PHARMACODYNAMIC MODELING OF BACTERIAL KINETICS - BETA-LACTAM ANTIBIOTICS AGAINST ESCHERICHIA-COLI

A simple pharmacodynamic model has been developed to describe the bact erial kinetics exhibited by P-lactam antibiotics. In contrast with pre vious models that only characterized the early killing phase of a time -kill curve, the present model is capable of simultaneously describing both the killing and regrowth phases. The model relied on the use of both first-order bactericidal and resistance formation rate constants to accurately define the time-dependent changes in the bacterial popul ations of an antibiotic-treated culture. The concentration dependency of the bactericidal rate constant was further delineated using a satur able-receptor model. Furthermore, an exponential decrease in the resis tance formation rate with increasing antibiotic concentrations was dem onstrated. The evolving pharmacodynamic model was also explored via co mputer simulations by perturbing the two governing rate constants. The model was subsequently applied to the description of time-kill data f or amoxicillin, penicillin G, and cephalexin against Escherichia coil. The description of amdinocillin's action against E. coil was not as c omprehensive because of the existence of a second killing phase. Howev er, this model can be applicable to many classes of antibiotics that d isplay the usual killing and regrowth phases in time-kill studies. The pharmacodynamic model can potentially improve the prediction of bacte rial killing and regrowth and foster an improved understanding of comp lex antimicrobial pharmacodynamics.