What is the best course of treatment for a 25-year-old female with a 2-month history of left lower leg discoloration and indentation, recently developed acute erythema and swelling, on rifampin (rifampicin) therapy for TB exposure?

Management of Rifampin-Associated Lower Leg Skin Lesion

Continue rifampin therapy without interruption and provide supportive care with close monitoring, as this presentation is most consistent with a benign, self-limited inflammatory skin reaction that does not require discontinuation of TB prophylaxis. 1

Immediate Management Approach

Your clinical assessment and planned workup are appropriate. The key decision point is whether to continue or discontinue rifampin therapy.

Continue Rifampin Therapy

• Rifampin should not be discontinued for this presentation, as the patient lacks signs of serious drug toxicity (no fever, no systemic symptoms, stable hemodynamics, and only mild transaminitis). 2

• The characteristic orange-red discoloration of body fluids (urine, sweat, tears) is expected with rifampin and occurs in essentially all patients—this is completely benign and does not indicate toxicity. 1

• Drug-induced hepatitis requiring rifampin discontinuation is defined as AST >3× upper limit of normal WITH symptoms, or >5× upper limit of normal WITHOUT symptoms—your patient's mild transaminitis does not meet these criteria. 2

Supportive Care Measures

• NSAIDs (ibuprofen or naproxen) are the first-line symptomatic treatment for inflammatory panniculitis-type reactions, including erythema nodosum-like lesions. 2, 3

• Elevation of the affected leg, rest, and cool compresses can provide additional symptomatic relief. 3

• For severe inflammatory reactions with significant systemic symptoms (which your patient does not have), prednisone 1-2 mg/kg per day for 1-2 weeks with gradual taper may be considered, though this is based on expert opinion rather than controlled trials. 2

Monitoring Strategy

Laboratory Monitoring

• Obtain CBC/CMP as planned to evaluate for infection and monitor liver enzymes given the mild baseline transaminitis. 2

• If AST/ALT remain <3× upper limit of normal and patient remains asymptomatic, continue rifampin without dose adjustment. 2

• Repeat liver function tests in 2-4 weeks to ensure stability, as close monitoring with repeat AST and bilirubin measurements is essential when managing patients with baseline transaminitis on rifampin. 2

Clinical Monitoring

• Weekly clinical evaluation for the first 2-3 weeks to assess lesion progression, development of systemic symptoms, or signs of true cellulitis (warmth, fever, spreading erythema). 3

• Monthly clinical evaluations thereafter for the duration of rifampin therapy, monitoring for drug side effects and signs of hepatitis (jaundice, dark urine, light stools, right upper quadrant pain). 4

Differential Diagnosis Considerations

Most Likely: Inflammatory Panniculitis

• The 2-month timeline, lack of trauma, central indentation, and yellow-brown discoloration are consistent with panniculitis or erythema nodosum-like reaction. 3

• Erythema nodosum-like lesions can occur with rifampin therapy and most commonly affect the legs, as in your patient. 3

• Histopathology of such lesions typically reveals panniculitis and/or vasculitis, though biopsy is not necessary for management in this stable patient. 3

Ruled Out by Clinical Presentation

• Cellulitis is unlikely given the absence of warmth, fever, systemic toxicity, and the 2-month indolent course—cellulitis would progress over days, not months. 2

• DVT is effectively excluded by the absence of calf pain, pain with ambulation, and presence of good perfusion. 2

When to Consider Rifampin Discontinuation

Absolute Indications to Stop Rifampin

• AST >3× upper limit of normal WITH symptoms (nausea, vomiting, abdominal pain, jaundice). 2

• AST >5× upper limit of normal even WITHOUT symptoms. 2

• Development of hypersensitivity reaction with fever, rash, and systemic symptoms. 2

If Rifampin Must Be Stopped

• If hepatotoxicity develops requiring rifampin discontinuation, obtain serologic testing for hepatitis A, B, and C, and carefully assess for other hepatotoxin exposure including alcohol. 2

• Alternative regimens for latent TB treatment include 9 months of isoniazid monotherapy (though this has lower completion rates) or 3-4 months of alternative agents, but consultation with TB specialist is essential. 4

Common Pitfalls to Avoid

• Do not discontinue rifampin prematurely for benign skin findings or mild transaminitis that doesn't meet discontinuation criteria—interrupting TB prophylaxis increases risk of progression to active TB. 2, 4

• Do not empirically start antibiotics for presumed cellulitis in the absence of warmth, fever, or systemic signs—this leads to unnecessary antibiotic exposure and delays correct diagnosis. 2

• Do not confuse the expected orange discoloration of body fluids (urine, sweat) with a sign of drug toxicity—this is a normal rifampin effect that can actually serve as a compliance marker. 1

• Do not add a single drug to the regimen if treatment failure is suspected—this promotes drug resistance; instead, add at least 2 drugs to which the organism is susceptible. 2, 5

Expected Clinical Course

• Inflammatory skin lesions associated with rifampin therapy typically resolve despite continued treatment in the majority of cases. 3

• Symptomatic management with NSAIDs is usually sufficient, and treatment discontinuation is rarely necessary. 3

• The lesion may take weeks to months to fully resolve, even with appropriate management. 3