Staphylococcal -Lactamase and Efficacy of -Lactam Antibiotics: In Vitro and in Vivo Evaluation

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Abstract
The susceptibility of five cephalosporins and nafcillin to changes in inoculum size of 26 isolates of Staphylococcus aureus was studied. The spectrum of antibiotic sensitivity to such changes was cefazolin = cephaloridine > cefamandole > cephalothin > cefoxitin = nafcillin. Half of the isolates resulted in large and half in minimal inoculum-induced changes in minimal inhibitory concentrations (MICs). These changes correlated with the amount of β-Iactamaseproduced by the isolates. The in vivo relevance of these findings was studied in a model of intraperitoneal infection in mice. The effect of β-Iactamase production on mortality was greatest among animals given cefazolin or cephaloridine, intermediate among those given cefamandole, and nonexistent among those given cefoxitin, cephalothin, or nafcillin. The number of organisms in the animals' spleens paralleled survival rates. An increase in the serum level of cefazolin increased the survival rate among mice given that drug. Hence, the survival of mice was influenced by (1) the ability of the infecting organism to increase the MIC of an antibiotic via inoculum increases, (2) the sensitivity of the antibiotic to β-Iactamase, and (3) the peak level of antibiotic attained in serum.