In-vitro and animal model data indicate that the time
beta-lactam serum concentrations remain above the MIC is an important determinant of the organism kill at the primary
infection site. Similarly, for
aminoglycosides, area under the curve and peak concentrations have been linked to organism kill and suppression of resistance. It is only in clinical patients that these data can be validated as to their significance. For
beta-lactams, little clinical data exist regarding these concepts. However, Bodey & colleagues have shown that profoundly, persistently neutropenic
cancer patients fared better when one of their
beta-lactams was administered continuously. Our group was able to correctly predict outcome in 9/10 patients bacteremic with a Gram-negative bacillus when receiving a single
beta-lactam on the basis of the time free
drug concentrations remained above the MIC. Schentag et al studied patients with lower
respiratory tract infection treated with
cefmenoxime alone and found a significant relationship between time greater than MIC & time to clearance of the pathogen from cultures of the tracheobronchial tree. These data would seem to validate the predictive nature of the findings from in-vitro & animal model studies. With
aminoglycosides, Moore, Smith & Lietman were able to demonstrate a highly significant correlation between outcome and the maximal peak concentrations to MIC ratio achieved for patients with single organism Gram-negative rod
infections. This is somewhat at variance with some animal models, but as the studies were performed with a fixed dosing interval, the outcome is not surprising. Little has been done with combinations of these agents in patients. Barriere & colleagues have proposed the AUC of the reciprocal serum bactericidal activity curve as a way to integrate the activity of combinations. We have developed a method employing logistic regression analysis to integrate the activity from the administration of multiple agents. The integration of this approach with each
drug's pharmacokinetics allows the generation of a plot of the probability of the blood remaining sterile over a steady state dosing interval. This approach has been preliminarily tested in 6 individuals with excellent concordance between outcome and prediction. Development of data in-vitro and in animal models with validation in patients will hopefully provide the impetus to optimize
therapy, and thence, outcome for the most seriously ill individuals.