First-Line Empiric Treatment for Tuberculosis
For drug-susceptible tuberculosis, initiate a four-drug regimen consisting of isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifampin for 4 months (total 6 months). 1, 2
Initial Intensive Phase (First 2 Months)
All four drugs must be started simultaneously to prevent the development of drug resistance, particularly in areas where isoniazid resistance exceeds 4% 1, 2:
- Isoniazid: 5 mg/kg daily (maximum 300 mg) 2, 3
- Rifampin: 10 mg/kg daily (maximum 600 mg) 2
- Pyrazinamide: 35 mg/kg daily for patients <50 kg; 2.0 g daily for patients ≥50 kg 2
- Ethambutol: 15 mg/kg daily 2, 4
Ethambutol can be discontinued once drug susceptibility testing confirms full susceptibility to isoniazid and rifampin, but only if there is <4% primary isoniazid resistance in your community, the patient has no prior TB treatment, is not from a high-prevalence country, and has no known exposure to drug-resistant cases 1, 2, 5.
Continuation Phase (Next 4 Months)
Continue isoniazid and rifampin only for an additional 4 months using the same daily dosing 1, 2. This continuation phase can be administered daily or 2-3 times weekly under directly observed therapy (DOT) 2.
When to Extend Treatment to 9 Months Total
A 7-month continuation phase (9 months total) is required for 1, 2:
- Patients with cavitary pulmonary TB who have positive sputum cultures after completing 2 months of treatment
- Patients whose initial treatment did not include pyrazinamide
- HIV-positive patients with CD4+ counts <100 cells/mm³
Administration Strategy
Directly observed therapy (DOT) should be used for all TB patients to ensure treatment completion and prevent drug resistance 1, 2, 5. The initial phase can be given 1:
- Daily throughout (preferred)
- Daily for 2 weeks, then twice weekly for 6 weeks
- Three times weekly throughout
Drug-Resistant TB Modifications
For isoniazid-resistant TB (confirmed by susceptibility testing), use rifampin, ethambutol, pyrazinamide, and a later-generation fluoroquinolone (levofloxacin or moxifloxacin) for 6 months 1. This regimen prevents the high rates of treatment failure (11%) and acquired multidrug resistance (8%) seen with standard four-drug therapy in isoniazid-resistant cases 6.
For multidrug-resistant TB (resistant to both isoniazid and rifampin), individualized regimens based on drug susceptibility testing must be used under specialist guidance 1, 2.
Critical Monitoring Requirements
- Drug susceptibility testing must be performed on all initial isolates and results reported promptly to guide therapy adjustments 1, 2
- Sputum cultures should be obtained at 2 months to assess treatment response 1, 2
- If cultures remain positive at 2 months or clinical response is inadequate, extend the continuation phase and reassess for drug resistance 1, 5
Common Pitfalls to Avoid
Never use fewer than four drugs initially when drug susceptibility is unknown, as this dramatically increases the risk of acquired drug resistance—particularly progression to multidrug-resistant TB in patients with unrecognized isoniazid resistance 1, 6. The probability of spontaneous resistance to both isoniazid and rifampin is 1 in 10¹⁴, making it virtually impossible when both drugs are used together from the start 1.
Do not discontinue ethambutol prematurely in high-risk populations or areas with >4% isoniazid resistance until susceptibility results confirm full drug susceptibility 1, 5.
HIV co-infection requires the same drug regimen but demands closer monitoring for treatment response and potential drug interactions with antiretroviral therapy, particularly with rifampin and protease inhibitors 2, 7, 5.