What is the best course of action for a patient experiencing skin pruritus while on HRZE (Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol) for tuberculosis treatment?

Management of Skin Pruritus During HRZE Therapy

For mild to moderate pruritus without systemic symptoms or rash, continue HRZE therapy and treat symptomatically with antihistamines, as most cases resolve spontaneously without requiring drug discontinuation. 1, 2

Initial Assessment and Risk Stratification

When a patient develops pruritus on HRZE therapy, immediately assess for:

• Presence of rash or skin lesions - Morbilliform rash, urticaria, erythema multiforme, or Stevens-Johnson syndrome indicate a true cutaneous adverse drug reaction requiring immediate intervention 1, 3
• Systemic symptoms - Fever, angioedema, breathing difficulties, or mucosal involvement suggest severe hypersensitivity requiring drug cessation 4
• Hepatotoxicity markers - Jaundice, dark urine, nausea, vomiting, or abdominal pain may indicate drug-induced hepatitis presenting with pruritus 1
• Timing of onset - 97% of cutaneous adverse drug reactions occur within 2 months of initiating therapy 3

Management Algorithm Based on Severity

Isolated Pruritus Without Rash (Mild)

• Continue all HRZE medications at full doses without interruption 1, 2
• Prescribe oral antihistamines (cetirizine 10 mg daily or diphenhydramine 25-50 mg every 6 hours) for symptomatic relief 1
• Monitor weekly for development of rash or systemic symptoms during the first 2 months 2
• Check baseline liver function tests (AST, ALT, bilirubin) to exclude subclinical hepatotoxicity 1, 2

Pruritus With Mild Rash (Moderate)

• For mild morbilliform rash without systemic symptoms, attempt continuation with antihistamine premedication 2
• Monitor twice weekly for progression to severe cutaneous reactions 1, 2
• If rash progresses or pruritus becomes intolerable, proceed to drug rechallenge protocol 1, 2

Pruritus With Severe Rash or Systemic Symptoms (Severe)

• Immediately discontinue all HRZE medications if Stevens-Johnson syndrome, angioedema, breathing difficulties, or mucosal involvement develops 1, 4
• Treat acute reaction with corticosteroids, antihistamines, and supportive care as clinically indicated 1
• Wait until all symptoms completely resolve before attempting rechallenge 1, 2

Sequential Drug Rechallenge Protocol for Cutaneous Reactions

The European Respiratory Society recommends a specific sequence for cutaneous reactions that differs from hepatotoxicity rechallenge: 2

1. Start with ethambutol (15 mg/kg daily) - least likely to cause cutaneous reactions 2

   • Give alone for 3-7 days while monitoring for reaction 2
   • Continue antihistamine premedication throughout rechallenge 2

2. Add isoniazid (5 mg/kg daily, maximum 300 mg) if ethambutol tolerated 2

   • Give both drugs for 3-7 days while monitoring 2
   • Add pyridoxine 25-50 mg daily to prevent peripheral neuropathy 1, 2

3. Add rifampin (10 mg/kg daily, maximum 600 mg) if isoniazid tolerated 2

   • Give all three drugs for 3-7 days while monitoring 2
   • Monitor liver enzymes every 2-3 days during this phase 2

4. Add pyrazinamide last (25 mg/kg daily) if rifampin tolerated 2

   • Pyrazinamide is the most common offending drug for cutaneous reactions (2.38% incidence) 3
   • If reaction recurs with pyrazinamide, it is definitively the causative agent 2

Alternative Regimen If Pyrazinamide Cannot Be Reintroduced

If pyrazinamide is confirmed as the offending agent and cannot be safely reintroduced, extend treatment duration to 9 months total using rifampin and isoniazid with ethambutol for the initial 2 months. 2

• Intensive phase: Rifampin + Isoniazid + Ethambutol daily for 2 months 2
• Continuation phase: Rifampin + Isoniazid daily for 7 additional months (9 months total) 2
• This regimen maintains treatment efficacy despite pyrazinamide exclusion 2

Monitoring Schedule During Rechallenge

• Baseline assessment: Liver function tests, complete blood count, visual acuity 1, 2
• During rechallenge: Clinical assessment daily for rash, pruritus, or systemic symptoms 2
• Liver enzymes: Twice weekly for first 2 weeks, then every 2 weeks for remainder of first 2 months 2
• Monthly thereafter: If stable and tolerating full regimen 2

Drug-Specific Considerations for Pruritus

Pyrazinamide is the most common cause of cutaneous adverse drug reactions among first-line TB drugs (2.38% incidence), followed by streptomycin (1.45%), ethambutol (1.44%), rifampin (1.23%), and isoniazid (0.98%). 3

Rifampin can cause rare but severe immediate hypersensitivity reactions with pruritus, angioedema, and bronchospasm occurring within 5 minutes of ingestion, requiring permanent discontinuation. 4

Pyrazinamide-induced flushing should be distinguished from true allergic pruritus, as flushing is a benign vasodilatory effect that does not require drug discontinuation. 4

High-Risk Patient Populations

Certain patients have increased risk for cutaneous adverse drug reactions and require closer monitoring: 3

• HIV-infected patients (27.7% of CADR cases) - highest risk group 3
• Polypharmacy (21.3% of CADR cases) - drug interactions increase risk 3
• Elderly patients (19.1% of CADR cases) - altered drug metabolism 3
• Autoimmune disorders (6.4% of CADR cases) - baseline immune dysregulation 3

Critical Pitfalls to Avoid

• Never discontinue all drugs for isolated pruritus without rash - this unnecessarily interrupts effective TB treatment and risks developing drug resistance 1, 2
• Never use fixed-dose combinations during rechallenge - you must identify the specific offending agent by sequential reintroduction 2
• Never add a single drug to a failing regimen - this creates functional monotherapy and promotes resistance 1
• Never confuse pyrazinamide-induced flushing with true allergic pruritus - flushing is benign and does not require intervention 4
• Never rechallenge with rifampin first in cutaneous reactions - ethambutol should always be first as it is least likely to cause reactions 2