Isoniazid vs Alternative Tuberculosis Drugs: A Detailed Comparison

Quick Take

• Isoniazid is the oldest first‑line TB drug, excellent for drug‑susceptible cases but can cause liver toxicity.
• Rifampin offers rapid killing, lowers relapse risk, but interacts with many meds.
• Ethambutol is eye‑safe at standard doses; higher doses raise optic neuritis risk.
• Pyrazinamide shortens therapy to six months but can cause hyperuricemia.
• Newer agents like bedaquiline and delamanid are reserved for multidrug‑resistant TB (MDR‑TB).

When treating active tuberculosis, Isoniazid is a first‑line oral antibiotic that inhibits mycolic acid synthesis in Mycobacterium tuberculosis. It’s been a cornerstone since the 1950s, praised for its low cost and potent bactericidal activity against replicating bacilli. Yet the drug isn’t a one‑size‑fits‑all solution. In many cases clinicians pair it with other agents to cover different bacterial populations and to hedge against resistance.

Below we compare isoniazid with the most common alternatives-Rifampin (a potent rifamycin that blocks RNA synthesis). Ethambutol (an inhibitor of arabinogalactan synthesis, protecting vision at standard doses). Pyrazinamide (a pro‑drug that works best in acidic environments). And for drug‑resistant cases, we’ll glance at Bedaquiline (a diarylquinoline that targets ATP synthase). and Delamanid (a nitro‑imidazooxazole interfering with mycolic acid production).

How Isoniazid Works and When It Shines

Isoniazid (INH) penetrates the mycobacterial cell wall and, after activation by the bacterial catalase‑peroxidase KatG, blocks the enzyme InhA. The result? No new mycolic acids, which are essential for the cell envelope. This mechanism makes it lethal to actively dividing bacilli but less effective against dormant populations.

Key advantages:

• Low price-often under $10 for a full six‑month course in many low‑income settings.
• Excellent oral bioavailability (≈95%).
• High early bactericidal activity, especially in the first two weeks.

Drawbacks to watch:

• Hepatotoxicity-up to 10% of patients develop elevated liver enzymes; severe hepatitis in 1‑2%.
• Peripheral neuropathy-preventable with pyridoxine (vitamin B6) supplementation.
• Resistance emerges quickly if used as monotherapy; KatG mutations are common.

Alternative First‑Line Agents

Rifampin

Rifampin works by binding the β‑subunit of bacterial RNA polymerase, halting transcription. It boasts the fastest kill rate among the standard four‑drug regimen, shortening the intensive phase from two to one month in many protocols. However, it is a strong inducer of cytochromeP450 enzymes, meaning it can lower the efficacy of oral contraceptives, anticoagulants, and some antiretrovirals.

Ethambutol

Ethambutol inhibits arabinosyl transferases, disrupting the assembly of the mycobacterial cell wall. At the usual 15mg/kg dose, visual side effects are rare, but higher doses (>25mg/kg) raise the risk of optic neuritis, manifesting as red‑green color blindness.

Pyrazinamide

Pyrazinamide is a pro‑drug that converts to pyrazinoic acid inside acidic phagosomes, where it interferes with fatty‑acid synthesis. This unique pH‑dependent activity lets it sterilize semi‑dormant bacilli, cutting the total treatment length to six months. Its main downsides are hepatotoxicity (synergistic with isoniazid) and hyperuricemia leading to gout attacks.

Newer Agents for MDR‑TB

When Mycobacterium tuberculosis becomes resistant to isoniazid and rifampin, clinicians turn to Bedaquiline and Delamanid. Both are expensive (≈$200‑$500 per month) and require careful cardiac monitoring because of QT‑interval prolongation. They are typically added to a backbone of fluoroquinolones and injectable agents.

Side‑Effect Profiles at a Glance

Dosing, Duration, and Regimen Design

Standard first‑line therapy for drug‑susceptible TB uses a four‑drug combo (INH, Rifampin, Ethambutol, Pyrazinamide) for two months, followed by INH+Rifampin for four more months. Here’s how the key drugs differ in dosing:

• Isoniazid: 5mg/kg (max 300mg) daily.
• Rifampin: 10mg/kg (max 600mg) daily; some guidelines allow 15mg/kg for intensified regimens.
• Ethambutol: 15-20mg/kg daily.
• Pyrazinamide: 20-25mg/kg daily.
• Bedaquiline: 400mg once daily for two weeks, then 200mg three times per week for 22weeks.
• Delamanid: 100mg twice daily for six months.

