What is the recommended first-line treatment regimen for tuberculosis (TB) in 2025, according to the latest American Thoracic Society (ATS) (ATS) and Centers for Disease Control and Prevention (CDC) guidelines?

Latest 2025 TB Treatment Guidelines

The recommended first-line treatment regimen for tuberculosis in 2025 consists of a 2-month intensive phase with isoniazid, rifampin, pyrazinamide, and ethambutol (2HRZE), followed by a 4-month continuation phase with isoniazid and rifampin (4HR), for a total duration of 6 months. 1, 2, 3

Initial Intensive Phase (First 2 Months)

All four drugs must be administered together during the initial phase to maximize effectiveness and prevent drug resistance, particularly in areas where isoniazid resistance exceeds 4%. 1

Standard Dosing:

• Isoniazid: 5 mg/kg daily (maximum 300 mg/day) 1
• Rifampin: 10 mg/kg daily (maximum 600 mg/day) 1, 3
• Pyrazinamide: 35 mg/kg daily for patients <50 kg; 2.0 g daily for patients ≥50 kg 1, 2
• Ethambutol: 15 mg/kg daily 1

Ethambutol can only be discontinued once drug susceptibility testing confirms full susceptibility to both isoniazid and rifampin—never discontinue it prematurely based on clinical response alone. 1

Continuation Phase (Next 4 Months)

Continue isoniazid and rifampin for an additional 4 months after completing the initial phase. 1

• Isoniazid: 5 mg/kg daily (maximum 300 mg/day) 1
• Rifampin: 10 mg/kg daily (maximum 600 mg/day) 1, 3

The continuation phase can be administered daily or 2-3 times weekly under directly observed therapy (DOT), though daily dosing is preferred for optimal outcomes. 1

Critical Treatment Modifications

Extended Treatment Duration (9 Months Total)

Extend the continuation phase to 7 months (total 9 months) in the following situations: 1

• Cavitary pulmonary TB with positive sputum cultures after 2 months of treatment 1
• Initial treatment that did not include pyrazinamide 1
• HIV-positive patients with CD4+ counts <100 cells/mm³ 1

HIV Co-infection Management

All TB patients should undergo HIV testing within 2 months of TB diagnosis. 1

• For HIV-positive patients with CD4+ counts <100 cells/mm³: Use daily therapy during the intensive phase, followed by daily or three times weekly therapy during the continuation phase—avoid twice-weekly dosing due to unacceptable failure/relapse rates. 4, 1
• Once-weekly isoniazid-rifapentine continuation phase is contraindicated in all HIV-infected patients due to high rates of treatment failure with rifamycin-resistant organisms. 4
• Be vigilant about drug interactions between rifampin and antiretroviral agents, particularly protease inhibitors and NNRTIs. 4, 5

Drug-Resistant TB

For isoniazid-resistant TB: Use rifampin, ethambutol, pyrazinamide, and a later-generation fluoroquinolone for 6 months. 1

For multidrug-resistant TB (MDR-TB): Individualized regimens based on drug susceptibility testing must be designed under the guidance of TB specialists—this is not optional. 1

Directly Observed Therapy (DOT)

DOT is the central element in comprehensive TB case management and should be used for all patients whenever possible. 1

• DOT involves watching the patient swallow each dose of medication. 6
• This approach prevents treatment failure, reduces drug resistance, and improves completion rates. 4, 6
• If universal DOT is not feasible, prioritize it for high-risk patients: those with drug-resistant disease, injection drug users, alcoholics, and homeless persons. 4

Special Populations

Pregnancy

• Treatment should be initiated whenever suspicion of TB is moderate to high due to risks to the fetus. 4
• Streptomycin is contraindicated in pregnancy—it is the only first-line agent documented to cause fetal harm. 4
• All other first-line medications (isoniazid, rifampin, pyrazinamide, ethambutol) can be used safely. 4
• Breastfeeding is safe while on first-line TB medications. 4

Children

• Infants and children younger than 4 years should begin treatment immediately when TB is suspected due to high risk of disseminated disease. 4
• Use the same regimen as adults with dosing adjusted by weight. 4
• Ethambutol is not routinely used in young children due to difficulty monitoring for optic neuritis. 4
• Extrapulmonary TB in children requires 6 months of treatment, except for disseminated TB and TB meningitis, which require 9-12 months. 4

Renal Insufficiency

• Administer all medications after hemodialysis to avoid premature drug removal, particularly pyrazinamide and cycloserine. 4

Hepatic Disease

• Rifampin, pyrazinamide, and isoniazid should still be used despite their hepatotoxic potential because of their superior effectiveness. 4
• Perform frequent clinical and laboratory monitoring to detect drug-induced liver damage early. 4

Treatment Monitoring

Obtain sputum smears and cultures at baseline, after 2 months, and at treatment completion to assess response. 4

Red Flags Requiring Immediate Reevaluation:

• Positive sputum smears at 3 months indicate possible nonadherence or drug-resistant disease. 4
• Positive cultures after 3 months warrant investigation for treatment failure. 4
• Clinical deterioration or lack of improvement by 2 months requires reassessment. 4

Drug susceptibility testing must be performed on all initial isolates from every TB patient—this is mandatory, not optional. 1, 5

Common Pitfalls to Avoid

• Never use fewer than four drugs in the initial phase unless drug susceptibility testing confirms full susceptibility to isoniazid and rifampin. 1, 5
• Never discontinue ethambutol before susceptibility results are available, even if the patient is improving clinically. 1, 5
• Never use once-weekly isoniazid-rifapentine in HIV-infected patients—this is associated with unacceptable treatment failure rates. 4
• Never use twice-weekly dosing in HIV-infected patients with CD4+ counts <100 cells/mm³—daily or three times weekly dosing is required. 4, 1
• Never assume treatment interruptions are inconsequential—gaps in therapy, especially early in treatment, may require restarting the entire regimen. 4

Public Health Reporting

Report all suspected TB cases promptly to the local public health department before culture confirmation. 4

This allows for:

• Contact tracing and source case investigations 4
• Monitoring of treatment adherence 4
• Identification and treatment of infected contacts 4
• Surveillance to assess TB control efforts 4