Antibacterial Spectrum and Resistance

Trimethoprim exhibits broad-spectrum activity. It is most commonly used in combination with sulfamethoxazole and is active against most gram-positive and gramnegative organisms, especially the Enterobacteriaceae. There is little activity against anaerobic bacteria; P. aerug-inosa, enterococci, and methicillin-resistant staphylo-cocci should be considered resistant to trimethoprim.

Resistance can develop from alterations in dihydro-folate reductase, bacterial impermeability to the drug, and by overproduction of the dihydrofolate reductase. The most important mechanism of bacterial resistance to trimethoprim clinically is the production of plasmid-encoded trimethoprim-resistant forms of dihydrofolate reductase.

Because trimethoprim and sulfamethoxazole have their effects at different points in the folic acid synthetic pathway, a synergistic effect results when the two are administered together. The incidence of bacterial resistance to the combination is less than that observed when the drugs are used individually. Resistance is an increasing problem in a number of bacteria, but is especially problematic in the Enterobacteriaceae, against which the combination is used in AIDS patients for Pneumocystis carinii pneumonia prophylaxis.

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