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March 25, 1974

Trimethoprim-Sulfamethoxazole (TMP-SMS)—Better Late Than Never

JAMA. 1974;227(12):1423. doi:10.1001/jama.1974.03230250047034

The arrival of a new antimicrobial agent is hardly likely to quicken the pulse, unless it represents a new group of compounds, a new mode of action, or a new approach to discovery. Trimethoprim-sulfamethoxazole (TMP-SMZ) fulfills these criteria, even though it is not altogether new. The drug had been used in England for five years before its recent acceptance in the United States.

Unlike most antimicrobial agents, TMP-SMZ was not discovered serendipitously or through an empirical route, wherein practice precedes theory, and understanding follows observation and experience. It was the end result of a logically planned, artfully designed strategy.

The attack centered on the first part of the folic acid metabolic pathway in the bacterial cell. This part— the synthesis of dihydrofolate from p-aminobenzoate, pteridine, and glutamate—is an ideal mark for selectively toxic drugs because it does not exist in the human host. In contradistinction to bacteria, which are impermeable