Drugs used in TB

Introduction

The successful treatment of tuberculosis (TB) relies on the principles of combination chemotherapy to ensure rapid killing of bacilli, prevention of drug resistance, and sterilization of lesions to prevent relapse. The bacterial population in a TB lesion consists of distinct subpopulations: rapidly multiplying extracellular bacilli, slowly growing intracellular bacilli (in acidic pH), and sporadic metabolizers in solid caseum. Anti-tubercular drugs are selected based on their bactericidal activity, sterilizing activity, and ability to prevent resistance.

Recent guidelines (NTEP 2022 and WHO) have revolutionized pediatric TB therapy with the introduction of child-friendly Fixed Dose Combinations (FDCs), upfront molecular testing for drug resistance, and the inclusion of newer drugs like Bedaquiline and Delamanid for children.

1. Classification of Anti-Tubercular Drugs

A. First-Line Drugs (For Drug-Sensitive TB)

These are the most effective and least toxic drugs, forming the backbone of standard therapy.

1. Isoniazid (H)
2. Rifampicin (R)
3. Pyrazinamide (Z)
4. Ethambutol (E)

B. Second-Line Drugs (For Drug-Resistant TB)

Classified by the WHO and NTEP (2021/2022) into three groups based on efficacy and safety:

• Group A (Prioritized): Levofloxacin (Lfx) or Moxifloxacin (Mfx), Bedaquiline (Bdq), Linezolid (Lzd).
• Group B (Add next): Clofazimine (Cfz), Cycloserine (Cs) or Terizidone (Trd).
• Group C (Complementary): Ethambutol (E), Delamanid (Dlm), Pyrazinamide (Z), Imipenem-cilastatin/Meropenem, Amikacin (Am), Ethionamide (Eto), p-Aminosalicylic acid (PAS).

2. First-Line Anti-Tubercular Drugs

Isoniazid (H)

• Mechanism: Bactericidal against rapidly dividing bacilli. It inhibits the synthesis of mycolic acid, an essential component of the mycobacterial cell wall, by targeting the inhA gene product (enoyl-ACP reductase).
• Pharmacokinetics: Metabolized in the liver by acetylation. Fast acetylators require higher doses, while slow acetylators are at risk of toxicity. It penetrates well into all body fluids, including CSF (CSF levels are 20–90% of plasma levels).
• Pediatric Dosage: 10 mg/kg/day (Range 7–15 mg/kg). Max: 300 mg.
• Adverse Effects:
  • Hepatotoxicity: Asymptomatic transaminase elevation is common. Clinical hepatitis is rare in children but increases with age.
  • Peripheral Neuropathy: Due to interference with pyridoxine metabolism. Rare in children unless malnourished.
  • Neurotoxicity: Seizures (in overdose), psychosis.

Rifampicin (R)

• Mechanism: Bactericidal against both dividing and semi-dormant (persister) bacilli. It inhibits DNA-dependent RNA polymerase (rpoB gene). It is the most potent sterilizing drug.
• Pharmacokinetics: Potent inducer of hepatic cytochrome P450 enzymes, leading to significant drug interactions (e.g., antiretrovirals, anticonvulsants). Excreted in bile.
• Pediatric Dosage: 15 mg/kg/day (Range 10–20 mg/kg). Max: 600 mg.
• Adverse Effects:
  • Hepatotoxicity: Synergistic with Isoniazid.
  • Discoloration: Orange-red discoloration of urine, sweat, and tears (stains contact lenses).
  • Flu-like syndrome: Fever, chills, myalgia (more common with intermittent dosing).

Pyrazinamide (Z)

• Mechanism: Bactericidal against intracellular bacilli in acidic environments (e.g., inside macrophages). Converted to active pyrazinoic acid by the enzyme pyrazinamidase (pncA gene). Its use allows shortening of therapy from 9 to 6 months.
• Pharmacokinetics: Good CSF penetration.
• Pediatric Dosage: 35 mg/kg/day (Range 30–40 mg/kg). Max: 2000 mg.
• Adverse Effects:
  • Hepatotoxicity: The most hepatotoxic first-line drug.
  • Hyperuricemia: Inhibits renal excretion of urates; can cause arthralgia (gout is rare in children).

Ethambutol (E)

• Mechanism: Bacteriostatic. Inhibits arabinosyl transferase, interfering with cell wall synthesis. It prevents the emergence of resistance to other drugs.
• Pharmacokinetics: Renally excreted (dose adjustment needed in renal failure). Poor CSF penetration unless meninges are inflamed.
• Pediatric Dosage: 20 mg/kg/day (Range 15–25 mg/kg). Max: 1200 mg.
• Adverse Effects:
  • Optic Neuritis: Retrobulbar neuritis causing decreased visual acuity and red-green color blindness. Rare at pediatric doses (<20-25 mg/kg).

3. Newer and Second-Line Drugs (For DR-TB)

Bedaquiline (Bdq)

• Mechanism: A diarylquinoline that inhibits mycobacterial ATP synthase. Bactericidal and sterilizing.
• Indications: Core drug for MDR/RR-TB in children $\ge$ 5 years and weighing $\ge$ 15 kg.
• Dosage (Children 15–30 kg): 200 mg daily for 14 days (loading), followed by 100 mg thrice weekly for 22 weeks.
• Adverse Effects: QTc prolongation (requires ECG monitoring), hepatotoxicity.
• Interactions: Metabolized by CYP3A4; avoid with Rifampicin and Efavirenz.

Delamanid (Dlm)

• Mechanism: Nitro-dihydro-imidazo-oxazole derivative. Inhibits mycolic acid synthesis and generates nitric oxide.
• Indications: MDR-TB in children $\ge$ 6 years. Can be used with Bedaquiline.
• Dosage (6–11 years): 50 mg twice daily for 24 weeks.
• Adverse Effects: QTc prolongation.

