Relationships of the area under the curve/MIC ratio to different integral endpoints of the antimicrobial effect: Gemifloxacin pharmacodynamics in an in vitro dynamic model

Most integral endpoints of the antimicrobial effect are determined over an arbitrarily chosen time period, such as the dosing interval (tau), regardle ss of the actual effect duration. Unlike the tau -related endpoints, the in tensity of the antimicrobial effect (I-E) does consider its duration-from t ime zero to the time when bacterial counts on the regrowth curve achieve th e same maximal numbers as in the absence of the antimicrobial, To examine t he possible impact of this fundamental difference on the relationships of t he antimicrobial effect to the ratio of the area under the concentration-ti me curve (AUC) to the MIG, a clinical isolate of Staphylococcus aureus was exposed to simulated gemifloxacin pharmacokinetics over a 40-fold range of AUC/MIC ratios, from 11 to 466 h, In each run, I-E and four tau -related en dpoints, including the area under the time-kill curve (AUBC), the area abov e the curve (AAC), the area between the control growth and time-kill curves (ABBC), and the ABBC related to the area under the control growth curve (A UGC), were calculated for tau = 24 h. Unlike the I-E, which displayed pseud olinear relationships with the AUC/MIC ratio; each tau -related endpoint sh owed a distinct saturation at potentially therapeutic AUC/MIC ratios (116 t o 466 h) when the antimicrobial effect persisted longer than tau, This satu ration results from the underestimation of the true effect and may be elimi nated if ABBC, AAC, and AUBC (but not AUGC) are modified and determined in the same manner as the I-E to consider the actual effect duration, These da ta suggest a marginal value of the tau -related endpoints as indices of the total antimicrobial effect. Since all of them respond to AUC/MIC ratio cha nges less than the I-E, the latter is preferable in comparative pharmacodyn amic studies.