Recommended Antitubercular Therapy Fixed-Dose Combination (FDC) Regimen for Drug-Susceptible Tuberculosis
The standard recommended FDC regimen for drug-susceptible tuberculosis consists of a 2-month intensive phase of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) followed by a 4-month continuation phase of isoniazid and rifampin (HR), administered daily for a total of 6 months. 1, 2
Initial Intensive Phase (First 2 Months)
- Fixed-dose combination of:
- Isoniazid (H): 5 mg/kg (typically 300 mg) daily for adults
- Rifampin (R): 10 mg/kg (typically 600 mg) daily for adults
- Pyrazinamide (Z): 15-30 mg/kg daily for adults (not to exceed 2g/day)
- Ethambutol (E): 15-25 mg/kg daily for adults
Continuation Phase (Next 4 Months)
- Fixed-dose combination of:
- Isoniazid (H): 5 mg/kg (typically 300 mg) daily for adults
- Rifampin (R): 10 mg/kg (typically 600 mg) daily for adults
Dosing Schedule
- Daily dosing is strongly preferred for both phases 1, 2
- Although 5-days-a-week administration by directly observed therapy (DOT) is considered an acceptable alternative to 7-days-a-week administration 1
- Thrice-weekly therapy may be considered only for patients who are not HIV-infected and at low risk of relapse (non-cavitary, smear-negative disease) 1
- Twice-weekly therapy is only recommended in limited circumstances after an initial 2 weeks of daily therapy 1
Important Considerations
Ethambutol Discontinuation
- Ethambutol can be discontinued as soon as drug susceptibility testing confirms that the isolate is susceptible to both isoniazid and rifampin 1, 2
Pyridoxine Supplementation
- Pyridoxine (vitamin B6, 25-50 mg/day) should be given with isoniazid to all persons at risk of neuropathy:
Monitoring Requirements
- Monthly clinical evaluations to assess treatment response and adverse effects
- Sputum cultures at 2 months to assess response
- Liver function tests for patients with pre-existing liver disease or symptoms of hepatotoxicity 2, 3
Benefits of Fixed-Dose Combinations
- Improved patient adherence due to reduced pill burden 4
- Decreased risk of developing drug resistance by preventing selective single-drug therapy 4
- Studies have demonstrated bioequivalence between FDC formulations and separate tablets for rifampicin, ethambutol, and pyrazinamide 5
Special Situations
Treatment Extension
- The continuation phase should be extended to 7 months (total 9 months) for patients with:
- Cavitary pulmonary TB with positive sputum cultures after 2 months of treatment 2
Drug-Resistant TB
- For isoniazid-resistant TB, a regimen of rifampin, ethambutol, and pyrazinamide for 6 months has shown good outcomes 6
- Patients with rifampin resistance or multidrug-resistant TB require specialized regimens and should be treated in specialized centers 2
Hepatotoxicity Monitoring
- Serum transaminase monitoring is recommended:
- Twice weekly during the first 2 weeks
- Every 2 weeks during the rest of the first 2 months
- Monthly thereafter
- Treatment should be stopped if transaminase levels exceed 3 times the upper limit of normal 3
The use of FDC tablets has been shown to be non-inferior in efficacy to separate tablet regimens while improving patient acceptability and potentially enhancing adherence to treatment 4.