What is the recommended anti-tuberculosis (TB) regimen for a patient with isoniazid (INH) resistance?

Anti-TB Regimen for Isoniazid (INH) Resistance

For confirmed isoniazid-resistant tuberculosis, treat with rifampin, ethambutol, pyrazinamide, and a fluoroquinolone (levofloxacin 750 mg daily) for 6 months total, with pyrazinamide given only during the first 2 months. 1

Initial Management When INH Resistance is Confirmed

Once drug susceptibility testing confirms isolated INH resistance, immediately modify the regimen to include at least three drugs to which the organism is susceptible:

• Rifampin 10 mg/kg daily (maximum 600 mg) - continue for entire 6-month course 1
• Ethambutol 15 mg/kg daily - continue for entire 6-month course (not just initial 2 months) 2, 1
• Pyrazinamide 35 mg/kg daily for patients <50 kg or 2.0 g daily for patients ≥50 kg - give for first 2 months only 1
• Levofloxacin 750 mg daily - continue for entire 6-month course 1

This four-drug regimen achieves treatment success rates with adjusted OR of 2.8 (95% CI: 1.1-7.3) according to WHO recommendations 1. The fluoroquinolone substitution is critical because you are effectively treating with one fewer first-line drug 1.

Alternative Regimen Without Fluoroquinolone

If fluoroquinolones cannot be used, an acceptable alternative is rifampin and ethambutol for a minimum of 12 months, supplemented by pyrazinamide for the first 2 months: 2

• This extended duration compensates for the absence of both INH and a fluoroquinolone
• The British Thoracic Society specifically recommends this approach when fluoroquinolones are contraindicated 2

Critical Treatment Modifications Based on Disease Severity

Extend treatment duration to 9 months (7-month continuation phase) if: 1

• Cavitary disease was present on initial chest radiograph AND the 2-month sputum culture remains positive
• This extension is essential to prevent relapse in patients with high bacillary burden

The Four-Drug Empiric Regimen (Before Susceptibility Results)

When treating empirically before susceptibility results are available, use INH, rifampin, pyrazinamide, and ethambutol (or streptomycin): 2

• This four-drug regimen is highly effective even for INH-resistant organisms when adherence is assured through directly observed therapy 2
• At least 95% of patients will receive an adequate regimen (at least two drugs to which organisms are susceptible) with this approach 2
• The four-drug regimen achieves more rapid sputum conversion than three-drug regimens, even with susceptible organisms 2

Once INH resistance is confirmed, discontinue INH and add levofloxacin as described above 1

Important Considerations Regarding INH Continuation

Do not continue INH at usual doses once resistance is confirmed: 3

• Research shows no significant advantage to adding standard-dose INH to regimens for INH-resistant TB 3
• Among patients treated with INH plus susceptible drugs, recurrence occurred in 15% (3/20), compared to 0% when INH was omitted and three susceptible drugs were used 3

Monitoring Requirements

Obtain monthly sputum specimens for smear and culture until two consecutive specimens are culture-negative: 1

• This is critical to document treatment response and detect treatment failure early
• If cultures fail to convert to negative within 3 months, repeat drug susceptibility testing 2

Monitor for fluoroquinolone-related adverse effects: 1

• Tendinopathy (particularly Achilles tendon)
• QT prolongation (obtain baseline and periodic ECGs in high-risk patients)
• CNS effects (insomnia, dizziness, confusion)

Special Populations

HIV-infected patients: 2

• Treat for a total of 9 months and for at least 6 months after sputum conversion 2
• If drug susceptibility results are unavailable, continue ethambutol for the entire course due to risk of rapid disease progression 2
• Daily therapy is preferred during the intensive phase for patients with CD4+ counts <100 cells/mm³

Pregnant women:

• The fluoroquinolone-containing regimen should be avoided; use the rifampin-ethambutol-pyrazinamide regimen for 12 months instead 2

Common Pitfalls to Avoid

Never treat INH-resistant TB with only two effective drugs:

• This risks developing additional resistance, particularly to rifampin, which would create multidrug-resistant TB 2
• Always ensure at least three drugs to which the organism is susceptible are used simultaneously 2

Do not shorten treatment duration below 6 months for the fluoroquinolone regimen or 12 months for the non-fluoroquinolone regimen:

• Research shows adequate efficacy with 12-month therapy using three susceptible drugs, regardless of pyrazinamide use 3
• Shorter durations risk relapse, particularly in patients with cavitary disease

Ensure rifampin susceptibility is confirmed:

• Rifampin is the cornerstone of the modified regimen 1
• Approximately 90% of rifampin-resistant cases are actually multidrug-resistant TB, requiring entirely different management 2
• Molecular methods can rapidly detect rifampin resistance in approximately 95% of resistant cases 2

Do not discontinue ethambutol after 2 months:

• Unlike standard TB treatment, ethambutol must continue throughout the entire treatment course for INH-resistant TB 1
• This is because you are treating with one fewer first-line drug

Directly Observed Therapy

Implement directly observed therapy (DOT) for all patients with drug-resistant TB: 2

• The four-drug regimen is highly effective for INH-resistant organisms when adherence is assured through DOT 2
• DOT can be administered intermittently (3 times weekly) from the beginning of therapy 2
• Patients treated with DOT who default are more likely to be cured and not relapse compared to self-administered therapy 2