Antituberculosis Drugs: A Comprehensive Masterclass
By Arvind Sharma, B.Pharm, M.Pharm, Assistant Professor, MUIT
Antituberculosis Drugs: A Comprehensive Masterclass
Learning Objectives
Upon successful completion of this module, students will be able to:
- Describe the global epidemiology and etiology of Tuberculosis (TB).
- Classify antituberculosis drugs based on their efficacy, toxicity, and usage.
- Elucidate the detailed mechanisms of action of all first-line and important second-line antituberculosis agents.
- Outline the pharmacokinetic profiles, therapeutic uses, and adverse effects of each major antituberculosis drug.
- Formulate standard treatment regimens for drug-susceptible, multidrug-resistant (MDR-TB), and extensively drug-resistant (XDR-TB) tuberculosis.
- Identify mechanisms of resistance developed by Mycobacterium tuberculosis against various drugs.
- Discuss the management strategies for drug toxicities and important drug interactions.
- Analyze the role of newer antituberculosis drugs in combating drug-resistant TB.
- Appreciate the significance of Directly Observed Treatment, Short-course (DOTS) in TB control.
Introduction to Tuberculosis (TB)
Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a formidable global health challenge, responsible for millions of deaths annually. It primarily affects the lungs (pulmonary TB) but can also manifest in other organs (extrapulmonary TB). The emergence of drug-resistant strains, particularly Multidrug-Resistant TB (MDR-TB) and Extensively Drug-Resistant TB (XDR-TB), complicates treatment and necessitates a thorough understanding of antituberculosis chemotherapy.
An infectious disease caused by the bacillus Mycobacterium tuberculosis, typically affecting the lungs but capable of impacting any part of the body. It is spread from person to person through the air.
Etiology and Pathogenesis of Tuberculosis
Mycobacterium tuberculosis is a slow-growing, aerobic, non-spore-forming bacillus characterized by its unique waxy cell wall rich in mycolic acid, which contributes to its acid-fast property and resistance to host defenses and many antibiotics. Infection occurs primarily through inhalation of aerosolized droplets containing the bacilli from an individual with active pulmonary TB.
Initial infection often leads to a latent phase, where the immune system contains the bacteria, forming granulomas (tubercles). Latent TB is asymptomatic and non-contagious. However, reactivation can occur years later, leading to active disease, especially in immunocompromised individuals.
Inhalation of M. tuberculosis aerosols → Alveolar macrophages phagocytose bacteria → Bacteria replicate intracellularly → Host immune response (T-cells, macrophages) form granuloma (tubercle) → Latent TB Infection (LTBI).
Immunosuppression / Compromised immunity → Granuloma breakdown → Bacterial proliferation and dissemination → Active TB Disease.
Classification of Antituberculosis Drugs
Antituberculosis drugs are broadly classified into first-line and second-line agents based on their efficacy, tolerability, and role in standard treatment regimens.
| Category | Drugs | Characteristics |
|---|---|---|
| First-Line Anti-TB Drugs | Isoniazid (INH), Rifampicin (RIF), Pyrazinamide (PZA), Ethambutol (EMB), Streptomycin (SM) | High efficacy, relatively low toxicity, essential for initial treatment regimens. |
| Second-Line Injectable Anti-TB Drugs | Amikacin, Kanamycin, Capreomycin | Used in drug-resistant TB; associated with more severe toxicities (ototoxicity, nephrotoxicity). |
| Second-Line Oral Anti-TB Drugs | Ethionamide, Prothionamide, Cycloserine, Para-aminosalicylic acid (PAS), Linezolid, Clofazimine, Fluoroquinolones (Moxifloxacin, Levofloxacin, Gatifloxacin) | Used for drug-resistant TB; generally less effective or more toxic than first-line drugs. |
| Newer Anti-TB Drugs | Bedaquiline, Delamanid, Pretomanid | Specifically developed for MDR/XDR-TB; novel mechanisms, often reserved for highly resistant cases. |
Detailed Mechanisms of Action, Pharmacokinetics, Pharmacodynamics, and Adverse Effects
1. First-Line Anti-TB Drugs
a. Isoniazid (INH)
A prodrug activated by the mycobacterial catalase-peroxidase enzyme (KatG) to form active metabolites that inhibit mycolic acid synthesis, a critical component of the mycobacterial cell wall.
