Ethionamide vs Alternatives: What Works Best for Drug-Resistant TB

When first-line TB drugs like isoniazid and rifampin fail, doctors turn to second-line medications-and ethionamide is one of them. But it’s not the only option. If you or someone you know is facing drug-resistant tuberculosis, knowing how ethionamide stacks up against other drugs isn’t just helpful-it can change outcomes.

What is ethionamide and how does it work?

Ethionamide is an antibiotic used almost exclusively for tuberculosis that doesn’t respond to standard treatment. It’s a second-line drug, meaning it’s not used at first because of side effects and complexity. It works by blocking the bacteria’s ability to build its cell wall, similar to isoniazid, but it’s activated differently inside the body.

It’s usually taken as a tablet, once or twice daily with food to reduce stomach upset. But it’s not easy to tolerate. Up to 70% of patients report nausea, vomiting, or a metallic taste. Some develop liver issues or nerve damage. That’s why doctors don’t reach for it unless they have to.

Ethionamide is part of the WHO-recommended regimen for multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB). It’s listed as a Group 4 drug in the 2024 WHO guidelines-meaning it’s effective but has moderate toxicity and requires careful monitoring.

Why look for alternatives to ethionamide?

The biggest problem with ethionamide isn’t that it doesn’t work-it’s that it’s hard to stick with. Many patients stop taking it because of side effects. In real-world clinics, adherence rates drop below 60% after six months. That’s dangerous. Incomplete treatment leads to even more resistant strains.

Thankfully, newer drugs have entered the market since 2012. Some are better tolerated. Others are more potent. And some can replace ethionamide entirely in shorter, simpler regimens.

Prothionamide: the close cousin

Prothionamide is almost identical to ethionamide in structure and function. In fact, many labs treat them as interchangeable. Both are activated by the same bacterial enzyme and target the same pathway.

The main difference? Prothionamide is slightly more potent and has a longer half-life. That means it can be taken once daily instead of twice. It’s also slightly less likely to cause severe nausea.

But here’s the catch: prothionamide isn’t available everywhere. It’s approved in Europe and parts of Asia but not in the U.S. or Australia. If you’re in Perth and prescribed ethionamide, you’re likely getting the only option available locally.

Linezolid: the powerful but risky option

Linezolid was originally an antibiotic for skin infections. But in 2012, researchers noticed it worked wonders against drug-resistant TB. Today, it’s a key player in MDR-TB regimens.

Compared to ethionamide, linezolid is stronger and faster. Studies show it reduces bacterial load in sputum twice as quickly. It’s also taken once a day and doesn’t cause the same metallic taste.

But linezolid has its own problems. Long-term use (over two months) can cause nerve damage, anemia, and low platelets. The WHO recommends limiting it to six months and monitoring blood counts every two weeks. It’s also expensive-up to $500 per month in some countries.

For patients who can’t handle ethionamide’s GI side effects, linezolid is often the next choice. But only if they can afford it and get regular blood tests.

Bedaquiline: the game-changer

Bedaquiline changed everything. Approved in 2012, it’s the first new TB drug in 40 years that targets the bacteria’s energy production. It’s now a first-choice drug for MDR-TB in most countries.

Compared to ethionamide, bedaquiline is more effective and safer. Clinical trials show cure rates over 80% with bedaquiline-based regimens, versus 50-60% with older drugs like ethionamide. It’s taken once daily. Side effects are mild-headache, nausea, and occasional heart rhythm changes.

The biggest downside? It’s not available everywhere. In Australia, it’s covered under the PBS (Pharmaceutical Benefits Scheme) for confirmed MDR-TB cases. But it requires specialist approval and an ECG before starting. Still, for many patients, it’s replaced ethionamide entirely.

Delamanid: another modern alternative

Delamanid works like bedaquiline but targets a different part of the bacteria’s cell wall. It’s approved in the EU and Australia for MDR-TB in adults who can’t use other drugs.

It’s taken twice daily, and side effects are generally mild: headache, dizziness, and a slight risk of QT prolongation (a heart rhythm issue). Like bedaquiline, it’s more effective than ethionamide in reducing treatment time.

But delamanid is expensive and requires monthly ECGs. It’s not used as a first replacement for ethionamide unless the patient has specific resistance patterns or can’t tolerate linezolid or bedaquiline.

Fluoroquinolones: levofloxacin and moxifloxacin

Fluoroquinolones like levofloxacin and moxifloxacin are older drugs, but they’ve become essential in modern TB regimens. They’re not as potent as bedaquiline, but they’re widely available, cheaper, and well-tolerated.

Levofloxacin is often used as a backbone in place of ethionamide. It’s taken once daily, has fewer side effects, and doesn’t require special monitoring. Studies show that adding levofloxacin to a regimen improves cure rates by 25% compared to ethionamide-only combinations.

Moxifloxacin is slightly stronger but can cause more GI upset. It’s also more likely to trigger tendon damage in older patients. Most clinics prefer levofloxacin for its balance of safety and effectiveness.

Comparing the alternatives side by side

When should you avoid ethionamide entirely?

If you have any of these, ethionamide is probably not the right choice:

• You’ve had liver problems before
• You’re pregnant or planning to be
• You’re over 65 and taking other medications
• You’ve had bad reactions to similar drugs
• You can’t commit to monthly blood tests

In these cases, doctors are more likely to push for bedaquiline, levofloxacin, or delamanid-even if they cost more. The goal isn’t just to kill the bacteria. It’s to finish the treatment without breaking the patient.

What’s the future of TB treatment?

By 2025, WHO recommends all MDR-TB patients get a 6-month regimen using bedaquiline, pretomanid, linezolid, and moxifloxacin. That’s called BPaLM. It replaces older, longer regimens that included ethionamide.

Even in places where bedaquiline isn’t fully available, clinics are moving away from ethionamide. In Australia, the TB Network has started switching patients to BPaLM when possible. Ethionamide is now mostly used as a fallback when newer drugs aren’t suitable.

For patients in Perth, that means if you’re diagnosed with drug-resistant TB today, your doctor will likely start you on something better than ethionamide. You’ll need a specialist, but you won’t be stuck with the old, harsh options.

Frequently Asked Questions

What to do next

If you’re on ethionamide and struggling with side effects, talk to your doctor about switching. Ask if bedaquiline or levofloxacin could work for you. If you’re in Australia, your specialist can apply for PBS coverage for newer drugs.

If you’ve been told you need ethionamide because other drugs failed, ask why. Is it because of resistance? Cost? Or just because it’s what’s always been used? Don’t accept the old way without asking if there’s a better option.

TB treatment has changed. You don’t have to suffer through the old regimens. There are safer, faster, more effective choices now-and you deserve to know about them.