Reassessment of the rationale for the combinations of sulphonamides with diaminopyrimidines.

Trimethoprim is the best known inhibitor of bacterial dihydrofolate reductase. Initially, this was always combined with sulphamethoxazole. It was later combined with other sulphonamides (eg. sulphamoxole, sulphadiazine or sulfametopyrazine), but the sulphonamide moiety as a contributor to clinical efficacy was increasingly questioned. Thus, in 1979 (in UK) trimethoprim alone was introduced. Justification for the combination was based on: (a) synergy occurs in vitro (b) bactericidal activity, while the two components are bacteriostatic (c) the emergence of resistance was claimed to be lower. However, these claims were not substantiated by studying the microbiological and pharmacokinetic properties of trimethoprim and the sulphonamides, but most importantly by the results of clinical trials. These show that in most indications, trimethoprim alone is as good, cheaper and causes considerably fewer adverse events than use with a sulphonamide. For urinary infections most agree that monotherapy is best. In respiratory infections diaminopyrimidines have relatively poor activity against important pathogens, eg pneumococci and especially Moraxella catarrhalis. It could be argued in these case that the addition of a sulphonamide may increase therapeutic efficacy. This can only be resolved by large clinical trials. In brucellosis and gonorrhoea, where sulphonamides are more microbiologically active than diaminopyrimidines, it is likely that combination with another antibiotic is needed. However, too much reliance must not be placed on extrapolating from trimethoprim to other diaminopyrimidines; conclusions should be drawn from work using the other compounds.