Rationale for use of antimicrobial combinations

In most cases antimicrobial combinations are employed to broaden the spectrum of coverage. This clinical application is likely to be successful as long as the combinations are not antagonistic. Most examples of antibiotic antagonism are those in which a bacteriostatic agent renders a bactericidal agent "static." Another type of antagonism occurs when cefoxitin (which has a propensity to induce beta-lactamase production) is combined with another beta-lactam antibiotic. Combination drug therapy prevents emergence of resistant strains in mycobacterial infections and in infections due to methicillin-resistant staphylococci and certain other resistant organisms. Synergistic combinations should allow the use of lower concentrations of drugs in combination and thus diminish the incidence of dose-related antibiotic toxicity, but the concept has met with only limited success so far. Three types of antimicrobial combination or interaction result in enhanced (synergistic) antimicrobial activity. These types include combinations of agents that inhibit bacterial cell wall synthesis with aminoglycosidic aminocyclitols, the use of beta-lactamase inhibitors in combination with beta-lactam antibiotics, and the administration of agents that act on sequential steps in one of the bacterial metabolic or synthetic pathways. Combinations of two beta-lactam antibiotics that bind to complementary penicillin-binding proteins may represent an analogous situation. Amdinocillin binds specifically to penicillin-binding protein 2, and in vitro studies have clearly demonstrated synergism when amdinocillin is combined with other penicillins and cephalosporins that have higher affinity for other penicillin-binding proteins.