Trimethoprim-sulfamethoxazole antimicrobial activity

Trimethoprim has a broad spectrum of antimicrobial activity. It is 20-100 times more active than sulfamethoxazole with respect to most bacterial forms. Trimethoprim is active with respect to Gram-positive, aerobic bacteria such as Staphylococcus aureus, Staphylococcus epidermidis, and various types of Streptococcus and Listeria monocytogenes. Trimethoprim is inferior to sulfonamides against forms of Nocardia. It is active... 

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 ... 

Trimethoprim is most often compounded with the sulfa drug, sulfamethoxazole. The resulting combination, called co-trimoxazole, shows greater antimicrobial activity than equivalent quantities of either drug used alone (Figure 29.6). The combination was selected because of the similarity in the pharmacokinetics of the two drugs. 

The synergistic antimicrobial activity of co-trimoxazole results from its inhibition of two sequential steps in the synthesis of tetrahydro-folic acid sulfamethoxazole inhibits the incorporation of PABA into folic acid, and trimethoprim prevents reduction of dihydrofolate to tetrahydrofolate (see Figure 29.5). Co-trimoxazole exhibits more potent antimicrobial activity than sulfamethoxazole or trimethoprim alone (seed Figure 29.6). 

The antimicrobial activity of the trimethoprim/sulfamethoxazole combination results from actions on two steps of the biosynthetic pathway for tetrahydrofolic acid. Trimethoprim prevents the reduction of dihydrofolate to tetrahydrofolate (Figure 43-2). Mammalian cells use preformed folates from the diet and do not synthesize the compound. Trimethoprim is a highly selective inhibitor of dihydrofolate reductase of lower organisms -100,000 times more drug is required to inhibit human reductase than the bacterial enzyme. This relative selectivity is vital because the enzyme is essential to all species. 

Folate analogs such as trimethoprim have potent antibacterial and antiprotozoal activity. Trimethoprim binds lO -fold less tightly to mammalian dihydrofolate reductase than it does to reductases of susceptible microorganisms. Small differences in the active-site clefts of these enzymes account for its highly selective antimicrobial action. The combination of trimethoprim and sulfamethoxazole (an inhibitor of folate synthesis) is widely used to treat infections. 

Increased activity of enzymes that make drags more polar is likely to inactivate an antimicrobial drug and will not lead to increased antibacterial activity. Specific examples of mechanisms that do result in synergy include (A) the combination of trimethoprim and sulfamethoxazole (B) the combination of a penicillin and an aminoglycoside and (D) the combination of clavu-lanic acid and amoxicillin. The answer is (C). 

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