A variety of different mechanisms are known to be responsible for either natural or acquired resistance to trimethoprim, the sulfonamides, or trimethoprim-sulfonamide combinations. Some mechanisms of obvious clinical importance have been studied intensively. Among these are unique bypass mechanisms such as the synthesis of drug-resistant, plasmid-coded dihydrofolate reductase or dihydropteroate synthetase; such mechanisms so far have not been encountered in studies of resistance to other drugs. This article focuses on several mechanisms of resistance that have rarely been discussed in the past, including metabolic alteration of trimethoprim or the sulfonamides and hyperproduction of p-aminobenzoic acid, and on the simultaneous presence of more than one mechanism. The role of these mechanisms in the resistance of clinical isolates requires further investigation.
