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) simulated in in vitro dynamic models, only one dose of antibiotic is usually mimicked. Such an experimental design can provide a prediction of the antimicrobial effect (AME) of a given combination of drug, clinical isolate, and infection site, but may be inappropriate for accurate comparison of MAs. An alternative design providing comparison of different MAs with various antibiotic doses in a wide range and with evaluation of the respective relationships between AME and the AUC was proposed and examined. Two series of meropenem pharmacokinetic profiles, i.e., monoexponentially decreasing concentrations (bolus doses) and constant concentrations (6-h continuous infusion), were in vitro simulated. The simulated initial concentrations (Co[from 0.62 to 48 micrograms/ml]) and steady-state concentrations (Css[from 0.016 to 8 micrograms/ml]) were chosen to provide similar AUC for 0 to 6 h (AUC0-6) ranges for both MAs (from 0.070 to 50.0 micrograms.h/ml and from 0.09 to 48.0 micrograms.h/ml, respectively). The AME of meropenem on Staphylococcus aureus ATCC 25923 (MIC, 0.06 micrograms/ml) was determined at each time (t) point as a difference (E) between the logarithms of viable counts (N) in the control cultures without antibiotic (NC) and in cultures exposed to antibiotics (NA). Time courses of E observed at different Co of Css levels were compared in terms of the areas under the E-t curves (ABBCt). The finite values of the ABBCt observed by the end of the 6 -h observation period, which are equivalent to the area between bacterial count-time curves observed in the absence and presence of antibiotic (ABBC), were plotted versus the respective AUCs produced by each of the MAs. The 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 Co or Css (i.e., at an AUC of > or = 0.4 micrograms.h/ml), the ABBC versus AUC curves plotted for each of the MAs could practically be superimposed. On the whole, both MAs appeared to be equiefficient in terms of the ABBC. These results suggest that AUC analysis of the AME may be a useful tool for comparing different MAs. Such comparative studies should be designed in a manner that provides the use of similar AUC ranges, since the AUC may be considered as a common pharmacokinetic denominator in comparing one MA or dosing regimen to another.