The steady state growth of E. coli cultures is inhibited by either sulfonamide (SA) or trimethoprim (TMP) with a rate constant, kapp1The new steady state is obtained immediately after the addition of TMP whereas a lag phase of about 5 generations is observed for SA. In TMP-treated cultures the slope of the logarithmic growth curve decreases after an initial inhibited growth and a second steady state is established, kapp2 The appearance of the second ‘phase’is dependent on the number of germs but not on the number of generations. Using prewashed cell cultures it was shown that the presence of the first phase is due to an antagonist excreted into the culture medium. The inhibitory effect of TMP is also partly antagonized by thymidine. The inhibitory effect of TMP is about 5 times larger than the effect of sulfamethoxazole (Gantanol®, GT) as evaluated from the plot of 1/k₀––kapp vs. 1/C or C k₀/k₀––kapp vs. C respectively. In cultures where the growth was totally stopped by high concentration of SA no inhibitory effect of TMP is observable. The inhibitory effect of TMP is found to be reversible if the drug containing culture is diluted. The antibacterial effects of TMP alone were seen to be considerably more complex than those of sulfonamides despite their presumable similar sites of action. Even at very high concentrations SA act only bacteriostatically, whereas TMP alone can cause bactericidal effects if a certain threshold of concentration (≥1 µmol/l) is passed. (A decrease in numbers of cells of about 90% can be obtained within 8 h.) Combinations of TMP and SA at concentrations where both drugs are acting merely bacteriostatically lead to effects considerably greater than would be expected from simple additivity. This study of generation rate constants in inhibited cultures indicates that the claim for synergism and bactericidal effect as usually defined is indeed valid for this combination. It seems possible that both the effects in inhibited cultures by TMP alone and its combination with sulfonamides might be explained if one were to assume that TMP has an additional mode of action separate from its known inhibition of dihydrofolate reductase.

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