INITIAL CONCENTRATION-TIME PROFILE OF GENTAMICIN DETERMINES EFFICACY AGAINST ENTEROBACTER-CLOACAE ATCC-13047

In vitro studies were designed to investigate the influence of peak dr ug concentration (C-max), the area under the concentration-time curve (AUC), and, consequently, the trough concentration on the bactericidal effects of gentamicin against Enterobacter cloacae (MIC, 0.5 mg/liter ) by simulating bolus versus infusion administration and bolus dosing with altered drug clearance. Bacteria in the lag phase were exposed to gentamicin concentration-time profiles modelling either bolus or infu sion dosing (AUC constant, C-max changing) with 30-min postdose peak c oncentrations (C-peak30) of 4, 6, 8, and 10 mg/liter or bolus dosing w ith normal and double drug clearance (C-max constant, AUC changing) co rresponding to normal clearance profiles with C-peak30 of 6 and 8 mg/l iter, Exposure to gentamicin caused early bactericidal effects apparen t by 2 h, followed by variable bacteriostatic and recovery phases. Exp osure to bolus profiles resulted in greater bactericidal activity than the corresponding infusion profile up to a C-peak30 of 8 mg/liter. At a C-peak30 of 10 mg/liter, there were no differences in bactericidal effect. Double clearance profiles had a reduced bactericidal effect at 6 mg/liter compared to the corresponding normal clearance profile, bu t no differences in bactericidal effect were observed for 8-mg/liter d ouble and normal clearance profiles. These results suggest that the in itial exposure (i,e,, 0 to 30 min) Is a more important determinant for bacterial killing than the AUC or trough concentration for this bacte rium, Subject to confirmation of these findings with other gram-negati ve bacteria, to optimize aminoglycoside efficacy the initial exposure (C-max) should be maximized by giving higher doses or bolus administra tion at intervals which may not produce detectable trough concentratio ns. Clinical trials with a broad range of patients, especially those w ith higher clearance, would confirm these in vitro observations and de fine optimal dosing recommendations.