Weight‑based dosing matters; under‑dosing can foster resistance, while overdosing raises toxicity risk. Pediatric regimens follow the same drug choices but adjust doses per WHO child‑specific tables.

Resistance Patterns and Relapse Rates

Isoniazid resistance alone (mono‑INH resistance) occurs in about 10‑15% of new cases worldwide, often due to KatG mutations. When paired with Rifampin resistance, you enter the MDR‑TB zone, which pushes relapse rates above 20% without newer agents.

Rifampin resistance is rarer (≈5%) but more ominous because it compromises the bactericidal backbone. Ethambutol resistance usually appears alongside other drug resistances, while Pyrazinamide resistance is uncommon (<2%) but can emerge during prolonged therapy.

For MDR‑TB, bedaquiline‑based regimens achieve sputum conversion in ~80% of patients within two months, a stark improvement over older injectable‑only protocols that hovered near 60%.

Cost and Accessibility Considerations

In low‑ and middle‑income countries, generic isoniazid and rifampin are often bundled in UNICEF‑procured kits, keeping the total six‑month regimen under $20. Ethambutol and pyrazinamide add another $5‑$10.

By contrast, bedaquiline and delamanid are patented, with prices ranging $200‑$500 per month in high‑income markets. Some global donors subsidize these drugs for MDR‑TB programs, but access remains uneven.

Choosing the Right Regimen - Practical Tips

1. Confirm drug‑susceptibility testing (DST) before deciding to drop isoniazid. In high‑prevalence INH‑resistance areas, many clinicians start with a rifampin‑ethambutol‑pyrazinamide backbone.
2. Screen for liver disease, alcohol use, and hepatitis B/C. If liver risk is high, consider a rifampin‑ethambutol‑pyrazinamide combo without isoniazid.
3. Never forget pyridoxine (25‑50mg daily) for patients on isoniazid, especially diabetics, pregnant women, or those on antiretrovirals.
4. Monitor vision in anyone taking ethambutol; a simple Ishihara chart can catch early color‑vision shifts.
5. For MDR‑TB, prioritize a bedaquiline‑based regimen, add delamanid only if additional resistance exists, and always include a fluoroquinolone where possible.

Next Steps and Troubleshooting

If a patient develops elevated transaminases (>3×ULN with symptoms or >5×ULN without), pause isoniazid and rifampin, re‑check labs in 48hours, and consider switching to a fluoroquinolone‑based rescue regimen.

Should optic neuritis appear on ethambutol, discontinue the drug immediately and replace with an additional dose of isoniazid (if liver function allows) or a later‑phase fluoroquinolone.

When QT prolongation exceeds 450ms on bedaquine or delamanid, hold the offending drug, correct electrolytes, and reassess the cardiac risk before restarting.

Frequently Asked Questions

Can I take isoniazid without pyridoxine?

No. Pyridoxine (vitaminB6) prevents peripheral neuropathy, which occurs in up to 4% of patients on isoniazid, especially those with diabetes, HIV, or alcohol use.

Is rifampin safe to use with birth control pills?

Rifampin induces liver enzymes that reduce hormonal contraception effectiveness. Women should use an additional barrier method while on rifampin.

Why is pyrazinamide added only during the first two months?

Its sterilizing effect on dormant bacilli is most needed in the intensive phase. Continuing it longer raises hepatotoxic risk without added benefit.

When should I consider a bedaquiline‑based regimen?

If DST shows resistance to at least isoniazid and rifampin (MDR‑TB) or if the patient cannot tolerate first‑line drugs due to severe toxicity, bedaquiline becomes a cornerstone of therapy.

How often should liver function be checked on isoniazid?

Baseline testing is required, then every 2‑4weeks for the first two months, and monthly thereafter. More frequent checks are advised if the patient drinks heavily or has hepatitis.