clofazimine

Mechanism of action: Clofazimine binds preferentially to mycobacterial DNA (guanine bases) and disrupts bacterial replication; it also generates reactive oxygen species and affects the bacterial cell membrane, contributing to bactericidal/bacteriostatic effects against Mycobacterium leprae and Mycobacterium tuberculosis (including MDR-TB strains). It has anti-inflammatory effects via inhibition of neutrophil chemotaxis and lymphocyte proliferation, which helps manage immune-mediated reactions like ENL.

Clinical use: A core component of WHO multidrug therapy for leprosy, typically combined with dapsone and rifampin to prevent resistance. It is also incorporated into regimens for MDR/XDR-TB (per WHO guidelines and the Bedaquiline-containing shorter regimens).

Pharmacokinetics: Highly lipophilic, accumulates in fatty tissue, skin, and reticuloendothelial system (macrophages), leading to a very long half-life (weeks to months). This property explains persistent tissue levels after discontinuation.

Adverse effects: - Skin discoloration (red-brown to black) — most characteristic and often distressing to patients, usually reversible over months after stopping. - GI disturbances: abdominal pain, diarrhea; rarely, crystal deposition in intestinal mucosa causing bowel obstruction or crystalline enteropathy (clofazimine crystals in macrophages). - Ichthyosis and dry skin. - QT prolongation — caution with other QT-prolonging drugs, especially when combined with bedaquiline in MDR-TB regimens. - Eosinophilic enteritis in rare cases.

Board relevance: Know clofazimine as part of leprosy triple therapy (dapsone + rifampin + clofazimine) and its role in managing ENL reactions (differentiate from thalidomide, which is also used for ENL but with different side effect profile - teratogenicity vs skin discoloration/GI issues for clofazimine). Recognize its lipophilic nature leading to skin pigmentation as a classic USMLE pattern-recognition fact.