THE USE of antimicrobial agents in combination continues to be evaluated for the ability to suppress the appearance of resistant bacterial mutants and to produce a synergistic effect . Both these properties were thought to apply to the use of a fixed combination of trimethoprim and sulphamethoxa-zole (co-trimoxazole). However, in the treatment of lower urinary-tract infections, there is evidence of the therapeutic effect being so dominated by trimethoprim that the potential synergistic effect between trimethoprim and sulphamethoxazole is not realised during clinical use (Brumfitt and Pursell, 1972; Koch , 1973; Anderson , 1974; Kasanen , 1974; Greenwood and O'Grady, 1976). Trimethoprim has also been used in combination with sulphadiazine (Männistö , 1973; Grey and Hamilton-Miller, 1977; Tuomisto, Kasanen and Renkonen, 1977); this preparation (co-trimazine) contains in each tablet 90 mg of trimethoprim and 410 mg of sulphadiazine and the recommended dosage is one tablet twice daily. Any advantage for such a combination over the use of individual components should be clearly established because the toxic effects of sulphadiazine and trimethoprim in a fixed combination seem likely to be greater than when they are used singly. During therapy, urine concentrations of active sulphadiazine can be anticipated to be higher than those of sulphamethoxazole on account of the lesser acetylation and higher solubility of sulphadiazine (e.g., Tuomisto , 1977). Thus, while we have previously failed to detect any synergistic effects between sulphamethoxazole and trimethoprim when added in therapeutic levels to naturally infected urine (Stokes and Lacey, 1978), sulphadiazine might be present in sufficient amounts for synergy to occur. Therefore, experiments were performed to determine whether such synergy had occurred. This paper describes the antibacterial effects of these agents in urine and in blood, and investigation of the possibility that trimethoprim resistance appears during exposure of organisms to trimethoprim in urine.


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