[Studies of dosing regimens and combination effects of aminoglycosides and beta-lactam in an experimental Pseudomonas aeruginosa infection in mice].
The optimal dosing regimens and combination effects of gentamicin (GM), or astromicin (ASTM) and piperacillin (PIPC) against P. aeruginosa in a mouse thigh infection model were studied. Therapeutic efficacy of the single regimen and duration of a postantibiotic effect (PAE) of GM and ASTM were dose dependent, but those of PIPC were dose independent. The optimal dosing of GM or ASTM with the same total daily dose was less frequent, but that of PIPC was frequent. Initial killing (the delta log bacteria changed at 2 hour after starting of the therapy) was the main significant pharmacokinetic and pharmacodynamic parameter determining efficacy for GM, whereas the time that serum levels exceeded the minimum inhibitory concentration (T greater than MIC) was the major parameter for PIPC. The optimal synergistic combinations of GM or ASTM plus PIPC in various dosing intervals with the same total daily dose were observed in the less frequent regimens of GM or ASTM and the frequent regimen of PIPC. The differences of therapeutic efficacy were observed in twice a day regimens of GM or ASTM plus PIPC in three dosing schedules (GM or ASTM before PIPC, with PIPC simultaneously, after PIPC). The effect of GM or ASTM after PIPC exposure was inferior to that of the other dosing regimens. These findings suggest that it may be possible to use the optimal regimens of aminoglycosides and beta-lactams against clinical P. aeruginosa infections in humans. Further careful, controlled clinical trials are needed.
Kikuchi
K
K
Department of Medicine, Tokyo Women's Medical College.
D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination / Q000008:administration & dosage / Q000627:therapeutic use; D005260:Female; D005839:Gentamicins / Q000008:administration & dosage* / Q000627:therapeutic use; D051379:Mice; D008813:Mice, Inbred ICR; D010878:Piperacillin / Q000008:administration & dosage* / Q000627:therapeutic use; D011552:Pseudomonas Infections / Q000188:drug therapy*
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D005839:Gentamicins; C023384:fortimicin A; D010878:Piperacillin