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After approximately 5 years of clinical use in Great Britain and other European countries, trimethoprim-sulfamethoxazole in fixed-dose combination was introduced into the United States in 1973. As a result of sequential blockade in the biosynthesis of tetrahydrofolic acid, the antimicrobial activity of the combination exceeds that of either agent alone. Although the drug is approved for use in only chronic urinary-tract infection, otitis media, shigellosis, and Pneumocystis carinii pneumonia, many experimental clinical trials suggest that this agent may be useful in a number of other infectious disorders. Trimethoprim-sulfamethoxazole is generally well tolerated even with long-term administration, but its potential for hematologic toxicity and nephrotoxicity must be monitored.