What is the current recommended treatment regimen for a newly diagnosed adult with drug‑susceptible tuberculosis?

Current Treatment Regimen for Drug-Susceptible Tuberculosis

The preferred treatment regimen for newly diagnosed drug-susceptible tuberculosis in adults is a 6-month course consisting of an intensive phase of 2 months with four drugs (isoniazid, rifampin, pyrazinamide, and ethambutol) followed by a continuation phase of 4 months with two drugs (isoniazid and rifampin), administered daily. 1, 2, 3

Intensive Phase (First 2 Months)

Four-drug regimen administered daily for 56 doses (8 weeks): 1

• Isoniazid (INH): 5 mg/kg daily (typically 300 mg) 1, 2
• Rifampin (RIF): 10 mg/kg daily (typically 600 mg for patients ≥50 kg, 450 mg for <50 kg) 1, 3
• Pyrazinamide (PZA): 35 mg/kg daily for patients <50 kg or 2.0 g daily for patients ≥50 kg 4, 2
• Ethambutol (EMB): 15 mg/kg daily 1, 2

Rationale for four drugs: The four-drug intensive phase is necessary because of the current proportion of new tuberculosis cases caused by organisms resistant to isoniazid worldwide. 1 However, if drug susceptibility testing confirms the isolate is susceptible to both isoniazid and rifampin, ethambutol can be discontinued immediately. 1, 4

Continuation Phase (Months 3-6)

Two-drug regimen administered daily for 126 doses (18 weeks): 1

• Isoniazid: 5 mg/kg daily (typically 300 mg) 1
• Rifampin: 10 mg/kg daily (typically 600 mg) 1

Important exception: Patients with cavitation on initial chest radiograph AND positive sputum cultures at completion of 2 months should receive an extended 7-month continuation phase (total 9 months of treatment). 1, 2

Administration Schedule

Daily dosing is strongly preferred for both phases. 1, 2 When directly observed therapy (DOT) is used, 5-days-per-week administration is an acceptable alternative to 7-days-per-week, based on extensive clinical experience. 1

Directly observed therapy (DOT) should be used for all tuberculosis patients to ensure treatment completion and prevent drug resistance. 4, 2 This is the standard of practice in the majority of tuberculosis programs. 1

Pyridoxine Supplementation

Pyridoxine (vitamin B6) 25-50 mg daily must be given with isoniazid to all persons at risk of neuropathy: 1, 4, 2

• Pregnant women 1
• Breastfeeding infants 1
• HIV-infected patients 1, 3
• Patients with diabetes 1
• Patients with alcoholism 1
• Patients with malnutrition or chronic renal failure 1
• Patients of advanced age 1

For patients who develop peripheral neuropathy, increase pyridoxine to 100 mg daily. 1

Alternative Regimens (Less Preferred)

Thrice-weekly dosing after initial 2 weeks of daily therapy may be considered only in patients who are HIV-negative AND at low risk of relapse (noncavitary and/or smear-negative disease). 1 This regimen should be used with caution as missed doses can lead to treatment failure and acquired drug resistance. 1

Twice-weekly dosing should NOT be used in HIV-infected patients or patients with smear-positive and/or cavitary disease, as missed doses result in effectively once-weekly therapy, which is inferior. 1

Monitoring and Drug Susceptibility Testing

Drug susceptibility testing must be performed on all initial isolates, and the regimen should be modified appropriately once results are available. 4

Monitor treatment response with: 2

• Follow-up sputum smear microscopy and culture at completion of 2 months
• Sputum culture at treatment completion

Baseline hepatic function tests (AST/ALT and bilirubin) should be performed in HIV-infected patients, pregnant women, patients with chronic liver disease history, and regular alcohol users. 2 Hepatotoxicity monitoring is especially important during the first 2 months of treatment. 3

Critical Pitfalls to Avoid

Do not use shortened 4-month regimens. Recent high-quality evidence demonstrates that fluoroquinolone-containing 4-month regimens (whether replacing ethambutol or isoniazid with moxifloxacin or gatifloxacin) substantially increase relapse rates compared to standard 6-month regimens (RR 3.56 for moxifloxacin, RR 2.11 for gatifloxacin). 5

Do not omit ethambutol from the initial regimen unless drug susceptibility results are already known and confirm full susceptibility to isoniazid and rifampin, or there is documented <4% primary isoniazid resistance in the community with no prior treatment history or exposure to drug-resistant cases. 1

Do not use twice-weekly dosing in high-risk patients (HIV-infected or cavitary/smear-positive disease), as this significantly increases risk of treatment failure and relapse. 1