Antituberculosis combinations

Introduction

• Antituberculosis (anti-TB) combinations are therapeutic regimens that use multiple antimycobacterial drugs to treat Mycobacterium tuberculosis infection.

• The rationale for combination therapy:

  • Prevent emergence of drug-resistant strains.

  • Achieve bactericidal and sterilizing effects on different bacterial populations (actively replicating and dormant).

  • Shorten treatment duration compared to monotherapy.

• Standard treatment protocols are defined by the World Health Organization (WHO) and national TB programs.

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Rationale for Multiple-Drug Therapy

• M. tuberculosis has a slow growth rate and can persist in dormant states.

• Spontaneous mutations that confer resistance occur at predictable frequencies for each drug; using multiple drugs reduces the probability that a bacillus is resistant to all simultaneously.

• Different drugs target different bacterial metabolic states and sites of infection.

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First-Line Antituberculosis Drugs (Core Agents)

Isoniazid (INH)

• Bactericidal against actively dividing bacilli.

• Inhibits mycolic acid synthesis in bacterial cell wall.

Rifampicin (RIF)

• Bactericidal against both rapidly dividing and slowly replicating bacilli.

• Inhibits DNA-dependent RNA polymerase.

Pyrazinamide (PZA)

• Sterilizing activity against semi-dormant bacilli in acidic environments (e.g., within macrophages).

• Mechanism: disrupts membrane energetics and inhibits fatty acid synthesis.

Ethambutol (EMB)

• Bacteriostatic; inhibits arabinosyl transferases, impairing cell wall synthesis.

Streptomycin (used less commonly now)

• Aminoglycoside; inhibits protein synthesis.

• Mainly for severe or drug-resistant cases.

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Standard Treatment Regimens for Drug-Susceptible TB

WHO-Recommended Short-Course Therapy

Intensive Phase (2 months):

• Isoniazid + Rifampicin + Pyrazinamide + Ethambutol (HRZE).

• Purpose: rapidly reduce bacterial load and infectiousness.

Continuation Phase (4 months):

• Isoniazid + Rifampicin (HR).

• Purpose: eliminate remaining bacilli and prevent relapse.

Total Duration: 6 months for most new, drug-susceptible TB cases.

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Fixed-Dose Combinations (FDCs)

• Contain multiple anti-TB drugs in a single tablet.

• Improve adherence, simplify logistics, reduce risk of inadvertent monotherapy.

• Examples:

  • 4-drug FDC: HRZE.

  • 3-drug FDC: HRZ or HRE.

  • 2-drug FDC: HR.

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Special Situations in Combination Use

Drug-Resistant TB (MDR-TB and XDR-TB)

• MDR-TB: resistant to at least INH and RIF.

• Requires second-line drugs: fluoroquinolones (levofloxacin, moxifloxacin), injectable agents (amikacin, capreomycin), linezolid, bedaquiline, delamanid, clofazimine, cycloserine.

• WHO now recommends all-oral regimens for most MDR-TB patients (e.g., BPaL: bedaquiline + pretomanid + linezolid).

TB in HIV Co-infection

• Use same combination regimens but carefully manage drug–drug interactions (notably rifampicin with antiretrovirals).

TB in Pregnancy

• Avoid streptomycin (ototoxic to fetus).

• HRZE generally considered safe.

Latent TB Infection (LTBI)

• Combinations used for shorter preventive therapy:

  • INH + rifapentine once weekly for 3 months (3HP).

  • INH + rifampicin daily for 3 months (3HR).

  • Rifampicin alone for 4 months (4R).

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Mechanisms for Resistance Prevention in Combinations

• Probability of resistance to one drug: ~10⁻⁶ bacilli.

• To two drugs with independent mechanisms: ~10⁻¹² bacilli.

• Using ≥2 active drugs virtually eliminates the chance of spontaneous resistance during therapy in drug-susceptible TB.

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Adverse Effects and Toxicity Considerations

Isoniazid

• Hepatotoxicity.

• Peripheral neuropathy (prevented with pyridoxine supplementation).

Rifampicin

• Hepatotoxicity.

• Orange discoloration of body fluids.

• Drug–drug interactions (potent CYP450 inducer).

Pyrazinamide

• Hepatotoxicity.

• Hyperuricemia and gout.

Ethambutol

• Optic neuritis (red–green color vision impairment).

Combination Toxicity Management

• Monitor liver function tests.

• Educate patients about signs of toxicity.

• Adjust regimen if severe adverse events occur.

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Drug–Drug Interaction Considerations

• Rifampicin: interacts with many drugs (antiretrovirals, warfarin, oral contraceptives, some antifungals).

• INH: inhibits certain CYP enzymes, altering metabolism of co-administered drugs.

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Pharmacokinetic Compatibility in Combinations

• Dosing schedules coordinated for optimal absorption and adherence.

• Most first-line drugs given once daily in standard regimens.

• FDCs designed to match pharmacokinetic profiles.

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Future Directions in Combination TB Therapy

• Development of shorter regimens for drug-susceptible TB (4 months) using rifapentine + moxifloxacin + PZA + INH.

• Novel drug combinations for MDR-TB: bedaquiline + pretomanid + linezolid (BPaL) and BPaLM (adds moxifloxacin).

• Investigating host-directed therapies alongside standard anti-TB drugs.