Understanding the Standard Regimen: Which drugs are used in DOTS?

October 8, 2025 •

4 min read

According to the World Health Organization (WHO), directly observed treatment, short-course (DOTS) is a highly effective strategy for managing tuberculosis, with its success fundamentally dependent on a specific combination of first-line anti-TB drugs. This treatment approach, which ensures patients complete their full medication course under supervision, is crucial for preventing treatment failure and the spread of drug-resistant strains.

Quick Summary

The DOTS regimen for tuberculosis primarily uses a combination of four potent first-line drugs: isoniazid, rifampin, pyrazinamide, and ethambutol. The treatment is split into two phases—intensive and continuation—to eliminate bacteria and prevent relapse effectively. Direct observation ensures adherence and success.

Key Points

Core Drugs: The standard DOTS regimen uses a combination of four first-line anti-TB drugs: isoniazid, rifampin, pyrazinamide, and ethambutol.
Two Phases: Treatment is divided into a 2-month intensive phase (HRZE) and a 4-month continuation phase (HR).
Intensive Phase Drugs: The intensive phase primarily uses four drugs to quickly reduce the bacterial load and prevent resistance.
Continuation Phase Drugs: The continuation phase continues with isoniazid and rifampin to eliminate persistent bacteria and prevent relapse.
Direct Observation: A key aspect of DOTS is that a healthcare worker observes the patient taking their medication to ensure complete adherence.
Drug-Resistant TB: For multidrug-resistant TB (MDR-TB), a more complex and longer regimen called DOTS-plus, which includes second-line drugs, is required.
Preventing Resistance: The full and correct combination of drugs, taken without interruption, is essential for preventing the development of drug resistance.

What is the DOTS Strategy?

Directly Observed Treatment, Short-course (DOTS) is the standard of care for treating drug-susceptible tuberculosis (TB). The strategy was developed by the World Health Organization (WHO) and is based on several key pillars, including government commitment, case detection via microscopy, a standardized short-course chemotherapy regimen, an uninterrupted drug supply, and a monitoring system. The cornerstone of its success, however, is the direct observation of medication intake by a healthcare worker, which dramatically improves treatment adherence and completion rates.

The Core Drugs of the Standard DOTS Regimen

The standard DOTS regimen for new cases of drug-susceptible TB is a multi-drug therapy that typically lasts six months. It is divided into an intensive phase and a continuation phase, using a combination of four potent first-line antituberculosis drugs.

Isoniazid (INH)

Isoniazid is a highly bactericidal drug, meaning it kills actively growing tubercle bacilli. It is effective against a large population of M. tuberculosis that multiplies rapidly within lesions. However, it can cause peripheral neuropathy due to pyridoxine (vitamin B6) deficiency, so B6 supplementation is often recommended, especially for those at higher risk.

Rifampin (RIF)

Rifampin is a potent sterilizing agent, meaning it targets and kills semi-dormant bacteria that are responsible for relapse. It inhibits bacterial RNA synthesis and is active against a broad range of mycobacteria. A significant side effect is its ability to induce hepatic enzymes, which can interfere with the metabolism of other medications, including oral contraceptives and certain antiretrovirals.

Pyrazinamide (PZA)

Pyrazinamide is a unique drug that is most effective in the acidic environment of macrophages and inflammatory lesions, areas where the tuberculosis bacteria can persist. It is crucial during the intensive phase of treatment to shorten the overall duration of therapy. A common side effect is hyperuricemia, which can lead to gout.

Ethambutol (EMB)

Ethambutol is primarily used to prevent the emergence of drug-resistant bacteria by delaying the development of resistance to other drugs in the regimen. It is not as bactericidal as the other three, but it is a critical component of the combination therapy. A notable adverse effect is optic neuritis, which can lead to vision problems. Patients receiving ethambutol must be monitored for changes in visual acuity and color perception.

The Two-Phase Treatment Approach

The standard DOTS regimen is structured into two phases to ensure the complete eradication of Mycobacterium tuberculosis.

Intensive Phase

Duration: The initial phase lasts for two months.
Medications: The patient receives a four-drug combination of isoniazid, rifampin, pyrazinamide, and ethambutol (abbreviated as 2HRZE).
Goal: The primary objective is to rapidly kill off the bulk of the bacterial population and prevent the emergence of drug resistance. This phase also makes patients non-infectious sooner, reducing community transmission.

Continuation Phase

Duration: This phase typically lasts for four months, following the intensive phase.
Medications: The regimen is simplified to two drugs: isoniazid and rifampin (abbreviated as 4HR).
Goal: The purpose is to eliminate any remaining, more persistent or slowly multiplying bacteria, ensuring a complete cure and preventing relapse.

