What Are the Four Drug Treatments for TB?

October 8, 2025 •

4 min read

According to the World Health Organization, an estimated 10 million people developed tuberculosis (TB) in 2020, and the standard, drug-susceptible treatment relies on a combination of powerful antimycobacterial agents. The question of what are the four drug treatments for TB is central to controlling this infectious disease and preventing the development of drug-resistant strains.

Quick Summary

The standard initial therapy for active tuberculosis disease involves a four-drug regimen known as RIPE. This consists of isoniazid, rifampin, pyrazinamide, and ethambutol, administered in an intensive and a continuation phase to eradicate the infection and prevent resistance. This regimen is crucial for combating the infectious disease and requires strict adherence for effective treatment.

Key Points

The Four First-Line Drugs: The standard initial treatment for active TB uses a combination of four drugs: isoniazid, rifampin, pyrazinamide, and ethambutol.
Two-Phase Treatment: TB therapy is split into an intensive phase (two months with all four drugs) and a continuation phase (four to seven months with isoniazid and rifampin).
Importance of Adherence: Completing the full, multi-month course of therapy is critical to cure TB and prevent the development of drug-resistant strains.
Risk of Drug Resistance: Incomplete or improper treatment is the primary driver of drug-resistant TB, including MDR-TB and XDR-TB, which are much harder to treat.
Key Drug Side Effects: Each drug has distinct side effects, such as vision changes from ethambutol and orange body fluids from rifampin, requiring careful monitoring.
Role of Directly Observed Therapy (DOT): For many patients, a healthcare worker must observe them taking their medication to ensure adherence, a standard practice known as DOT.

The standard initial treatment for active tuberculosis (TB) disease is a multi-drug regimen that uses four first-line drugs. This aggressive approach is essential for rapidly reducing the bacterial load and preventing the development of drug-resistant strains. The four drugs used in this intensive phase are Isoniazid, Rifampin, Pyrazinamide, and Ethambutol, often remembered by the acronym RIPE. After an initial intensive phase, the treatment transitions to a continuation phase with fewer drugs over a longer period.

The Four First-Line Drugs for TB

Isoniazid (INH)

Mechanism of Action: Isoniazid is a pro-drug that inhibits the biosynthesis of mycolic acid, a crucial component of the mycobacterial cell wall. This action is bactericidal, meaning it kills the bacteria, especially those that are rapidly multiplying.
Key Side Effects: Common side effects include gastrointestinal upset, fever, and rash. A serious, though rare, side effect is hepatotoxicity, or liver injury, which is more common in older patients. Peripheral neuropathy can also occur, and to prevent this, pyridoxine (vitamin B6) is often prescribed concurrently.

Rifampin (RIF)

Mechanism of Action: Rifampin works by reversibly inhibiting DNA-dependent RNA polymerase, which stops the bacteria from transcribing new proteins necessary for its survival. It is effective against both fast- and slow-growing bacilli.
Key Side Effects: A notable, though harmless, side effect is the reddish-orange discoloration of bodily fluids, including urine, sweat, and tears. Patients should also be aware of potential drug interactions, especially with hormonal contraceptives and certain HIV medications, and liver toxicity.

Pyrazinamide (PZA)

Mechanism of Action: Pyrazinamide is a bacteriostatic drug, meaning it stops the bacteria from multiplying. It is most effective in the acidic environment found inside macrophages, where M. tuberculosis can hide. The active form, pyrazinoic acid, is thought to inhibit critical functions like trans-translation and potentially fatty acid synthesis.
Key Side Effects: Like other TB drugs, PZA can cause liver injury. It is also known to increase uric acid levels, which can lead to arthralgia (joint pain) and gout.

Ethambutol (EMB)

Mechanism of Action: Ethambutol prevents the biosynthesis of the mycobacterial cell wall by inhibiting the enzyme arabinosyltransferase. This is a crucial function for the bacteria's structural integrity.
Key Side Effects: The most significant and serious side effect is optic neuritis, which can cause blurred or changed vision and the inability to see the color red. This is why regular eye examinations are necessary during treatment with ethambutol, and patients must report any vision changes immediately.

The Standard Multi-Phase Treatment Regimen

The treatment for drug-susceptible TB is divided into two distinct phases to ensure the complete eradication of the infection.

