Trimethoprim-Sulfamethoxazole: The Present Position

Virtually all the agents now available for the treatment of infections were discovered by chance, or at best developed without a specific plan rather than on the basis of a sequence of logical experiments. An element of reason went into the original decision to screen samples of soil for the presence of microorganisms (usually molds) capable of producing antibiotic substances, but thereafter the procedures used were, of necessity, entirely empirical. Although there are notable exceptions, such as hexamine, mandelic acid, nalidixic acid, the nitrofurans, sulfonamides, p-aminosalicylate, and isoniazid, nearly all the clinically useful antibacterial compounds such as the (3-lactam compounds, aminoglycosides, tetracyclines, and macrolides were developed by observation and experiment without any background theory. Admittedly, some of the more sophisticated refinements have been planned by chemical methods, and the introduction of the semisynthetic penicillins and cephalosporins was a major advance in antimicrobial therapy. Nevertheless, empiricism was inevitable, and history has shown that the mode of action of an antibacterial compound is rarely known until some time after its introduction into clinical practice. The best example is penicillin. The explanation for selective toxicity of penicillin was not known until more than 20 years after its discovery, and the method of transport of wall components by lipid intermediates in the membrane remains to be elucidated.