Mechanism of action oftrimethoprim and sulphonamides: relevance to synergy in vivo

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 a!., 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 ofsulphonamides (iv) the presence ofp-amino benzoic acid does not destroy synergy. In vivo synergy between sulphonamide and trimethoprim can only be antici-pated where the local concentration oftrimethoprim 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 f1xed combinations of trimethoprim with sulphonamides for treating most urinary tract infections and for a variety of other infections, notably those of the respiratory tract. Wahrscheinlich bewirkt die Kombination von Trimethoprim und Sulfonamiden in vitro ihren synergistischen Effekt eher durch ihre gleichzeitige Bindung an die bakteriellen Dihydrofolsiiure-Reduktase (Poe, 1977) als durch sequentielle Blockade. Gleichzeitig wird (I) die menschliche Hiimatopoese und die Ratten-Hiimatopoese durch Sulfamethoxazol in vitro verhindert (Golde et al., I 978). (II) Bei einigen klinischen Kulturen, die gegen Sulfonamide resistent waren, zeigte die Kombination eine synergistische Wi.rkung. (III) Das Bild der geringen Resistenz gegen Sulfonamide bei E. coli Mutanten, die in vitro selektiert wurden, deuten auf 2 Angriffspunkte der Sulfonamide hin. (IV) Das Vorhandensein von p-Aminobenzoesiiure stort den Synergism us nicht