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Antitubercular Drugs - Complete Notes

Classification of Antitubercular Drugs

I. First Line (Primary) Drugs

• Isoniazid (H)
• Rifampin (R)
• Pyrazinamide (Z)
• Ethambutol (E)
• Streptomycin (S)

II. Second Line (Secondary) Drugs

• Thiacetazone (Thz), Para-aminosalicylic acid (PAS), Ethionamide (Eto), Cycloserine (Cs), Terizidone (Trd), Rifabutin
• Fluoroquinolones: Ofloxacin (Ofx), Levofloxacin (Lvx/Lfx), Moxifloxacin (Mfx), Ciprofloxacin (Cfx)
• Injectable: Kanamycin (Km), Amikacin (Am), Capreomycin (Cm)

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First Line Drugs - Detailed

Isoniazid (H) [2068]

• Primarily tuberculocidal; bacteriostatic for resting bacilli, bactericidal for rapidly dividing organisms
• Acts on extracellular and intracellular TB bacilli

• Given orally, completely absorbed
• Penetrates body tissues, tubercular cavities, placenta, and meninges
• Metabolized in liver
  • Fast acetylator (t½ = 1 hr) → more risk of hepatotoxicity
  • Slow acetylator (t½ = 3 hr) → more risk of peripheral neuritis
• Dose: 5 mg/kg/day; Max: 300 mg/day
• Aluminum hydroxide inhibits INH absorption
• PAS inhibits INH metabolism and prolongs its t½

• Peripheral neuritis (INH interferes with pyridoxine utilization and excretion) - treat with 100 mg/day pyridoxine; 10 mg/kg/day pyridoxine given prophylactically
• Hepatotoxicity (hepatocellular damage and necrosis)
• Lethargy, Rashes (rarely SLE), Acne, Arthralgia
• CNS: Psychotic behaviour

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Rifampin (R) [2055, 2075]

• Broad spectrum anti-TB drug; highly effective antibiotic

• Affects both extracellular and intracellular organisms
• Inhibits DNA-dependent RNA polymerase → bactericidal effect

• Well absorbed orally; take at least 1/2 hr before breakfast
• Penetrates cavities, caseous masses, placenta, and meninges
• Microsomal enzyme inducer → ↑ metabolism of OCP, HIV protease inhibitors, warfarin, corticosteroids, sulfonylureas

• Hepatitis
• Respiratory syndrome
• Flu syndrome (chills, fever, malaise, bone pain)
• Abdominal syndrome (nausea, vomiting, cramps)
• Cutaneous syndrome (flushing, pruritus, rash, red watery eye)
• Purpura, hemolysis, shock, renal failure
• Orange-red coloration of urine/body secretions (harmless)

Note: Rifampicin reduces effectiveness of oral contraceptive pill - advise higher dose oestrogen (50 mcg) or alternative contraception.

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Pyrazinamide (Z)

• Chemically similar to INH; weak tuberculocidal
• High sterilizing activity
• More active in acidic media (e.g., inflammation sites)
• Lethal to intracellular bacilli
• Highly effective during first 2 months of therapy when inflammatory changes are present

• Hepatotoxicity
• Hyperuricemia (inhibits uric acid secretion) → Gout
• Fever, Arthralgia, Flushing, Rashes, Loss of diabetes control
• Contraindication: Liver disease

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Ethambutol (E)

• Selective tuberculostatic drug

• Inhibits arabinosyltransferase synthesis, interfering with mycolic acid incorporation into cell wall
• Suppresses growth of most INH and streptomycin-resistant bacilli
• Prevents/delays emergence of resistant bacilli

• Optic neuritis - ↓ visual acuity, unable to differentiate green, visual field defects
• Not recommended for children under 5 years of age
• Rashes, Hyperuricemia, Fever

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Streptomycin (S)

• First clinically effective drug
• Acts only on extracellular bacilli
• Given IM (15 mg/kg; 750 mg above 50 yrs)
• Does not cross BBB normally; reaches CSF in inflamed meninges (up to 20% of plasma concentration)
• Not commonly used due to IM injection requirement
• Low safety margin

• Ototoxicity
• Nephrotoxicity
• Neuromuscular blockade
• Resistance develops when used alone rapidly

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Second Line Drugs - Detailed

Thiacetazone (Thz)

• Tuberculostatic; low cost, low efficacy
• Used with isoniazid to delay resistance; needs prolonged therapy
• ADR: Hepatitis, Anorexia, loose motion
• Not used in HIV + TB - fatal ADRs: Stevens-Johnson syndrome, Toxic epidermal necrolysis

Ethionamide (Eto)

• Tuberculostatic; chemically related to INH
• Inhibition of mycolic acid synthesis
• ADR: Anorexia, nausea, vomiting (common), Hepatitis, Salivation, metallic taste, sulfurous belching, Impotence, goiter, Peripheral/optic neuritis
• Seldom used; only if better-tolerated drugs unavailable

Para-Aminosalicylic Acid (PAS)

• Chemical properties/MOA related to sulfonamides
• Competitively inhibits folate synthesizing enzyme → prevents THFA formation → inhibits bacterial multiplication
• Tuberculostatic effect
• Rapidly absorbed orally; poor BBB penetration
• PAS reduces absorption of rifampicin from gut and competitively inhibits acetylation of INH (thus increasing plasma level of INH)
• ADR: Anorexia, nausea, epigastric pain, Rashes, fever, malaise, Liver dysfunction, blood dyscrasias, hypokalemia, Goiter

Cycloserine (Cs)

