PARAMETERS OF BACTERIAL KILLING AND REGROWTH KINETICS AND ANTIMICROBIAL EFFECT EXAMINED IN TERMS OF AREA UNDER THE CONCENTRATION-TIME CURVERELATIONSHIPS - ACTION OF CIPROFLOXACIN AGAINST ESCHERICHIA-COLI IN AN IN-VITRO DYNAMIC-MODEL

Although many parameters have been described to quantitate the killing and regrowth of bacteria, substantial shortcomings are inherent in mo st of them, such as low sensitivity to pharmacokinetic determinants of the antimicrobial effect, an inability to predict a total effect, ins ufficient robustness, and uncertain interrelations between the paramet ers that prevent an ultimate determination of the effect. To examine d ifferent parameters, the kinetics of killing and regrowth of Escherich ia coli (MIC, 0.013 mu g/ml) were studied in vitro by simulating a ser ies of ciprofloxacin monoexponential pharmacokinetic profiles. Initial ciprofloxacin concentrations varied from 0.02 to 19.2 mu g/ml, wherea s the half-life of 4 h was the same in all experiments. The following parameters were calculated and estimated: the time to reduce the initi al inoculum (N-0) 10-, 100-, and 1,000-fold (T-90%, T-99%, and T-99.9% , respectively), the rate constant of bacterial elimination (k(elb)), the nadir level (N-min) in the viable count (N)-versus-time (t) curve, the time to reach N-min (t(min)), the numbers of bacteria that surviv ed (N-tau) by the end of the observation period (tau), the area under the bacterial killing and regrowth curve (log N-A-t curve) from the ze ro point (time zero) to tau (AUBC), the area above this curve (AAC), t he area between the control growth curve (log N-C-t curve) and the bac terial killing and regrowth curve (log N-A-t curve) from the zero poin t to tau (ABBC) or to the time point when log N-A reaches the maximal values observed in the log N-C-t curve (I-E; intensity of the effect), and the time shift between the control growth and regrowth curves (T- E; duration of the effect). Being highly sensitive to the AUC, I-E and T-E showed the most regular AUC relationships: the effect expressed b y I-E or T-E increased systematically when the AUG or initial concentr ation of ciprofloxacin rose. Other parameters, especially T-90%, T-99% , T-99.9%, t(min), and log N-0 - log N-min = Delta log N-min, related to the AUC less regularly and were poorly sensitive to the AUC. T-E pr oved to be the best predictor and t(min) proved to be the worst predic tor of the total antimicrobial effect reflected by I-E. Distinct feedb ack relationships between the effect determination and the experimenta l design were demonstrated. It was shown that unjustified shortening o f the observation period, i.e., cutting off the log N-A-t curves, may lead to the degeneration of the AUG-response relationships, as express ed by log N-0 - log N-tau = Delta log N-tau, AUBC, AAC, or ABBC, to a point where it gives rise to the false idea of an AUC- or concentratio n-independent effect. Thus, use of I-E and T-E provides the most unbia sed, robust, and comprehensive means of determining the antimicrobial effect.