Mechanism of Action (MOA)
Isoniazid is a prodrug requiring activation by the mycobacterial enzyme KatG (catalase-peroxidase). This activation leads to the formation of several reactive species, including isonicotinic acyl-NADH, which inhibits InhA (an enoyl-ACP reductase enzyme). InhA is crucial for the biosynthesis of mycolic acid, a unique lipid component of the mycobacterial cell wall. Inhibition of mycolic acid synthesis disrupts cell wall integrity, leading to bacterial death. INH is bactericidal against rapidly dividing bacilli and bacteriostatic against slowly growing bacilli.
INH → Activated by KatG → Forms Isonicotinic acyl-NADH → Inhibits InhA → Blocks Mycolic Acid Synthesis → Cell Wall Disruption → Bactericidal Action.
Pharmacokinetics (PK)
- Absorption: Well absorbed orally; food may delay absorption.
- Distribution: Widely distributed to all body tissues and fluids, including CSF, caseous lesions, and pleural fluid.
- Metabolism: Primarily metabolized in the liver by N-acetylation by N-acetyltransferase 2 (NAT2). Genetic polymorphism in NAT2 divides individuals into “fast acetylators” and “slow acetylators,” influencing drug half-life and potential toxicity. Hydrolysis also occurs.
- Excretion: Mainly excreted in urine as metabolites.
- Half-life: 1-4 hours (variable due to NAT2 polymorphism).
Pharmacodynamics (PD)
INH exhibits concentration-dependent killing against rapidly dividing organisms. Its efficacy is related to the area under the curve (AUC)/MIC ratio.
Adverse Effects (AEs)
- Peripheral Neuropathy: Most common dose-dependent AE, due to competitive inhibition of pyridoxine (Vitamin B6) metabolism. Prevented by co-administration of pyridoxine.
- Hepatotoxicity: Ranging from asymptomatic elevation of transaminases to severe hepatitis (rare, but potentially fatal). Risk increases with age, alcohol use, and pre-existing liver disease.
- CNS Effects: Optic neuritis, convulsions, psychosis (less common).
- Hypersensitivity Reactions: Rash, fever.
- Hematologic: Agranulocytosis, hemolytic anemia.
Therapeutic Uses
- Essential component of all standard regimens for drug-susceptible TB.
- Prophylaxis for latent TB infection (LTBI).
b. Rifampicin (RIF)
A broad-spectrum antibiotic that inhibits bacterial DNA-dependent RNA polymerase, thereby blocking RNA synthesis.
Mechanism of Action (MOA)
Rifampicin is a potent bactericidal drug that specifically inhibits bacterial DNA-dependent RNA polymerase (DDRP) by binding to its β-subunit, preventing the initiation of RNA synthesis. This effectively halts transcription in mycobacteria. Importantly, rifampicin does not affect human RNA polymerase at therapeutic concentrations.
Rifampicin → Binds to β-subunit of bacterial DDRP → Inhibits RNA synthesis → Bactericidal Action.
Pharmacokinetics (PK)
- Absorption: Well absorbed orally; food may decrease absorption.
- Distribution: Widely distributed throughout the body, including CSF, even in uninflamed meninges. Highly lipophilic.
- Metabolism: Undergoes enterohepatic recirculation and is auto-induced (induces its own metabolism by inducing hepatic cytochrome P450 enzymes, particularly CYP3A4). Desacetylrifampicin is the main active metabolite.
- Excretion: Primarily excreted in bile and feces, with some renal excretion.
- Half-life: 2-5 hours, decreasing with repeated doses due to auto-induction.
Pharmacodynamics (PD)
RIF exhibits concentration-dependent killing and has a prolonged post-antibiotic effect. Its efficacy is related to the AUC/MIC ratio.
Adverse Effects (AEs)
- Hepatotoxicity: Can cause asymptomatic elevation of liver enzymes; severe hepatitis is less common than with INH but risk is increased with co-administration of INH or PZA.
- Orange-Red Discoloration of Secretions: Urine, tears, sweat, saliva, and contact lenses may turn orange-red, which is harmless but can be alarming.