• Tuberculostatic; inhibits bacterial cell wall synthesis
• Serious CNS side effects: Sleepiness, Headache, Tremor, Psychosis, Seizures
• Adverse effects limit usefulness

Kanamycin (Km), Amikacin (Am), Capreomycin (Cm)

• Kanamycin & Amikacin → Aminoglycosides
• Capreomycin → Polypeptide
• Given by IM route
• All exhibit nephrotoxicity and ototoxicity - never combine together or with streptomycin
• Used when not responding to usual therapy or for atypical mycobacteria

Rifabutin

• Related to rifampin in structure and MOA
• Hepatic microsomal enzyme inducer (lesser degree than rifampin)
• Lesser interaction with protease inhibitors → dose ↓ from 300 to 150 mg/day
• Used in TB with HIV
• Prophylaxis of MAC infection in HIV-infected individuals

Fluoroquinolones (FQs)

• Ciprofloxacin, Ofloxacin, Moxifloxacin, Levofloxacin
• Inhibitory activity against Mycobacterium tuberculosis and MAC infection
• Uses:
  • Salvage therapy for MAC in HIV: Ciprofloxacin + clarithromycin + rifabutin + amikacin
  • TB therapy with quinolones reserved for MDR-TB or those who cannot tolerate 1st line drugs

Macrolides (Clarithromycin, Azithromycin)

• Clarithromycin more active than azithromycin by 4 times
• For MAC infection: Clarithromycin 500 mg BD or azithromycin 500 mg OD + ethambutol ± rifabutin
• Continue throughout lifetime of HIV patient

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Goals of Antitubercular Chemotherapy

1. Kill dividing bacilli - reduce bacillary load rapidly; achieve quick sputum negativity; interrupt transmission
2. Kill persisting bacilli - cure and prevent relapse; depends on sterilizing capacity of drug
3. Prevent emergence of resistance - keep bacilli susceptible

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Standardized Treatment Categories [2069]

National Treatment Regimen

WHO Treatment Regimen

Note: Pyrazinamide used only in initial phase (max sterilizing effect in first 2 months; no benefit with longer use)

DOTS (Directly Observed Treatment Short Course) recommended by WHO since 1995.

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Rationale for Combination Therapy

• Single drug → emergence of resistant organisms and relapse in almost 3/4th patients
• Average pulmonary TB patient harbours 10^8 to 10^10 bacilli
• Incidence of resistance to most drugs: 10^-8 to 10^-6
• Number of organisms resistant to a single drug is high - dealt by host defence and combination
• Incidence of H resistance among bacilli resistant to R will be 10^-6 × 10^-6 = 10^-12 (handled by host defence)

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MDR-TB Treatment (DOTS Plus Guideline)

• MDR-TB = resistance to both H and R + possibly other 1st line drugs
• More rapid course with worse outcomes
• Requires complex multiple 2nd line regimens (longer, more expensive, more toxic)

• Regimen should have at least 4 drugs certain to be effective (often 5-6)
• Rely on antibiotic susceptibility test results
• Avoid combining cross-resistance drugs (e.g., two FQs, Km with Am or Eto with Pto or Cs with terizidone)

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Extensively Drug Resistant TB (XDR-TB)

• MDR-TB cases also resistant to FQs and at least one injectable 2nd line drug
• Resistant to at least 4 most effective cidal drugs: H, R, FQ, and one of Km/Am/Cm
• Very difficult to treat; rapid course and high mortality
• Standardized MDR regimen must be stopped when XDR-TB is detected/suspected
• Group V drugs (uncertain efficacy): Thiacetazone, Clarithromycin, Clofazimine, Linezolid, Amoxicillin/clavulanate, Imipenem/cilastatin

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TB with Pregnancy and Lactation

• Safe in pregnancy: 2HRZ + 4HR (Isoniazid, Rifampicin, Pyrazinamide, Ethambutol)
• Ethambutol can be added in 3rd trimester (not earlier)
• Treatment should NOT be withheld due to pregnancy/lactation
• In Lactation: Full course given; infant should receive chemoprophylaxis

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Role of Corticosteroids in TB

• Seriously ill patients (miliary or severe pulmonary TB) to buy time for drugs to act
• Hypersensitivity reactions to anti-TB drugs
• Meningeal/renal/adrenal/pericardial TB - reduce exudation, prevent pleural effusion, prevent organization and strictures
• AIDS patients with severe TB manifestations
• TB laryngitis - prevent life-threatening airway obstruction

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Hepatotoxicity with Antitubercular Drugs

• Most common problem with anti-TB drugs
• H, R, or Z can each be causative
• Reaction more frequent when combination is used
• Protocol when hepatitis develops:
  1. Stop all drugs; allow reaction to subside
  2. If TB severe, start non-hepatotoxic drugs: S + E + One FQ
  3. Restart drugs one at a time: R first, then H 7 days later
  4. If hepatitis recurs, stop last added drug permanently; reconstruct regimen
  5. If both R and H tolerated - do not restart Z; prolong therapy with R and H to 9 months
  6. If R is culprit: HES for 2 months then HE for 10 months
  7. If H is implicated: REZ for 9 months
  8. If neither R nor H can be given: S, E, FQ regimen for 18-24 months

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Use of Anti-TB Drugs in Renal Failure

• Safe: Rifampicin, Isoniazid, Pyrazinamide
• Partly renal excretion: Ethambutol, Thiacetazone (avoid if alternatives; or give reduced doses at less frequent intervals)
• Renal excretion: Streptomycin (avoid if alternatives)
• Never give Thiacetazone in renal failure - narrow therapeutic/toxic margin