Intensive Phase

This phase typically lasts for two months and involves the simultaneous administration of all four first-line drugs: isoniazid, rifampin, pyrazinamide, and ethambutol. The goal is to quickly reduce the bacterial population, especially the rapidly multiplying organisms, to prevent the selection of drug-resistant bacteria.

Continuation Phase

Following the intensive phase, the treatment is reduced to a combination of isoniazid and rifampin for an additional four to seven months. The specific duration depends on factors such as the patient's response to therapy, the site of the infection, and whether the initial intensive phase included daily or intermittent dosing. This phase is designed to eliminate the remaining, slower-growing bacteria to prevent relapse.

Comparison of First-Line TB Drugs


Drug (Abbreviation)	Mechanism of Action	Primary Side Effects	Special Considerations
Isoniazid (INH)	Inhibits mycolic acid biosynthesis.	Hepatotoxicity, peripheral neuropathy.	Often requires vitamin B6 (pyridoxine) supplementation.
Rifampin (RIF)	Inhibits DNA-dependent RNA polymerase.	Orange discoloration of bodily fluids, drug interactions.	Can reduce the effectiveness of birth control and other medications.
Pyrazinamide (PZA)	Becomes active in acidic environments; disrupts membrane potential.	Hepatotoxicity, increased uric acid, gout, joint pain.	More active against bacteria in macrophages.
Ethambutol (EMB)	Inhibits mycobacterial cell wall biosynthesis.	Optic neuritis (vision changes), eye damage.	Contraindicated in young children who cannot report visual changes.

Importance of Adherence and Management of Drug Resistance

Completing the full course of TB therapy is critically important. Incomplete or inadequate treatment is the primary cause of drug-resistant TB (DR-TB), which includes multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains. The treatment for drug-resistant forms of TB is longer, more complex, and involves different, often more toxic, second-line drugs. To maximize adherence and ensure treatment completion, Directly Observed Therapy (DOT) is the standard of care for many patients, where a healthcare worker observes the patient taking their medication.

For some patients, a shorter four-month regimen of isoniazid, rifapentine, pyrazinamide, and moxifloxacin (HPZM) can also be used for specific forms of drug-susceptible pulmonary TB. However, the RIPE regimen remains a foundational approach.

Conclusion

Answering the question, "What are the four drug treatments for TB?" is the first step in understanding effective TB management. The combination of isoniazid, rifampin, pyrazinamide, and ethambutol in a phased regimen is the cornerstone of therapy for drug-susceptible tuberculosis. Each drug plays a unique and essential role in targeting the bacterium from different angles. Given the complexities of potential side effects and the critical need for complete adherence, close medical supervision is vital for all patients undergoing treatment. Adherence to these protocols is the most effective way to cure TB and prevent the rise of more challenging drug-resistant infections.

For more in-depth information and up-to-date guidelines on tuberculosis treatment, refer to the Centers for Disease Control and Prevention's Division of Tuberculosis Elimination.

The CDC website is a reliable source for current TB treatment guidelines and health information.

Frequently Asked Questions

The primary treatment for drug-susceptible TB is a multi-drug regimen known as RIPE, consisting of isoniazid, rifampin, pyrazinamide, and ethambutol. It is delivered in an intensive phase and a continuation phase.

Isoniazid can cause liver injury (hepatotoxicity), peripheral neuropathy (nerve damage), gastrointestinal upset, and rash. To prevent neuropathy, patients often take vitamin B6 (pyridoxine).

The most important side effect of ethambutol is optic neuritis, which can cause vision problems or colorblindness. Patients are monitored with regular eye exams and should immediately report any changes in vision.

Finishing the full course of therapy, even after feeling better, is essential. Stopping early can allow the remaining bacteria to become drug-resistant, making future infections more difficult and expensive to treat.

The intensive phase uses all four first-line drugs for about two months to rapidly kill most bacteria. The continuation phase uses fewer drugs, typically isoniazid and rifampin, for an additional four to seven months to eradicate any remaining bacteria.

Drug-resistant TB (DR-TB) requires a much longer treatment course (18 to 24 months or more) using more toxic, second-line medications. It is often necessary to consult a TB expert for specialized guidance.

Treatment for latent TB infection (LTBI) is different from active disease and uses fewer drugs for a shorter duration. Common LTBI regimens include shorter courses of isoniazid, rifampin, or a combination of isoniazid and rifapentine.