Additional PZA needed if >90 kg. 1
Critical caveat: Never add only one effective drug to a failing regimen, as this accelerates resistance development. 1, 6
Second-Line Drugs for Drug-Resistant TB
WHO Hierarchical Drug Selection for MDR-TB
For multidrug-resistant TB (resistant to at least INH and RIF), construct regimens using Group A drugs as the mandatory backbone, supplemented with Group B drugs to achieve at least 4-5 effective medications. 1, 6
Group A Drugs (All three should be included if possible):
- Levofloxacin: 750-1000 mg daily. Preferred over moxifloxacin due to fewer adverse events and less QTc prolongation. Mechanism: inhibits DNA gyrase and topoisomerase IV. 1, 6, 7
- Moxifloxacin: 400 mg daily (alternative to levofloxacin). 1, 6
- Bedaquiline: 400 mg daily for 2 weeks, then 200 mg three times weekly for at least 22 weeks (can extend beyond 6 months with careful monitoring). Mechanism: inhibits mycobacterial ATP synthase. Strong recommendation despite very low certainty evidence. 1, 6
- Linezolid: 600 mg daily (reduce to 300 mg daily if myelosuppression or neuropathy develops). Mechanism: inhibits bacterial protein synthesis by binding 23S ribosomal RNA. 1, 6
Group B Drugs (Add to reach 4-5 total drugs):
- Clofazimine: 100 mg daily. Mechanism: binds to mycobacterial DNA and generates reactive oxygen species. 1, 6
- Cycloserine/Terizidone: 10-15 mg/kg daily (max 1000 mg), usually 500-750 mg/day in two divided doses. Mechanism: inhibits cell wall synthesis by blocking D-alanine incorporation. Toxicity more common at doses >500 mg/day. Give pyridoxine 100-200 mg daily to prevent neurotoxicity. 1, 6
Group C Drugs (Use only when Groups A and B insufficient):
- Ethionamide/Prothionamide: 15-20 mg/kg daily (max 1 g), usually 500-750 mg/day. Mechanism: inhibits mycolic acid synthesis (similar to INH). Causes severe gastrointestinal side effects; take with food or at bedtime. Hepatotoxicity occurs in ~2% of patients. 1
- p-Aminosalicylic acid (PAS): Use only when more effective drugs unavailable. Minimal hepatotoxicity (0.3% hepatitis rate). 1, 8
Group D Drugs (Injectable agents - use only when needed):
- Amikacin: Preferred injectable when susceptibility confirmed. Dose: 15 mg/kg daily (max 1 g). Mechanism: inhibits protein synthesis by binding 30S ribosomal subunit. Monitor for nephrotoxicity and ototoxicity. 1, 8
- Streptomycin: Alternative injectable when susceptibility confirmed. 1
- Carbapenems (imipenem-cilastatin or meropenem): Always use with amoxicillin-clavulanate. 1
Strong recommendation AGAINST: Kanamycin, capreomycin, macrolides (azithromycin/clarithromycin), and amoxicillin-clavulanate alone (without carbapenem). 1
Special Regimen Options
Shorter All-Oral Regimen (9-12 months):
For eligible MDR-TB patients without fluoroquinolone resistance, extensive disease, prior second-line drug exposure, severe extrapulmonary TB, or pregnancy, use bedaquiline + levofloxacin/moxifloxacin + clofazimine + pyrazinamide + ethambutol + high-dose isoniazid + ethionamide/prothionamide. 1, 6, 9
BPaL Regimen (6-9 months):
For fluoroquinolone-resistant MDR-TB under operational research conditions, use bedaquiline + pretomanid + linezolid with ≤2 weeks prior exposure to bedaquiline/linezolid. 6
Standard Longer Regimen:
Duration: 18-20 months from start OR 15-17 months after culture conversion, whichever is longer. 6
Critical Adverse Effects and Monitoring
QTc Prolongation:
- Drugs causing QTc prolongation: Fluoroquinolones, bedaquiline, delamanid, clofazimine. Avoid combining multiple QT-prolonging agents when possible. 1, 6, 10
- Monitoring: Baseline and monthly ECGs required. 6
Peripheral Neuropathy:
- Causative drugs: Linezolid, cycloserine, ethionamide, isoniazid. 1, 6, 10
- Prevention: Pyridoxine 100-200 mg daily with cycloserine; 25-50 mg daily with isoniazid. 1, 6
Myelosuppression:
- Causative drug: Linezolid. Reduce dose to 300 mg if occurs. 1, 6, 10
- Monitoring: Monthly complete blood counts. 6
Optic Neuropathy:
- Causative drugs: Ethambutol, linezolid. 6, 10
- Monitoring: Regular visual acuity and color vision testing. 6
Hepatotoxicity:
- High-risk drugs: Isoniazid, rifampin, pyrazinamide, ethionamide (2% rate). 1, 8
- Low-risk alternatives for hepatic disease: Levofloxacin, moxifloxacin, cycloserine, amikacin, clofazimine, PAS. 8
- Monitoring: Baseline liver function tests; monthly if underlying liver disease. 8
CNS Toxicity:
- Cycloserine: Causes headache, restlessness, psychosis, seizures (16% at 500 mg twice daily vs 3% at 500 mg once daily). Exacerbates underlying seizure disorders or mental illness. 1, 10
Nephrotoxicity and Ototoxicity:
- Causative drugs: Aminoglycosides (amikacin, streptomycin, kanamycin). Avoid in pregnancy due to fetal risks. 8, 10
Special Populations
Pregnancy:
- Safe: Rifamate® (INH + RIF), first-line drugs except PZA. 1
- Avoid: Rifater® (contains PZA), ethionamide (teratogenic in animals), aminoglycosides (fetal nephrotoxicity/hearing loss), cycloserine (limited safety data). 1, 8
Renal Disease:
- Rifamate® safe; avoid Rifater® (PZA requires dose adjustment). 1
- Cycloserine: Reduce dose and monitor serum concentrations (target peak 20-35 mg/mL). 1
Hepatic Disease:
- Use single-drug formulations until safety established; avoid fixed-dose combinations initially. 1
- Preferred drugs: Fluoroquinolones, cycloserine, aminoglycosides, clofazimine. 8
HIV Co-infection:
- Start antiretroviral therapy within 8 weeks of TB treatment initiation, regardless of CD4 count. 6
- Monitor drug-drug interactions: Bedaquiline and delamanid metabolized via CYP450 (interactions with protease inhibitors, efavirenz). 6
- Mortality risk: Up to fourfold higher in HIV/MDR-TB co-infection. 6