What is the approach to treating tuberculosis in patients with allergies to Isoniazid (INH) and Rifampicin?

Approach to Allergies to INH and Rifampicin

For patients with true allergies to both isoniazid and rifampicin, use a rifamycin-free regimen consisting of a fluoroquinolone (levofloxacin or moxifloxacin), ethambutol, pyrazinamide, and an injectable agent (streptomycin, amikacin, or kanamycin) for 2 months, followed by fluoroquinolone, ethambutol, and pyrazinamide for 7-10 additional months, totaling 9-12 months of therapy. 1, 2

Initial Assessment: Distinguish True Allergy from Other Reactions

Before abandoning first-line therapy, confirm the nature of the reaction:

• Hepatotoxicity is NOT an allergy and represents the most common reason for discontinuing INH and rifampin 2. If transaminases are <5× upper limit of normal without symptoms, continue therapy with close monitoring 1
• True allergic reactions include rash, pruritus, angioedema, Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), or immediate hypersensitivity reactions 3, 4
• Rifampin-induced thrombocytopenia or acute renal failure (rare with intermittent dosing) requires permanent discontinuation 1

Consider Desensitization Before Abandoning First-Line Drugs

Desensitization should be attempted for delayed-type hypersensitivity reactions (rash, mild cutaneous reactions) but NOT for severe reactions like Stevens-Johnson syndrome, DRESS with organ involvement, or immediate anaphylaxis. 5, 4

Desensitization Protocol Success Rates:

• Rifampin desensitization: 79% success rate, starting with 1-150 mg and escalating to 300-450 mg over 1-29 days 5
• Isoniazid desensitization: 83% success rate, starting with 2.5-100 mg and escalating to 200-400 mg over 3-25 days 5
• Overall desensitization success: 78.9% in patients with severe reactions including Stevens-Johnson syndrome and erythema multiforme 4

Key caveat: Desensitization failures typically result in mild maculopapular rashes, not severe reactions, making this a relatively safe approach when appropriate 4

Rifamycin-Free Regimen When Both INH and Rifampin Cannot Be Used

Intensive Phase (2 months):

• Streptomycin (or amikacin/kanamycin if streptomycin-resistant)
• Pyrazinamide
• Ethambutol
• Fluoroquinolone (levofloxacin or moxifloxacin preferred) 1, 2

Continuation Phase (7-10 months):

• Fluoroquinolone
• Ethambutol
• Pyrazinamide 1, 2

Total treatment duration: 9-12 months minimum 1, 2

Evidence Supporting This Approach:

• The CDC recommends a 9-month streptomycin-based regimen when rifamycins are contraindicated 1
• Real-world data from 114 patients with rifampin intolerance showed 80.7% favorable response with median treatment duration of 10.2 months using fluoroquinolone-based regimens 2
• Recurrence rate was only 2.2% after median follow-up of 3.4 years with this approach 2

Alternative: INH-Free Regimen (If Only INH Allergy)

If rifampin can be tolerated but INH cannot:

• Rifampin, ethambutol, pyrazinamide, and fluoroquinolone for 2 months, then rifampin, ethambutol, and fluoroquinolone for 4-7 months 2
• This maintains the critical rifampin component while substituting fluoroquinolone for INH 2

Critical Monitoring Requirements

• Baseline and serial complete blood counts: Monitor weekly for first month, then every 2 weeks during intensive phase for drug-induced cytopenias 6
• Liver function tests: Check at baseline, 2 weeks, then every 2 weeks if stable. Stop all hepatotoxic drugs if AST/ALT >5× normal 6
• Visual acuity testing: Required before starting ethambutol and monthly during treatment due to optic neuritis risk 1, 7
• Sputum cultures: At 2 months, 5 months, and end of treatment to assess response 1

Common Pitfalls to Avoid

• Do not use three-drug regimens without a rifamycin, aminoglycoside, or fluoroquinolone (i.e., INH-ethambutol-pyrazinamide alone). These require 18 months minimum and have high failure rates 1
• Do not assume rifabutin avoids allergic reactions if rifampin caused true allergy—cross-reactivity is common 6
• Do not extend treatment beyond 12 months for drug-susceptible TB with rifamycin-free regimens unless cultures remain positive 1, 2
• Do not attempt desensitization for immediate hypersensitivity reactions (angioedema, anaphylaxis, severe wheeze within minutes of ingestion) 3

Special Populations

HIV Co-infection:

• Use the same rifamycin-free regimen but add pyridoxine 25-50 mg daily to prevent INH-related neuropathy if INH is reintroduced 1
• Avoid once-weekly regimens entirely in HIV-positive patients 1
• Monitor CD4 counts and viral load every 3 months during TB treatment 1

Pregnancy:

• Streptomycin is contraindicated due to congenital deafness risk 8
• Use levofloxacin, ethambutol, and pyrazinamide if both INH and rifampin cannot be used, though fluoroquinolone data in pregnancy are limited 8