- Flu-like Syndrome: Fever, chills, myalgia, arthralgia, especially with intermittent dosing.
- Rash, Pruritus.
- Thrombocytopenia, Leukopenia, Hemolytic anemia (rare).
- Potent Enzyme Inducer: Induces various CYP P450 enzymes (especially CYP3A4, CYP2C9, CYP2C19), leading to significant drug interactions (e.g., reduces efficacy of oral contraceptives, anticoagulants, antiretrovirals, corticosteroids, anti-diabetic drugs).
Therapeutic Uses
- Crucial component of all standard regimens for drug-susceptible TB.
- Used in prophylaxis for contacts of INH-resistant TB.
- Used in some non-tuberculous mycobacterial infections and leprosy.
c. Pyrazinamide (PZA)
A prodrug activated by mycobacterial pyrazinamidase (PZase) to pyrazinoic acid (POA), which disrupts mycobacterial membrane energetics and fatty acid synthesis, primarily active in acidic environments.
Mechanism of Action (MOA)
Pyrazinamide is a prodrug that is converted to its active metabolite, pyrazinoic acid (POA), by the mycobacterial enzyme pyrazinamidase (PZase) (encoded by the pncA gene). POA then diffuses into the bacillus and accumulates in the acidic environment of macrophages and caseous lesions, where it disrupts mycobacterial membrane function, fatty acid synthesis (e.g., FAS I), and potentially inhibits trans-translation, leading to bacterial death. It is particularly effective against slowly growing bacilli residing in acidic intracellular environments.
PZA → Activated by PZase (pncA) → Forms Pyrazinoic Acid (POA) → Accumulates in acidic environment → Disrupts Membrane Function & Fatty Acid Synthesis → Bactericidal Action (especially on dormant bacilli).
Pharmacokinetics (PK)
- Absorption: Well absorbed orally.
- Distribution: Widely distributed throughout the body, including CSF.
- Metabolism: Hydrolyzed in the liver to active POA, then further metabolized by xanthine oxidase to inactive metabolites.
- Excretion: Primarily renal.
- Half-life: 9-10 hours.
Pharmacodynamics (PD)
PZA exhibits concentration-dependent killing and is uniquely effective in acidic environments, targeting persistent, slow-growing bacilli.
Adverse Effects (AEs)
- Hepatotoxicity: Dose-dependent, can be severe and is a major concern, especially when combined with INH and RIF.
- Hyperuricemia: Common, due to inhibition of renal excretion of uric acid. Can cause acute gouty arthritis in predisposed individuals, but asymptomatic hyperuricemia usually does not require discontinuation.
- Arthralgia, Myalgia.
- Gastrointestinal disturbances: Nausea, vomiting, anorexia.
- Rash.
Therapeutic Uses
- Crucial component of the intensive phase of TB treatment, shortening the overall duration of therapy due to its activity against persistent bacilli.
d. Ethambutol (EMB)
A bacteriostatic drug that inhibits arabinosyl transferases, enzymes critical for the synthesis of the mycobacterial arabinogalactan layer in the cell wall.
Mechanism of Action (MOA)
Ethambutol is a bacteriostatic drug that inhibits arabinosyl transferases (specifically EmbA, EmbB, EmbC, encoded by the embCAB operon), enzymes involved in the synthesis of arabinogalactan, a polysaccharide component of the mycobacterial cell wall. Inhibition of arabinogalactan synthesis impairs cell wall integrity and permeability, making the bacteria more susceptible to other antituberculosis drugs.
Ethambutol → Inhibits Arabinogalactan Synthesis (via Arabinosyl transferases) → Impairs Cell Wall Integrity → Bacteriostatic Action.
Pharmacokinetics (PK)
- Absorption: Well absorbed orally; food has little effect.
- Distribution: Widely distributed, but CSF penetration is poor unless meninges are inflamed.
- Metabolism: Partially metabolized in the liver to aldehyde and carboxylic acid derivatives.
- Excretion: Primarily renal (50% unchanged drug). Dose adjustment is necessary in renal impairment.
- Half-life: 3-4 hours.
Pharmacodynamics (PD)
EMB's effect is time-dependent, meaning its efficacy is related to the duration of time the drug concentration remains above the MIC.
