RELATIONSHIPS BETWEEN ANTIMICROBIAL EFFECT AND AREA UNDER THE CONCENTRATION-TIME CURVE AS A BASIS FOR COMPARISON OF MODES OF ANTIBIOTIC ADMINISTRATION - MEROPENEM BOLUS INJECTIONS VERSUS CONTINUOUS INFUSIONS

In comparative studies of different modes of administration (MAs) simu lated in in vitro dynamic models, only one dose of antibiotic is usual ly mimicked. Such an experimental design can provide a prediction of t he antimicrobial effect (AME) of a given combination of drug, clinical isolate, and infection site, but may be inappropriate for accurate co mparison of MAs. An alternative design providing comparison of differe nt MAs with various antibiotic doses in a wide range and with evaluati on of the respective relationships between AME and the AUC was propose d and examined, Two series of meropenem pharmacokinetic profiles, i.e. , monoexponentially decreasing concentrations (bolus doses) and consta nt concentrations (6-h continuous infusion), mere in vitro simulated, The simulated initial concentrations (C-o [from 0.062 to 48 mu g/ml]) and steady-state concentrations (C-ss [from 0.016 to 8 mu g/ml]) were chosen to provide similar AUC for 0 to 6 h (AUG(0-6)) ranges for both MAs (from 0.070 to 50.0 mu g . h/ml and from 0.09 to 48.0 mu g . h/ml, respectively), The AME of meropenem on Staphylococcus aureus ATCC 259 23 (MIC, 0.063 mu g/ml) was determined at each time (t) point as a dif ference (E) between the logarithms of viable counts (N) in the control cultures without antibiotic (N-C) and in cultures exposed to antibiot ics (N,). Time courses of E observed at different C-o or C-ss levels w ere compared in terms of the areas under the E-t curves (ABBC(t)). The finite values of the ABBC(t) observed by the end of the 6-h observati on period, which are equivalent to the area between bacterial count-ti me curves observed in the absence and presence of antibiotic (ABBC), w ere plotted versus the respective AUCs produced by each of the MAs. Th e ABBC versus AUC curves had a similar pattern: a plateau achieved at high AUCs followed by a steep rise in ABBC at relatively low AUCs was inherent in both of the MAs. The superiority of bolus dosing over the infusions could be documented only for meropenem concentrations below the MIC. At higher C-o or C-ss (i.e., at an AUC of greater than or equ al to 0.4 mu g . h/ml), the ABBC versus AUC curves plotted for each of the MAs could practically be superimposed. On the whole, both MAs app eared to be equiefficient in terms of the ABBC, These results suggest that AUC analysis of the AME may be a useful tool for comparing differ ent MAs. Such comparative studies should be designed in a manner that provides the use of similar AUC ranges, since the AUC may be considere d as a common pharmacokinetic denominator in comparing one MA or dosin g regimen to another.