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Influence of protein binding on therapeutic efficacy of cefoperazone

The effect of protein binding of cefoperazone (89.3% bound to rabbit serum) on antibacterial activity in serum was tested in a model that simulated a closed-space infection in a neutropenic host. Four gram-negative bacilli were tested in the model with cefoperazone doses of 20 and 200 mg/kg administered intramuscularly every 6 h for 16 doses. Cefoperazone efficacy was measured at 92 h by determining the log10 decrease in bacterial count from that of the control for five paired studies with three isolates. A significantly better response was demonstrated when the free (non-protein-bound) drug concentration exceeded the MICs and MBCs for the infecting microorganisms at the infection site at all times (P less than 0.005). This supports the concept that free (unbound) drug is the active component in treating bacterial infections.