The activity of mecillinam, ampicillin and moxalactam alone and in combination was determined in a lapin meningitis model and a mouse meningitis model against two Escherichia coli strains isolated from infants with meningitis. Both strains were highly susceptible in vitro to the antibiotics, and responded well in systemic mouse protection tests (PD50 less than 4 mg/kg). Continuous infusion of mecillinam in the lapin model over nine hours was effective in sterilizing the CSF of three of four animals infected with one strain. This prompt bacteriologic response to mecillinam alone precluded the possibility of constant infusion administration for synergy studies. Therefore, single dose administration was used to demonstrate the synergistic potential of mecillinam with ampicillin in the lapin meningitis model against the E. coli Kl # 2 strain. The combination of moxalactam and mecillinam was synergistic against the E. coli Kl # 2 strain in the mouse meningitis model. The synergistic potential of these combinations could not be reliably predicted by in vitro tests, time kill curves or systemic mouse protection tests.