Interactions between antibacterial drugs below the minimal inhibitory concentration

Interaction between antibacterial agents is often assessed in chessboard titrations, in which bacteriostatic synergy is detected as a mutual reduction in the minimal inhibitory concentrations (MICs) of the agents being tested. If MIC titrations are continually monitored turbidimetrically, the conventionally determined "end point" is seen to reflect the final outcome of a series of events that have occurred during the incubation period. One factor that influences the end point is the emergence, during overnight incubation, of a bacterial population with slightly increased drug resistance. A frequent component of the synergy recorded in chessboard titrations is the mutual suppression of such adaptive resistance. Synergy can also be expressed in terms of the minimal antibiotic concentration (MAC), i.e., the lowest concentration needed to produce an observable antibacterial effect. Antibacterial agents that exhibit true biochemical synergy interact to cause a mutual reduction in the MAC, but the degree of synergy recorded in this way is substantially lower than that determined by conventional chessboard titration. The benefits of antibacterial synergy in therapy cannot be predicted based on chessboard titrations alone. Dramatic synergy of the trimethoprim-sulfamethoxazole type may be of limited clinical use, whereas other drug combinations may be more useful than the results of cross-titration suggest.