Adverse Effects (AEs)
- Optic Neuritis: Most significant dose-dependent AE, characterized by decreased visual acuity, red-green color blindness, and visual field defects. Usually reversible upon discontinuation, but permanent blindness can occur. Requires regular ophthalmic monitoring.
- Peripheral Neuropathy (rare).
- Hyperuricemia (less common than with PZA).
- Allergic reactions.
Therapeutic Uses
- Component of initial treatment for drug-susceptible TB, especially in areas with high INH resistance or in cases where INH cannot be used.
- Used to prevent development of resistance to other drugs.
e. Streptomycin (SM)
An aminoglycoside antibiotic that binds to the 30S ribosomal subunit, inhibiting protein synthesis and causing misreading of mRNA.
Mechanism of Action (MOA)
Streptomycin is an aminoglycoside antibiotic that binds irreversibly to the 16S rRNA of the 30S ribosomal subunit of mycobacteria. This binding interferes with the initiation complex of protein synthesis, causes misreading of mRNA, and results in premature termination of protein synthesis, leading to bactericidal action. It is primarily active against extracellular, rapidly multiplying bacilli.
Streptomycin → Binds to 30S Ribosomal Subunit → Inhibits Protein Synthesis & Causes mRNA Misreading → Bactericidal Action.
Pharmacokinetics (PK)
- Absorption: Poorly absorbed orally, so administered intramuscularly (IM) or intravenously (IV).
- Distribution: Distributes well into extracellular fluid but poor penetration into CSF and caseous lesions.
- Metabolism: Not metabolized.
- Excretion: Excreted unchanged by glomerular filtration. Dose adjustment is necessary in renal impairment.
- Half-life: 2-3 hours.
Pharmacodynamics (PD)
SM exhibits concentration-dependent killing and a significant post-antibiotic effect. Its efficacy correlates with peak concentration to MIC ratio (Cmax/MIC).
Adverse Effects (AEs)
- Ototoxicity: Can cause vestibular dysfunction (dizziness, vertigo, ataxia) and cochlear damage (hearing loss), often irreversible. Monitoring of audiometry is crucial.
- Nephrotoxicity: Tubular necrosis, usually reversible. Requires monitoring of renal function.
- Neuromuscular Blockade: Can cause respiratory depression, especially at high doses or in patients with pre-existing neuromuscular disorders.
- Hypersensitivity reactions.
Therapeutic Uses
- Used in severe forms of TB, such as miliary TB or TB meningitis, where rapid bactericidal activity is needed.
- Historically part of initial treatment, now largely replaced by other first-line oral agents due to its parenteral administration and toxicity profile. Still important in some drug-resistant regimens.
2. Second-Line Anti-TB Drugs
These drugs are generally used for drug-resistant TB or when first-line drugs are contraindicated or poorly tolerated. They typically have lower efficacy, higher toxicity, or both.
a. Fluoroquinolones (Moxifloxacin, Levofloxacin, Gatifloxacin)
Mechanism of Action (MOA)
Fluoroquinolones inhibit bacterial DNA gyrase (topoisomerase II) and topoisomerase IV, enzymes essential for DNA replication, transcription, repair, and recombination, leading to DNA strand breaks and bacterial cell death. They are bactericidal against M. tuberculosis.
Fluoroquinolones → Inhibits DNA Gyrase & Topoisomerase IV → Blocks DNA Synthesis → Bactericidal Action.
Pharmacokinetics (PK)
- Absorption: Well absorbed orally.
- Distribution: Widely distributed, good penetration into lung tissue and macrophages.
- Metabolism: Minimal hepatic metabolism.
- Excretion: Primarily renal (Levofloxacin), mixed (Moxifloxacin).
- Half-life: 6-12 hours.
Adverse Effects (AEs)
- Gastrointestinal: Nausea, vomiting, diarrhea.
- CNS: Headache, dizziness, insomnia, seizures (rare).
- QT Prolongation: Especially Moxifloxacin.
- Tendinitis and Tendon Rupture: Particularly in older patients or those on corticosteroids.
- Photosensitivity.
Therapeutic Uses
- Key component in regimens for MDR-TB.
