Chronic granulomatous disease: mode of action of sulfamethoxazole/trimethoprim.
Four possible modes of action for the clinically observed effectiveness of sulfamethoxazole/trimethoprim in chronic granulomatous disease were evaluated: (1) inhibition of bacterial catalase, (2) improvement of granulocyte oxygen metabolism, (3) synergism of the antibiotic with nonoxygen-dependent granulocyte killing mechanisms, and (4) a purely antibiotic effect based on uptake and concentration of the antibiotic by and within granulocytes. While the first three mechanisms were excluded, the fourth mechanism is highly probable; sulfamethoxazole was found to reach granulocyte associated concentrations 1.7-fold and trimethoprim 4.1-fold of extracellular levels. Penicillin G, a known nonpenetrating antibiotic, reached 0.3-fold, and tetracycline, a known penetrating agent, 7.1-fold the extracellular level. These findings indicate that sulfamethoxazole/trimethoprim is an antibiotic combination uniquely suited for the long-term prophylaxis of infections in patients with defects of intracellular phagocyte killing.
D002374:Catalase / Q000037:antagonists & inhibitors; D004359:Drug Therapy, Combination; D006098:Granulocytes / Q000187:drug effects / Q000378:metabolism; D006105:Granulomatous Disease, Chronic / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D066298:In Vitro Techniques; D009504:Neutrophils / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects; D013420:Sulfamethoxazole / Q000494:pharmacology*; D014295:Trimethoprim / Q000494:pharmacology*
D014295:Trimethoprim; D002374:Catalase; D013420:Sulfamethoxazole