Comparison of First-Line Anti-TB Drugs in DOTS


Feature	Isoniazid (INH)	Rifampin (RIF)	Pyrazinamide (PZA)	Ethambutol (EMB)
Mechanism of Action	Inhibits mycolic acid synthesis, disrupting the cell wall.	Inhibits RNA synthesis by binding to bacterial RNA polymerase.	Exact mechanism unknown; active in acidic pH of macrophages and lesions.	Inhibits arabinosyltransferases, interfering with cell wall synthesis.
Primary Activity	Highly bactericidal against actively replicating bacilli.	Potent sterilizing activity against semi-dormant bacilli.	Potent sterilizing effect in acidic environments.	Bacteriostatic; prevents resistance from emerging.
Key Side Effects	Peripheral neuropathy (prevented with pyridoxine), hepatotoxicity.	Hepatotoxicity, gastrointestinal issues, flu-like symptoms, orange-colored bodily fluids, drug interactions.	Hepatotoxicity, hyperuricemia (gout), gastrointestinal upset.	Optic neuritis (affects vision), gastrointestinal disturbances.
Phase of Use	Both intensive and continuation phases.	Both intensive and continuation phases.	Intensive phase only.	Intensive phase only, or discontinued if resistance ruled out.

The Importance of Directly Observed Therapy

Directly Observed Therapy (DOT) is a critical component of the DOTS strategy and involves a healthcare worker or a trained treatment supporter observing the patient as they swallow each dose of medication. This process is vital for several reasons:

Enhances adherence: It ensures that patients take their medications consistently and for the entire prescribed duration, which can be challenging due to the long treatment period.
Prevents drug resistance: Inconsistent or incomplete treatment is a primary cause of drug resistance. By ensuring adherence, DOTS minimizes the risk of developing Multidrug-Resistant TB (MDR-TB).
Monitors for side effects: The observer can promptly identify and report any adverse drug reactions, allowing for timely adjustments to the treatment plan and improving patient safety.

Alternative Regimens for Different TB Types

While the standard RIPE regimen is the foundation of DOTS, variations exist for specific circumstances. For instance, in cases of confirmed drug-susceptible TB, a 4-month regimen containing rifapentine and moxifloxacin is an alternative for eligible patients. The treatment of drug-resistant TB, or MDR-TB, involves a different and more complex regimen known as DOTS-plus, which includes second-line drugs such as bedaquiline, linezolid, and fluoroquinolones. The specific drugs and duration are tailored based on the patient's drug susceptibility test results.

Conclusion

The success of the DOTS strategy in combating tuberculosis is a testament to the effectiveness of its standardized, multi-drug regimen, coupled with direct observation to ensure adherence. The use of first-line drugs—isoniazid, rifampin, pyrazinamide, and ethambutol—in their respective treatment phases is designed to kill the bacteria, prevent resistance, and ultimately cure the patient. Adherence to this protocol is not only critical for individual recovery but also for preventing the spread of TB and controlling drug resistance on a public health level.

For more detailed information on tuberculosis treatment guidelines, you can consult resources from the Centers for Disease Control and Prevention.

Frequently Asked Questions

DOTS stands for Directly Observed Treatment, Short-course, a strategy for treating tuberculosis (TB). It is important because it ensures patient adherence to their full course of medication, which is critical for curing the disease, preventing relapse, and curbing the spread of drug-resistant TB strains.

For a new case of drug-susceptible TB, the standard DOTS regimen uses a combination of four first-line drugs: Isoniazid (H), Rifampin (R), Pyrazinamide (Z), and Ethambutol (E).

The standard DOTS treatment for new TB cases typically takes six months. This includes a 2-month intensive phase followed by a 4-month continuation phase.

Stopping medication early can lead to treatment failure, disease relapse, and the development of drug-resistant tuberculosis (MDR-TB). This is why direct observation is so crucial to the DOTS strategy.

No. The intensive phase starts with all four first-line drugs (isoniazid, rifampin, pyrazinamide, and ethambutol), while the continuation phase is simplified to just isoniazid and rifampin.

Historically, streptomycin was an option as a replacement for ethambutol in the intensive phase. However, due to its injectable nature and potential for toxicity, ethambutol is generally preferred, and streptomycin is now reserved for specific cases.

Common side effects include hepatotoxicity (liver damage), nausea, joint pain, peripheral neuropathy (nerve damage, especially with isoniazid), and optic neuritis (vision problems, especially with ethambutol). Rifampin also causes harmless orange discoloration of body fluids.

DOTS is for drug-susceptible TB using standard first-line drugs. DOTS-plus is a modified strategy for treating multidrug-resistant TB (MDR-TB), which involves using second-line drugs that are more expensive, more toxic, and require a longer treatment duration.