What is the standard adult treatment regimen, dosing, monitoring, and management for drug‑sensitive pulmonary tuberculosis using the four‑drug fixed‑dose combination tablet (isoniazid, rifampicin, pyrazinamide, ethambutol)?

Standard Four-Drug Fixed-Dose Combination Regimen for Drug-Sensitive Pulmonary Tuberculosis

For adults with newly diagnosed drug-sensitive pulmonary tuberculosis, administer a four-drug regimen (isoniazid, rifampicin, pyrazinamide, ethambutol) daily for 2 months, followed by isoniazid and rifampicin daily for 4 months, for a total treatment duration of 6 months. 1, 2

Initial Intensive Phase (First 2 Months)

Four-drug combination (HRZE):

• Isoniazid: 5 mg/kg daily (maximum 300 mg) 1, 2
• Rifampicin:
  • 450 mg daily for patients <50 kg 1, 2
  • 600 mg daily for patients ≥50 kg 1, 2
• Pyrazinamide:
  • 1.5 g daily for patients <50 kg 1
  • 2.0 g daily for patients ≥50 kg 1
• Ethambutol: 15 mg/kg daily 1

Daily dosing is strongly recommended throughout treatment rather than intermittent regimens, as this provides optimal efficacy. 1

When to Omit Ethambutol

Ethambutol may be omitted from the initial phase only if:

• Drug susceptibility testing confirms full sensitivity to isoniazid and rifampicin, AND
• The patient is at low risk for drug resistance (previously untreated, HIV-negative, not a contact of a known resistant case) 1, 2

However, in routine practice, include all four drugs initially until susceptibility results are available, as resistance patterns cannot be reliably predicted clinically. 1

Continuation Phase (Months 3-6)

Two-drug combination (HR):

• Isoniazid: 300 mg daily 1, 2
• Rifampicin:
  • 450 mg daily for patients <50 kg 1, 2
  • 600 mg daily for patients ≥50 kg 1, 2

The continuation phase should only begin once susceptibility to isoniazid and rifampicin is confirmed. 1 If susceptibility results are not available after 2 months, continue the four-drug regimen until full susceptibility is documented. 1

Fixed-Dose Combination Tablets

Fixed-dose combination tablets containing 2,3, or 4 drugs are recommended as they provide more convenient administration and may improve adherence without compromising efficacy or safety. 1, 3, 4 These formulations are bioequivalent to separate drug formulations and produce similar treatment outcomes. 3, 4

Treatment Duration Modifications

Extended Treatment (9 Months Total)

Extend the continuation phase to 7 months (total 9 months) if:

• Cavitary pulmonary TB remains culture-positive after 2 months of treatment 2
• Pyrazinamide cannot be included in the initial regimen 1

CNS/Meningeal Tuberculosis

For tuberculous meningitis or CNS involvement, extend treatment to 12 months total: 2 months of HRZE followed by 10 months of HR. 1, 2, 5

Monitoring Requirements

Bacteriological Monitoring

For pulmonary TB, obtain sputum smear microscopy and culture:

• At baseline (before treatment) 1
• At 2 months (end of intensive phase) 1
• At treatment completion 1
• If clinical response is poor at any time 1

Hepatotoxicity Monitoring

Measure serum transaminases (ALT/AST):

• Twice weekly during the first 2 weeks 6
• Every 2 weeks during the remainder of the first 2 months 6
• Monthly thereafter 6

If transaminases rise to >3 times the upper limit of normal, stop isoniazid, rifampicin, and pyrazinamide immediately. 6 After normalization, reintroduce isoniazid at a low dose without rifampicin; do not reintroduce pyrazinamide due to risk of severe recurrent hepatitis. 6

Rifampicin Level Monitoring

Consider measuring rifampicin blood levels if:

• Poor clinical or bacteriological response despite adherence 1
• Suspected malabsorption 1
• Significant drug-drug interactions are present 1

Essential Adjunctive Measures

Pyridoxine Supplementation

Administer pyridoxine (vitamin B6) 25-50 mg daily to all patients receiving isoniazid to prevent peripheral neuropathy, particularly in HIV-infected patients, pregnant women, diabetics, alcoholics, and malnourished individuals. 2

Corticosteroid Therapy

Add adjunctive corticosteroids (dexamethasone or prednisone) for the first 6-8 weeks in:

• TB meningitis (improves neurologic outcomes and survival) 1, 5
• TB pericarditis (prevents constrictive pericarditis) 1
• Renal TB with ureteric involvement (prevents stenosis) 1
• Spinal TB with cord compression 1

Treatment Adherence Strategy

Implement directly observed therapy (DOT) or a patient-centered adherence support strategy tailored to individual circumstances, with supervision and support measures that are mutually acceptable to patient and provider. 1 This is a public health responsibility to prevent ongoing transmission and development of drug resistance. 1

Drug Interactions and Contraindications

Rifampicin Interactions

Rifampicin significantly reduces levels of:

• Oral contraceptives (use alternative contraception) 2
• Warfarin (increase warfarin dose and monitor INR closely) 7
• Antiretroviral drugs (particularly protease inhibitors and NNRTIs—consider rifabutin substitution) 2
• Sulfonylureas (monitor glucose closely) 5

Rifampicin does not significantly interact with:

• ACE inhibitors (no dose adjustment needed) 7
• Calcium channel blockers like amlodipine (monitor blood pressure but no routine dose change required) 7

Hepatotoxicity Considerations

Avoid pyrazinamide in patients with:

• Pre-existing liver disease or abnormal baseline liver function tests 6
• Active hepatitis 7
• End-stage liver disease 7

Ethambutol is not hepatotoxic and can be used in patients with liver disease, but monitor for optic neuritis. 5, 6

Common Pitfalls and How to Avoid Them

Never shorten treatment below 6 months for pulmonary TB, even if cultures become negative earlier. Shortened 4-month fluoroquinolone-containing regimens substantially increase relapse rates (RR 3.56 for moxifloxacin regimens, RR 2.11 for gatifloxacin regimens) and are not recommended. 8

Never add a single drug to a failing regimen, as this promotes drug resistance. If treatment failure occurs, add at least two new drugs based on susceptibility testing. 5

Never extend pyrazinamide beyond 2 months in drug-sensitive TB, as prolonged use increases hepatotoxicity without additional benefit. 5 The exception is when treating drug-resistant TB with specialized regimens.

Never use streptomycin routinely as a fifth drug, as it adds no benefit beyond the initial weeks and increases toxicity risk. 5

Do not delay treatment while awaiting culture confirmation if clinical and radiographic findings strongly suggest TB. Start empiric therapy promptly, as delays worsen outcomes. 1

Ensure accurate weight-based dosing of ethambutol to reduce risk of optic toxicity, which is dose-dependent. 1

Do not assume low resistance risk without documentation. Include all four drugs initially until susceptibility is confirmed, as clinical prediction of resistance is unreliable. 1