Effects of Subminimal Inhibitory Concentrations of Antibiotics in Experimental Infections

The antibacterial effects of subminimal inhibitory concentrations (sub-MICs) of antibiotics were studied in two animal models. In mice, the oral cephalosporin CGP 9000 was effective in 11 of 20 different gram-negative infections and cephalexin was effective in one of these infections, both at 50% effective doses (ED₅₀) that produced peak concentrations of drug in plasma equal to one-half to one-sixteenth the minimal inhibitory concentration (MIC) for the infecting organism. In gram-positive infections, both antibiotics were effective only at concentrations above the MIC. In rabbits, sub-MICs of cephaloridine, ampicillin, and gentamicin were maintained for 6-10 hr by intravenous infusion. At steady-state concentrations equal to one-half to one-eighth the MIC, the β-lactam antibiotics caused elongation and filamentation, and gentamicin caused enlargement, of Proteus mirabilis, Escherichia coli, and Salmonella typhimurium in peritoneal exudate; the number of viable cells of each of these bacteria was temporarily reduced. In infections with E. coli and P. mirabilis, sub-MICs of β-lactam antibiotics and of gentamicin prolonged the survival rates for infected animals beyond those for control animals. Rabbits infected with S. typhimurium and treated with ampicillin at a concentration of one-third the MIC tended to die sooner than did control animals.