- Moxifloxacin is generally preferred due to higher mycobacterial activity.
b. Ethionamide / Prothionamide
Mechanism of Action (MOA)
Similar to INH, these prodrugs are activated by mycobacterial enzymes (e.g., EthA) to inhibit InhA, thereby blocking mycolic acid synthesis. They are bacteriostatic.
Pharmacokinetics (PK)
- Absorption: Well absorbed orally.
- Distribution: Good tissue penetration, including CSF.
- Metabolism: Extensive hepatic metabolism.
- Excretion: Primarily renal.
Adverse Effects (AEs)
- Gastrointestinal: Severe nausea, vomiting, metallic taste (dose-limiting).
- Hepatotoxicity.
- Neurological: Peripheral neuropathy, depression, psychosis (can be severe), requiring pyridoxine co-administration.
- Hypothyroidism.
Therapeutic Uses
- Used in MDR-TB regimens.
c. Cycloserine
Mechanism of Action (MOA)
Cycloserine is an analog of D-alanine that inhibits D-alanine ligase and alanine racemase, enzymes involved in the synthesis of D-alanyl-D-alanine, a crucial component of peptidoglycan synthesis in the mycobacterial cell wall. This leads to inhibition of cell wall synthesis.
Pharmacokinetics (PK)
- Absorption: Well absorbed orally.
- Distribution: Excellent penetration into all body fluids, including CSF.
- Metabolism: Minimal metabolism.
- Excretion: Primarily renal (60-70% unchanged). Dose adjustment in renal impairment.
Adverse Effects (AEs)
- CNS Toxicity: Dose-dependent, including headache, irritability, depression, anxiety, confusion, psychosis, and seizures. Requires careful monitoring, especially in patients with psychiatric history. Co-administration of pyridoxine can reduce CNS effects.
Therapeutic Uses
- Used in MDR-TB and XDR-TB regimens.
d. Para-aminosalicylic acid (PAS)
Mechanism of Action (MOA)
PAS is a bacteriostatic drug that inhibits mycobacterial folate synthesis by acting as a competitive inhibitor of dihydrofolate synthase, an enzyme involved in synthesizing dihydrofolic acid. This disrupts purine and pyrimidine synthesis, essential for bacterial growth.
Pharmacokinetics (PK)
- Absorption: Well absorbed orally.
- Distribution: Good tissue distribution, poor CSF penetration.
- Metabolism: Hepatic acetylation.
- Excretion: Primarily renal.
Adverse Effects (AEs)
- Gastrointestinal: Nausea, vomiting, diarrhea, abdominal pain (very common).
- Hypersensitivity reactions: Rash, fever.
- Hepatotoxicity.
- Hypothyroidism (rare, with prolonged use).
Therapeutic Uses
- Used in MDR-TB regimens when other agents are not tolerated or effective. Often given in large doses.
e. Injectable Second-Line Drugs (Amikacin, Kanamycin, Capreomycin)
Mechanism of Action (MOA)
These are aminoglycosides/polypeptides that inhibit bacterial protein synthesis by binding to the 30S ribosomal subunit (Amikacin, Kanamycin) or by interfering with translocation and protein synthesis (Capreomycin, which is a cyclic polypeptide). They are bactericidal.
Pharmacokinetics (PK)
- Absorption: Administered parenterally (IM/IV).
- Distribution: Distribute well into extracellular fluid; poor CSF penetration.
- Metabolism: Not metabolized.
- Excretion: Primarily renal. Dose adjustment required in renal impairment.
Adverse Effects (AEs)
- Ototoxicity: Both vestibular and cochlear damage, often irreversible. High incidence.
- Nephrotoxicity: Acute tubular necrosis.
- Neuromuscular Blockade.
Therapeutic Uses
- Crucial in the intensive phase of MDR-TB and XDR-TB regimens.
3. Newer Anti-TB Drugs
Developed specifically to address the challenge of drug-resistant TB, often with novel mechanisms.
a. Bedaquiline (BDQ)
Mechanism of Action (MOA)
Bedaquiline is a diarylquinoline derivative that inhibits mycobacterial ATP synthase, an enzyme vital for energy generation in M. tuberculosis. This unique mechanism leads to rapid killing of both actively replicating and dormant bacilli.
Bedaquiline → Inhibits Mycobacterial ATP Synthase → Impairs Energy Generation → Bactericidal Action (on active & dormant bacilli).
