Trimethoprim synergism

The concept of clinical synergism, which m be extremely difficult to demonstrate convincingly. Even with trimethoprim plus sulphamethoxazole, where tme synergism occurs in vitro, the optimum ratio of the two components may not always be present in vivo, i.e. at the site of infection in a particular tissue. 

Trimethoprim, a trimethoxybenzylpyrimidine, selectively inhibits bacterial dihydrofolic acid reductase, which converts dihydrofolic acid to tetrahydrofolic acid, a step leading to the synthesis of purines and ultimately to DNA (Figure 46-2). Trimethoprim is about 50,000 times less efficient in inhibition of mammalian dihydrofolic acid reductase. Pyrimethamine, another benzylpyrimidine, selectively inhibits dihydrofolic acid reductase of protozoa compared with that of mammalian cells. As noted above, trimethoprim or pyrimethamine in combination with a sulfonamide blocks sequential steps in folate synthesis, resulting in marked enhancement (synergism) of the activity of both drugs. The combination often is bactericidal, compared with the bacteriostatic activity of a sulfonamide alone. 

Other synergistic antimicrobial combinations have been shown to be more effective than monotherapy with individual components. Trimethoprim-sulfamethoxazole has been successfully used for the treatment of bacterial infections and Pneumocystis jiroveci (carinii) pneumonia. 3-Lactamase inhibitors restore the activity of intrinsically active but hydrolyzable 3-lactams against organisms such as S aureus and Bacteroides fragilis. Three major mechanisms of antimicrobial synergism have been established ... 

Synergism between trimethoprim and sulfamethoxazole on the inhibition of growth of Escherichia coli... 

Table 38 Synergism between trimethoprim (Tm) and trimeprazine (Tz) with respect to Gram- positive and Gram-negative bacteria...

Pyrimethamine and trimethoprim reversibly inhibit the second step in the synthesis of folic acid by inhibiting the enzyme dihydrofolate reductase, which catalyzes the reduction of dihydrofolic acid to tetrahydrofolic acid. The trimethoprim-binding affinity is much stronger for the bacterial enzyme than the corresponding mammalian enzyme, which produces selective toxicity. A powerful synergism exists between either pyrimethamine or trimethoprim and sulfonamides (e g., sulfemethoxazole and trimethoprim) because of sequential blockage of the same biosynthetic pathway. 

Richards RM, Taylor RB, Zhu ZY. Mechanism for synergism between sulphonamides and trimethoprim clarified. J Pharm Pharmacol 1996 48(9) 981. ... 

Supra-additive interactions and potentiation appear to be much less common than antagonism and the simple additive interactions described above. Supra-additive (synergistic) interaction is said to occur if the result of interaction is greater than the sum of the drugs used alone the best example is the therapeutic synergism of certain antibiotic combinations such as sulfonamides and dihydrofolic acid reductase inhibitors such as trimethoprim. Potentiation is said to occur when a drug s effect is increased by another agent that has no such effect. The best example of this type of interaction is the therapeutic interaction of beta-lactamase inhibitors such as clavulanic acid with lactamase-susceptible penicillins. 

Fig. 9.5 Synergism of trimethoprim and sulfadiazine in treatment of mice infected with Proteus vulgaris. The units on the axes represent doses of each drug needed lo give half the maximal percentage survival. Each point on the graph represents a combination of fractions of these doses. (The sulfadiazine unit was 0.14 mg, and that of trimethoprim 4 mg, per mouse.) (Hitchings and Burchall, 1965.)...

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