CORRELATION OF PHARMACODYNAMIC PARAMETERS OF 5 BETA-LACTAM ANTIBIOTICS WITH THERAPEUTIC EFFICACIES IN AN ANIMAL-MODEL

The MIC is the main microbiologic parameter used to predict the effica cies of antibiotics, However, it is well known that MICs may vary acco rding to the inoculum size used (inoculum effect), especially with som e beta-lactam antibiotics, In order to correlate the pharmacologic and microbiologic properties of some beta-lactams, an experimental model of intraperitoneal infection caused by Escherichia coil in nonneutrope nic and neutropenic mice was developed, The animals were treated with three different doses of either ampicillin, piperacillin, aztreonam, c efazolin, or cefotaxime, The linear regression analysis obtained in ou r model shows a better correlation between in vitro activity and effic acy when the MICs considered were those obtained with a large inoculum (ca, 1 x 10(8) CFU/ml) instead of the standard inoculum (5 x 10(5) CF U/ml), The correlations for the MICs obtained with the large inoculum were 0.78 for log(2) maximum concentration of drug in serum (C-max)/MI C, 0.72 the time that the concentrations exceeded the MIC, and 0.79 fo r log(2) area under the serum concentration-time curve (AUC)/MIC at 24 h in nonneutropenic mice, The corresponding values in neutropenic mic e, also for the MICs obtained with the large inoculum, were 0.54, 0.68 , and 0.64, respectively, at 24 h, A good correlation was also obtaine d for the same parameters in nonneutropenic mice at 48 h, The values o f C-max, AUG, and the time that the concentrations exceeded the MIC we re parallel among the antibiotics studied, and our study confirms that the time that the levels in serum exceed the MIC is a significant par ameter determining the efficacies of beta-lactam antibiotics, but the correlation is much better when the MICs obtained with the large inocu lum instead of those obtained with the standard (low) inoculum are con sidered.