MECHANISM OF ACTION OF TRIMETHOPRIM AND SULFONAMIDES - RELEVANCE TO SYNERGY INVIVO

Trimethoprim and sulphonamides probably produce a synergistic effect in vitro by their simultaneous binding to bacterial dihydrofolate reductase (Poe, 1977), rather than through sequential blockade. Consistent with this is (i) that human and murine haematopoiesis is inhibited by sulphamethoxazole in vitro (Golde et al., 1978) (ii) some clinical cultures resistant to sulphonamides show synergy (iii) the pattern of low level resistance to sulphonamides in mutants of E. coli selected in vitro suggest two points of action of sulphonamides (iv) the presence of p-amino benzoic acid does not destroy synergy. In vivo synergy between sulphonamide and trimethoprim can only be anticipated where the local concentration of trimethoprim is sub-inhibitory. Data from clinical trials suggest that the anticipated dominance of trimethoprim in treating urinary tract infections is realised. Trimethoprim alone should replace fixed combinations of trimethoprim with sulphonamides for treating most urinary tract infections and for a variety of other infections, notably those of the respiratory tract. © 1979 Oxford University Press.