Pharmacokinetics (PK)
- Absorption: Poor absorption; absorption increased with food.
- Distribution: Highly lipophilic, extensive tissue distribution.
- Metabolism: Primarily metabolized by CYP3A4.
- Excretion: Fecal.
- Half-life: Very long terminal half-life (up to 5.5 months).
Adverse Effects (AEs)
- QT Prolongation: Most significant AE, requires baseline and regular ECG monitoring.
- Hepatotoxicity.
- Arthralgia, nausea.
Therapeutic Uses
- Approved for the treatment of MDR-TB and XDR-TB as part of combination regimens.
b. Delamanid
Mechanism of Action (MOA)
Delamanid is a nitro-dihydro-imidazooxazole derivative that acts as a prodrug. Its active metabolites inhibit mycolic acid synthesis by interfering with the methoxy-mycolic and keto-mycolic acid pathways, distinct from INH.
Delamanid → Active metabolites → Inhibits specific steps in Mycolic Acid Synthesis → Cell Wall Disruption → Bactericidal Action.
Pharmacokinetics (PK)
- Absorption: Increased with fatty food.
- Distribution: Widely distributed.
- Metabolism: Metabolized by various enzymes, including albumin, not primarily CYP.
- Excretion: Fecal.
- Half-life: ~30-38 hours.
Adverse Effects (AEs)
- QT Prolongation: Requires baseline and regular ECG monitoring.
- Insomnia, anxiety, tremor.
Therapeutic Uses
- Approved for MDR-TB when other effective treatment options are limited.
c. Pretomanid
Mechanism of Action (MOA)
Pretomanid is a nitroimidazole prodrug that, upon activation, releases nitric oxide, which is toxic to mycobacteria. It also inhibits mycolic acid synthesis. It is active against both replicating and non-replicating bacilli.
Pharmacokinetics (PK)
- Absorption: Good oral absorption.
- Half-life: ~16-20 hours.
Adverse Effects (AEs)
- Peripheral neuropathy, myelosuppression, hepatotoxicity.
Therapeutic Uses
- Approved for highly drug-resistant TB, as part of specific combination regimens (e.g., with bedaquiline and linezolid for XDR-TB).
d. Linezolid
Mechanism of Action (MOA)
Linezolid is an oxazolidinone antibiotic that inhibits bacterial protein synthesis by binding to the 23S rRNA of the 50S ribosomal subunit, preventing the formation of the 70S initiation complex. This unique mechanism makes it effective against drug-resistant bacteria, including M. tuberculosis.
Pharmacokinetics (PK)
- Absorption: Excellent oral bioavailability (approx. 100%).
- Distribution: Widely distributed, including CSF.
- Metabolism: Oxidative metabolism.
- Excretion: Renal and non-renal pathways.
Adverse Effects (AEs)
- Myelosuppression: Thrombocytopenia, anemia (most common with prolonged use).
- Peripheral and Optic Neuropathy: Dose- and duration-dependent, can be irreversible.
- Lactic Acidosis.
- Serotonin Syndrome: When combined with serotonergic drugs (SSRIs).
Therapeutic Uses
- Crucial component of regimens for MDR-TB and XDR-TB, but use is limited by its toxicity profile, especially with prolonged administration.
e. Clofazimine
Mechanism of Action (MOA)
Clofazimine is a riminophenazine dye with anti-mycobacterial and anti-inflammatory properties. Its exact mechanism is not fully understood but involves binding to mycobacterial DNA, generating reactive oxygen species, and inhibiting bacterial growth and proliferation. It also impairs bacterial electron transport chains.
Pharmacokinetics (PK)
- Absorption: Slowly and variably absorbed orally; increased with food.
- Distribution: Highly lipophilic, accumulates extensively in fatty tissues, reticuloendothelial system.
- Excretion: Fecal, very long half-life (up to 70 days).
Adverse Effects (AEs)
- Skin Discoloration: Reversible red-brown to black pigmentation of skin and conjunctiva (most common).
- Gastrointestinal: Nausea, vomiting, diarrhea, abdominal pain (due to crystal deposition in the gut wall, can be severe).
- QT Prolongation (less common).
Therapeutic Uses
- Used in MDR-TB and