Fluoroquinolones (Levofloxacin/Moxifloxacin)

• Role: Bactericidal backbone of MDR-TB regimens (Group A). Levofloxacin (Lfx) is preferred in children due to safety data; Moxifloxacin (Mfx) is used if Lfx cannot be used.
• Pediatric Dosage:
  • Levofloxacin: 15–20 mg/kg (for $\le$ 5 yrs) or 10–15 mg/kg (>5 yrs).
  • Moxifloxacin: 7.5–10 mg/kg.
• Adverse Effects: Arthropathy (theoretical risk in growing cartilage, but benefits outweigh risks in MDR-TB), QTc prolongation (Moxifloxacin).

Linezolid (Lzd)

• Role: Group A drug for MDR-TB.
• Adverse Effects: Bone marrow suppression (anemia, thrombocytopenia), peripheral and optic neuropathy, lactic acidosis. Requires CBC monitoring.
• Dosage: 10–12 mg/kg (<6 yrs) or 10 mg/kg (>6 yrs). Dose often tapered to prevent toxicity in long regimens.

Clofazimine (Cfz)

• Role: Group B drug.
• Adverse Effects: Red-brown skin discoloration (reversible but distressing), ichthyosis, GI upset.

4. Standard Treatment Regimens (NTEP 2022)

A. Drug-Sensitive TB (DS-TB)

All new and previously treated cases with Rifampicin sensitivity are treated with a standard 6-month regimen.

• Intensive Phase (IP): 2 months of HRZE.
• Continuation Phase (CP): 4 months of HRE.
• Total Duration: 6 months. (Extended to 12 months for CNS/Spinal/Osteoarticular TB).
• Note: Daily therapy is mandatory. FDCs are used to ensure adherence.

B. Isoniazid (H) Mono/Poly-Resistant TB

For patients with H resistance but R sensitivity.

• Regimen: 6 Lfx R E Z (Levofloxacin, Rifampicin, Ethambutol, Pyrazinamide) for 6 months.
• No separate IP/CP.

C. MDR/Rifampicin-Resistant TB (RR-TB)

Treatment depends on age and eligibility:

1. Shorter Oral Bedaquiline-containing Regimen:

   • Eligibility: Children $\ge$ 5 years, $\ge$ 15 kg, no FQ resistance, no severe EPTB.
   • Duration: 9–11 months.
   • Regimen:
     • IP (4–6 months): Bdq, Lfx, Cfz, Z, E, High-dose Isoniazid (Hh), Ethionamide (Eto).
     • CP (5 months): Lfx, Cfz, Z, E. (Bdq is given for 6 months total).

2. Longer Oral M/XDR-TB Regimen:

   • Eligibility: Children < 5 years, FQ resistance, or severe disease (TBM).
   • Duration: 18–20 months.
   • Composition: Customized using Group A (Lfx, Bdq, Lzd) and Group B (Cfz, Cs) drugs. (e.g., 18-20 Lfx, Bdq, Lzd, Cfz, Cs).

5. Adjunct Therapies

Pyridoxine (Vitamin B6)

• Indication: Recommended for all children and adolescents on Isoniazid-containing regimens (DS-TB and TPT) to prevent peripheral neuropathy.
• Dosage: 10 mg/day (Prophylactic). 50–100 mg/day (Therapeutic).

Corticosteroids (Prednisolone)

• Indications:
  • TB Meningitis (reduces mortality and sequelae).
  • TB Pericarditis.
  • Severe miliary TB with alveolocapillary block.
  • Endobronchial TB with obstruction/respiratory distress.
• Dosage: 1–2 mg/kg/day for 2–4 weeks, then tapered over 4–6 weeks.

6. Adverse Drug Reactions (ADR) Management

Adverse Event	Suspected Drug	Management
Hepatotoxicity	Z, H, R, Eto, Bdq	Stop all hepatotoxic drugs if ALT >5x ULN (asymptomatic) or >3x ULN (symptomatic). Reintroduce sequentially (R $\to$ H) once LFTs normalize.
Gastrointestinal	Z, Eto, PAS	Symptomatic tx (antiemetics), take with food (except R if possible).
Cutaneous Rash	Any	Antihistamines. Stop drugs if severe (Stevens-Johnson).
Peripheral Neuropathy	H, Lzd, Cs	Pyridoxine therapy (100 mg).
Visual Impairment	E, Lzd	Stop the drug immediately.
QT Prolongation	Bdq, Mfx, Cfz, Dlm	Monitor ECG. Stop drug if QTc > 500ms.
Arthralgia	Z, FQ	NSAIDs.

7. Special Situations

A. HIV Co-infection

• Drug Interactions: Rifampicin decreases levels of Protease Inhibitors (PIs) and NNRTIs.
  • Dolutegravir (DTG): Dose must be doubled to 50 mg BD when used with Rifampicin.
  • Efavirenz: Safe with Rifampicin.
  • Bedaquiline: Avoid with Efavirenz (use DTG instead).
• IRIS: Paradoxical worsening after starting ART; managed with steroids.
• CPT: Cotrimoxazole prophylaxis is mandatory.

B. Pregnancy

• Safe Drugs: Isoniazid, Rifampicin, Ethambutol.
• Contraindicated: Aminoglycosides (Streptomycin - ototoxicity), Ethionamide (teratogenic).
• MDR-TB: Bedaquiline and Delamanid safety is not fully established but considered if benefits outweigh risks.

C. Renal Failure

• Dose Adjustment: Required for Ethambutol, Aminoglycosides, and Levofloxacin (excreted by kidneys).
• Safe: Isoniazid, Rifampicin, Pyrazinamide (metabolized by liver), though metabolites may accumulate.