Synergism, bacterial

Synergism can occur as a result of various mechanisms of action, such as subsequent blockage of the general metabolic pathway or increasing the permeability of bacterial cells. 

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 ... 

Cel9A is also of interest because it possesses very high activity on bacterial microcrystalline cellulose (BMCC) and an unusual synergistic activity in cellulase mixtures. It is unique in that it shows synergism with endocellulases and both types of exocellulases (20,21). It also retains more than 70% of its activity from pH 4.7 to 10.1. 

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. 

The concept of synergistically overcoming p-lactamase resistance by concomitant use of a P-lactam antibiotic resistant to P-lactamase hydrolysis with one sensitive to it is theoretically sound. The expectation is that the sensitive compound would be spared destruction and would add its bacterial effect to that of the resistant compound. Even though in vitro results seemed promising, clinically the synergism achieved was not enough. 

Many in vitro studies have firmly established a synergism between sulbactam and various P-lactam antibiotics including piperacillin, amdinocillin, ampicillin, and penicillin G. These studies included bacterial strains resistant to ampicillin or penicillin G alone, which became sensitive upon addition of sulbactam. Carbenicillin-resistant Pseudomonas, however, was not potentiated. 

---