CHANGES IN MIC ALTER RESPONSES OF PSEUDOMONAS-AERUGINOSA TO TOBRAMYCIN EXPOSURE

The pharmacokinetic parameters determining antibiotic efficacy are pea k concentrations (C-max), minimum (trough) concentrations (C-min), and area under the concentration-time curve (AUC), There is general agree ment about the importance of C-max and AUC for aminoglycosides, but th is is not so for maintenance of C With in vitro exposures modelling in vivo administration, Pseudomonas aeruginosa reference strain ATCC 278 53 (MIC, 1 mg/liter) and a higher-MIC (relatively resistant) clinical isolate (MIC, 4 mg/liter) were used to explore bacteriostatic and bact ericidal outcomes. With P. aeruginosa ATCC 27853, kill followed a comp lete bolus profile with a 30-min postdistribution peak (C-peak30) of 1 0 mg/liter. The clinical isolate required a C-peak30 bolus profile of 20 mg/liter for kill, and there was no difference between the efficaci es of the bolus and infusion exposures. Bolus profiles that were trunc ated at 8.5 h and producing sublethal effects were then combined with a wide range of C(min)s, With a C-peak30 profile of 8 mg/liter, P. aer uginosa ATCC 27853 showed a graded bacteriostatic response until a C-m in of greater than or equal to 0.8 mg/liter, when complete kill result ed. In contrast, bactericidal effects on the clinical isolate required a C-peak30 profile of 18 mg/liter with a C-min of greater than or equ al to 1.0 mg/liter, Therefore, C-min also contributes to the bacterici dal effect of tobramycin, with requirements showing minor variation wi th change in MIC. Dosing principles for relatively resistant (higher-M IC) organisms are suggested from the data. Relatively higher aminoglyc oside doses via infusion regimens are likely to be needed to generate higher peak concentrations and higher AUC values necessary for bacteri cidal effect in resistant organisms. Maintenance of trough concentrati ons on the order of 1.0 mg/liter during the interdose interval will te nd to guard against the possibility of inadequate peak and AUC exposur es for kill.