Synergism and antagonism

Among the reasons for use of antimicrobials in combination is the desire to achieve synergistic inhibitory or bactericidal activity. Several methods have been used to test for the presence of synergistic interactions, but virtually all are either very time consuming or nonstandardized. With combinations of cell wall-active agents plus aminoglycosides, bactericidal synergism has been associated with enhanced intracellular uptake of the aminoglycoside. Combinations of beta-lactamase inhibitors with beta-lactams susceptible to enzymatic hydrolysis have yielded synergistic activity against a number of common pathogens. The example of trimethoprim-sulfamethoxazole illustrates the potential value of combination of drugs acting at proximate steps along a single metabolic pathway. By analogy, combinations of antimicrobials active at various steps in peptidoglycan synthesis might also result in synergistic interactions. Use of certain drug combinations does pose the risk, however, of unwanted antagonistic interactions. The clinical importance of synergism in the treatment of bacterial infections has been documented in only a few limited circumstances.