In vitro antibiotic sensitivity testing breakpoints and therapeutic activity in induced infections in animal models

Antimicrobial susceptibility breakpoints are artificially designated to classify organisms as susceptible, intermediate or resistant but such values may differ according to the relative weight given to the microbiological, pharmacological and clinical information. Animal models of bacterial infections are considered necessary to establish tentative breakpoints before initiating clinical trials in humans. Studies in animals provide a preliminary indication of the most effective and least toxic concentration of the antibiotic and give a rational basis for the selection of dosages and schedules. Animal models of therapeutic efficacy have demonstrated the importance of the inoculum effect, showing that the minimum inhibitory concentration (MIC) determined with high inoculum (10(7)-10(8) CFU/ml) is, under some experimental conditions, a better predictor of therapeutic efficacy than the value obtained with standard (10(4)-10(5) CFU/Ml) inoculum. Studies in animals have demonstrated the failure of some fluoroquinolones in respiratory tract infections where Streptococcus pneumoniae was present or the efficacy of penicillins and third-generation cephalosporins for treating respiratory tract infections and meningitis by pneumococci with diminished susceptibility to such agents. Although most therapeutic models in animals should be carried out during preclinical studies, many are done during later phases of antibiotic development, as explicate models of what is seen in clinical practice.